Trifluoromethylation of camphorquinone and its monoimine derivatives

Article abstract of DOI:10.1016/j.tetasy.2008.07.003

Treatment of (1R)-camphorquinone 2 with (trifluoromethyl)trimethylsilane in the presence of catalytic amounts of caesium fluoride in DME at room temperature yields two pairs of exo/endo isomers of trifluoromethylated silylated alcohols 5 and 6. In this case, nucleophilic addition of the CF₃ anion occurs neither regio- nor stereoselectively. On the other hand, the analogous reaction with (1R)-camphorquinone 3-imines 3, followed by hydrolysis with 5 M HCl in ethanol, leads stereoselectively to (1R,2S)-2-hydroxy-2-(trifluoromethyl)bornan-3-one 8. The attempted reductions of the intermediate adducts with NaBH₄ in ethanol gave the corresponding (1R,2S)-3-imino-2-(trifluoromethyl)bornan-2-ols 9 as the sole isomers in high yield. The configuration of C(2), that is, the endo course of the nucleophilic CF₃ addition, was proven by X-ray crystallography. Furthermore, the reduction of the C{double bond, long}N bond in 9 with DIBAL-H leads stereoselectively to the exo amino derivatives 10, which, by treatment with phosgene, smoothly form the fused 1,3-oxazolidin-2-ones 11. In contrast, the reduction of ketone 8 yields a mixture of the exo,exo- and exo,endo-2,3-diols 12.

Full text of DOI:10.1016/j.tetasy.2008.07.003

Tetrahedron: Asymmetry 19 (2008) 1676–1683
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Trifluoromethylation of camphorquinone and its monoimine derivatives
a,
b
b,
Emilia Obijalska a, , Grzegorz Mloston , Anthony Linden , Heinz Heimgartner
*
*
´
a
´
´
Department of Organic and Applied Chemistry, University of Łódz, Narutowicza 68, PL-90-136 Łódz, Poland
b Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 May 2008
Accepted 2 July 2008
Treatment of (1R)-camphorquinone 2 with (trifluoromethyl)trimethylsilane in the presence of catalytic
amounts of caesium fluoride in DME at room temperature yields two pairs of exo/endo isomers of triflu-
oromethylated silylated alcohols 5 and 6. In this case, nucleophilic addition of the CF3 anion occurs
neither regio- nor stereoselectively. On the other hand, the analogous reaction with (1R)-camphorqui-
none 3-imines 3, followed by hydrolysis with 5 M HCl in ethanol, leads stereoselectively to (1R,2S)-
2-hydroxy-2-(trifluoromethyl)bornan-3-one 8. The attempted reductions of the intermediate adducts
with NaBH4 in ethanol gave the corresponding (1R,2S)-3-imino-2-(trifluoromethyl)bornan-2-ols 9 as
the sole isomers in high yield. The configuration of C(2), that is, the endo course of the nucleophilic
CF3 addition, was proven by X-ray crystallography. Furthermore, the reduction of the C@N bond in 9 with
DIBAL-H leads stereoselectively to the exo amino derivatives 10, which, by treatment with phosgene,
smoothly form the fused 1,3-oxazolidin-2-ones 11. In contrast, the reduction of ketone 8 yields a mixture
of the exo,exo- and exo,endo-2,3-diols 12.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
catalyst,6 new variants with DMSO7a or DMF as the solvent and
carbonates,7b as well as acetates,7c as catalyst, were reported. The
Camphor derivatives are important chiral auxiliaries and li-
gands for stereocontrolled reactions and organocatalysis.1 Special
attention has been focused on the enantiomerically pure 2,3-diols
and 3-amino-2-ols derived from camphor.2,3 A very important
modification of the structure of organic molecules is the introduc-
tion of fluorine atoms or perfluoroalkyl residues, which in most
cases results in significant changes in their physical and chemical
properties.4a–d In spite of this obvious fact and rapidly growing
interest in the chemistry of fluorinated compounds, relatively little
is known about applications of fluorine-containing chiral auxilia-
ries and chiral ligands in asymmetric synthesis.4e,f To the best of
our knowledge, recent reports are limited to the synthesis and suc-
cessful exploration of chiral 2-trifluoromethyloxazolidines as chi-
ral auxiliaries.4g,h Of special interest is the introduction of the CF3
group, which can be conveniently introduced via nucleophilic
enantioselective trifluoromethylation of aldehydes and ketones
has been investigated, with the enantioselectivity resulting from
the use of a catalyst containing either a chiral cation8a–d or anion.8d
Another paper has reported the diastereoselective nucleophilic tri-
fluoromethylation of some aromatic aldehydes, which contain a
sulfinyl auxiliary at the ortho-position.9
Trifluoromethylations of imines are also known, although, in
comparison with carbonyl compounds, the number of reports con-
cerning this reaction is much smaller. In a recent paper, activated
N-tosyl aldimines have been shown to undergo reaction with the
Ruppert-Prakash reagent under fluoride catalysis.10 The C@N bond
in N-sulfinylimines is also sufficiently activated to undergo nucle-
ophilic trifluoromethylation under typical conditions. In this case,
the application of enantiomerically pure substrates led to the for-
mation of trifluoromethylated products in a diastereoselective
manner.11 Subsequent desulfinylation under mild conditions pro-
addition
using
(trifluoromethyl)trimethylsilane
(Me3SiCF3,
Ruppert-Prakash reagent).5 The trifluoromethylation of aldehydes
and ketones with the Ruppert-Prakash reagent has been
extensively studied, and along with classical procedures based on
the application of an ether as the solvent and fluoride ion as a
vides convenient access to enantiomerically pure a-(trifluoro-
methyl)amines. The activation of the C@N bond by the strong
electron withdrawing CF3 substituents allows the addition of the
CF3 anion to ketimines derived from hexafluoroacetone.12
To the best of our knowledge, camphor derivatives, which bear
trifluoromethyl groups, have scarcely been described,13 and the
fluoride catalyzed nucleophilic trifluoromethylation of camphor
led to the adduct in less than 1% yield.6,14 On the other hand, there
is a report on the highly efficient reaction with norbornan-2-one,
leading stereoselectively to the exo-trifluoromethyl norbornanole.6
* Corresponding authors. Tel.: +48 42 635 5761; fax: +48 42 665 5162 (G.M.), tel.:
+41 44 635 4282; fax: +41 44 635 6812 (H.H.).
E-mail addresses: gmloston@uni.lodz.pl (G. Mloston´ ), heimgart@oci.uzh.ch
(H. Heimgartner).
Part of the planned PhD thesis, University of Lodz.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.07.003

E. Obijalska et al. / Tetrahedron: Asymmetry 19 (2008) 1676–1683
1677
Herein, we report the introduction of the trifluoromethyl group
into the camphor skeleton by using camphorquinone and its
monoimines as substrates.
quinone 2 reacted with CF3SiMe3, and, after typical workup, the
crude mixture was examined by 19F NMR spectroscopy. Four sig-
nals at ꢀ68.7, ꢀ69.5, ꢀ71.6 and ꢀ72.2 ppm in a ratio of 39:35:
4:22 showed the formation of two pairs of endo/exo-isomers of
the adducts 5 and 6 (Scheme 2).
2. Results and discussion
The complex mixture was not separated, and therefore the con-
figurations and the chemical shifts could not be correlated. Never-
theless, the result shows that there is no significant selectivity in
the nucleophilic addition of CF3 to camphorquinone.
The preparation of camphorquinone 2 was carried out by oxida-
tion of (1R)-camphor 1 with SeO2 in Ac2O.16 Subsequent reaction of
2 with primary amines led to the 3-monoimines 3 (Scheme 1).17,18
Two imines 3a and 3g were stereoselectively converted to the 3-
endo-amino camphor derivatives 4a and 4g, respectively, by reduc-
tion with Zn/KOH.17a
The first trifluoromethylations were attempted with 4a and 4g
in 1,2-dimethoxyethane (DME) using CsF as the initiator. In both
cases, after 24 h at room temperature, the starting amino ketones
were recovered almost quantitatively, and no new product could
be detected in the reaction mixture. Under the same conditions,
In contrast to 2, imino ketone 3a reacted with CF3SiMe3 to give
only one product, which showed
a
19F NMR absorption at
ꢀ68.5 ppm. According to the IR spectrum, the C@N group is pre-
served, but the product does not contain a C@O group. The 1H
NMR signal at 0.07 ppm confirmed the presence of an Me3Si group.
