Use of 3-Hydroxy-4-(trifluoromethyl)azetidin-2-ones as Building Blocks for the Preparation of Trifluoromethyl-Containing Aminopropanes, 1,3-Oxazinan-2-ones, Aziridines, and 1,4-Dioxan-2-ones

SYNTHESIS

0

3

9

-

7

8

1

4

3

7

-

2

1

0

X

2018, 50, A–R

feature

A

en

H. Dao Thi et al.

Feature

Synthesis

Use of 3-Hydroxy-4-(trifluoromethyl)azetidin-2-ones as Building

Blocks for the Preparation of Trifluoromethyl-Containing Amino-

propanes, 1,3-Oxazinan-2-ones, Aziridines, and 1,4-Dioxan-2-

ones

Hang Dao Thi^a,b

Giang Le Nhat Thuy^b

Saron Catak^c

Veronique Van Speybroeck^c

Tuyen Van Nguyen*^b

Matthias D’hooghe*^a

Cl

CF₃

R

Nu

CF₃

R

N

Me

OH

Nu = OAc, NH^tBu

R

N

HO

O

CF₃

R

Cl

CF₃

R

O

CF₃

R

N

F₃C

COOMe

O

^aSynBioC Research Group, Department of Green Chemistry and

Technology, Faculty of Bioscience Engineering, Ghent University,

Coupure Links 653, 9000 Ghent, Belgium

R = PMP, PMB

Cl

O

matthias.dhooghe@UGent.be

Cl

O

CF₃

R

^bInstitute of Chemistry, Vietnam Academy of Science and

Technology, 18-Hoang Quoc Viet, CauGiay, Hanoi, Vietnam

ngvtuyen@hotmail.com

H

HO

CF₃

R

O

NHR

O

N

HN

O

CF₃

^cCenter for Molecular Modeling, Ghent University,

Technologiepark 903, 9052 Zwijnaarde, Belgium

veronique.vanspeybroeck@UGent.be

Received: 30.11.2017

Accepted after revision: 08.01.2018

Published online: 07.02.2018

pharmacological properties, azetidin-2-ones or β-lactams

also represent important compounds in organic synthesis

due to their high ring strain, which allows for further elabo-

ration toward a variety of nitrogen-containing acyclic and

heterocyclic target compounds. In light of the favorable ef-

fects of fluorine introduction, β-lactams bearing a trifluo-

romethyl group comprise interesting entities for the con-

struction of novel targets with promising bioactivities. For

example, CF₃-substituted β-lactams have been applied for

the modification of the taxol side chain to generate second-

generation fluoro-taxoids, which exhibit substantially bet-

ter in vitro potency against several human cancer cell lines

than the parent taxoids.⁴In general, CF₃-containing mole-

cules can be synthesized by either a late-stage trifluoro-

methylation approach or by a building block strategy.⁵The

preparation of sensitive and strained CF₃-decorated struc-

tures, however, is often hampered by difficulties associated

with the late-stage introduction of the CF₃group. As an al-

ternative, the application of CF₃-containing building blocks

can be practiced, thus avoiding the use of trifluoromethyl-

ating agents during the synthesis. The most important syn-

thetic routes toward 4-(trifluoromethyl)azetidin-2-ones

using the building block strategy are based on [2+2] ketene-

imine cyclocondensations (Staudinger synthesis), enolate-

imine cyclocondensations, intramolecular N-acylations, in-

tramolecular C-alkylations, ring expansions of aziridines,

the Kinugasa reaction, and the Reformatsky reaction.⁶How-

ever, the reactivity study of 4-(trifluoromethyl)azetidin-2-

ones toward both ring opening and ring transformation for

DOI: 10.1055/s-0036-1591537; Art ID: ss-2017-z0773-fa

Abstract 3-Hydroxy-4-(trifluoromethyl)azetidin-2-ones were synthe-

sized from the corresponding 3-benzyloxy-β-lactams and successfully

transformed into new 3-chloro-4-(trifluoromethyl)azetidin-2-one build-

ing blocks. The latter chlorides were shown to be eligible precursors for

the construction of CF₃-containing aminopropanes, 1,3-oxazinanes,

1,3-oxazinan-2-ones, and aziridines. In addition, 3-hydroxy-4-(trifluoro-

methyl)azetidin-2-ones proved to be interesting substrates for the syn-

thesis of novel 3-[2,2,2-trifluoro-1-(arylamino)ethyl]-1,4-dioxan-2-ones

via intramolecular cyclization of 3-(2-hydroxyethoxy)-β-lactam inter-

mediates.

Introduction

Given the fact that nearly 30% of the leading blockbuster

drugs contain at least one fluorine atom in their structure,

fluorinated molecules are considered to be key building

blocks in medicinal chemistry and hence attractive targets

in organic synthesis.¹The increasing interest in fluorinated

compounds is due to the beneficial effect of fluorine on dif-

ferent properties of bioactive agents, and thus, organic

chemistry has witnessed the development of numerous

synthetic methods to incorporate one or more fluorine at-

oms into organic structures in recent years.²An important

part of these endeavors has been devoted to the introduc-

tion of a trifluoromethyl group into (constrained) nitrogen

ring systems,³such as β-lactams. Besides their interesting

B

H. Dao Thi et al.

Feature

Synthesis

Biographical Sketches

Hang Dao Thi was born in 1987 in Hai

Duong (Vietnam). She obtained a Mas-

ter’s degree in Natural Products Syn-

thesis Medicinal Chemistry, Chemical

composition of the hexane fraction

from S. philipinense (Stereocaulaceae)

using different methods. Currently,

she is a Ph.D. student working at the

Department of Sustainable Organic

Chemistry and Technology at Ghent

University (Belgium) under the guid-

ance of Prof. Matthias D’hooghe. Her

research interests are in the synthesis

and synthetic application of CF₃-sub-

stituted β-lactams for the construction

of biologically CF₃-substituted mono-

and spirocyclic azaheterocycles.

Sciences at Rennes

I

University

(France) in 2011, with a thesis on the

isolation of the low polar chemical

Giang Le Nhat Thuy was born in 1984

in Dong Nai (Vietnam). She received a

Ph.D. in 2014 (Doctor in Organometal-

lic Chemistry) from Irkutsk National

Research Technical University, Russia,

under the supervision of Prof. Dr. Bary-

shok V. P. Since 2015, she became re-

searcher at Laboratory of Medicinal

Chemistry at the Institute of Chemis-

try, Vietnam Academy of Science and

Technology in Hanoi (Vietnam). She

performed a short postdoctoral stay

with Prof. Dr. Matthias D’hooghe at

the Department of Sustainable Organ-

ic Chemistry and Technology, Faculty

of Bioscience Engineering, Ghent Uni-

versity (Belgium) in the field of synthe-

sis of β-lactams in 2016. Her main

research interests are focused on the

synthesis and deployment of CF₃-sub-

stituted β-lactams for the construction

of biologically CF₃-substituted mono-

and spirocyclic azaheterocycles and

the synthesis of different classes of

bioactive heterocyclic compounds.

Saron Catak joined the Department of

Chemistry at Bogazici University as

full-time faculty in 2013 and is current-

ly an Associate Professor working in

the field of computational chemistry.

She is also a Guest Professor at the

Center for Molecular Modeling (CMM),

Ghent University since 2015. She ob-

tained a joint Ph.D. in Computational

Chemistry from the University of Lor-

raine (Nancy, France) and Bogazici Uni-

versity in 2008. She was a postdoctoral

researcher in Prof. Ken N. Houk’s

group at the University of California,

Los Angeles, before joining the Center

for Molecular Modeling (CMM) at

Ghent University as a research associ-

ate. Prior to joining the Department of

Chemistry at Bogazici University, she

worked at Syngenta Crop Protection

(Basel, Switzerland) as team leader in

‘computer-aided drug design’. In

2014, she co-founded the ‘Computa-

tional Chemistry and Biochemistry’ re-

search group at Bogazici University.

Her main research topics consist of

first principles modeling of catalytic

processes, biological reactions in pro-

teins, heterogeneous reactions on sur-

faces, and multiscale-modeling of

nanomaterials for environmental pur-

poses.

Veronique Van Speybroeck is full pro-

fessor at the Ghent University within

the Faculty of Engineering and Archi-

tecture. She obtained her Ph.D. in

2001 at Ghent University on a subject

dealing with theoretical simulations of

chemical reactions with static and dy-

namical approaches. Together with

Prof. M. Waroquier she founded the

Center for Molecular Modeling (CMM)

at that time. She is now leading the

center, which is currently composed of

about 40 researchers. She built up a

large expertise in first principle kinetics

in nanoporous materials in the frame

of an ERC starting grant, awarded in

2009. Her current research focuses on

first principle molecular dynamics sim-

ulations of complex chemical transfor-

mation in nanoporous materials, for

which she received an ERC Consolida-

tor grant in 2015. She is an elected

member of the Royal (Flemish) Acade-

my for Science and the Arts of Bel-

gium.

Tuyen Van Nguyen was born in Thanh

Hoa province, Vietnam, in 1961. He re-

ceived his Ph.D. under the supervision

of Professor Dr. P. F. Vlad in 1991,

Kishinev, Moldavia. From May 1993 to

October 1995, he worked as a post-

doctoral fellow at the Department of

Pharmacognosy, College of Pharmacy,

University of Illinois at Chicago, USA

under the supervision of Prof. Dr. H. S.

H. Fong. From 1998 to 2003, he per-

formed postdoctoral research at the

Department of Organic Chemistry,

Faculty of Bioscience Engineering,

Ghent University, Belgium, under the

guidance of Prof. N. De Kimpe. Since

1993, he has been head of the Labora-

tory of Medicinal Chemistry at the In-

stitute of Chemistry, Vietnamese

Academy of Science and Technology in

Hanoi (Vietnam) and since 2007 he has

been Deputy Director of the Institute

of Chemistry, then since 2010 he has

been Director of the Institute of Chem-

istry. He is full professor at the Institute

of Chemistry – Vietnam Academy of

Science and Technology established in

2013. He has published over 120 peer-

reviewed articles. His research is fo-

cused on azaheterocyclic chemistry

and the synthesis of biologically active

compounds used in medicine.

Matthias D’hooghe was born in Kor-

trijk, Belgium, in 1978. He received a

Master’s degree in 2001 (Master of Sci-

ence in Bioscience Engineering: Chem-

istry) and a Ph.D. in 2006 (Doctor in

Applied Biological Sciences: Chemis-

try), both from Ghent University, Bel-

gium, with Prof. N. De Kimpe as

promoter. In 2007, he became post-

doctoral assistant at the Department

of Sustainable Organic Chemistry and

Technology, Faculty of Bioscience Engi-

neering, Ghent University, and in 2009

he performed

a

short postdoctoral

and β-lactams, and the synthesis of

different classes of bioactive heterocy-

clic compounds. Prof. D’hooghe has

been elected as a laureate of the DSM

Science & Technology Awards 2007, fi-

nalist of the European Young Chemist

Award 2012 and recipient of the

Thieme Chemistry Journal Award

2013. He is the author of 140 publica-

tions in international peer-reviewed

journals.

stay with Prof. D. Vogt at Eindhoven

University of Technology (The Nether-

lands) in the field of homogeneous ca-

talysis. In October 2010, he was

promoted to Professor (Research Pro-

fessor) at the Department of Sustain-

able

Organic

Chemistry

and

Technology (Ghent University), and he

was granted tenure in 2015. His main

research interests include the chemis-

try of small-ring azaheterocycles, with

a special focus on aziridines, azetidines

C

H. Dao Thi et al.

Feature

Synthesis

the preparation of trifluoromethylated amines and hetero-

cyclic compounds has received very little attention up to

now, in sharp contrast to their non-fluorinated analogues.^4,7

Because of the versatile synthetic potential of β-lactams

on the one hand and the beneficial impact of the trifluoro-

methyl group on biological properties on the other hand,

we recently embarked on the synthesis and synthetic appli-

cation of 4-trifluoromethyl-β-lactams as new building

blocks in organic chemistry. Within that framework, [2+2]

cyclocondensation between 2,2,2-trifluoroethan-1-imines,

prepared from the commercially available 1-ethoxy-2,2,2-

trifluoroethanol under Dean–Stark conditions, and the

ketenes derived from alkoxy/aryloxyacetyl chlorides pro-

vided a convenient access to 3-alkoxy/aryloxy-4-trifluoro-

methyl-β-lactams I as a first new class of building blocks

(Scheme 1). The aptitude of these systems I with respect to

ring-opening reactions was explored to enable an entry to

functionalized aminopropane systems bearing a terminal

CF₃group. This study resulted in two successful routes,

based on either direct reductive β-lactam ring opening or

initial carbonyl removal to azetidine intermediates, fol-

lowed by ring opening. In both cases, C2–N bond fission af-

forded the proposed aminopropanols or diaminopropanes

in high yields and purity.⁸For 3-benzyloxy-β-lactams I (R²=

Bn), hydrogenolysis of the benzyl ether fragment allowed

the formation of 3-hydroxy-4-trifluoromethyl-β-lactams II

as a second class of potential (but mainly unexplored) new

building blocks. So far, only alcohol oxidation was evaluat-

ed, which gave rise to 3-oxo-β-lactams III as a third class of

new building blocks. Attempts to form and trap the corre-

sponding 2,3-dioxoazetidin-4-yl anions unexpectedly re-

sulted in ring opening through C3–C4 bond fission, culmi-

nating in 2-[(2,2-difluorovinyl)amino]-2-oxoacetate prod-

ucts. This peculiar mechanism was investigated in depth,

both experimentally and computationally.⁹Furthermore,

an addition/elimination sequence applied to 3-oxo-β-

lactams III afforded 3-methylene-β-lactams IV as a fourth

class of new building blocks, which were shown to be eligi-

ble substrates for Michael additions, electrophilic additions,

and cycloadditions en route to a variety of stereodefined

mono- and spirocyclic 4-trifluoromethyl-β-lactams.¹⁰In or-

der to further demonstrate the broad diversity of these 4-

trifluoromethyl-β-lactam building blocks, we recently ex-

plored the synthetic applicability of 3-hydroxy-4-trifluoro-

methyl-β-lactams II. In particular, manipulation of the

alcohol group enabled the construction of trifluoromethyl-

containing ring-rearranged products, including aziridines

through a ring-contraction protocol via 3-chloro-β-lactam

intermediates and dioxan-2-ones via initial O-allylation,

about which will be communicated in this paper.

Results and Discussion

In addition to the preparation of 3-hydroxy-4-trifluoro-

methyl-β-lactams 3a,b as described in our previous

study,^8,10a set of four new 3-hydroxy-4-trifluoromethyl-β-

lactams 3c–f was successfully synthesized, with slight

modifications in the procedure. In the first step, 1-ethoxy-

2,2,2-trifluoroethanol (1) was condensed with (a) isopro-

pylamine in dichloromethane in the presence of MgSO₄as

drying agent and with (b) different arylamines (p-pheneti-

dine, p-toluidine, 4-iodoaniline) in toluene in the presence

of a catalytic amount of p-toluenesulfonic acid under Dean–

Stark conditions. The resulting mixtures of imines and their

hemiaminal precursors were immediately used for the

Staudinger synthesis, yielding cis-3-benzyloxy-β-lactams

2c–f in acceptable yields (Table 1). Besides the expected

O

R²O

O

CF₃

R¹

HO

O

CF₃

R¹

H

O

CF₃

R¹

CF₃

R¹

Cl

N

F₃C

Et₃N

R¹

O

I

II

III

IV

conjugate addition

and cycloaddition

ring opening via

C3–C4 bond fission

ring opening via

C2–N bond fission

ring rearrangement

R¹

N

R¹

O

R¹

N

F

CF₃

R⁵S

NH

OH

F₃C

R⁴O

F

N

F₃C

OH

O

R¹

O

OR²

Me

O

Ph

Ref. 9

O

NHR¹

CF₃

This work

R¹

R⁶

N

CF₃

R¹

O

F₃C

NHR³

N

OR²

Ref. 8

O

Ref. 10

Scheme 1 Overview of and interconnection between different 4-trifluoromethyl-β-lactam building blocks and their synthetic applications

D

H. Dao Thi et al.

Feature

Synthesis

cis-β-lactams 2c–f, minor to rather significant amounts of

trans-isomers of 2c–f were also detected (2–46%). The for-

mation of these trans-β-lactams was confirmed based on

¹H NMR analysis, showing a coupling constant of 1–2 Hz

(CDCl₃) between the two vicinal protons at the C3 and C4

position, as opposed to cis-β-lactams (5–6 Hz, CDCl₃).^8,11

The previously reported synthesis of β-lactams 2a,b was

achieved through a [2+2] ketene-imine cyclocondensation

between a trifluoromethylaldimine and benzyloxyacetyl

chloride in the presence of Et₃N. Under these conditions,

the cis-β-lactams 2a,b were obtained in a relatively high

stereoselectivity (cis/trans 95–98:5–2). However, the rela-

tive amount of trans-β-lactams in the 2c–f cases was higher

compared to those of 2a,b (cis/trans 54–78:46–22, Table 1).

