Synthesis of enantlopure 2-Aryl(Alkyl)-2-trIfluoromethyl-substituted morpholines and oxazepanes

Article abstract of DOI:10.1002/ejoc.200900387

The synthesis of morpholines and oxazepanes derivatives containing a trifluoromethyl group on a quaternary carbon has been achieved from a common enantiopure O-allyl ami no ether precursor. Classic 6-exo iodoamination provided the iodomorpholines, versati

Full text of DOI:10.1002/ejoc.200900387

FULL PAPER
DOI: 10.1002/ejoc.200900387
Synthesis of Enantiopure 2-Aryl(Alkyl)-2-trifluoromethyl-Substituted
Morpholines and Oxazepanes
Jean Nonnenmacher,[a] Fabienne Grellepois,[a] and Charles Portella*[a]
Keywords: Cyclization / Asymmetric synthesis / Fluorine / Heterocycles / Enantiopurity
The synthesis of morpholines and oxazepanes derivatives
containing a trifluoromethyl group on a quaternary carbon
has been achieved from a common enantiopure O-allyl
amino ether precursor. Classic 6-exo iodoamination provided
the iodomorpholines, versatile synthetic intermediates,
whereas a hydrozirconation/iodination sequence allowed the
synthesis of oxazepanes by a 7-endo cyclisation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
(Scheme 1). The enantiopure aldehydes D, which have re-
cently been synthesised by our group,[9] might then serve as
suitable precursors for intermediate amines of type C.
Introduction
A wide variety of highly active agrochemicals and phar-
maceuticals contain one or more fluorine atoms due to the
unique properties created by this atom.[1] Moreover, N,O-
heterocycles such as morpholines and oxazepanes are of
great interest due to their presence in a number of biolo-
gically active compounds.[2] However, only a very few tri-
fluoromethylated analogues of these heterocycles are
known to date. 2-(Trifluoromethyl)morpholines have been
described as subunits in compounds with interesting antitu-
moral,[3] antibacterial,[4] TPK1 inhibition[5] or herbicidal[6]
activities. The synthetic route for their preparation involves
the cyclisation of an α-halogenoacyl chloride with a suitable
1-CF3-amino alcohol. The cyclic amide thus formed is then
reduced to the corresponding morpholine. Various (trifluoro-
methyl)morpholino-substituted lactols[7] and morpholin-
ones[8] have also been reported as synthetic intermediates
or as components of biologically active compounds.
In this paper, we present a new synthetic approach to the
preparation of novel chiral morpholines and oxazepanes
containing a trifluoromethyl group at a quaternary carbon
adjacent to the oxygen atom.
Scheme 1. Retrosynthetic scheme for the preparation of CF3-sub-
stituted morpholines and oxazepanes.
The reductive amination[10] of the enantiopure aldehydes
(R)-1a,b[9] with benzylamine in the presence of sodium tri-
acetoxyborohydride directly afforded the amino ethers (R)-
2a,b in 71 and 57% yields, respectively (Scheme 2).
Results and Discussion
Retrosynthetically we envisaged that the desired (trifluoro-
methyl)morpholines
reached from the same O-allyl amino ethers C by a regiose-
lective 6-exo or 7-endo intramolecular iodocyclisation
A and oxazepanes B might be
Scheme 2. Reductive amination of the aldehydes (R)-1a,b to the
key amino ethers (R)-2a,b.
The 6-exo ring-closure of the allylic amino ethers 2a,b
into the corresponding (iodomethyl)morpholines 3a,b was
performed under classic conditions[11] using iodine in aceto-
nitrile under basic conditions (Table 1). This cyclisation was
not stereoselective, both morpholines 3a,b being obtained
[a] Université de Reims-Champagne-Ardenne, Institut de Chimie
Moléculaire de Reims, UMR CNRS 6229, UFR des Sciences
Exactes et Naturelles,
B. P. 1039, 51687 Reims Cedex 2, France
Fax: +33-3-26913166
E-mail: charles.portella@univ-reims.fr
3726
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3726–3731

Synthesis of Enantiopure Substituted Morpholines and Oxazepanes
as mixtures of two diastereomers in ratios of 63:37 and ammonium formate[14] as the catalytic hydrogen transfer
53:47, respectively. However, the diastereomers were sepa- agent in the presence of Pd/C at reflux in methanol gave
rated by chromatography on silica gel.
the free morpholine (2R,5S)-5a (73% yield; Scheme 3).
Table 1. Iodocyclisation of the amino ethers (R)-2a,b to the iodo-
morpholines (2R,5R)-3a,b and (2R,5S)-3a,b.
Scheme 3. Preparation of the 5-methyl-2-phenyl-2-(trifluorometh-
yl)morpholines (2R,5S)-4a and (2R,5S)-5a and the 2-ethyl-5-
methyl-2-(trifluoromethyl)morpholine (2R,5S)-4b.
Amino ether
(R)-2
R
Iodomorpholine
(2R,5R)-3/(2R,5S)-3
[dr][a]
% Yield
% Yield
(2R,5R)-3[b]
(2R,5S)-3[b]
Treatment of the trans-(iodomethyl)morpholines
(2R,5S)-3a and (2R,5S)-3b with ammonium formate at re-
flux in methanol led to the hydroxy analogues (2R,5R)-
6a[13] and (2R,5R)-6b[13] in 73 and 65% yields, respectively
(Scheme 4). Subsequent removal of the benzyl group under
the conditions described above[14] led to the free (hy-
droxymethyl)morpholines (2R,5R)-7a and (2R,5R)-7b in 69
and 91% yields, respectively (Scheme 4).
(R)-2a
(R)-2b
Ph
Et
3a [63:37]
3b [53:47]
55
37
33
39
[a] Diastereomeric ratio (dr) determined by 19F NMR analysis of
the crude mixture. [b] Isolated yields.
No conclusive information regarding the relative stereo-
chemistry of these 2,2,5-trisubstituted morpholines 3a,b
could be obtained from extensive NMR analyses. The stereo-
chemistry of the minor isomer of 3a was thus unambigu-
ously established by X-ray crystallography (Figure 1).[12]
This analysis revealed a chair-like conformation of the
morpholine ring with the phenyl substituent in an axial po-
sition and a 2,5-trans-diequatorial relationship of the tri-
fluoromethyl and iodomethyl substituents. Similar trends in
Scheme 4. Preparation of the 5-(hydroxymethyl)-2-phenyl-2-(tri-
the 13C NMR chemical shifts observed for both phenyl- and fluoromethyl)morpholines (2R,5R)-6a,7a and the 2-ethyl-5-(hy-
droxymethyl)-2-(trifluoromethyl)morpholines (2R,5R)-6b,7b.
ethyl-substituted morpholines allowed the assignment of
the same stereochemistry to the minor isomer of 3b. Specifi-
cally, the iodomethyl signal in the 13C NMR spectra ap-
peared at δ = 4.5 and 5.7 ppm for the minor “trans isomers”
(2R,5S)-3a and (2R,5S)-3b, respectively, whereas this signal
appeared upfield (at 1.0–1.1 ppm) for the major “cis iso-
mers” (2R,5R)-3a and (2R,5R)-3b.
