Diastereoselective, one-pot synthesis of γ-amino alcohols from ketimines

Article abstract of DOI:10.1055/s-2001-15146

Deprotonation of ketimines with lithium diisopropyl amide, followed by reaction with aldehydes and subsequent reduction with aluminium hydrides gave γ-amino alcohols with moderate to good syn selectivity. The scope and limitations of this preparative meth

Full text of DOI:10.1055/s-2001-15146

LETTER
1109
Diastereoselective, One-Pot Synthesis of -Amino Alcohols from Ketimines
Siem J. Veenstra,a* Sape S. Kindermanb
aNovartis Pharma AG, Klybeckstrasse 141, 4057 Basel, Switzerland
bNew address: Instituut voor Moleculaire Chemie, Universiteit van Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam,
The Netherlands
Fax +41 61 6968676; E-mail: siem.veenstra@pharma.novartis.com
Received 3 April 2001
In this paper we want to disclose the scope and limitations
Abstract: Deprotonation of ketimines with lithium diisopropyl
of reductions of the intermediate lithiated β-hydroxy-imi-
amide, followed by reaction with aldehydes and subsequent reduc-
nes derived from acyclic ketimines and aldehydes. For
tion with aluminium hydrides gave -amino alcohols with moderate
matters of simplicity we only studied imines of acetone or
acetophenone. Deprotonations of unsymmetrical imines
have been studied in great detail but is a complex matter.12
Reductions of 2 generally produce syn γ-aminoalcohols
with moderate to good selectivity.
to good syn selectivity. The scope and limitations of this preparative
method are reported.
Key words: diastereoselectivity, reduction, amino alcohols,
ketimines, amide bases
Deprotonation of the imine 1 (R1 = Me, R2 = nBu)13 with
1.1 equivalent lithium diisopropyl amide (LDA) in THF at
−78 °C, followed by reaction with benzaldehyde and sub-
sequent reduction with LiAlH4 at 50 °C for 3 hours gave
after work-up a 6.7: 1 mixture of syn and anti γ-amino al-
cohols 4 (R1 = Me, R2 = nBu) in 76% yield.15 It was nec-
essary to carry out the deprotonation of 1 with LDA, as the
use of bases like NaHMDS or KHMDS resulted in com-
plex reaction mixtures. A series of reducing agents were
investigated and the results are summarized in Table 1.
The aluminum hydrides LiAlH4, DIBAL-H, Red-Al and
AlH3 all gave good yields of 4 with useful syn selectivity
(entries 9-12). The syn selectivity of these reductions
might be explained by intermolecular attack of the hy-
dride onto a chelated alkoxy-imine. Borohydrides like
NaBH4, NaCNBH3, Me4NHB(OAc)3, LiBH4, Zn(BH4)2
and LiHB(Et)3 (entries 1-6) gave lower yields and poor se-
lectivity. Reduction with sodium in the presence of
i-PrOH gave a good yield but was unselective (entry 14).
As part of a drug discovery programme, we became inter-
ested in a general synthesis for γ-amino alcohols. Known
procedures for the synthesis of γ-amino alcohols1-3 in-
clude reduction of isoxazoles and isoxazolines,4 β-amino
ketones,5 α-cyano-esters,6 enaminones7 or reductive ami-
nation of β-hydroxy ketones via Schiff bases8 or oxime
ethers.9 More than three decades ago Wittig developed the
directed aldol condensation where a metallated Schiff
base, after reaction with a carbonyl compound, gave the
lithiated β-hydroxy-imine 2 (Scheme 1).10 The in situ re-
duction of a cyclic alkoxy imine with DIBAL-H for the
synthesis of (±) nor-sedamine has been reported.11
The lithium ion does not seem to play a particular role as
chelator since AlH3 or BH3 reductions of the free hy-
droxy-imine 3 (vide infra) do give roughly the same selec-
tivity compared to the in situ reduction (compare entries 7
with 8 and 12 with 13). The free hydroxy-imine 3 was iso-
lated after an aqueous NaHCO3 quench of the intermedi-
ate alkoxide 2. Imine 3 is unstable and dissociates
spontaneously into 1 and benzaldehyde. It should be used
immediately and reductions of the free hydroxy-imine 3
resulted in lower yields of amino alcohols. Imine 3 has a
defined conformation due to the internal hydrogen
bridge.10a Hydrogenation with Pd-C as a catalyst was not
effective and hydrogenation with PtO2 gave a modest
yield with poor selectivity (entry 15).
