Synthesis of 2,2,6,6-tetrafluoro-4-phenylmethylmorpholin-3-ones: A simple approach from fluorinated triethylene glycol

Article abstract of DOI:10.1016/j.jfluchem.2009.05.014

2,2,6,6-Tetrafluoro-4-phenylmethylmorpholin-3-ones are obtained from a new single step, preparative route by reacting triethylene glycol di(trifluoromethanesulfonate), which contains poly -CF₂O- groups, with benzylamine. Reaction of trifluorome

Full text of DOI:10.1016/j.jfluchem.2009.05.014

Journal of Fluorine Chemistry 130 (2009) 727–732
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of 2,2,6,6-tetrafluoro-4-phenylmethylmorpholin-3-ones: A simple
approach from fluorinated triethylene glycol
Zhuo Zeng a,b, Jean’ne M. Shreeve b,
*
a College of Chemistry & Environment, South China Normal University, Guangzhou, Guangdong 510006, PR China
b Department of Chemistry, University of Idaho, Moscow, ID 83844-2343, United States
A R T I C L E I N F O
A B S T R A C T
Article history:
2,2,6,6-Tetrafluoro-4-phenylmethylmorpholin-3-ones are obtained from a new single step, preparative
route by reacting triethylene glycol di(trifluoromethanesulfonate), which contains poly –CF2O– groups,
with benzylamine. Reaction of trifluoromethylsulfonate and trifluoromethoxy derivatives with
benzylamine gave either the nucleophilically-substituted product or the product resulting from the
basic hydrolysis of the difluoromethoxy group. Replacement of a fluoroether chain by a fluoroalkane
gave rise to fluorinated phenylmethylpiperidine and phenylmethylazepine via the combination of
trifluoromethanesulfonic fluoroalkyldiyl esters and benzylamine.
Received 5 April 2009
Received in revised form 14 May 2009
Accepted 18 May 2009
Available online 27 May 2009
This contribution is dedicated to Professor
Qing-Yun Chen on the occasion of his
80th birthday.
ß 2009 Elsevier B.V. All rights reserved.
Keywords:
Fluoroether
Piperidine
Azepine
Fluoroalkane
Difluoroacetamide
1. Introduction
of fluorinated ethanolamines which arises from the likelihood of
elimination of hydrogen fluoride precludes their use. Previously,
It is well-known that the introduction of a fluorine atom or a
fluoroalkyl group into heterocyclic compounds has a profound
influence on their chemical, physical and biological properties [1].
Many biologically important compounds that possess a lactone or
lactam structure are known, e.g., morpholin-3-one and its
derivatives, which are essentially lactams with important biolo-
gical and pharmacological activity, are used as building blocks for
an HIV-1 protease inhibitor [2], tachykinin receptors [3], cornea
permeable calpain inhibitors [4], and an A549 lung cancer cell
inhibitor [5]. Synthetic routes to morpholin-3-ones are diverse,
e.g., by direct oxidation of morpholine in the presence of a cobalt
catalyst to give morpholin-3-ones in 24% yield [6], or by treating
ethanolamine derivatives with chloroacetyl chloride in the present
of base to form morpholin-3-ones in moderate yield [7]. N-
substituted morpholin-3-one derivatives have been obtained
under rigorous conditions [8]. However, few reports describing
the synthesis of fluorinated morpholin-3-ones are available. For
example, the direct fluorination of morpholin-3-ones with a strong
fluorinating reagent results in ring opening, and the lack of stability
fluorinated
morpholin-3-ones,
N-aryl-2-methyl-2-trifluoro-
methylmorpholin-3-ones, were prepared by condensation of 2-
hydroxy-2-(trifluoromethyl)propanoic acid and aniline, followed
by further treatment with1-bromo-2-chloroethane under basic
conditions for one week [9]. 4-(4-Aminophenyl)-6,6-difluoro-3-
morpholinone has been reported as a pharmacological active
molecule [10].
2. Results and discussion
Our efforts are directed toward the development of fluorinated
heterocyclic compounds as potential bioactive molecules as well as
nitrogen-rich energetic, functional materials. A large number of
fluorinated imidazole-, pyrazole-, triazole-, and tetrazole-contain-
ing compounds with promise of ionic liquids are in the literature
[11]. Polyfluoroalkyl-bridged diimidazolium ionic liquids were
prepared by us earlier using the combination of trifluorometha-
nesulfonic acid polyfluoro alkyldiyl esters, 2a–2d (Scheme 1) and
alkylimidazoles. These diimidazolium ionic liquids with high
fluorine content showed good thermal stability and consistently
low friction up to 300 8C [12].
Previously, a two-step reaction of trifluoromethanesulfonic
acid 3,3,4,4-tetrafluoro-1,4-butanediyl ester, and benzylamine
* Corresponding author. Fax: +1 208 885 9146.
E-mail address: jshreeve@uidaho.edu (J.M. Shreeve).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.05.014

728
Z. Zeng, J.M. Shreeve / Journal of Fluorine Chemistry 130 (2009) 727–732
Scheme 1. Syntheses of trifluoromethanesulfonic acid polyfluoroalkyldiyl esters.