This stereoselectivity issue might be due to the outcome of

the cyclocondensation reaction between either a hemiami-

nal or a mixture of hemiaminal and imine, with benzyloxy-

acetyl chloride in the presence of Et₃N in the synthetic pro-

cedure toward β-lactams 2c–f. It should indeed be noted

that the treatment of 1-ethoxy-2,2,2-trifluoroethan-1-ol

(1) with isopropylamine (a) led to 2,2,2-trifluoro-1-(isopro-

pylamino)ethan-1-ol, whereas the use of arylamines (b) af-

forded a mixture of hemiaminals and imines. The cis-β-

lactams 2c–f were easily isolated through chromatography

and subjected to hydrogenolysis (Pd/C) to produce the cor-

responding cis-alcohols 3c–f in excellent yields (Table 1). In

the case of cis-3-benzyloxy-1-(4-iodophenyl)-4-(trifluoro-

methyl)azetidin-2-one (2d), the hydrogenolysis furnished

cis-3-benzyloxy-1-phenyl-4-(trifluoromethyl)azetidin-2-

one instead of the expected cis-3-hydroxy-1-(4-iodo-

phenyl)-4-(trifluoromethyl)azetidin-2-one, probably due to

hydrogenolytic scission of the C_arene–I bond over the Pd/C

catalyst.¹²Because the high adsorption of the in situ pro-

duced iodide anion led to a decrease in the catalytic activity

of Pd/C, the resulting cis-3-benzyloxy-1-phenyl-4-(trifluo-

romethyl)azetidin-2-one was filtered through Celite prior

to debenzylation.¹²The latter was finally transformed into

the corresponding cis-3-hydroxy-1-phenyl-4-(trifluoro-

methyl)azetidin-2-one (3d), in an overall yield of 84%.

In the next part, the eligibility of these 3-hydroxy-4-tri-

fluoromethyl-β-lactams 3 as building blocks for the synthe-

sis of functionalized trifluoromethyl-substituted com-

pounds was assessed. In that respect, representative cis-3-

hydroxy-4-(trifluoromethyl)azetidin-2-ones 3a,b were

transformed into trans-3-chloro-β-lactams 4a,b in excel-

lent yields (91–97%, Scheme 2) upon treatment with 2

equivalents of Ph₃P and a small amount of NaHCO₃as cata-

lyst in CCl₄under reflux for 10 hours.¹³The trans-configura-

tion of β-lactams 4a,b was confirmed based on the ¹H NMR

spectrum (J_H3,H4= 1–2 Hz, CDCl₃), implying a clean S_N2 pro-

cess. In order to simplify the synthetic procedure, the

preparation of β-lactams 4 was attempted directly through

the Staudinger synthesis using the same imines combined

with chloroacetyl chloride and a variety of bases (2,6-luti-

dine, Et₃N, pyridine, proton sponge), in analogy with the

synthesis of their non-fluorinated β-lactam counterparts.¹⁴

However, this direct approach appeared to be unsuccessful

for the preparation of trifluoromethylated β-lactams 4.

Therefore, a short detour was necessary, utilizing alcohols

3a,b as valuable synthons to obtain the desired β-lactams

4a,b. Besides this method, two complementary approaches

have been reported to furnish 3-chloro-4-trifluoromethyl-

Table 1 Isolated Yields of Compounds 2, 3, and cis/trans Ratios of Compounds 2

1) (a) 1 equiv ⁱPrNH₂, 2 equiv MgSO₄

CH₂Cl₂, Δ, 2 h

or (b) 0.8–1.2 equiv RNH₂

0–0.01 equiv PTSA

toluene, Δ, 6–37 h, Dean– Stark

HO

O

CF₃

R

BnO

CF₃

R

OH

20–50% Pd/C, H₂

N

F₃C

O

MeOH, 5 bar, r.t., 41 h

2) 4 equiv BnOCH₂COCl

5 equiv Et₃N

O

CH₂Cl₂, Δ, 19 h to 3 d, N₂

1

2a–f

(31–72%)

3a–f

(84–97%)

Entry

R

2

cis/transa 2

3

1

2

3

4

5

6

4-MeOC₆H₄

2a (49%)

2b (72%)

2c (47%)

2d (35%)^b

2e (31%)

2f (59%)

98:2

3a (87%)

3b (93%)

3c (94%)

3d (84%)^c

3e (87%)

3f (97%)

4-MeOC₆H₄CH₂

4-EtOC₆H₄

4-IC₆H₄/Ph

4-MeC₆H₄

i-Pr

95:5

78:22

54:46

67:33

75:25

^aDetermined by ¹⁹F NMR spectroscopy (CDCl₃) of the crude reaction mixture 2.

^bR = 4-IC₆H₄.

^cR = Ph.

E

H. Dao Thi et al.

Feature

Synthesis

β-lactam analogues, either by intramolecular cyclization of

the corresponding β-amino esters¹¹or by ring expansion of

the corresponding aziridines.¹⁵The reactivity of 3-chloro-

4-trifluoromethyl-β-lactams is virtually unexplored in the

literature to date, in contrast to 3-chloro-β-lactams having

no trifluoromethyl group at the C4 position. In that respect,

the selective reduction of trans-3-chloro-4-trifluorometh-

yl-β-lactams 4a,b by means of monochloroalane was evalu-

ated to provide an entry into trans-3-chloro-2-(trifluoro-

methyl)azetidines 5a,b.⁸Treatment of β-lactams 4a,b with

two equivalents of monochloroalane, in diethyl ether at

room temperature for five minutes, produced the desired

azetidines 5a,b in good yields (54–78%, Scheme 2).⁸In con-

trast to the reduction of 3-non-chlorinated 4-trifluoro-

methyl-β-lactams, the use of monochloroalane for the re-

duction of 3-chloro-2-(trifluoromethyl)azetidin-2-ones 4

required precise and optimized reaction conditions (time,

temperature, and molar equivalents of the reductant) to

limit the formation of side products due to ring opening.

Having these azetidines 5 in hand, their eligibility for the

synthesis of a diversity of functionalized trifluoromethyl-

substituted aminopropanes was evaluated. N-Alkylation of

3-chloro-2-(trifluoromethyl)azetidines 5 was performed

prior to ring opening, upon treatment with trimethyloxoni-

um tetrafluoroborate, furnishing the corresponding azeti-

dinium salts 6a,b in a quantitative way (Scheme 2). Subse-

quently, these salts were subjected to ring opening by using

an oxygen and nitrogen nucleophile, providing a conve-

nient entry toward a variety of α-(trifluoromethyl)amines.

In particular, azetidinium salts 6 were treated with four

equivalents of sodium acetate or tert-butylamine, affording

anti-2-chloro-3-amino-4,4,4-trifluorobutyl acetates 7a,b

and anti-2-chloro-4,4,4-trifluorobutane-1,3-diamines 8a,b,

respectively (Scheme 2), accompanied by a certain amount

of azetidines 5 (20–47%). These results can be rationalized

by considering the competition between a ring-opening re-

action at the C4 position and an N-demethylation reaction

of azetidinium salts 6a,b by the nucleophiles utilized.^8,16

Sodium acetate and tert-butylamine were selected as nuc-

leophiles in analogy with previous investigations on the

ring opening of cis-3-alkoxy-2-(trifluoromethyl)azeti-

dines.⁸In line with our previous findings on the chemistry

of 2-(trifluoromethyl)azetidinium ions,^3b,8ring opening of

trans-3-chloro-2-(trifluoromethyl)azetidinium salts 6 pro-

ceeded regiospecifically at the non-substituted C4 position,

in contrast with the reactivity of azetidinium salts bearing

other types of electron-withdrawing groups (acyl, cyano). It

is also noteworthy that the treatment of non-chlorinated 2-

(trifluoromethyl)azetidinium salts with nucleophiles exclu-

sively led to a regiospecific ring opening at the C4 position,

without an accompanying N-demethylation pathway.^3b,16

In analogy with 3-non-chlorinated 4-(trifluorometh-

yl)azetidin-2-ones, 3-chloro-β-lactams 4a,b might be valu-

able precursors for the stereoselective synthesis of fluori-

HO

O

CF₃

R

N

3a,b

2 equiv PPh₃

0.15 equiv NaHCO₃

CCl₄, Δ, 10 h

Cl

O

CF₃

Cl

CF₃

R

2 equiv AlH₂Cl

N

Et₂O, 0 °C to r.t., 5 min, Ar

R

4a (R = PMP, 97%)

4b (R = PMB, 91%)

5a (R = PMP, 54%)

5b (R = PMB, 78%)

2 equiv Me₃OBF₄

Cl

CH₂Cl₂, r.t., 1 h, N₂

O

CF₃

R

4 equiv NaOAc

MeCN, Δ, 1 h

O

N

Me

Cl

CF₃

R

7a (R = PMP, 43%)

7b (R = PMB, 18%)

N

BF₄

Me

Cl

4 equiv ^tBuNH₂

MeCN, Δ, 1 h

H

N

CF₃

R

6a,b (quant.)

N

Me

8a (R = PMP, 38%)

8b (R = PMB, 11%)

Scheme 2 Reactions of 3a,b

nated β-amino alcohols.⁸In that respect, trans-3-chloro-4-

(trifluoromethyl)azetidin-2-ones 4a,b were subjected to a

LiAlH₄-mediated reductive ring opening, using 1 equivalent

of LiAlH₄in Et₂O at room temperature for five minutes, fur-

nishing the corresponding anti-3-amino-2-chloro-4,4,4-tri-

fluorobutanols 9a,b in excellent yields (90–96%, Scheme 3).

It should be noted that use of a stoichiometric amount of

LiAlH₄and a precise timing are required to avoid the gener-

ation of undesired side products. The use of 2 equivalents of

LiAlH₄in different solvents (Et₂O, THF) at room temperature

or under reflux only led to decomposition of the starting

material 4, as opposed to the results obtained upon treat-

ment of non-trifluoromethyl-substituted 2-chloro-β-

lactams with LiAlH₄.¹⁷Trifluoromethyl-substituted 1,3-

amino alcohols have been recognized as potential sub-

strates for the preparation of a wide range of interesting tri-

fluoromethyl-containing azaheterocyclic compounds.^8,18

For that purpose, the cyclization of anti-3-amino-2-chloro-

4,4,4-trifluorobutanols 9a,b was pursued to generate novel

trifluoromethylated oxazinanes and oxazinan-2-ones. As

such, the treatment of 3-aminopropan-1-ols 9a,b with

formaldehyde (37% in water) in THF resulted in the corre-

sponding new trans-5-chloro-4-trifluoromethyl-1,3-ox-

azinanes 10a,b in 54–80% yield (Scheme 3). 1,3-Oxazinane

scaffolds have been encountered as a core structure in

many natural products and pharmaceuticals, because they

F

H. Dao Thi et al.

Feature

Synthesis

possess a wide spectrum of biological activities such as

anti-HIV, antibacterial, antitumor, antituberculosis, and

fungicidal properties.¹⁹Hence, a number of methods has

been developed to enable their synthesis. However, reports

on the synthesis of 1,3-oxazinanes with new functional

groups remain rather scarce in the literature.^3b,8,18bIn that

respect, the utilization of β-amino alcohols bearing a tri-

fluoromethyl group might provide interesting trifluorinat-

ed 1,3-oxazinanes with promising biological properties.

azetidin-2-ones toward aziridines was directly achieved

utilizing LiAlH₄in THF or Et₂O.^14b,17aHowever, the analogous

reduction of trans-3-chloro-4-trifluoromethyl-β-lactams 4

with 1–2 equivalents of LiAlH₄in Et₂O at room temperature

or under reflux for two hours did not furnish the desired

aziridines 12. This could be due to the strong inductive ef-

fect of the trifluoromethyl group, rendering the nitrogen

atom less basic, thus prohibiting the cyclization. To provide

access to the aziridines 12a,b, a base-induced ring closure

of amino alcohols 9a,b upon treatment with 0.8–1 equiva-

lent of t-BuOK in THF was explored successfully (Scheme

3).²²On the other hand, treatment of trans-3-chloro-4-(tri-

fluoromethyl)azetidine-2-ones 4a,b with 2 equivalents of

KOH in methanol under reflux for 20 minutes afforded the

corresponding aziridine-2-carboxylates 13a,b in 25–73%

yield. Although 2-substituted 3-(trifluoromethyl)aziridines

constitute eligible substrates for the synthesis of valuable

fluorinated compounds, synthetic pathways toward these

structures remain scarce, and most of these methods use

diazo compounds or require harsh reaction conditions. For

instance, Akiyama et al. have reported the preparation of

cis-2-chloro-3-(trifluoromethyl)aziridine 12a from the cor-

responding trifluoromethyl-substituted aziridine carboxyl-

ate, which was also derived from a diazoacetate.²³In recent

research of our group, a novel stereoselective approach to-

ward the synthesis of trans-2-substituted 3-(trifluorometh-

yl)aziridines starting from the commercially available tri-

fluoromethyl ketones has been developed.²⁴The use of

trans-3-chloro-4-trifluoromethyl-β-lactams as versatile

substrates for the synthesis of trifluoromethylated aziri-

dines offers a new approach to this interesting aziridine

subclass.

R

Cl

CF₃

R

N

2 equiv KOH

F₃C

COOMe

N

MeOH, Δ, 20 min

O

13a (R = PMP, 73%)

13b (R = PMB, 25%)

4a,b

Cl

2 equiv–excess CH₂=O

CF₃

R

(37% in H₂O)

1 equiv

LiAlH₄

O

N

THF, r.t. to Δ, 3–14 h

Et₂O

0 °C to r.t.

5 min, N₂

10a (R = PMP, 54%)

10b (R = PMB, 80%)

Cl

3 × 1 equiv ClCOOEt

3 × 2 equiv Et₃N

CF₃

HO

CF₃

O

N

CH₂Cl₂, 0 °C to r.t., 3 x 3 h

R

HN

R

O

9a (R = PMP, 96%)

9b (R = PMB, 90%)

11a (R = PMP, 29%)

11b (R = PMB, 85%)

R

N

0.8–1 equiv ^tBuOK

THF, r.t., 10 min

OH

F₃C

12a (R = PMP, 27%)

12b (R = PMB, 61%)

In the final part of this study, alcohols 3a–f were evalu-

ated as building blocks toward the synthesis of novel tri-

fluoromethyl-containing 1,4-dioxan-2-ones. In that re-

spect, cis-alcohols 3a–f were subjected to initial O-allyla-

tion, yielding the corresponding cis-3-allyloxy-4-

(trifluoromethyl)azetidin-2-ones 14a–f in high yields (71–

95%, Table 2) upon treatment with 1.6 equivalents of allyl

bromide in the presence of TBAI as a catalyst, under basic

conditions (Table 2).²⁵The direct preparation of β-lactams

14 was attempted using the Staudinger synthesis between

the corresponding imine and allyloxyacetyl chloride, in ac-

cordance with the preparation of their non-fluorinated β-

lactam counterparts.²⁶However, this approach only result-

ed in a complex mixture instead of the desired products 14.

In the following step, cis-3-allyloxy-4-(trifluorometh-

yl)azetidin-2-ones 14a–f were subjected to an ozonolysis

reaction followed by a reductive workup with 2.5 equiva-

lents of Me₂S, providing the corresponding aldehyde inter-

mediates. These aldehydes were immediately reduced with

2.5 equivalents of BH₃(1 M in Et₂O) in THF at room tem-

perature for three hours, furnishing the corresponding cis-

3-(2-hydroxyethoxy)-4-(trifluoromethyl)azetidin-2-ones

15a–f in yields of 47–95% (Table 2).²⁶It should be noted that

Scheme 3 Reactions of 4a,b

In addition, the cyclization of 3-aminopropan-1-ols 9a,b

was performed utilizing three times one equivalent of ethyl

chloroformate and two equivalents of triethylamine in

CH₂Cl₂at room temperature for three hours, furnishing the

corresponding

trans-5-chloro-4-trifluoromethyl-1,3-ox-

azinan-2-ones 11a,b in 29–85% yield (Scheme 3).^8,201,3-

Oxazinan-2-ones are of interest due to their valuable bio-

logical activities as well. For example, they have been em-

ployed in the treatment of Alzheimer’s disease, in herbi-

cides with excellent crop-weed selectivity, in the treatment

of diseases related to kinase activity, and in the regulation

of cholesterol.^20,21Therefore, new trans-5-chloro-4-trifluo-

romethyl-1,3-oxazinan-2-ones 11a,b might possess inter-

esting properties for further applications.

In addition, the reactivity of trans-3-chloro-4-trifluoro-

methyl-β-lactams 4a,b was explored to effect ring contrac-

tion toward the synthesis of 2-substituted 3-(trifluoro-

methyl)aziridines. According to a previous study from our

group, reductive ring contraction of trans-4-aryl-3-chloro-

G

H. Dao Thi et al.

Feature

Synthesis

Table 2 Isolated Yields of Compounds 14, 15, 16 and syn/anti Ratios of Compounds 16

1) O₃

then 2.5 equiv Me₂S

OH

Br

1.6 equiv

CH₂Cl₂/MeOH 3:2

–78 °C to r.t., 1 h

O

HO

O

CF₃

R

excess K₂CO₃

0.01 equiv TBAI

O

NHR

O

CF₃

R

O

CF₃

R

N

50% NaOH

toluene, Δ, 20 h to 6 d

2) 2.5 equiv BH₃

THF, 0 °C to r.t., 3 h

O

CF₃

CH₂Cl₂/H₂O 1:1, r.t., 3 h

N

16a–f

3a–f

14a–f

15a–f

(71–98%)

(71–95%)

(47–95%)

Entry

R

14

15

16

d.r. 16

1

2

3

4

5

6

4-MeOC₆H₄

4-MeOC₆H₄CH₂

4-EtOC₆H₄

Ph

14a (94%)

14b (95%)

14c (84%)

14d (77%)

14e (71%)

14f (79%)

15a (72%)

16a (81%)

16b (0%)

16c (86%)

16d (71%)

16e (98%)

16f (0%)

78:22

–

15b (77%)

15c (72%)

15d (95%)

15e (63%)

15f (47%)

72:28

69:31

75:25

–

4-MeC₆H₄

i-Pr

the use of BH₃(1 M in Et₂O) was observed to be superior to

the use of NaBH₄or LiBH₄in this reductive reaction, be-

cause attempts with the latter agents were always accom-

panied by a reductive β-lactam ring opening.

