Simple methodology for the preparation of amino alcohols from amino acid esters using nabh4-methanol in THF

Article abstract of DOI:10.1080/00397911.2010.481747

Amino alcohols constitute a very useful and versatile class of organic compounds, with important applications in synthetic and medicinal chemistry. However, in most of the procedures described in the literature for the obtainment of these compounds, considerable limitations can be found, such as drastic conditions, long time reactions, poor yields, and purification problems. The present article describes a methodology that gives amino alcohols and N-protected amino alcohols based on the reduction of amino acid esters under mild conditions, employing NaBH₄ in the presence of methanol. The reactions occurred in a short time (15-20min) and provide yields of 50-95%.

Full text of DOI:10.1080/00397911.2010.481747

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Simple Methodology for the Preparation
of Amino Alcohols from Amino Acid
Esters Using NaBH4–Methanol in THF
R. S. B. Gonçalves a b , A. C. Pinheiro a , E. T. da Silva a , J. C. S. da
Costa a , C. R. Kaiser b & M. V. N. de Souza a b
a FioCruz-Fundação Oswaldo Cruz, Instituto de Tecnologia em
Fármacos-Far Manguinhos, Rio de Janeiro, Brazil
b Programa de Pós-Graduação em Química, Instituto de Química,
Universidade Federal de Rio de Janeiro, Rio de Janeiro, Brazil
Version of record first published: 30 Mar 2011.
To cite this article: R. S. B. Gonçalves , A. C. Pinheiro , E. T. da Silva , J. C. S. da Costa , C. R. Kaiser
& M. V. N. de Souza (2011): Simple Methodology for the Preparation of Amino Alcohols from Amino
Acid Esters Using NaBH4–Methanol in THF, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 41:9, 1276-1281
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Synthetic Communications1, 41: 1276–1281, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.481747
SIMPLE METHODOLOGY FOR THE PREPARATION
OF AMINO ALCOHOLS FROM AMINO ACID
ESTERS USING NaBH4–METHANOL IN THF
R. S. B. Gonc¸alves,1,2 A. C. Pinheiro,1 E. T. da Silva,1
J. C. S. da Costa,1 C. R. Kaiser,2 and M. V. N. de Souza1,2
1
´
FioCruz-Fundac¸a˜o Oswaldo Cruz, Instituto de Tecnologia em Farmacos-Far
Manguinhos, Rio de Janeiro, Brazil
2
´
´
´
Programa de Pos-Graduac¸a˜o em Quımica, Instituto de Quımica,
Universidade Federal de Rio de Janeiro, Rio de Janeiro, Brazil
GRAPHICAL ABSTRACT
Abstract Amino alcohols constitute a very useful and versatile class of organic compounds,
with important applications in synthetic and medicinal chemistry. However, in most of the
procedures described in the literature for the obtainment of these compounds, considerable
limitations can be found, such as drastic conditions, long time reactions, poor yields, and
purification problems. The present article describes a methodology that gives amino alco-
hols and N-protected amino alcohols based on the reduction of amino acid esters under mild
conditions, employing NaBH4 in the presence of methanol. The reactions occurred in a short
time (15–20 min) and provide yields of 50–95%.
Keywords Amino alcohol; reduction; sodium borohydride
INTRODUCTION
Amino alcohols constitute a very useful and versatile class of organic compounds,
with important applications in synthetic and medicinal chemistry. As synthetic exam-
ples, amino alcohols have been used as chiral auxiliaries in asymmetric synthesis,[1] in
resolution of racemic mixtures,[2] in the synthesis of heterocycles, and as building blocks
of drugs.[3] In medicinal chemistry, amino alcohols appear as pharmacophoric
Received September 16, 2009.
Address correspondence to M. V. N. de Souza, FioCruz-Fundac¸a˜o Oswaldo Cruz, Instituto de
´
Tecnologia em Farmacos-Far Manguinhos, Rua Sizenando Nabuco, 100, Manguinhos, 21041-250 Rio
de Janeiro, RJ, Brazil. E-mail: marcos_souza@far.fiocruz.br
1276

