Oxazolidine Ring Opening and Isomerization to (E)-Imines. Asymmetric Synthesis of Aryl-α-fluoroalkyl Amino Alcohols

Article abstract of DOI:10.1021/ol036486g

(Matrix presented) A base-induced ring opening/imine isomerization/ diastereoselective organometallic addition sequence on 4-substituted 2-perfluoroalkyl-1,3-oxazolidines has been developed for the asymmetric synthesis of aryl α-perfluoroalkylamine deriva

Full text of DOI:10.1021/ol036486g

ORGANIC
LETTERS
2004
Vol. 6, No. 4
641-644
Oxazolidine Ring Opening and
Isomerization to (E)-Imines. Asymmetric
Synthesis of Aryl-r-fluoroalkyl Amino
Alcohols
,†
Francis Gosselin,* Ame´lie Roy,† Paul D. O’Shea,† Cheng-yi Chen,‡ and
Ralph P. Volante‡
Department of Process Research, Merck Frosst Centre for Therapeutic Research,
16711 Route Transcanadienne, Kirkland, Que´bec, Canada H9H 3L1, and
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
francis_gosselin@merck.com
Received December 22, 2003
ABSTRACT
A base-induced ring opening/imine isomerization/diastereoselective organometallic addition sequence on 4-substituted 2-perfluoroalkyl-1,3-
oxazolidines has been developed for the asymmetric synthesis of aryl r-perfluoroalkylamine derivatives. This practical method provides
chiral amino alcohols in 60−95% yield with uniformely high diastereoselectivities ranging from 35:1 to >100:1.
The development of practical methods for the preparation
of chiral organofluorine compounds continues to challenge
and attract synthetic chemists. Introduction of the fluorine
atom can confer unusual chemical reactivity to organic
molecules and often exert profound effects on the physical
properties of biologically active compounds.1,2 In particular,
the asymmetric synthesis of perfluoroalkylamines has re-
ceived much attention due to their potential use as compo-
nents of pharmaceutical agents.3
A practical approach to the asymmetric synthesis of
R-alkyl phenethylamines involves addition of organometallics
to 1,3-oxazolidines formed by condensation of the appropri-
ate aldehyde and chiral amino alcohol.4 Diastereromeric
2-alkyl and 2-aryl-1,3-oxazolidines are known to exist as
solvent-dependent mixtures of imine-oxazolidine tautomers4c,5
and organometallic addition to these mixtures provides the
(3) Asymmetric syntheses of perfluoroalkylamines include the follow-
ing: (a) Surya Prakash, G. K.; Mandal, M.; Olah, G. A. Angew. Chem.,
Int. Ed. 2001, 40, 589-590. (b) Surya Prakash, G. K.; Mandal, M.; Olah,
G. A. Org. Lett. 2001, 3, 2847-2850. (c) Enders, D.; Funabiki, K. Org.
Lett. 2001, 3, 1575-1577. (d) Soloshonok, V. A.; Ono, T. J. Org. Chem.
1997, 62, 3030-3031. (e) Ishii, A.; Higashiyama, K.; Mikami, K. Synlett
1997, 1381-1382. (f) Wang, Y.; Mosher, H. S. Tetrahedron Lett. 1991,
32, 987-990. (g) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1977, 42,
2436-2439. For reviews on organometallic additions to imines and their
derivatives see: Bloch, R. Chem. ReV. 1998, 98, 1407-1438. Enders, D.;
Reinhold: U. Tetrahedron: Asymmetry 1997, 8, 1895-1946.
(4) (a) Takahashi, H.; Suzuki, Y.; Hori, T. Chem. Pharm. Bull. 1983,
31, 2183-2191. (b) Takahashi, H.; Chida, Y.; Yoshii, T.; Suzuki, T.;
Yanaura, S. Chem. Pharm. Bull. 1986, 34, 2071-2077. (c) Wu, M-. J.;
Pridgen, L. M. J. Org. Chem. 1991, 56, 1340-1344. (d) Pridgen, L. N.;
Mokhallalati, M. K.; Wu, M.-J. J. Org. Chem. 1992, 57, 1237-1241.
