Palladium-catalyzed tert-butoxycarbonylation of trifluoroacetimidoyl iodides

Article abstract of DOI:10.1021/jo991917n

A modification and details of the palladium-catalyzed tert-butoxycarbonylation of 2,2,2-trifluoroacetimidoyl iodides 1, which gave the iminocarboxylates 2, one of the promising precursors to fluorinated α-amino acids, are described. The Pd-catalyzed carbonylation reaction was remarkably promoted by the use of DMF or DMI as an additive, enough to achieve the selective formation of tert-butyl iminoesters. Nucleophilic alkylation of the imine moiety of 2 and subsequent removal of N- and O-protecting groups gave a variety of 2-substituted 2-amino-3,3,3-trifluoropropanoic acid derivatives 3 in high yields.

Full text of DOI:10.1021/jo991917n

3404
J . Org. Chem. 2000, 65, 3404-3408
P a lla d iu m -Ca ta lyzed ter t-Bu toxyca r bon yla tion of
Tr iflu or oa cetim id oyl Iod id es
Hideki Amii, Yosuke Kishikawa, Katsuhiko Kageyama, and Kenji Uneyama*
Department of Applied Chemistry, Faculty of Engineering, Okayama University,
Okayama 700-8530, J apan
Received December 14, 1999
A modification and details of the palladium-catalyzed tert-butoxycarbonylation of 2,2,2-trifluoro-
acetimidoyl iodides 1, which gave the iminocarboxylates 2, one of the promising precursors to
fluorinated R-amino acids, are described. The Pd-catalyzed carbonylation reaction was remarkably
promoted by the use of DMF or DMI as an additive, enough to achieve the selective formation of
tert-butyl iminoesters. Nucleophilic alkylation of the imine moiety of 2 and subsequent removal of
N- and O-protecting groups gave a variety of 2-substituted 2-amino-3,3,3-trifluoropropanoic acid
derivatives 3 in high yields.
In tr od u ction
processes for the introduction of a carbonyl group into
the molecule.8 The facile CO insertion into organometallic
compounds, followed by the nucleophilic attack of various
nucleophiles, affords ketones,9 carboxylic acids,10 esters,11
and amides.12 Carboalkoxylation of organic halides gives
the homologated esters by the use of a catalytic amount
of transition metal complexes. While much has been
learned preparing the methyl, ethyl, and n-butyl esters
as a carboalkoxylation product, to our knowledge very
few studies have been performed on the synthesis of the
tert-butyl esters,13,14 which act as an easily removable
O-protecting group. One serious drawback to the transi-
tion-metal-catalyzed carboalkoxylation of organic halide
is the structural restriction, especially of the reactant
alcohols. Actually, methanol, butanol, and benzyl alcohol
can be used and gave the corresponding esters in good
yield, whereas with tertiary alcohols, the carbonylation
did not work well, probably as a result of steric hindrance
of the alcohol nucleophiles.13,15 For example, Tanaka15a
and Watanabe15b reported that the reactions of organic
Fluorinated amino acids and peptides are an important
class of unnatural molecules that have been successfully
used in an expanded repertoire of biological applications,
and they are receiving increasing attention in the me-
dicinal, agricultural, and material sciences.1,2 These
compounds owe their unique biological properties to the
profound electron-withdrawing effect caused by fluorine
atom(s) that occurs without significant steric conse-
quence. Some fluorine-containing amino acid derivatives
exhibit enzyme inhibition activities.3 So, the development
of new synthetic methodology for preparing fluorine-
containing R-amino acids is of particular interest.4,5
Despite a growing interest, there are few synthetic
methods available for the preparation of fluoro R-amino
acids, and many of these methods utilize hazardous and
expensive reagents or require harsh reaction conditions.6
A more practical and general preparative method must
be devised.7
The transition-metal-catalyzed carbonylation of organic
halides is one of the most versatile and convenient
(7) For recent reports, see (a) Soloshonok, V. A.; Avilov, D. V.;
Kukhar, V. P. Tetrahedron: Asymmetry 1996, 7, 1547. (b) Soloshonok,
V. A.; Kukhar, V. P. Tetrahedron 1997, 53, 8307. (c) Shi, G.-Q.; Cao,
Z.-Y.; Zhang, X.-B. J . Org. Chem. 1995, 60, 6608. (d) Bravo, P.;
Crucianelli, M.; Vergani, B.; Zanda, M. Tetrahedron Lett. 1998, 39,
7771. (e) Percy, J . M.; Prime, M. E.; Broadhurst, M. J . J . Org. Chem.