The scope of the reaction was further evaluated by vary-
ing the imine and the aldehyde components. The results
are summarized in Table 2. Whereas the acetone derived
imines were effectively deprotonated in THF at −78 °C,
the acetophenone imines needed temperatures of 0 °C
(imines 7-9, entries 12-16) or even room temperature
Scheme 1
Synlett 2001, No. 7, 1109–1112 ISSN 0936-5214 © Thieme Stuttgart · New York

1110
S. J. Veenstra, S. S. Kinderman
LETTER
Table 1 Reaction conditions and yields for the reduction step of Scheme 2 (R1 = Me, R2 = uBu, R3 = Ph)
a) The alcohol component was added at the reduction step. b) Acetic acid (5 eq.) was added prior to reduction. c) Isolated
yield after bulb to bulb distillation (0.4 mbar and 120 °C) of the crude reaction product. d) The reducing agent was
added after the reaction mixture had been diluted with ether, washed with cold sat. aq. NaHCO3, dried (Na2SO4) and
concentrated in vacuo. e) Reduction performed at rt. f) Reduction performed at 50 °C. g) Reduction performed at 0 °C.
(imines 10 and 11, entries 17-19). Before addition of the
aldehyde the mixture was cooled to -78 °C. DIBAL-H re-
ductions were carried out at 0 °C, AlH3 reductions at room
temperature and LiAlH4 reductions at 50 °C respective-
ly.16 Aldehydes with larger side chains led to slightly in-
creased selectivities (entries 1-4). The substituent on the
nitrogen atom of the imine plays a minor role except for
phenyl (entry 9) and the bulky t-butyl (entry 15), which
gave poor selectivity. Reduction of phenyl substituted
imines with AlH3 in the absence of lithium ions show use-
ful selectivities (entries 10 and 11), presumably because
of better chelating properties of the aluminum ion over the
lithium ion.
(4) (a) Lunn, G. J. Org. Chem. 1987, 52, 1043; (b) Kotera, K.;
Takano, Y.; Matsuura, A.; Kitahonoki, K. Tetrahedron 1970,
26, 539; (c) Perold, G.V.; von Reiche, F.V.K. J. Am. Chem.
Soc. 1957, 79, 465; (d) Drefahl, G.; Hörhold, H.H. Chem. Ber.
1964, 97, 159; (e) Jäger, V.; Buss, V.; Schwab, W. Liebigs
Ann. Chem. 1980, 122; (f) Stuehmer, H.; Heinrich, W. Chem.
Ber. 1951, 84, 224.
(5) (a) Pilli, R.A.; Russowsky, D.; Dias, L.C. J. Chem. Soc.
Perkin Trans. 1 1990, 1213; (b) Barluenga, J.; Olano, B.;
Fustero, S. J. Org. Chem. 1985, 50, 4052; (c) Lora Tamayo,
M.; Mandronero, R.; Garcia Munoz, G.; Leipprand, H. Chem.
Ber. 1964, 97, 2234; (d) Samaddar, A.K.; Konar, S.K.;
Nasipuri, D. J. Chem. Soc. Perkin Trans. 1 1983, 1449;
(e) Andrisano, R.; Angiolini, L. Tetrahedron 1970, 26, 5247;
(f) Andrews, M.G.; Mosbo, J.A. J. Org. Chem. 1977, 42, 650.
(g) English Jr., J.; Bliss, A.D. J. Am. Chem. Soc. 1956, 78,
4057; (h) Brienne, M.J.; Fouquey, C.; Jacques, J. Bull. Soc
Chim. Fr. 1969, 2395.
(6) (a) Meschino, J.A.; Bond, C.H. J. Org. Chem. 1963, 28, 3129;
(b) Dornow, A.; Fust, K. Chem. Ber. 1954, 87, 985.
(7) (a) Bartoli, G.; Cimarelli, C.; Palmieri, G. J. Chem. Soc.
Perkin Trans. 1 1994, 537 and references there cited.
(b) Maroni, P.; Cazaux, L.; Tisnes, P.; Zambeti, M. Bull. Soc.