These data suggest the formation of a 1:1-adduct of type 7 (Scheme
3), and in analogy with the known reaction of MeLi with 3d, which
yields the product of the endo-attack (i.e., the exo-hydroxy
R
RNH2
N
SeO2
Ac2O, reflux
O
O
O
O
1
2
3a R = Me
b
c
R = Et
R =
R =
R =
i
t
Pr
Bu
Hex
Ph
H
d
e
Zn, KOHaq
Et2O
3a, 3g
c
NHR
O
f
R =
4a R = Me
Me
g
R = Ph
g
h
R = Ph
R = 4-MeOC6H4
Scheme 1.
OSiMe3
CF3
DME, CsF
r.t.
O
2
+ CF3SiMe3
+
OSiMe3
O
CF3
5
6
Scheme 2.
R
R
DME, CsF
NaBH4
EtOH, reflux
N
N
3a-h
+ CF3SiMe3
OSiMe3
OH
CF3
9a-h
(yields: 65-88%)
r.t.
CF3
7a-h
EtOH,
reflux
5M HCl
(for 7a,b,g)
O
OH
CF3
8
(yields: 75-85%)
Scheme 3.

1678
E. Obijalska et al. / Tetrahedron: Asymmetry 19 (2008) 1676–1683
compound),17c the same orientation of substituents can be pro-
posed for 7.
The imino alcohols 9 are promising starting materials for the
preparation of trifluoromethylated amino alcohols.22 Widely ap-
plied methods for the conversion of imines into the corresponding
amines are treatment with NaBH4 or LiAlH4.24 In the case of the
silylated imino alcohols 7, the attempted reaction with NaBH4 in
ethanol failed. Furthermore, the imino alcohols 9 were resistant to-
wards the reaction with LiAlH4. Another powerful reducing agent is
diisobutyl aluminium hydride (DIBAL-H).24 In the case of 9a and
9g, heating with DIBAL-H in refluxing THF solution for 30 min
yielded the desired amino alcohols 10a and 10g (Scheme 4).
In each case, the 19F NMR spectra of the crude mixture revealed
the presence of only one signal of the CF3 group. Pure products 10
were obtained as single stereoisomers by column chromatography
on alumina. Based on the fact that nucleophiles attack the camphor
derivatives from the endo side, we attribute the 2-exo-OH, 3-exo-
NHR configuration to products 10a and 10g. This preliminary
assumption was confirmed by the cyclization of isolated amino
alcohol 10a to the 1,3-oxazolidin-2-one derivative 11a by treat-
ment with phosgene in toluene solution. The absorption band of
The attempted desilylation of 7a by heating with aqueous 5 M
HCl in ethanol led to the removal of the Me3Si group and to the
hydrolysis of the imino group to yield the corresponding 2-hydro-
xyketone 8. The same product was obtained from 7b and 7g. The
structure of the crystalline product 8 was unambiguously con-
firmed by X-ray crystallography (Fig. 1a), which proved the pro-
posed endo-addition of the CF3 group.
The hydroxy group of molecule 8 forms an intermolecular
hydrogen bond with the carbonyl O-atom of a neighbouring mole-
cule. The interaction links the molecules into extended chains,
which run parallel to the [100] direction and can be described
by a graph set motif20 of C(5).
The selective desilylation of 7a–h was smoothly performed by
treatment with NaBH4 in methanolic or ethanolic solution.21a Un-
der these conditions, the imino group was preserved, and the prod-
ucts obtained are imino alcohols of type 9 (Scheme 3). In the case
of 9a, the structure of the racemate was determined by X-ray crys-
tallography (Fig. 1b).21b
the C@O group appeared in the IR spectrum at 1765 cmꢀ1
.
The hydroxy group of the molecule rac-9a forms an intermolec-
ular hydrogen bond with the N-atom of a neighbouring molecule,
which in turn forms an identical hydrogen bond with the original
molecule. These interactions link pairs of the molecules into cen-
trosymmetric dimers and generate a graph set motif20 of R22ð10Þ.
The same product 9a was obtained when adduct 7a was hydro-
lyzed by treatment with 5 M HCl in ethanol for 20 days at room
temperature. It is worth mentioning that the attempted reduction
of adducts of type 7 with LiAIH4 in diethyl ether failed, and neither
desilylation nor reduction of the C@N group was observed.
The hydroxy ketone 8 was reduced with NaBH4 as well as with
DIBAL-H. In both cases, mixtures of stereoisomeric 2,3-diols 12
were obtained (Scheme 5). The selectivity of these reactions was
determined by using 19F NMR spectroscopy. The major isomer
exhibited a signal for the CF3 group at ꢀ73.7 ppm and a minor
one at ꢀ69.2 ppm. The comparison of the intensities of these sig-
nals showed that the selectivity of the reactions with NaBH4 in
methanol at 0 °C was ca. 9:1 (de 79%). The selectivity slightly in-
creased to 10:1 (de 91%) with DIBAL-H in dichloromethane at ꢀ5
to 0 °C, but decreased to 4:1 (de 63%) at ꢀ30 °C.
Figure 1. ORTEP plots19 of the molecular structures of (a) 8 and (b) rac-9a (arbitrary numbering of the atoms, 50% probability ellipsoids).
O
R
Me
NHR
OH
N
Cl
Cl
N
DIBAL-H
THF, reflux
OH
O
O
toluene, Et N, r.t.
3
(for R = Me)
H
CF
H
CF
3
CF
3
3
9a,g
10a,g
Scheme 4.
11a

E. Obijalska et al. / Tetrahedron: Asymmetry 19 (2008) 1676–1683
1679
standard. Assignments of signals in 13C NMR spectra were made on
the basis of DEPT 135 experiments. The IR spectra were measured
using an NEXUS FT-IR spectrophotometer. The MS spectra
(CI, EI) were obtained using a LKB-2091, Finnigan MAT-95 or
Finnigan MAT-90 spectrometer. Optical rotations were measured
on Perkin–Elmer 241 MC spectropolarimeter for k = 589 nm.
Elemental analyses were performed in the Microanalytical Labora-
tory of Centre of Molecular and Macromolecular Studies PAS in
O
OH
OH
OH
[H]
H
OH
OH
+
H
CF3
CF3
CF3
8
2-exo,3-endo-12
2-exo,3-exo-12
major
minor
´
Łódz.
O
4.2. Materials
Et3N, CH2Cl2,
r.t.
N
N
Commercial (1R)-camphor 1, 1,10-carbonyldiimidazol, sodium
borohydride and a solution of diisobutylaluminium hydride (DI-
BAL-H) in dichloromethane (1 M) were purchased from Sigma–
Aldrich. A commercial solution of phosgene in toluene (20%) was
purchased from Fluka. (1R)-Camphorquinone 2,16 iminoketones
3a and 3b,17a 3c,e,f,3b 3d17b 3g,h17c and aminoketones 4a and
4b17a were prepared according to known protocols. Dimethoxyeth-
ane (DME) and tetrahydrofuran (THF) were dried over sodium with
benzophenone and dichloromethane over sodium hydride, and
they were freshly distilled prior to use.
N
N
O
O
H
O
CF3
13
Scheme 5.
4.3. Reactions of iminoketones 3 with
(trifluoromethyl)trimethylsilane—a general procedure
Chromatographic separation of the mixture afforded the major
product in pure form in 83% yield. Based on the same argumenta-
tion as in the case of the imino alcohols 10, we attribute the 2-exo-
OH, 3-exo-OH configuration to this product (2-exo,3-exo-12). The
postulated structure was proved by the reaction with carbonyl
diimidazole in dichloromethane in the presence of triethylamine
at room temperature. Under these conditions, carbonate 13 was
obtained in 91% yield. This result confirms the proposed structure
of the major isomer 2-exo,3-exo-12.
