An efficient synthesis of enantiomerically enriched trifluoromethylated 1,2-diols and 1,2-amino alcohols with quaternary stereocenters by diastereoselective addition of TMSCF3 to chiral 2-acyl-1,3- perhydrobenzoxazines

Article abstract of DOI:10.1021/jo052458v

TMSCF₃ adds to chiral 2-acyl-1,3-perhydrobenzoxazines with total diastereoselectivity leading to quaternary trifluoromethyl alcohols. Further transformation of the addition products yields enantiomerically enriched trifluoromethylated 1,2-diols

Full text of DOI:10.1021/jo052458v

compounds.4 Although the asymmetric version of these reactions
is less common,5 some routes to enantiopure fluorinated amino
acids,6 amino alcohols,7 and related compounds8 have recently
been described.
Nucleophilic trifluoromethylation using TMSCF3 as reagent
needs activation of the reagent, and although both Lewis bases9
or fluorine-containing additives10 have been used, the latter gave
better results. The diastereoselectivity of the reaction has also
been studied on different substrates and varies from moderate
to good depending on the structure of the carbonyls.11 On the
other hand, some R-trifluromethylated alcohols have been
prepared, in moderate ee, by enantioselective addition of
TMSCF3 to ketones and aldehydes catalyzed by chiral am-
monium fluorides.12
An Efficient Synthesis of Enantiomerically
Enriched Trifluoromethylated 1,2-Diols and
1,2-Amino Alcohols with Quaternary
Stereocenters by Diastereoselective Addition of
TMSCF3 to Chiral
2-Acyl-1,3-perhydrobenzoxazines
Rafael Pedrosa,* Sonia Sayalero,† Martina Vicente, and
Alicia Maestro
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias,
UniVersidad de Valladolid, Dr. Mergelina s/n,
47011-Valladolid, Spain
Continuing our interest in the synthesis of fluorinated
derivatives,13 we present now a facile and direct entry to
enantiomerically enriched trifluoromethyl 1,2-diols and 1,2-
amino alcohols based on the diastereoselective addition of
pedrosa@qo.uVa.es
ReceiVed NoVember 29, 2005
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Tetrahedron Lett. 1996, 37, 6115-6116. (b) Prakash G. K. S.; Yudin, A.
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Singh, R. P.; Shreeve Tetrahedron 2000, 56, 7613-7632. (f) Prakash, G.
K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123-131. (g) Prakash, G.
K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int. Ed. 2001, 40, 589-
590. (h) Sevenard, D. V.; Kirch, P.; Ro¨schenthaler, G.-V.; Movchun, V.
N.; Kolomeitsev, A. A. Synlett 2001, 379-381. (i) Kim, J.; Shreeve, J. M.
Org. Biomol. Chem. 2004, 2, 2728-2734 and references therein. (j)
Hoffmann-Ro¨der, A.; Seiler, P.; Diederich, F. Org. Biomol. Chem. 2004,
2, 2267-2269.
TMSCF3 adds to chiral 2-acyl-1,3-perhydrobenzoxazines
with total diastereoselectivity leading to quaternary triflu-
oromethyl alcohols. Further transformation of the addition
products yields enantiomerically enriched trifluoromethylated
1,2-diols and 1,2-amino alcohols.
(5) Asymmetric Fluoroorganic Chemistry. Synthesis, Applications and
Future Directions; Ramachandran, P. V., Ed.; American Chemical Soci-
ety: Washington, DC, 2000.
(6) (a) Fluorine-Containing Amino Acids: Synthesis and Properties;
Kukharv, P., Soloshonok, V. A., Eds.; Wiley: Chichester, U.K., 1995. (b)
Soloshonok, V.; Soloshonok, I.; Kukhar, V. P.; Svedas, V. K. J. Org. Chem.
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Arellano, C. R.; Simo´n, A. J. Org. Chem. 2002, 67, 4667-4679. (d) Jiang,
Z.-X.; Quin, Y.-Y.; Qing, F.-L. J. Org. Chem. 2003, 68, 7544-7547 and
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Peregrina, J. M. J. Org. Chem. 2002, 70, 5721-5724.
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Olah, G. A. Org. Lett. 2000, 2, 3173-3176. (b) Fustero, S.; Jime´nez, D.;
Sanz-Cervera, J. F.; Sa´nchez-Rosello´, M.; Esteban, E.; Simo´n-Fuentes, A.