Chim. Fr. 1980, 179.
(8) Haddad, M.; Dorbais, J.; Larchevêque, M. Tetrahedron Lett.
1997, 38, 5981.
(9) (a) Narasaka, K.; Ukaji, Y. Chem. Lett. 1984, 147;
(b) Narasaka, K.; Yamazaki, S.; Ukaji, Y. Chem. Lett. 1984,
2065; (c) Narasaka, K.; Ukaji, Y.; Yamazaki, S. Bull. Chem.
Soc. Jpn. 1986, 59, 525.
The steric bulk of N-tbutyl imines seemed to ruin the se-
lectivity of the reaction (entries 15 and 16). Good to excel-
lent selectivities were obtained when additional chelating
atoms are present (entries 17-19). For the cyclic imine 12
(in entries 20 and 21) no selectivity was found when the
reduction was carried out with LiAlH4.11 The selectivity
was partially regained when the reduction was carried out
with AlH3 after washing the intermediate alkoxy imine
with aqueous NaHCO3.
In conclusion, a useful one-pot synthesis for various
γ-amino alcohols has been developed.
References and Notes
(10) (a) Wittig, G.; Reiff, H. Angew. Chem. 1968, 80, 8; (b) Wittig,
G.; Hesse, A. Liebigs Ann. Chem. 1971, 746, 149; (c) Stork,
G.; Dowd, S.R. J. Am. Chem. Soc. 1963, 85, 2178.
(d) Cuvigny, T.; Larchevêque, M.; Normant, H. Liebigs Ann.
Chem. 1975, 719.
(1) For a review on stereoselective synthesis of diastereomeric
amino alcohols see Tramontini, M. Synthesis 1982, 605.
(2) Jäger, V.; Schwab, W.; Buss, V. Angew. Chem. Int. Ed. Engl.
1981, 20, 601.
(3) Zhu, Q-C,; Hutschins, R.O.; Hutschins, MG.K. Org. Prep.
Proc. Int. 1994, 26, 193.
(11) Tirel, P.-J.; Vaultier, M.; Carrié, R. Tetrahedron Lett 1989,
30, 1947.
Synlett 2001, No. 7, 1109–1112 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Diastereoselective, One-Pot Synthesis of -Amino Alcohols from Ketimines
1111
Table 2 Reaction conditions, selectivities and yields of amino alcohols
a)
b)
c)
Reduction performed with LiAlH4/THF at 50 °C. All isolated yields are unoptimized and after distillation. Syn/anti ratio was
determined by 1H NMR after derivatization with 1,1-carbonyl-diimidazole to the corresponding cyclic carbamate. d) After reaction with
the aldehyde, the reaction mixture was taken into ether, washed with cold saturated NaHCO3 solution, cold brine, dried over Na2SO4,
concentrated in vacuo and taken into dry THF under N2 atmosphere and then reduced with AlH3. e) Syn/anti ratio was determined by
1H NMR after derivatization with formaldehyde to the corresponding oxazine.7 f) Deprotonation with LDA in THF at −78 °C. g) Depro-
tonation with LDA in THF at 0 °C. h) Deprotonation with LDA in THF at rt. i) Reduction performed with DIBAL-H/THF at 0 °C.
(12) (a) Smith, J.K.; Bergbreiter, D.E.; Newcomb, M. J. Am. Chem.
Soc. 1983, 105, 4396 and references there cited. (b) Smith,
J.K.; Bergbreiter, D.E.; Newcomb, M. J. Org. Chem. 1981,
46, 3157; (c) Hosomi, A.; Araki, Y.; Sakurai, H. J. Am. Chem.
Soc. 1982, 104, 2081.
(13) Except when stated otherwise imines used in this study were
prepared via azeotropic removal of water in a refluxing
hydrocarbon solvent with an appropriate boiling point,
followed by distillation of the product.
(14) Imine 7 was synthesized using azeotropic water removal
followed by standing over molecular sieves, see: Kyba, E.P.