† Merck Frosst Centre for Therapeutic Research.
‡ Merck Research Laboratories, Rahway.
(1) For reviews on the biological significance of organofluorine com-
pounds see: (a) Resnati, G., Soloshonok, V. A., Eds.; Tetrahedron
Symposia-in-Print No 58; Fluoroorganic Chemistry: Synthetic Challenges
and Biomedical Rewards. Tetrahedron 1996, 52, 1-330. (b) Fluorine
Containing Amino Acids: Synthesis and Properties; Kuhar, V. P., Solos-
honok, V. A. Eds.; Wiley: Chichester, UK, 1994. (c) Biomedicinal Aspects
of Fluorine Chemistry; Filler, R., Kobayashi, Y., Yagupolskii, L. M., Eds.;
Elsevier: Amsterdam, The Netherlands, 1993.
(2) For reviews on asymmetric synthesis of organofluorine compounds
see: (a) Iseki, K. Tetrahedron 1998, 54, 13887-13914. (b) Bravo, P.;
Resnati, G. Tetrahedron: Asymmetry 1990, 1, 661-692.
10.1021/ol036486g CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/28/2004

expected adducts in moderate to excellent yields and di-
astereoselectivities. A related approach has been reported for
the asymmetric synthesis of trifluoroethylamines.3e We were
interested in applying a similar methodology to the asym-
metric synthesis of aryl R-fluoroalkyl amino alcohols.
A series of 4-substituted 2-perfluoroalkyl-1,3-oxazolidines
2a-h were readily prepared on multigram scale by heating
commercially available chiral amino alcohols (1a-f) with
the corresponding perfluorinated aldehyde hemiacetal or
aldehyde hydrate in toluene with azeotropic removal of
water/alcohol (Table 1). The crude diastereomeric oxazo-
To verify that the putative imine intermediates generated
from oxazolidines 2a-h would undergo diastereoselective
addition with organometallic reagents we prepared O-
TBDMS protected trifluoroethylimine 4. Treatment of imine
4 with phenyllithium at -78 °C followed by deprotection
of the TBDMS ether gave adduct 3c in ∼75% yield over 2
steps and dr 40:1 as determined by HPLC (Scheme 2).7
Scheme 2. Diastereoselective Organometallic Addition to
Trifluoroethyliminea
Table 1. Synthesis of 2-Perfluoroalkyl 1,3-Oxazolidines 2a-ha
a Reagents and consitions: (a) PhLi, THF, -78 °C. (b) TBAF,
THF, 0 °C to rt.
yield
(%)b
Having verified that imine 4 underwent highly diastereo-
selective addition of organolithium reagents, we next focused
our attention on developing a bench-stable surrogate of imine
4 that would avoid tedious chromatographic separations3e,6
and circumvent separate protection/deprotection steps.
We reasoned that treatment of oxazolidines 2a-g with a
suitable base should induce, after deprotonation, ring opening
to generate the corresponding imine A or B (Scheme 3). In
entry
no.
R1
R2
CF3
CF3
CF3
CF3
CF3
CF3
CF2CF3
CF2H
product
drc
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Et
i-Pr
i-Bu
2a
2b
2c
2d
2e
2f
61
68
87
93
64
99
82
57
2.3:1
2.6:1
2.0:1
1.5:1
1.4:1
1.2:1
1.7:1
2.0:1
PhCH2
t-Bu
(CH2)2SMe
i-Bu
1c
1c
2g
2h
i-Bu
a Conditions: (a) F3CC(OMe)OH or F3CF2C(OH)2, or F2CHC(OH)OEt,
ppts, PhCH3. b Isolated yield. c Determined by 500 MHz 1H NMR spec-
troscopy (CDCl3).
Scheme 3. Base-Induced Oxazolidine Ring Opening, Imine
Isomerization, and Organometallic Additiona
lidines 2a-h were isolated in 57-99% yield (unoptimized).