In a dry two-necked flask equipped with a septum and a tube
filled with anhydrous calcium chloride, 1 mmol of the correspond-
ing iminoketone 3a–h dissolved in 1.5 ml of anhydrous DME was
placed. Then, a catalytic amount of freshly dried caesium fluoride
and 157 mg (0.17 ml, 1.1 mmol) Ruppert-Prakash reagent were
added. The mixture was stirred at room temperature and, after
ca. 1 h (TLC control), the reaction was quenched by the addition
of water (1 ml). The solution was extracted three times with
dichloromethane. The organic layers were combined and dried
over anhydrous MgSO4. After filtration, the solvents were evapo-
rated and the crude oily products 7a–h were used for further reac-
tions without purification.
3. Conclusions
The presented results show that, in contrast to camphor, both
camphorquinone 2 and its monoimines 3 undergo nucleophilic tri-
fluoromethylation to give the corresponding silylated alcohols.
Whereas the reaction with 2 leads to a mixture of regio- and ste-
reoisomeric adducts, the analogous reaction with 3 occurs chemo-
and diastereoselectively from the endo side to exclusively give the
silylated imino alcohols 7. Hydrolysis of the latter opens up access
to the hydroxy ketone 8, which cannot be prepared directly from 2,
as a sole product.
The desilylation of adducts 7 with NaBH4 in alcoholic solution
leads to imino alcohols 9, which subsequently could be reduced
stereoselectively to the amino alcohols 10. The hydroxy ketone 8,
upon treatment with NaBH4 reacts to give the 2-exo,3-exo-diol 12
as the major product, which was isolated in pure form. Taking into
account that b-amino alcohols and diols derived from camphor are
important building blocks for the synthesis of chiral auxiliaries2a,3b
and in organocatalysis,1,25 the trifluoromethylated derivatives 10
and 2-exo,3-exo-12 can find further applications in organic
synthesis.
4.3.1. Hydrolysis of adducts 7—a general procedure
To a solution of crude 7a, 7b or 7g in 2 ml of ethanol, 1 ml of a
5 M solution of hydrochloric acid was added and the mixture was
refluxed for 15 h. Then, the mixture was basified with aqueous so-
dium hydroxide (20%). The mixture was diluted with water and ex-
tracted with dichloromethane. The organic layers were combined
and dried over anhydrous MgSO4. After filtration, the solvents were
evaporated. The crude product was purified by column chromatog-
raphy on silica gel using hexane with an increasing amount of
dichloromethane (0–50%) as an eluent. Product 8 was isolated as
a yellowish solid. Yields: 180–200 mg (75–85%). Analytically pure
product 8 was obtained by crystallization.
4.3.1.1. (1R,2S)-2-Hydroxy-2-(trifluoromethyl)bornan-3-one 8.
Colourless crystals, mp 140–142 °C (Et2O/hexane). 1H NMR
(200 MHz): d 1.01, 1.07, 1.10 (3s, 3H each, 3CH3), 1.57–2.03 (m,
3
4H, 2CH2), 2.34 (d, JH,H = 4.8 Hz, 1H, CH),26 3.22 (br s, 1H, OH)
ppm. 13C NMR (50 MHz): d 9.5, 18.2, 22.0 (3CH3), 20.8; 28.6
2
(2CH2), 46.2, 59.4 (2Cq), 59.1 (CH), 79.2 (q, JC,F = 27.1 Hz, Cq),
1
4. Experimental
4.1. General
124.3 (q, JC,F = 287.3 Hz, CF3), 211.2 (C@O) ppm. 19F NMR
(188 MHz): d ꢀ70.5 (s, CF3) ppm. IR (KBr):
m 3402s (br, OH),
3017w, 2998w, 2948w, 2884w, 1754vs (C@O), 1636w, 1463w,
1403w, 1376w, 1365w, 1265m, 1173s, 1159vs, 1120s, 986w,
968w, 825w, 741w, 607w cmꢀ1. MS (CI, isobutane): m/z 237
(100, [M+1]+), 69 (9, [CF3]+). Anal. Calcd for C11H15F3O2 (236.24):
Melting points were determined on a Melt-Temp. II apparatus
(Aldrich) in capillary, and are uncorrected. The 1H, 13C{1H} and
19F NMR spectra were recorded using a Bruker AC-200 or Bruker
Avance II Plus 700 spectrometer in CDCl3 with TMS as an internal
C, 55.93; H, 6.40. Found: C, 55.96; H, 6.41. [
CHCl3).
a]
D = ꢀ119.2 (c 1.0,

1680
E. Obijalska et al. / Tetrahedron: Asymmetry 19 (2008) 1676–1683
4.3.2. Desilylation of adducts 7 with sodium borohydride—a
general procedure
NH3): m/z 279 (14), 278 (100, [M+1]+). Anal. Calcd for C14H22F3NO
(277.33): C, 60.63; H, 8.00. Found: C, 60.53; H, 7.96. [
1.0, CHCl3).
a]D = +5.4 (c
To a solution of the corresponding adduct 7 in 2 ml of methanol
(or ethanol), 190 mg (5 mmol) of sodium borohydride was added
in small portions while cooling the reaction flask in an ice-bath.
When the evolution of hydrogen ceased, the mixture was heated
at reflux for 18 h. Then, the mixture was cooled to room tempera-
ture and the solvent evaporated. The semisolid residue was dis-
solved in water and extracted with dichloromethane. The organic
layers were combined and dried over anhydrous MgSO4. After fil-
tration, the solvents were evaporated and the crude products were
purified by column chromatography on silica gel using hexane
with an increasing amount of dichloromethane (0–90%) as an elu-
ent. In some cases, analytically pure samples were obtained after
crystallization.
4.3.2.4. (1R,2S)-3-(tert-Butyl)imino-2-(trifluoromethyl)bornan-
2-ol 9d. Yield: 230 mg (79%). Colourless crystals, mp 46–49 °C
(hexane, dry ice). 1H NMR (200 MHz): d 0.97, 1.03, 1.10 (3s, 3H
each, 3CH3), 1.26 (s, 9H, (CH3)3C), 1.43–1.90 (m, 4H, 2CH2), 2.79
3
(d, JH,H = 5.0 Hz, 1H, CH), 3.21 (br s, 1H, OH) ppm. 13C NMR
(50 MHz):
d 9.8, 18.5, 22.2 (3CH3), 21.9, 28.7 (2CH2), 30.0
((CH3)3C), 47.6, 50.1, 55.0 (2Cq, (CH3)3C), 52.8 (CH), 80.3 (q,
1
2JC,F = 25.6 Hz, Cq), 125.4 (q, JC,F = 288.2 Hz, CF3), 172.9 (C@N)
ppm. 19F NMR (188 MHz): d ꢀ70.5 (s, CF3) ppm. IR (KBr):
m 3388s
(br, OH), 3017w, 2971s, 2883w, 1685m (C@N), 1656w, 1474w,
1460w, 1398w, 1391w, 1364w, 1283m, 1266s, 1214m, 1199m,
1161vs, 1154vs, 1101s, 998w, 968s, 923w, 850w, 828w, 747w,
688w cmꢀ1. MS (EI): m/z 291 (20, M+Å), 235 (26, [(M+1ꢀC4H9)]+),
166 (20), 109 (16), 69 (47, [CF3]+), 57 (100, [C4H9]+), 41 (18). Anal.
Calcd for C15H24F3NO (291.36): C, 61.84; H, 8.30; N, 4.81. Found: C,
4.3.2.1. (1R,2S)-3-Methylimino-2-(trifluoromethyl)bornan-2-ol
9a. Yield: 200 mg (80%). Colourless crystals, mp 166–168 °C (Et2O/
hexane). 1H NMR (200 MHz): d 0.95, 0.99, 1.07 (3s, 3H each, 3CH3),
1.32–1.92 (m, 4H, 2CH2), 2.74 (d, 3JH,H = 4.8 Hz, 1H, CH), 3.20 (s, 3H,
CH3N), 3.67 (br s, 1H, OH) ppm. 13C NMR (50 MHz): d 9.9, 18.7
(2CH3), 21.8 (CH2, CH3), 29.0 (CH2), 40.1 (CH3N), 48.9 (CH), 47.5,
61.83; H, 8.36; N, 4.87. [a]D = +13.0 (c 1.3, CHCl3).
