Highly diastereoselective addition of organometallic reagents to a trifluoroacetaldehyde hydrazone derived from (R)-N-benzylphenylglycinol

Article abstract of DOI:10.1016/j.tetlet.2005.05.040

Organolithium and Grignard reagents add efficiently with very high stereoselectivity (>98% de) to a trifluoroacetaldehyde hydrazone derived from (R)-N-benzylphenylglycinol. The addition proceeds on the re face of the chelated hydroxyhydrazone providing th

Full text of DOI:10.1016/j.tetlet.2005.05.040

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4761–4764
Highly diastereoselective addition of organometallic reagents
to a trifluoroacetaldehyde hydrazone derived from
(R)-N-benzylphenylglycinol
*
´
Stephane Fries, Julien Pytkowicz and Thierry Brigaud
`
Laboratoire ‘Synthese Organique Selective et Chimie Organometallique’ (SOSCO), UMRCNRS 8123,
Universite de Cergy-Pontoise, 5 Mail Gay-Lussac, Neuville sur Oise, 95031 Cergy-Pontoise cedex, France
´
´
´
Received 29March 2005; revised 25 April 2005; accepted 11 May 2005
Available online 31 May 2005
This article is dedicated to Professor Iwao Ojima on the occasion of his 60th birthday
Abstract—Organolithium and Grignard reagents add efficiently with very high stereoselectivity (>98% de) to a trifluoroacetaldehyde
hydrazone derived from (R)-N-benzylphenylglycinol. The addition proceeds on the re face of the chelated hydroxyhydrazone pro-
viding the (R)-a-trifluoromethylated amine after hydrogenolysis.
Ó 2005 Elsevier Ltd. All rights reserved.
Chiral amines are very important substructures of bio-
active compounds and their asymmetric synthesis is a
major objective of organic synthesis. To this purpose,
nucleophilic addition of organometallic reagents to the
CN double bond is one of the most widely used meth-
od.1 Generally the stereoselectivity of the reaction is
controlled by a stereogenic N-substituent which can be
removed in the last step in order to give the free amino
compounds. Because of their large availability, aryleth-
ylamines, b-amino alcohols and their O-substituted
derivatives are some of the most frequently used auxilia-
ries. Unfortunately, these chiral auxiliaries are generally
lost during the removal step. The addition of organome-
tallic reagents to the CN double bond of hydrazones
constitutes a major improvement of this strategy. In this
case, the N–N bond can be cleaved under reductive con-
ditions to give the optically active amine and the chiral
auxiliary can be recovered.2
cally active compounds exhibit unique physiological
activities. Therefore there is an increasing interest in
the stereoselective synthesis of fluorinated compounds.4
For instance, the nucleophilic addition of organometal-
lic reagents to the CN double bond is the subject of
considerable interest for the synthesis of a-fluorometh-
ylamino compounds. Several groups reported the stereo-
selective addition of organometallic species on chiral
trifluoromethylated aldimines5 and ketimines.6
Recently, Enders et al. reported the stereoselective prep-
aration of a-trifluoromethylated amines by addition of
organolithium reagent to SAMP- and RAMP-hydraz-
ones derived from fluoral hemiacetal.7 This methodol-
ogy allowed an efficient recovery of the chiral auxiliary
but the reactivity of Grignard reagents was not men-
tioned. In the course of our study concerning the synthe-
sis of enantiopure a-fluoromethylamino compounds,8
we were interested in the development of the stereoselec-
tive addition of Grignard reagents to a fluoral based
hydrazone. Since the pioneering work of Takahashi
et al.9 and more recent one of Brown and co-workers,10
the addition of Grignard reagents to hydrazones derived
from amino alcohols showing a free hydroxyl group is
known to occur with a very high stereoselectivity. How-
ever, this reaction appears to be limited to aryl hydraz-
ones. Therefore, in order to expand the scope of the
hydrazone methodology in the fluorinated series, we
decided to evaluate the stereoselectivity of the addition
The incorporation of fluorine atoms or fluorine-contain-
ing groups into a molecule often drastically perturbs its
physical, chemical and biological properties.3 It has been
shown that very often fluorinated analogues of biologi-
Keywords: Chiral hydrazone; Organofluorine chemistry; a-Trifluoro-
methylated amine.