AMINO ALCOHOLS FROM AMINO ACID ESTERS
1277
Scheme 1. Reduction of amino acid esters using NaBH4 methanol in THF.
groups in several drugs, such as the antiretroviral protease inhibitors (PIs), saquinavir
(Fortovase), ritonavir (Norvir), lopinavir (Kaletra¼ ritonavir þlopinavir), indinavir
(Crivixan), nelfinavir (Viracept), and amprenavir (Prozei). These drugs are used to
block HIV replication by specifically inactivating the protease enzymes, which are
essential for HIV virus survival.[4]
Different methods described in the literature report the syntheses of amino
alcohols. In the earliest reports, these substances were prepared by reduction of the
corresponding amino acid esters with sodium in ethanol.[5] Subsequently, hydride
reagents were employed,[6] and later still, amino acids were directly reduced by sodium
bis(2-methoxyethoxy)aluminum hydride, lithium borohydride with trimethylchloror-
osilane, borane–dimethyl sulfide complex activated by boron trifluoride–etherate,
sodium borohydride with H2SO4 or I2, and sodium borohydride–trimethylchloro-
silane or boron trifluoride–etherate.[7] However, in most of these procedures, con-
siderable limitations can be found, such as drastic conditions, long time reactions,
poor yields, and purification problems.
One important reduction agent is sodium borohydride (NaBH4). This reagent
is inexpensive and mild, and since its discovery by Brown and coworkers,[8] has been
the hydride most frequently used in the reduction of functional groups such as alde-
hydes, ketones, and imines. Furthemore, depending on the reaction conditions,
acids, esters, oximes, nitriles, amides, azides, and double and triple bonds can also
be reduced. However, it is important to note that reduction of acids and esters with
NaBH4 is relatively difficult to achieve and has been not widely explored.[9]
Because of the importance of amino alcohols in drug discovery and other fields,
and our interest in the development of new methodologies using sodium borohy-
dride,[10] the aim of the present article is to describe the application of NaBH4–methanol
as an efficient new methodology for the reduction of amino acid esters (Scheme 1).
RESULTS AND DISCUSSION
Table 1 lists the amino alcohols and N-protected amino alcohols obtained by
the reduction of the corresponding amino acid esters. The treatment of commercial
amino acids with thionyl chloride in methanol at reflux temperature afforded the cor-
responding amino acid methyl ester.[11] Cbz and Bz N-protected amino acid esters
were prepared according to standard procedure.[11,12] The reduction of the amino
acid esters was complete within 15–20 min on refluxing in tetrahydrofuran (THF),
and alcohol products were isolated after aqueous workup. The best results were
reached for free and Bz-protected amino alcohols, which were obtained pure and

1278
R. S. B. GONC¸ ALVES ET AL.
Table 1. Reduction of amino acids esters using NaBH4–methanol system
24
½aꢀD
a
Entry
1
Substrate
Product
Yield (%)
[a]b
76
ꢁ24.1
ꢁ33.5
ꢁ24.1[7i]
2
73
ꢁ32[7i]
3
4
5
70
83
95
ꢁ15.1
ꢁ14[7i]
—
—
ꢁ30.8
ꢁ31.3[13]
6
70
ꢁ145.5
ꢁ154.8[14]
7
8
9
80
76
79
ꢁ81.3
—
ꢁ81.3[13]
—
—
—
10
11
87
75
ꢁ38.3
ꢁ14.6
Not available
ꢁ14.6[14]
12
13
60c
95c
—
—
ꢁ9.89
ꢁ4.9[15]
14
50c
ꢁ39.10
ꢁ40.6[16]
ac ¼ 1, methanol.
bLiterature values.
cYields obtained after purification by chromatography column.
in good yields (Table 1). However, purification by chromatographic column was
required for the Cbz-protected amino alcohols. The method was found to be stereo-
specific, and no racemization occurred.