In contrast to 2-alkyl and 2-aryl-1,3-oxazolidines, 1H NMR
spectra of 2-perfluoroalkyl-1,3-oxazolidines in CDCl3 and
d8-THF showed that 2a-h existed solely as the oxazolidine
tautomers.
As exemplified in Scheme 1, addition of phenyllithium
or phenylmagnesium bromide to oxazolidine 2c gave amino
Scheme 1. Organometallic Addition to Trifluoromethyl
Oxazolidine 2ca
a Reagents and conditions: (a) Me3SiCl, LiN(SiMe3)2, d8-THF,
-60 °C, then warm to rt. (b) PhBr, n-BuLi, THF, -78 °C, H3O+.
a Reagents and conditions: (a) PhLi or PhMgBr, THF, -78 °C.
situ trapping of the resulting alkoxide, followed by addition
of an organometallic reagent would then provide the desired
amino alcohol adducts. We chose to examine this protocol
by variable-temperature 1H NMR spectroscopy. Addition of
Me3SiCl and LiN(SiMe3)2 to a solution of oxazolidine 2c
alcohol adduct 3c in variable yields and poor diastereomeric
ratios (dr) ranging from 2:1 to 5:1. Modification of solvent
composition and addition of Lewis acids failed to improve
significantly the stereoselectivity of the addition.6
(6) See ref 3e. As noted by these authors, chromatographic separation
of diastereoisomers of (R)-phenylglycinol-derived 2-trifluoromethyl-1,3-
oxazolidine prior to organometallic addition was required to obtain adducts
with diastereomeric ratios up to ∼8:1.
(5) Miao, C. K.; Sorcek, R.; Jones, P.-J. Tetrahedron Lett. 1993, 34,
2259-2262.
642
Org. Lett., Vol. 6, No. 4, 2004

(dr ∼2:1) in d8-THF at -60 °C gave immediate and complete
deprotonation and ring opening to provide a stable 2:1
mixture of (E)- and (Z)-imines A. Addition of PhLi to this
mixture at -60 °C gave the expected adduct 3c with a similar
dr of ∼2:1. The ratio of imines A remained unchanged from
-60 to 0 °C; however, upon warming to room temperature,
the (Z)-imine methine resonance at 7.71 ppm gradually
disappeared and was concomitantly converted over ∼1 h to
a single (E)-imine B methine signal at 7.78 ppm. Addition
of PhLi in THF at -78 °C gave amino alcohol 3c in 64%
yield and diastereomeric ratio >40:1 as determined by
HPLC. By using this procedure, amino alcohol 3c could be
generated by a simple one-pot base-mediated oxazolidine ring
opening/imine isomerization/organometallic addition process
(Scheme 3).8
Table 3. Diastereoselective Organometallic Addition to Iminea
prod- yield
entry no.
R
Ar
1-naphthyl
4-bromophenyl
4-methoxyphenyl
uct
(%)b drc
1
2
2c CF3
2c CF3
4a
4b
4c
89 40:1
82 40:1
89 40:1
95 40:1
74 69:1
89 40:1
76 36:1
60 40:1
89 77:1
94 40:1
92 69:1
75 40:1
78 40:1
82 40:1
3
4
5
6
7
8
2c CF3
2c CF3
2c CF3
2c CF3
2c CF3
2c CF3
3-trifluoromethylphenyl 4d
2-methylthiophenyl
3-fluoro-4-methoxy
3-pyridyl
4e
4f
4g
4h
4i
We explored the scope of this procedure with respect to
the nature of the chiral amino alcohol (Table 2). Treatment
2-furyl
9
2g CF2CF3 phenyl
10
11
12
13
14
2g CF2CF3 3-trifluoromethylphenyl 4j
2g CF2CF3 2-methylthiophenyl
2h CF2H
2h CF2H
2h CF2H
4k
4l
phenyl
Table 2. Diastereoselective Organometallic Addition to Iminea
3-trifluoromethylphenyl 4m
2-methylthiophenyl 4n
a Conditions: (a) Me3SiCl, LiN(SiMe3)2, THF, 0 °C to rt; ArLi, THF,
-78 °C; H3O+. b Isolated yield after column chromatography. c Diastereo-
meric ratios determined by HPLC analysis of the crude products.