Scheme 2. Synthesis of fluorinated piperidine, and azepine.
gave the fluorinated five member heterocycle, 3,3,4,4-tetrafluor-
opyrrolidine (F content > 53%) [13]. We anticipated that utilization
of this simple synthetic pathway, i.e., to react trifluoromethane-
sulfonic acid perfluoroalkyldiyl ester, 2a–2d, having high C
fluorocarbon alkyl groups, with amines would facilitate prepara-
tion of N-based heterocycles with higher fluorine content, e.g., six-
membered piperidine (F content > 59%), seven-membered azepine
(F content > 62%), and macro rings. Although diimidazolium ionic
liquids with high fluorine content showed good tribological
characteristics in our earlier report, the low stability of imidazo-
lium ionic liquids in basic systems limited their scope of use as new
lubricants [14]. These new heterocycles with high fluorine content
would be expected to replace the imidazole ring in the synthesis of
potential high temperature ionic liquid lubricants.
(mol ratio 1:1), in ethanol at reflux for 24 h, generated the
fluorinated piperidine, 3,3,4,4,5,5-hexafluoro-1-(phenylmethyl)-
piperidine, 3a, and azepine, 3,3,4,4,5,5,6,6-octafluoro-1-(phenyl-
methyl)azepine, 3b, in 50% yield (Scheme 2).
The formation of 3aand3bencouragedustoextendthisapproach
toemploylongerchaintrifluoromethanesulfonicacid fluoroalkyldiyl
esters in order to synthesize fluorinated macro rings. An attempt to
synthesize a fluorinated macro ring by using benzylamine and
triethylene glycol di(trifluoromethane) disulfonate, 2c, was unsuc-
cessful as determined by 19F NMR. However, increasing the reaction
temperature to 110 8C for 48 h, resulted in a mixture of 2,2-difluoro-
2-{2-[2-(phenylmethyl)amino-difluoroethoxy]-tetrafluoroethoxy}
ethanol, 5a, and the unexpected 2,2,6,6-tetrafluoro-4-phenyl-
methyl-morpholin-3-one, 6a (Scheme 3).
Following this strategy, we first explored the synthesis of
fluorinated piperidine and azepine. Previously, 3,3,4,4,5,5-hexa-
The polarities of 5a and 6a are similar based on TLC. The mixture
was carefully separated using chromatography to give 5a (15%)
and 6a (25%) (Scheme 3) [16]. The structure of compound 6a was
confirmed by 19F, and 1H NMR, and mass spectral, and elemental
fluoro-2,2,6,6-tetradeutero-1-(phenylmethyl)piperidine
was
synthesized by a multistep, complex procedure by using lithium
aluminum deuteride and polyfluorocyclic dione [15]. Cyclization of
4a with trifluoromethanesulfonic fluoroalkyldiyl ester, 2a or 2b
analysis; there are two 19F resonance bands at
d
À75.38, and
À72.03 ppm, and in the 1H NMR spectrum, a triplet resonance at
Scheme 3. Synthesis of 2,2,6,6-tetrafluoro-4-phenylmethylmor-pholin-3-one.

Z. Zeng, J.M. Shreeve / Journal of Fluorine Chemistry 130 (2009) 727–732
729
Table 1
separation of the reaction mixture, N-(2-trifluoromethoxy-2-
difluoroethyl)-benzenemethane-amine, (20% yield), and 2-
Synthesis of 2,2,6,6-tetrafluoro-4-phenylmethyl-morpholin-3-ones.
8
Entry
Amine
Conditiona
5, %Yieldb
6, %Yieldb
trifluoromethoxy-N-(phenylmethyl)difluoro-acetamide,
(Scheme 4).
9 (15%)
1
2
3
4
5
6
4a
4a
4a
4b
4c
4d
A
B
C
B
B
B
15
20
25
35
Previously, hydrolysis of ethers by sulfuric acid which contain
the –CF2O– group, a procedure for formation of hydrogen fluoride
and fluorosulfonic acid, had been used for the synthesis of the
esters of various fluorinated acids [17]. The acetamide product, 9,
or lactam product, 6, obtained from the poly –CF2O– groups found
in 2e or 2c in the presence of Et3N, may involve the basic hydrolysis
of the difluoromethyleneoxy group. It is suggested that the
reaction may take place according to Scheme 5.
Basic hydrolysis of 2c at 110 8C gives rise to fluorinated alcohol
A. The formation of the intermediate acetyl fluoride, B, likely the
key procedure, rapidly reacts with the amine to give acetamide C
with concomitant loss of HF. Then C undergoes intramolecular
cyclization to yield 2,2,6,6-tetrafluoro-4-phenylmethyl-morpho-
lin-3-one, 6.
25
20
15
35
20
15c
35
30c
a
Condition A: amine (1 mmol), mole ratio of amine:2c:Et3N = 1:1:3; Condition B:
amine (1 mmol), mole ratio of amine:2c:Et3N = 1:1:5; Condition C: amine
(1 mmol), mole ratio of amine:2c:Et3N = 1:1:10; reaction in Pyrex tube 110 8C,
2 ml EtOH as solvent, for 48 h.
b
After chromatographic purification.
c
By GC–MS analysis.