*
Corresponding author. Tel.: +33 (01) 3425 7066; fax: +33 (01) 3425
7071; e-mail: thierry.brigaud@chim.u-cergy.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.040

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S. Fries et al. / Tetrahedron Letters 46 (2005) 4761–4764
Table 1. Synthesis of hydrazone 2
Ph
Ph
N
Ph
N
Ph
N
Ph
N
O
Ph
OH
H2N
Tol., Dean Stark
catalyst
HN
F3C
OEt
HO
F3C HO
F3C
3
1
2
Entry
Catalyst (equiv)
Time
Ratio 2:3a
Yield (%)b
72
1
2
3
PPTS (0.1)
APTS (0.1)
No catalyst
1.5 h
2 h
76:24
71:299
100:0
8
35 min
96
a Measured by 19F NMR spectroscopy of the crude reaction mixture. Compound 3 was obtained as a 75:25 mixture of diastereomers.
b Yields of isolated products.
of organometallics to a (R)-phenylglycinol derived
trifluoromethylhydrazone.
analogues which required reflux temperature and ten-
fold molar excess of Grignard reagents to give the corre-
sponding hydrazine.10 Modification of the reactions
conditions and the amount of organometallic reagent
in THF failed to improve significantly the yield of
hydrazines 4. Two unexpected side products were iden-
tified. The (R)-N-benzylphenylglycinol 6 should result
from the N–N bond cleavage. The unfluorinated benzyl-
amine 5c14 (Table 2, entry 6) should arise from the
stereoselective addition of benzylmagnesium chloride
on the re face of an intermediate imine obtained by
elimination of the electron withdrawing fluorinated
fragment (Fig. 1).
The hydrazone 211 was readily prepared in high yield by
condensation of trifluoroacetaldehyde ethyl hemiacetal
and hydrazine 112 in toluene at reflux with azeotropic re-
moval of water and ethanol (Table 1). Under acidic
catalysis (entries 1 and 2), the ring closure of the hydroxy-
hydrazone 2 into 3 occurred as a side reaction. This
undesired side reaction could easily be avoided with
short reaction time under neutral conditions (entry 3).
The results of the reactions of 2 with various organome-
tallic reagents are summarized in Table 2. The addition
of n-butyllithium to hydrazone 2 in THF at ꢀ78 °C gave
the hydrazine 4a in low yield (37%) but with excellent
stereoselectivity (>98% de)13 (Table 2, entry 1). Because
of the deprotonation of the free hydroxyl group, at least
2 equiv of organometallic reagent were necessary for the
reaction to occur. The addition of n-butylmagnesium
and vinylmagnesium chloride (1.8 M in THF) proceeded
at room temperature to give the expected hydrazines 4a
in 44–58% yield and 4b in 23–47% yield as a single dia-
stereomer13 (Table 2, entries 2–5). The trifluoromethyl
hydrazone is thus much more reactive than its aromatic
A significant improvement of the CN 1,2-addition selec-
tivity was noticed when the reaction was performed in
Et2O as the solvent. The addition of 3 equiv of n-butyl-
lithium proceeded selectively at ꢀ30 °C and the hydra-
zine 4a15 was obtained as a single diastereomer in 65%
yield (Table 2, entry 7). In a similar manner vinylmagne-
sium chloride (1.8 M in THF, 3 equiv) and benzylmag-
nesium chloride (1.35 M in THF, 3 equiv) were added
smoothly to the hydrazone 2 at room temperature.
The corresponding hydrazine 4b and 4c were obtained
in 75% and 68% yields with complete stereoselectivity13
Table 2. RM addition to hydrazone 2
Ph
HN
R
Ph
Ph
HN
Ph
Ph
N
R
Ph
Ph
N
Ph
HN
F3C
N
RM
OH
OH
OH
F3C HO
6
4 (> 98%de)
5
2
Entry
RM (equiv)
Solvent
Conditions
Yield of 4 (%)a
Yield of 5 (%)a
Yield of 6 (%)a
1
2
3
4
5
6
7
8
n-BuLi (2.2)
THF
THF
THF
THF
THF
THF
Et2O
Et2O
2O
ꢀ78 °C, 2 h
4a (37)
4a (44)
4a (58)
4b (23)
4b (47)
n-BuMgCl (2.2)
n-BuMgCl (3.3)
VinylMgCl (4)
VinylMgCl (3.3)
BnMgCl (4)
ꢀ78 °C, 2 h, then rt, 12 h
ꢀ40 °C, 3 h, then rt, 3 h
ꢀ78 °C, 30 min, then rt, 3 h
ꢀ50 °C, 2 h, then rt, 4 h
0 °C to rt, 4 h
6 (16)
6 (50)
5c (34)b
n-BuLi (3)
VinylMgCl (3)
ꢀ30 °C, 4 h
4a (65)
4b (75)
4c (68)
0 °C to rt, 4 h
9BnMgCl (3)
Et
0 °C to rt, 4 h
a Yields of isolated products.
b One single diastereomer.

