In situ generation of 3,3,3-trifluoropropanal and its use for carbon-carbon bond-forming reactions

Article abstract of DOI:10.1021/jo052434o

The DIBAL reduction of 2-phenylethyl 3,3,3-trifluoro-2-methylpropionate 2 at -78 °C afforded the aluminum acetal 3, and this intermediate, on worming up to 0 °C, was found to slowly decompose into the corresponding aldehyde 4, which smoothly reacted with

Full text of DOI:10.1021/jo052434o

SCHEME 1
In Situ Generation of 3,3,3-Trifluoropropanal
and Its Use for Carbon-Carbon Bond-Forming
Reactions
Takashi Yamazaki,*,† Rei Kobayashi,‡
Tomoya Kitazume,‡ and Toshio Kubota§
Center of Future Nanomaterials, Institute of Symbiotic Sciences
and Technology, Tokyo UniVersity of Agriculture and
Technology, 2-24-16, Nakamachi, Koganei 184-8588, Japan,
Graduate School of Bioscience and Bioengineering, Tokyo
Institute of Technology, 4259 Nagatsuta-cho, Midori-ku,
Yokohama 226-8501, Japan, and Department of Materials
Science, Ibaraki UniVersity, Nakanarusawa 4-12-1, Hitachi,
Ibaraki 316-8511, Japan
weak bases such as tertiary amines,2 and the resultant anionic
intermediates usually follow the smooth delivery of a fluoride
ion to furnish 3,3-difluoroprop-2-enal. The fate of this unstable
intermediate is most likely to lose all fluorine atoms by a
repetitive addition-elimination sequence of appropriate nu-
cleophiles at the highly positively charged terminal sp2 carbon
atom possessing two fluorine atoms.3
tyamazak@cc.tuat.ac.jp
ReceiVed NoVember 24, 2005
Our interest in stereoselective construction of trifluorinated
aldol structures,4 R1-CH(CF3)-CH(OH)-R2, prompted us to
investigate the utilization of 2-substituted 3,3,3-trifluoropropa-
nals as substrates that apparently open the direct access to these
targets by just a single-step reaction with various types of
enolates or their equivalents. In connection with the fact that
the corresponding 3,3,3-trifluoropropionates are relatively more
stable and readily synthesized by various methods,5 we envis-
aged the application of the procedure by Polt and co-workers
(Scheme 1, eq 1),6 which allowed us to utilize the in situ
generated aluminum acetals for the reaction with appropriate
nucleophiles. However, despite its usefulness, to the best of our
knowledge, only limited examples could be found in the
The DIBAL reduction of 2-phenylethyl 3,3,3-trifluoro-2-
methylpropionate 2 at -78 °C afforded the aluminum acetal
3, and this intermediate, on worming up to 0 °C, was found
to slowly decompose into the corresponding aldehyde 4,
which smoothly reacted with appropriate nucleophiles in a
one-pot manner in good to excellent yields with up to 93%
diastereoselectivity.
(2) CnF2n+1CH2CHO was found to follow dehydrofluorination only by
treating with Et3N to give (Z)-Cn-1F2n-1CFdCHCHO stereoselectively.
Le´veˆque, L.; Le Blanc, M.; Pastor, R. Tetrahedron Lett. 1998, 39, 8857. A
similar situation was noticed under 1 mol/L NaOH/EtOH conditions. Hedhli,
A.; Baklouti, A.; Cambon, A. Tetrahedron Lett. 1994, 35, 6877.
(3) The F2CdC carbon is known to possess strongly positive charges.
See: (a) Ueki, H.; Chiba, T.; Yamazaki, T.; Kitazume, T. J. Org. Chem.
2004, 69, 7616. (b) Ichikawa, J.; Wada, Y.; Fujiwara, M.; Sakoda, K.
Synthesis 2002, 1917.
(4) These targets were successfully prepared by a very few research
groups. (a) Hanamoto, T.; Fuchikami, T. J. Org. Chem. 1990, 55, 4969.