3.79 ppm was assigned to the proton at the 5 position for 6a.This is
the first example of the synthesis of a fluorinated morpholin-3-one
by direct reaction of a fluorinated triethylene glycol di(trifluor-
omethanesulfonate) with an amine. When K2CO3 or the stronger
base, KOH, was used in place of Et3N, the cyclized product 6a was
not observed. However, when the reaction conditions were
optimized by increasing the mole ratio of reactants
4a:2c:Et3N = 1:1:5 at 110 8C over 48 h (Table 1), the yield of 6a
was increased to 35%.
2,2-Difluoro-2-{2-[2-(phenylmethyl)amion-difluoroethoxy]te-
trafluoro-ethoxy}ethanol, 5a was thought to be the intermediate in
the formation of 2,2,6,6-tetrafluo-4-phenylmethylmorpholin-3-
one, 6a, occurring by intramolecular cyclization (Scheme 3).
However, no reaction occurred when 0.5 mmol 5a was mixed with
1 mmol Et3N in a Pyrex tube and all of the 5a was recovered.
When changing the fluorinated alkyl chain from triethylene
glycol to tetraethylene glycol, 2d, and reacting with benzylamine,
4a, under the same conditions, resulted in only the nucleophili-
cally-substituted product 7 (Scheme 4).
N-fluoroalkylbenzenamine was isolated from reaction of ani-
line and fluoroalkyl alcohol methanesulfonate or benzenesulfonate
in 50% yield [17]. When 4-iodo-benzenamine, 4d, was heated with
2c in ethanol at 110 8C, in an effort to obtain the cyclization
product,
2,2,6,6-tetrafluoro-4-iodophenylmor-pholin-3-one,
approximately five products were observed by TLC. These were
subsequently isolated from the reaction mixture by column
chromatography (Scheme 6). Two major products,2,2-difluoro2-
{2-[2-(4-iodo-phenylmethyl-amino)difluoroethoxy]-tetra-fluoro-
ethoxy}ethanol, 10 (20%) and N,N’-1,2-[2,2-difluoroethanediylbi-
s(oxy-2,1-tetrafluoroethanediyl)]-bisbenzenamine, 11 (15%) were
found.
In conclusion, a new, straightforward approach was developed
for the preparation of fluorinated morpholin-3-ones. Reaction of
fluorinated triethylene glycol di(trifluoromethanedisulfonate), 2c,
and benzylamine resulted in 2,2,6,6-tetrafluoro-4-phenylmethyl-
morpholin-3-one. Changing the fluorinated alkyl chain from
triethylene glycol to tetraethylene glycol, 2d, and reacting with
benzylamine, 4a, under the same conditions, resulted solely in the
nucleophilically-substituted product. Replacing the trifluoro-
methane sulfonate substituent in 2c by the trifluoromethoxy
Replacing the trifluoromethane sulfonate substituent in 2c by
the diethylene glycol trifluoromethanesulfonatetrifluoromethoxy
derivative 2e, 2,2-difluoro-2-[1,1,2,2-tetrafluoro-2-(trifluoro-
methoxy)-ethoxy]ethyl-trifluoromethanesulfonate ester, which
then was reacted under the same conditions with 4a gave, after
Scheme 4. Reaction of trifluoromethylsulfonate and trifluoromethoxy derivatives with benzylamine.
Scheme 5. A plausible reaction mechanism for the formation of 6.

730
Z. Zeng, J.M. Shreeve / Journal of Fluorine Chemistry 130 (2009) 727–732
Scheme 6. Reaction of 2c with 4-iodobenzenamine.
moiety in 2e, and reacting with 4a, gave the nucleophilically-
substituted compounds 8, and 9 which result from the basic
hydrolysis of the difluoromethoxy group. Combination of the
trifluoromethanesulfonic fluoroalkyldiyl ester with benzylamine
resulted in fluorinated phenylmethylpiperidine and phenylmethy-
lazepine.
3.3. Preparation 3,3,4,4,5,5-hexafluoro-1-(phenylmethyl)piperidine
3a, and 3,3,4,4,5,5,6,6-octafluoro-1-(phenylmethyl)azepine 3b
Trifluoromethanesulfonic acid 2,2,3,3,4,4-hexafluoro-1,5-pen-
tanedily ester, 2a (1 mmol), or trifluoromethaneulfonic acid
2,2,3,3,4,4,5,5-octafluoro-1,6-hexanedily ester, 2b (1 mmol), 4a
(1 mmol), and Et3N (3 mmol) in 2 mL ethanol are placed in a
round-bottomed-flask fitted with a reflux condenser, and heated at
reflux for 24 h. After cooling, the organic solvent was removed
under reduced pressure and to the residue was added 30 mL
dichloromethane then washed with water (3Â 20 mL), and the
organic layer was dried over anhydrous Na2SO4. After the solvent
was removed, the crude product was purified by silica gel column
chromatography (DCM:Hexane = 1:5) to give 3,3,4,4,5,5-hexa-
fluoro-1-(phenylmethyl)piperidine 3a, or 3,3,4,4,5,5,6,6-octa-
fluoro-1-(phenylmethyl)azepine 3b.