We then studied the synthesis of the oxazepane deriva-
tives 8a,b by the ring-closure of the allylic amino ethers (R)-
2a,b at the less substituted allylic terminus. The 7-endo
cyclisation reaction leading to the oxazepanes was at-
tempted by using a strategy based on organozirconium
chemistry. Indeed, taking advantage of the properties of or-
ganozirconocenes,[15] Szymoniak and co-workers recently
reported the synthesis of four-, five- and six-membered
N-heterocycles applying an hydrozirconation/iodination
sequence to the corresponding unsaturated amines
(Scheme 5).[16] Owing to the regioselectivity of the hydrozir-
conation step,[15] this sequence provided a straightforward
synthesis of the endo cyclisation products.
Figure 1. Molecular structure of (2R,5S)-3a.
Scheme 5. Synthesis of N-heterocycles by the zirconation/iodin-
ation sequence.[16]
The presence of the iodine substituent in morpholines
3a,b allowed us to envisage the synthesis of a few analogues.
Hydrogenolysis of the cis-morpholines (2R,5R)-3a and
We adapted this strategy to our trifluoromethylated sub-
(2R,5R)-3b in methanol in the presence of triethylamine af- strates. As expected, the reaction of the allylic amino ether
forded the 5-methylmorpholines (2R,5S)-4a[13] and (2R,5S)- (R)-2a with the Schwartz reagent followed by iodine in the
4b[13] in 96 and 77% yields, respectively (Scheme 3). Cleav- presence of triethylamine led to the oxazepane (R)-8a in
age of the N-benzyl-protecting group of (2R,5S)-4a with 66% yield (Scheme 6). When applied to the ethyl analogue
Eur. J. Org. Chem. 2009, 3726–3731
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J. Nonnenmacher, F. Grellepois, C. Portella
FULL PAPER
ether. The combined organic layers were washed three times with
brine and dried (MgSO4). Evaporation of the solvent under re-
duced pressure and chromatography on silica gel (PE/EtOAc) af-
forded the amino ether (R)-2.
(R)-2b, the reaction was more sluggish and the oxazepane
(R)-8b was isolated in only 44% yield. Deprotection[14] of
(R)-8a gave the free oxazepane (R)-9a in 79% yield.
(R)-N-(2-Allyloxy-2-phenyl-3,3,3-trifluoropropyl)benzylamine [(R)-
2a]: According to the general procedure, aldehyde (R)-1a (1.63 g,
6.67 mmol) in THF/acetic acid (15 mL:5 mL) was treated with benz-
ylamine (1.46 mL, 13.34 mmol, 2.0 equiv.) and sodium acetoxy-
borohydride (3.11 g, 14.67 mmol, 2.2 equiv.) for 3 h. Chromatog-
raphy (PE/AcOEt, 90:10) yielded the amino ether (R)-2a (1.59 g,
71%) as a colourless oil. [α]2D0 = +4.6 (c = 0.96, CHCl3). 19F NMR
(235.3 MHz, CDCl3): δ = –73.1 (s, 3 F, CF3) ppm. 1H NMR
(250 MHz, CDCl3): δ = 1.54 (br. s, 1 H), 3.17 (dd, J = 13.0, 1.5 Hz,
1 H), 3.34 (d, J = 13.0 Hz, 1 H), 3.77 (d, J = 14.0 Hz, 1 H), 3.83
(d, J = 14.0 Hz, 1 H), 4.05 (dd, J = 13.0, 5.0 Hz, 1 H), 4.13 (dd, J
= 13.0, 5.0 Hz, 1 H), 5.21 (tdd, J = 1.5, 10.5, 3.0 Hz, 1 H), 5.38
(tdd, J = 1.5, 17.0, 3.5 Hz, 1 H), 5.98 (tdd, J = 17.0, 10.5, 5.0 Hz,
1 H), 7.24–7.31 (m, 5 H), 7.36–7.39 (m, 3 H), 7.49 (m, 2 H) ppm.
Scheme 6. Preparation of the 2-phenyl-2-(trifluoromethyl)oxaz-
epanes(R)-8a,9a and the 2-ethyl-2-(trifluoromethyl)oxazepane (R)-
8b.
Conclusions
2
13C NMR (62.9 MHz, CDCl3): δ = 51.3, 54.0, 65.7, 81.9 (q, JC,F
We have described two complementary approaches to the
preparation of enantiopure six- and seven-membered N,O-
heterocycles containing a quaternary trifluoromethyl group
from a common enantiopure O-allyl amino ether precursor.
A classic 6-exo iodoamination provided the key iodomor-
pholines, synthetic intermediates for further elaborations,
whereas a hydrozirconation/iodination sequence allowed
the synthesis of oxazepanes by a 7-endo cyclisation. The
latter reaction is an extension of the scope of this recently
developed strategy[16] to organofluorine chemistry as well
as to the synthesis of seven-membered heterocycles.
1
= 26.0 Hz, C-CF3), 116.5, 125.4 (q, JC,F = 289.0 Hz, CF3), 127.2,
127.4, 128.2, 128.49, 128.51, 128.8, 134.3, 135.1, 140.0 ppm.
HMRS (ESI): calcd. for C19H21F3NO [M + H]+ 336.1575; found
336.1564.