1998, 63, 8049. (f) Osipov, S. N.; Golubev, A. S.; Sewald, N.; Michel,
T.; Kolomiets, A. F.; Fokin, A. V.; Burger, K. J . Org. Chem. 1996, 61,
7521. (g) Osipov, S. N.; Bruneau, C.; Picquet, M.; Kolomiets, A. F.;
Dixneuf, P. H. Chem. Commun. 1998, 2053. (h) Fustero, S.; Pina, B.;
Garc´ıa de la Torre, M.; Navarro, A.; Ram´ırez de Arellano, C.; Simo´n,
A. Org. Lett. 1999, 1, 977.
(8) (a) Heck, R. F. Palladium Reagents in Organic Syntheses;
Academic Press: New York, 1985. (b) Colquhoun, H. M.; Thompson,
D. J .; Twigg, M. V. Carbonylation; Plenum Press: New York, 1991.
(c) Tsuji, J . Palladium Reagents and Catalysts; J ohn Wiley & Sons:
New York, 1995. (d) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94,
1047.
* Ph: 81-86-251-8075. Fax: 81-86-251-8075. E-mail: uneyamak@
cc.okayama-u.ac.jp.
(1) (a) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; J ohn Wiley & Sons: New York, 1991. (b) Biomedical
Frontiers of Fluorine Chemistry; Ojima, I.; McCarthy, J . R.; Welch, J .
T., Eds.; ACS Symposium Series 639; American Chemical Society:
Washington, DC, 1996. (c) Filler, R.; Kobayashi, Y. Biomedicinal
Aspects of Fluorine Chemistry; Kodansha Ltd.: Tokyo, 1982. (d)
Synthesis and Speciality of Organofluorine Compounds; Ishikawa, N.,
Ed.; CMC: Tokyo, 1987. (e) Biologically Active Organofluorine Com-
pounds; Ishikawa, N., Ed.; CMC: Tokyo, 1990.
(2) Kukhar, V. P.; Soloshonok, V. A. Fluorine-containing Amino
Acids: Synthesis and properties; J ohn Wiley & Sons: New York, 1995.
(3) (a) Faraci, W. S.; Walsh, C. T. Biochemistry 1989, 28, 431. (b)
Kumadaki, I. J . Synth. Org. Chem. J pn. 1984, 42, 786. (c) Kollonitsch,
J . Isr. J . Chem. 1978, 17, 53.
(4) Uneyama, K. In Enantiocontrolled Synthesis of Fluoro-Organic
Compounds; Soloshonok, V. A., Ed.; J ohn Wiley & Sons, Ltd.: Chich-
ester, 1999; pp 391-418.
(9) (a) Tanaka, M. Tetrahedron Lett. 1979, 28, 2601. (b) Kobayashi,
T.; Tanaka, M. J . Organomet. Chem. 1981, 205, C27.
(10) Bumagin, N. A.; Nikitin, K. V.; Beletskaya, I. P. J . Organomet.
Chem. 1988, 358, 563.
(5) Welch, J . T. Tetrahedron 1987, 43, 3123.
(6) (a) Bey, P.; Vevert, J . P.; Van Dorrelaer, V.; Kolb, M. J . Org.
Chem. 1979, 44, 2732. (b) Metcalf, B. W.; Bey, P.; Danzin, C.; J ung,
M. J .; Casara, P.; Vevert, J . P. J . Am. Chem. Soc. 1978, 100, 2551. (c)
Weygand, F.; Steglich, W.; Oettmeier, W.; Maierhofer, A.; Roy, R. S.
Angew. Chem., Int. Ed. Engl. 1966, 5, 600. (d) Burger, K.; Hubl, D.;
Gertitschke, P. J . Fluorine Chem. 1985, 27, 327. (e) Knunyants, I. L.;
Shokina, V. V.; Tyuleneva, V. V. Dokl. Akad. Nauk SSSR 1966, 169,
594; Proc. Acad. Sci. USSR, Chem. Sect. 1966, 169, 722; Chem. Abstr.
1966, 65, 15218d.
(11) (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J . Org. Chem. 1974,
39, 3318. (b) Stille, J . K.; Wong, P. K. J . Org. Chem. 1975, 40, 532.
(12) (a) Schoenberg, A.; Heck, R. F. J . Org. Chem. 1974, 39, 3327.
(b) Futigami, T.; Ojima, I. Tetrahedron Lett. 1982, 23, 4099.
(13) Huth, A.; Beetz, I.; Schumann, I.; Thielert, K. Tetrahedron Lett.
1986, 27, 1071.
(14) (a) Adapa, S. R.; Prasad, C. S. N. J . Chem. Soc., Perkin Trans.
1 1989, 1706. (b) Alper, H.; Hamel, N.; Smith, D. J . H.; Woell, J . B.