3. Experimental section
3.1. General considerations
All the reagents used were analytical reagents purchased from
commercial sources and used as received. 1H, 19F NMR and 13C
NMR spectra were recorded on a 300 MHz nuclear magnetic
resonance spectrometer operating at 300.13, 282 and 75.48 MHz,
respectively. Chemical shifts were reported relative to Me4Si for
1H, and 13C, CCl3F for 19F. The solvent was CDCl3 unless otherwise
specified. GC–MS was carried out using a SHIMADZU GCMS-
QP5000 Gas Chromatography/Mass Spectrometer. Elemental
analyses were performed on an EXETER CE-440 Elemental
Analyzer.
3a. 3,3,4,4,5,5-hexafluoro-1-(phenylmethyl)piperidine: 50% yield,
colorless liquid; 1H NMR (CDCl3)
d (ppm): 7.34 (m, 5H), 3.79 (s, 2H),
3.02 (t, J = 8.8 Hz, 4H). 19F NMR
d
(ppm): À139.28 (m, 2F), À121.96
(s, 4F). GC–MS (EI) m/z: 283 (M+). Anal. Calcd (%) for C12H11F6N
(283.08): C, 50.89; H, 3.91; N, 4.95. Found: C, 50.78; H, 3.90; N,
4.89.
3.2. General procedure for the preparation of
3b. 3,3,4,4,5,5,6,6-octafluoro-1-(phenylmethyl)azepine: 45%
trifluoromethanesulfonic acid polyfluoroalkyldiyl ester
yield, colorless liquid; 1H NMR (CDCl3)
d (ppm): 7.37 (m, 5H),
3.95 (s, 2H), 3.56 (t, J = 14.2 Hz, 4H). 19F NMR
d
(ppm): À128.04 (s,
2,2,3,3,4,4-Hexafluoro-1,5-pentanediol, 1a (1 mmol), 2,2,3,3,4,
4,5,5-octafluoro-1,6-hexanediol, 1b (1 mmol), 1H,1H,8H,8H-octa-
fluoro-3,6-dioxaoctane-1,8-diol, 1c (1 mmol), or 1H,1H,11H,11H-
perfluoro-3,6,9-trioxaundecane-1,8-diol, 1d, pyridine (2.3 mmol)
and dichloromethylene (20 mL) were stirred at room tempera-
ture under a nitrogen atmosphere. After 20 min, trifluorometha-
nesulfonic anhydride (2.5 mmol) in 10 mL dichloromethylene
was slowly added over 1 h by using an addition funnel.
The mixture was stirred for 24 h, then washed with water
(3Â 10 mL), 10% sodium bicarbonate (2Â 10 mL), and dried over
anhydrous sodium sulfate. The solvent was removed under
vacuum to give trifluoromethanesulfonic acid polyfluoroalk-
yldiyl ester, 2a–2d.
4F), À112.73 (s, 4F). GC–MS (EI) m/z: 333 (M+). Anal. Calcd (%) for
C
13H11F8N (333.08): C, 46.86; H, 3.33; N, 4.20. Found: C, 46.46; H,
3.37; N, 4.09.
3.4. General procedure for the preparation 2,2,6,6-tetrafluoro-4-
phenyl-morpholin-3-one
Fluorinated triethylene glycol di(trifluoromethanesulfonate),
2c (1 mmol), benzylamine, 4a (1 mmol), and Et3N (5 mmol) in
2 mL ethanol are placed in a Pyrex glass tube, sealed and heated at
110 8C for 48 h. After cooling, the organic solvent was removed
under reduced pressure and the residue was added 30 mL
dichloromethane then washed with water (3Â 20 mL), and the
organic layer was dried over anhydrous Na2SO4. After the solvent is
removed, the crude product was purified by silica gel column
chromatography (DCM:hexane = 1:3) to give 2,2-difluoro-2-{2-[2-
(phenylmethyl)amino-difluoroethoxy]-tetrafluoroethoxy} etha-
nol, 5a, and 2,2,6,6-tetrafluoro-4-phenyl-morpholin-3-one, 6a.
5a. 2,2-Difluoro-2-{2-[2-(phenylmethyl)amino-difluoroethoxy]-
tetrafluoroethoxy} ethanol: 20% yield, colorless liquid; 1H NMR
2a. Trifluoromethanesulfonic acid 2,2,3,3,4,4-hexafluoro-1,5-pen-
tanediyl ester: 80% yield, colorless solid: 1H NMR
d
(CDCl3, ppm):
4.85 (t, J = 11.6 Hz, 4H); 19F NMR
d
(CDCl3, ppm): À124.38 (s, 2F),
À119.56 (t, J = 11.6 Hz, 4F), À73.88 (s, 6F).
2b. Trifluoromethaneulfonic acid 2,2,3,3,4,4,5,5-octafluoro-1,6-
hexanediyl ester: 80% yield, colorless solid: 1H NMR
d
(CDCl3, ppm):
4.83 (t, J = 11.9 Hz, 4H); 19F NMR
d
(CDCl3, ppm): À122.91 (s, 4F),
À119.61 (t, J = 11.6 Hz, 4F), À73.85 (s, 6F).
