Efficient Asymmetric Synthesis of α-Trifluoromethyl-Substituted Primary Amines via Nucleophilic 1,2-Addition to Trifluoroacetaldehyde SAMP- or RAMP-Hydrazone

Article abstract of DOI:10.1021/ol015869g

matrix presented An efficient asymmetric synthesis of α-trifluoromethyl-substituted primary amines via nucleophilic 1,2-addition of alkyllithium reagents to trifluoroacetaldehyde SAMP- or RAMP-hydrazone followed by benzoylation and Sml₂-promoted nitrogen-nitrogen single bond cleavage is described.

Full text of DOI:10.1021/ol015869g

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1575-1577
Efficient Asymmetric Synthesis of
r-Trifluoromethyl-Substituted Primary
Amines via Nucleophilic 1,2-Addition to
Trifluoroacetaldehyde SAMP− or
RAMP−Hydrazone
Dieter Enders* and Kazumasa Funabiki†
Institut fu¨r Organische Chemie, Rheinisch-Westfa¨lische Technische Hochschule,
Professor-Pirlet-Strasse 1, 52074 Aachen, Germany
enders@rwth-aachen.de
Received March 20, 2001
ABSTRACT
An efficient asymmetric synthesis of r-trifluoromethyl-substituted primary amines via nucleophilic 1,2-addition of alkyllithium reagents to
trifluoroacetaldehyde SAMP− or RAMP−hydrazone followed by benzoylation and SmI2-promoted nitrogen−nitrogen single bond cleavage is
described.
The development of novel methods for the asymmetric
synthesis of fluorine-containing molecules is one of the most
challenging topics in organofluorine chemistry.1 Many suc-
cessful procedures for the enantioselective synthesis of
R-trifluoromethylated alcohols have hitherto appeared.2 In
contrast, there have been only a few reports on the asym-
metric synthesis of R-trifluoromethyl-substituted primary
amines. In these reports, where there still remain unsatisfac-
tory enantioselectivities, chemical yields, and/or diversity.3
Because of their importance in pharmaceutical research based
on the special electronic properties of the trifluoromethyl
group,4 it is of particular interest to develop more general,
efficient, and enantioselective routes to the title compounds.
The 1,2-addition of organometallic reagents to CN double
bonds is one of the most efficient routes to R-branched
amines.5 Among them, the asymmetric 1,2-addition reaction
using SAMP6 or RAMP as a chiral auxiliary provides a
(3) (a) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1977, 42, 2436. (b)
Wang, Y.; Mosher, H. S. Tetrahedron Lett. 1991, 32, 987. (c) Soloshonok,
V. A.; Ono, T. J. Org. Chem. 1997, 62, 3030. (d) Ishii, A.; Higashiyama,
K.; Mikami, K. Synlett 1997, 1381. (e) Ishii, A.; Miyamoto, F.; Higashiyama,
K.; Mikami, K. Chem. Lett. 1998, 119. (f) Ishii, A.; Miyamoto, F.;
Higashiyama, K.; Mikami, K. Tetrahedron Lett. 1998, 39, 1199. (g) Prakash,
G. K. S.; Mandal. M.; Olah, G. A. Angew. Chem. 2001, 113, 609; Angew.
Chem., Int. Ed. 2001, 40, 589. For a review on functionalized R-trifluo-
romethylated amines using the sulfinyl or 1-phenylethyl group as a chiral
auxiliary, see: (h) Bravo, P.; Zanda, M. In ref 1a, p 107. (i) Bravo, P.;
Bruche, L.; Crucianell, M.; Viani, F.; Zanda, M. In ref 1b, p 98. (j)
Soloshonok, V. A. In ref 1b, p 74.
† On leave from Department of Chemistry, Faculty of Engineering, Gifu
University, 1-1, Yanagido, Gifu 501-1193, Japan.
(1) (a) Enantiocontrolled Synthesis of Fluoro-organic Compounds;
Soloshonok, V. A., Ed.; John Wiley & Sons: Chichester, 1999. (b)
Asymmetric Fluoroorganic Chemistry: Synthesis, Application, and Future
Directions; Ramachandran, P. V., Ed.; American Chemical Society,
Washington, DC, 1999. (c) Iseki, K. Tetrahedron 1998, 54, 13887.
(2) For reviews, see: (a) Ramachandran, P. V.; Brown, H. C. In ref 1a,
p 179. (b) Soloshonok, V. A. In ref 1a, p 229. (c) Fujisawa, T.; Shimizu,
M. In ref 1a, p 557. (d) Mikami, K.; Yajima, T. In ref 1a, p 557. (e)
Ramachandran, P. V.; Brown, H. C. In ref 1b, p 22.