Tetrahedron Lett. 1985, 26, 2273.
10.1021/jo991917n CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/28/2000

Palladium-Catalyzed tert-Butoxycarbonylation
J . Org. Chem., Vol. 65, No. 11, 2000 3405
Sch em e 1
Sch em e 3
yield.16,19 tert-Butyl ester 5 (R ) t-Bu; 5a ) is an interesting
alternate source of fluoro amino acids, because the tert-
butyl group can be readily removed by treatment with
an acid. However, the use of tert-butyl alcohol resulted
in the production of a trace amount of tert-butyl ester
5a .
In this paper, we describe details of the carboalkoxy-
lation of the fluorinated imidoyl halides 4 under mild
conditions and show a dramatic additive effect upon the
reaction, which overcomes the limitations for the tert-
butyl ester preparation, leading to a variety of fluorinated
R-amino acids.
Sch em e 2
Resu lts a n d Discu ssion
A Mod el Exp er im en t: Stoich iom etr ic Rea ction s
of Or gan opalladiu m (II) Species with Alcoh ols. There
remains a difficulty in introducing a tert-butoxycarbonyl
group to an organic molecule by catalytic carboalkoxy-
lation, probably due to steric hindrance of the alcohol
nucleophiles. However, the carboalkoxylation with ter-
tiary alcohols has received much less attention despite
its great synthetic potential. To overcome this drawback,
we have particularly investigated the nucleophilic sub-
stitution reaction of alkanoyl palladium(II) complexes
with alcohols by direct observation of the reaction
intermediates.
halides with tert-butyl alcohol under pressure of CO at
high temperature gave the corresponding esters 1-3 in
poor yields (Scheme 1).
In our previous communication, we reported an ef-
ficient route to prochiral fluoro R-amino acid derivatives
5 via the palladium-catalyzed carboalkoxylation of flu-
orinated imidoyl halides 4.16 The simple procedure, mild
reaction conditions (rt, 1 atm of CO), and availability of
the starting materials17,18 render this method a valuable
protocol for the preparation of fluoro amino acid deriva-
tives19,20 (Scheme 2).
The Pd-catalyzed carboalkoxylation reactions are con-
sidered to proceed via an acylpalladium(II) intermediate
8 that is formed by oxidative addition of palladium(0) to
halides 6, followed by insertion of carbon monoxide into
the palladium-carbon bond of 7. The following nucleo-
philic attack of the alcoholic hydroxyl group at the
acylpalladium intermediate 8 would terminate the cata-
lytic cycle, affording the ester 9 as depicted in Scheme
3.
In this reaction, there seem to be two important
steps: one is the carbonyl-insertion step to generate the
acylpalladium complex 8, and another is the nucleophilic
attack of the alcohols to the acylpalladium 8. The latter
step is considered to be especially significant because the
reaction rates of the carboalkoxylation decreased with
increase of the bulkiness of the alcohol nucleophiles.
We investigated details of the reaction of acylpalla-
dium(II) species with alcohols by stoichiometric use of
benzoylchlorobis(triphenylphosphine)palladium(II) com-
plex (10)21 as a model intermediate of the acylpalladium
8 (Scheme 4).
In amino acid synthesis, the choice of the N- and
O-protecting groups is of paramount importance. There
remains a serious problem with deprotection in asym-
metric amino acid syntheses, despite a wide number of
amino acid derivatives having been made. For instance,
hydrolysis of ethyl esters (removal of ethyl group) under
basic conditions occasionally involves racemization of the
stereogenic center(s) of the products, and in particular,
dehydrofluorination is a serious side reaction in the
alkaline hydrolysis of â-fluorinated amino esters. Thus,
it is necessary to investigate the iminoesters 5 that have
easily removable protecting groups under neutral or
acidic conditions. From this viewpoint, benzyl ester 5 (R
) Bn), which is a good precursor to the free amino acid
as a result of the easy removal of the benzyl group (H2,
Pd/C) under neutral conditions, was obtained in high
(15) (a) Sakakura, T.; Yamashita, H.; Kobayashi, T.; Hayashi, T.;
Tanaka, M. J . Org. Chem. 1987, 52, 5733. (b) Takeuchi, R.; Tsuji, Y.;
Fujita, M.; Kondo, T.; Watanabe, Y. J . Org. Chem. 1989, 54, 1831.
(16) Watanabe, H.; Hashizume, Y.; Uneyama, K. Tetrahedron Lett.
1992, 33, 4333.
(17) Uneyama, K. J . Fluorine Chem. 1999, 97, 11.