(CDCl3)
d (ppm): 7.32 (m, 5H), 4.61 (m, 2H), 3.94 (s, 2H), 3.22 (t,
2c. Fluorinated triethylene glycol di(trifluoromethanesulfonate):
J = 10.5 Hz, 2H). 19F NMR
d
(ppm): À88.67 (m, 4F), À80.51 (m, 2F),
80% yield, colorless liquid: 1H NMR
d
(CDCl3, ppm): 4.68 (t,
À74.89 (m, 2F). GC–MS (EI) m/z: 384 (M++1). Anal. Calcd (%) for
J = 7.9 Hz, 4H); 19F NMR
d
(CDCl3, ppm): À88.63 (m, 4F), À77.68 (m,
C13H13F8NO3 (383.08): C, 40.74; H, 3.42; N, 3.65. Found: C, 41.00;
4F), À74.13 (s, 6F). GC–MS (EI) m/z: 674 (M+). Anal. Calcd (%) for
H, 3.22; N, 3.37.
C
10H4F18O9S2 (673.90): C, 17.81; H, 0.60. Found: C, 17.76; H, 0.47.
6a. 2,2,6,6-Tetrafluoro-4-phenyl-morpholin-3-one: 35% yield,
2d. Fluorinated tetraethylene glycol di(trifluoromethanesulfo-
nate): 80% yield, colorless liquid: 1H NMR
colorless liquid; 1H NMR (CDCl3)
d
(ppm): 7.43 (m, 3H), 7.26 (m,
d
(CDCl3, ppm): 4.68
2H), 4.71 (s, 2H), 3.79 (t, J = 8.1 Hz, 2H). 19F NMR
d
(ppm): À75.38
(t, J = 7.9 Hz, 4H); 19F NMR
d
(CDCl3, ppm): À88.63 (m, 8F), À77.68
(t, J = 8.1 Hz, 2F), À72.03 (m, 2F). GC–MS (EI) m/z: 263 (M+). Anal.
Calcd (%) for C11H9F4NO2 (263.06): C, 50.20; H, 3.45; N, 5.32.
Found: C, 49.57; H, 3.40; N, 5.32.
(m, 4F), À74.13 (s, 6F). Anal. Calcd (%) for C10H4F18O9S2 (674.23): C,
17.81; H, 0.60. Found: C, 17.76; H, 0.47.

Z. Zeng, J.M. Shreeve / Journal of Fluorine Chemistry 130 (2009) 727–732
731
5b. 2,2-Difluoro-2-{2-[2-(4-bromophenylmethyl-amino)difluor-
oethoxy]tetrafluoro-ethoxy}ethanol: 20% yield, colorless liquid; 1H
at room temperature under a nitrogen atmosphere. After 20 min,
trifluoromethanesulfonic anhydride (2.5 mmol) in 10 mL dichlor-
omethylene was slowly added (over 1 h) by using an addition
funnel. The mixture was stirred for 24 h, then washed with water
(3Â 10 mL), 10% sodium bicarbonate (2Â 10 mL), and dried over
anhydrous sodium sulfate. The solvent was removed under
vacuum to give trifluoromethanesulfonic acid 2,2-difluoro-2-
[1,1,2,2-tetrafluoro-2-(trifluoromethyoxy)ethoxy]-ethyl esters, 2e.
2e. Trifluoromethanesulfonic acid 2,2-difluoro-2-[1,1,2,2-tetra-
fluoro-2-(trifluoro-methyoxy)-ethoxy]-ethyl esters: 80% yield, color-
NMR (CDCl3)
d (ppm): 7.49 (d, J = 7.5 Hz, 2H), 7.26 (d, J = 10.4 Hz,
2H), 4.61 (m, 2H), 3.89 (s, 2H), 3.21 (t, J = 10.5 Hz, 2H). 19F NMR
d
(ppm): À88.71 (m, 4F), À80.48 (m, 2F), À74.92 (m, 2F). GC–MS (EI)
m/z: 463 (M+). Anal. Calcd (%) for C13H11BrF9NO2 (462.98): C,
33.79; H, 2.62; N, 3.03. Found: C, 34.01; H, 2.32; N, 3.17.
6b.
35% yield, colorless liquid; 1H NMR (CDCl3)
J = 4.2, 2H), 7.16 (d, J = 8.3, 2H), 4.66 (s, 2H), 3.80 (t, J = 8.1 Hz, 2H).
19F NMR
2,2,6,6-Tetrafluoro-4-(4-bromophenyl)-morpholin-3-one:
d
(ppm): 7.57 (d,
d
(ppm): À75.38 (t, J = 8.3 Hz, 2F), À72.05 (m, 2F). GC–MS
less liquid: 1H NMR (CDCl3, ppm): 4.69 (t, J = 7.7 Hz, 2H); 19F NMR
d
(EI) m/z: 341 (M+). Anal. Calcd (%) for C11H8BrF4NO2 (340.97): C,
38.62; H, 2.36; N, 4.09. Found: C, 38.61; H, 2.34; N, 4.19.