4.3.2.5. (1R,2S)-3-(Cyclohexyl)imino-2-(trifluoromethyl)bornan-
2-ol 9e. Yield: 210 mg (65%). Colourless crystals, mp 98–102 °C
(pentane, dry ice). 1H NMR (700 MHz): d 0.95, 1.00, 1.08 (3s, 3H
each, 3CH3), 1.25–1.33, 1.42–1.46, 1.56–1.68, 1.77–1.87 (4m,
2
1
51.6 (2Cq), 79.9 (q, JC,F = 26.3 Hz, Cq), 125.4 (q, JC,F = 287.8 Hz,
CF3), 178.4 (C@N) ppm. 19F NMR (188 MHz): d ꢀ70.7 (s, CF3)
ppm. IR (KBr):
m 3405s (br, OH), 2995s, 2983m, 2970s, 1698s
3
14H, 7CH2), 2.70 (d, JH,H = 4.9 Hz, 1H, CH), 3.23–3.27 (m, 2H, CH,
(C@N), 1636w, 1496w, 1458w, 1394m, 1339m, 1287s, 1272s,
1159vs, 1121s, 1030m, 966s, 830m, 741m cmꢀ1. MS (EI): m/z
249 (21, M+Å), 109 (12), 96 (13), 69 (100, [CF3]+), 59 (10), 42 (32).
Anal. Calcd for C12H18F3NO (236.24): C, 57.82; H, 7.28, N, 5.62.
OH) ppm. 13C NMR (50 MHz): d 9.7, 18.4, 21.9 (3CH3), 22.3, 24.3,
25.3, 28.8, 32.9, 33.4 (7CH2), 47.3, 51.1, (2Cq), 49.3, 60.8 (2CH),
2
1
79.7 (q, JC,F = 26.1 Hz, Cq), 125.3 (q, JC,F = 288.0 Hz, CF3), 174.6
(C@N) ppm. 19F NMR (188 MHz): d ꢀ70.6 (s, CF3) ppm. IR (KBr):
Found: C, 57.78; H, 7.14; N, 5.60. [
a
]
D = ꢀ3.7 (c 0.9, CHCl3).
m
3300s (br, O–H), 3002m, 2987m, 2934vs, 2858m, 1751w,
Analogously, rac-9a was prepared from rac-3a (mp 60–62 °C,
hexane) in 78% yield. Colourless crystals; mp 153–155 °C (Et2O/
hexane).
1686m, 1680m, 1655w, 1496w, 1477m, 1406w, 1397w, 1352m,
1284m, 1272s, 1227w, 1163vs, 1147vs, 1116s, 1075w, 1060w,
1010w, 995w, 967m, 943w, 891w, 829w, 642w, 675w cmꢀ1. MS
(CI, NH3): m/z 319 (20), 318 (100, [M+1]+). Anal. Calcd for
4.3.2.2. (1R,2S)-3-Ethylimino-2-(trifluoromethyl)bornan-2-ol 9b.
Yield: 220 mg (83%). Colourless crystals; mp 58–60 °C (hexane). 1H
NMR (200 MHz): d 0.98, 1.02, 1.14 (3s, 3H each, 3CH3), 1.18 (t, 3H,
C17H36F3NO (317.40): C, 63.33; H, 8.26; N, 4.41. Found: C, 64.23;
H, 8.23, N, 4.37. [
a]
D = ꢀ5.5 (c 0.9, CHCl3).
3JH,H = 7.3 Hz, CH3CH2), 1.37–1.96 (m, 4H, 2CH2), 2.74 (d,
4.3.2.6. (1R,2S)-3-[(10R)-10-(Phenylethyl)imino]-2-(trifluoromet-
hyl)bornan-2-ol 9f. Yield: 300 mg (88%). Isolated after chroma-
tography as a pale yellow oil. 1H NMR (200 MHz): d 0.83, 0.96,
3
3JH,H = 4.8 Hz, 1H, CH), 3.20 (br s, 1H, OH), 3.46 (q, 2H, JH,H
=
7.3 Hz, CH3CH2) ppm. 13C NMR (50 MHz): d 9.7, 15.1, 18.5, 21.9
(4CH3), 22.0, 28.8 (2CH2), 47.1, 51.2 (2Cq), 47.3 (CH2N), 48.9 (CH),
2
1.11 (3s, 3H each, 3CH3), 1.48 (d, 3H, JH,H = 6.6 Hz, CH3CH), 1.53–
2
1
79.7 (q, JC,F = 26.4 Hz, Cq), 125.3 (q, JC,F = 288.2 Hz, CF3), 176.4
3
2.02 (m, 4H, 2CH2), 2.83 (d, JH,H = 4.9 Hz, 1H, CH), 3.22 (br s, 1H,
(C@N) ppm. 19F NMR (188 MHz): d ꢀ70.6 (s, CF3) ppm. IR (KBr):
OH), 4.64 (q, 1H, 32JH,H = 6.6 Hz, CHN), 7.23–7.46 (m, 5H, C6H5)
ppm. 13C NMR (50 MHz): d 9.8, 18.5, 21.7 (3CH3), 22.2, 28.9
(2CH2), 24.3 (CH3CH), 49.5 (CHN), 47.7, 51.1 (2Cq), 80.0 (q,
m
3416vs (br, OH), 2984s, 2971s, 2938m, 2833m, 1689m (C@N),
1496w, 1459w, 1395w, 1395w, 1356w, 1286m, 1270s, 1227w,
1161vs, 1145s, 1119s, 1094m, 1042w, 1011w, 970m, 848w,
741w cmꢀ1. MS (EI): m/z 263 (28, M+Å), 248 (13), 110 (17), 82
(10), 69 (92, [CF3]+), 56 (100), 41 (16). Anal. Calcd for C13H20F3NO
(263.31): C, 59.30; H, 7.66; N, 5.32. Found: C, 59.24; H, 7.69; N,
1
2JC,F = 26.2 Hz, Cq), 125.2 (q, JC,F = 287.9 Hz, CF3), 61.1 (CH3CH),
126.4, 126.8, 128.3 (5CH arom.), 144.8 (Cq, arom.), 175.2 (C@N)
ppm. 19F NMR (188 MHz): d ꢀ70.6 (s, CF3) ppm. IR (film):
m
3543m (br, OH), 3087w, 3063w, 2970vs, 2927vs, 2882s, 1948w,
1875w, 1806w, 1692vs, (C@N), 1604w, 1494s, 1452s, 1395s,
1373s, 353m, 1281vs, 1269vs, 1226m, 1197s, 1166vs, 1146vs,
1104vs, 1031w, 1011s, 995s, 968vs, 918w, 831m, 761s, 742s,
700vs cmꢀ1. MS (CI, NH3): m/z 341 (21), 340 (100, [M+1]+). Anal.
Calcd for C19H24F3NO (339.40): C, 67.24; H, 7.13. Found: C, 67.25;
5.23. [a]D = +11.4 (c 1.1, CHCl3).
4.3.2.3. (1R,2S)-3-(Isopropyl)imino-2-(trifluoromethyl)bornan-
2-ol 9c. Yield: 230 mg (82%). Isolated after chromatography as a
pale yellow oil. 1H NMR (700 MHz): d 0.95, 1.00, 1.08 (3s, 3H each,
3CH3), 1.11, 1.13 (2d, 3JH,H = 6.3 Hz, 3H each, (CH3)2CH), 1.41–1.43,
H, 7.07. [a]D = +72.6 (c 1.0, CHCl3).