(R)-N-[2-Allyloxy-2-(trifluoromethyl)butyl]benzylamine
[(R)-2b]:
According to the general procedure, aldehyde (R)-1b (1.01 g,
25.0 mmol) in THF/acetic acid (15 mL:5 mL) was treated with ben-
zylamine (1.12 mL, 10.25 mmol, 2.0 equiv.) and sodium aceto-
xyborohydride (2.39 g, 11.26 mmol, 2.2 equiv.) for 2 h. Chromatog-
raphy (PE/AcOEt, 95:5) yielded the amino ether (R)-2b (836 mg,
57%) as a colourless oil. [α]2D0 = –4.8 (c = 1.24, CHCl3). 19F NMR
(235.3 MHz, CDCl3): δ = –73.8 (s, 3 F, CF3) ppm. 1H NMR
(250 MHz, CDCl3): δ = 0.94 (td, J = 7.5, 1.0 Hz, 3 H), 1.50 (br. s,
1 H), 1.92 (q, J = 7.5 Hz, 2 H), 2.85 (d, J = 1.0 Hz, 2 H), 3.81 (s,
2 H), 4.03 (dd, J = 13.0, 5.5 Hz, 1 H), 4.10 (dd, J = 13.0, 5.5 Hz,
1 H), 5.15 (tdd, J = 1.5, 10.5, 3.0 Hz, 1 H), 5.29 (tdd, J = 1.5, 17.0,
3.5 Hz, 1 H), 5.89 (tdd, J = 17.0, 10.5, 5.5 Hz, 1 H), 7.32–7.34 (m,
5 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 7.4, 22.6, 49.3, 54.3,
Experimental Section
General: THF was distilled from sodium benzophenone. CH2Cl2
and MeCN were distilled from CaH2. Thin-layer chromatography
using precoated aluminium-backed plates (Merck Kieselgel
60F254) were visualised by UV light and by aqueous solutions of
potassium permanganate. Gas chromatography (GC) analyses were
performed with a polymethyldisiloxane DB-1 capillary column
(30 mϫ0.25 mm IDϫ0.25 µm). Silica gel (Macherey–Nagel, 40–
63 µm, ASTM for column chromatography) was used for flash
chromatography. Melting points were determined with a Tottoli ap-
paratus and are uncorrected. Optical rotations were measured at
room temperature (ca. 20 °C). NMR spectra were recorded in
2
1
64.8, 79.9 (q, JC,F = 24.5 Hz, C-CF3), 116.4, 126.6 (q, JC,F
=
290.5 Hz, CF3), 127.1, 128.1, 128.4, 134.6, 140.3 ppm. HMRS
(ESI): calcd. for C15H21F3NO [M + H]+ 288.1575; found 288.1569.
General Procedure for the Preparation of the (Iodomethyl)morph-
olines 3a,b:
A suspension of amino ether (R)-2a,b, iodine
(3.0 equiv.) and potassium carbonate (3.0 equiv.) in MeCN was
stirred at room temp., under Ar and in the dark. After the complete
disappearance of the amino ether (monitored by GC), the reaction
mixture was diluted with Et2O and hydrolysed with sat. aq. sodium
thiosulfate. The organic layer was washed twice with brine and
dried (MgSO4). Evaporation of the solvent under reduced pressure
and chromatography on silica gel (PE/EtOAc) afforded the cis-
iodomorpholine (2R,5R)-3a,b followed by the trans-iodomorpho-
line (2R,5S)-3a,b.
1
CDCl3 at frequencies of 250 MHz for H, 235.3 MHz for 19F and
62.9 or 125.8 MHz for 13C NMR spectroscopy. Chemicals shifts (δ)
1
are reported in ppm relative to TMS for H and 13C NMR spectra
and relative to CFCl3 for 19F NMR spectra. In the 13C NMR data,
reported signal multiplicities relate to C–F coupling. The following
abbreviations have been used to indicate the multiplicities: s (sing-
let), d (doublet), t (triplet), q (quartet), m (multiplet), br. s (broad
singlet). Signals were completely assigned on the basis of 2D NMR
experiments. Diastereomeric ratios (dr) were determined by 19F
NMR spectroscopy. HRMS (ESI+) were recorded by using an elec-
trospray source in positive mode.
(2R,5R)-4-Benzyl-5-(iodomethyl)-2-phenyl-2-(trifluoromethyl)morph-
oline [(2R,5R)-3a] and (2R,5S)-4-Benzyl-5-(iodomethyl)-2-phenyl-2-
(trifluoromethyl)morpholine [(2R,5S)-3a]: According to the general
procedure, amino ether (R)-2a (174 mg, 0.52 mmol) in MeCN
(3 mL) was treated with iodine (396 mg, 1.56 mmol, 3.0 equiv.) in
the presence of K2CO3 (216 mg, 1.56 mmol, 3.0 equiv.) for 3 h.
Chromatography (PE/EtOAc, 95:5) of the crude mixture (mixture
of two diastereomers, cis/trans = 63:37) yielded the cis-iodomor-
pholine (2R,5R)-3a (132 mg, 55%) as a colourless oil and then the
trans-iodomorpholine (2R,5S)-3a (79 mg, 33%) as a colourless so-
lid.
General Procedure for the Preparation of the Amino Ethers (R)-2a,b:
A solution of aldehyde (R)-1[9] and benzylamine (2.0 equiv.) in a
mixture of THF and acetic acid (3:1) was stirred at room temp.
and under Ar. After 20 min of stirring, sodium acetoxyborohydride
(2.2 equiv.) was added to the reaction mixture. After completion of
the reaction (monitored by GC), the solution was hydrolysed with
sat. aq. sodium carbonate and extracted three times with diethyl
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Eur. J. Org. Chem. 2009, 3726–3731

Synthesis of Enantiopure Substituted Morpholines and Oxazepanes
2
3
4
cis Isomer (2R,5R)-3a: [α]2D0 = +9.6 (c = 0.97, CHCl3). 19F NMR
(235.3 MHz, CDCl3): δ = –79.92 (s, 3 F, CF3) ppm. 1H NMR
CH3), 1.79 (qdd, JH,H = 15.0, JH,H = 7.5, JH,F = 1.0 Hz, 1 H,
2
CHaHbCH3), 2.16 (m, 2 H, NCH, CHaHbCH3), 2.42 (d, JH,H
12.0 Hz, 1 H, NCHaHb), 2.58 (d, JH,H = 12.0 Hz, 1 H, NCHaHb),
=
3
2
(250 MHz, CDCl3): δ = 3.06 (br. d, JH,H = 11.0 Hz, 1 H, NCH),
2
2
2
3.21 (d, 2JH,H = 12.5 Hz, 1 H, NCHaHb), 3.28 (d, JH,H = 12.5 Hz,
3.09 (d, JH,H = 13.0 Hz, 1 H, CHaHbPh), 3.24 (dd, JH,H = 11.0,
1 H, NCHaHb), 3.61 (d, JH,H = 9.5 Hz, 1 H, CHaHbI), 3.76 (d, 3JH,H = 2.0 Hz, 1 H, CHaHbI), 3.41 (d, JH,H = 11.0, JH,H
=
=
2
2
3
2
2
2JH,H = 13.0 Hz, 1 H, CHaHbPh), 3.86 (d, JH,H = 13.0 Hz, 1 H,
6.5 Hz, 1 H, CHaHbI), 3.84 (m, 2 H, OCH2), 4.07 (d, JH,H
2
2
CHaHbPh), 3.88 (d, JH,H = 9.5 Hz, 1 H, CHaHbI), 3.95 (d, JH,H
13.0 Hz, 1 H, CHaHbPh), 7.28–7.40 (m, 5 H, H aromatic) ppm.
= 11.5 Hz, 1 H, OCHaHb), 4.28 (d, JH,H = 11.5 Hz, 1 H, OCHa- 13C NMR (125.9 MHz, CDCl3): δ = 5.7 (CH2I), 7.1 (CH3), 22.7
2
Hb), 7.32–7.39 (m, 4 H, H aromatic), 7.44–7.49 (m, 6 H, H aro- (CH2CH3), 49.9 (NCH2), 57.6 (CH), 57.7 (CH2Ph), 65.8 (OCH2),
1
matic) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 1.0 (CH2I), 44.2
76.8 (q, 2JC,F = 27.0 Hz, C-CF3), 125.5 (q, JC,F = 286.0 Hz, CF3),
127.6, 128.5, 128.9 (5 CH aromatic), 137.2 (C aromatic) ppm.