S. Fries et al. / Tetrahedron Letters 46 (2005) 4761–4764
4763
Ph
Ph
Ph
M
N
H
Ph
N
H
R M
R M
N
N
R
Ph
5
O
CF3
M
N
Ph
O
M
re face attack
F3C
OM
Figure 2. Postulated transition state for diastereoselective addition to
hydrazone 2.
R M
4
Figure 1. Competitive reactions occurring in THF.
In conclusion, we have developed a highly stereoselective
method for the synthesis of a-trifluoromethyl amines.
Grignard reagents proved to add as efficiently as organo-
lithium reagents to the hydroxyhydrazone provided
that the reaction was performed at room temperature
in Et2O. Further experiments are in progress to enlarge
the scope of this reaction.
(Table 2, entries 8 and 9). However a poor conversion
of 2 (<15%) was obtained with phenyllithium (2 M in
dibutylether, 3 equiv) in Et2O.
We next focused our attention on the removal of the chi-
ral auxiliary and the assignment of the absolute config-
uration of the newly formed chiral centre. To this
purpose, hydrazine 4a resulting from n-butyllithium or
n-butylmagnesium chloride addition to hydrazone 2
was submitted to hydrogenolysis (Scheme 1). In the
presence of Pd(OH)2 the selective debenzylation of
nitrogen gave hydrazine 7 without any detectable epi-
merization. The complete reduction was achieved in
more drastic conditions by treatment of 4a with H2
(6 bar), 10% Pd/C, in MeOH–concd HCl at 60 °C for
12 h. In these conditions the expected trifluoromethyl-
ated amine hydrochloride 8 was quantitatively obtained
but the chiral auxiliary was not recovered. The (R) con-
figuration was assigned by comparison of the optical
rotation value of the corresponding benzoate 9 with
the literature values.16 We assume that the hydrazines
4b,c also present the (R) configuration.
Acknowledgements
We wish to thank Central Glass Company for the
generous gift of trifluoroacetaldehyde hemiacetal.
Supplementary data
Experimental procedure and characterization data for
compounds 4b, 4c, 7, 8 and 9 are available. Supplemen-
tary data associated with this article can be found, in the
online version at doi:10.1016/j.tetlet.2005.05.040.
References and notes
1. For reviews on the 1,2-addition of organometallic reagents
to the CN double bond see: (a) Denmark, S. E.; Nicaise,
O. J.-C. Chem. Commun. 1996, 999–1004; (b) Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895–1946;
(c) Bloch, R. Chem. Rev. 1998, 98, 1407–1438; (d)
Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069–
1094; (e) Merino, P.; Franco, S.; Merchan, F. L.; Tejero,
T. Synlett 2000, 442–454; (f) Alvaro, G.; Savoia, D.
Synlett 2002, 651–673.
This result confirmed that the stereochemical outcome
of the reaction was consistent with the re face attack
of the hydrazone. The high level of stereoselectivity
can be explained by a six member ring intermediate
involving a chelation of both the hydroxyl group and
a nitrogen atom of the hydrazone (Fig. 2).
2. For a review on the SAMP/RAMP methodology see: Job,
A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 12, 2253–2329, and references cited
therein.
Ph
H
N
Ph
(a)
N
Ph
HN
F3C
HN
F3C
3. (a) Hiyama, T. In Organofluorine Compounds, Chemistry
and Applications; Yamamoto, H., Ed.; Springer: Berlin,
Heidelberg, 2000; (b) Organofluorine Chemistry, Principles
and Commercial Applications; Banks, R. E., Smart, B. E.,
Tatlow, J. C., Eds.; Plenum: New York, 1994; (c)
Biomedical Frontiers of Fluorine Chemistry; Ojima, I.,
McCarthy, J. R., Welch, J. T., Eds.; American Chemical
Society: Washington, DC, 1996; (d) Smart, B. E. J.