(b) Angert, H.; Czerwonka, R.; Reissig, H.-U. Liebigs Ann. 1997, 2215.
(c) Iseki, K.; Kuroki, Y.; Nagai, T.; Kobayashi, Y. Chem. Pharm. Bull.
1996, 44, 477. (d) Konno, T.; Yamazaki, T.; Kitazume, T. Tetrahedron
1996, 52, 199. (e) Konno, T.; Umetani, H.; Kitazume, T. J. Org. Chem.
1997, 62, 137. (f) Loh, T.-P.; Li, X.-R. Eur. J. Org. Chem. 1999, 1893.
(5) (a) Everett, T. S.; Purrington, S. T.; Bumgardner, C. L. J. Org. Chem.
1984, 49, 3702. (b) Miura, K.; Takeyama, Y.; Oshima, K.; Utimoto, K.
Bull. Chem. Soc. Jpn. 1991, 64, 1542. (c) Bouillon, J.-P.; Maliverney, C.;
Mere´nyi, R.; Viehe, H. G. J. Chem. Soc., Perkin Trans. 1 1991, 2147. (d)
Umemoto, T.; Adachi, K. J. Org. Chem. 1994, 59, 5692. (e) Dan-oh, Y.;
Uneyama, K. Bull. Chem. Soc. Jpn. 1995, 68, 2993.
Taking the strong electron-withdrawing properties of a
trifluoromethyl (CF3) group into account,1 it is not difficult to
understand that the lability of the hydrogen atom R to the
carbonyl moiety in 3,3,3-trifluoropropanals is due to the double
activation by both the CF3 and CdO groups. In fact, abstraction
of this hydrogen atom was readily performed even by relatively
* To whom correspondence should be addressed. Fax: +81-42-388-7038.
† Tokyo University of Agriculture and Technology.
‡ Tokyo Institute of Technology.
§ Ibaraki University.
(1) The electron-withdrawing nature of a CF3 group is sometimes
compared with the one of an ester functional group. For example, the pKa
values of CHF2CF3 and CHF2CO2Me were reported to be 28.2 and 25,
respectively. See: Smart, B. E. J. Fluorine Chem. 2001, 109, 3. Moreover,
pKa values of CF3CO2H and HO2CCO2H were 0.5 and 1.271. Lange’s
Handbook of Chemistry, 14th ed.; Dean, J. A., Ed.; McGraw-Hill: New
York, 1992; Section 8.
(6) (a) Polt, R.; Peterson, M. A.; DeYoung, L. J. Org. Chem. 1992, 57,
5469. (b) Razavi, H.; Polt, R. J. Org. Chem. 2000, 65, 5693.
10.1021/jo052434o CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/24/2006
J. Org. Chem. 2006, 71, 2499-2502
2499

TABLE 1. Reaction of Various Nucleophiles to in Situ Prepared
Aldehyde 4a
SCHEME 2
isolated
yield (%)
diastereomer
andi:syn
Prob
R1
R2
R3
5ac
5ad
5ae
5bf
5c
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph
complex
78
75
50
66
84
64
76
71
83:17
83:17
86:14
72:28
61:39
71:29
90:10
93:7
PhCtCg
6a
6b
H
H
Mw
me
H
Ph
EtO
Me
Me
Me2N
Me
6ce,h
6ch
6dh
6e
41
63
65:35
87:13
me
a To an ethereal solution of 2 was added 1.05 equiv of DIBAL and the
mixture was stirred at -78 °C for 0.5 h, when 2 equiv of a nucleophile
was added at the same temperature and the mixture was stirred at 0 °C for
1.5 h. b Product. c THF was employed as the solvent. d Reaction temperature
at -78 and -40 °C after addition of a nucleophile furnished the product
5a in 22% and 68% NMR yields, respectively. e The commercially available
aldehyde 4 was employed instead of the in situ generated aluminum acetal.
f See ref 11. g The corresponding Li salt was used. h Their anti preference
was assumed from the other results.