3
1.64–1.71, 1.78–1.88 (3m, 4H, 2CH2), 2.70 (d, JH,H = 4.9 Hz, 1H,
CH), 3.21 (br s, 1H, OH), 3.59–3.63 (m, 1H, (CH3)2CH) ppm. 13C
4.3.2.7. (1R,2S)-3-Phenylimino-2-(trifluoromethyl)bornan-2-ol
9g. Yield: 230 mg (74%). Colourless crystals, mp 86–88 °C (hex-
ane). 1H NMR (200 MHz): d 0.91, 1.07, 1.14 (3s, 3H each, 3CH3),
4
NMR (175 MHz): d 10.1 (q, JC,F = 1.4 Hz, CH3), 18.9, 22.3, 23.3,
4
23.8 (4CH3), 22.5 (CH2), 29.2 (q, JC,F = 2.6 Hz, CH2), 47.08 (q,
3JC,F = 1.4 Hz, Cq), 49.6, 53.1 (2CH), 51.5 (Cq), 80.1 (q, 2JC,F = 26.4 Hz,
3
1.53–1.96 (m, 4H, 2CH2), 2.52 (d, JH,H = 4.7 Hz, 1H, CH), 3.41 (br
1
Cq), 125.7 (q, JC,F = 286.9 Hz, CF3), 174.3 (C@N) ppm. 19F NMR
s, 1H, OH), 6.78–7.37 (m, 5H, C6H5) ppm. 13C NMR (50 MHz): d
(188 MHz): d ꢀ70.6 (s, CF3) ppm. IR (film):
m 3393s (br, OH),
9.8, 18.3, 21.9 (3CH3), 22.6, 28.8 (2CH2), 51.2 (CH); 47.8, 51.6
2
1
2970vs, 2940vs, 2881s, 1692vs (C@N), 1605w, 1497m, 1459s,
1395s, 1380s, 1364s, 1345m, 1282vs, 1271vs, 1228m, 1166vs,
1145vs, 1102vs, 1011s, 996s, 967s, 836s, 742s cmꢀ1. MS (CI,
(2Cq), 79.9 (q, JC,F = 26.6 Hz, Cq), 125.2 (q, JC,F = 287.9 Hz, CF3),
119.8, 124.3, 128.8 (5CH arom.), 149.4 (Cq arom.), 178.7 (C@N)
ppm. 19F NMR (188 MHz): d ꢀ70.6 (s, CF3) ppm. IR (KBr):
m 3400s

E. Obijalska et al. / Tetrahedron: Asymmetry 19 (2008) 1676–1683
1681
(br, OH), 3082w, 3061w, 3022w, 2998m, 2988m, 2970s, 2947m,
2884m, 1688s (C@N), 1669s, 1597m, 1490m, 1449w, 1396m,
1385m, 1281s, 1268s, 1172vs, 1268vs, 1150vs, 1104vs, 1011m,
995s, 968s, 908m, 834m, 771m, 741s, 692s cmꢀ1. MS (EI): m/z
311 (27, M+Å), 158 (14), 104 (100), 77 (28, [C6H5]+), 69 (42,
[CF3]+), 41 (11). Anal. Calcd for C17H20F3NO2 (311.35): C, 65.58;
4.4.2. (1R,2S,3R)-3-Phenylamino-2-(trifluoromethyl)bornan-2-
ol 10g
Yield: 230 mg (73%). Isolated after chromatography as a yellow-
ish oil. 1H NMR (700 MHz): d 0.89, 1.08, 1.27 (3s, 3H each, 3CH3),
1.28–1.30, 1.46–1.51, 1.74–1.77, 1.83–1.87 (4m, 5H, CH and
2CH2), 1.56 (br s, 1H, NH), 3.62 (br s, 1H, OH), 3.71 (s, 1H,
C6H5CH), 6.72–6.73, 6.84–6.86, 7.21–7.23 (3m, 5H, C6H5) ppm.
H, 6.47; N 4.50. Found: C, 65.61; H, 6.29; N, 4.47. [
0.8, CHCl3).
a]D = +237.9 (c
4
13C NMR (175 MHz): d 10.8 (q, JC,F = 1.6 Hz, CH3), 21.7, 22.1
(2CH3), 26.9 (CH2), 28.4 (q, 4JC,F = 3.2 Hz, CH2), 50.5 (q, 3JC,F = 1.8 Hz,
3
4.3.2.8. (1R,2S)-3-(40-Methoxyphenyl)imino-2-(trifluoromethyl)-
bornan-2-ol 9h. Yield: 290 mg (85%). Colourless crystals, mp 68–
70 °C (hexane). 1H NMR (200 MHz): d 0.93, 1.05, 1.16 (3s, 3H each,
3CH3), 1.55–1.93 (m, 4H, 2CH2), 2.61 (d, 3JH,H = 4.6 Hz, 1H, CH), 3.57
Cq), 51.4 (CH), 52.2 (Cq), 65.3 (q, JC,F = 1.9 Hz, CHN), 82.2 (q,
2JC,F = 25.2 Hz, Cq), 115.3, 120.1, 129.65 (5CH arom.), 127.1 (q,
1JC,F = 288.7 Hz, CF3), 147.7 (Cq arom.) ppm. 19F NMR (188 MHz):
d ꢀ70.9 (s, CF3) ppm. IR (KBr):
m 3394vs (NH), 3370s (br, OH),
(br s, 1H, OH), 3.82 (s, 3H, CH3O), 6.77–6.92 (m, 4H, C6H4) ppm. 13
C
3038m, 3004s, 2959vs, 2938vs, 2891s, 2878s, 1717w, 1605vs,
1505vs, 1468s, 1393s, 1371m, 1309s, 1293s, 1292s, 1240vs,
1213vs, 1143vs, 1066s, 1028w, 976s, 917w 820w, 752s, 728s,
695s, cmꢀ1. MS (EI): m/z 313 (34, M+Å), 174 (42), 161 (16), 160
(100), 132 (13), 118 (14), 106 (17), 104 (23), 93 (15), 77 (18). Anal.
Calcd for C17H22F3NO (313.37): C, 65.16; H, 7.08; N, 4.47. Found: C,
NMR (50 MHz): d 9.9, 18.5, 22.0 (3CH3), 22.6, 28.9 (2CH2), 51.3
2
(CH), 47.9, 51.5 (2Cq), 55.4 (CH3O), 80.1 (q, JC,F = 26.5 Hz, Cq),
1
125.4 (q, JC,F = 287.9 Hz, CF3), 114.2, 121.5 (4CH arom.), 142.5,
156.9 (2Cq arom.), 178.2 (C@N) ppm. 19F NMR (188 MHz): d
ꢀ71.6 (s, CF3) ppm. IR (KBr):
m 3380s (br, OH), 3019m, 2998m,
65.26; H, 7.12; N, 4.42. [a]D = +12.0 (c 1.0, CHCl3).
2980m, 2971m, 2942m, 2918m, 2879m, 2838m, 2063w, 1874w,
1679s (C@N), 1608m, 1506vs, 1456m, 1442m, 1374m, 1295s,
1283s, 1274s, 1250s, 1158vs, 1145vs, 1108s, 1038s, 1010m,
993m, 972m, 966m, 906m, 844s, 827m, 745m, 674m cmꢀ1. MS
(EI): m/z 342 (10), 341 (61, M+Å), 188 (20), 134 (100), 77 (5,
[C6H5]+), 69 (28, [CF3]+). Anal. Calcd for C18H22F3NO2 (341.38): C,
63.33; H, 6.50; N, 4.10. Found: C, 63.55; H, 6.38; N, 4.06.
4.5. Cyclization of amino alcohol 10a with phosgene
To a solution of 250 mg (1 mmol) of 10a and 230 mg (2.3 mmol)
of triethylamine in 2 ml of abs. toluene, 0.8 ml (1.5 mmol) of a 20%
solution of phosgene in toluene was added while cooling the reac-
tion flask in a water-ice bath. The solution was magnetically stirred
for 12 h, then the mixture was diluted with water (10 ml) and
extracted three times with dichloromethane (3 ꢁ ca. 10 ml). The
organic layers were combined, dried over anhydrous MgSO4,
filtered, and the solvents were evaporated. The residue obtained
was purified by fast filtration through an alumina layer using a
mixture of petroleum ether and dichloromethane (1:1) as the
eluent. The isolated product 11a was additionally purified by
crystallization.
[a]D = +395.4 (c 1.0, CHCl3).
4.4. Reduction of imino alcohols 9 with DIBAL-H—a general
procedure
To a solution of 1 mmol of the corresponding imino alcohol 9 in
10 ml of anhydrous THF, 2.5 ml of a 1 M solution (2.5 mmol) of DI-
BAL-H in dichloromethane was added while cooling the reaction
flask in an ice-bath. When the addition of DIBAL-H was complete,
the mixture was heated at reflux for 40 min. Then, the mixture was
cooled in a water-ice bath and carefully treated with a 1% aqueous
solution of hydrochloric acid. THF was removed in vacuo, and the
residual crude mixture was cooled in a water-ice bath and slowly
basified with a saturated aqueous solution of sodium hydroxide.