(4) (a) Ojima, I.; Kato, K.; Jameison, F. A. Bioorg. Med. Chem. Lett.
1992, 2, 219. (b) Shirlin, D.; Tarnus, C.; Baltzer, S. Bioorg. Med. Chem.
Lett. 1992, 2, 651.
10.1021/ol015869g CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/07/2001

When 3 equiv of n-BuLi was added slowly to an Et2O
solution of 2 at -78 °C and the reaction mixture was
gradually warmed to room temperature, a low yield (36%)
of the product 3a was obtained together with a complex
mixture, probably due to the low stability of trifluoromethy-
lated lithium hydrazide (Table 1, entry 1).
Scheme 1. Asymmetric Synthesis of
R-Trifluoromethyl-Substituted Primary Aminesa
Table 1. Screening of the Reaction Conditions of Nucleophilic
1,2-Addition
entrya
n-BuLi (equiv)
solvent
yield (%)b
de (%)c
1d
2
3
4
5
3
1.5
3
1.5
3
Et2O
Et2O
Et2O
THF
THF
36
63
79
43 (37)
45 (39)
>96 (>98)
>96 (>98)
>96 (>98)
82 (>98)
82 (>98)
a The reactions were carried out with trifluoroacetaldehyde SAMP-
hydrazone 2 at -78 °C for 1 h. b Yields of isolated products. Values in
parentheses are for the major diastereomer. c Measured by 19F NMR before
isolation. Values in parentheses after column chromatography. d After
n-BuLi was added at -78 °C, the reaction mixture was warmed to room
temperature overnight.
a (a) RLi, -78 °C; (b) catalytic DMAP, Et3N, PhCOCl, rt or
n-BuLi, PhCOCl, -78 °C to rt; (c) SmI2, THF-DMPU, rt.
promising synthetic route to enantioenriched amines, which
has been successfully applied for the asymmetric synthesis
of natural products.7
Herein we describe the highly enantioselective synthesis
of R-trifluoromethylated amines via nucleophilic 1,2-addition
of alkyl- or phenyllithium reagents to trifluoroacetaldehyde
SAMP- or RAMP-hydrazone, followed by benzoylation
and SmI2-promoted nitrogen-nitrogen single bond cleavage,
as described in Scheme 1.
Treatment of 2 with 1.5 equiv of n-BuLi in Et2O at low
temperature (-78 °C) for a shorter reaction time (1 h) gave
trifluoromethylated hydrazine 3a in 63% yield (entry 2). The
use of 3 equiv of n-BuLi gave a higher yield (entry 3).
Employing THF as reaction solvent resulted in unsatisfactory
yields of 3a with decrease in diastereoselectivities (entries
4 and 5). The major diastereoisomer was readily separated
by flash column chromatography.
The results of the reaction of 2 with various alkyllithium
reagents as well as PhLi are summarized in Table 2.9
Trifluoroacetaldehyde SAMP-hydrazone 2 was readily
obtained in 83% yield from commercially available trifluo-
roacetaldehyde ethyl hemiacetal 1 and SAMP in the presence
of a catalytic amount of p-TsOH in benzene (eq 1).8
Table 2. Reaction of Trifluoroacetaldehyde SAMP- or
RAMP-Hydrazone 2 with RLi
entrya
R
product yield (%)b
de (%)c
[R]D (c, CHCl3)d
1
n-Bu
n-Bu
Etf
n-Prf
n-Hex
t-Bu
Ph
3a
3a ′
3b
3c
3d
3e
3f
79
74
48
65
68
58 (50)
15g
>96 (>98)
>96 (>98)
>96 (>98)
>96 (>98)
>96 (>98)
72 (>98)
-39.7 (0.88)
+43.5 (0.95)
-42.3 (0.90)
-45.9 (1.15)
-39.7 (0.90)
-33.8 (1.25)
-38.2 (1.20)
2e
3
4
5
6
7
86 (88)
Trifluoroacetaldehyde RAMP-hydrazone was prepared in
the same manner in 66% yield.
a The reactions were carried out with trifluoroacetaldehyde SAMP-
hydrazone 2 and RLi (3 equiv) in Et2O at -78 °C for 1 h. b Yields of isolated
products. Values in parentheses are for the major diastereomer. c Measured
by 19F NMR before isolation. Values in parentheses after column chroma-
tography. d All optical rotations were measured in Uvasol grade CHCl3 at
26 °C. e Trifluoroacetaldehyde RAMP-hydrazone was used instead of 2.
f Prepared from t-BuLi and the corresponding RI according to ref 10. g There
were many unidentified byproducts in the 19F NMR of the crude reaction
mixture.
