New, convenient methods of synthesis and resolution of 1,2-amino alcohols

Article abstract of DOI:10.1055/s-2003-41046

Oximes of α-keto esters are reduced to obtain the corresponding amino alcohols using NaBH₄ in combination with I₂, CH ₃COOH, TiCl₄, ZrCl₄, COCl₂, H ₂SO₄, and TMS-Cl in 60-85% yields. The racemic phenylglycinol, phenylalaninol, and 2-aminobutanol are resolved using dibenzoyl-L-tartaric acid to obtain enantiomeric samples of >98% ee.

Full text of DOI:10.1055/s-2003-41046

SHORT PAPER
1965
New, Convenient Methods of Synthesis and Resolution of 1,2-Amino Alcohols
S
ynthesis and Resoluti
a
on of 1, 2-A
r
mino A
l
i
c
oholsappan Periasamy,* Sangarappan Sivakumar, Meda Narsi Reddy
School of Chemistry, University of Hyderabad, Central University P. O., Hyderabad - 500 046, India
E-mail: mpsc@uohyd.ernet.in
Received 12 May 2003; revised 2 June 2003
Table 1 Reduction of Oxime Ester 1 to Phenylglycinol using
NaBH4 in the Presence of Additives
Abstract: Oximes of a-keto esters are reduced to obtain the corre-
sponding amino alcohols using NaBH4 in combination with I2,
CH3COOH, TiCl4, ZrCl4, COCl2, H2SO4, and TMS–Cl in 60–85%
yields. The racemic phenylglycinol, phenylalaninol, and 2-aminob-
utanol are resolved using dibenzoyl-L-tartaric acid to obtain
enantiomeric samples of >98% ee.
Entry
Additives
Time (h) Temp (ºC) Yield (%)
a
1
2
3
4
5
6
7
8
9
I2
4
48
4
67
25
67
25
25
25
25
25
25
85
70
70
60
65
60
65
70
60
b
I2
Key words: esters, oximes, boron, amino alcohols, enantiomeric
resolution
CH3COOHc
d
ZrCl4
24
4
e
Amino alcohols are an important class of organic com-
pounds and these moieties have found much use in medic-
inal chemistry as therapeutic agents for a wide variety of
human diseases and disorders.1 During the past few de-
cades, the enantiomerically pure amino alcohols, espe-
cially 1,2-amino alcohols, have also been employed as
chiral auxiliaries and resolving agents for acids and as
chiral ligands in catalysts for applications in catalytic
asymmetric synthesis.2 Chiral 1,2-amino alcohols are gen-
erally prepared from naturally occurring amino acids,3 re-
duction of a-amino carbonyl compounds,4 a-hydroxy
carbonyl compounds,5 from the stereo-, regio- and
enantioselective ring opening of epoxides,6 amino hydro-
xylations of olefins7 and asymmetric hydroboration of
enamines.8 These amino alcohols can also be obtained in
enantiomerically pure form via resolution of racemic ami-
no alcohols, especially for obtaining both enantiomers in
enantiomerically pure forms, but only a few methods are
available.9 We wish to report here a general method for
the synthesis of racemic 1,2-amino alcohols through re-
duction of oximes, which are accessible from a-keto es-
ters, using the easy to handle NaBH4/I2 reagent system.
Also, a method of resolution of these racemic amino alco-
hols using the dibenzoyl-L-tartaric acid is described.
ZrCl4
f
COCl2
4
g
TiCl4
4
TMS-Clh
4
i
H2SO4
4
a NaBH4 was added to a stirred solution of oxime ester in THF. I2 in
THF was added dropwise for 1 h at 0 oC. The reaction mixture was
refluxed for 4 h.
b The reaction mixture was stirred at 25 °C for 48 h.
c NaBH4 was added to a stirred solution of the oxime ester in THF.
Then, CH3COOH in THF was added dropwise for 1 h at 0 oC. The re-
action mixture was refluxed for 4 h.
d ZrCl4 was added slowly to the NaBH4 in THF and the reaction mix-
ture was stirred for 24 h at 25 °C. Then, the oxime ester in THF was
added dropwise and the reaction mixture was stirred at 25 °C for 12 h.
e The reaction mixture was refluxed for 4 h.
f NaBH4 was added in portions to the stirred solution of COCl2 in
THF. Oxime ester in THF was added dropwise and the reaction mix-
ture was refluxed for 4 h
g TiCl4 in CH2Cl2 was added to a stirred slurry of NaBH4 in THF. The
oxime ester was added dropwise and the reaction mixture was re-
fluxed for 4 h.
h TMSCl and NaBH4 in THF were refluxed for 2 h. The oxime ester
in THF was added dropwise and the reaction mixture was refluxed for
4 h.