In the course of our study on trifluoromethyl-substitut-

ed β-lactams, we realized that a trifluoromethyl group does

significantly affect the behavior of these molecules. There-

fore, in order to gain insight into the influence of the

trifluoromethyl group with respect to intramolecular

Due to the combination of the constrained β-lactam

ring system and a nucleophilic alcohol group at a remote

position, 3-(2-hydroxyethoxy)- and 3-(2-hydroxyethyl)-β-

lactams have been documented to undergo ring rearrange-

ment to generate five- and six-membered azahetero-

cycles.^26,27Hence, the potency of cis-3-(2-hydroxyethoxy)-

4-(trifluoromethyl)azetidin-2-ones 15a–f with respect to

ring transformation toward 1,4-dioxan-2-ones 16 was eval-

uated in the next step. In order to transform β-lactams 15a–

f into ring-rearranged products 16, a set of different reac-

tion conditions was assessed. In particular, treatment of β-

lactams 15 with a variety of bases (NaH, pyridine, Et₃N, Li-

OH) in different solvents (THF, toluene, DMF, CH₂Cl₂) under

different temperatures (0 °C, r.t., reflux) led to either com-

plex mixtures or recovery of the substrates. Fortunately,

treatment of cis-3-(2-hydroxyethoxy)-4-(trifluorometh-

yl)azetidin-2-ones 15 with an excess of K₂CO₃in toluene

under reflux proved to be optimal to enable the desired in-

tramolecular ring-opening reaction, furnishing an insepa-

rable diastereomeric mixture of 3-[2,2,2-trifluoro-1-(aryl-

amino)ethyl]-1,4-dioxan-2-ones 16 in excellent yields (71–

98%, Table 2).^26,27Only in the case of β-lactams 15b,f, no

ring transformation products 16b,f were observed. These

results show that the presence of electron-withdrawing

substituents at the N1 position might accelerate the intra-

molecular ring opening of β-lactams to give trifluorometh-

ylated 1,4-dioxan-2-ones 16. Indeed, the stabilizing effect

of an aromatic ring at nitrogen in 15a,c–e promotes the for-

mation of the corresponding nitrogen anion after ring

opening, whereas the presence of an electron-donating al-

kyl group in 15b,f impedes this process.

cyclization,

cis-3-(2-hydroxyethoxy)-1,4-bis(4-methoxy-

phenyl)azetidin-2-one (19) was synthesized (Scheme 4),

which bears a 4-methoxyphenyl group at the C4 position

(instead of the trifluoromethyl group). This compound 19

was prepared from the corresponding cis-3-allyloxy-1,4-

bis(4-methoxyphenyl)azetidin-2-one 18, derived from al-

cohol 17,²⁸using the above-described procedure (Scheme

4). The preparation of β-lactam 18 has also been reported

by Zarei upon treatment of allyloxyacetic acid with Schiff

base and phosphonitrilic chloride in the presence of tri-

ethylamine.²⁹Surprisingly, the treatment of cis-3-(2-hy-

droxyethoxy)-1,4-bis(4-methoxyphenyl)azetidin-2-one

(19) with an excess of K₂CO₃in toluene under reflux for four

days solely led to recovery of the starting material 19. As

K₂CO₃might not be strong enough as a base to realize nuc-

leophilic ring opening in this case, a more potent base

(NaH) was used. However, the intramolecular cyclization

toward 1,4-dioxan-2-one 20 was never observed, and this

approach resulted in either the recovery of starting materi-

al 19 or a complex mixture (Scheme 4). This observation in-

dicates that the specific combination of the aromatic group

at N1 and the trifluoromethyl group at C4, as in cis-3-(2-

hydroxyethoxy)-4-(trifluoromethyl)azetidin-2-ones 15, is

important for the base-induced transformation into trifluo-

romethyl-substituted 1,4-dioxan-2-ones 16. It should be

stressed that the synthetic chemistry concerning 1,4-diox-

an-2-one scaffolds, starting from monocyclic β-lactams, has

been sporadically documented in the literature (as side

products).²⁶These 1,4-dioxan-2-one derivatives have been

mainly synthesized from 1,2-diols,³⁰glycolic acid³¹and

H

H. Dao Thi et al.

Feature

Synthesis

glycerol derivatives.³²In addition, 1,4-dioxan-2-one deriva-

tives play an important role as intermediates in the syn-

thetic field of polymers, corrosion inhibitors, and biomate-

rials.³³In that respect, the convenient approach toward tri-

fluoromethyl-substituted 1,4-dioxan-2-ones 16 using

trifluoromethyl-substituted β-lactam alcohols 15 as build-

ing blocks provided new insights and opportunities from

both a fundamental and applied point of view.

first experiment, the intramolecular cyclization of trans-1-

(4-ethoxyphenyl)-3-(2-hydroxyethoxy)-4-(trifluorometh-

yl)azetidin-2-one (21) [the trans counterpart of cis-β-

lactam 15c, derived from the corresponding trans-1-(4-

ethoxyphenyl)-3-allyloxy-4-(trifluoromethyl)azetidin-2-

one in an overall yield of 11%] as a model compound toward

3-{1-[(4-ethoxyphenyl)amino]-2,2,2-trifluoroethyl}-1,4-di-

oxan-2-one (16c) was tested. Remarkably, the use of identi-

cal reactions conditions (excess of K₂CO₃in toluene under

reflux for five days) applied to trans-1-(4-ethoxyphenyl)-3-

(2-hydroxyethoxy)-4-(trifluoromethyl)azetidin-2-one (21)

also led to a mixture of two isomers 16c in a ratio of 66:34,

similar to the 72:28 mixture obtained from 15c (Scheme 5).

In the second experiment, the pure diastereoisomer cis-

3-allyloxy-1-(4-ethoxyphenyl)-4-(trifluoromethyl)azeti-

din-2-one (14c) was treated with an excess of K₂CO₃in tol-

uene under reflux for five days, resulting in a cis/trans mix-

ture of 3-allyloxy-1-(4-ethoxyphenyl)-4-(trifluorometh-

yl)azetidin-2-one in a ratio of 40:60 (cis/trans). In the last

experiment, the diastereomeric mixture of 3-{1-[(4-

ethoxyphenyl)amino]-2,2,2-trifluoroethyl}-1,4-dioxan-2-

one 16c (d.r. 72:28) was treated with an excess of K₂CO₃in

toluene under reflux for one day, which did not affect the

diastereomeric ratio.

OMe

Br

1.6 equiv

HO

O

0.01 equiv TBAI

50% NaOH

N

CH₂Cl₂/H₂O (1:1), r.t., 2 h

OMe

18

(85%)

17

1) O₃

then 2.5 equiv Me₂S

CH₂Cl₂/MeOH (3:2)

-78 °C - r.t., 1 h

2) 2.5 equiv BH₃

THF, 0 °C - r.t., 2 h

OH

OMe

O

Based on these experimental results, we propose that a

dynamic equilibrium between intramolecular ring opening

and epimerization of cis-alcohols 15 occurred in the pres-

ence of K₂CO₃, which led to the corresponding

(3S,1′R;3R,1′S)-3-[2,2,2-trifluoro-1-(arylamino)ethyl]-1,4-

dioxan-2-ones 16 (as major products) and trans-alcohols

15. Then, trans-alcohols 15 were in turn subjected to intra-

molecular ring opening, leading to the corresponding

(3R,1′R;3S,1′S)-3-[2,2,2-trifluoro-1-(arylamino)ethyl]-1,4-

dioxan-2-ones 16 (as minor isomers). In addition to the ex-

periments, DFT calculations were performed to assess the

stability of the diastereomeric pairs. Relative Gibbs free en-

ergies indicate that (3S,1′R;3R,1′S)-16 is more stable than

(3R,1′R;3S,1′S)-16 if the mixture of the two diastereoiso-

mers is considered (see Supporting Information). Hence, 3-

(2,2,2-trifluoro-1-aminoethyl-1,4-dioxan-2-ones (3S,1′R)-

and (3R,1′S)-16 are proposed to be the major products in

the inseparable mixture of diastereoisomers (Figure 1).

excess K₂CO₃

toluene, Δ, 4 d

O

NH

OMe

O

X

N

or 1.2 equiv NaH

THF, 0 °C - r.t. - Δ, 2 h

OMe

20

19

(51%)

Scheme 4 Attempted peparation of 1,4-dioxan-2-one 20

Because the resulting diastereoisomers 16 could not be

separated by means of column chromatography on silica

gel, preparative HPLC (Supelco Ascentis C18; H₂O/MeCN),

and recrystallization (CH₂Cl₂/Et₂O 1:1 or Et₂O), other at-

tempts were made to determine the relative stereochemis-

try of 3-[2,2,2-trifluoro-1-(arylamino)ethyl]-1,4-dioxan-2-

ones 16. For that reason, three additional experiments were

performed to examine the behavior of cis-β-lactams 15 to-

ward intramolecular cyclization under basic conditions. In the

OH

O

CF₃

O

CF₃

H

excess K₂CO₃

O

N

toluene, Δ, 28 h

toluene, Δ, 5 d

N

O

CF₃

OEt

15c

16c

21

d.r. 72:28 from 15c

d.r. 66:34 from 21

Scheme 5 Preparation of 1,4-dioxan-2-one 16c

I

H. Dao Thi et al.

Feature

Synthesis

ed via direct injection on an Agilent 1100 Series (ES, 4000 V) LC/MSD

type SL mass spectrometer with Electron Spray Ionization Geometry

(ESI 70 eV) and using a Mass Selective Detector (quadrupole). High-

resolution electron spray (ES) mass spectra were obtained with an

Agilent Technologies 6210 Series Time-of-Flight. IR spectra were re-

corded on a PerkinElmer Spectrum BX FT-IR spectrometer (in neat

form) with an ATR (Attenuated Total Reflectance) accessory. Melting

points of crystalline compounds were measured using a Büchi B-540

apparatus or a Kofler bench, type WME Heizbank of Wagner & Munz.

O

H

O

NHR

O

NHR

O

CF₃

O

CF₃

(3S,1'R)-16

(3R,1'S)-16

major isomers

The ozonolysis reaction was performed with an Ozonia Triogen Model

LAB2B laboratory ozone generator, connected to a Bronkhorst Flow-

Bus E-7000 type mass flow meter to control the dry air inflow and an

Anseros Ozomat Model GM Non-Dispersive UV-analyzer to measure

the ozone concentration.

O

H

O

NHR

O

NHR

O

CF₃

O

CF₃

(3R,1'R)-16

minor isomers

(3S,1'S)-16

3-Benzyloxy-4-(trifluoromethyl)azetidin-2-ones 2

Figure 1 Overview of possible isomers for structures 16

The synthesis of 3-benzyloxy-4-(trifluoromethyl)azetidin-2-ones

2a,b was reported in a previous study.¹⁰A slightly modified proce-

dure for the synthesis of 2c–e is described below.

Conclusion

In conclusion, a set of cis-3-hydroxy-4-(trifluoromethyl)-

azetidin-2-ones were effectively synthesized and success-

fully used as versatile new building blocks for the construc-

tion of a variety of trifluoromethyl-containing amines and

heterocyclic molecules. To that end, cis-3-hydroxy-4-tri-

fluoromethyl-β-lactams were transformed into trans-3-

chloro-4-trifluoromethyl-β-lactams, which served as eligi-

ble substrates for the preparation of α-trifluoromethyl-sub-

stituted aminopropane derivatives through a regiospecific

ring opening of intermediate azetidinium salts. Besides,

new trans-5-chloro-4-trifluoromethyl-1,3-oxazinanes and

trans-5-chloro-4-trifluoromethyl-1,3-oxazinan-2-ones were

produced through cyclization of trifluoromethylated γ-ami-

no alcohols, with formaldehyde or ethyl chloroformate, re-

spectively. Moreover, 2-substituted 3-trifluoromethylated

aziridines were synthesized, either by base-induced ring

closure of γ-amino alcohols or upon direct treatment of 3-

chloro-γ-lactams with KOH. In addition, 3-hydroxy-4-(tri-

fluoromethyl)azetidin-2-ones proved to be suitable sub-

strates for the synthesis of novel 3-[2,2,2-trifluoro-1-(aryl-

amino)ethyl]-1,4-dioxan-2-ones in high yields through ring

rearrangement.

cis-3-Benzyloxy-1-(4-ethoxyphenyl)-4-(trifluoromethyl)azetidin-

2-one (2c); Typical Procedure

To a solution of 1-ethoxy-2,2,2-trifluoroethanol (1; 1.00 g, 0.82 mL,

6,94 mmol, 1 equiv) in toluene (30 mL) was added p-phenetidine

(0.76 g, 0.71 mL, 5.55 mmol, 0.8 equiv) and PTSA as catalyst (13.2 mg,

0.07 mmol, 0.01 equiv). The resulting mixture was heated at reflux

temperature for 3 h under Dean–Stark conditions, affording N-(4-

ethoxyphenyl)-2,2,2-trifluoroethan-1-imine in high purity (>90%

based on NMR analysis). Due to its hydrolytic instability, after evapo-

ration of the crude mixture, the resulting product (1.23 g, 5.67 mmol,

1 equiv) was immediately dissolved in anhyd CH₂Cl₂(50 mL) at 0 °C

under argon atmosphere and Et₃N (2.87 g, 3.95 mL, 28.4 mmol, 5

equiv) was added to the solution. Benzyloxyacetyl chloride (4.17 g,

3.57 mL, 22.68 mmol, 4 equiv) was then added dropwise to the reac-

tion mixture. After stirring the mixture for 3 days under reflux, H₂O

(20 mL) was added to the mixture. Extraction with CH₂Cl₂(3 × 20 mL),

washing the combined organic layers with brine (3 × 20 mL), drying

(MgSO₄), filtration, and evaporation of solvent afforded a mixture of

two isomers cis/trans in a ratio of 78:22. The two isomers were sepa-

rated by means of column chromatography on silica gel (PE/EtOAc

9:1), then recrystallization from EtOH was performed to obtain ana-

lytically pure 2c and trans-3-benzyloxy-1-(4-ethoxyphenyl)-4-(tri-

fluoromethyl)azetidin-2-one.

2c

Yield: 0.97 g (2.66 mmol, 47%); white crystals; mp 83 °C (EtOH); R_f=

0.23 (PE/EtOAc 9:1).

All reagents were purchased as commercially available sources with-

out further purification. Et₂O, THF, and toluene were distilled from Na

benzophenone ketyl or Na, while CH₂Cl₂was distilled from CaH₂prior

to use. Solvents were removed under reduced pressure using a rotary

evaporator. Silica gel (0.035–0.070 mm, pore diameter ca. 6 nm) was

used for column chromatography. Solvent systems were determined

via initial TLC analysis on glass-backed silica plates (Merck Kieselgel

60 with F254 indicator, precoated 0.25 mm). These plates were devel-

oped using standard visualization techniques or agents, UV fluores-

cence (254 and 366 nm) and/or coloring with a KMnO₄solution.

High-resolution ¹H NMR (400 MHz), ¹³C NMR (100.6 MHz), and ¹⁹F

NMR (376 MHz) spectra were recorded with a Bruker Avance III

Nanobay NMR spectrometer using deuterated solvents and TMS and

CFCl₃as internal standards. Low-resolution mass spectra were record-

IR (ATR): 1749, 1514, 1364, 1267, 1163, 1136, 1022, 922, 825, 735,

505 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.32–7.41 (m, 7 H), 6.87 (d, J = 9.0 Hz, 2

H), 4.98 (d, J = 5.4 Hz, 1 H), 4.85 (d, J = 11.8 Hz, 1 H), 4.80 (d, J = 11.8

Hz, 1 H), 4.61 (quint, J = 5.4 Hz, 1 H), 4.01 (q, J = 7.0 Hz, 2 H), 1.40 (t, J =

7.0 Hz, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 163.8, 156.6, 136.1, 129.3, 128.6 (2

C), 128.3, 127.9 (2 C), 123.8 (q, J = 284.4 Hz), 119.4 (2 C), 115.0 (2 C),

80.2, 73.8, 63.7, 57.7 (q, J = 33.1 Hz), 14.8.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –68.37 (d, J = 5.4 Hz, 3 F).

MS (70 eV): m/z = 366 ([M⁺+ 1], 100).

J

H. Dao Thi et al.

Feature

Synthesis

trans-3-Benzyloxy-1-(4-ethoxyphenyl)-4-(trifluoromethyl)azeti-

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –68.29 (d, J = 5.3 Hz, 3 F).

din-2-one

MS (70 eV): m/z = 336 ([M⁺+ 1], 100).

Yield: 0.20 g (0.55 mmol, 10%); white crystals; mp 71 °C (EtOH); R_f=

0.49 (PE/EtOAc 9:1).

trans-3-Benzyloxy-1-(4-methylphenyl)-4-(trifluoromethyl)azeti-

IR (ATR): 1763, 1514, 1398, 1281, 1244, 1148, 1113, 1045, 843, 735,

din-2-one

694 cm^–1

.