Org. Lett. 2005, 7, 3433-3436 and references therein.
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127, 8826-8828. (e) Steiner, D. D.; Mase, N.; Barbas, C. F., III. Angew.
Chem., Int. Ed. 2005, 44, 3706-3710. (f) Marigo, M.; Fielenbach, D.;
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2005, 44, 3703-3706.
(9) Prakash, G. K. S.; Mandal, M.; Panja, C.; Mathew, T.; Olah, G. A.
J. Fluorine Chem. 2003, 123, 61-63 and references therein.
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Y. J. Org. Chem. 1997, 62, 246-252. (b) Singh, R. P.; Shreeve, J. M. J.
Org. Chem. 2000, 65, 3241-3243.
Organofluorine compounds show remarkable physical, chemi-
cal, and biological properties, and they have been used in the
development of pharmaceuticals, agrochemicals, and materials.1
Trifluoromethylated derivatives have special lipophilicity and
metabolic characteristics.1b,2 For these reasons, their synthesis
has attracted considerable attention,3 albeit some of the reported
methods require many synthetic steps or not easily available
trifluoromethylated compounds.
One of the most useful method to introduce a trifluoromethyl
group consists on the nucleophilic addition of TMSCF3, induced
by a fluoride ion, to aldehydes, ketones, esters, and related
† Present address: Institute of Chemical Research of Catalonia (ICIQ), Av.
Pa¨ısos Catalans 16, 43007 Tarragona, Spain.
(1) (a) Biomedical Aspects of Fluorine Chemistry; Filler, R., Kobayashi,
Y., Eds.; Elsevier: Amsterdam, 1982. (b) Organofluorine Chemistry:
Principles and Commercial Applications; Banks, R. E., Smart, B. E., Tatlow,
J. C., Eds.; Plenun: New York, 1994. (c) Biomedical: Frontiers of Fluorine
Chemistry; Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; ACS Symposium
Series 639; American Chemical Society: Washington, DC, 1996. (d)
Hiyama, T. Organofluorine Compounds, Chemistry and Applications;
Springer: Berlin, 2000. (f) Singh, R. P.; Shreeve, J. M. Acc. Chem. Res.
2004, 37, 31-44.
(2) (a) Schlosser, M.; Michel, D. Tetrahedron 1996, 52, 99-108. (b)
O’Hagan, D.; Rzepa, H. S. Chem. Commun. 1997, 645-652. (c) Smart, B.
E. J. Fluorine Chem. 2001, 109, 3-11.
(3) (a) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48,
6555-6666. (b) Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635-3671. (c)
Langlois, B. R.; Billard, T. Synthesis 2003, 185-194.
(11) (a) Skiles, J. W.; Fuchs, V.; Miao, C.; Sorcek, R.; Grozinger, K.
G.; Mauldin, S. C.; Vitous, J.; Mui, P. W.; Jacober, S.; Chow, G.; Matteo,
M.; Skoog, M.; Weldon, S. M.; Possanza, G.; Keirns, J.; Letts, G.; Rosenthal,
S. S. J. Med. Chem. 1992, 35, 641-662. (b) Walter, M. W.; Adlington, R.
M.; Baldwin, J. E.; Schofield, C. J. Tetrahedron 1997, 53, 7275-7290. (c)
Qing, F.-L.; Peng, S.; Hu, C.-M. J. Fluorine Chem. 1998, 88, 79-81.
(12) (a) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1994, 35,
3137-3138. (b) Caron, S.; Do, N. M.; Arpin, P.; Larive´e, A. Synthesis
2003, 1693-1698.
(13) Andre´s, J. M.; Pedrosa, R.; Pe´rez-Encabo, A. Eur. J. Org. Chem.
2004, 1558-1566.