(18) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.; Uneyama,
K. J . Org. Chem. 1993, 58, 32.
(19) Previously in our laboratory, enantiomerically enriched 3,3,3-
trifluoroalanine (up to 62% ee) was synthesized by the asymmetric
reduction of 5 with a chiral oxazaborolidine catalyst; see: (a) Sakai,
T.; Yan, F.; Uneyama, K. Synlett. 1995, 753. (b) Sakai, T.; Yan, F.;
Kashino, S.; Uneyama, K. Tetrahedron 1996, 52, 233.
(20) (a) Uneyama, K.; Yan, F.; Hirama, S.; Katagiri, T. Tetrahedron
Lett. 1996, 37, 2045. (b) Uneyama, K.; Kato, T. Tetrahedron Lett. 1998,
39, 587.
Several attempts to transform 10 to tert-butyl benzoate
(11) have been made by the choice of temperature,
solvents, ligands, and bases, but they were of limited
success. Even use of tert-butyl alcohol as a solvent
produced only 24% of tert-butyl ester 11. Interestingly,
the reaction was accelerated using DMF as an additive,
(21) Suzuki, K.; Nishida, M. Bull. Chem. Soc. J pn. 1973, 46, 2887.

3406 J . Org. Chem., Vol. 65, No. 11, 2000
Amii et al.
Sch em e 4
iodides 4 (entries 5-7). As shown in Table 1, it is obvious
that secondary alcohols such as isopropyl alcohol and (l)-
menthol worked well in this modified protocol, while
reactions in the absence of additives resulted in low
conversion (entries 7 and 9).
The additives DMF and DMI might act as a polar
solvent to enhance the nucleophilicity of tert-butyl alcohol
and/or as a weak enough ligand to reduce aggregation23
of the intermediate palladium species, which blocks Pd
coordination sites, and to accelerate coordination of CO
to palladium.
Ta ble 1. P d -Ca ta lyzed Ca r bon yla tion w ith Bu lk y
Alcoh ols
Syn th esis of F lu or in a ted r-Am in o Acid s. Fluori-
nated iminoester 5a , hardly accessible by means of other
methods, possesses both an easily removable N-protect-
ing group (PMP) and an O-protecting group (t-Bu) and
can act as a precursor to fluorinated amino acids by
reaction with a range of nucleophiles to the imino carbon
of 5.7d,f,g,19 The iminoester 5a has been converted to tert-
butyl N-(p-methoxyphenyl)amino-3,3,3-trifluoropropanoate
by nucleophilic alkylation of the imine moiety (Scheme
5). Oxidative removal of the p-methoxyphenyl group by
treatment with CAN (cerium ammonium nitrate) gave
the corresponding 2-amino-3,3,3-trifluoropropanoates.
The tert-butyl aminoesters 12-15, which are an alter-
native precursor to fluoro amino acids, readily underwent
deprotection of the t-Bu group under acidic conditions
(HCl (aq)) to give the corresponding 2-amino-3,3,3-
trifluoropropanoic acid derivatives 16-19 in high yields.
It is noted that alkene and alkyne functionalities in 14
and 15, which would be fragile under Pd-catalyzed
hydrogenolytic conditions, were compatible under the
present acidic conditions.
solvent/
time
(days) (% yield)
5
entry
Rf
R′
additivea
1
2
3
4
5
6
CF3 (4a )
CF3 (4a )
CF3 (4a )
C3F7 (4b)
t-Bu
t-Bu
t-Bu
t-Bu
t-BuOH
2
4
3
4
4
5
1
1
2
2
5a (25)
5a (52)
5a (62)
5b (71)
5c (74)
5d (41)
5e (49)
5e (72)
5f (12)
5f (51)
t-BuOH/DMF
t-BuOH/DMI
t-BuOH/DMI
t-BuOH/DMI
t-BuOH/DMI
toluene
C7F15(4c) t-Bu
CF2Cl (4d ) t-Bu
7b CF3 (4a )
i-Pr
i-Pr
8b CF3 (4a )
toluene/DMF
9
10
CF3 (4a )
CF3 (4a )
(l)-menthyl toluene
(l)-menthyl toluene/DMI
a
t-BuOH/DMF (9:1 v/v), t-BuOH/DMI (9:1 v/v), toluene/DMF
b
(9:1 v/v), and toluene/DMI (9:1 v/v). Pd2(dba)3‚CHCl3 (Pd, 0.04
equiv) was used.
and the yields of the benzoate increased up to 44%.
Addition of aprotic polar solvents induced a moderate
acceleration of the reaction.
Con clu sion
P d -Ca t a lyzed Ca r b oa lk oxyla t ion of Tr iflu or o-
a cetim id oyl Iod id es: An Im p r oved P r oced u r e. In-
deed, in our case we have found that the carboalkoxyla-
tion with secondary and tertiary alcohols afforded the
iminoesters 5 (R ) i-Pr, t-Bu) in poor yields (Scheme 2).