Fluorine Chem. 2001, 109, 3–11; (e) OÕHagan, D.; Rzepa,
H. S. Chem. Commun. 1997, 645–652; (f) Schlosser, M.
Angew. Chem., Int. Ed. 1998, 37, 1496–1513.
Bu OH
Bu OH
4a
7
(b)
NHBz
Bu
NH2 .HCl
Bu
(c)
F3C
F3C
4. (a) Enantiocontrolled Synthesis of Fluoro-organic Com-
pounds; Soloshonok, V. A., Ed.; Wiley: Chichester, 1999;
(b) Asymmetric Fluoroorganic Chemistry: Synthesis, Appli-
cations, and Future Directions; Ramachandran, P. V., Ed.;
American Chemical Society: Washington, DC, 1999.
8
(R)-9
Scheme 1. Configuration assignment of 4a. Reagents, yields: (a) H2
6 bar, Pd(OH)2, MeOH–HCl 3 N, rt, 24 h, 41% (>98% de); (b) H2
6 bar, 10% Pd/C, MeOH–concd HCl, 60 °C, 12 h, quantitative; (c)
PhCOCl, Et3N, DMAP, CH2Cl2, 12 h, 25%.
´
5. (a) Tam, N. T. N.; Magueur, G.; Ourevitch, M.; Crousse,
B.; Begue, J.-P.; Bonnet-Delpon, D. J. Org. Chem. 2005,
´
´

4764
S. Fries et al. / Tetrahedron Letters 46 (2005) 4761–4764
70, 699–702; (b) Legros, J.; Meyer, F.; Coliboeuf, M.;
4.32 (m, 3H), 4.62 (dd, 3JHH = 8.6 Hz, 3JHH = 3.8 Hz, 1H),
Crousse, B.; Bonnet-Delpon, D.; Begue, J. P. J. Org.
Chem. 2003, 68, 6444–6446; (c) Ishii, A.; Higashiyama, K.;
Mikami, K. Synlett 1997, 1381–1382; (d) Gosselin, F.;
Roy, A.; OÕShea, P. D.; Chen, C.-Y.; Volante, R. Org.
Lett. 2004, 6, 641–644.
6.36 (q, JHF = 3.8 Hz, 1H), 7.03–7.34 (m, 10H). 13C NMR
´
´
2
(63 MHz, CDCl3) d: 54.2, 66.1, 75.4, 116.3 (q, JCF
38.3 Hz), 119.6 (q, JCF = 269.0 Hz), 126.3, 127.5, 127.9,
=
1
128.0, 128.1, 128.6, 128.8, 133.8, 137.8, 138.2. 19F NMR
20
(235 MHz, CDCl3) d: ꢀ64.7 (d, 3JHF = 3.8 Hz). ½aꢁD +89.1
6. (a) Bravo, P.; Crucianelli, M.; Vergani, B.; Zanda, M.
Tetrahedron Lett. 1998, 39, 7771–7774; (b) Asensio, A.;
Bravo, P.; Crucianelli, M.; Farina, A.; Fustero, S.; Soler,
J. G.; Meille, S. V.; Panzeri, W.; Viani, F.; Volontario, A.;
Zanda, M. Eur. J. Org. Chem. 2001, 1449–1458; (c)
Lazzaro, F.; Crucianelli, M.; De Angelis, F.; Frigerio, M.;
Malpezzi, L.; Volontario, A.; Zanda, M. Tetrahedron:
Asymmetry 2004, 15, 889–893; (d) Ishii, A.; Miyamoto, F.;
Higashiyama, K.; Mikami, K. Tetrahedron Lett. 1998, 39,
1199–1202.
7. (a) Enders, D.; Funabiki, K. Org. Lett. 2001, 3, 1575–
1577; (b) Funabiki, K.; Nagamori, M.; Matsui, M.;
Enders, D. Synthesis 2002, 2585–2588.
8. Lebouvier, N.; Laroche, C.; Huguenot, F.; Brigaud, T.
Tetrahedron Lett. 2002, 43, 2827–2830.
9. (a) Takahashi, H.; Tomita, K.; Otomasu, H. J. Chem.
Soc., Chem. Commun. 1979, 668–669; (b) Takahashi, H.;
Tomita, K.; Noguchi, H. Chem. Pharm. Bull. 1981, 29,
3387–3391; (c) Takahashi, H.; Inagaki, H. Chem. Pharm.
Bull. 1982, 30, 922–926; (d) Takahashi, H.; Suzuki, Y.
Chem. Pharm. Bull. 1983, 31, 4295–4299.