10.1021/jo052458v CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/07/2006
J. Org. Chem. 2006, 71, 2177-2180
2177

TABLE 1. Trifluoromethylation of
2-Acyl-1,3-perhydrobenzoxazines
SCHEME 1. Synthesis of 2-Acyl-1,3-perhydrobenzoxazines
2b and 2f
products
entry ketone solvent/catalyst
products (ratio)a
(yield, %)b
1
2
3
4
5
6
7
2a
2a
2a
2b
2b
2c
2d
Et2O/TBAF
THF/TBAF
THF/CsF
THF/TBAF
THF/CsF
3a/epi-3a (21:1)
3a/epi-3a (22:1)
3a (80)
3a (82)
3a/epi-3a (>50:<1)c 3a (95)
3b/epi-3b (>50:<1)c 3b (85)
3b/epi-3b (>50:<1)c 3b (93)
3c/epi-3c (>50:<1)c 3c (96)
THF/CsF
THF/TBAF
3d/epi-3d (12:1)
3d (82),
epi-3d (6)
8
9
2d
2e
THF/CsF
Et2O/TBAF
3d/epi-3d (>50:<1)c 3d (90)
3e/epi-3e (11:1)
3e/epi-3e (18:1)
3e (85),
epi-3e (3)
3e (87),
epi-3e (2)
10
2e
THF/TBAF
SCHEME 2. Synthesis of Trifluoromethyl Alcohols 3a-f
11
12
13
2e
2e
2f
Et2O/CsF
THF/CsF
THF/TBAF
3e/epi-3e (>50:<1)c 3e (93)
3e/epi-3e (>50:<1)c 3e (95)
3f/epi-3f (32:1)
3f (92),
epi-3f (2)
3f (94)
14
2f
THF/CsF
3f/epi-3f (>50:<1)c
a Determined by integration of the signals of 1H NMR or 19F NMR
spectra of the reaction mixtures. b Isolated products. c Only one diastere-
oisomer was observed in the 1H NMR or 19F NMR spectra of the reaction
mixtures.
FIGURE 1. Felkin-Anh model for the diastereoselective trifluorom-
ethylation.
diastereoselectivity, although both the yield and diastereose-
lectivity were slightly higher when THF, instead of Et2O was
used as solvent (compare entry 9 vs 10 in Table 1). In addition,
CsF was a better catalyst than TBAF increasing the yields of
the reactions probably as a consequence of the hygroscopic
character of the ammonium fluoride.4b The diastereoselection
was also improved by using anhydrous CsF as catalyst. The
reaction of 2a and 2e with TMSCF3 and CsF yielded 3a and 3e
as single compounds, whereas TBAF led to mixtures of these
compounds and the diastereoisomers epi-3a and epi-3e.
The use of THF as solvent and CsF as catalyst allows for
the trifluoromethylation of both aromatic and aliphatic deriva-
tives 2a-f, leading to 3a-f in excellent yields and high
diastereoselectivity (Table 1).
All of the alcohols were isolated and purified by column
chromatography or recrystallization, and the stereochemistry of
the formed quaternary stereocenter was determined as S by
X-ray diffraction analysis18 for the aryl (3b), isopropyl (3e),
and butyl (3f) derivatives and extended for all the compounds.
The stereochemistry of the single diastereoisomers formed
can be explained by considering the proposed mechanism for
the trifluoromethylation of carbonyl compounds,4b as a conse-
quence of a 1,2-stereoinduction processes. The addition occurs
on the less hindered Re face of the carbon-oxygen double bond,
in agreement with the Felkin-Anh models summarized in
Figure 1, and previously proposed for the reaction of TMSCF3
with imines.4g
TMSCF3 to an acyl group placed at C-2 in a chiral 1,3-perhydro
benzoxazine derived from (-)-8-benzylamino menthol.14 Further
transformations of the addition products allows for the synthesis
of enantioenriched diols and amino alcohols with a quaternary
stereocenter in good yields. Our synthetic strategy uses easily
available (-)-8-benzylamino menthol14 and commercial or
previously prepared glyoxal derivatives.
The starting 2-acyl-1,3-perhydro benzoxazines 2a,14 2c,15
2d,16 and 2e16 have been previously described, while compound
2b was synthesized by condensation of (-)-8-benzylamino-
menthol with 4-methoxyphenylglyoxal hydrate17 in refluxing
benzene and 2f by reaction of the Weinreb amide 115 with
n-butyllithium (Scheme 1).
The feasibility of the reaction was first explored on aromatic
(2a) and aliphatic (2e) derivatives. To this end, a solution of
either 2a or 2e in THF or diethyl ether was reacted with
TMSCF3 (1.5 equiv) in the presence of a catalytic amount (2.5%
mol) of tetrabutylammonium fluoride (TBAF) or CsF at 0 °C
for 1.5-2 h. Once the starting compound had disappeared, 1
equiv of TBAF was added, and the mixture was stirred for 1 h
at room temperature to transform the formed TMS-ethers into
the final alcohols 3a-f (Scheme 2).