The alkaline solution was thoroughly extracted with diethyl ether,
and the organic layers were combined, dried over anhydrous
MgSO4, filtered, and the solvent was removed in vacuo. Purifica-
tion of the crude mixture was performed by column chromatogra-
4.5.1. (1R,2S,6R)-1,5,10,10-Tetramethyl-2-(trifluoromethyl)-3-
oxa-5-aza-tricyclo[5.2.1.02,6]-decan-4-one 11a
Yield: 250 mg (90%). Colourless crystals, mp 66–68 °C (petro-
leum ether). 1H NMR (700 MHz): d 0.96, 1.06, 1.11 (3s, 3H each,
3CH3), 1.09–1.14, 1.54–1.57, 1.73–1.76, 1.85–1.90 (4m, 4H,
3
2CH2), 2.06 (d, JH,H = 5.6 Hz, 1H, CH), 2.88 (s, 3H, CH3N), 3.68 (s,
4
1H, CHN) ppm. 13C NMR (175 MHz): d 10.1 (q, JC,F = 1.6 Hz, CH3),
4
19.4 (CH2), 23.5, 24.7 (2CH3), 27.7 (q, JC,F = 3.2 Hz, CH2), 29.6
3
phy on alumina using
a
mixture of petroleum ether and
(CH), 44.9 (CH3N), 50.1 (q, JC,F = 1.8 Hz, Cq), 51.3 (Cq), 67.1 (q,
2
dichloromethane (1:1) containing ca. 0.05% of triethylamine as
the eluent.
3JC,F = 1.8 Hz, CHN), 87.6 (q, JC,F = 28.3 Hz, Cq), 124.9 (q,
1JC,F = 285.2 Hz, CF3), 156.9 (C@O) ppm. 19F NMR (188 MHz): d
ꢀ73.2 (s, CF3) ppm. IR (KBr):
m 3016w, 2979w, 2952w, 2900w,
2886w, 1765s (C@O), 1636w, 1502w, 1483w, 1432w, 1405w,
1321w, 1308w, 1284w, 1231w, 1178m, 1170m, 1150m, 1117w,
1077m, 1038m, 1024w, 983m, 754w cmꢀ1. MS (CI, isobutane):
m/z 278 (100, [M+1]+). Anal. Calcd for C13H18F3NO2 (277.29): C,
4.4.1. (1R,2S,3R)-3-Methylamino-2-(trifluoromethyl)bornan-2-
ol 10a
Yield: 190 mg (76%). Colourless crystals, mp 38–40 °C (hexane).
1H NMR (700 MHz): d 0.82, 1.03, 1.07 (3s, 3H each, 3CH3), 1.21–
1.24, 1.39–1.43, 1.68–1.73, 1.78–1.83 (4m, 5H, CH and 2CH2),
1.57 (br s, 1H, NH), 2.47 (s, 3H, CH3N), 2.72 (s, 1H, CH) ppm. 13C
56.31; H, 6.54. Found: C, 56.33; H, 6.52. [
a
]
D = ꢀ16.5 (c 1.0, CHCl3).
4
NMR (175 MHz): d 10.9 (q, JC,F = 1.4 Hz, CH3), 22.0, 22.2 (2CH3),
4.6. Reduction of hydroxy ketone 8
4.6.1. Method A
4
27.3 (CH2), 28.4 (q, JC,F = 3.5 Hz, CH2), 37.4 (CH), 50.5 (q,
3
3JC,F = 1.9 Hz, Cq), 51.6, 51.7 (CH3N, Cq), 69.0 (q, JC,F = 1.9 Hz,
2
1
CHN), 80.5 (q, JC,F = 25.0 Hz, Cq), 127.3 (q, JC,F = 285.2 Hz, CF3)
To a magnetically stirred and cooled (water-ice bath) solution of
240 mg (1 mmol) of 8 in 2 ml of methanol, 150 mg (4 mmol) of so-
dium borohydride was added in small portions. The mixture was
stirred for 6 h, and then the solvent was evaporated to dryness.
The solid residue was treated with water and extracted with
dichloromethane (5 ꢁ ca. 10 ml). The organic solutions were com-
bined, dried over anhydrous MgSO4, filtered, and the solvents were
evaporated. Based on the 19F NMR spectrum, the ratio of the diaste-
ppm. 19F NMR (188 MHz): d ꢀ71.6 (s, CF3) ppm. IR (KBr):
m
3439s (br, OH), 3375s (NH), 3008m, 2982s, 2968s, 2924s, 2893w,
1636w, 1478w, 1457w, 1432w, 1392w, 1294s, 1285s, 1243s,
1152vs, 1141s, 1123s, 1112m, 1024w, 974s, 960w, 930w 911w,
784w, 730m cmꢀ1. MS (EI): m/z 251 (13, M+Å), 154 (13), 112 (37),
98 (100). Anal. Calcd for C12H20F3NO (251.29): C, 57.36; H, 8.02.
Found: C, 57.43; H, 8.04. [
a
]D = ꢀ5.5 (c 0.8, CHCl3).

1682
E. Obijalska et al. / Tetrahedron: Asymmetry 19 (2008) 1676–1683
reoisomers 2-exo,3-exo-12 and 2-exo,3-endo-12 was determined to
be 9:1.
1173s, 1159s, 1128m, 1080s, 1065s, 1052m, 984m, 812w, 767m,
728w, 673w cmꢀ1. MS (EI): m/z 264 (6, M+Å), 205 (11), 202 (26),
189 (11), 177 (22), 163 (15), 162 (33), 160 (25), 110 (31), 109
(28), 95 (100), 93 (16), 70 (10), 69 (19, [CF3]+), 55 (12), 43 (11),
41 (19). Anal. Calcd for C12H15F3O3 (264.25): C, 54.55; H, 5.72.
4.6.2. Method B
To a magnetically stirred and cooled (water-ice bath) solution of
240 mg (1 mmol) of 8 in 2 ml of abs. THF, 2.5 ml of a 1 M solution
(2.5 mmol) of DIBAL-H in dichloromethane was added drop-wise
while cooling in an ice-bath. The mixture was stirred for 2 h and
then treated with water and a 1% aqueous solution of hydrochloric
acid. Subsequently, the reaction mixture was extracted with
dichloromethane (5 ꢁ ca. 10 ml). The combined organic layers
were dried over anhydrous MgSO4, filtered, and the solvents were
evaporated. Based on the 19F NMR spectrum, the ratio 2-exo,3-exo-
12/2-exo,3-endo-12 was determined to be 10:1.
The crude product obtained either by method A or by method B
was purified by column chromatography on silica gel, and a mix-
ture of petroleum ether with increasing amounts of dichlorometh-
ane (0–90%) was used as the eluent. The isolated material was
additionally purified by crystallization to give an analytically pure
sample of the major product 2-exo,3-exo-12.
Found: C, 54.40; H, 5.59. [
a]
D = ꢀ8.6 (c 1.0, CHCl3).
4.8. X-ray crystal-structure determination of 8 and rac-9a
All measurements were performed on a Nonius KappaCCD area-
detector diffractometer27 using graphite-monochromated MoK
a
radiation (k 0.71073 Å) and an Oxford Cryosystems Cryostream
700 cooler. The data collection and refinement parameters are gi-
ven below,28 and views of the molecules are shown in Figure 1.
29
Data reduction was performed with HKL DENZO and SCALEPACK
.