literature for direct employment of these intermediary acetals,7
mainly because success of this partial reduction is highly
substrate-dependent.8
On the other hand, it is well-known that poly- and perflu-
orinated aldehydes show clear tendency to form the stable
hydrate structure by their significantly electron-withdrawing
nature, which effectively decreases the LUMO energy level and
thus strongly increases the nucleophile-accepting ability of the
carbonyl group.9 For example, the efficient C-C bond formation
of trifluoroacetate-based aluminum acetals was recently realized
by Ishihara’s group9b using allylic stannanes in the presence of
appropriate Lewis acids at 40 °C, which is in sharp contrast to
the case of the Polt procedure proceeding at -78 °C (Scheme
1, eq 2). At this stage, we anticipated that insertion of an
additional CH2 group between CF3 and carbonyl moieties would
render the thermodynamic stability of the corresponding alu-
minum acetals lower. If this is the case, these intermediates such
as 3 would be converted into the aldehyde 4 at higher
temperature, allowing smooth reaction with appropriate nucleo-
philes. Realization of this pathway provides ready access to the
desired CF3-containing aldol structure without need to isolate
such unstable fluorinated aldehydes.10
experimental evidence was interpreted as the result of the smooth
half reduction of 2 by DIBAL, and the resultant aluminum acetal
3 was, as our expectation, stable enough at temperatures as low
as -78 °C. If this is not the case, decomposition of 3 would
mainly produce 4, which should predominantly consume
DIBAL, leading to incomplete conversion of 2 under the
conditions employed.
At the next stage, successfully generated aluminum acetal
intermediate 3 was reacted with PhCH2CH2MgBr as the
representative nucleophile. It appeared that the desired trans-
formation occurred more cleanly in Et2O rather than in THF.
After 30 min of DIBAL reduction at -78 °C, this Grignard
reagent was added, and the temperature was raised to 0 °C just
by changing the dry ice-acetone bath to an ice bath. Stirring
for a further 1.5 h eventually furnished the desired product 5a
in 78% isolated yield in a diastereomeric ratio of anti:syn )
83:17. Less clean reaction in THF would be mainly due to its
higher coordinating ability to Al, which rendered the Al-O bond
weaker, resulting in destabilization of the acetal 3.
Throughout the text, 2-phenylethyl 3,3,3-trifluoro-2-methyl-
propionate 2 was employed as the representative substrate
because it is readily accessible in a simple three-step procedure
starting from the commercially available trifluorinated meth-
acrylic acid 111 (Scheme 2). Partial reduction of this ester 2
was performed at -78 °C using a slight excess (1.05 equiv) of
DIBAL in Et2O, and the TLC analysis of the reaction mixture
after 0.5 h at that temperature clearly demonstrated the produc-
tion of 2-phenylethanol and total disappearance of 2. This
As we have successfully disclosed this optimized condition
at the steps of the acetal formation and its reaction with the
Grignard reagent, various nucleophiles were employed for
proving the usefulness of this process by way of the unique
intermediate 3, whose results were collected in Table 1. Good
to excellent chemical yields were attained in every instance with
good to excellent levels of diastereoselectivity.
Relative stereochemistries of the adducts 5 and 6 were
unambiguously determined by chemical correlation (Scheme 3)
except for the adduct 5b, which was already reported previously.4a
Chromatographic purification of 6a enabled us to partially
resolve the diastereomer mixture, and the fraction collected was
found to be composed of a 95:5 mixture of anti and syn isomers.
Because this sample was fortunately solidified and recrystalli-
zation afforded a good quality of crystal, the X-ray crystal-
lographic analysis was carried out to clearly demonstrate that
the major isomer of 6a possessed an anti relative stereochemical
relationship between the hydroxy- and CF3-attached carbon
atoms. At the next stage, the carbonyl group in 6a and the C-C
triple bond in 5c were independently reduced12 to yield the same
compound 5a, whose NMR comparison led to the conclusion
(7) (a) Takacs, J. M.; Helle, M. A.; Seely, F. L. Tetrahedron Lett. 1986,
27, 1257. (b) Thenappan, A.; Burton, D. J. J. Org. Chem. 1990, 55, 4639.