Under these conditions the trifluoromethylated alcohols 3a
and 3e were obtained in very good yields and good to total
(14) He, X.-C.; Eliel, E. L. Tetrahedron 1987, 43, 4979-4987.
(15) Pedrosa, R.; Andre´s, C.; Nieto, J.; del Pozo, S. J. Org. Chem. 2005,
70, 1408-1416.
(16) Eliel, E. L.; He, X.-C. J. Org. Chem. 1990, 55, 2114-2119.
(17) Floyd, M. B.; Du, M. T.; Fabio, P. F.; Jacob, L. A.; Johnson, B. D.
J. Org. Chem. 1985, 50, 5022-5027.
Compounds 3a-f were easily transformed into the final
products in one or two steps. The conversion of these derivatives
(18) For ORTEP representations of the X-ray diffraction analyses of
compounds 3b, 3e, and 3f, see the Supporting Information.
2178 J. Org. Chem., Vol. 71, No. 5, 2006

SCHEME 3. Synthesis of Trifluoromethylated Hydroxy
Aldehydes and 1,2-Diols
Experimental Section
Synthesis of Trifluoromethyl Alcohols 3a-f. General Method.
To a solution of ketone 2 (2 mmol) and CsF (0.05 mmol) in THF
(50 mL), cooled to 0 °C, under argon was added dropwise a solution
of trifluoromethyltrimethylsilane (TMSCF3) in THF (1.5 mL, 3
mmol), and the mixture was stirred at that temperature until the
reaction was finished (TLC). Subsequently, TBAF (2 mmol) was
added, and the reaction mixture was stirred for 1 h at room
temperature. THF was removed under vacuum, and the residue was
purified by flash chromatography on silica gel using hexanes-ethyl
acetate 8:1 as eluent.
(1S,2′S,4a′S,7′R,8a′R)-1-(3-Benzyl-4’,4’,7’-trimethyloctahydro-
2H-benz[e][1,3]oxazin-2′-yl)-2,2,2-trifluoro-1-phenylethanol (3a).
Yield: 95%. White solid. Mp: 109-110 °C (from ethanol). [R]23
D
-3.6 (c ) 1.0, CHCl3). 1H NMR (δ): 0.64 (s, 3H); 0.80-1.04 (m,
2H); 0.96 (d, 3H, J ) 6.5 Hz); 1.19 (q, 1H, J ) 11.2 Hz); 1.33 (s,
3H); 1.52-1.71 (m, 4H); 2.01 (m, 1H); 3.68 (d, 1H, J ) 17.5 Hz);
3.76 (td, 1H, J1 ) 10.6 Hz, J2 ) 3.9 Hz); 4.17 (s, 1H, OH), 4.39
(d, 1H, J ) 17.5 Hz); 5.53 (s, 1H); 6.32 (d, 2H, J ) 6.8 Hz), 6.81-
6.89 (m, 3H); 7.21-7.23 (m, 3H); 7.43-7.46 (m, 2H). 19F NMR
(δ): -78.3 (s, 3F). 13C NMR (δ): 22.2; 22.4; 24.7; 27.3; 31.4;
SCHEME 4. Synthesis of Trifluoromethylated 1,2-Amino
Alcohols
2
35.0; 41.2; 43.5; 47.3; 58.7; 78.1; 78.3 (q, JCF ) 26.4 Hz); 84.9;
124.9 (2C); 125.9 (3C); 127.1 (3C); 128.0 (2C); 133.6; 143.3. IR
(KBr): 3486; 3070; 3028; 1603; 1455; 1375; 1314; 756; 708; 660
cm-1. MS (m/z): 448 (M + 1, 57), 294 (100), 272 (87). Anal.
Calcd for C26H32F3NO2: C, 69.78; H, 7.21; N, 3.13. Found: C,
69.66; H, 7.18; N, 3.32.