(5) For reviews, see: (a) Denmark, S. E.; Nicaise, O. J.-C. J. Chem.
Soc., Chem. Commun. 1996, 999. (b) Enders, D,; Reinhold: U. Tetrahe-
dron: Asymmetry 1997, 8, 1895. (c) Bloch, R. Chem. ReV. 1998, 98, 1407.
(d) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (e) Merino, P.;
Franco, S,; Merchan, F. L.; Tejero, T. Synlett 2000, 442.
(6) (a) Enders, D.; Klatt, M. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; John Wiley & Sons: Chichester, 1995; Vol.
1, p 178. (b) Enders, D. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1984; Vol. 3, p 275. (c) Enders, D.; Fey, P.;
Kipphardt, H. Org. Synth. 1987, 65, 173, 183.
(7) For a review on the synthesis of alkaloids, see: Enders, D.; Thiebes,
C. Pure Appl. Chem. In press.
(8) Trifluoroacetaldehyde SAMP-hydrazone is much more stable than
trifluoroacetaldehyde imines. Therefore in contrast the hydrazone can be
purified by flash column chromatography.
Commercially available alkyllithiums, such as n-BuLi and
n-hexyllithium, reacted well in the nucleophilic 1,2-addition
to give the corresponding trifluoromethylated hydrazines
3a,a′,d in good yields with excellent diastereoselectivity
1576
Org. Lett., Vol. 3, No. 10, 2001

(entries 1, 2, and 5). Ethyllithium and n-propyllithium, easily
prepared from t-BuLi and the corresponding alkyl iodide,10
also reacted with hydrazone 2 to provide the corresponding
hydrazines 3c,d in 48 and 65% yields, respectively (entries
3 and 4). Treatment of of 2 with t-BuLi gave a moderate
yield of 3e in moderate de (entry 6). However, the diaste-
reomer could be readily separated by column chromatogra-
phy, affording diastereomerically pure 3e. When hydrazone
2 was treated with PhLi under the same conditions, 15% of
the product 3f was obtained in 86% de along with a complex
mixture of byproducts (entry 7). Unfortunately, even in the
presence of the trifluoromethyl group, the reaction of 2 with
3 equiv of MeLi in Et2O or toluene at -78 °C did not
proceed efficiently, giving only a small amount of the product
together with recovery of 2 (58-75%). Raising the reaction
temperature from -78 °C to room temperature in analogy
to fluorine-free hydrazones as well as using MeMgI at -20
°C or MeCeCl2 at -78 °C in place of MeLi did not improve
the reaction.
Table 3. SmI2 Cleavage of the N-N Single Bond of
Trifluoromethylated SAMP- or RAMP-Hydrazides 4
entrya
R
product yield (%)b ee (%)c [R]D (c, CHCl3)d
1
n-Bu
n-Bu
n-Bu
n-Pr
n-Hex
t-Bu
Ph
5a
5a
5a ′
5b
5c
5d
5e
87
4 (90)
98
+40.8 (0.80)
2e
3f
4
95
83
97
71
73
97
98
98
>99
g
-40.2 (0.95)
+29.6 (0.82)
+43.6 (0.90)
+22.9 (0.85)
-2.58 (0.66)
5
6
7
a The reactions were carried out with hydrazide 4 and SmI2 (3 equiv) in
the presence of DMPU in THF at room temperature for 30 min. b Isolated
yields. Values in parentheses refer to the recovery of 4. c Measured by HPLC
analysis using a chiral stationary phase column (DAICEL OD or (S,S)-
Whelk-O, 1-heptane/2-propanol ) 9/1 or 95/5). d All optical rotations were
measured in Uvasol grade CHCl3 at 25 or 27 °C. e MeOH was used as a
solvent in the absence of DMPU. f RAMP-hydrazide 4a′ was used. g The
ee could not be determined yet.
As shown in Table 3, various SAMP- or RAMP-
hydrazides 4 participated successfully in the reaction to
provide the corresponding amides 5 in good to excellent
yields with excellent ee (up to >99%).15 The reaction in
MeOH gave a trace amount of the product 5a, together with
recovery of the starting hydrazide (90%).
In summary, we have succeeded in the highly enantiose-
lective synthesis of R-trifluoromethylated amines through the
1,2-addition of various organolithium species to trifluoro-
acetaldehyde SAMP- or RAMP-hydrazone and subsequent
SmI2-promoted cleavage of the nitrogen-nitrogen single
bond.