AMINO ALCOHOLS FROM AMINO ACID ESTERS
1279
General Procedure
Finely powdered sodium borohydride (0.0870 mol) was suspended in THF
(15 mL) with the respective ester (0.0174 mol). The resulting mixture was stirred
for 15 min at 65 ꢂC. Methanol (10 mL) was then added, and effervescence was
observed. Stirring at 65 ꢂC was maintained for a further period of 15–20 min,
depending on the ester. After that, the solvent was removed by rotary evaporation,
leaving a white paste, which was dissolved by addition of 1 M aqueous HCl (50 mL).
The solution was stirred for 2 h, neutralized with 2 M NaOH, and extracted with
4 ꢃ 50 mL of CH2Cl2. The organic extracts were dried over MgSO4 and concentrated
to give the respective alcohol. All the alcohols were fully characterized by LC-MS,
1
IR, and H and 13C NMR spectra.
CONCLUSION
In conclusion, the present methodology for the one-pot reduction of amino
acids esters to the corresponding amino alcohol is simple, safe, and inexpensive.
Reactions occurred in a short time, without any racemization, and anhydrous con-
ditions or inert atmospheres were not necessary, a great advantage over other meth-
odologies. Furthemore, this method has the potential of being a very useful industry
process. Further studies to develop the method on a large scale and to apply the
methodology in drug synthesis are under way in our laboratory.
ACKNOWLEDGMENT
´
Marcus Vinıcius N. de Souza gratefully acknowledges FAPERJ for financial
support.
REFERENCES
1. (a) Kano, T.; Ueda, M.; Maruoka, K. Direct Asymmetric iodination of aldehydes using an
axially chiral bifunctional amino alcohol catalyst. J. Am. Chem. Soc. 2008, 130, 3728–3729;
(b) Hobuss, D.; Baro, A.; Laschat, S.; Frey, W. Catalytic enantioselective borane reduction
of aryl ketones with pinene-derived amino alcohols. Tetrahedron 2008, 64, 1635–1640; (c)
Metro, T.-X.; Pardo, D. G.; Cossy, J. Syntheses of (S,S)-reboxetine via a catalytic stereo-
specific rearrangement of b-amino alcohols. J. Org. Chem. 2008, 73, 707–710.
2. (a) Sawayama, T.; Tsukamoto, M.; Sasagawa, T.; Naruto, S.; Matsumoto, J.; Uno, H. An
improved optical resolution of 3-acetylthio-2-methylpropionic acid by use of a new chiral
amine, N-isopropyl(phenylalaninol). Chem. Pharm. Bull. 1989, 37, 1382–1383; (b) Horiuchi,
F.; Matsui, M. Chrysanthemic acid, XXIII: New resolving agents: 2-Benzylamino alcohols
synthesized from natural amino acids. Agr. Biol. Chem. 1973, 37, 1713–1716; (c) Kawai, M.;
Omori, Y.; Yamamura, H.; Butsugan, Y. Optical resolution of N-carbobenzoxy-a -methox-
yglycine. Tetrahedron: Asymmetry 1992, 3, 1019–1020.
3. (a) Ella-Menye, J.-R.; Wang, G. Synthesis of chiral 2-oxazolidinones, 2-oxazolines, and
their analogs. Tetrahedron 2007, 63, 10034–10041; (b) Breuning, M.; Winnacker, M.;
Steiner, M. Efficient one-pot synthesis of enantiomerically pure 2-(hydroxymethyl)-
morpholines. Eur. J. Org. Chem. 2007, 13, 2100–2106; (c) Ager, D. J.; Prakash, I.; Schaad,