HMRS (ESI): calcd. for C15H20F3INO [M + H]+ 414.0542; found
414.0555.
2
(NCH2), 59.4 (CH2Ph), 60.0 (NCH), 63.4 (OCH2), 78.1 (q, JC,F
=
1
28.0 Hz, C-CF3), 124.1 (q, JC,F = 284.5 Hz, CF3), 127.9, 128.3,
128.4, 128.9, 129.3 (10 CH aromatic), 133.0, 137.1 (2 C aro-
matic) ppm. HMRS (ESI): calcd. for C19H20F3INO [M + H]+
462.0542; found 462.0538.
General Procedure for the Preparation of the N-Benzyl-5-methyl-
morpholines (2R,5S)-4a,b: A suspension of cis-iodomorpholine
(2R,5R)-3a,b, triethylamine (2.0 equiv.) and Pd/C (10 %,
trans Isomer (2R,5S)-3a: M.p. 126 °C. [α]2D0 = +18.1 (c = 1.03,
CHCl3). 19F NMR (235.3 MHz, CDCl3): δ = –79.85 (s, 3 F, 0.05 equiv.) in methanol was hydrogenated (gas bag of H2) at room
CF3) ppm. 1H NMR (250 MHz, CDCl3): δ = 2.30 (m, 1 H, NCH),
temp. After 15 h of stirring, the suspension was filtered through
Celite and the filtrate was concentrated under reduced pressure.
Chromatography on silica gel (PE/EtOAc) afforded the cis-methyl-
morpholine (2R,5S)-4a,b.
2
2.72 (d, 2JH,H = 12.0 Hz, 1 H, NCHaHb), 3.02 (d, JH,H = 13.0 Hz,
2
1 H, CHaHbPh), 3.12 (d, JH,H = 11.5 Hz, 1 H, CHaHbI), 3.19 (d,
2
2JH,H = 11.5 Hz, 1 H, CHaHbI), 3.38 (d, JH,H = 12.0 Hz, 1 H,
NCHaHb), 3.63 (dd, 2JH,H = 11.0, 3JH,H = 10.5 Hz, 1 H, OCHaHb),
(2R,5S)-4-Benzyl-5-methyl-2-phenyl-2-(trifluoromethyl)morpholine
[(2R,5S)-4a]: According to the general procedure, cis-iodomorpho-
line (2R,5R)-3a (610 mg, 1.32 mmol) was hydrogenated in MeOH
(10 mL) in the presence of Pd/C (10 %, 70 mg, 0.066 mmol,
0.05 equiv.) and Et3N (368 µL, 0.73 mmol, 2.0 equiv.). Chromatog-
raphy (PE/EtOAc, 88:12) yielded the cis-methylmorpholine
(2R,5S)-4a (426 mg, 96%) as a colourless oil. [α]2D0 = +88.9 (c =
0.97, CHCl3). 19F NMR (235.3 MHz, CDCl3): δ = –79.0 (s, 3 F,
2
3
3.92 (dd, JH,H = 11.0, JH,H = 3.5 Hz, 1 H, OCHaHb), 4.12 (d,
2JH,H = 13.0 Hz, 1 H, CHaHbPh), 7.20 (m, 2 H, H aromatic), 7.37
(br. s, 8 H, H aromatic) ppm. 13C NMR (62.9 MHz, CDCl3): δ =
4.6 (CH2I), 50.4 (NCH2), 57.8 (CH2Ph), 58.5 (NCH), 67.0 (OCH2),
1
78.8 (q, 2JC,F = 28.0 Hz, C-CF3), 124.0 (q, JC,F = 284.5 Hz, CF3),
128.0, 128.2, 128.5, 128.6, 128.9, 129.6 (10 CH aromatic), 133.1,
137.0 (2 C aromatic) ppm. HMRS (ESI): calcd. for C19H20F3INO
[M + H]+ 462.0542; found 462.0531. A small amount of this isomer
was recrystallised from Et2O/EP for X-ray analysis.
1
CF3) ppm. H NMR (250 MHz, CDCl3): δ = 1.21 (d, J = 6.5 Hz,
3 H), 2.75 (m, 1 H), 2.99 (d, J = 12.0 Hz, 1 H), 3.15 (d, J = 12.0 Hz,
(2R,5R)-4-Benzyl-2-ethyl-5-(iodomethyl)-2-(trifluoromethyl)morph- 1 H), 3.54 (d, J = 14.5 Hz, 1 H), 3.61 (d, J = 14.5 Hz, 1 H), 3.62
oline [(2R,5R)-3b] and (2R,5S)-4-Benzyl-2-ethyl-5-(iodomethyl)-2-
(trifluoromethyl)morpholine [(2R,5S)-3b]: According to the general
procedure, amino ether (R)-2b (169 mg, 0.59 mmol) in MeCN
(3 mL) was treated with iodine (448 mg, 1.77 mmol, 3.0 equiv.) in
the presence of K2CO3 (245 mg, 1.77 mmol, 3.0 equiv.) for 3 h.
Chromatography (PE/Et2O, 95:5) of the crude mixture (mixture of
two diastereomers cis/trans = 53:47) yielded the cis-iodomorpholine
(2R,5R)-3b (91 mg, 37 %) and then the trans-iodomorpholine
(2R,5S)-3b (96 mg, 39%) both as pale-yellow oils.
(dd, J = 2.5, 11.0 Hz, 1 H), 3.85 (dd, J = 3.0, 11.0 Hz, 1 H), 7.25–
7.32 (m, 5 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 9.1, 45.8,
2
53.0, 59.6, 68.1, 78.3 (q, JC,F = 28.5 Hz, C-CF3), 124.8 (q, 1JC,F
=
284.5 Hz, CF3), 127.1, 127.8, 128.5, 128.7, 128.8, 129.0, 129.6,
134.6, 138.4 ppm. HMRS (ESI): calcd. for C19H21F3NO [M +
H]+ 336.1575; found 336.1583.