Org. Prep. Proced. Int. 1970, 2, 149 and Tsuchimoto, M.;
Nishimura, S.; Iwamura, H. Bull. Chem. Soc. Jpn. 1973, 46,
675. Imines 8 and 10 were prepared via a modification of a
literature procedure: Moretti, I.; Torre, G. Synthesis 1970,
141. Imine 13 was synthesized following a literature
procedure: Harada, K.; Mizoe, Y.; Furukawa, J.; Yamashita,
S. Tetrahedron 1970, 26, 1579.
(15) Stereochemical assignments are based on comparison of the
1H NMR coupling constants of relevant protons with the
spectra of syn- and anti-17.16
(16) A representative experiment is as follows: Under a N2
atmosphere imine 5 (2.22 g, 16 mmol) was added to LDA (16
mmol) in dry THF (10 mL) at 78 C. After 1.5 h a solution
of acetaldehyde (0.87 g, 19.7 mmol) in 2 ml THF was added
at once. After 10 min a 1 M LiAlH4 solution in THF (16 mL)
was added and the reaction mixture was heated at 50 C for 16
h. The excess hydride was carefully quenched with 2 N HCl
(50 mL), followed by washing with t-BuOMe (2 25 mL).
The acidic aqueous layer was basified to pH 14 with 4 N
NaOH and extracted with t-BuOMe (3 25 mL). The
combined organic layers were dried over Na2SO4 and
concentrated in vacuo. Bulb to bulb distillation (80 C, 0.3
mbar) yielded 2.49 g (84%) of -amino alcohol 17 as a 5: 1
mixture of syn and anti diastereomers. The diastereomers
were partially separated by chromatography on silica gel
Synlett 2001, No. 7, 1109–1112 ISSN 0936-5214 © Thieme Stuttgart · New York

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S. J. Veenstra, S. S. Kinderman
LETTER
using CH2Cl2/MeOH/25% aq NH3 (90/9.5/0.5) as an eluent.
NMR spectra are in agreement with the literature.7
syn-4-(Cyclohexylamino)pentan-2-ol syn-17. Oil; 1H (400
MHz; CDCl3) 1.07 (3H, d, J 6.2), 1.11 (3H, d, J = 6.2 Hz),
1.02-1.33 (5H, m), 1.18 (1H, ddd, J = 14.1, 11.3 and 10.4 Hz),
1.50 (1H, ddd, J = 14.1, 2.5 and 1.8 Hz), 1.55-1.74 (4H, m),
1.88-1.94 (1H, m), 2.56 (1H, tt,J = 10 and 3.7 Hz), 2.92 (1H,
dqd, J = 11.3, 6.2 and 2.7 Hz), 3.94 (1H, dqd, J = 10.4, 6.2 and
1.8 Hz); 13C (100 MHz; CDCl3) 22.11 (C-5), 24.14 (C-1),
24.62, 25.17, 26.22, 32.99, 35.17, 45.60 (C-3), 51.35 (C-4),
53.46 and 69.19 (C-2).
anti-4-(Cyclohexylamino)pentan-2-ol anti-17. Oil; 1H (400
MHz; CDCl3) 0.92-1.06 (2H, m), 1.14 (3H, d, J = 6.4 Hz),
1.15 (3H, d, J = 6.2 Hz), 1.15-1.31 (3H, m), 1.39 (1H, ddd,
J = 14.3, 5.4 and 2.8 Hz), 1.57 (1H, ddd, J = 14.4, 8.4 and 3.6
Hz), 1.56-1.64 (1H, m), 1.66-1.74 (2H, m), 1.84-1.94 (2H, m),
2.54 (1H, tt, J = 10.1 and 3.6 Hz), 3.24 (1H, dqd, J = 6.0, 6.4
and 3.7 Hz), 4.12 (1H, dqd, J = 8.5, 6.2 and 2.8 Hz); 13C (100
MHz; CDCl3) 20.65 (C-5), 23.88 (C-1), 25.29, 25.41, 26.28,
33.90, 34.09, 41.61 (C-3), 47.80 (C-4), 53.59 and 65.37 (C-2).
The hydrochloride salt of the pure syn-diastereomer was
obtained in 72% yield after treatment with HCl/EtOH and
crystallisation from EtOH/tBuOMe. Mp. 154-155 °C.
Article Identifier:
1437-2096,E;2001,0,07,1109,1112,ftx,en;G06601ST.pdf
Synlett 2001, No. 7, 1109–1112 ISSN 0936-5214 © Thieme Stuttgart · New York