Yield: 0.25 g (0.75 mmol, 14%); white crystals; mp 62 °C (EtOH); R_f=

¹H NMR (400 MHz, CDCl₃): δ = 7.33–7.39 (m, 5 H), 7.32 (d, J = 8.9 Hz, 2

H), 6.88 (d, J = 8.9 Hz, 2 H), 4.88 (d, J = 1.1 Hz, 1 H), 4.82 (d, J = 11.5 Hz,

1 H), 4.76 (d, J = 11.5 Hz, 1 H), 4.41 (qd, J = 5.6, 1.1 Hz, 1 H), 4.01 (q, J =

7.0 Hz, 2 H), 1.40 (t, J = 7.0 Hz, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 162.5, 156.8, 135.9, 128.9, 128.7 (2

C), 128.5, 128.2 (2 C), 123.6 (q, J = 280.5 Hz), 120.1 (2 C), 115.0 (2 C),

82.0, 73.2, 63.7, 59.8 (q, J = 34.2 Hz), 14.8.

0.52 (PE/EtOAc 9:1).

IR (ATR): 1759, 1512, 1391, 1348, 1277, 1163, 1138, 1109, 810, 739,

698, 509, 436 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.25–7.30 (m, 5 H), 7.22 (d, J = 8.3 Hz, 2

H), 7.08 (d, J = 8.3 Hz, 2 H), 4.80 (d, J = 1.2 Hz, 1 H), 4.74 (d, J = 11.6 Hz,

1 H), 4.67 (d, J = 11.6 Hz, 1 H), 4.35 (qd, J = 5.6, 1.2 Hz, 1 H), 2.24 (s, 3

H).

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –71.38 (d, J = 5.6 Hz, 3 F).

MS (70 eV): m/z = 366 ([M⁺+ 1], 100).

¹³C NMR (100.6 MHz, CDCl₃): δ = 162.6, 135.9, 135.6, 133.4, 129.8 (2

C), 128.7 (2 C), 128.5, 128.2 (2 C), 123.6 (q, J = 280.4 Hz), 118.2 (2 C),

82.0 (q, J = 2.0 Hz), 73.2, 59.6 (q, J = 34.4 Hz), 21.0.

cis-3-Benzyloxy-1-(4-iodophenyl)-4-(trifluoromethyl)azetidin-2-

one (2d)

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –71.22 (d, J = 5.6 Hz, 3 F).

MS (70 eV): m/z = 336 ([M⁺+ 1], 100).

Yield: 1.05 g (2.35 mmol, 35%); white crystals; mp 125 °C (EtOH); R_f=

0.15 (PE/EtOAc 12:1).

cis-3-Benzyloxy-1-isopropyl-4-(trifluoromethyl)azetidin-2-one

IR (ATR): 1761, 1489, 1364, 1267, 1238, 1165, 1128, 816, 737, 694,

(2f)

498 cm^–1

.

To a solution of 1-ethoxy-2,2,2-trifluoroethanol (1; 1.00 g, 0.82 mL,

6,94 mmol, 1 equiv) in anhyd CH₂Cl₂(20 mL) was added i-PrNH₂(0.41

g, 0.60 mL, 6.94 mmol, 1 equiv) and MgSO₄(1.67 g, 13.88 mmol, 2

equiv). After stirring for 2 h under reflux, MgSO₄was removed by fil-

tration. Evaporation of the solvent in vacuo gave 2,2,2-trifluoro-1-

(isopropylamino)ethan-1-ol (0.76 g, 4.84 mmol, 70%) as white crys-

tals. Benzyloxyacetyl chloride (3.56 g, 3.04 mL, 19.36 mmol, 4 equiv)

was added dropwise to an ice-cooled solution of the latter N-isopro-

pyl hemiaminal (0.76 g, 4.84 mmol, 1 equiv) and Et₃N (2.44 g, 3.37

mL, 24.2 mmol, 5 equiv) in anhyd CH₂Cl₂(30 mL). After stirring for 19

h under reflux, H₂O (30 mL) was added to the reaction mixture and

extracted with CH₂Cl₂(2 × 25 mL). Drying the combined organic lay-

ers (MgSO₄), filtration, and removal of the solvent afforded a mixture

of two isomers cis/trans in a ratio of 75:25. Pure 2f (0.82 g, 2.86

mmol, 59%) was obtained by means of column chromatography on

silica gel (PE/EtOAc 9:1); yield: 0.82 g (2.86 mmol, 59%); yellowish

solid; mp 45 °C; R_f= 0.11 (PE/EtOAc 9:1).

¹H NMR (400 MHz, CDCl₃): δ = 7.67 (d, J = 8.7 Hz, 2 H), 7.32–7.39 (m, 5

H), 7.23 (d, J = 8.7 Hz, 2 H), 4.99 (d, J = 5.4 Hz, 1 H), 4.85 (d, J = 11.8 Hz,

1 H), 4.79(d, J = 11.8 Hz, 1 H), 4.64 (quint, J = 5.4 Hz, 1 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 164.1, 138.2 (2 C), 135.9, 135.8,

128.7 (2 C), 128.4, 128.0 (2 C), 123.6 (q, J = 280.1 Hz), 119.4 (2 C), 89.0,

80.2, 73.9, 57.4 (q, J = 33.4 Hz).

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –68.21 (d, J = 5.4 Hz, 3 F).

MS (70 eV): m/z (%) = 465 ([M⁺+ 18], 100), 448 ([M⁺+ 1], 55).

trans-3-Benzyloxy-1-(4-iodophenyl)-4-(trifluoromethyl)azetidin-

2-one

Yield: 0.81 g (1.81 mmol, 27%); white crystals; mp 78 °C (EtOH); R_f=

0.52 (PE/EtOAc 9:1).

IR (ATR): 1757, 1587, 1489, 1393, 1364, 1111, 1001, 696, 498 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.61 (d, J = 8.7 Hz, 2 H), 7.28–7.34 (m, 5

H), 7.11 (d, J = 8.7 Hz, 2 H), 4.82 (d, J = 1.3 Hz, 1 H), 4.76 (d, J = 11.6 Hz,

1 H), 4.69 (d, J = 11.6 Hz, 1 H), 4.36 (qd, J = 5.6, 1.3 Hz, 1 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 162.6, 138.3 (2 C), 135.6, 128.74 (2

C), 128.65, 128.2 (2 C), 123.4 (q, J = 280.2 Hz), 119.8 (2 C), 89.4, 82.2

(q, J = 1.5 Hz), 73.3, 59.6 (q, J = 34.5 Hz).

IR (ATR): 1763, 1393, 1354, 1277, 1161, 1138, 1113, 735, 696 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.28–7.36 (m, 5 H), 4.77 (d, J = 11.8 Hz,

1 H), 4.75 (d, J = 5.2 Hz, 1 H), 4.73 (d, J = 11.8 Hz, 1 H), 4.11 (qd, J = 6.1,

5.2 Hz, 1 H), 3.88 (sept, J = 6.8 Hz, 1 H), 1.29 (d, J = 6.8 Hz, 3 H), 1.25 (d,

J = 6.8 Hz, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 166.1, 136.3, 128.5 (2 C), 128.2,

127.9 (2 C), 123.9 (q, J = 279.8 Hz), 80.0, 73.4, 56.5 (q, J = 33.1 Hz),

45.1, 21.1, 19.4.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –71.12 (d, J = 5.6 Hz, 3 F).

MS (70 eV): m/z = 448 ([M⁺+ 1], 50).

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –69.33 (d, J = 6.1 Hz, 3 F).

MS (70 eV): m/z = 288 ([M⁺+ 1], 100).

cis-3-Benzyloxy-1-(4-methylphenyl)-4-(trifluoromethyl)azetidin-

2-one (2e)

Yield: 0.63 g (1.88 mmol, 31%); white crystals; mp 113 °C (EtOH); R_f=

0.25 (PE/EtOAc 9:1).

cis-3-Benzyloxy-1-phenyl-4-(trifluoromethyl)azetidin-2-one

This product was obtained by hydrogenolysis of cis-3-benzyloxy-1-

(4-iodophenyl)-4-(trifluoromethyl)azetidin-2-one (2d) by applying a

literature procedure;¹⁰yield: 0.65 g (2.02 mmol, 86%); white crystals;

mp 95 °C.

IR (ATR): 1769, 1514, 1360, 1265, 1167, 1130, 812, 760, 694, 494 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.33–7.40 (m, 7 H), 7.14 (d, J = 8.3 Hz, 2

H), 4.96 (d, J = 5.3 Hz, 1 H), 4.84 (d, J = 11.8 Hz, 1 H), 4.78 (d, J = 11.8

Hz, 1 H), 4.63 (quint, J = 5.3 Hz, 1 H), 2.31 (s, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 164.0, 136.1, 135.3, 133.7, 129.8 (2

C), 128.6 (2 C), 128.3, 127.9 (2 C), 123.8 (q, J = 280.4 Hz), 117.7 (2 C),

80.2, 73.8, 57.4 (q, J = 33.2 Hz), 20.9.

IR (ATR): 1757, 1499, 1366, 1167, 1138, 739, 752, 669, 490 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.46 (d, J = 8.1 Hz, 2 H), 7.31–7.41 (m, 7

H), 7.17 (t, J = 7.4 Hz, 1 H), 4.98 (d, J = 5.4 Hz, 1 H), 4.85 (d, J = 11.8 Hz,

1 H), 4.80 (d, J = 11.8 Hz, 1 H), 4.67 (quint, J = 5.4 Hz, 1 H).

K

H. Dao Thi et al.

Feature

Synthesis

¹³C NMR (100.6 MHz, CDCl₃): δ = 164.2, 136.2, 136.1, 129.3 (2 C),

128.6 (2 C), 128.4, 128.0 (2 C), 125.5, 123.7 (q, J = 281.0 Hz), 117.6 (2

C), 80.1, 73.8, 57.4 (q, J = 33.3 Hz).

cis-3-Hydroxy-1-(4-methylphenyl)-4-(trifluoromethyl)azetidin-2-

one (3e)

Yield: 0.32 g (1.31 mmol, 87%); white crystals; mp 176 °C.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –68.26 (d, J = 5.4 Hz, 3 F).

MS (70 eV): m/z = 322 ([M⁺+ 1], 100).

IR (ATR): 2455, 1732, 1512, 1389, 1281, 1248, 1167, 1082, 860, 810,

646, 471 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.36 (d, J = 8.3 Hz, 2 H), 7.17 (d, J = 8.3

Hz, 2 H), 5.28 (dd, J = 8.2, 5.5 Hz, 1 H), 4.66 (quint, J = 5.5 Hz, 1 H), 3.22

(br s, 1 H), 2.33 (s, 3 H).

3-Hydroxy-4-(trifluoromethyl)azetidin-2-ones 3; General Proce-

dure

¹³C NMR (100.6 MHz, CD₃OD): δ = 166.8, 134.9, 134.1, 129.2 (2 C),

124.3 (q, J = 279.9 Hz), 117.5 (2 C), 74.9, 57.8 (q, J = 31.5 Hz), 19.5.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –68.41 (d, J = 5.5 Hz, 3 F).

MS (70 eV): m/z (%) = 263 ([M⁺+ 18], 100), 246 ([M⁺+ 1], 40).

The synthesis of 3-hydroxy-4-(trifluoromethyl)azetidin-2-ones 3c–f

was performed according to a procedure described in a previous

study.¹⁰

cis-1-(4-Ethoxyphenyl)-3-hydroxy-4-(trifluoromethyl)azetidin-2-

one (cis-3c)

cis-3-Hydroxy-1-isopropyl-4-(trifluoromethyl)azetidin-2-one (3f)

Yield: 0.33 g (1.68 mmol, 97%); white crystals; mp 85 °C.

Yield: 0.54 g (1.96 mmol, 94%); white crystals; mp 144 °C (hex-

ane/EtOAc 30:1).

IR (ATR): 3240, 1719, 1580, 1385, 1371, 1217, 1153, 1119, 1053, 932,

IR (ATR): 3306, 1728, 1514, 1296, 1250, 1167, 1136, 1038, 860, 822,

854, 810, 646 cm^–1

.

652, 522 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 5.07 (dd, J = 5.9, 5.1 Hz, 1 H), 4.61 (d, J =

5.9 Hz, 1 H), 4.12 (qd, J = 6.3, 5.1 Hz, 1 H), 3.87 (sept, J = 6.8 Hz, 1 H),

1.30 (d, J = 6.8 Hz, 3 H), 1.26 (d, J = 6.8 Hz, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 168.6, 123.8 (q, J = 279.7 Hz), 74.7,

57.2 (q, J = 32.1 Hz), 45.4, 21.0, 19.3.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –69.44 (d, J = 6.3 Hz, 3 F).

MS (70 eV): m/z = 198 ([M⁺+ 1], 70).

¹H NMR (400 MHz, CDCl₃): δ = 7.37 (d, J = 9.0 Hz, 2 H), 6.87 (d, J = 9.0

Hz, 2 H), 5.31 (d, J = 5.5 Hz, 1 H), 4.63 (quint, J = 5.5 Hz, 1 H), 4.20 (s, 1

H), 4.01 (q, J = 7.0 Hz, 2 H), 1.40 (t, J = 7.0 Hz, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 165.6, 156.8, 129.1, 123.7 (q, J =

281.6 Hz), 119.5 (2 C), 115.0 (2 C), 75.2, 63.8, 58.2 (q, J = 32.0 Hz),

14.8.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –68.48 (d, J = 5.5 Hz, 3 F).

MS (70 eV): m/z = 276 ([M⁺+ 1], 70).

trans-3-Chloro-4-(trifluoromethyl)azetidin-2-ones 4; trans-3-

Chloro-1-(4-methoxyphenyl)-4-(trifluoromethyl)azetidin-2-one

(4a); Typical Procedure

trans-1-(4-Ethoxyphenyl)-3-hydroxy-4-(trifluoromethyl)azetidin-

2-one (trans-3c)

To a solution of cis-3-hydroxy-1-(4-methoxyphenyl)-4-(trifluoro-

methyl)azetidin-2-one (3a; (1.49 g, 5.71 mmol, 1 equiv) in CCl₄(10

mL) at r.t. was added Ph₃P (2.99 g, 11.42 mmol, 2 equiv) and NaHCO₃

as a catalyst (0.07 g, 0.86 mmol, 0.15 equiv). The mixture was heated

under reflux for 10 h. Filtration of the heterogenous mixture through

Celite and evaporation of the solvent in vacuo afforded 4a (1.54 g,

5.52 mmol, 97%), which was purified by means of column chromatog-

raphy on silica gel (PE/EtOAc 8:1); yield: 1.54 g (5.52 mmol, 97%), col-

orless solid; mp 52 °C; R_f= 0.32 (PE/EtOAc 8:1).

Yield: 0.11 g (0.40 mmol, 84%); white crystals; mp 102 °C (hex-

ane/EtOAc 30:1).

IR (ATR): 3237, 1736, 1512, 1479, 1400, 1283, 1250, 1144, 1103, 1049,

876, 822, 696 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.26 (d, J = 9.0 Hz, 2 H), 6.85 (d, J = 9.0

Hz, 2 H), 5.03 (~s, 1 H), 4.93 (s, 1 H), 4.42 (qd, J = 5.7, 1.1 Hz, 1 H), 4.00

(q, J = 7.0 Hz, 2 H), 1.41 (t, J = 7.0 Hz, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 166.0, 157.1, 128.3, 123.5 (q, J =

280.3 Hz), 120.4 (2 C), 115.0 (2 C), 76.2 (q, J = 2.2 Hz), 63.8, 61.4 (q, J =

34.2 Hz), 14.7.

IR (ATR): 1771, 1510, 1269, 1256, 1173, 1159, 1132, 1113, 1090, 1038,

878, 820, 800, 689, 588, 511, 424 cm^–1

.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –71.72 (d, J = 5.7 Hz, 3 F).

MS (70 eV): m/z = 276 ([M⁺+ 1], 100).

¹H NMR (400 MHz, CDCl₃): δ = 7.35 (d, J = 9.1 Hz, 2 H), 6.91 (d, J = 9.1

Hz, 2 H), 4.93 (d, J = 1.8 Hz, 1 H), 4.55 (qd, J = 5.3, 1.8 Hz, 1 H), 3.80 (s,

3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 159.0, 157.8, 128.7, 123.1 (q, J =

281.1 Hz), 120.1 (2 C), 114.6 (2 C), 61.8 (q, J = 34.9 Hz), 55.8 (q, J = 2.0

Hz), 55.5.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –72.36 (d, J = 5.3 Hz, 3 F).

MS (70 eV): m/z = 297 ([M⁺+ 18], 100).

cis-3-Hydroxy-1-phenyl-4-(trifluoromethyl)azetidin-2-one (3d)

Yield: 0.42 g (1.82 mmol, 84%); white crystals; mp 164 °C (hex-

ane/EtOAc 30:1).

IR (ATR): 2448, 1724, 1499, 1393, 1281, 1252, 1142, 758, 691, 664 cm^–1

¹H NMR (400 MHz, CD₃OD): δ = 7.51 (d, J = 7.8 Hz, 2 H), 7.39 (t, J = 7.8

Hz, 2 H), 7.19 (t, J = 7.7 Hz, 1 H), 5.29 (d, J = 5.7 Hz, 1 H), 4.98 (quint, J =

5.7 Hz, 1 H).

.

trans-3-Chloro-1-(4-methoxybenzyl)-4-(trifluoromethyl)azeti-

din-2-one (4b)

¹³C NMR (100.6 MHz, CD₃OD): δ = 167.0, 136.7, 128.8 (2 C), 124.9,

124.3 (q, J = 279.7 Hz), 117.4 (2 C), 74.9, 57.8 (q, J = 31.5 Hz).