The
intensities were corrected for Lorentz and polarization effects but
not for absorption. Equivalent reflections were merged. The struc-
tures were solved by direct methods using SIR92,30 which revealed
the positions of all non-H-atoms. The non-H-atoms were refined
anisotropically. The hydroxy H-atoms were placed in the positions
indicated by difference electron density maps, and their positions
were allowed to refine together with individual isotropic displace-
ment parameters. All remaining H-atoms were placed in geometri-
cally calculated positions and refined using a riding model where
each H-atom was assigned a fixed isotropic displacement parame-
ter with a value equal to 1.2Ueq of its parent C-atom (1.5Ueq for the
methyl groups). The refinements of the structures were carried out
on F2 using full-matrix least-squares procedures, which minimized
4.6.2.1. (1R,2S,3R)-2-(Trifluoromethyl)bornane-2,3-diol 2-exo,
3-exo-12. Yield: 200 mg (83%) for method A and 220 mg (90%)
for method B. Colourless crystals, mp 99–101 °C (hexane). 1H
NMR (200 MHz): d 0.85, 1.04, 1.19 (3s, 3H each, 3CH3), 1.07–1.83
2
(m, 5H, CH, 2CH2), 2.46 (br. d, JH,H = 6.2 Hz, 1H, CHOH), 3.49 (br
2
s, 1H, OH), 3.99–4.02 (d, JH,H = 6.1 Hz, 1H, CHOH) ppm. 13C NMR
(50 MHz): d 10.3, 21.6 (3CH3), 24.2; 28.0 (2CH2), 50.2, 51.7 (2Cq),
P
2
51.1 (CH), 76.1 (CHOH), 81.9 (q, JC,F = 25.2 Hz, Cq), 126.6 (q,
the function
wðF2o ꢀ F2c Þ . A correction for secondary extinction
2
1JC,F = 286.6 Hz, CF3) ppm. 19F NMR (188 MHz): d ꢀ73.7 (s, CF3)
ppm. IR (KBr): 3408s (br, OH), 3008w, 2959m, 2941m, 2881w,
1636w, 1497w, 1483w, 1464w, 1448w, 1397m, 1373w, 1316m,
1291m, 1254m, 1162vs, 1146vs, 1132vs, 1060s, 989w, 977m,
961m, 941w, 816w, 768w, 737m, 726w cmꢀ1. MS (CI, isobutane):
m/z 239 ([M+1]+, 3), 221 ([M+1ꢀH2O]+, 100), 203 (13), 109 (11),
95 (17). Anal. Calcd for C11H17F3O2 (238.25): C, 55.45; H, 7.19.
was applied in the case of 8. Two and three reflections, respec-
tively, whose intensities were considered to be extreme outliers,
were omitted from the final refinement of 8 and rac-9a. Neutral
atom scattering factors for non-H-atoms were taken from Ref. 31,
and the scattering factors for H-atoms were taken from Ref. 32.
Anomalous dispersion effects were included in Fc;33 the values
for f0 and f0 were those of Ref. 34. The values of the mass attenua-
tion coefficients are those of Ref. 35. All calculations were per-
formed using the SHELXL9736 program.
Found: C, 55.63; H, 7.13. [
a]
D = ꢀ28.9 (c 1.1, CHCl3).
4.7. Cyclization of the diol 2-exo,3-exo-12 with 1,10-carbonyl-
diimidazole
4.8.1. Crystal data for 8
C11H15F3O2, M = 236.23, colourless, prism, crystal dimensions
To a solution of 240 mg (1 mmol) of 2-exo,3-exo-12 and 230 mg
(2.3 mmol) of triethylamine in 2 ml of abs. dichloromethane,
200 mg (1.2 mmol) of 1,10-carbonyldiimidazole was added. The
mixture was magnetically stirred for 48 h at room temperature,
then diluted with dichloromethane and subsequently washed with
a 5% solution of hydrochloric acid and water. The organic layer was
separated and dried over anhydrous MgSO4. After filtration, the
solvents were evaporated, and the crude product was purified by
column chromatography on silica gel using hexane with increasing
amounts of dichloromethane (0–50%) as the eluent. Additional
crystallization afforded an analytically pure sample.
0.10 ꢁ 0.15 ꢁ 0.25 mm, orthorhombic, space group P212121, Z = 4,
a = 7.1321(4) Å, b = 7.4872(3) Å, c = 21.007(1) Å, V = 1121.8(1) Å3,
T = 160 K, Dx = 1.399 g cmꢀ3 (MoK ) = 0.127 mmꢀ1, scan type /
, l
a
and
x
, 2h(max) = 50°, total reflections measured 14,503, symmetry
independent reflections 1171, reflections with I > 2
r
(I) 1002,
reflections used in refinement 1169, parameters refined 153, R(F)
[I > 2
r
(I) reflections] = 0.0486, ꢀ1wR(F2) [all data] = 0.1228 (w ¼
2
½
r2ðF2oÞ þ ð0:0585PÞ þ 0:4099Pꢂ , where P ¼ ðFo2 þ 2Fc2Þ=3), good-
ness of fit 1.147, secondary extinction coefficient 0.11(1), final
Dmax
/
r
0.001,
D
q
(max; min) = 0.27; ꢀ0.24 e Åꢀ3
.
4.8.2. Crystal data for rac-9a
12H18F3NO, M = 249.28, colourless, prism, crystal dimensions
4.7.1. (1R,2S,6R)-1,10,10-Trimethyl-2-(trifluoromethyl)-3,5-
dioxa-tricyclo[5.2.1.02,6]decan-4-one 13
C
0.20 ꢁ 0.20 ꢁ 0.20 mm, monoclinic, space group P21/n, Z = 4,
Yield: 250 mg (94%). Colourless crystals, mp 128–130 °C
(CH2Cl2/hexane). 1H NMR (700 MHz): d 1.00, 1.14, 1.15 (3s, 3H
each, 3CH3), 1.11–1.13, 1.54–1.60, 1.69–1.73, 1.89–1.94 (4m, 4H,
a = 9.2167(3) Å, b = 13.6986(5) Å, c = 9.6071(3) Å, b = 92.446(2);
V = 1211.85(7) Å3,
T = 160 K,
0.117 mmꢀ1, scan type / and
measured 26,775, symmetry independent reflections 2782, reflec-
tions with I > 2 (I) 2239, reflections used in refinement 2779,
Dx = 1.366 g cmꢀ3
,
l(MoK ) =
a
x
, 2h(max) = 55°, total reflections
3
2CH2), 2.24 (d, JH,H = 5.6 Hz, 1H, CH), 4.66 (s, 1H, CH(O)) ppm.
4
13C NMR (175 MHz): d 10.0 (q, JC,F = 1.6 Hz, CH3), 19.9 (CH2),
r
4
23.0, 23.1 (2CH3), 27.3 (q, JC,F = 3.5 Hz, CH2), 47.4 (CH), 49.8 (q,
parameters refined 162, R(F) [I > 2r(I) reflections] = 0.0437,
2
3JC,F = 1.8 Hz, Cq), 51.4 (Cq), 84.2 (q, JC,F = 1.6 Hz, CH(O)), 90.7 (q,
wR(F2) [all data] = 0.1186 (w ¼ ½r2ðFo2Þ þ ð0:0593PÞ þ 0:3486Pꢂꢀ1
,
3
2JC–F = 29.0 Hz, Cq), 124.3 (q, JC,F = 283.4 Hz, CF3), 153.7 (C@O)
where P ¼ ðF2o þ 2Fc2Þ=3), goodness of fit 1.043, final Dmax
/r 0.001,
1
ppm. 19F NMR (188 MHz): d ꢀ72.3 (s, CF3) ppm. IR (KBr):
m
D
q
(max; min) = 0.27; ꢀ0.27 e Åꢀ3
.
3024w, 3002w, 2979w, 2940m, 2884w, 1813s (C@O), 1629w,
The crystallographic data for the ethylimino analogue of rac-9a
1505w, 1457w, 1401w, 1366w, 1310m, 1270w, 1205s, 1190s,
have also been deposited.28

E. Obijalska et al. / Tetrahedron: Asymmetry 19 (2008) 1676–1683
1683
18. In Preliminary experiments, rac-3a (mp 60–62 °C, hexane) was prepared by
using racemic camphor. The pure 1(R)-configured 3a showed a mp 84–85 °C, in
good agreement with the literature.17a
19. Johnson, C. K. ORTEP II, Report ORNL-5138, Oak Ridge National Laboratory, Oak
Ridge, Tennessee, 1976.
20. Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew. Chem., Int. Ed. Engl.
1995, 34, 1555–1573.
21. (a) Whereas desilylation of an ether derivative under acidic conditions (diluted
solutions of HCl, CF3COOH, etc.) offers a typical approach for the removal of the
Me3Si residue after nucleophilic trifluoromethylation of aldehydes and ketones
(e.g., numerous examples are reported in the literature.5a,b), the application of
Acknowledgements
The authors thank the Polish Ministry for Science and Higher
Education for a Grant (Application # NN 204 130 635) (G.M.,
E.O.), and financial support by F. Hoffmann-La Roche AG, Basel is
also gratefully acknowledged (H.H.).