5c. 2,2-Difluoro -2-{2-[2-(4-Methoxyphenylmethy-amino)difluor-
oethoxy]-tetrafluoro-ethoxy}ethanol: 20% yield, colorless liquid; 1H
d
(CDCl3, ppm): À90.58 (t, J = 8.7 Hz, 2F), À88.54 (t, J = 12.7 Hz, 2F),
À77.56 (m, 2F), À74.06 (s, 3F), À55.18 (t, J = 8.7 Hz, 3F). GC–MS (EI)
m/z: 414 (M+). Anal. Calcd (%) for C6H2F12O5SÁH2O (431.95): C,
16.68; H, 0.93. Found: C, 17.01; H, 0.47.
NMR (CDCl3)
d
(ppm): 7.23 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H),
Then, 2e (1 mmol), benzylamine, 4a (1 mmol), and Et3N
(3 mmol) in 2 mL ethanol are placed in a Pyrex glass tube, sealed
and heated at 110 8C for 48 h. After cooling, the organic solvent was
removed under reduced pressure and to the residue was added
30 mL dichloromethane then washed with water (3Â 20 mL), and
the organic layer was dried over anhydrous Na2SO4. After the
solvent is removed, the crude product was purified by silica gel
column chromatography to give N-(2-trifluoromethoxy-2-difluor-
oethyl)-benzenemethaneamine, 8 (20% yield) and 2-trifluoro-
methoxy-N(phenylmethyl)-difluoroacetamide, 9 (15%).
4.57 (m, 2H), 3.84 (s, 2H), 3.79 (s, 3H), 3.17 (t, J = 10.6 Hz, 2H). 19F
NMR
d
(ppm): À88.69 (m, 4F), À80.48 (m, 2F), À74.83 (m, 2F). GC–
MS (EI) m/z: 415 (M+). Anal. Calcd (%) for C14H14F9NO3 (415.08): C,
40.49; H, 3.40; N, 3.37. Found: C, 40.85; H, 3.57; N, 3.41.
6c.
35% yield, colorless liquid; 1H NMR (CDCl3)
J = 8.5, 2H), 6.90 (d, J = 8.3, 2H), 4.62 (s, 2H), 3.80 (s, 3H), 3.73 (t,
2,2,6,6-Tetrafluoro-4-(4-methoxyphenyl)-morpholin-3-one:
d
(ppm): 7.17 (d,
J = 8.1 Hz, 2H). 19F NMR
d
(ppm): À75.44 (t, J = 8.3 Hz, 2F), À72.05
(m, 2F). GC–MS (EI) m/z: 293 (M+). Anal. Calcd (%) for C12H11F4NO3
(293.07): C, 49.15; H, 3.78; N, 4.78. Found: C, 49.46; H, 3.88; N, 4.72.
8.
mine: 20% yield, colorless liquid: 1H NMR
(m, 5H), 3.93 (s, 2H), 3.21 (t, J = 10.5 Hz, 2H); 19F NMR
N-(2-Trifluoromethoxy-2-difluoroethyl)-benzenemethanea-
(CDCl3, ppm): 7.36
(CDCl3,
d
3.5. Preparation 2,2-difluoro-2-{2-[2-
d
(butylamino)difluoroethoxy]tetrafluoroethoxy}ethanol and 2,2,6,6-
tetrafluoro-4-butyl-morpholin-3-one 6d
ppm): À90.89 (m, 2F), À88.58 (m, 2F), À74.97 (t, J = 13.2 Hz, 2F),
À55.30 (t, J = 9.0 Hz, 3F); GC–MS (EI) m/z: 371 (M+); Anal. Calcd (%)
for C12H10F9NO2 (317.06): C, 38.83; H, 2.72; N, 3.77. Found: C,
38.53; H, 2.54; N, 3.77.
The reaction was carried out as above with 2c and 4d.
Mixture of 5d and 6d: 45% yield, colorless liquid; 1H NMR
9. 2-Trifluoromethoxy-N-(phenylmethyl)-difluoroacetamide: 15%
(CDCl3)
d
(ppm): 3.92 (t, J = 8.1 Hz, 2H), 3.52 (d, J = 7.4 Hz, 4H), 1.63
(ppm):
yield, colorless liquid: 1H NMR
d (CDCl3, ppm): 7.35 (m, 5H), 6.48
(m, 4H), 1.37 (m, 4H), 0.96 (t, J = 8.2 Hz, 6H). 19F NMR
d
(s, 1H), 4.53 (d, J = 5.7 Hz, 2H); 19F NMR
d
(CDCl3, ppm): À80.06 (m,
À88.79 (m, 4F), À80.53 (m, 2F), À77.71 (m, 2F), À75.97 (t, J = 4.5,
2F), À72.31 (m, 2F). GC – two peaks at 8.2 min and 8.7 min. GC–MS
(EI) m/z: 350 (M++1, 8.2 min), 229 (M+, 8.7 min).
2F), À54.93 (m, 3F); GC–MS (EI) m/z: 269 (M+); HRMS Calcd for
C10H8F5NO2: 269.0457. Found: 269.0450.