(1S,2′S,4a′S,7′R,8a′R)-1-(3-Benzyl-4′,4′,7′-trimethyloctahydro-
2H-benz[e][1,3]oxazin-2′-yl)-2,2,2-trifluoro-1-(4-methoxyphenyl)-
ethanol (3b). Yield: 93%. White solid. Mp: 184-185 °C (from
1
ethanol). [R]23 +7.1 (c ) 1.0, CHCl3). H NMR (δ): 0.68 (s,
D
into R-hydoxy acids as previously described14 was not possible
because hydrolytic workup followed by oxidation with sodium
hypochlorite led to a very complex mixture of compounds.
Instead, the trifluromethylated R-hydroxy aldehyde 4b was
obtained in 64% yield from 3b by hydrolysis with 2% HCl in
refluxing ethanol for 1 h. The same treatment applied to 3a
and 3c, followed by reduction of the reaction mixtures with
sodium borohydride in ethanol at 0 °C for 1.5 h, yielded
trifluoromethylated 1,2-diols 5a19 and 5c in 62% and 60% yield,
respectively (Scheme 3). (-)-8-Benzylaminomenthol was re-
covered in 90% from the aqueous phase by neutralization.
A different approach was used for the synthesis of enantio-
merically enriched trifluoromethyl-1,2-amino alcohols. In this
case, compounds 3a,c-f were subjected to reductive ring
opening to 6a,c-f by reaction with in situ prepared aluminum
hydride in THF at -10 °C. Oxidation of these amino menthol
derivatives with PCC in methylene chloride, followed by
treatment with a solution of NaOH led to 1,2-amino alcohol
derivatives 7a,c-f in 42-60%, and (+)-pulegone (Scheme 4).
The stereochemical integrity and the configuration of the
stereocenter was established for 7d20 by comparison of the
optical rotation with that previously described, and generalized
for all the final compounds.
3H); 0.93-1.00 (m, 2H); 0.97 (d, 3H, J ) 6.4 Hz); 1.18 (q, 1H, J
) 11.7 Hz); 1.34 (s, 3H); 1.50-1.75 (m, 4H); 2.01 (m, 1H); 3.67
(d, 1H, J ) 17.6 Hz); 3.75 (s, 3H); 3.76 (td, 1H, J1 ) 10.6 Hz, J2
) 4.0 Hz); 4.14 (s, 1H); 4.37 (d, 1H, J ) 17.6 Hz); 5.48 (s, 1H);
6.40-6.42 (m, 2H); 6.72 (m, 2H); 6.87-7.28 (m, 3H); 7.33 (d,
2H, J ) 8.5 Hz). 19F NMR (δ): -78.8 (s, 3F). 13C NMR (δ): 22.2;
22.4; 24.8; 27.1; 31.4; 35.1; 41.2; 43.6; 47.1; 55.1; 58.6; 78.0; 78.3
(q, 2JCF ) 26.5 Hz); 84.9; 113.2; 124.9; 126.0; 127.1; 128.3 (9C);
125.7; 143.4; 159.6 (3C). IR (KBr): 3521; 3086; 3058; 1615; 1586;
1516; 1462; 1388; 1376; 1314; 1299; 1251; 939; 834; 804; 756;
701 cm-1. MS (m/z): 478 (M + 1, 100), 324 (38), 272 (66). Anal.
Calcd for C27H34F3NO3: C, 67.91; H, 7.18; N, 2.93. Found: C,
67.76; H, 6.99; N, 2.98.
(1R,2′S,4a′S,7′R,8a′R)-1-(3-Benzyl-4′,4′,7′-trimethyloctahydro-
2H-benz[e][1,3]oxazin-2′-yl)-2,2,2-trifluoro-1-(furan-2-yl)etha-
nol (3c). Yield: 96%. Yellow oil. [R]23D +3.2 (c ) 0.84, CHCl3).
1H NMR (δ): 0.70 (s, 3H); 0.71-1.05 (m, 2H); 0.95 (d, 3H, J )
6.5 Hz); 1.17 (q, 1H, J ) 11.9 Hz); 1.32 (s, 3H); 1.51-1.73 (m,
4H); 1.96 (m, 1H); 3.73 (td, 1H, J1 ) 10.6 Hz, J2 ) 3.9 Hz); 3.77
(d, 1H, J ) 17.6 Hz); 4.00 (br s, 1H); 4.49 (d, 1H, J ) 17.6 Hz);
5.45 (s, 1H); 6.13 (dd, 1H, J1 ) 3.2 Hz, J2 ) 1.8 Hz), 6.20 (dd,
1H, J1 ) 3.2 Hz, J2 ) 0.8 Hz), 6.66 (dd, 2H, J1 ) 8.0 Hz, J2 ) 1.8
Hz); 6.98-7.24 (m, 3H); 7.41 (dd, 1H, J1 ) 1.8 Hz, J2 ) 0.8 Hz).