References
NaBH4 in boiling alcoholic solution in
described so far. Moreover, according to a recent paper, treatment of a complex
,b-unsaturated ketone containing a (tert-butyl)diphenylsilyloxy group with
NaBH4 (EtOH, ꢀ20 °C, CeCl3ꢃH2O) led selectively to the reduction of the C@O
group without deprotection (see: Fujiwara, K.; Aki, Y.; Yamamoto, F.;
Kawamura, M.; Kobayashi, M.; Okano, A.; Awakura, D.; Shiga, S.; Murai, A.;
Kawai, H.; Suzuki, T. Tetrahedron Lett. 2007, 26, 4523–4527). (b) The compound
rac-9a (mp 153–155 °C, Et2O/hexane) was prepared from rac-3a analogously to
the enantiomerically pure 9a.
a similar procedure has not been
1. Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley Interscience: New
York, 1994. pp 261–278.
2. (a) Gravel, M.; Lachance, H.; Lu, X.; Hall, D. G. Synthesis 2004, 1290–1302; (b)
Lachance, H.; St.-Onge, M.; Hall, D. G. J. Org. Chem. 2005, 70, 4180–4183; (c)
Lachance, H.; Lu, X.; Gravel, M.; Hall, D. G. J. Am. Chem. Soc. 2003, 125, 10160–
10161.
a
3. (a) Bonner, M. P.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113, 1299–1308; (b)
Denmark, S. E.; Rivera, I. J. Org. Chem. 1994, 59, 6887–6889.
4. (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, Germany,
2004; (b) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell: Oxford,
2004; (c) Smart, B. E. J. Fluorine Chem. 2001, 109, 3–11; (d) Hiyama, T. In
Organofluorine Compounds, Chemistry and Applications; Yamamoto, H., Ed.;
Springer: Berlin, 2000; (e) Kubota, T. In Enantiocontrolled Synthesis of Fluoro-
Organic Compounds; Soloshonok, V. A., Ed.; Wiley: Chichester, 1999; pp 469–
495; (f) Asymmetric Fluoroorganic Chemistry: Synthesis, Applications, and Future
Directions; Ramachandran, P. V., Ed. ACS Symposium Series 746; American
Chemical Society: Washington, DC, 2000; (g) Tessier, A.; Pytkowicz, J.; Brigaud,
T. Angew. Chem., Int. Ed. 2006, 45, 3677–3680; (h) Hein, J. E.; Hultin, P. G.
Tetrahedron: Asymmetry 2005, 16, 2341–2347.
5. (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757–786; (b) Singh, R. P.;
Shreeve, J. M. Tetrahedron 2000, 56, 7613–7632; (c) Prakash, G. K. S.; Mandal,
M. J. Fluorine Chem. 2001, 112, 123–131; (d) Ma, J.-A.; Cahard, D. J. Fluorine
Chem. 2007, 128, 975–996.
6. Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. J. Org. Chem. 1991, 56, 984–989.
7. (a) Iwanami, K.; Oriyama, T. Synlett 2006, 112–114; (b) Prakash, G. K. S.; Panja,
C.; Vaghoo, H.; Surampudi, V.; Kultyshev, R.; Mandal, M.; Rasul, G.; Mathew, T.;
Olah, G. A. J. Org. Chem. 2006, 71, 6806–6813; (c) Mukayama, T.; Kawano, Y.;
Fujisawa, H. Chem. Lett. 2005, 34, 88–89.
8. (a) Caron, S.; Do, N. M.; Arpin, P.; Larivée, A. Synthesis 2003, 1693–1698; (b)
Mizuta, S.; Shibata, N.; Hibino, M.; Nagano, S.; Nakamura, S.; Toru, T.
Tetrahedron 2007, 63, 8521–8528; (c) Mizuta, S.; Shibata, N.; Akiti, S.;
Fujimoto, H.; Nakamura, S.; Toru, T. Org. Lett. 2007, 9, 3707–3710; (d) Zhao,
H.; Qin, B.; Liu, X.; Feng, X. Tetrahedron 2007, 63, 6822–6826.
9. Sugimoto, H.; Nakamura, S.; Shibata, Y.; Shibata, N.; Toru, T. Tetrahedron Lett.
2006, 47, 1337–1340.
10. (a) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Synlett 2001, 77–78; (b) Kawano,
Y.; Fujisawa, H.; Mukaiyama, T. Chem. Lett. 2005, 34, 422–423.
11. (a) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int. Ed. 2001, 40,
589–590; (b) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett. 2001, 3, 2847–
2850.
22. Two main procedures for the synthesis of
have already been described. The first method is based on the ring opening of a
corresponding 2-(trifluoromethyl)oxirane with
primary amine.23a,b The
second protocol involves multi-step procedure starting with the
a-trifluoromethyl-b-amino alcohols
a
a
nucleophilic addition of the CF3SiMe3 to
a,b-unsaturated aldehydes followed
by ozonolysis and Petasis amination.23c
23. (a) Begue, J. P.; Bonnet-Delpon, D.; Sdassi, H. Tetrahedron Lett. 1992, 33, 1879–
1882; (b) Yamauchi, Y.; Kawate, T.; Katagiri, T.; Uneyama, K. Tetrahedron 2003,
59, 9839–9847; (c) Prakash, G. K. S.; Mandal, M.; Schweizer, S.; Petasis, N. A.;
Olah, G. A. Org. Lett. 2000, 2, 3173–3176.
24. House, H. O. In Modern Synthetic Reactions; W.A. Benjamin, 1972. Chapter 2.
25. (a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108,
6071–6072; (b) Kitamura, M.; Suga, S.; Niwa, M.; Noyori, R. J. Am. Chem. Soc.
1995, 117, 4832–4842.
26. It is worth mentioning that this signal appears as a d and not as the expected
dd. This fact shows that the coupling occurs with only one H-atom located at
C(5) of the camphor skeleton. It is likely that the effective coupling results from
the interaction with the exo-H. The same phenomenon is observed in other
camphor derivatives described in this paper.
27. Hooft, R. KAPPACCD Collect Software; Nonius BV: Delft, The Netherlands,
1999.
28. CCDC 684655–684657 contain 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.
29. Otwinowski, Z.; Minor, W. In Methods in Enzymology; Carter, C. W., Jr., Sweet, R.
M., Eds.; Macromolecular Crystallography, Part A; Academic Press: New York,
1997; Vol. 276, pp 307–326.
30. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.;
Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435.
31. Maslen, E. N.; Fox, A. G.; O’Keefe, M. A. In International Tables for
Crystallography; Wilson, A. J. C., Ed.; Kluwer Academic: Dordrecht, 1992; Vol.
C, pp 477–486. Table 6.1.1.1.
32. Stewart, R. F.; Davidson, E. R.; Simpson, W. T. J. Chem. Phys. 1965, 42, 3175–
3187.
33. Ibers, J. A.; Hamilton, W. C. Acta Crystallogr. 1964, 17, 781–782.
34. Creagh, D. C.; McAuley, W. J. In International Tables for Crystallography; Wilson,
A. J. C., Ed.; Kluwer Academic: Dordrecht, 1992; Vol. C, pp 219–222. Table
4.2.6.8.
35. Creagh, D. C.; Hubbell, J. H. In International Tables for Crystallography; Wilson, A.
J. C., Ed.; Kluwer Academic: Dordrecht, 1992; Vol. C, pp 200–206. Table 4.2.4.3.
36. Sheldrick, G. M. SHELXL97, Program for the Refinement of Crystal Structures;
University of Göttingen: Germany, 1997.
12. Petrov, V. Tetrahedron Lett. 2000, 41, 6959–6963.
13. Dmowski, W. J. Fluorine Chem. 2001, 109, 33–37.
14. Interestingly, the reaction of trimethylsilyl cyanide with camphor, catalyzed by
BF3ꢃEt2O gave a 2:1-mixture of the endo- and exo-nitriles in nearly quantitative
yield.15
15. Dimitrov, V.; Dobrikov, G.; Genov, M. Tetrahedron: Asymmetry 2001, 12, 1323–
1329.
16. Meyer, W. L.; Lobo, A. P.; McCarty, R. N. J. Org. Chem. 1967, 32, 1754–1762.
17. (a) Rupe, H.; Di Vignano, A. T. Helv. Chim. Acta 1937, 20, 1078–1097; (b)
Denmark, S. E.; Chatani, N.; Pansare, S. Tetrahedron 1992, 48, 2191–2208; (c)
Forster, M. O.; Thornley, T. J. Chem. Soc. 1909, 95, 942–956.