3.8. 2,2-Difluoro2-{2-[2-(4-iodo-phenylmethyl-
amino)difluoroethoxy]-tetra-fluoro-ethoxy}ethanol, 10 and N,N’-
[1,2-[2,2-difluoro-ethanediylbis(oxy-2,1-tetrafluoroethanediyl)]-
bisbenzenamine, 11
3.6. Preparation 2,2-difluoro -2-{2-[2-(2-benzylamino-
difluoroethoxy)-tetrafluoro-ethoxy]tetrafluoroethoxy}ethanol 7
Fluorinated tetraethylene glycol di(trifluoromethanesulfonate),
2d (1 mmol), benzylamine, 4a (1 mmol), and Et3N (3 mmol) in 2 mL
ethanol are placed in a Pyrex glass tube, sealed and heated at 110 8C
for 48 h. After cooling, the organic solvent was removed under
reduced pressure and to the residue was added 30 mL dichlor-
omethane thenwashedwithwater(3Â 20 mL), andtheorganiclayer
was dried over anhydrous Na2SO4. After the solvent was removed,
the crude product was purified by silica gel column chromatography
(DCM:Hexane = 1:5) to give 2,2-difluoro -2-{2-[2-(2-benzylamino-
difluoroethoxy)-tetrafluoro-ethoxy]tetrafluoroethoxy}ethanol, 7.
7. 2,2-Difluoro -2-{2-[2-(2-benzylamino-difluoroethoxy)-tetra-
fluoro-ethoxy]tetrafluoroethoxy}ethanol: 15% yield, colorless liquid;
Fluorinated triethylene glycol di(trifluoromethanesulfonate),
2c (1 mmol), 4-iodophenylamine, 4d (1 mmol), and Et3N (5 mmol)
in 2 mL ethanol are placed in a Pyrex glass tube, sealed and heated
at 110 8C for 48 h. After cooling, the organic solvent was removed
under reduced pressure and the residue was added 30 mL
dichloromethane then washed with water (3Â 20 mL), and the
organic layer was dried over anhydrous Na2SO4. After the solvent
was removed, the crude product was purified by silica gel column
chromatography (DCM:Hexane = 1:2) to give, 2,2-difluoro -2-[2-
[2-[(4-iodophenylmethyl)amino]difluoroethoxy]tetrafluoroethox-
y]ethanol, 10 (20% yield) and N,N’-[1,2-[2,2-difluoroethanediylbi-
s(oxy-2,1-tetrafluoroethanediyl)]bisbenzenamine, 11 (15%).
1H NMR (CDCl3)
3.19 (t, J = 10.5 Hz, 2H). 19F NMR
d (ppm): 7.31 (m, 5H), 4.53 (m, 2H), 3.94 (s, 2H),
d
(ppm): À88.77 (m, 4F), À88.55
10.
oethoxy]-tetra-fluoro-ethoxy}ethanol: 20% yield, colorless liquid:
1H NMR
(CDCl3, ppm): 7.45 (d, J = 8.8 Hz, 2H), 6.47 (d, J = 8.8 Hz,
2H), 4.53 (m, 2H), 3.96 (s, 2H), 3.75 (m, 2H); 19F NMR
(CDCl3,
2,2-Difluoro2-{2-[2-(4-iodo-phenylmethyl-amino)difluor-
(m, 4F), À80.51 (m, 2F), À74.87 (m, 2F). GC–MS (EI) m/z: 499 (M+).
Anal. Calcd (%) for C15H13F12NO4 (499.07): C, 36.09; H, 2.62; N,
2.81. Found: C, 36.39; H, 2.48; N, 2.95.
d
d
ppm): À89.19 (m, 4F), À80.95 (m, 2F), À76.31 (m, 2F); GC–MS (EI)
m/z: 497 (M++1); Anal. Calcd (%) for C12H10F8INO3 (495.1): C,
29.36; H, 1.74; N, 2.83. Found: C, 29.36; H, 1.76; N, 2.83.
11. N,N’-[1,2-[2,2-Difluoroethanediylbis(oxy-2,1-tetrafluoroetha-
3.7. Preparation N-(2-trifluoromethoxy-2-difluoroethyl)-
benzenemethaneamine, 8 and 2-trifluoromethoxy-N-(phenylmethyl)-
difluoroacetamide, 9
nediyl)]bis-benzenamine: 15% yield, colorless solid: 1H NMR
(CDCl3, ppm): 7.45 (d, J = 8.9 Hz, 4H), 6.45 (d, J = 8.9 Hz, 4H), 3.92
(t, J = 6.9 Hz, 2H), 3.67 (m, 4H); 19F NMR
(CDCl3, ppm): À89.30 (m,
d
1H,1H,8H,8H-Nonafluoro-3,6-dioxaheptan-1-ol, 1e (1 mmol),
pyridine (2.3 mmol) and dichloromethylene (20 mL) were stirred
d

732
Z. Zeng, J.M. Shreeve / Journal of Fluorine Chemistry 130 (2009) 727–732
4F), À76.31 (m, 4F); GC–MS (EI) m/z: 696 (M+); Anal. Calcd (%) for
[7] (a) P.S. Brown, A.J. Foubister, D. Stribling, J. Chem. Soc. Perkin Trans. 1 (1987)
547–551;
C
18H14F8I2N2O2 (695.90): C, 31.06; H, 2.03; N, 4.02. Found: C,
(b) C. Kashima, K. Harada, J. Chem. Soc. Perkin Trans. 1 (1988) 1521–1526;
(c) P. Vieles, J. Seguin, Compt. Rend. 238 (1954) 1819–1821;
(d) P. Vieles, J. Seguin, Bull. Soc. Chim. Fr. (1953) 287–289;
(e) E. Pfeil, U. Harder, Angew. Chem. Int. Ed. 6 (2) (1967) 178.