10. (a) Bataille, P.; Paterne, M.; Brown, E. Tetrahedron:
Asymmetry 1998, 9, 2181–2192; (b) Bataille, P.; Paterne,
M.; Brown, E. Tetrahedron: Asymmetry 1999, 10, 1579–
1588.
(c 0.68, CHCl3). GC/MS: m/z (%) 322 (M+) (3), 291 (78),
121 (8), 91 (100).
12. The hydrazine 1 was prepared in a three step procedure in
78% overall yield from (R)-phenylglycinol: Roussi, F.;
Chauveau, A.; Bonin, M.; Micouin, L.; Husson, H.-P.
Synthesis 2000, 1170–1179.
13. A single diastereomer was detected by 19F NMR in the
crude mixture before isolation.
14. Wu, M. J.; Pridgen, L. J. Org. Chem. 1991, 56, 1340–1344.
15. Hydrazine 4a. In a 50 ml Schlenk round bottom flask filled
with argon, 2 (684 mg, 2.12 mmol) was dissolved in dry
diethyl ether (30 ml). The solution was cooled down to
ꢀ30 °C and n-butyllithium (2.95 ml, 2.15 M, 6.4 mmol)
was added dropwise. The dark yellow solution was stirred
for 4 h at this temperature and quenched with NH4Cl
(saturated solution 20 ml). The reaction was extracted
twice with diethyl ether, dried on magnesium sulfate and
evaporated under reduced pressure to afford a yellow oil
which was purified by chromatography (petroleum ether/
diethyl ether 70/30) to provide 4a as a pale yellow oil
(524 mg, 65% yield). IR (film): 3408, 3030, 2960, 1602,
.
1455, 1275 cmꢀ1 1H NMR (250 MHz, CDCl3) d: 0.79
(m, 3H), 1.09–1.33 (m, 5H), 1.46 (m, 1H), 2.62 (s, 1H),
3.04 (q, JHF = 6.8 Hz, 1H), 3.24 (d, JHH = 13.8, 1H),
3
2
3
3.45 (dd, JHH = 11.5 Hz, JHH = 2.9Hz, 1H), 3.74 (dd,
2
2
2
11. Synthesis of hydrazone 2. In a 250 ml round bottom flask
equipped with a Dean–Stark apparatus, hydrazine 1
(2.62 g, 10.8 mmol) was dissolved in toluene (150 ml).
Trifluoroacetaldehyde ethylhemiacetal (1.68 g, 13 mmol)
was added dropwise and the solution was heated to reflux
for 35 min. After this time, the reaction was cooled down
to room temperature and evaporated under reduced
pressure. The hydrazone 2 was obtained as a colourless
oil (3.33 g, 96% yield). IR (film): 3412, 3065, 3031, 2928,
3JHH = 9.2 Hz, JHH = 2.9Hz, 1H), 3.92 (d, JHH = 13.8,
1H), 4.10 (dd, JHH = 11.5 Hz, JHH = 9.2 Hz, 1H), 7.01–
3
3
7.25 (m, 10H). 13C NMR (63 MHz, CDCl3) d: 13.9, 22.8,
28.0, 28.5, 60.2 (q, JCF = 34.3 Hz), 60.8, 65.9, 69.9, 126.5
2
1
(q, JCF = 282.8 Hz), 127.4, 128.0, 128.3, 128.8, 136.7,
138.2. 19F NMR (235 MHz, CDCl3) d: ꢀ73.6 (d,
20
3JHF = 6.8 Hz). ½aꢁD ꢀ20.1 (c 0.44, CHCl3). GC/MS: m/z
(%) 380 (M+) (6), 349(19), 259(73), 121 (14), 91 (100).
Anal. Calcd for C21H27F3N2O: C, 66.30; H, 7.15; N, 7.36.
Found: C, 66.47; H, 7.33; N, 7.25.
1592, 1265, 1131 cmꢀ1
2.86 (dd, JHH = 8.8 Hz, JHH = 5.5 Hz, 1H), 3.87 (ddd,
2JHH = 12.2 Hz, 3JHH = 5.5 Hz, 3JHH = 3.8 Hz, 1H), 4.24–
.
1H NMR (250 MHz, CDCl3) d:
16. ½aꢁD +35.0 (c 0.50, CHCl3) (lit.7a 98% ee ½aꢁD20 +40.8 (c 0.80,
20
3
3
CHCl3)).