The Pd-catalyzed carboalkoxylation of 2,2,2-trifluoro-
acetimidoyl iodide 4 is also considered to proceed via
insertion of CO into the Pd-C bond of the imidoyl
palladium intermediate,22 followed by nucleophilic attack
of the alcohol. As mentioned above, formation of the tert-
butyl esters from acylpalladium intermediates was ac-
celerated using aprotic polar solvents as an additive.
Encouraged by the promising effect of the additives, we
next explored the catalytic version of the corresponding
carboalkoxylation of fluorinated imidoyl iodides 4 accord-
ing to this modified method.
Now, fluorine-containing amino acids and their deriva-
tives are receiving increasing attention in the medicinal,
agricultural, and material sciences. So there still remains
a great demand for more practical, versatile, and reliable
methods for the synthesis of fluorinated amino acids. One
of the potential advantages of our method is demon-
strated by the ready availability of the starting materials
and reagents. Furthermore, the success in introducing
the easily removable tert-butyl group by fine-tuning of
the palladium-catalyst system might well contribute to
asymmetric amino acid synthesis. Enantioselective re-
duction or alkylation of the imine moiety of 5 is one of
the subjects worthy of further investigation.19
Exp er im en ta l Section
A mixture of trifluoroacetimidoyl iodide 4a , Pd2(dba)3‚
CHCl3 (Pd atom; 0.10 equiv), K2CO3, 0.9 mL of tert-butyl
alcohol, and 0.1 mL of DMI was sttirred at room tem-
perature for 4 days under CO atmosphere (1 atm). The
present modification dramatically increased the yield of
the tert-butyl iminoester 5a to 62%.
Other examples of the selective formation of the
fluorinated tert-butyl iminoesters 5b-d are given in
Table 1. Generally, this optimized procedure was found
to work well with various kinds of the fluorinated imidoyl
1H and 19F NMR spectra were recorded at 200 and 188 MHz,
respectively. The chemical shifts are reported in δ (ppm) values
relative to TMS (δ 0 ppm for 1H NMR), C6F6 (δ 0 ppm for 19F
NMR in CDCl3), and CF3CO2H (δ 0 ppm for 19F NMR in D2O).
Coupling constants are reported in hertz (Hz). All air- and/or
water-sensitive reactions were carried out under argon atmo-
sphere with dry, freshly distilled solvents using standard
syringe-cannula/septa techniques. THF was distilled from
sodium/benzophenone ketyl. Toluene, DMF, DMI, and tert-
butyl alcohol were distilled from CaH2. All other reagents and
(23) Recently, trifluoroacetimidoyl palladium(II) complex ([Pd(µ-I)-
{µ-C(CF3)dN(PMP)}]4:20), which is considered to be a key intermediate
of Pd-catalyzed carboalkoxylation of imidoyl iodides, has been synthe-
sized by the reaction of 4 with Pd2(dba)3‚CHCl3 and has been confirmed
a cyclic tetranuclear complex by X-ray crystal structure analysis. The
details of the structure and reactions of the complex 20 will be
discussed in a future paper.
(22) Imidoyl palladium complexes: (a) Tanaka, M.; Alper, H. J .
Organomet. Chem. 1979, 168, 97. (b) Uso´n, R.; Fornie´s, J .; Espinet,
P.; Lalinde, E.; J ones, P. G.; Sheldrich, G. M. J . Chem. Soc., Dalton
Trans. 1982, 2395. (c) Uso´n, R.; Fornie´s, J .; Espinet, P.; Garcia, A.;
Tomas, M.; Foces-Foces, C.; Cano, F. H. J . Organomet. Chem. 1985,
282, C35.

Palladium-Catalyzed tert-Butoxycarbonylation
J . Org. Chem., Vol. 65, No. 11, 2000 3407
Sch em e 5
solvents were employed without further purification. E. Merck
silica gel (Kieselgel 60, 230-400 mesh) was employed for the
chromatography.