(2R,5S)-4-Benzyl-2-ethyl-5-methyl-2-(trifluoromethyl)morpholine
[(2R,5S)-4b]: According to the general procedure, cis-iodomorpho-
line (2R,5R)-3b (339 mg, 0.82 mmol) was hydrogenated in MeOH
(8 mL) in the presence of Pd/C (10 %, 44 mg, 0.066 mmol,
0.05 equiv.) and Et3N (229 µL, 1.64 mmol, 2.0 equiv.). Chromatog-
raphy (PE/EtOAc, 90:10) yielded the cis-methylmorpholine
(2R,5S)-4b (182 mg, 77%) as a colourless oil. [α]2D0 = +72.8 (c =
1.00, CHCl3). 19F NMR (235.3 MHz, CDCl3): δ = –76.4 (s, 3 F,
CF3) ppm. 1H NMR (250 MHz, CDCl3): δ = 0.90 (td, J = 1.0,
7.5 Hz, 3 H), 1.09 (d, J = 6.5 Hz, 3 H), 1.72 (sext, J = 7.5 Hz, 1
H), 1.95 (sext, J = 7.5 Hz, 1 H), 2.14 (dd, J = 1.0, 12.0 Hz, 1 H),
2.62 (m, 1 H), 2.81 (d, J = 11.5 Hz, 1 H), 3.31 (d, J = 13.5 Hz, 1
H), 3.64 (ddd, J = 1.0, 5.5, 12.0 Hz, 1 H), 3.82 (d, J = 11.5 Hz, 1
H), 3.82 (d, J = 13.5 Hz, 1 H), 7.26 (m, 2 H), 7.32 (m, 3 H) ppm.
cis Isomer (2R,5R)-3b: [α]2D0 = +4.0 (c = 0.99, CHCl3). 19F NMR
(235.3 MHz, CDCl3): δ = –78.36 (s, 3 F, CF3) ppm. 1H NMR
3
5
(250 MHz, CDCl3): δ = 0.92 (td, JH,H = 7.5, JH,F = 1.0 Hz, 3 H,
2
3
CH3), 1.75 (qd, JH,H = 15.0, JH,H = 7.5 Hz, 1 H, CHaHbCH3),
2.17 (qdd, JH,H = 15.0, JH,H = 7.5, JH,F = 1.0 Hz, 1 H,
2
3
4
2
CHaHbCH3), 2.24 (d, JH,H = 12.0 Hz, 1 H, NCHaHb), 2.82 (d,
2JH,H = 12.0 Hz, 1 H, NCHaHb), 2.85 (dt, JH,H = 10.0, JH,H
=
3
3
2
3
3.0 Hz, 1 H, NCH), 3.41 (dt, JH,H = 10.0, JH,H = 2.0 Hz, 1 H,
CHaHbI), 3.56 (t, JH,H = 10.0 Hz, 1 H, CHaHbI), 3.65 (d, JH,H
13.5 Hz, 1 H, CHaHbPh), 3.73 (d, JH, H = 13.5 Hz, 1 H,
2
2
=
2
2
3
CHaHbPh), 3.89 (m, 1 H, OCHaHb), 4.09 (dd, JH,H = 11.5, JH,H
= 2.5 Hz, 1 H, OCHaHb), 7.30–7.35 (m, 5 H, H aromatic) ppm.
4
13C NMR (62.9 MHz, CDCl3): δ = 7.6 (d, JC,F = 1.5 Hz, CH2-
13C NMR (125.9 MHz, CDCl3): δ = 1.1 (CH2I), 7.2 (CH3), 22.3 CH3), 11.2, 24.7, 49.7, 53.5, 58.9, 68.7, 76.0 (q, 2JC,F = 26.0 Hz, C-
1
(CH2CH3), 46.8 (NCH2), 58.97 (CH2Ph), 58.99 (NCH), 63.7 CF3), 126.6 (q, JC,F = 288.5 Hz, CF3), 127.5, 128.8, 128.9,
2
1
(OCH2), 75.8 (q, JC,F = 27.0 Hz, C-CF3), 125.6 (q, JC,F
=
138.9 ppm. HMRS (ESI): calcd. for C15H21F3NO [M + H]+
288.1575; found 288.1581.
286.0 Hz, CF3), 127.7, 128.6, 128.7 (5 CH aromatic), 137.5 (C aro-
matic) ppm. HMRS (ESI): calcd. for C15H20F3INO [M + H]+
414.0542; found 414.0540.
Preparation of (2R,5S)-5-Methyl-2-phenyl-2-(trifluoromethyl)-
morpholine [(2R,5S)-5a]: A suspension of N-benzylmethylmorph-
oline (2R,5S)-4a (197 mg, 0.59 mmol), ammonium formate
(189 mg, 2.99 mmol, 5.1 equiv.) and Pd/C (10 %, 156 mg,
0.15 mmol, 0.25 equiv.) in methanol (5 mL) was heated at reflux
trans Isomer (2R,5S)-3b: [α]2D0 = –45.8 (c = 0.99, CHCl3). 19F NMR
(235.3 MHz, CDCl3): δ = –78.40 (s, 3 F, CF3) ppm. 1H NMR
3
5
(250 MHz, CDCl3): δ = 0.86 (td, JH,H = 7.5, JH,F = 1.5 Hz, 3 H,
Eur. J. Org. Chem. 2009, 3726–3731
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3729

J. Nonnenmacher, F. Grellepois, C. Portella
FULL PAPER
for 2 h30 min. The reaction mixture was then cooled to room temp.
and filtered through Celite. Evaporation of the filtrate under re-
duced pressure and chromatography on silica gel (PE/EtOAc/Et3N,
50:50:0.1) yielded the unprotected methylmorpholine (2R,5S)-5a
(105 mg, 73%) as a colourless oil. [α]2D0 = +2.0 (c = 0.93, CHCl3).
19F NMR (235.3 MHz, CDCl3): δ = –74.9 (s, 3 F, CF3) ppm. 1H
NMR (250 MHz, CDCl3): δ = 1.17 (d, J = 6.5 Hz, 3 H), 1.43 (br.
s, 1 H), 2.90 (m, 1 H), 3.24 (dd, J = 1.5, 14.5 Hz, 1 H), 3.64 (ddd,
J = 1.5, 7.0, 11.5 Hz, 1 H), 3.81 (m, 2 H), 7.35–7.39 (m, 3 H), 7.40–
7.43 (m, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 17.6, 46.2,
droxymethyl)morpholine (2R,5R)-6a,b, ammonium formate (5.1–
5.2 equiv.) and Pd/C (10 %, 0.25–0.27 equiv.) in methanol was
heated at reflux. After the complete disappearance of the protected
morpholine (monitored by GC), the reaction mixture was cooled
to room temp. and filtered through Celite. The filtrate was washed
twice with brine and dried (MgSO4). Evaporation of the solvent
under reduced pressure and subsequent chromatography on silica
gel (PE/EtOAc/Et3N) if necessary afforded the deprotected (hy-
droxymethyl)morpholine (2R,5R)-7a,b.
(2R,5R)-5-(Hydroxymethyl)-2-phenyl-2-(trifluoromethyl)morpholine
[(2R,5R)-7a]: According to the general procedure, the protected
morpholine (2R,5R)-6a (124 mg, 0.35 mmol) was treated with am-
monium formate (114 mg, 1.81 mmol, 5.1 equiv.) and Pd/C (10%,
94 mg, 0.089 mmol, 0.25 equiv.) in methanol (5 mL) for 2 h30 min.