(c) Kiyooka, S.; Shirouchi, M. J. Org. Chem. 1992, 57, 1.
(8) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191.
(9) (a) Lanier, M.; Haddach, M.; Pastor, R.; Riess, J. G. Tetrahedron
Lett. 1993, 34, 2469. (b) Ishihara, T.; Hayashi, H.; Yamanaka, H.
Tetrahedron Lett. 1993, 34, 5777. (c) Haas, A. M.; Ha¨gele, G. J. Fluorine
Chem. 1996, 78, 75. (d) Ishihara, T.; Takahashi, A.; Hayashi, H.; Yamanaka,
H.; Kubota, T. Tetrahedron Lett. 1998, 39, 4691.
(10) Ishihara also used 3,3,3-trifluoro-2-(tosyloxy)propionate as the
substrate, and the aluminum acetal generated was reacted with allylic
stannanes. Ishihara, T. J. Synth. Org. Chem. Jpn. 1999, 57, 313.
(11) Yamazaki, T.; Ichige, T.; Takei, S.; Kawashita, S.; Kitazume, T.;
Kubota, T. Org. Lett. 2001, 3, 2915.
2500 J. Org. Chem., Vol. 71, No. 6, 2006

SCHEME 3
would reasonably occupy a position perpendicular to the
carbonyl group. The incoming nucleophile would encounter the
unfavorable steric interference with the methyl group when it
approaches to the carbonyl si face, and as a result energetically
more favorable attack from the re face led to the predominant
production of the anti stereoisomers in every instance. Entry
of two methyl groups to R2 in enolates resulted in higher anti
preference, which is understood by an increase of steric
bulkiness at the reaction site to more effectively differentiate
the two diastereomeric transition states. The opposite is also
true when lithium acetylide from phenylacetylene was used. The
selectivity dropped since this molecule possesses sterically less
bulky linear structure.
In this note, we have shown a novel carbon-carbon bond-
forming method by utilization of in situ generated R-CF3-
aldehyde 4 for reaction with organometallic species as well as
various types of enolates. Avoidance of any direct handling of
the usually labile aldehydes such as 4 is one of the most
important advantages of our process, which will widely open
the way to construct unique CF3-containing aldol structures
whose general preparation procedure has not established yet.
SCHEME 4
Experimental Section
General Procedure for Reaction of 2-Phenylethyl 2-Methyl-
3,3,3-trifluoropropionate 2 by Way of Aluminum Acetal Inter-
mediate 3. To an ethereal solution (5 mL) of 2-phenylethyl
2-methyl-3,3,3-trifluoropropionate 216 (246 mg, 1.00 mmol) was
added at -78 °C a 1 mol/L hexane solution of DIBAL (1.05 mL,
1.05 mmol), and the mixture was stirred for 0.5 h at that
temperature. An appropriate nucleophile (2.00 mmol), preformed
alkylmetals or enolates by the conventional methods, was added
to this solution, and after changing the dry ice-acetone bath to an
ice bath, the whole solution was stirred for 1.5 h at 0 °C. The
reaction was quenched by addition of 3 mol/L aqueous HCl, then
the resultant crude materials were extracted with Et2O twice, and
the ethereal layer was dried over anhydrous MgSO4. Evaporation
of the volatiles was performed, and the resultant crude oil was
purified by silica gel column chromatography to give the final
product as a diastereoisomeric mixture.
that all 5a synthesized from 5c and 6a and directly obtained
from 2 were totally identical. Thus, it was clarified that 5a and
5c were also constructed in an anti preferential fashion. The
major isomer of 6b was also proved to be anti as the result of
its elaborated transformations into 6a.