The a-keto esters are obtained by the Grignard addition to
the diethyl oxalate. The corresponding oxime esters were
prepared using hydroxylamine following a reported pro-
cedure.10 The preparation of racemic 1,2-amino alcohols
was examined through reduction of oximes of the a-keto
esters by NaBH4 activated by the presence of additives.
The results obtained are summarised in Table 1.
i H2SO4 in anhyd Et2O was added dropwise to a stirred suspension of
NaBH4 and the oxime ester in THF. Then the reaction mixture was re-
fluxed for 4 h.
NOH
NH2
NaBH4 /I2
RCCOOEt
RCHCH2OH
Comparison of the results (Table 1) indicates that the easy
to handle NaBH4/I2 reagent system11 gives better yields.
Accordingly, reduction of various oxime esters have been
1, R=Ph-
1a, 85%
2a, 80%
3a, 75%
4a, 60%
5a, 60%
2, R=Ph-CH2-
3, R=(CH3)2CH-
4, R= C2H5-
5, R= CH3-
Synthesis 2003, No. 13, Print: 18 09 2003. Web: 22 08 2003.
Art Id.1437-210X,E;2003,0,13,1965,1967,ftx,en;Z06203SS.pdf.
DOI: 10.1055/s-2003-41046
Scheme 1 Reduction of oxime esters to the corresponding amino
alcohols
© Georg Thieme Verlag Stuttgart · New York

1966
M. Periasamy et al.
SHORT PAPER
examined with this reagent system. The results are sum-
marised in Scheme 1.
Table 2 Resolution of Racemic Amino Alcohols Using Dibenzoyl-
L-tartaric Acida
We have examined the asymmetric synthesis of these ami-
no alcohols using the CBS oxazaborolidine catalyst.12
These efforts were not successful. However, we have ob-
served that these racemic 1,2-amino alcohols are readily
resolved using dibenzoyl-L-tartaric acid (Scheme 2) and
the results are summarized in Table 2.
Entry Substrate,
ee (%)
Solvent
Amino Alcohol Obtained from
Precipitate Filtrate
eec (%) Yieldd eec (%) Yieldd
(Config) (%)
(Conf.) (%)
45 (S) 30
98 (S) 52
97 (R) 53
47 (R) 28
99 (S) 24
62 (R) 25
98 (R) 52
25 (S) 20
40 (R) 20
30 (S) 20
50 (R) 22
98 (R) 20
50 (S) 25
98 (S) 32
1
2
3
4b
5
6
7
8
9
1a, 00
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
MeCN
30 (R)
28 (R)
30 (S)
20 (S)
20 (R)
10 (S)
0
60
38
34
28
60
60
35
60
60
55
52
52
60
58
(S)-1a, 45
(R)-1a, 30
1a, 00
1N KOH
(R) or (S) isomer
Precipitate
CH2Cl2
NH2
dibenzoyl-L-tartaric acid
Acetone, r.t., 6 h
OH
R
(±)
2a, 00
1a R = Ph-
(R) 2a, 20
(R)-2a, 62
3a, 00
2a R = PhCH2-
3a R = (CH3)2CH-
4a R = CH3CH2-
1N KOH
CH2Cl2
(S) or (R) isomer
Filtrate
15 (R)
10 (S)
15 (R)
10 (S)
20 (S)
10 (R)
5 (R)
Scheme 2 Resolution of 1, 2-amino alcohols using dibenzoyl-L-tar-
taric acid
3a, 00
10
(S)-3a, 25
(R)-3a, 40
4a, 00
Acetone
MeCN
A sample of 98% ee was obtained from the precipitate in
a single step from racemic compounds 2a and 4a using
dibenzoyl-L-tartaric acid (entry 5 and 12, Table 2). The
compounds 1a and 3a were only partially resolved under
these conditions. However, 1a can be further enriched to
obtain samples of 98% ee. Also, we have observed an in-
teresting solvent effect in the case of the resolution of 3a.