illustrated in Table 3, a variety of aryllithium reagents10 added
smoothly to the imine derived from 4-isobutyl-2-trifluoro-
methyl-1,3-oxazolidine 2c (entries 1-8). Nonsubstituted,
mono- and disubstituted including para-, meta-, and ortho-
substituted aryllithium, and heteroaryllithium reagents added
in 60-95% yields and diastereoselectivities ranging from
dr 36:1 to 69:1. The procedure was extended to 2-pentafluo-
roethyl-1,3-oxazolidine 2g, which behaved similarly to
oxazolidine 2c, affording amino alcohol adducts 4i-k in 89-
94% yields without erosion in stereoselectivity (dr 40:1 to
77:1). The use of 2-difluoromethyl-1,3-oxazolidine 2h also
yield
(%)b
entry
no.
R1
product
drc
49:1
>100:1
44:1
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
Et
i-Pr
i-Bu
3a
3b
3c
3d
3e
3f
97
97
64
81
88
86
PhCH2
t-Bu
(CH2)2SMe
40:1
35:1
38:1
a Conditions: (a) Me3SiCl, LiN(SiMe3)2, THF, 0 °C to rt; PhBr, n-BuLi,
THF, -78 °C; H3O+. b Isolated yield after column chromatography.
c Diastereomeric ratios determined by HPLC analysis of the crude products.
1
proved successful. However, in this case H NMR analysis
in CDCl3 showed that imine A (R2 ) CF2H in Scheme 3),
generated by treatment of oxazolidine 2h with Me3SiCl and
LiN(SiMe3)2, existed as a 2:1 mixture of geometric isomers
of diastereomeric oxazolidines 2a-f with Me3SiCl and LiN-
(SiMe3)2 in THF at 0 °C and warming to room temperature
over 1 h gave single imine (E)-isomer B in all cases as
1
ascertained by H and 19F NMR spectroscopy. Subsequent
(11) Representative procedure: To a solution of oxazolidine 2c (247.2
mg, 1 mmol) in THF (2 mL) at 0-5 °C was added Me3SiCl (152 µL, 1.20
mmol, 1.2 equiv) and LiN(SiMe3)2 (1.20 mL, 1.20 mmol, 1.2 equiv, 1 M
in THF). The solution was stirred for 30 min, the cooling bath was removed,
and the mixture was warmed to room temperature for 1 h. In a separate
flask 3-bromobenzotrifluoride (418 µL, 3 mmol, 3.0 equiv) was charged in
THF (6 mL). The solution was cooled to -78 °C and n-BuLi (1.88 mL, 3
mmol, 3.0 equiv, 1.6 M in hexanes) was added. After being stirred for 15
min, the solution of imine was transferred via cannula and the mixture was
stirred at -78 °C for 2 h. The reaction was quenched with 1 N HCl (2 mL)
then warmed to room temperature for 30 min, NaOH (5 mL, 2.5 N) was
added, and the solution was extracted with MTBE (15 mL). The layers
were separated and the organic layer was washed with brine (2 mL), dried
with MgSO4, and concentrated under vacuum. Chromatography of the
addition of phenyllithium at -78 °C gave amino alcohol
products 3a-f in 63-97% yields, with diastereomeric ratios
ranging from 35:1 to >100:1.9-11
We then investigated the scope of this methodology with
respect to the nature of the aryllithium nucleophile. As
(7) Imine 4 was prepared in 2 steps and 80% yield by protection of
commercially available (S)-leucinol (1c) with TBDMSCl, followed by
reaction with trifluoroacetaldehyde methyl hemiacetal (ppts, PhCH3, ∆).