For obtaining mechanistic support, the commercially available
aldehyde 4 was employed for the reaction with PhCH2CH2MgBr
and the enolate from isobutyrate under the same conditions. As
shown in Table 1, results were obtained that were basically
identical in terms of both the chemical yields and diastereo-
selectivities to the ones by way of the in situ generated reactive
species 3. In connection with the various anti:syn ratios recorded
in the same table (from 61:39 to 93:7),13 it is highly expected
for this reaction to proceed by way of the aldehyde 4 by slow
conversion of the intermediary acetal 3 during increase of the
reaction temperature.
(2S*,3R*)-1,1,1-Trifluoro-2-methyl-5-phenylpentan-3-ol (5a):
78% yield as a separable 83:17 anti:syn diastereomer mixture. Major
1
isomer: Rf 0.53 (Hex/AcOEt ) 10:3); H NMR δ 1.16 (3 H, d, J
) 7.1 Hz), 1.62 (1 H, d, J ) 4.7 Hz), 1.65-1.76 (1 H, m), 1.84-
1.97 (1 H, m), 2.22 (1 H, dqq, J ) 2.3, 7.3, 9.5 Hz), 2.67 (1 H,
ddd, J ) 6.7, 9.5, 13.7 Hz), 2.85 (1 H, ddd, J ) 5.2, 9.8, 13.7 Hz),
4.04 (1 H, dddd, J ) 2.0, 4.5, 4.6, 9.1 Hz), 7.18-7.33 (5 H, m);
13C NMR δ 6.4 (q, J ) 2.8 Hz), 32.2, 36. 5, 42.9 (q, J ) 24.1 Hz),
67.9 (q, J ) 2.6 Hz), 125.8, 127.8 (q, J ) 279.7 Hz), 128.2, 128.3,
141.2; 19F NMR δ 91.5 (d, J ) 9.5 Hz); IR (neat) ν 3579, 3449,
3022, 2950, 2552, 1604, 1498, 1458, 1270, 1137, 937, 700 cm-1
.
Anal. Calcd for C12H15F3O: C, 62.06; H, 6.51. Found: C, 61.72;
H, 6.65. Minor isomer: Rf 0.44 (Hex/AcOEt ) 10:3); 1H NMR δ
1.13 (3 H, d, J ) 7.1 Hz), 1.72-1.96 (3 H, m), 2.38 (1 H, dqq, J
) 5.5, 7.3, 9.3 Hz), 2.68 (1 H, ddd, J ) 6.9, 9.6, 13.7 Hz), 2.85 (1
H, ddd, J ) 5.0, 9.4, 14.4 Hz), 3.85 (1 H, ddt, J ) 2.9, 5.5, 9.6
Hz), 7.18-7.33 (5 H, m); 13C NMR δ 8. 9 (q, J ) 2.9 Hz), 32.0,
34.8, 43.9 (q, J ) 23.9 Hz), 69.5 (q, J ) 2.0 Hz), 125.7, 127.5 (q,
J ) 279.9 Hz), 128.1, 128.5, 141.4; 19F NMR δ 93.3 (d, J ) 9.5
Hz); IR (neat) ν 3421, 3027, 2932, 2364, 1943, 1869, 1752, 1604,
As described above, the major diastereoisomers in Table 1
possessed an anti relative stereochemical relationship, and this
selectivity was consistently explained by the well-accepted
Felkin-Anh transition state models (Scheme 4).14 Thus, the
most electron-withdrawing and sterically demanding CF3 group15
(12) Burdeska, K. Synthesis 1982, 940.
(13) When the intermediate 3 was treated with trimethylsilyl trifluo-
romethanesulfonate (TMSOTf) in the presence of pyridine, formation of
2-phenylethyl trimethylsilyl acetal 7 was observed by 1H and 19F NMR as
a diastereomeric mixture in a range of 65:35 to 70:30 (due to its inherent
instability, we have not successfully isolated it yet). This is clearly supported
that the present reaction is not the SN2-type process.