Chromatography (PE/EtOAc/Et3N, 20:80:0.5) yielded the free
trans-hydroxymorpholine (2R,5R)-7a (64 mg, 69%) as a white so-
lid; m.p. 81–82 °C. [α]2D0 = +49.2 (c = 1.05, CHCl3). 19F NMR
(235.3 MHz, CDCl3): δ = –80.1 (s, 3 F, CF3) ppm. 1H NMR
(250 MHz, CDCl3): δ = 1.88 (br. s, 2 H), 2.99 (m, 1 H), 3.18 (dd,
J = 6.0, 11.0 Hz, 1 H), 3.24–3.41 (m, 3 H), 3.69 (br. d, J = 13.5 Hz,
2 H), 7.34–7.45 (m, 5 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ =
46.0, 55.8, 62.7, 64.0, 124.5 (q, 1JC,F = 284.0 Hz, CF3), 129.0, 129.4,
129.5, 132.9 ppm; C–CF3 not observed. HMRS (ESI): calcd. for
C12H15F3NO2 [M + H]+ 262.1055; found 262.1054.
2
1
48.0, 68.4, 74.0 (q, JC,F = 26.5 Hz, C-CF3), 125.8 (q, JC,F
=
288.5 Hz, CF3), 127.4, 128.8, 129.1, 136.4 ppm. HMRS (ESI):
calcd. for C12H15 F3NO [M + H]+ 246.1106; found 246.1100.
General Procedure for the Preparation of the N-Benzyl-5-(hy-
droxymethyl)morpholines (2R,5R)-6a,b: A solution of trans-iodo-
morpholine (2R,5S)-3a,b and ammonium formate (5.0 equiv.) in
methanol was heated at reflux. After the complete disappearance
of the iodomorpholine (monitored by GC), the reaction mixture
was cooled to room temp. and hydrolysed with sat. aq. sodium
carbonate and extracted three times with diethyl ether. The com-
bined organic layers were washed three times with brine and dried
(MgSO4). Evaporation of the solvent under reduced pressure and
chromatography on silica gel (PE/EtOAc/Et3N) afforded the trans
(hydroxymethyl)morpholine (2R,5R)-6a,b.
(2R,5R)-4-Benzyl-5-(hydroxymethyl)-2-phenyl-2-(trifluoromethyl)-
morpholine [(2R,5R)-6a]: According to the general procedure, trans-
iodomorpholine (2R,5S)-3a (266 mg, 0.58 mmol) was treated with
ammonium formate (181 mg, 2.88 mmol, 5.0 equiv.) in methanol
(8 mL) for 8 h. Chromatography (PE/EtOAc/Et3N, 80:20:0.5)
yielded the trans-hydroxymorpholine (2R,5R)-6a (147 mg, 73%) as
an off-white solid; m.p. 90–92 °C. [α]2D0 = +77.9 (c = 1.04, CHCl3).
19F NMR (235.3 MHz, CDCl3): δ = –80.2 (s, 3 F, CF3) ppm. 1H
NMR (250 MHz, CDCl3): δ = 1.91 (br. s, 1 H), 2.59 (m, 1 H), 2.61
(d, J = 12.0 Hz, 1 H), 3.04 (d, J = 13.0 Hz, 1 H), 3.28 (dd, J =
12.0, 2.0 Hz, 1 H), 3.37 (d, J = 12.0 Hz, 1 H), 3.65 (d, J = 11.5 Hz,
1 H), 3.76 (dd, J = 12.0, 9.5 Hz, 1 H), 3.76 (d, J = 11.5 Hz, 1 H),
(2R,5R)-2-Ethyl-5-(hydroxymethyl)-2-(trifluoromethyl)morpholine
[(2R,5R)-7b]: According to the general procedure, the protected
morpholine (2R,5R)-6b (207 mg, 0.66 mmol) was treated with am-
monium formate (225 mg, 3.46 mmol, 5.2 equiv.) and Pd/C (10%,
187 mg, 0.18 mmol, 0.27 equiv.) in methanol (5 mL) for 3 h. After
work-up and evaporation of the solvent, the free trans-hydroxy-
morpholine (2R,5R)-7b (130 mg, 91%) was obtained as a colourless
oil. [α]2D0 = +17.6 (c = 1.08, CHCl3). 19F NMR (235.3 MHz,
CDCl3): δ = –78.5 (s, 3 F, CF3) ppm. 1H NMR (250 MHz, CDCl3):
δ = 0.98 (td, J = 7.5, 1.5 Hz, 3 H), 1.81 (sext, J = 7.5 Hz, 1 H),
2.13 (m, 3 H), 2.88 (d, J = 13.0 Hz, 1 H), 2.94 (m, 1 H), 3.05 (d, J
= 13.0 Hz, 1 H), 3.48 (dd, J = 8.5, 2.5 Hz, 1 H), 3.52 (dd, J = 8.5,
1.5 Hz, 1 H), 3.60 (dd, J = 11.5, 4.5 Hz, 1 H), 3.74 (dd, J = 11.5,
4.14 (d, J = 13.0 Hz, 1 H), 7.14 (m, 2 H), 7.21 (m, 2 H), 7.25–7.32
3
(m, 6 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 50.4 (q, JC,F
=
4
4.0 Hz, 1 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 7.1 (d, JC,F
2
1.5 Hz, NCH2), 58.2, 59.4, 60.8, 63.7, 78.5 (q, JC,F = 28.0 Hz, C-
CF3), 124.0 (q, JC,F = 284.0 Hz, CF3), 128.0, 128.4, 128.6, 128.7,
3
= 1.0 Hz, CH3), 21.1, 45.5 (d, JC,F = 1.0 Hz, NCH2), 54.5, 62.0,
1
2
1
62.9, 74.5 (q, JC,F = 26.5 Hz, C-CF3), 124.7 (q, JC,F = 285.5 Hz,
CF3) ppm. HMRS (ESI): calcd. for C8H14F3NO2 [M + H]+
214.1055; found 214.1064.
129.0, 129.3, 132.8, 137.0 ppm. HMRS (ESI): calcd. for
C19H21F3NO2 [M + H]+ 352.1524; found 352.1516.