Yield: 2.10 g (7.17 mmol, 91%); yellowish oil; R_f= 0.40 (PE/EtOAc 8:1).

¹⁹F NMR (376.5 MHz, CD₃OD): δ = –70.18 (d, J = 5.7 Hz, 3 F).

MS (70 eV): m/z = 249 ([M⁺+ 18], 100).

IR (ATR): 1786, 1514, 1275, 1246, 1190, 1161, 1132, 1107, 1032, 835,

687, 621 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.19 (d, J = 8.6 Hz, 2 H), 6.91 (d, J = 8.6

Hz, 2 H), 4.86 (d, J = 15.0 Hz, 1 H), 4.81 (d, J = 1.4 Hz, 1 H), 3.96 (d, J =

15.0 Hz, 1 H), 3.811 (s, 3 H), 3.808 (qd, J = 5.7, 1.4 Hz, 1 H).

L

H. Dao Thi et al.

Feature

Synthesis

¹³C NMR (100.6 MHz, CDCl₃): δ = 161.9, 159.8, 129.9 (2 C), 125.3,

123.1 (q, J = 280.2 Hz), 114.5 (2 C), 60.1 (q, J = 34.7 Hz), 55.9 (q, J = 2.4

Hz), 55.3, 45.6.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –73.72 (d, J = 5.7 Hz, 3 F).

MS (70 eV): m/z (%) = 294 ([M⁺+ 1], 10), 311 ([M⁺+ 18], 100).

g, 0.37 mmol, 1 equiv) in anhyd CH₂Cl₂(5 mL). After stirring for 1 h at

r.t., the solvent was evaporated and the resulting residue was redis-

solved in MeCN (5 mL), after which NaOAc (0.12 g, 1.48 mmol, 4

equiv) was added. After stirring at reflux temperature for 1 h, the

mixture was extracted with CH₂Cl₂(3 × 5 mL) and the combined or-

ganic layers were washed with brine (3 × 5 mL). Drying (MgSO₄), fil-

tration, and evaporation of the solvent afforded a crude mixture of

product 7a (0.05 g, 0.16 mmol, 43%) and the starting material 5a (0.02

g, 0.08 mmol) in a ratio of 53:47, which were separated by means of

preparative TLC (hexane/EtOAc 9:1) to obtain analytically pure com-

pounds; yellowish solid; mp 48 °C; R_f= 0.30 (hexane/EtOAc 9:1);

yield: 0.05 g (0.16 mmol, 43%).

trans-3-Chloro-2-(trifluoromethyl)azetidines 5; trans-3-Chloro-

1-(4-methoxyphenyl)-2-(trifluoromethyl)azetidine (5a); Typical

Procedure

To an ice-cooled solution of AlCl₃(0.38 g, 2.86 mmol, 2 equiv) in an-

hyd Et₂O (10 mL), was carefully added a 1 M solution of LiAlH₄in THF

(2.86 mL, 0.11 g, 2.86 mmol, 2 equiv) dropwise. The reaction mixture

was allowed to reach r.t., and then heated for 30 min at reflux tem-

perature. Afterwards, the mixture was cooled to 0 °C and trans-3-

chloro-1-(4-methoxyphenyl)-4-(trifluoromethyl)azetidin-2-one (4a;

0.40 g, 1.43 mmol, 1 equiv) was added. After stirring for 5 min at r.t.,

the reaction was quenched with H₂O (10 mL) and filtered through a

short pad of Celite. Extraction with Et₂O (3 × 10 mL), drying the com-

bined organic layers (MgSO₄), filtration, and evaporation of the sol-

vent afforded a crude mixture. The ¹H NMR and ¹⁹F NMR of this mix-

ture showed it to consist of product 5a and the ring-opened product

anti-2-chloro-4,4,4-trifluoro-3-[(4-methoxyphenyl)amino]butan-1-

ol in a ratio of 66:34. The mixture was separated by flash column

chromatography (PE/EtOAc 12:1) to give pure 5a; yield: 0.21 g (0.79

mmol, 54%); yellow solid; mp 50 °C; R_f= 0.55 (PE/EtOAc 12:1).

IR (ATR): 1734, 1514, 1252, 1227, 1163, 1140, 1107, 1045, 1034, 826

cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 6.73–6.78 (m, 4 H), 4.33–4.43 (m, 3 H),

4.20–4.25 (m, 1 H), 3.70 (s, 3 H), 2.79 (q, J = 1.3 Hz, 3 H), 1.93 (s, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 170.3, 153.6, 143.5, 125.5 (q, J =

289.4 Hz), 116.5 (2 C), 114.7 (2 C), 65.2, 64.7 (q, J = 27.2 Hz), 55.6,

52.5, 33.2, 20.5.

¹⁹F NMR (376 MHz, CDCl₃): δ = –64.59 (d, J = 6.1 Hz, 3 F).

MS (70 eV): m/z = 340 ([M⁺+ 1], 100).

anti-2-Chloro-4,4,4-trifluoro-3-[N-(4-methoxybenzyl)-N-methyl-

amino]butyl Acetate (7b)

Yield: 0.02 g (0.06 mmol, 18%); yellowish solid; mp 47 °C; R_f= 0.23

(hexane/EtOAc 10:1).

IR (ATR): 1508, 1273, 1263, 1242, 1157, 1126, 1034, 824, 795, 692,

529 cm^–1

.

IR (ATR): 1744, 1512, 1233, 1169, 1119, 1107, 1061, 1034 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 6.85 (d, J = 9.0 Hz, 2 H), 6.61 (d, J = 9.0

Hz, 2 H), 4.69 (ddd, J = 6.7, 6.7, 5.5 Hz, 1 H), 4.49 (dd, J = 7.9, 6.7 Hz, 1

H), 4.38 (q, J = 5.5 Hz, 1 H), 3.78 (dd, J = 7.9, 6.7 Hz, 1 H), 3.76 (s, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 154.1, 143.6, 123.9 (q, J = 279.6 Hz),

114.8 (2 C), 114.0 (2 C), 73.0 (q, J = 33.4 Hz), 61.3, 55.7, 44.2 (q, J = 3.4

Hz).

¹H NMR (400 MHz, CDCl₃): δ = 7.15 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6

Hz, 2 H), 4.55 (dd, J = 11.8, 2.7 Hz, 1 H), 4.25–4.35 (m, 2 H), 3.82 (d, J =

12.8 Hz, 1 H), 3.80 (s, 3 H), 3.77 (d, J = 12.8 Hz, 1 H), 3.49 (dq, J = 9.1,

7.7 Hz, 1 H), 2.38 (q, J = 1.8 Hz, 3 H), 2.05 (s, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 170.6, 159.1, 130.1 (2 C), 129.7,

126.6 (q, J = 293.4 Hz), 113.9 (2 C), 65.6, 65.0 (q, J = 24.9 Hz), 60.0,

55.3, 53.1, 36.5, 20.7.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –75.70 (d, J = 5.5 Hz, 3 F).

MS (70 eV): m/z = 266 ([M⁺+ 1], 100).

¹⁹F NMR (376 MHz, CDCl₃): δ = –62.33 (d, J = 7.7 Hz, 3 F).

MS (70 eV): m/z = 371 ([M⁺+ 18], 40).

trans-3-Chloro-1-(4-methoxybenzyl)-2-(trifluoromethyl)azeti-

dine (5b)

anti-N¹-(tert-Butyl)-2-chloro-4,4,4-trifluoro-N³-(4-methoxyben-

zyl/phenyl)-N³-methylbutane-1,3-diamines 8; anti-N¹-(tert-Bu-

tyl)-2-chloro-4,4,4-trifluoro-N³-(4-methoxyphenyl)-N³-

methylbutane-1,3-diamine (8a); Typical Procedure

Yield: 0.54 g (1.94 mmol, 78%); yellowish solid; mp 56 °C; R_f= 0.78

(PE/EtOAc 12:1).

IR (ATR): 1514, 1283, 1250, 1236, 1161, 1142, 1123, 1082, 1032, 827,

781, 762, 696 cm^–1

.

In a flame-dried flask under N₂atmosphere, Me₃OBF₄(0.11 g, 0.74

mmol, 2 equiv) was added to an ice-cooled solution of trans-3-

chloro-1-(4-methoxyphenyl)-2-(trifluoromethyl)azetidine (5a; 0.10

g, 0.37 mmol, 1 equiv) in anhyd CH₂Cl₂(5 mL). After stirring for 1 h at

r.t., the solvent was evaporated and the resulting residue was redis-

solved in MeCN (5 mL), followed by the addition of tert-butylamine

(0.11 g, 0.16 mL, 1.48 mmol, 4 equiv). After stirring at reflux tempera-

ture for 1 h, the mixture was extracted with CH₂Cl₂(3 × 5 mL) and the

combined organic layers were washed with brine (3 × 5 mL). Drying

(MgSO₄), filtration, and evaporation of the solvent afforded a crude

mixture of product 8a (0.05 g, 0.14 mmol, 38%) and the recovery of

the starting material 5a (0.005 g, 0.02 mmol) in a ratio of 80:20,

which were separated by means of preparative TLC (hexane/EtOAc

10:1) to obtain analytically pure samples; yellow oil, solidified in

fridge; yield: 0.05 g (0.14 mmol, 38%); R_f= 0.14 (hexane/EtOAc 10:1).

¹H NMR (400 MHz, CDCl₃): δ = 7.18 (d, J = 8.6 Hz, 2 H), 6.87 (d, J = 8.6

Hz, 2 H), 4.39 (q, J = 6.7 Hz, 1 H), 3.93 (d, J = 12.7 Hz, 1 H), 3.80 (s, 3 H),

3.69–3.75 (m, 2 H), 3.54 (d, J = 12.7 Hz, 1 H), 3.05 (t, J = 7.4 Hz, 1 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 159.2, 130.1 (2 C), 127.8, 123.9 (q, J =

278.6 Hz), 113.9 (2 C), 72.7 (q, J = 32.3 Hz), 61.1, 60.2, 55.3, 43.6 (q, J =

3.5 Hz).

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –75.98 (d, J = 6.7 Hz, 3 F).

MS (70 eV): m/z = 280 ([M⁺+ 1], 13).

anti-2-Chloro-4,4,4-trifluoro-3-[N-(4-methoxybenzyl/phenyl)-N-

methylamino]butyl Acetates 7; anti-2-Chloro-4,4,4-trifluoro-3-

[N-(4-methoxyphenyl)-N-methylamino]butyl Acetate (7a); Typical

Procedure

In a flame-dried flask under N₂atmosphere, Me₃OBF₄(0.11 g, 0.74

mmol, 2 equiv) was added to an ice-cooled solution of trans-3-

chloro-1-(4-methoxyphenyl)-2-(trifluoromethyl)azetidine (5a; 0.10

IR (ATR): 2959, 1512, 1246, 1225, 1165, 1132, 1101, 1038, 818, 698

cm^–1

.

M

H. Dao Thi et al.

Feature

Synthesis

¹H NMR (400 MHz, CDCl₃): δ = 6.85 (d, J = 9.3 Hz, 2 H), 6.76 (d, J = 9.3

Hz, 2 H), 4.53 (dq, J = 9.6, 7.5 Hz, 1 H), 4.32 (ddd, J = 9.6, 5.6, 3.2 Hz, 1

H), 3.70 (s, 3 H), 2.94 (dd, J = 12.3, 3.2 Hz, 1 H), 2.83 (dd, J = 12.3, 5.6

Hz, 1 H), 2.76 (q, J = 1.4 Hz, 3 H), 0.94 (s, 9 H).

¹H NMR (400 MHz, CDCl₃): δ = 7.28 (d, J = 8.6 Hz, 2 H), 6.91 (d, J = 8.6

Hz, 2 H), 4.17 (q, J = 5.6 Hz, 1 H), 4.02 (d, J = 12.7 Hz, 1 H), 3.99 (dd, J =

12.3, 5.0 Hz, 1 H), 3.877 (dd, J = 12.3, 4.5 Hz, 1 H), 3.876 (d, J = 12.7 Hz,

1 H), 3.83 (s, 3 H), 3.54 (qd, J = 7.4, 5.6 Hz, 1 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 153.2, 144.0, 125.9 (q, J = 290.0 Hz),

116.5 (2 C), 114.5 (2 C), 64.7 (q, J = 26.5 Hz), 57.1, 55.6, 50.1, 45.5,

32.9, 29.0.

¹³C NMR (100.6 MHz, CDCl₃): δ = 159.2, 130.4, 129.8 (2 C), 125.6 (q, J =

285.6 Hz), 114.0 (2 C), 64.8 (q, J = 1.2 Hz), 62.3 (q, J = 27.1 Hz), 58.6,

55.3, 52.4.

¹⁹F NMR (376 MHz, CDCl₃): δ = –64.15 (d, J = 7.5 Hz, 3 F).

MS (70 eV): m/z = 353 ([M⁺+ 1], 100).

¹⁹F NMR (376 MHz, CDCl₃): δ = –70.36 (d, J = 7.4 Hz, 3 F).

GC-MS: m/z (%) = 297 (M⁺, 2), 174 (6), 136 (11), 121 (100), 78 (8).

anti-N¹-(tert-Butyl)-2-chloro-4,4,4-trifluoro-N³-(4-methoxyben-

zyl)-N³-methylbutane-1,3-diamine (8b)

trans-5-Chloro-3-(4-methoxybenzyl/phenyl)-4-trifluoromethyl-

1,3-oxazinanes 10; trans-5-Chloro-3-(4-methoxyphenyl)-4-triflu-

oromethyl-1,3-oxazinane (10a); Typical Procedure

Yield: 0.04 g (0.11 mmol, 11%); yellowish oil; R_f= 0.25 (PE/EtOAc

12:1).

To a solution of anti-2-chloro-4,4,4-trifluoro-3-[(4-methoxyphe-

nyl)amino]butan-1-ol (9a; 0.10 g, 0.35 mmol, 1 equiv) in THF (5 mL)

in a pressure vial was added an excess of formaldehyde (37% solution

in H₂O, 1 mL) at r.t. The resulting mixture was stirred for 3 h under

reflux, after which H₂O (5 mL) was added to the mixture. Extraction

with EtOAc (3 × 7 mL), drying of the combined organic layers (MgSO₄),

filtration, and evaporation of the solvent afforded 10a, which was pu-

rified by means of preparative of TLC (hexane/EtOAc 10:1) to provide

an analytically pure sample; yield: 0.06 g (0.20 mmol, 54%); yellowish

solid; mp 64 °C; R_f= 0.53 (hexane/EtOAc 10:1).

IR (ATR): 2967, 2928, 1512, 1244, 1169, 1103, 1034, 829, 814 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.21 (d, J = 8.6 Hz, 2 H), 6.84 (d, J = 8.6

Hz, 2 H), 3.80 (s, 3 H), 3.79 (d, J = 13.3 Hz, 1 H), 3.73 (d, J = 13.3 Hz, 1

H), 2.70 (quint, J = 8.3 Hz, 1 H), 2.44 (q, J = 1.2 Hz, 3 H), 2.02 (ddd, J =

8.3, 6.5, 3.1 Hz, 1 H), 1.63 (d, J = 6.5 Hz, 1 H), 1.49 (d, J = 3.1 Hz, 1 H),

0.98 (s, 9 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 158.8, 131.0, 129.6 (2 C), 127.2 (q, J =

290.9 Hz), 113.8 (2 C), 66.8 (q, J = 24.6 Hz), 58.9, 55.3, 53.2, 38.2, 29.4,

26.4, 24.5.

IR (ATR): 1508, 1238, 1223, 1182, 1167, 1136, 1109, 1074, 1051, 1034,

¹⁹F NMR (376 MHz, CDCl₃): δ = –67.19 (d, J = 8.3 Hz, 3 F).

MS (70 eV): m/z = 331 ([M⁺– 35], 100).

999, 972, 851, 833, 824, 785, 665, 530 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.22 (d, J = 9.0 Hz, 2 H), 6.86 (d, J = 9.0

Hz, 2 H), 5.04 (d, J = 11.7 Hz, 1 H), 4.98 (dq, J = 11.7, 1.4 Hz, 1 H), 4.26–

4.33 (m, 2 H), 4.11–4.20 (m, 2 H), 3.81 (s, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 155.7, 145.0, 124.8 (q, J = 284.8 Hz),

122.0 (2 C), 114.4 (2 C), 78.7 (q, J = 1.7 Hz), 69.4, 66.5 (q, J = 29.6 Hz),

55.5, 49.9.

anti-2-Chloro-4,4,4-trifluoro-3-[(4-methoxybenzyl/phenyl)ami-

no]butan-1-ols 9;anti-2-Chloro-4,4,4-trifluoro-3-[(4-methoxy-

phenyl)amino]butan-1-ol (9a); Typical Procedure

To an ice-cooled solution of trans-3-chloro-1-(4-methoxyphenyl)-4-

(trifluoromethyl)azetidin-2-one (4a; 0.50 g, 1.79 mmol, 1 equiv) in

Et₂O (10 mL) was added a 1 M solution of LiAlH₄in THF (1.79 mL, 0.07

g, 1.79 mmol, 1 equiv) in small portions whilst stirring. After stirring

for 5 min at r.t., the mixture was cooled to 0 °C, quenched with H₂O (5

mL), and filtered through a short pad of Celite. Extraction with Et₂O

(3 × 5 mL), drying the combined organic layers (MgSO₄), filtration,

and evaporation of the solvent afforded 9a, which was purified by

means of column chromatography on silica gel (hexane/EtOAc 3:1) to

obtain an analytically pure sample; yield: 0.49 g (1.73 mmol, 96%);

yellowish oil; R_f= 0.32 (hexane/EtOAc 3:1).