19F NMR (δ): -79.1 (s, 3F). 13C NMR (δ): 22.2; 22.5; 24.7; 26.9;
31.4; 35.0; 41.1; 43.6; 47.4; 58.6; 78.0; 83.9; 110.1; 110.6; 125.1;
126.3 (2C); 127.2 (2C); 142.4; 143.6; 147.1. 13C NMR (acetone-
d6, δ): 22.6; 23.0; 25.5; 27.5; 32.1; 35.8; 42.1; 44.4; 48.3; 59.4;
78.0 (q); 78.7; 85.1; 110.7; 111.4; 125.9; 127.4 (2C); 128.1 (2C);
143.6; 145.3; 149.6. IR (film): 3505; 3045; 3020; 1600; 1450; 1382;
1368; 1315; 1263; 1240; 1190; 730; 710; 690 cm-1. Anal. Calcd
for C24H30F3NO3: C, 65.89; H, 6.91; N, 3.20. Found: C, 65.71;
H, 7.06; N, 3.04.
In summary, the described strategy allows for the preparation
of enantiomerically enriched trifluoromethylated 1,2-amino
alcohols and 1,2-diols with quaternary stereocenters by total
diastereoselective addition of TMSCF3 to chiral 2-acyl-1,3-
perhydro benzoxazines. Aryl, heteroaryl, and alkyl groups can
be introduced as substituents at the quaternary carbon atom in
good yields from easily accessible starting reagents.
(2S,2′S,4a′S,7′R,8a′R)-2-(3-Benzyl-4’,4’,7’-trimethyloctahydro-
2H-benz[e][1,3]oxazin-2′-yl)-1,1,1-trifluorobutan-2-ol
(3d).
(19) Bennani, Y. L.; Vanhessche, K. P. M.; Sharpless, K. B. Tetra-
hedron: Asymmetry 1994, 5, 1473-1476.
(20) Arnone, A.; Bravo, P.; Frigerio, M.; Viani, F.; Soloshonok, V. A.
Tetrahedron 1998, 54, 11841-11860.
Yield: 90%. Colorless oil. [R]23D +10.8 (c ) 0.8, CHCl3). 1H NMR
(δ): 0.90-1.04 (m, 2H); 0.93 (s, 3H); 1.01 (d, 3H, J ) 6.5 Hz);
1.12 (td, 3H, J1 ) 6.6 Hz, J2 ) 1.1 Hz); 1.20 (q, 1H, J ) 11.8
J. Org. Chem, Vol. 71, No. 5, 2006 2179

Hz); 1.40 (s, 3H); 1.50-1.80 (m, 6H); 2.00 (m, 1H); 3.55 (s, 1H);
3.71 (td, 1H, J1 ) 10.6 Hz, J2 ) 3.9 Hz); 4.03 (d, 1H, J ) 18.4
Hz); 4.73 (d, 1H, J ) 18.4 Hz); 5.08 (s, 1H); 7.22 (t, 1H, J ) 7.2
Hz); 7.34 (dd, 2H, J1 ) 7.6 Hz, J2 ) 7.2 Hz); 7.43 (d, 2H, J ) 7.6
Hz). 19F NMR (δ): -76.5 (s, 3F). 13C NMR (δ): 7.79; 22.2; 22.4;
Yield: 94%. White solid. Mp: 108-109 °C (from methanol). [R]23
D
1
+9.1 (c ) 0.88, CHCl3). H NMR (δ): 0.94-1.09 (m, 2H); 0.97
(t, 3H, J ) 6.0 Hz); 0.97 (s, 3H); 1.03 (d, 3H, J ) 6.5 Hz); 1.17-
1.38 (m, 4H), 1.42 (s, 3H); 1.59-1.80 (m, 7H); 2.02 (m, 1H); 3.55
(s, 1H); 3.72 (td, 1H, J1 ) 10.7 Hz, J2 ) 3.8 Hz); 4.04 (d, 1H, J
) 18.4 Hz); 4.75 (d, 1H, J ) 18.4 Hz); 5.06 (s, 1H); 7.23 (t, 1H,
J ) 7.3 Hz); 7.35 (t, 2H, J ) 7.3 Hz); 7.46 (d, 2H, J ) 7.3 Hz).