1H NMR spectroscopic analysis confirmed that imine 4 was a single
geometric isomer.
(8) During the course of our work, a conceptually related method for
opening acetals and oxazolidines was reported: Iwata, A.; Tang, H.; Kunai,
A.; Ohshita, J.; Yamamoto, Y.; Matui, C. J. Org. Chem. 2002, 67, 5170-
5175.
residue (20% EtOAc in hexanes) gave amino alcohol 4d: colorless oil,
1
370 mg, 95% yield, dr 40:1; [R]20 +48.3 (c 6.9, MeOH); H NMR (500
D
MHz, CDCl3) δ 7.65 (m, 2H), 7.60 (m, 1H), 7.53 (m, 1H), 4.40 (dd, 1H,
J ) 15.7, 11.9 Hz), 3.50 (dd, 1H, J ) 10.9, 3.5 Hz), 3.29 (dd, 1H, J )
10.8, 7.3 Hz), 2.55 (m, 1H), 2.06 (br s, 2H), 1.54 (m, 1H), 1.31 (m, 1H),
1.20 (m, 1H), 0.88 (d, 3H, J ) 6.6 Hz), 0.75 (d, 3H, J ) 6.5 Hz); 13C
NMR (125 MHz, CDCl3) δ 135.6, 132.2, 131.1 (q, J ) 33 Hz), 129.3,
125.9, 125.8, 123.8 (q, J ) 272 Hz), 119.1 (dt, J ) 287, 36 Hz), 114.3 (qt,
J ) 258, 34 Hz), 64.7, 60.0 (app t, J ) 22 Hz), 54.8, 40.3, 24.8, 23.2,
22.2; LRMS calcd for C16H19F8NO 393.32, found 393.9 [M+1].
(9) The minor diastereomer was quantified by HPLC, using enriched
samples prepared by direct organolithium addition to oxazolidines 2a-g
that typically gave ∼2:1 diastereomeric ratios.
(10) Solutions of aryllithium species were freshly generated from the
corresponding aryl bromides via halogen-metal exchange with n-BuLi or
by deprotonation of the corresponding hydrocarbon in the case of furan.
Org. Lett., Vol. 6, No. 4, 2004
643

at room temperature (Scheme 3). Heating to 60 °C for 1 h
completed the isomerization and gave imine B as a single
(E)-isomer that underwent organometallic addition at -78
°C to provide amino alcohols 4l-n in 75-82% yields and
consistently high diastereoselectivities (dr 40:1).11
Oxidative cleavage of the amino alcohol moiety from
adduct 3c with Pb(OAc)4 gave 2,2,2-trifluoro-1-phenethyl-
amine (S)-5 (Scheme 4).12 The (S)-stereochemistry was
(c 0.65, MeOH)]). This result confirmed that the stereo-
chemical outcome of the organometallic addition was
consistent with preferential attack on the si face of the (E)-
imine intermediate.
In conclusion, we have developed a practical method for
the asymmetric synthesis of aryl R-fluoroalkyl amino alco-
hols using a one-pot base-induced oxazolidine ring opening/
imine isomerization/diastereoselective organometallic addi-
tion sequence.
Acknowledgment. The authors thank Dr. Laird Trimble
for assistance in performing variable-temperature H NMR
and 19F spectroscopy experiments.
Scheme 4. Determination of Stereochemistrya
1
Supporting Information Available: Experimental pro-
cedures and characterization for compounds 2a-h, 3a-f,
and 4a-n. This material is available free of charge via the
Internet at http://pubs.acs.org.
a Reagents and conditions: (a) Pb(OAc)4, MeOH, CH2Cl2, 0 °C,
then aq HCl, EtOH.
OL036486G
assigned by comparison of optical rotation values with
literature ([R]20D +22.2 (c 0.75, MeOH) [lit.3a [R]20D +28.6
(12) Mokhallalati, M. K.; Pridgen, L. N. Synth. Commun. 1993, 23,
2055-2064.
644
Org. Lett., Vol. 6, No. 4, 2004