(15) This group is considered to possess a volume similar to that of the
nonfluorinated isobutyl group on the basis of the revised Taft’s Es value,
Es′. See: MacPhee, J. A.; Panaye, A.; Dubois, J.-E. Tetrahedron 1978, 34,
3553.
(16) Yamazaki, T.; Ichige, T.; Kitazume, T. Collect. Czech. Chem.
Commun. 2002, 67, 1479.
(14) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191.
J. Org. Chem, Vol. 71, No. 6, 2006 2501

1497, 1380, 1266, 1175, 1136, 1046, 938, 750, 699 cm-1. Anal.
Calcd for C12H15F3O: C, 62.06; H, 6.51. Found: C, 62.04; H, 6.92.
Reactions of Nucleophiles with 2-Methyl-3,3,3-trifluoropro-
panal. An appropriate nucleophile (2 mmol) was added to an
ethereal solution (5 mL) containing 2-methyl-3,3,3-trifluoropropanal
4 (0.127 g, 1.000 mmol) freshly distilled with a few drops of BF3‚
OEt2 at -78 °C, and the whole solution was stirred for 1.5 h at 0
°C. Usual workup and purification by silica gel furnished the adduct,
whose physical properties were consistent with those obtained by
way of the aluminum acetal as shown above.
Determination of Relative Stereochemistry. Transformation
of 6a into 5a. To a mixture of concentrated HCl (60 mg) and H2O
(0.84 mL) containing 10% Pd/C (21 mg) was added 6a (0.049 g,
0.199 mmol; major:minor ) 95:5), and the whole mixture was
stirred overnight at room temperature under H2 atmosphere.
Filtration and evaporation of this mixture afforded a crude material
from which 5a (0.042 g, 0.181 mmol; major:minor ) 95:5) was
isolated by column chromatography in 90% yield. The physical
properties of the obtained material were consistent with those of
5a as shown above.
Transformation of 5c into 5a. To a MeOH solution (3 mL)
containing 10% Pd/C (6 mg) was added 5c (0.160 g, 0.701 mmol;
major:minor ) 78:22), and the whole mixture was stirred over-
night at room temperature under H2 atmosphere. Filtration and
evaporation of this mixture afforded a crude material from which
5a (0.151 g, 0.650 mmol; major:minor ) 80:20) was isolated by
column chromatography in 93% yield. The physical properties of
the obtained material were consistent with those of 5a as shown
above.
Transformation of 6b into 6a. To an Et2O solution (10 mL)
containing a catalytic amount of p-TsOH were successively added
6b (0.214 g, 0.999 mmol; major:minor ) 76:24) and dihydoropyran
(0.170 g, 2.021 mmol), and the whole mixture was stirred for 4 h
at room temperature. After quenching with saturated aqueous
NaHCO3, the usual workup gave a crude material that was used
for the next step without further purification. The resultant crude
THP ether was reduced with LAH (28.5 mg, 0.75 mmol) in Et2O
(10 mL) at 0 °C, and the reaction was continued for 3 h at room
temperature. The reaction was stopped by the addition of saturated
aqueous NaSO4, and the usual workup gave a crude alcohol that
was subjected to the usual Swern oxidation conditions. To this
aldehyde was added at -78 °C PhLi (1.05 mmol) in THF (5 mL),
and the stirring was continued for 1 h at the same temperature.
After addition of H2O the workup gave a crude alcohol that was
again oxidized to the corresponding ketone by way of the Swern
procedure, and the THP protection was removed by the conventional
method (cat. p-TsOH in MeOH) to give the crude material.
Purification by column chromatography afforded 0.056 g (0.227
mmol, 23% total yield) of 6a as a 76:24 diastereomer mixture. The
physical properties of the obtained material were consistent with
those for 6a as shown above.
Supporting Information Available: Experimental details and
spectral data for the compounds 5b,c, 6a-e, and 7 and Cartesian
coordinates of the compound 6a obtained by X-ray crystallographic
analysis. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO052434O
2502 J. Org. Chem., Vol. 71, No. 6, 2006