19F NMR (δ): -76.5 (s, 3F). 13C NMR (δ): 14.0; 22.2; 22.5; 23.0;
24.8; 25.0; 26.7; 31.3; 31.4; 35.1; 41.2; 43.6; 47.3; 58.8; 77.9; 83.8;
125.7; 126.4 (2C); 127.8 (2C); 143.6. IR (Nujol): 3545; 3080; 1600;
1490; 1450; 1375; 1315; 1180; 1160; 755; 725; 700 cm-1. Anal.
Calcd for C24H36F3NO2: C, 67.42; H, 8.49; N, 3.28. Found: C,
67.25; H, 8.36; N, 3.26.
24.4; 24.8; 26.8; 31.4; 35.1; 41.2; 43.5; 47.5; 58.8; 77.8 (q, 2JCF
)
24.7 Hz); 77.9; 83.4; 125.7; 126.3 (2C); 127.9 (2C); 143.8. IR
(film): 3537; 3080; 3063; 1604; 1493; 1453; 1390; 1373; 1308;
1245; 1192; 755; 724; 698 cm-1. Anal. Calcd for C22H32F3NO2:
C, 66.14; H, 8.07; N, 3.51. Found: C, 66.32; H, 7.91; N, 3.66.
(2S,2′S,4a′S,7′R,8a′R)-2-(3-Benzyl-4′,4′,7′-trimethyloctahydro-
2H-benz[e][1,3]oxazin-2′-yl)-1,1,1-trifluoro-3-methylbutan-2-
ol (3e). Yield: 95%. White solid. Mp: 117-118 °C (from ethanol).
1
[R]23 +3.1 (c ) 1.0, CHCl3). H NMR (δ): 0.84-1.00 (m, 5H);
D
0.84 (s, 3H); 0.95 (d, 3H, J ) 6.6 Hz); 1.08-1.20 (m, 4H); 1.32
(s, 3H); 1.40-1.71 (m, 4H); 1.93 (m, 1H); 2.22 (m, 1H); 3.55 (s,
1H); 3.63 (td, 1H, J1 ) 10.8 Hz, J2 ) 4.0 Hz); 3.94 (d, 1H, J )
18.3 Hz); 4.59 (d, 1H, J ) 18.3 Hz); 5.02 (s, 1H); 7.15 (t, 1H, J )
7.1 Hz); 7.24-7.29 (m, 2H); 7.34 (d, 2H, J ) 6.9 Hz). 19F NMR
(δ): -71.7 (s, 3F). 13C NMR (δ): 16.4; 17.4; 22.2; 22.4; 24.8;
Acknowledgment. We thank the Spanish Ministerio de
Educacio´n y Ciencia (DGI, Project No. BQU2002-01046) and
Junta de Castilla y Leo´n (Project No. VA042/03) for financial
support. We also thank Dr. A. Pe´rez-Encabo for the determi-
nation of X-ray structures.
27.0; 30.1; 31.4; 35.1; 41.2; 43.5; 47.7; 59.1; 78.2; 79.1 (q, 2JCF
)
Supporting Information Available: Experimental details and
full characterization including copies of 13C NMR spectra for all
the compounds. ORTEP representations of the X-ray structures for
3b,e,f and CIF data. This material is available free of charge via
the Internet at http://pubs.acs.org.
23.6 Hz); 84.4; 125.8; 126.3 (2C); 128.0 (2C); 143.9. IR (KBr):
3517; 3080; 1603; 1493; 1458; 1373; 1363; 1315; 1247; 1190; 1167;
779; 756; 719; 697 cm-1. Anal. Calcd for C23H34F3NO2: C, 66.80;
H, 8.29; N, 3.39. Found: C, 66.70; H, 8.19; N, 3.48.
(2S,2′S,4a′S,7′R,8a′R)-2-(3-Benzyl-4′,4′,7′-trimethyloctahydro-
2H-benz[e][1,3]oxazin-2’-yl)-1,1,1-trifluorohexan-2-ol
(3f).
JO052458V
2180 J. Org. Chem., Vol. 71, No. 5, 2006