¹⁹F NMR (376 MHz, CDCl₃): δ = –70.96 (d, J = 9.0 Hz, 3 F).

MS (70 eV): m/z = 296 ([M⁺+ 1], 100).

trans-5-Chloro-3-(4-methoxybenzyl)-4-trifluoromethyl-1,3-ox-

azinane (10b)

Yield: 0.04 g (0.13 mmol, 80%); white yellowish solid; mp 89 °C; R_f=

0.41 (hexane/EtOAc 10:1).

IR (ATR): 1510, 1246, 1182, 1167, 1109, 1090, 1053, 1034, 999, 970,

837, 665, 515 cm^–1

.

IR (ATR): 3387, 1510, 1233, 1171, 1125, 1032, 820 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.28 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7

Hz, 2 H), 4.59 (dq, J = 11.5, 1.1 Hz, 1 H), 4.38 (d, J = 11.5 Hz, 1 H), 4.30

(d, J = 13.3 Hz, 1 H), 4.20–4.25 (m, 3 H), 4.06 (dd, J = 14.2, 3.4 Hz, 1 H),

3.81 (s, 3 H), 3.65 (qd, J = 9.2, 2.3 Hz, 1 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 159.2, 130.4 (2 C), 129.5, 124.5 (q, J =

283.9 Hz), 113.8 (2 C), 80.2 (q, J = 1.2 Hz), 70.8, 62.6 (q, J = 29.0 Hz),

57.8, 55.3, 49.2.

¹H NMR (400 MHz, CDCl₃): δ = 6.80 (d, J = 8.9 Hz, 2 H), 6.70 (d, J = 8.9

Hz, 2 H), 3.92–4.29 (m, 5 H), 3.74 (s, 3 H), 2.43 (t, J = 6.4 Hz, 1 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 153.6, 139.9, 125.1 (q, J = 284.8 Hz),

115.9 (2 C), 115.0 (2 C), 64.1 (q, J = 2.0 Hz), 60.8 (q, J = 28.5 Hz), 59.0,

55.7.

¹⁹F NMR (376 MHz, CDCl₃): δ = –71.30 (d, J = 6.6 Hz, 3 F).

MS (70 eV): m/z = 284 ([M⁺+ 1], 100).

¹⁹F NMR (376 MHz, CDCl₃): δ = –69.60 (d, J = 9.2 Hz, 3 F).

GC-MS: m/z (%) = 309 (M⁺, 8), 121 (100), 78 (8).

anti-2-Chloro-4,4,4-trifluoro-3-[(4-methoxybenzyl)amino]butan-

1-ol (9b)

trans-5-Chloro-3-(4-methoxybenzyl/phenyl)-4-trifluoromethyl-

1,3-oxazinan-2-ones 11; trans-5-Chloro-3-(4-methoxyphenyl)-4-

trifluoromethyl-1,3-oxazinan-2-one (11a); Typical Procedure

Yield: 0.46 g (1.55 mmol, 90%); yellowish oil; R_f= 0.43 (hexane/EtOAc

3:1).

To

a solution of anti-2-chloro-4,4,4-trifluoro-3-[(4-methoxyphe-

IR (ATR): 3356, 1512, 1244, 1163, 1126, 1032, 831, 816 cm^–1

.

nyl)amino]butan-1-ol (9a; 0.10 g, 0.35 mmol, 1 equiv) in anhyd

CH₂Cl₂(8 mL) was added Et₃N (0.07 g, 0.1 mL, 0.70 mmol, 2 equiv) at

0 °C. Ethyl chloroformate (0.04 g, 0.04 mL, 0.35 mmol, 1 equiv) was

added dropwise to the solution. The mixture was stirred at r.t. for 3 h,

N

H. Dao Thi et al.

Feature

Synthesis

after which the reaction mixture was extracted with CH₂Cl₂(3 × 5 mL)

and the combined organic layers were washed with brine (3 × 5 mL).

Drying (MgSO₄), filtration, and removal of the solvent in vacuo afford-

ed a mixture of 9a and product 11a in a ratio of 66:34. The mixture

was redissolved in anhyd CH₂Cl₂(5 mL) and an analogous procedure

was repeated two more times. In this way, the starting material 9a

was completely converted into product 11a, which was purified by

means of preparative TLC (hexane/EtOAc 4:1) to obtain an analytical-

ly pure sample; yield: 0.03 g (0.10 mmol, 29%); white yellowish solid;

mp 100 °C; R_f= 0.12 (hexane/EtOAc 4:1).

¹³C NMR (100.6 MHz, CDCl₃): δ = 153.3, 139.9, 125.4 (q, J = 284.0 Hz),

115.1 (2 C), 115.0 (2 C), 55.7, 55.6 (q, J = 29.3 Hz), 48.1 (q, J = 2.7 Hz),

42.3.

¹⁹F NMR (376 MHz, CDCl₃): δ = –74.78 (d, J = 7.9 Hz, 3 F).

MS (70 eV): m/z = 248 ([M⁺+ 1], 100).

trans-2-Hydroxymethyl-1-(4-methoxybenzyl)-3-(trifluorometh-

yl)aziridine (12b)

Yield: 0.04 g (0.15 mmol, 61%); light yellow oil; R_f= 0.46 (hexane/EtO-

Ac 4:1).

IR (ATR): 1705, 1514, 1429, 1319, 1184, 1167, 1134, 1115, 1026, 827,

748, 665, 581 cm^–1

.

IR (ATR): 3350, 1512, 1246, 1150, 1123, 1105, 1034, 831, 816 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.25 (d, J = 8.9 Hz, 2 H), 6.94 (d, J = 8.9

Hz, 2 H), 4.83 (dd, J = 13.3, 2.3 Hz, 1 H), 4.68 (q, J = 2.3 Hz, 1 H), 4.51 (d,

J = 13.3 Hz, 1 H), 4.43 (qt, J = 6.5, 2.3 Hz, 1 H), 3.82 (s, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 159.3, 150.2, 134.2, 128.7 (2 C),

123.1 (q, J = 285.7 Hz), 114.8 (2 C), 69.0 (q, J = 2.2 Hz), 67.0 (q, J = 29.9

Hz), 55.5, 46.8 (q, J = 1.2 Hz).

¹H NMR (400 MHz, CDCl₃): δ = 7.28 (d, J = 8.7 Hz, 2 H), 6.89 (d, J = 8.7

Hz, 2 H), 3.98 (d, J = 13.1 Hz, 1 H), 3.90 (d, J = 13.1 Hz, 1 H), 3.83 (s, 3

H), 3.17 (td, J = 4.3, 2.6 Hz, 1 H), 3.05 (qd, J = 7.3, 4.3 Hz, 1 H), 2.82 (dd,

J = 5.1, 4.3 Hz, 1 H), 2.78 (dd, J = 5.1, 2.6 Hz, 1 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 158.9, 131.2, 129.5 (2 C), 125.8 (q, J =

284.3 Hz), 113.9 (2 C), 59.1 (q, J = 27.5 Hz), 55.3, 51.0, 49.7 (q, J = 2.9

Hz), 43.6.

¹⁹F NMR (376 MHz, CDCl₃): δ = –71.67 (d, J = 6.5 Hz, 3 F).

MS (70 eV): m/z = 310 ([M⁺+ 1], 100).

¹⁹F NMR (376 MHz, CDCl₃): δ = –73.15 (d, J = 7.3 Hz, 3 F).

GC-MS: m/z (%) = 261 (M⁺, 17), 136 (19), 121 (100), 78 (9).

trans-5-Chloro-3-(4-methoxybenzyl)-4-trifluoromethyl-1,3-ox-

azinan-2-one (11b)

trans-2-Methoxycarbonyl-1-(4-methoxybenzyl/phenyl)-3-(triflu-

oromethyl)aziridines 13; trans-2-Methoxycarbonyl-1-(4-methoxy-

phenyl)-3-(trifluoromethyl)aziridine (13a); Typical Procedure

Yield: 0.07 g (0.22 mmol, 85%); yellow solid; mp 68 °C; R_f= 0.21 (hex-

ane/EtOAc 4:1).

KOH (0.02 g, 0.36 mmol, 2 equiv) was added to a solution of trans-3-

chloro-1-(4-methoxyphenyl)-4-(trifluoromethyl)azetidin-2-one (4a;

0.05 g, 0.18 mmol, 1 equiv) in MeOH (6 mL). After stirring for 20 min

under reflux, the reaction mixture was cooled to 0 °C, and quenched

with H₂O (5 mL). Extraction with EtOAc (3 × 5 mL), drying of the com-

bined organic layers (MgSO₄), filtration, and evaporation of the sol-

vent afforded 13a, which was purified by means of preparative TLC

(hexane/EtOAc 5:1) to provide white yellowish solid; yield: 0.04 g

(0.14 mmol, 73%); mp 74 °C; R_f= 0.40 (hexane/EtOAc 5:1).

IR (ATR): 1697, 1512, 1435, 1250, 1231, 1209, 1165, 1148, 1111, 1092,

1032, 1011, 750, 669, 588 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.26 (d, J = 8.5 Hz, 2 H), 6.89 (d, J = 8.5

Hz, 2 H), 5.54 (d, J = 14.8 Hz, 1 H), 4.68 (dd, J = 13.1, 2.4 Hz, 1 H), 4.45

(q, J = 2.4 Hz, 1 H), 4.31 (dq, J = 13.1, 1.1 Hz, 1 H), 3.96 (d, J = 14.8 Hz, 1

H), 3.91 (qt, J = 6.5, 2.4 Hz, 1 H), 3.81 (s, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 159.8, 151.0, 130.8 (2 C), 125.9,

123.6 (q, J = 286.1 Hz), 114.2 (2 C), 68.3 (q, J = 2.0 Hz), 59.8 (q, J = 30.0

Hz), 55.3, 51.0 (q, J = 1.2 Hz), 46.3 (q, J = 1.2 Hz).

IR (ATR): 1730, 1508, 1265, 1246, 1148, 1080, 1030, 1013, 872, 833,

¹⁹F NMR (376 MHz, CDCl₃): δ = –71.03 (d, J = 6.5 Hz, 3 F).

MS (70 eV): m/z = 324 ([M⁺+ 1], 60).

696 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 6.71–6.76 (m, 4 H), 3.68 (s, 3 H), 3.57

(s, 3 H), 3.30–3.33 (m, 2 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 165.7, 156.2, 139.3, 122.9 (q, J =

273.9 Hz), 120.3 (2 C), 114.5 (2 C), 55.4, 52.8, 42.1 (q, J = 40.7 Hz), 39.2

(q, J = 1.9 Hz).

trans-2-Hydroxymethyl-1-(4-methoxybenzyl/phenyl)-3-(trifluo-

romethyl)aziridines 12; trans-2-Hydroxymethyl-1-(4-methoxy-

phenyl)-3-(trifluoromethyl)aziridine (12a); Typical Procedure

A 1 M solution of t-BuOK in THF (0.28 mL, 0.03 g, 0.28 mmol, 0.8

equiv) was added dropwise to a stirred solution of anti-2-chloro-

4,4,4-trifluoro-3-[(4-methoxyphenyl)amino]butan-1-ol (9a; 0.10 g,

0.35 mmol, 1 equiv) in anhyd THF (5 mL), and the resulting suspen-

sion was stirred at r.t. under argon for 10 min. The reaction mixture

was extracted with EtOAc (3 × 5 mL) and the combined organic layers

were washed with brine (3 × 5 mL). Drying (MgSO₄), filtration, and

removal of the solvent in vacuo afforded 12a, which was purified by

means of preparative TLC (hexane/EtOAc 5:1) to obtain an analytical-

ly pure sample; yield: 0.02 g (0.08 mmol, 27%); orange solid; mp

53 °C; R_f= 0.38 (hexane/EtOAc 5:1).

¹⁹F NMR (376 MHz, CDCl₃): δ = –71.08 (~s, 3 F).

MS (70 eV): m/z = 276 ([M⁺+ 1], 100).

trans-1-(4-Methoxybenzyl)-2-methoxycarbonyl-3-(trifluoro-

methyl)aziridine (13b)

Yield: 0.02 g (0.07 mmol, 25%); light yellow oil; R_f= 0.21 (hexane/EtO-

Ac 5:1).

IR (ATR): 1736, 1514, 1344, 1246, 1207, 1175, 1144, 1032, 804 cm^–1

¹H NMR (400 MHz, CDCl₃): δ = 7.17 (d, J = 8.6 Hz, 2 H), 6.79 (d, J = 8.6

Hz, 2 H), 3.94 (d, J = 13.0 Hz, 1 H), 3.80 (d, J = 13.0 Hz, 1 H), 3.73 (s, 3

H), 3.66 (s, 3 H), 2.86–2.91 (m, 2 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 167.3, 159.0, 129.53 (2 C), 129.49,

123.0 (q, J = 273.9 Hz), 113.8 (2 C), 55.2, 53.8, 52.2, 43.7 (q, J =39.7 Hz),

37.3.

.

IR (ATR): 3374, 1514, 1258, 1231, 1165, 1148, 1125, 1111, 1034, 824,

764, 525 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 6.78 (d, J = 8.9 Hz, 2 H), 6.62 (d, J = 8.9

Hz, 2 H), 4.03–4.11 (m, 1 H), 3.74 (s, 3 H), 3.65 (d, J = 9.4 Hz, 1 H),

3.37–3.39 (m, 1 H), 2.79 (dd, J = 4.8, 4.2 Hz, 1 H), 2.68 (dd, J = 4.8, 2.6

Hz, 1 H).

¹⁹F NMR (376 MHz, CDCl₃): δ = –71.28 (~s, 3 F).

O

H. Dao Thi et al.

Feature

Synthesis

GC-MS: m/z (%) = 290 (M⁺, 4), 274 (10), 258 (8), 220 (17), 188 (16),

136 (16), 121 (100), 78 (7).

¹³C NMR (100.6 MHz, CDCl₃): δ = 164.0, 156.6, 132.8, 129.3, 123.7 (q,

J = 280.8 Hz), 119.4 (2 C), 118.8, 115.0 (2 C), 80.5, 73.0, 63.7, 57.8 (q, J

= 33.0 Hz), 14.8.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –68.54 (d, J = 5.4 Hz, 3 F).

MS (70 eV): m/z = 316 ([M⁺+ 1], 100).

cis-3-Allyloxy-4-(trifluoromethyl)azetidin-2-ones 14; cis-3-Ally-

loxy-1-(4-methoxybenzyl)-4-(trifluoromethyl)azetidin-2-one

(14b); Typical Procedure

To

a solution of cis-3-hydroxy-1-(4-methoxybenzyl)-4-(trifluoro-

cis-3-Allyloxy-1-phenyl-4-(trifluoromethyl)azetidin-2-one (14d)

methyl)azetidin-2-one (3b; 0.30 g, 1.09 mmol, 1 equiv), Bu₄NI (0.003 g,

0.01 mmol, 0.01 equiv), and allyl bromide (0.21 g, 0.15 mL, 1.74

mmol, 1.6 equiv) in CH₂Cl₂(10 mL) was added 50% aq NaOH (5 g, 10

mL). After stirring for 3 h at r.t., the reaction mixture was extracted

with CH₂Cl₂(3 × 5 mL). The combined organic extracts were washed

with brine (3 × 5 mL), dried (MgSO₄), filtered, and the solvent evapo-

rated in vacuo to afforded 14b, which was purified by means of col-

umn chromatography (hexane/EtOAc 5:1) to obtain an analytically

pure sample; yield: 0.33 g (1.04 mmol, 95%); white crystals; mp

67 °C; R_f= 0.27 (hexane/EtOAc 5:1).

Yield: 0.28 g (1.03 mmol, 77%); white yellowish solid; mp <45 °C; R_f=

0.36 (PE/EtOAc 4:1).

IR (ATR): 1767, 1599, 1499, 1360, 1279, 1134, 989, 930, 752, 689, 490

cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.47 (d, J = 7.7 Hz, 2 H), 7.36 (t, J = 7.7

Hz, 2 H), 7.18 (t, J = 7.7 Hz, 1 H), 5.94 (ddt, J = 17.3, 10.6, 5.4 Hz, 1 H),

5.40 (dq, J = 17.3, 1.5 Hz, 1 H), 5.31 (dq, J = 10.6, 1.3 Hz, 1 H), 4.98 (d,

J = 5.4 Hz, 1 H), 4.67 (quint, J = 5.4 Hz, 1 H), 4.24–4.32 (m, 2 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 164.3, 136.2, 132.8, 129.3 (2 C),

125.5, 123.7 (q, J = 280.8 Hz), 119.0, 117.6 (2 C), 80.3, 73.1, 57.5 (q, J =

33.2 Hz).

IR (ATR): 1759, 1514, 1352, 1279, 1244, 1152, 1126, 1113, 1032, 920,

837, 669, 635, 590, 519 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.16 (d, J = 8.5 Hz, 2 H), 6.87 (d, J = 8.5

Hz, 2 H), 5.88 (ddt, J = 17.2, 10.6, 5.5 Hz, 1 H), 5.33 (dq, J = 17.2, 1.5 Hz,

1 H), 5.25 (d, J = 10.6 Hz, 1 H), 4.81 (d, J = 14.8 Hz, 1 H), 4.74 (d, J = 5.6

Hz, 1 H), 4.18 (d, J = 5.5 Hz, 2 H), 3.95 (d, J = 14.8 Hz, 1 H), 3.87 (quint,

J = 5.6 Hz, 1 H), 3.80 (s, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 166.4, 159.6, 132.9, 129.9 (2 C),

126.1, 123.9 (q, J = 280.2 Hz), 118.7, 114.4 (2 C), 81.1, 72.8, 56.4 (q, J =

32.7 Hz), 55.3, 44.5.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –68.41 (d, J = 5.4 Hz, 3 F).

MS (70 eV): m/z = 272 ([M⁺+ 1], 100).

cis-3-Allyloxy-1-(4-methylphenyl)-4-(trifluoromethyl)azetidin-2-

one (14e)

Yield: 0.29 g (1.02 mmol, 71%); white crystals; mp 78 °C (CH₂Cl₂/Et₂O

1:3).