1280
R. S. B. GONC¸ ALVES ET AL.
D. R. 1,2-Amino alcohols and their heterocyclic derivatives as chiral auxiliaries in
asymmetric synthesis. Chem. Rev. 1996, 96, 835–875.
4. Vasconcelos, T. R. A.; Ferreira, M. L.; Gonc¸alves, R. S. B.; da Silva, E. T.; de Souza, M. V.
N. Lamivudine, an important drug in aids treatment. J. Sulfur Chem. 2008, 29, 559–571.
´
5. Karrer, P.; Karrer, W.; Thoman, H.; Horlacher, E. Mader, W. The isolation of amino
alcohols and cholines from natural amino acids. Helv. Chim. Acta 1921, 4, 76–99.
6. (a) Karrer, P.; Portmann, P.; Suter, M. D-3.5-Cholestadiene-7-one from cattle liver. Helv.
Chim. Acta 1948, 31, 1617; (b) Seki, H.; Koga, K.; Matsuo, H.; Ohki, S.; Matsuo, I.;
Yamada, S. Optically active amino acids, V: Synthesis of optically active a-amino
alcohols by the reduction of a -amino acid esters with sodium borohydride. Chem. Phar.
Bull. 1965, 13, 995–1000.
7. (a) Prasad, B.; Saund, A. K.; Bora, J. M.; Mathur, N. K. Course of reduction of
dicarboxylic amino acids with sodium bis(2-methoxyethoxy)aluminum hydride. Indian
J. Chem. 1974, 12, 290–291; (b) Saund, A. K.; Mathur, N. K. Reduction of a-amino acids
and esters with lithium aluminum hydride. Indian J. Chem. 1971, 9, 936–937; (c) Stanfield,
C. F.; Parker, J. E.; Kanellis, P. Synthesis of protected amino alcohols: A comparative
study. J. Org. Chem. 1981, 46, 4799–4800; (d) Abiko, A.; Masamune, S. An improved,
convenient procedure for reduction of amino acids to amino alcohols: Use of sodium
borohydride–sulfuric acid. Tetrahedron Lett. 1992, 33, 5517–5518; (e) McKennon, M. J.;
Meyers, A. I.; Drauz, K.; Schwarm, M. A convenient reduction of amino acids and their
derivatives. J. Org. Chem. 1993, 58, 3568–3571; (f) Anand, R. C.; Vimal, A. A convenient
and mild procedure for the reduction of amino acids using Amberlyst 15-NaBH4-LiCl.
Tetrahedron Lett. 1998, 39, 917–918; (g) Feng, D. Z.; Song, Y. L.; Jiang, X. H.; Chen,
L.; Long, Y.-Q. Forward and reverse synthesis of piperazinopiperidine amide analogs:
A general access to structurally diverse 4-piperazinopiperidine-based CCR5 antagonists.
Org. Biomol. Chem. 2007, 5, 2690–2697; (h) Sekhri, L.; Drid, M. A convenient procedure
for the reduction of amino acids using tetrabutylammonium fluoride and polymethyl-
hydrosiloxane. Org. J. Chem. 2007, 23, 869–872; (i) McKennon, M. J.; Meyers, A. I. A
convenient reduction of amino acids and their derivatives. J. Org. Chem. 1993, 58,
3568–3571; (j) Dharanipragada, R.; Alarcon, A.; Hruby, V. J. A convenient synthesis
of (2S)-2-amino-3-phenylpropanol. Org. Prep. Proc. Int. 1991, 23, 396–397.
8. de Souza, M. V. N.; Vasconcelos, T. R. A. Recent methodologies mediated by sodium
borohydride in the reduction of different classes of compounds. Appl. Organomet. Chem.
2006, 20, 798–810.
9. Soai, K.; Oyamada, H.; Takase, M. preparation of N-protected amino alcohols and
N-protected peptide alcohol by reduction of the corresponding esters with sodium
borohydride: An improved procedure involving a slow addition of a small amount of
methanol. Bull. Chem. Soc. Jpn. 1984, 57, 2327–2328.
10. (a) Boechat, N.; da Costa, J. C. S.; Mendonc¸a, J. S.; Oliveira, P. S. M.; De Souza, M. V.
N. A simple reduction of methyl aromatic esters to alcohols using sodium borohydride–
methanol system. Tetrahedron Lett. 2004, 45, 6021; (b) da Costa, J. C. S.; Pais, K. C.;
Fernandes, E. L.; Oliveira, P. S. M.; Mendonc¸a, J. S.; de Souza, M. V N.; Peralta,
M. A.; Vasconcelos, T. R. A. Simple reduction of ethyl, isopropyl, and benzyl
aromatic esters to alcohols using sodium borohydride–methanol system. Arkivoc 2006,
1, 128–133.
11. Pinheiro, A. C.; Kaiser, C.; Lourenc¸o, M. C. S.; Souza, M. V. N..; Wardell, J. L.; Wardell,
S. M. S. V. Synthesis and in vitro activity towards Mycobacterium tuberculosis of L-serinyl
ester and amino derivatives of pyrazinoic acid. J. Chem. Res. 2007, 3, 180–184.
12. Mesaik, M. A.; Rahat, S.; Khan, K. M.; Ullah, Z.; Choudhary, M. I.; Ismail, Z.; Rahman,
A.; Ahmad, A. Synthesis and immunomodulatory properties of selected oxazolone deriva-
tives. Bioorg. Med. Chem. 2004, 12, 2049–2057.

AMINO ALCOHOLS FROM AMINO ACID ESTERS
1281
13. Lee, K.-Y.; Kim, Y.-H.; Park, M.-S.; Oh, C.-Y.; Ham, W.-H. Stereoselective intramolecu-
lar cyclization of allyl and homoallyl benzamide via P-allylpalladium complex catalyzed
by Pd(0). J. Org. Chem. 1999, 64, 9450–9458.
14. Takahashi, H.; Kawabata, A.; Higashiyama, K. Enantioselective carbon–carbon bond
formation by chiral organotitanium compounds: Methyltitanium (S)-N-acylpyrrolidinyl-
methoxide diisopropoxides. Chem. Pharm. Bull. 1987, 35, 1604–1607.
15. Mijovic, M. P. V.; Walker, J. Chemistry of micrococcin P, II. J. Chem. Soc. 1960,
909–916.
16. Katarzynska, J.; Mazur, A.; Bilska, M.; Adamek, E.; Zimecki, M.; Jankowski, S.;
Zabrocki, J. Synthesis and immunosuppressive activity of new cyclolinopeptide A analogs
modified with b-prolines. J. Pept. Sci. 2008, 14, 1283–1294.