ter t-Bu tyl 2-[N-(p-Meth oxyp h en yl)im in o]-3-ch lor o-3,3-
d iflu or op r op a n oa te (5d ). Yellow oil; IR (neat) 1738, 1604
1
cm-1; H NMR (CDCl3) δ 7.01 (d, J ) 9.0, 2 H), 6.88 (d, J )
9.0, 2 H), 3.82 (s, 3 H), 1.38 (s, 9 H); 19F NMR (CDCl3) δ 104.4
(s, 2 F); MS m/z 319 (M+, 15), 263 (89), 218 (78), 178 (17), 134
(100). Anal. Calcd for C14H16ClF2NO3: C, 52.59; H, 5.04; N,
4.38. Found: C, 52.46; H, 5.27; N, 4.68.
Trifluoroacetimidoyl iodide 4a was prepared by replacement
of the chlorine atom of the corresponding chloride 21 with
sodium iodide in acetone quantitatively, which was prepared
in 80-90% yields by refluxing a mixture of TFA (1 equiv),
arylamines (1 equiv), triphenylphosphine (3 equiv), and tri-
ethylamine (1 equiv) in CCl4. Other perfluoroalkaneimidoyl
chlorides were also prepared by the same method using the
corresponding perfluoroalkanoic acids as a starting material.
ter t-Bu tyl 2-[N-(p-Meth oxyp h en yl)im in o]-3,3,3-tr iflu o-
r op r op a n oa te (5a ). Typical procedure for the synthesis of
tert-butyl ester. A two-necked flask with a CO (1 atm) balloon
attached was charged with Pd2(dba)3‚CHCl3 (0.017 g, 0.016
mmol) and K2CO3 (0.088 g, 0.64 mmol). Then 0.100 g (0.30
mmol) of trifluoroacetimidoyl iodide (4a ) in 0.9 mL of tert-butyl
alcohol was added to the catalyst mixture. Subsequently, 0.1
mL of additive (DMI) was added. The reaction vessel was
wrapped in aluminum foil to minimize exposure to light, and
the mixture was stirred for 4 days at room temperature. The
resulting suspension was filtered through a short Florisil
column (CH2Cl2). After evaporation of the solvent, the residue
was purified by silica gel column chromatography (hexane/
ether, 15:1) to give a yellow oil (0.057 g, 0.19 mmol, 62%): IR
(neat) 1740, 1606 cm-1; 1H NMR (CDCl3) δ 7.01 (d, J ) 9.1, 2
H), 6.89 (d, J ) 9.1, 2 H), 3.82 (s, 3 H), 1.39 (s, 9 H); 19F NMR
(CDCl3) δ 92.1 (s, 3 F); MS m/z 303 (M+, 16), 247 (100), 202
(91), 134 (20). Anal. Calcd for C13H16F3NO3: C, 55.45; H, 5.32;
N, 4.62. Found: C, 55.54; H, 5.55; N, 4.66.
ter t-Bu t yl 2-[N-(p -Met h oxyp h en yl)a m in o]-2-t r iflu o-
r om eth ylh exa n oa te (12). To a THF (3.0 mL) solution of tert-
butyl iminoester 5a (0.201 g, 0.66 mmol) stirring under an
argon atmosphere at -78 °C was added n-butyllithium (1.57
M, 0.46 mL, 0.72 mmol) dropwise. The reaction mixture was
stirred for 10 min and quenched with saturated aqueous NH4-
Cl. The aqueous layer was extracted with ether (5 mL × 3),
and the combined organic phase was washed with brine and
dried over MgSO4. The solvent was removed under reduced
pressure, and the residue was purified by silica gel column
chromatography (hexane/ether, 15:1) to give a slightly yellow
oil (0.2314 g, 0.64 mmol, 97%): IR (neat) 3388, 1740 cm-1; 1H
NMR (CDCl3) δ 6.84 (d, J ) 9.2, 2 H), 6.75 (d, J ) 9.2, 2 H),
3.76 (s, 3 H), 2.23-2.00 (m, 2 H), 1.51 (s, 9 H), 1.30-1.00 (m,
4 H), 0.76 (t, J ) 6.6, 3 H), NH not observable; 19F NMR
(CDCl3) δ 88.5 (s, 3 F); MS m/z 361 (M+, 10), 305 (59), 260
(100), 236 (11), 217 (8), 202 (13). Anal. Calcd for C18H26F3-
NO3: C, 59.82; H, 7.25; N, 3.88. Found: C, 59.86; H, 7.49; N,
4.19.
ter t-Bu tyl 2-P h en yl-2-[N-(p-m eth oxyp h en yl)]-3,3,3-tr i-
flu or op r op a n oa te (13). To a THF (0.5 mL) solution of tert-
butyl iminoester 5a (0.050 g, 0.167 mmol) stirring under an
argon atmosphere at -78 °C was added phenyllithium (0.88
M, 0.21 mL, 0.183 mmol) dropwise. The reaction mixture was
stirred for 5 min and quenched with saturated aqueous NH4-
Cl. The aqueous layer was extracted with ether (2 mL × 3),
and the combined organic phase was washed with brine and
dried over MgSO4. After rotary evaporation of the solvent, the
residue was purified by silica gel column chromatography
(hexane/ether, 15:1) to give a slightly yellow oil (0.0606 g, 0.159
ter t-Bu tyl 2-[N-(p-Meth oxyp h en yl)im in o]-3,3,4,4,5,5,5-
h ep ta flu or op en ta n oa te (5b). Yellow oil; IR (neat) 1738,
1
1606 cm-1; H NMR (CDCl3) δ 7.02 (d, J ) 8.7, 2 H), 6.88 (d,
J ) 8.7, 2 H), 3.82 (s, 3 H), 1.38 (s, 9 H); 19F NMR (CDCl3) δ
81.5 (t, J ) 8.8, 3 F), 48.0 (q, J ) 8.8, 2 F), 36.3-36.1 (m, 2 F);
MS m/z 403 (M+, 10), 347 (70), 302 (100), 178 (10), 134 (54).