Whereas the S-isomer precipitated when acetone was used
11
12
13
14
Acetone
Acetone
Acetone
(S)-4a, 20
(S)-4a, 50
a Unless otherwise mentioned all the reactions were performed using
as a solvent, the R-isomer precipitated out when acetoni- racemic 1a, 2a, 3a and 4a (5 mmol) and dibenzoyl-L-tartaric acid (5
mmol) in the solvent (60 mL) and stirred at 25 °C.
trile was used as a solvent (entry 8 and 9, Table 2).
b Racemic 1a (5 mmol) and dibenzoyl-L-tartaric acid (2.5 mmol) were
The amount of the chiral resolving agent used had an ef-
fect in the resolution of phenylglycinol 1a. It was ob-
served that, whereas the 1a enriched in S-isomer
precipitated when 1a and dibenzoyl-L-tartaric acid were
used in 1:1 ratio (entry 1, Table 2), the 1a enriched in R-
isomer precipitated out when they were used in 2:1 ratio
(entry 4, Table 2). Also, samples of its R and S isomers
were obtained in >98% ee by adding dibenzoyl-L-tartaric
acid in portions as outlined in the Scheme 3.
used in the solvent (25 mL) and stirred at 25 °C.
c All ee values reported here are based on reported maximum13
[a]D25 +33 [c 0.75, aq HCl (1 M)] for (S)-1a, [a]D25 +23 [c 1.2, aq HCl
(1 M)] for (R)-2a, [a]D25 +17 (c 10, EtOH) for (S)-3a, and [a]D25 +12.5
(c 2, EtOH) for (S)-4a.
d The yields are of the recoverd products, based on the total amount of
the starting racemic mixture used.
1N KOH
In summary, the NaBH4/I2 reagent system is useful for the
reduction of oximes of a-keto esters to obtain the corre-
sponding racemic 1,2-amino alcohols in moderate to good
yields. The racemic amino alcohols are resolved using
dibenzoyl-L-tartaric acid to obtain samples of >98% ee. In
view of the applications of 1,2-amino alcohols in the prep-
aration of the chiral oxazoline catalysts and in the synthe-
ses of biologically active compounds, this synthetic
method of chiral 1,2-amino alcohols has good synthetic
potential.14
Precipitate
dibenzoyl-L-tartaric acid
R-(-)-1a
12%, 98% ee
CH2Cl2
NH2
2.5 mmol
_____________________
OH
Acetone 15 ml
r.t., 6 h
Ph
(±)1a (10 mmol)
Filtrate
dibenzoyl-L-tartaric acid
2.5 mmol
Filtrate
Precipitate
1N KOH
CH2Cl2
1N KOH
CH2Cl2
Reduction of Oxime Esters to the Corresponding Racemic Ami-
no Alcohols; General Procedure
NaBH4 (0.57 g, 15 mmol) was added to a stirred solution of the
oxime ester (5mmol) in THF. I2 (1.9 g, 7.5 mmol) in THF was added
through an addition funnel for 1 h at 0 oC. The reaction mixture was
refluxed for 4 h. The reaction mixture was brought to 25 °C and
R-(-)-1a
42%, 15% ee
S-(+)-1a
13%, 98% ee
Scheme 3 Resolution of phenylglycinol by adding dibenzoyl-L-tar-
taric acid in portions
Synthesis 2003, No. 13, 1965–1967 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis and Resolution of 1,2-Amino Alcohols
1967
then quenched with MeOH. The solvents was removed under re-
duce pressure. The residue was refluxed with KOH solution for 3 h.
The aq layer was extracted with CH2Cl2 (3 × 20 mL). The solvent
was evaporated and the crude product was distilled to obtain the ra-
cemic 1,2-amino alcohols. All the compounds were identified from
the spectral data IR, 1H, 13C and comparison with the reported data.
brine, dried (MgSO4) and evaporated to dryness to obtain the S-iso-
mer (45% ee, 30% yield). The filtrate was concentrated and the res-
idue was treated as outlined above to obtain the R-isomer (30% ee,
60% yield). The partially resolved S-isomer was further enriched to
obtain the sample of 98% ee (52% yield).
[a]D25 +31 [c 1, aq HCl (1 M)] {lit.13 [a]D25 +31.7.1 (c 0.75, aq HCl
(1 M)}.