(2R,5R)-4-Benzyl-2-ethyl-5-(hydroxymethyl)-2-(trifluoromethyl)-
morpholine [(2R,5R)-6b]: According to the general procedure, trans-
iodomorpholine (2R,5S)-3b (640 mg, 1.55 mmol) was treated with
ammonium formate (502 mg, 7.72 mmol, 5.0 equiv.) in methanol
(5 mL) for 4 h. Chromatography (PE/EtOAc/Et3N, 80:20:0.5)
yielded the trans-hydroxymorpholine (2R,5R)-6b (315 mg, 65%) as
General Procedure for the Preparation of the Oxazepanes (R)-8a,b:
A solution of amino ether (R)-2a,b and the Schwartz reagent (80%
purity, ca. 1.8 equiv.) in dichloromethane was stirred at room temp.
under Ar and in the dark for 1 h before the addition of iodine
(1.1 equiv.) and triethylamine (1.3 equiv.). The reaction was moni-
tored by GC and the reaction mixture was then hydrolysed with
1  HCl and the aqueous layer was extracted three times with
dichloromethane. The combined organic layers were washed with
sat. aq. sodium carbonate and dried (MgSO4). Evaporation of the
solvent under reduced pressure and chromatography on silica gel
(PE/EtOAc/Et3N) afforded the oxazepane (R)-8a,b.
a
yellow oil. [α]2D0 –33.9 (c = 1.00, CHCl3). 19F NMR
=
(235.3 MHz, CDCl3): δ = –79.0 (s, 3 F, CF3) ppm. 1H NMR
(250 MHz, CDCl3): δ = 0.88 (td, J = 7.5, 1.5 Hz, 3 H), 1.79 (sextd,
J = 7.5, 1.0 Hz, 1 H), 2.12 (br. s, 1 H), 2.20 (sextd, J = 7.5, 1.0 Hz,
1 H), 2.56 (m, 1 H), 2.43 (d, J = 12.0 Hz, 1 H), 2.65 (d, J = 12.0 Hz,
1 H), 3.21 (d, J = 13.5 Hz, 1 H), 3.53 (dd, J = 11.5, 2.0 Hz, 1 H),
3.87 (d, J = 7.0 Hz, 2 H), 3.93 (dd, J = 11.5, 4.5 Hz, 1 H), 4.17 (d,
J = 13.5 Hz, 1 H), 7.28–7.38 (m, 5 H) ppm. 13C NMR (62.9 MHz,
(R)-4-Benzyl-2-phenyl-2-(trifluoromethyl)-1,4-oxazepane [(R)-8a]:
According to the general procedure, amino ether (R)-2a (788 mg,
2.28 mmol) was treated with the Schwartz reagent (1.34 g, ca.
4.2 mmol, ca. 1.8 equiv.), iodine (643 mg, 2.53 mmol, 1.1 equiv.)
and triethylamine (0.40 mL, 2.9 mmol, 1.3 equiv.) for 3 h (1 h +
2 h). Chromatography (PE/EtOAc/Et3N, 98:2:0.5) yielded the ox-
azepane (R)-8a (504 mg, 66%) as a white solid; m.p. 118–119 °C.
[α]2D0 = +3.4 (c = 0.98, CHCl3). 19F NMR (235.3 MHz, CDCl3): δ
4
3
CDCl3): δ = 7.1 (d, JC,F = 2.0 Hz, CH3), 22.0, 50.9 (q, JC,F
2.0 Hz, NCH2), 58.4, 60.1, 60.6 (CH), 63.1, 76.5 (q, JC,F
26.5 Hz, C-CF3), 125.5 (q, JC,F = 286.0 Hz, CF3), 127.6, 128.6,
128.7, 137.7 ppm. HMRS (ESI): calcd. for C15H21F3NO2 [M +
H]+ 304.1524; found 304.1522.
=
=
2
1
General Procedure for the Preparation of the (Hydroxymethyl)-
morpholines (2R,5R)-7a,b: A suspension of N-benzyl(hy-
1
= –77.4 (s, 3 F, CF3) ppm. H NMR (250 MHz, CDCl3): δ = 1.81
3730
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3726–3731

Synthesis of Enantiopure Substituted Morpholines and Oxazepanes
(m, 2 H), 2.53 (t, J = 6.0 Hz, 2 H), 3.31 (d, J = 15.0 Hz, 1 H), 3.47 We thank Dr. Jean Luc Vasse for a gift of Schwartz reagent and
(d, J = 15.0 Hz, 1 H), 3.59 (d, J = 13.0 Hz, 1 H), 3.69 (d, J =
13.0 Hz, 1 H), 3.93 (ddd, J = 13.0, 7.0, 2.5 Hz, 1 H), 4.12 (ddd, J
= 13.0, 7.0, 2.5 Hz, 1 H), 7.07 (m, 2 H), 7.21–7.25 (m, 3 H), 7.32–
7.34 (m, 3 H), 7.44 (m, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3):
fruitful discussions. We also express our thanks to Aurélien Lebrun
for the NMR analyses, Emmanuel Wenger (Université de Nancy)
for the X-ray structure and Dominique Harakat for the HRMS
analyses.
2
δ = 31.8, 56.3, 59.0, 64.4, 66.0, 82.1 (q, JC,F = 25.5 Hz, C-CF3),
1
125.5 (q, JC,F = 287.5 Hz, CF3), 127.2, 128.2, 128.3, 129.1, 137.6,
[1] a) J. P. Bégué, D. Bonnet-Delpon, Bioorganic and Medicinal
Chemistry of Fluorine, Wiley-VCH, Weinheim, 2008; b) S.
Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc.
Rev. 2008, 37, 320–330; c) K. L. Kirk, Org. Process Res. Dev.
2008, 12, 305–321; d) W. K. Hagmann, J. Med. Chem. 2008,
51, 4359–4369.
[2] D. Letnicer, Organic Chemistry of Drug Synthesis, vol. 7, Wiley,
New York, 2008.
[3] S. Kamashima, T. Matsuno S. Yaguchi, T. Watanabe, M. Inaba,
PCT Int. Appl., WO 9905138, 1999 .
138.9 ppm. HMRS (ESI): calcd. for C19H21F3NO [M + H]+
336.1575; found 336.1580.
(R)-4-Benzyl-2-ethyl-2-(trifluoromethyl)-1,4-oxazepane [(R)-8b]: Ac-
cording to the general procedure, amino ether (R)-2b (169 mg,
0.59 mmol) was treated with the Schwartz reagent (341 mg, ca.
1.0 mmol, ca. 1.8 equiv.), iodine (164 mg, 0.65 mmol, 1.1 equiv.)
and triethylamine (0.11 mL, 0.76 mmol, 1.3 equiv.) for 7 h (1 h +
6 h). Chromatography (PE/EtOAc/Et3N, 96:4:0.5) yielded the ox-
azepane (R)-8b (75 mg, 44%) as a colourless oil. [α]2D0 = –16.8 (c =
1.02, CHCl3). 19F NMR (235.3 MHz, CDCl3): δ = –77.0 (s, 3 F,
CF3) ppm. 1H NMR (250 MHz, CDCl3): δ = 0.74 (tq, J = 7.5,
1.5 Hz, 3 H), 1.76 (m, 1 H), 1.80 (qd, J = 7.5, 1.0 Hz, 2 H), 1.86
(m, 1 H), 2.28 (td, J = 11.0, 4.0 Hz, 1 H), 2.81–2.92 (m, 3 H), 3.60
(d, J = 13.0 Hz, 1 H), 3.73 (d, J = 13.0 Hz, 1 H), 3.86 (m, 1 H),
3.98 (d, J = 12.5 Hz, 1 H), 7.28–7.35 (m, 5 H) ppm. 13C NMR
[4] M. R. Barbachyn, P. J. Dobrowolski, A. R. Hurd, D. J. McNa-
mara, J. R. Palmer, A. G. Romero, J. C. Ruble, D. A. Sherry,
L. M. Thomasco, P. L. Toogood, PCT Int. Appl., WO
2004031195, 2004.