Anal. Calcd for C16H16F7NO3: C, 47.65; H, 4.00; N, 3.47.
Found: C, 47.51; H, 4.04; N, 3.52.
1
mmol, 95%): IR (neat) 3416, 1742 cm-1; H NMR (CDCl3) δ
7.60-7.50 (m, 2 H), 7.40-7.30 (m, 3 H), 6.59 (d, J ) 9.0, 2 H),
6.45 (d, J ) 9.0, 2 H), 3.67 (s, 3 H), 1.34 (s, 9 H), NH not
observable; 19F NMR (CDCl3) δ 92.7 (s, 3 F); MS m/z 381 (M+,
5), 325 (24), 280 (100), 256 (5), 210 (45), 202 (10). Anal. Calcd
for C20H22F3NO3: C, 62.98; H, 5.81; N, 3.67. Found: C, 62.61;
H, 6.01; N, 3.83.
ter t-Bu tyl 2-[N-(p-Meth oxyp h en yl)]-2-tr iflu or om eth yl-
4-p en ten oa te (14). To a THF (1.0 mL) solution of tert-butyl
iminoester 5a (0.300 g, 0.989 mmol) stirring under an argon
ter t-Bu t yl 2-[N-(p -Met h oxyp h en yl)im in o]-3,3,4,4,5,5,-
6,6,7,7,8,8,9,9,9-p en ta d eca flu or on on a n oa te (5c). Yellow
oil; IR (neat) 1738, 1604 cm-1; 1H NMR (CDCl3) δ 7.03 (d, J )
9.0, 2 H), 6.88 (d, J ) 9.0, 2 H), 3.82 (s, 3 H), 1.37 (s, 9 H); 19
F
NMR (CDCl3) δ 81.0 (t, J ) 9.4, 3 F), 49.0 (t, J ) 12.6, 2 F),
41.0-40.1 (m, 4 F), 40.0-39.4 (m, 2 F), 39.4-38.5 (m, 2 F),
35.9-35.4 (m, 2 F); MS m/z 603 (M+, 5), 547 (55), 502 (100),
134 (87). Anal. Calcd for C20H16F15NO3: C, 39.82; H, 2.67; N,
2.32. Found: C, 40.06; H, 2.65; N, 2.53.

3408 J . Org. Chem., Vol. 65, No. 11, 2000
Amii et al.
atmosphere at 0 °C was added allylmagnesium chloride (0.158
M, 8.1 mL, 1.28 mmol) dropwise. The reaction mixture was
stirred for 10 min and quenched with saturated aqueous NH4-
Cl. The aqueous layer was extracted with ether (5 mL × 3),
and the combined organic phase was washed with brine and
dried over MgSO4. Rotary evaporation and chromatography
(hexane/ether, 15:1) gave the product 14 as a slightly yellow
oil (0.324 g, 0.938 mmol, 95%): IR (neat) 3388, 1738, cm-1; 1H
NMR (CDCl3) δ 6.85 (d, J ) 9.1, 2 H), 6.75 (d, J ) 9.1, 2 H),
5.70-5.35 (m, 1 H), 5.20-5.00 (m, 2 H), 3.76 (s, 3 H), 3.02
(dd, J ) 14.6, 5.8, 1 H), 2.77 (dd, J ) 14.6, 8.1, 1 H), 1.48 (s,
9 H), NH not observable; 19F NMR (CDCl3) δ 89.0 (s, 3 F); MS
m/z 345 (M+, 9), 289 (54), 244 (55), 202 (100), 174 (13). Anal.