IR (ATR): 1748, 1516, 1396, 1364, 1275, 1246, 1167, 1134, 1005, 816,

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –69.33 (d, J = 5.6 Hz, 3 F).

MS (70 eV): m/z = 316 ([M⁺+ 1], 100).

646, 482 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.28 (d, J = 8.2 Hz, 2 H), 7.09 (d, J = 8.2

Hz, 2 H), 5.87 (ddt, J = 17.2, 10.7, 5.5 Hz, 1 H), 5.32 (d, J = 17.2 Hz, 1 H),

5.23 (d, J = 10.7 Hz, 1 H), 4.89 (d, J = 5.4 Hz, 1 H), 4.57 (quint, J = 5.4 Hz,

1 H), 4.15–4.24 (m, 2 H), 2.25 (s, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 164.1, 135.3, 133.7, 132.8, 129.7 (2

C), 123.7 (q, J = 280.9 Hz), 118.9, 117.7 (2 C), 80.3, 73.1, 57.5 (q, J =

33.2 Hz), 20.9.

cis-3-Allyloxy-1-(4-methoxyphenyl)-4-(trifluoromethyl)azetidin-

2-one (14a)

Yield: 0.20 g (0.66 mmol, 94%); white crystals; mp 81 °C (CH₂Cl₂/Et₂O

1:3); R_f= 0.61 (hexane/EtOAc 2:1).

IR (ATR): 1759, 1516, 1389, 1273, 1134, 982, 837, 808, 642, 505 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.40 (d, J = 9.0 Hz, 2 H), 6.89 (d, J = 9.0

Hz, 2 H), 5.94 (ddt, J = 17.2, 10.6, 5.4 Hz, 1 H), 5.39 (dq, J = 17.2, 1.6 Hz,

1 H), 5.30 (dq, J = 10.6, 1.3 Hz, 1 H), 4.96 (d, J = 5.4 Hz, 1 H), 4.61

(quint, J = 5.4 Hz, 1 H), 4.22–4.32 (m, 2 H), 3.80 (s, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 163.9, 157.2, 132.8, 129.4, 123.7 (q,

J = 280.7 Hz), 119.4 (2 C), 118.9, 114.4 (2 C), 80.4, 73.1, 57.8 (q, J = 33.0

Hz), 55.5.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –68.46 (d, J = 5.4 Hz, 3 F).

MS (70 eV): m/z = 286 ([M⁺+ 1], 100).

cis-3-Allyloxy-1-isopropyl-4-(trifluoromethyl)azetidin-2-one

(14f)

Yield: 0.32 g (1.35 mmol, 79%); white yellowish oil, solidified in

fridge; R_f= 0.42 (PE/EtOAc 4:1).

IR (ATR): 1761, 1281, 1213, 1148, 1123, 1009, 928, 660 cm^–1

¹H NMR (400 MHz, CDCl₃): δ = 5.90 (dqt, J = 17.2, 10.6, 5.4 Hz, 1 H),

5.35 (dq, J = 17.2, 1.6 Hz, 1 H), 5.26 (dq, J = 10.6, 1.4 Hz, 1 H), 4.74 (d,

J = 4.8 Hz, 1 H), 4.15–4.24 (m, 2 H), 4.11 (qd, J = 6.0, 4.8 Hz, 1 H), 3.88

(sept, J = 6.8 Hz, 1 H), 1.29 (d, J = 6.8 Hz, 3 H), 1.26 (d, J = 6.8 Hz, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 166.2, 133.0, 123.9 (q, J = 279.8 Hz),

118.5, 80.2, 72.7, 56.6 (q, J = 33.0 Hz), 45.1, 21.1, 19.3.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –68.52 (d, J = 5.4 Hz, 3 F).

MS (70 eV): m/z = 302 ([M⁺+ 1], 100).

.

cis-3-Allyloxy-1-(4-ethoxyphenyl)-4-(trifluoromethyl)azetidin-2-

one (14c)

Yield: 0.31 g (0.98 mmol, 84%); white crystals; mp 83 °C (CH₂Cl₂/Et₂O

1:3).

IR (ATR): 1757, 1518, 1391, 1258, 1136, 1111, 980, 922, 824, 650,

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –69.49 (d, J = 6.0 Hz, 3 F).

MS (70 eV): m/z = 238 ([M⁺+ 1], 100).

525 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.37 (d, J = 9.0 Hz, 2 H), 6.86 (d, J = 9.0

Hz, 2 H), 5.93 (ddt, J = 17.2, 10.7, 5.4 Hz, 1 H), 5.38 (dq, J = 17.2, 1.6 Hz,

1 H), 5.29 (dq, J = 10.7, 1.4 Hz, 1 H), 4.95 (d, J = 5.4 Hz, 1 H), 4.61

(quint, J = 5.4 Hz, 1 H), 4.21–4.30 (m, 2 H), 4.00 (q, J = 7.0 Hz, 2 H), 1.39

(t, J = 7.0 Hz, 3 H).

3-(2-Hydroxyethoxy)-4-(trifluoromethyl)azetidin-2-ones 15;

cis-3-(2-Hydroxyethoxy)-1-(4-methoxyphenyl)-4-(trifluorometh-

yl)azetidin-2-one (15a); Typical Procedure

In a 250 mL flame-dried flask, cis-3-allyloxy-1-(4-methoxyphenyl)-4-

(trifluoromethyl)azetidin-2-one (14a; 0.12 g, 0.40 mmol, 1 equiv)

P

H. Dao Thi et al.

Feature

Synthesis

was dissolved in a mixture of anhyd CH₂Cl₂(15 mL) and anhyd MeOH

(10 mL). A small pinch of Sudan III indicator was added to the reaction

mixture. The mixture was sparged with O₃at –78 °C until the red col-

or of the reaction mixture dissipated. The mixture was stirred for 1 h

at r.t. in the presence of Me₂S (0.06 g, 0.07 mL, 1 mmol, 2.5 equiv),

after which the mixture was extracted with H₂O (10 mL). The aque-

ous phase was then extracted with CH₂Cl₂(3 × 5 mL). The combined

organic extracts were washed with brine (3 × 5 mL), dried (MgSO₄),

filtered, and concentrated under reduced pressure, affording a crude

mixture. To the crude mixture in anhyd THF (6 mL) at 0 °C was added

gradually BH₃(1 M in Et₂O, 1 mL, 1 mmol, 2.5 equiv). The temperature

was allowed to rise to r.t. and the reaction mixture was stirred for 3 h

at this temperature. The mixture was extracted with EtOAc (3 × 8 mL)

and the combined extracts were washed with brine (3 × 5 mL). Drying

(MgSO₄), filtration, and evaporation of the solvent in vacuo afforded

15a, which was purified by means of column chromatography (hex-

ane/EtOAc 3:1) to obtain an analytically pure sample; yield: 0.09 g

(0.30 mmol, 72%); yellow oil; R_f= 0.14 (hexane/EtOAc 3:1).

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –68.44 (d, J = 5.4 Hz, 3 F).

MS (70 eV): m/z = 320 ([M⁺+ 1], 100).

cis-3-(2-Hydroxyethoxy)-1,4-bis(4-methoxyphenyl)azetidin-2-one

(19)

Yield: 0.06 g (0.17 mmol, 51%); white crystals; mp 105 °C; R_f= 0.10

(PE/EtOAc 1:1).

IR (ATR): 3273, 1736, 1510, 1396, 1298, 1236, 1175, 1132, 1028, 835,

800, 540 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.24 (d, J = 8.6 Hz, 2 H), 7.19 (d, J = 9.0

Hz, 2 H), 6.84 (d, J = 8.6 Hz, 2 H), 6.71 (d, J = 9.0 Hz, 2 H), 5.11 (d, J = 4.8

Hz, 1 H), 4.85 (d, J = 4.8 Hz, 1 H), 3.72 (s, 3 H), 3.66 (s, 3 H), 3.30–3.55

(m, 4 H), 2.32 (t, J = 6.7 Hz, 1 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 164.5, 160.0, 156.5, 130.4, 129.3 (2

C), 125.1, 118.9 (2 C), 114.3 (2 C), 114.1 (2 C), 83.9, 73.4, 62.0, 61.9,

55.4, 55.3.

MS (70 eV): m/z = 344 ([M⁺+ 1], 100).

IR (ATR): 3393, 1744, 1512, 1233, 1128, 1032, 822, 681 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.32 (d, J = 9.0 Hz, 2 H), 6.83 (d, J = 9.0

Hz, 2 H), 4.95 (d, J = 5.4 Hz, 1 H), 4.60 (quint, J = 5.4 Hz, 1 H), 3.85–3.91

(m, 1 H), 3.75–3.80 (m, 3 H), 3.73 (s, 3 H), 2.67 (t, J = 5.7 Hz, 1 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 164.6, 157.4, 129.1, 123.6 (q, J =

281.0 Hz), 119.6 (2 C), 114.5 (2 C), 82.2, 74.9, 62.2, 58.0 (q, J = 33.1

Hz), 55.5.

trans-1-(4-Ethoxyphenyl)-3-(2-hydroxyethoxy)-4-(trifluorometh-

yl)azetidin-2-one (21)

Yield: 0.02 g (0.06 mmol, 11%); colorless oil; R_f= 0.42 (PE/EtOAc 1:1).

IR (ATR): 3447, 1755, 1512, 1395, 1246, 1159, 1115, 1045, 829, 700,

515 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.33 (d, J = 8.9 Hz, 2 H), 6.89 (d, J = 8.9

Hz, 2 H), 4.87 (d, J = 1.3 Hz, 1 H), 4.45 (qd, J = 5.6, 1.3 Hz, 1 H), 4.02 (q,

J = 7.0 Hz, 2 H), 3.78–3.93 (m, 4 H), 2.77 (t, J = 5.5 Hz, 1 H), 1.41 (t, J =

7.0 Hz, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 163.2, 157.0, 128.6, 123.5 (q, J =

280.3 Hz), 120.2 (2 C), 115.1 (2 C), 83.3 (q, J = 1.5 Hz), 73.6, 63.8, 61.9,

60.1 (q, J = 34.3 Hz), 14.8.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –68.42 (d, J = 5.4 Hz, 3 F).

MS (70 eV): m/z = 306 ([M⁺+ 1], 100).

cis-3-(2-Hydroxyethoxy)-1-(4-methoxybenzyl)-4-(trifluorometh-

yl)azetidin-2-one (15b)

Yield: 0.10 g (0.31 mmol, 77%); yellowish oil; Rf = 0.15 (hexane/EtOAc

1:1).

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –71.48 (d, J = 5.6 Hz, 3 F).

MS (70 eV): m/z = 320 ([M⁺+ 1], 100).

IR (ATR): 3431, 1759, 1514, 1279, 1246, 1159, 1130, 1030, 800, 664,

513 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.16 (d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.6

Hz, 2 H), 4.81 (d, J = 14.5 Hz, 1 H), 4.80 (d, J = 4.9 Hz, 1 H), 3.97 (d, J =

14.5 Hz, 1 H), 3.94 (qd, J = 6.1, 4.9 Hz, 1 H), 3.82–3.88 (m, 1 H), 3.81 (s,

3 H), 3.71–3.79 (m, 3 H), 2.89 (t, J = 6.6 Hz, 1 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 167.2, 159.6, 129.9 (2 C), 125.8,

123.8 (q, J = 280.2 Hz), 114.4 (2 C), 82.7, 74.8, 62.2, 56.7 (q, J = 32.9

Hz), 55.3, 44.6.

cis-3-(2-Hydroxyethoxy)-1-phenyl-4-(trifluoromethyl)azetidin-2-

one (15d)

Yield: 0.06 g (0.22 mmol, 95%); yellowish oil; R_f= 0.31 (PE/EtOAc 1:1).

IR (ATR): 3428, 1761, 1599, 1499, 1360, 1277, 1136, 752, 689, 486 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.40 (d, J = 7.8 Hz, 2 H), 7.31 (t, J = 7.8

Hz, 2 H), 7.13 (t, J = 7.8 Hz, 1 H), 4.97 (d, J = 5.4 Hz, 1 H), 4.67 (quint, J =

5.4 Hz, 1 H), 3.72–3.92 (m, 4 H), 2.55 (t, J = 5.6 Hz, 1 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 164.9, 136.0, 129.3 (2 C), 125.7,

123.6 (q, J = 280.2 Hz), 117.7 (2 C), 82.1, 74.9, 62.2, 57.7 (q, J = 33.3

Hz).

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –69.26 (d, J = 6.1 Hz, 3 F).

MS (70 eV): m/z = 320 ([M⁺+ 1], 100).

cis-1-(4-Ethoxyphenyl)-3-(2-hydroxyethoxy)-4-(trifluorometh-

yl)azetidin-2-one (15c)

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –68.31 (d, J = 5.4 Hz, 3 F).

MS (70 eV): m/z = 276 ([M⁺+ 1], 100).

Yield: 0.12 g (0.38 mmol, 72%); white solid; mp 81 °C; R_f= 0.10

(PE/EtOAc 2:1).

cis-3-(2-Hydroxyethoxy)-1-(4-methylphenyl)-4-(trifluorometh-

yl)azetidin-2-one (15e)

IR (ATR): 3399, 1759, 1510, 1391, 1250, 1169, 1146, 1121, 1043, 841,

824, 656 cm^–1

.

Yield: 0.10 g (0.35 mmol, 63%); white crystals; mp 79 °C; R_f= 0.14

(PE/EtOAc 2:1).

¹H NMR (400 MHz, CDCl₃): δ = 7.37 (d, J = 9.0 Hz, 2 H), 6.88 (d, J = 9.0

Hz, 2 H), 5.02 (d, J = 5.4 Hz, 1 H), 4.67 (quint, J = 5.4 Hz, 1 H), 4.01 (q,

J = 7.0 Hz, 2 H), 3.91–395 (m, 1 H), 3.77–3.89 (m, 3 H), 2.93 (t, J = 6.2

Hz, 1 H), 1.40 (t, J = 7.0 Hz, 3 H).

IR (ATR): 3358, 1753, 1514, 1398, 1366, 1275, 1244, 1140, 1028, 814,

646, 494 cm^–1

.

¹³C NMR (100.6 MHz, CDCl₃): δ = 164.6, 156.8, 129.0, 123.6 (q, J =

280.9 Hz), 119.5 (2 C), 115.0 (2 C), 82.1, 74.9, 63.8, 62.1, 58.0 (q, J =

33.1 Hz), 14.8.

¹H NMR (400 MHz, CDCl₃): δ = 7.28 (d, J = 8.3 Hz, 2 H), 7.10 (d, J = 8.3

Hz, 2 H), 4.95 (d, J = 5.4 Hz, 1 H), 4.63 (quint, J = 5.4 Hz, 1 H), 3.73–3.91

(m, 4 H), 2.65 (br s, 1 H), 2.26 (s, 3 H).

Q

H. Dao Thi et al.

Feature

Synthesis

¹³C NMR (100.6 MHz, CDCl₃): δ = 164.8, 135.6, 133.5, 129.8 (2 C),

123.6 (q, J = 281.0 Hz), 117.8 (2 C), 82.1, 74.9, 62.2, 57.8 (q, J = 33.1

Hz), 21.0.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –68.36 (d, J = 5.4 Hz, 3 F).

MS (70 eV): m/z = 290 ([M⁺+ 1], 100).

IR (ATR): 3393, 2922, 1721, 1520, 1458, 1244, 1233, 1140, 1123, 1074,

826, 694, 519 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 6.65–6.77 (m, 4 H), 4.47–4.67 (m, 3 H),

4.32–4.36 (m, 1 H), 3.73–4.05 (m, 3 H), 3.69 and 3.68 (s, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 166.2 and 165.9, 154.0, 138.9 and

138.0, 124.9 (q, J = 285.9 Hz), 116.8 and 116.5 (2 C), 115.1 and 114.8

(2 C), 75.4 and 74.1 (q, J = 1.9 and 1.5 Hz), 68.55 and 68.53, 62.8 and

62.7, 59.0 (q, J = 28.8 Hz), 55.7 and 55.6.

cis-3-(2-Hydroxyethoxy)-1-isopropyl-4-(trifluoromethyl)azetidin-

2-one (15f)

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –69.98 and –72.22 (d, J = 6.9 and 7.5

Yield: 0.07 g (0.29 mmol, 47%); yellow oil; R_f= 0.15 (PE/EtOAc 1:1).

Hz, 3 F).

IR (ATR): 3428, 1755, 1281, 1217, 1148, 1042, 849, 660 cm^–1

.

MS (70 eV): m/z = 306 ([M⁺+ 1], 100).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₃H₁₅F₃NO₄⁺: 306.0948; found:

¹H NMR (400 MHz, CDCl₃): δ = 4.79 (d, J = 4.9 Hz, 1 H), 4.17 (qd, J = 6.1,

4.9 Hz, 1 H), 3.71–3.91 (m, 5 H), 3.12 (t, J = 6.4 Hz, 1 H), 1.31 (d, J = 6.8

Hz, 3 H), 1.27 (d, J = 6.8 Hz, 3 H).