[5] C. Luethy, A. Edmunds, R. Beaudegnies, S. Wendeborn, J.
Schaetzer, W. Lutz, PCT Int. Appl. WO 2005058830, 2005.
[6] K. Fukunaga, T. Kohara, K. Watanabe, Y. Usui, F. Uehara, S.
Yokoshima, D. Sakai, S. Kusaka, K. Nakayama, PCT Int.
Appl., WO 2007119463, 2007.
[7] a) L. ElKaïm, E. Pinot-Périgord, Tetrahedron 1998, 54, 3799–
3806; b) M. W. Walter, N. Thaker, J. E. Baldwin, M. Muller,
C. J. Schofield, J. Chem. Res. (S) 2000, 7, 310–311; c) M. H.
Serrano-Wu, D. R. StLaurent, T. M. Carroll, M. Dodier, Q.
Gao, P. Gill, C. Quesnelle, A. Marinier, C. E. Mazzucco, A.
Regueiro-Ren, T. M. Stickle, D. Wu, H. Yang, Z. Zandg, M.
Zheng, M. E. Zoeckler, D. M. Vyas, B. N. Balasubramanian,
Bioorg. Med. Chem. Lett. 2003, 13, 1419–1423; d) S. Fustero,
L. Albert, J. L. Acena, J. F. Sanz-Cervera, A. Asensio, Org.
Lett. 2008, 10, 605–608.
[8] a) P. H. Liang, L. W. Hsin, C. Y. Cheng, Bioorg. Med. Chem.
2002, 10, 3267–3276; b) M. Eberle, H. Ziegler, F. Cederbaum,
P. Ackermann, PCT Int. Appl., WO 2002053560, 2002; c) G.
Chaume, M. C. VanSeveren, S. Marinkovic, T. Brigaud, Org.
Lett. 2006, 8, 6123–6126; d) C. Caupène, G. Chaume, L.
Ricard, T. Brigaud, Org. Lett. 2009, 11, 209–212.
[9] J. Nonnenmacher, F. Massicot, F. Grellepois, C. Portella, J.
Org. Chem. 2008, 73, 7990–7995.
4
(62.9 MHz, CDCl3): δ = 7.9 (d, JC,F = 2.0 Hz, CH3), 27.2, 32.5,
2
55.7, 57.4, 64.8, 65.6, 80.4 (q, JC,F = 24.0 Hz, C-CF3), 127.0 (q,
1JC,F = 289.5 Hz, CF3), 127.4, 128.4, 129.3, 139.1 ppm. HMRS
(ESI): calcd. for C15H20F3NO [M + H]+ 288.1575; found 288.1581.
Preparation of the Free Oxazepane (R)-2-Phenyl-2-(trifluoro-
methyl)-1,4-oxazepane [(R)-9a]:
A suspension of N-benzylox-
azepane (R)-8a (390 mg, 1.16 mmol), ammonium formate (304 mg,
4.68 mmol, 4.0 equiv.) and Pd/C (10%, 381 mg, 0.36 mmol,
0.31 equiv.) in methanol (5 mL) was heated at reflux for 4 h. The
reaction mixture was then cooled to room temp. and filtered
through Celite. The filtrate was washed twice with brine and dried
(MgSO4). Evaporation of the solvent under reduced pressure and
chromatography on silica gel (PE/EtOAc/Et3N, 60:40:0.5) yielded
the free oxazepane (R)-9a (225 mg, 79%) as a yellow liquid. [α]2D0
= +10.6 (c = 1.07, CHCl3). 19F NMR (235.3 MHz, CDCl3): δ =
–78.7 (s, 3 F, CF3) ppm. 1H NMR (250 MHz, CDCl3): δ = 1.63 (br.
s, 1 H), 1.75 (m, 1 H), 1.94 (m, 1 H), 2.69 (m, 1 H), 3.08 (m, 1 H),
3.37 (dd, J = 15.5, 1.5 Hz, 1 H), 3.75 (ddd, J = 13.0, 9.5, 1.5 Hz,
1 H), 3.90 (d, J = 15.5 Hz, 1 H), 4.12 (ddd, J = 13.0, 5.5, 2.0 Hz,
1 H), 7.36–7.45 (m, 3 H), 7.51 (m, 2 H) ppm. 13C NMR (62.9 MHz,
CDCl3): δ = 34.7, 50.3, 53.4, 66.2, 82.7 (q, 2JC,F = 25.0 Hz, C-CF3),
[10] For a review on the reductive amination of aldehydes and
ketones using NaBH(OAc)3, see: A. F. Abdel-Magid, S. J.
Mehrman, Org. Process Res. Dev. 2006, 10, 971–1031.
[11] For reviews on iodocyclisation, see for example: a) G. Cardillo,
M. Orena, Tetrahedron 1990, 46, 3321–3408; b) H. Togo, S.
Ida, Synlett 2006, 2159–2175.
[12] CCDC-726924 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1
125.3 (q, JC,F = 286.5 Hz, CF3), 127.2, 128.4, 128.6, 137.1 ppm.
HMRS (ESI): calcd. for C12H14F3NO [M + H]+ 246.1106; found
246.1102.
[13] The inversion of the configuration of C5 reflects only the
change in priority of substituents at this stereocentre.
[14] S. Ram, L. D. Spicer, Tetrahedron Lett. 1987, 28, 515–516.
[15] For a review, see: J. Wipf, H. Jahn, Tetrahedron 1996, 52,
12853–12910.
[16] M. Ahari, A. Joosten, J. L. Vasse, J. Szymoniak, Synthesis
2008, 1, 61–68.
Acknowledgments
We thank the Centre National de la Recherche Scientifique
(CNRS) and the Région Champagne-Ardenne for a fellowship to
J. N. This project has been supported (programme GLYCOVAL)
by the “Contrat de Plan Etat-Région” (Ministère de la Recherche,
Région Champagne-Ardenne, Ville de Reims) and the Sanofi-
Aventis pharmaceutical company (Drs. E. Nicolai and C. Philippo).
Received: April 8, 2009
Published Online: June 24, 2009
Eur. J. Org. Chem. 2009, 3726–3731
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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