Calcd for C17H22F3NO3: C, 59.12; H, 6.42; N, 4.06. Found: C,
59.37; H, 6.68; N, 4.19.
ter t-Bu tyl 6-P h en yl-2-[N-(p-m eth oxyp h en yl)]-2-tr iflu o-
r om eth yl-5-h exyn oa te (15). To a THF (2.0 mL) solution of
tert-butyl iminoester 5a (0.201 g, 0.664 mmol) and 4-iodo-1-
phenyl-2-butyne (0.204 g, 0.795 mmol) stirring under an argon
atmosphere at -100 °C was added tert-butyllithium (1.64 M,
0.96 mL, 1.57 mmol) dropwise. The reaction mixture was
stirred for 5 min and quenched by adding saturated aqueous
NH4Cl. The aqueous layer was extracted with ether (5 mL ×
3), and the combined organic phase was washed with brine
and dried over MgSO4. After filtration and evaporation of the
solvent, the residue was used in the next deprotection steps
without further purification: 19F NMR (CDCl3) δ 88.8 (s, 3 F).
2-Am in o-2-tr iflu or om eth ylh exa n oic Acid Hyd r och lo-
r id e (16). Typical procedure for oxidative deprotection of
p-methoxyphenyl group and subsequent hydrolytic removal of
tert-butyl group. A water (1.7 mL) solution of CAN (cerium-
(IV) ammonium nitrate) (0.341 g, 0.622 mmol) was added
dropwise to 12 (0.075 g, 0.208 mmol) in acetonitrile (5 mL).
The mixture was stirred at room temperature for 1.5 h, poured
into water (2 mL), and succesively extracted with ether (5 mL
× 3). The combined organic phase was washed with brine and
dried over MgSO4. After evaporation of the solvent, the residue
was purified by silica gel column chromatography to afford tert-
butyl 2-amino-3,3,3-trifluoromethylhexanoate (0.0357 g, 0.14
mmol). Concentrated hydrochloric acid (1.0 mL) was added
dropwise to the tert-butyl ester (0.0357 g, 0.14 mmol) in MeOH
(0.5 mL). The mixture was stirred at room temperature for 12
h. Evaporation of the solvent gave a colorless solid (0.033 g,
0.138 mmol, 99%): mp > 143 °C (decomp); IR (KBr) 3400-
1
2300 (br), 1754, 1532 cm-1; H NMR (D2O) δ 2.20-1.92 (m, 1
H), 1.90-1.70 (m, 1 H), 1.30-0.98 (m, 4 H), 0.72 (t, J ) 6.8, 3
H); 19F NMR (D2O) δ 1.3 (s, 3 F). Anal. Calcd for C7H13ClF3-
NO2: C, 35.68; H, 5.56; N, 5.94. Found: C, 35.67; H, 5.65; N,
6.07.
2-Am in o-2-p h en yl-3,3,3-tr iflu or op r op a n oic Acid Hy-
d r och lor id e (17). Pale yellow solid; mp > 158 °C (decomp);
1
IR (KBr) 3400-2300 (br), 1726, 1504 cm-1; H NMR (D2O) δ
7.49-7.37 (m, 5 H); 19F NMR (D2O) δ 5.6 (s, 3 F). Anal. Calcd
for C9H9ClF3NO2: C, 42.29; H, 3.55; N, 5.48. Found: C, 42.01;
H, 3.36; N, 5.62.
2-Am in o-2-tr iflu or om eth yl-4-p en ten oic Acid Hyd r o-
ch lor id e (18). Colorless solid; mp > 139 °C (decomp); IR (KBr)
3400-2300 (br), 1728, 1512 cm-1; 1H NMR (D2O) δ 5.70-5.40
(m, 1 H), 5.35-5.15 (m, 2 H), 2.86 (dd, J ) 14.6, 6.0, 1 H),
2.58 (dd, J ) 14.6, 8.0, 1 H); 19F NMR (D2O) δ 1.9 (s, 3 F).
Anal. Calcd for C6H9ClF3NO2: C, 32.82; H, 4.13; N, 6.38.
Found: C, 32.75; H, 3.88; N, 6.31.
2-Am in o-6-p h en yl-2-tr iflu or om eth yl-5-h exyn oic Acid
Hyd r och lor id e (19). Colorless solid; mp > 146 °C (decomp);
1
IR (KBr) 3300-2300 (br), 1760, 1516 cm-1; H NMR (D2O) δ
7.30-7.13 (m, 5 H), 2.50-2.27 (m, 3 H), 2.25-2.00 (m, 1 H);
19F NMR (D2O) δ 1.7 (s, 3 F). Anal. Calcd for C13H13ClF3NO2:
C, 50.75; H, 4.26; N, 4.55. Found: C, 51.02; H, 4.50; N, 4.38.
Ack n ow led gm en t. We thank SC-NMR Laboratory
1
of Okayama University for H and 19F NMR analyses.
Financial support by the Ministry of Education, Science,
Sports and Culture of J apan (No. 09305058) is also
gratefully acknowledged.
J O991917N