[8] (a) S.A. Glickman, H.S. Schultz, N-alkyl-3-morpholones, US Patent 3,092,630.
S.A. Glickman, H.S. Schultz, Chem. Abstr. 59 (1963) 62375;
(b) W.E. Walles, N-halo-3-morpholone, US Patent 3,850,920.
W.E. Walles, Chem. Abstr. 82 (1974) 125410.
[9] P.H. Liang, L.W. Hsin, C.Y. Cheng, Bioorg. Med. Chem. (10) (2002) 3267–3276.
[10] A. Marhold, W. Ebenbeck, PCT Int. WO 2006042634 (2006).
A. Marhold, W. Ebenbeck, Chem. Abstr. 144 (2006) 412520.
[11] C.M. Jin, C. Ye, B.S. Phillips, J.S. Zabinski, X. Liu, W. Liu, J.M. Shreeve, J. Mater. Chem.
16 (2006) 1529–1535.
31.53; H, 2.13; N, 3.82.
Acknowledgements
The authors gratefully acknowledge the support of the Defense
Threat Reduction Agency (HDTRA1-07-1-0024), the National
Science Foundation (CHE-0315275), and the Office of Naval
Research (N00014-06-1-1032).
References
[12] Z. Zeng, B.S. Phillips, J.-C. Xiao, J.M. Shreeve, Chem. Mater. 8 (2008) 2719–2726.
[13] (a) B. Hulin, PCT Int. WO 2003101449 (2003).
[1] (a) D. O’Hagan, Chem. Soc. Rev. 37 (2008) 308–319;
(b) M. Hudlicky, A. Pavlath, Chemistry of Organic Fluorine Compounds II: A
Critical Review, American Chemical Society, Washington DC, USA, 1995;
(c) J.T. Welch, S. Ewwarakrishnan, Fluorine in Bioorganic Chemistry, Wiley–VCH,
Weinheim, 1991;
B. Hulin, Chem. Abstr. 140 (2003) 16964;
(b) B. Hulin, J.C. Parker, PCT Int. WO 2003101958 (2003).
B. Hulin, J.C. Parker, Chem. Abstr. 140 (2003) 16965;
(c) B. Hulin, S. Cabral, M.G. Lopaze, M.A. Van Volkenburg, K.M. Andrews, J.C.
Parker, Bioorg. Med. Chem. Lett 21 (2005) 4770–4773.
[14] (a) S.T. Handy, J. Org. Chem. 5 (2005) 1915–1918;
(b) S.T. Handy, J. Org. Chem. 12 (2006) 4659–4662.
(d) R. Filler, T. Kobayashi (Eds.), Biomedicinal Aspects of Fluorine Chemistry,
Kodansa & Elsevier Biomedical, Japan, 1982;
(e) C.D. Hewitt, M.J. Silvester, Aldrichim. Acta 21 (1988) 3–10.
[2] W.M. Kazmierski, E. Furfine, A. Spaltenstein, L.L. Wright, Bioorg. Med. Chem. Lett.
19 (2006) 5226–5230.
[3] D.C. Horwell, A.I. Morrell, E. Roberts, Bioorg. Med. Chem. Lett. 2 (1996) 165–166.
[4] M. Nakamura, H. Miyashita, M. Yamaguchi, Y. Shirasaki, Y. Nakamura, J. Inoue,
Bioorg. Med. Chem. 24 (2003) 5449–5460.
[15] (a) R. Tung, PCT Int. WO 2007033366 (2007).
R. Tung, Chem. Abstr. 146 (2007) 337883;
(b) M.T. Chaudhry, G.A. Powers, R. Stephens, J.C. Tatlow, J. Chem. Soc. (1964) 874–
876.
[16] (a) K. Inukai, Y. Maki, J. Chem. Soc. Japan 65 (1962) 1189–1191;
K. Inukai, Y. Maki, Chem. Abstr. 58 (1963) 33011;
[5] Q.X. He, X.S. Zhu, M. Shi, B.X. Zhao, J. Zhao, S.L. Zhang, J.Y. Miao, Bioorg. Med. Chem.
11 (2007) 3889–3895.
[6] Preparation of heterocyclic carboxylic acids or ketones by oxidation of hetero-
cyclic compounds. Daicel Chemical Industries Ltd., Jpn Kokai Koho, JP 11106377
(1999).
(b) H. Yamanaka, M. Kuwabara, M. Komori, M. Otani, K. Kase, K. Fukunishi, M.
Nomura, Nippon Kagaku Kaishi J. Chem. Soc. Japan 1 (1983) 112–117;
H. Yamanaka, M. Kuwabara, M. Komori, M. Otani, K. Kase, K. Fukunishi, M.
Nomura, Chem. Abstr. 98 (1983) 178838.
[17] E.R. Larsen, J. Org. Chem. 28 (1963) 1133–1134.