The absolute configuration of the stereogenic center
generated by the 1,2-addition using SAMP was established
unambiguously as R by X-ray crystallography of 3e.11
Significantly, after benzoylation, the chiral auxiliary was
12
easily cleaved by treatment of 4 with 3 equiv of SmI2 in
the presence of 1,3-dimethyltetrahydro-2(1H)-pyrimidone
(DMPU)13 in THF at room temperature for 30 min, affording
the (R)-N-benzoyl R-trifluoromethylated amines 5 without
detectable epimerization or racemization (Table 3).14
(9) General Procedure of 1,2-Addition to Trifluoroacetaldehyde
SAMP-Hydrazone. A solution of n-BuLi (1.6 M) in hexane (3.08 mmol)
was slowly added to a dry Et2O (1 mL) solution of trifluoroacetaldehyde
SAMP-hydrazone 2 (1.03 mmol) at -78 °C. After being stirred at that
temperature for 1 h, the reaction mixture was quenched with a mixture of
crushed ice, a saturated NaHCO3 solution (50 mL), and Et2O (30 mL). The
aqueous portion was extracted with Et2O (30 mL × 3), and the combined
organic layers weredried over anhydrous Na2SO4 and concentrated in vacuo.
After the isomer ratio was determined, flash column chromatography of
the residue on silica gel eluting with pentane-Et2O (10/1) gave 3a in 79%
yield.
Further studies toward the asymmetric synthesis of tri-
fluoromethylated bioactive compounds are now in progress.
Acknowledgment. We thank Degussa AG, BASF AG,
Bayer AG, and Aventis for the donation of chemicals. We
also thank Dr. G. Raabe for the X-ray structure analysis of
3e as well as Dr. J. Runsink for measuring the 19F NMR
spectra. K.F. is grateful to the Alexander von Humboldt
Foundation for a postdoctoral fellowship (2000-2001).
(10) (a) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404.
(b) Negishi, E.; Swanson, D. R.; Rousset, C. J. J. Org. Chem. 1990, 55,
5406.
(11) Details of X-ray structure analysis will be described in a full paper.
(12) SmI2 (0.1 M in THF) was purchased from Aldrich Chemical Co.
Inc. The purity of SmI2 is very important for high yields. For the pioneering
work for SmI2-induced cleavage of the nitrogen-nitrogen single bond of
hydrazines, see: (a) Souppe, J.; Danon, L.; Namy, J. L.; Kagan, H. B. J.
Organomet. Chem. 1983, 250, 227. For examples in MeOH or t-BuOH,
see: (b) Burk, M. J.; Feaster, J. E. J. Am. Chem. Soc. 1992, 114, 6266. (c)
Atkinson, S. R.; Kelly, B. J.; Williams, J. Tetrahedron 1992, 48, 7713. (d)
Burk, M. J.; Martinez, J. P.; Feaster, J. E.; Cosford, N. Tetrahedron 1994,
50, 4399. (e) Overman, L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C.
J. Am. Chem. Soc. 1997, 119, 7159. (f) Kobayashi, S.; Hirabayashi, R. J.
Am. Chem. Soc. 1999, 121, 6942. For examples in THF in the presence of
HMPA, see: (g) Sturino, C. F.; Fallis, A. G. J. Am. Chem. Soc. 1994, 116,
7447. (h) Kadota, I.; Park, J.-Y.; Yamamoto, Y. J. Chem. Soc., Chem.
Commun. 1996, 841. (i) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2000,
122, 8329.
OL015869G
(14) General Procedure. A THF solution of SmI2 (0.9 mmol, 8.8 mL
of a 0.1 M THF solution) was added dropwise to a THF solution (2 mL)
of SAMP-hydrazide 4a (0.29 mmol) and DMPU (0.5 mL) at room
temperature under argon. After 30 min at room temperature, the reaction
mixture was quenched with a mixture of a diluted NaHCO3 solution (50
mL) and CH2Cl2 (20 mL), extracted with CH2Cl2 (30 mL × 2), dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was subjected
to flash chromatography on silica gel using pentane-Et2O (5/1) as the eluent,
affording 5a in 87% yield.
(15) This result is also the first example for SmI2-induced cleavage of
the nitrogen-nitrogen single bond of SAMP- or RAMP-hydrazides in
our laboratory. Very recently, Lassaletta and Llera reported the removal of
the (S)-(-)-1′-methoxy-1′-ethylpropyl)pyrrolidyl group by the use of SmI2,
see: Ferna´ndez, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.; Monge, A.
Angew. Chem. 2000, 112, 3015; Angew. Chem., Int. Ed. 2000, 39, 2893.
(13) DMPU was distilled over CaH2 in vacuo. Beck, A. K.; Seebach, D.
In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Eds.;
John Wiley & Sons: Chichester, 1995; Vol. 3, p 2123.
Org. Lett., Vol. 3, No. 10, 2001
1577