Reduction of Oxime of Ethyl Phenylglyoxylate to Phenylglyci-
nol (1a)
The R-isomer was also further enriched using dibenzoyl-L-tartaric
acid to obtain the sample of 97% ee (53% yield).
[a]D25 –32 [c 1, aq HCl (1 M)] {lit.13 [a]D25 –33 (c 0.75, aq HCl (1
M)}.
Yield: 0.58 g (85%); mp 72–75 °C (lit.3b 75–78 °C).
IR (neat): 3362, 1048 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.0 (br s, 3 H), 3.5 (dd, J = 12 Hz,
1 H), 3.6 (dd, J = 8 Hz, 1 H), 4.0 (dd, J = 8 Hz, 1 H), 7.3 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 57.4, 67.8, 126.0 126.9, 127.5,
Acknowledgements
137.5.
We are thankful to the CSIR and UGC (New Delhi) for financial
support. The DST support of a research grant is gratefully acknow-
ledged.
Reduction of Oxime of Ethyl Benzylglyoxylate to Phenylalani-
nol (2a)
Yield: 0.6 g (80%); mp 92–94 °C (lit.3b 93–95 °C).
IR (neat): 3350, 1053 cm–1.
References
1H NMR (200 MHz, CDCl3): d = 2.5 (dd, J = 8 Hz, 1 H), 2.7 (dd,
J = 5.6 Hz, 1 H), 3.1 (br s, 3 H), 3.3 (m, 1 H), 3.4 (dd, J = 6.6 Hz, 1
H), 3.62 (dd, J = 3.8 Hz, 1 H), 7.2 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 40.6, 54.2, 66.0,126.4, 128.59,
129.23, 138.67.
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Reduction of Oxime of Ethyl Isopropylglyoxylate to Valinol (3a)
Yield: 0.38 g (75%); bp 77 °C/8 mmHg (lit.3b 75–77 °C/8 mmHg).
IR (neat): 3350, 1051 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.8 (d, J = 6.8 Hz, 3 H), 0.9 (d,
J = 6.8 Hz, 3 H), 1.4–1.6 (m, 1 H), 2.4–2.6 (m, 1 H), 3.29 (t, J = 10
Hz, 1 H), 3.6 (dd, J = 4 Hz, 1 H), 4.1 (br s, 3 H).
13C NMR (50 MHz, CDCl3): d = 18.3, 19.2, 31.2, 58.4, 64.6.
Reduction of Oxime of Ethyl Ethylglyoxylate to 2-Aminobu-
tanol (4a)
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Yield: 0.26 g (60%); bp 176 °C (lit.13 176–178 °C).
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IR (neat): 3350, 1050 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.9 (t, J = 7.8 Hz, 3 H), 1.4 (m, 2
H), 2.7 (m, 1 H), 3.3 (br s, 3 H), 3.5 (dd, J = 7.8 Hz, 1 H), 3.7 (dd,
J = 3.9 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 10.4, 26.5, 54.3, 65.8.
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Reduction of Oxime of Ethyl Methylglyoxylate to Alaninol (5a)
Yield: 0.22 g (60%); bp 172–174 °C (lit.13 167–180 °C).
IR (neat): 3352, 1051 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.0 (d, J = 6.8 Hz, 3 H), 2.5 (br s,
3 H), 3.2 (m, 1 H), 3.25 (m, 1 H), 3.7 (dd, J = 7.8 Hz, 1 H)
13C NMR (50 MHz, CDCl3): d = 17.2, 45.5, 65.6.
Resolution of 1,2-Amino Alcohols Using Dibenzoyl-l-tartaric
acid; General Procedure
(12) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37,
1986.
The dibenzoyl-L-tartaric acid (1.8 g, 5 mmol) and the phenylglyci-
nol 1a (0.7 g, 5 mmol) were taken in acetone (60 mL) and the con-
tents were stirred at r.t. for 6 h and filtered. The precipitate was
suspended in a mixture of CH2Cl2 and aq KOH (1 M) and stirred un-
til dissolution occurred. The organic extracts were washed with
(13) Aldrich Catalog Handbook of Fine Chemicals; Aldrich:
Milwaukee, 2000-2001.
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C. J. Am. Chem. Soc. 1961, 83, 2212.
Synthesis 2003, No. 13, 1965–1967 © Thieme Stuttgart · New York