306.0935.

¹³C NMR (100.6 MHz, CDCl₃): δ = 167.2, 123.7 (q, J = 279.8 Hz), 81.8,

74.8, 62.2, 56.9 (q, J = 33.1 Hz), 45.4, 21.0, 19.4.

3-[2,2,2-Trifluoro-1-(phenylamino)ethyl]-1,4-dioxan-2-one (16d)

Yield: 0.02 g (0.07 mmol, 71%); syn/anti = 69:31; yellowish solid; mp

85 °C; R_f= 0.38 (PE/EtOAc 2:1).

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –69.40 (d, J = 6.1 Hz, 3 F).

MS (70 eV): m/z = 242 ([M⁺+ 1], 100).

The spectral data given below correspond to a mixture of diastereo-

mers.

3-[2,2,2-trifluoro-1-(arylamino)ethyl]-1,4-dioxan-2-ones 16;

3-{1-[(4-Ethoxyphenyl)amino]-2,2,2-trifluoroethyl}-1,4-dioxan-

2-one (16c); Typical Procedure

IR (ATR): 3385, 1722, 1603, 1254, 1167, 1140, 1111, 1074, 930, 750,

691, 505 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.19–7.27 and 6.71–6.89 (m, 5 H),

4.56–4.89 (m, 3 H), 4.41–4.44 (m, 1 H), 3.75–4.29 (m, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 166.0 and 165.7, 145.0 and 144.2,

129.7 and 129.4 (2 C), 124.8 and 124.4 (q, J = 285.7 and 282.2 Hz),

120.11 and 120.10, 114.6 and 114.4 (2 C), 75.3 and 74.4 (q, J = 1.9 and

1.5 Hz), 68.6 and 68.5, 62.9 and 62.8, 57.6 and 57.1 (q, J = 28.8 and

29.5 Hz).

A solution of cis-1-(4-ethoxyphenyl)-3-(2-hydroxyethoxy)-4-(trifluo-

romethyl)azetidin-2-one (15c; 0.05 g, 0.16 mmol, 1 equiv) in toluene

was heated with an excess of K₂CO₃at reflux temperature for 28 h.

The reaction mixture was then filtered through a small pad of Celite

and concentrated under reduced pressure, resulting in a crude mix-

ture. The ¹⁹F NMR of this mixture showed it to consist of syn-3-{1-[(4-

ethoxyphenyl)amino]-2,2,2-trifluoroethyl}-1,4-dioxan-2-one

and

anti-3-{1-[(4-ethoxyphenyl)amino]-2,2,2-trifluoroethyl}-1,4-dioxan-

2-one (16c) in a ratio of 72:28. The mixture was purified by means of

preparative TLC (PE/EtOAc 6:1), providing a pure but inseparable mix-

ture of syn- and anti-16c (syn/anti = 72:28); yield: 0.04 g (0.13 mmol,

86%); yellow crystals; mp 108 °C; R_f= 0.08 (PE/EtOAc 6:1).

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –70.00 and –72.51 (d, J = 6.8 and 7.2

Hz, 3 F).

MS (70 eV): m/z = 276 ([M⁺+ 1], 100).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₃F₃NO₃⁺: 276.0842; found:

276.0846.

The spectral data given below correspond to a mixture of diastereo-

mers.

3-{2,2,2-Trifluoro-[1-(4-methylphenyl)amino]ethyl}-1,4-dioxan-

2-one (16e)

IR (ATR): 3374, 3352, 1721, 1520, 1231, 1105, 1049, 949, 926, 808,

694, 521 cm^–1

.

Yield: 0.01 g (0.03 mmol, 98%); syn/anti 75:25; white solid; mp 109

°C; R_f= 0.38 (PE/EtOAc 2:1).

¹H NMR (400 MHz, CDCl₃): δ = 6.71–6.83 (m, 4 H), 4.54–4.74 (m, 3 H),

4.39–4.42 (m, 1 H), 3.80–4.11 (m, 5 H), 1.38 and 1.37 (t, J = 7.1 and 6.9

Hz, 3 H).

¹³C NMR (100.6 MHz, CDCl₃): δ = 166.2 and 165.9, 153.3, 138.8 and

137.9, 124.9 and 124.5 (q, J = 285.9 and 283.5 Hz), 116.8 and 116.5 (2

C), 115.9 and 115.6 (2 C), 75.4 and 74.1 (q, J = 1.9 and 1.5 Hz), 68.5,

63.95 and 63.86, 62.8 and 62.7, 59.2 and 59.0 (q, J = 28.3 and 29.0 Hz),

14.9.

The spectral data given below correspond to a mixture of diastereo-

mers.

IR (ATR): 3383, 3360, 1721, 1526, 1252, 1159, 1125, 1105, 1070, 1047,

930, 812, 692, 519 cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.05 and 6.69 (d, J = 8.4 Hz, 2 H), 7.01

and 6.68 (d, J = 8.3 Hz, 2 H), 4.70–4.83 and 4.54–4.61 (m, 3 H), 4.39–

4.43 (m, 1 H), 3.79–4.16 (m, 3 H), 2.26 and 2.24 (s, 3 H).

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –70.00 and –72.21 (d, J = 6.9 and 7.7

¹³C NMR (100.6 MHz, CDCl₃): δ = 166.1 and 165.8, 142.7 and 141.8,

130.2 and 129.9 (2 C), 129.6 and 129.5, 124.9 and 124.5 (q, J = 285.8

and 283.6 Hz), 115.0 and 114.8 (2 C), 75.3 and 74.2 (q, J = 1.8 and 1.2

Hz), 68.5, 62.8 and 62.7, 58.2 and 57.8 (q, J = 28.8 and 29.3 Hz), 20.45

and 20.43.

Hz, 3 F).

MS (70 eV): m/z = 320 ([M⁺+ 1], 100).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₄H₁₇F₃NO₄⁺: 320.1104; found:

320.1094.

¹⁹F NMR (376.5 MHz, CDCl₃): δ = –70.00 and –72.41 (d, J = 6.9 and 7.0

Hz, 3 F).

MS (70 eV): m/z = 290 ([M⁺+ 1], 100).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₃H₁₅F₃NO₃⁺: 290.0999; found:

3-{2,2,2-Trifluoro-1-[(4-methoxyphenyl)amino]ethyl}-1,4-dioxan-

2-one (16a)

Yield: 0.03 g (0.10 mmol, 81%); syn/anti = 78:22; yellow oil; R_f= 0.18

(PE/EtOAc 3:1).

290.0985.

The spectral data given below correspond to a mixture of diastereo-

mers.

R

H. Dao Thi et al.

Feature

Synthesis

Funding Information

(14) (a) Van Driessche, B.; Van Brabandt, W.; D’hooghe, M.;

Dejaegher, Y.; De Kimpe, N. Tetrahedron 2006, 62, 6882.

(b) Mollet, K.; Decuyper, L.; Vander Meeren, S.; Piens, N.; De

Winter, K.; Desmet, T.; D’hooghe, M. Org. Biomol. Chem. 2015,

13, 2716.

(15) Decamps, S.; Sevaille, L.; Ongeri, S.; Crousse, B. Org. Biomol.

Chem. 2014, 12, 6345.

(16) Ma, S.-h.; Yoon, D. H.; Ha, H.-J.; Lee, W. K. Tetrahedron Lett.

2007, 48, 269.

The authors are indebted to the Research Foundation – Flanders

(FWO, Project G0F4816N) and to the National Foundation for Science

and Technology Development, Vietnam (NAFOSTED, Project FWO-

104-2015.01) for financial support in the framework of a FWO-

NAFOSTED bilateral research cooperation. The authors are also in-

debted to Ghent University – Belgium (Special Research Fund, BOF)

for financial support.

Research

F

o

u

n

d

oaitn

–

Faln

d

ers

F(

W

O)

G(

0

F

4

8

1

6

N

N)oaitn

a

l

F

o

u

n

d

oaitn

o

f

r

Secince

a

n

d

Tech

n

o

lg

y

D

e

v

oelp

m

e

n

,t

Veitn

a

m

N(A

F

O

S

T

E

D)

F(

W

O-1

0

4-2

0

1

50.1)

(17) (a) D’hooghe, M.; Vandekerckhove, S.; Mollet, K.; Vervisch, K.;

Dekeukeleire, S.; Lehoucq, L.; Lategan, C.; Smith, P. J.; Chibale,

K.; De Kimpe, N. Beilstein J. Org. Chem. 2011, 7, 1745. (b) Mollet,

K.; D’hooghe, M.; De Kimpe, N. J. Org. Chem. 2011, 76, 264.

(18) (a) Burke, W. J.; Murdock, K. C.; Ec, G. J. Am. Chem. Soc. 1954, 76,

1677. (b) Zanatta, N.; Squizani, A. M. C.; Fantinel, L.; Nachtigall,

F. M.; Borchhardt, D. M.; Bonacorso, H. G.; Martins, M. A. P.

J. Braz. Chem. Soc. 2005, 16, 1255. (c) Mathis, C. L.; Gist, B. M.;

Frederickson, C. K.; Midkiff, K. M.; Marvin, C. C. Tetrahedron Lett.

2013, 54, 2101.

(19) (a) Deb, M. L.; Pegu, C. D.; Borpatra, P. J.; Saikia, P. J.; Baruah, P.

K. Green Chem. 2017, 19, 4036. (b) Zhang, G.-Y.; Xiang, Y.; Guan,

Z.; He, Y.-H. Catal. Sci. Technol. 2017, 7, 1937.

(20) Aricò, F.; Bravo, S.; Crisma, M.; Tundo, P. Pure Appl. Chem. 2016,

88, 227.

(21) Toniolo, S.; Aricò, F.; Tundo, P. ACS Sustainable Chem. Eng. 2014,

2, 1056.

(22) Malkov, A. V.; Stončius, S.; Kočovský, P. Angew. Chem. Int. Ed.

2007, 46, 3722.

(23) Akiyama, T.; Ogi, S.; Fuchibe, K. Tetrahedron Lett. 2003, 44, 4011.

(24) Moens, M.; De Kimpe, N.; D’hooghe, M. J. Org. Chem. 2014, 79,

5558.

(25) (a) Alcaide, B.; Almendros, P.; Salgado, N. R. J. Org. Chem. 2000,

65, 3310. (b) Alcaide, B.; Almendros, P.; Redondo, M. C. Eur. J.

Org. Chem. 2007, 3707.

Supporting Information

Supporting information for this article is available online at

https://doi.org/10.1055/s-0036-1591537.

S

u

p

ortiInfogrmoaitn

S

u

p

ortioInfgrmoaitn

References

(1) (a) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071. (b) Fujiwara,

T.; O’Hagan, D. J. Fluorine Chem. 2014, 167, 16. (c) Wang, J.;

Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.;

Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432.

(2) (a) Bégué, J.-P.; Bonnet-Delpon, D. In Bioorganic and Medicinal

Chemistry of Fluorine; Wiley: New York, 2007, 72.

(b) Richardson, P. Expert Opin. Drug Discovery 2016, 11, 983.

(3) (a) Kenis, S.; D’hooghe, M.; Verniest, G.; Nguyen Duc, V.; Dang

Thi, T. A.; Van Nguyen, T.; De Kimpe, N. Org. Biomol. Chem. 2011,

9, 7217. (b) Kenis, S.; D’hooghe, M.; Verniest, G.; Dang Thi, T. A.;

Pham The, C.; Van Nguyen, T.; De Kimpe, N. J. Org. Chem. 2012,

77, 5982. (c) Kenis, S.; D’hooghe, M.; Verniest, G.; Reybroeck,

M.; Dang Thi, T. A.; Pham The, C.; Pham Thi, T.; Törnroos, K. W.;

Van Nguyen, T.; De Kimpe, N. Chem. Eur. J. 2013, 19, 5966.

(d) Dolfen, J.; Kenis, S.; Van Hecke, K.; De Kimpe, N.; D’hooghe,

M. Chem. Eur. J. 2014, 20, 10650.

(26) Banfi, L.; Guanti, G.; Rasparini, M. Eur. J. Org. Chem. 2003, 1319.

(27) (a) Fleck, T. J.; McWhorter, W. W.; DeKam, R. N.; Pearlman, B. A.

J. Org. Chem. 2003, 68, 9612. (b) Banfi, L.; Basso, A.; Guanti, G.;

Paravidino, M.; Riva, A.; Scapollab, C. ARKIVOC 2006, (vi), 15.

(28) (a) Dubey, A.; Kandula, S. R. V.; Kumar, P. Synth. Commun. 2008,

38, 746. (b) Shaikh, A. L.; Banik, B. K. Helv. Chim. Acta 2012, 95,

839.

(4) Kuznetsova, L. V.; Pepe, A.; Ungureanu, I. M.; Pera, P.; Bernacki,

R. J.; Ojima, I. J. Fluorine Chem. 2008, 129, 817.

(5) Bégué, J.-P.; Bonnet-Delpon, D. In Bioorganic and Medicinal

Chemistry of Fluorine; Wiley: New York, 2007, 23.

(6) Kowalski, M. K.; Mlostoń, G.; Obijalska, E.; Linden, A.;

Heimgartner, H. Tetrahedron 2016, 72, 5305.

(7) (a) Ojima, I.; Slater, J. C.; Pera, P.; Veith, J. M.; Abouabdellah, A.;

Bégué, J.-P.; Bernacki, R. J. Bioorg. Med. Chem. Lett. 1997, 7, 133.

(b) Garbi, A.; Allain, L.; Chorki, F.; Ourévitch, M.; Crousse, B.;

Bonnet-Delpon, D.; Nakai, T.; Bégué, J.-P. Org. Lett. 2001, 3,

2529. (c) Kuznetsova, L.; Ungureanu, I. M.; Pepe, A.; Zanardi, I.;

Wu, X.; Ojima, I. J. Fluorine Chem. 2004, 125, 487.

(8) Dao Thi, H.; Decuyper, L.; Mollet, K.; Kenis, S.; De Kimpe, N.; Van

Nguyen, T.; D’hooghe, M. Synlett 2016, 27, 1100.

(9) Dao Thi, H.; Goossens, H.; Hertsen, H.; Otte, V.; Van Nguyen, T.;

Van Speybroeck, V.; D’hooghe, M. Chem. Asian J. 2018, 13, doi:

10.1002/asia.201701636.

(10) Dao Thi, H.; Danneels, B.; Desmet, T.; Van Hecke, K.; Van

Nguyen, T.; D’hooghe, M. Asian J. Org. Chem. 2016, 5, 1480.

(11) Davoli, P.; Forni, A.; Franciosi, C.; Moretti, I.; Prati, F. Tetrahe-

dron: Asymmetry 1999, 10, 2361.

(12) Ma, X.; Liu, S.; Liu, Y.; Gu, G.; Xia, C. Sci. Rep. 2016, 6, 25068.

(13) D’hooghe, M.; Van Brabandt, W.; De Kimpe, N. J. Org. Chem.

2004, 69, 2703.

(29) Zarei, M. Tetrahedron 2013, 69, 6620.

(30) (a) Schwertfeger, W.; Siegemund, G. Angew. Chem., Int. Ed. Engl.

1980, 19, 126. (b) Fujioka, H.; Matsunaga, N.; Kitagawa, H.;

Nagatomi, Y.; Kondo, M.; Kita, Y. Tetrahedron: Asymmetry 1995,

6, 2117. (c) Tian, H.-y.; Sun, B.-g.; Tang, L.-w.; Ye, H.-l. Flavour

Fragr. J. 2011, 26, 65.

(31) (a) Ley, S. V.; Diez, E.; Dixon, D. J.; Guy, R. T.; Michel, P.; Nattrass,

G. L.; Sheppard, T. D. Org. Biomol. Chem. 2004, 2, 3608. (b) Gassa,

F.; Contini, A.; Fontana, G.; Pellegrino, S.; Gelmi, M. L. J. Org.

Chem. 2010, 75, 7099.

(32) (a) Broggini, G.; Zecchi, G. Org. Prep. Proced. Int. 1991, 23, 762.

(b) Li, M.-X.; Zhuo, R.-X.; Qu, F.-Q. React. Funct. Polym. 2003, 55,

185. (c) Yu, X.-h.; Feng, J.; Zhuo, R.-x. Macromolecules 2005, 38,

6244.

(33) (a) Kim, S.-I.; Kim, C.-U.; Park, S.-J. J. Chem. Eng. Data 2005, 50,

1871. (b) He, F.; Jia, H.-L.; Liu, G.; Wang, Y.-P.; Feng, J.; Zhuo, R.-

X. Biomacromolecules 2006, 7, 2269. (c) Penso, M.; Foschi, F.;

Pellegrino, S.; Testa, A.; Gelmi, M. L. J. Org. Chem. 2012, 77, 3454.

Article Doi

Use of 3-Hydroxy-4-(trifluoromethyl)azetidin-2-ones as Building Blocks for the Preparation of Trifluoromethyl-Containing Aminopropanes, 1,3-Oxazinan-2-ones, Aziridines, and 1,4-Dioxan-2-ones

DOI: 10.1055/s-0036-1591537

Source and publish data:

Authors:

Article abstract of DOI:10.1055/s-0036-1591537

Full text of DOI:10.1055/s-0036-1591537

Products guided by the article

R&D Labs maybe for 54638-43-6

Relevant to this article

Hot Product