A convenient one-step synthesis of stable β-amino alcohol N-boranes from α-amino acids

Article abstract of DOI:10.1055/s-0031-1289727

Novel, non-cyclic -amino alcohol N-boranes are isolated from the sodium borohydride-sulfuric acid assisted direct reduction of a series of -amino acids. The reduction takes place in one step under mild conditions and affords the products in good yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289727

PAPER
1057
A Convenient One-Step Synthesis of Stable b-Amino Alcohol N-Boranes
from a-Amino Acids
S
a
ynthesis of Stable
f
b
-Amin
r
o Alcoh
o
ol
N
-Borane
d
s
iti Pinaka,a,b Georgios C. Vougioukalakis,*a,c Dimitra Dimotikali,b Vassilis Psyharis,d Kyriakos Papadopoulos*a
Institute of Physical Chemistry, NCSR Demokritos, 15310 Athens, Greece
Fax +30(210)6511766; E-mail: kyriakos@chem.demokritos.gr
b
c
Department of Chemical Engineering, NTU Athens, 15780 Athens, Greece
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
Fax +30(210)6511766; E-mail: vougiouk@chem.uoa.gr
d
Institute of Materials Science, NCSR Demokritos, 15310 Athens, Greece
Received 23 January 2012; revised 3 February 2012
employed the sodium borohydride–sulfuric acid assisted
direct reduction of a-amino acids.26 Our choice was based
on the fact that this was a safe, cheap and reliable synthet-
ic method toward b-amino alcohols. However, during the
course of our experiments, we noticed that apart from the
targeted b-amino alcohols, unexpected side products were
also formed in significant amounts. These side products
were observed in all the amino acid reductions we per-
formed. The characterization of these compounds was
carried out utilizing a variety of techniques (vide infra)
and eventually led to the conclusion that they were the
corresponding non-cyclic b-amino alcohol N-borane ad-
ducts 3a–f shown in Scheme 1.
Abstract: Novel, non-cyclic b-amino alcohol N-boranes are isolat-
ed from the sodium borohydride–sulfuric acid assisted direct reduc-
tion of a series of a-amino acids. The reduction takes place in one
step under mild conditions and affords the products in good yields.
Key words: amino acids, b-amino alcohols, reduction, sodium
borohydride, b-amino alcohol N-boranes
The importance of amine–borane adducts is profound
both in industry and academia. These compounds, charac-
terized by thermal and hydrolytic stability and solubility
in a wide variety of solvents,1 are utilized in a large num-
ber of applications including, but not limited to, asymmet-
ric synthesis,2–5 chemical hydrogen storage,6–8 the
synthesis of cyclic azaboranes and borazines,9,10 and coor-
dination chemistry.11,12
NaBH4
H2SO4
R
O
R
R
+
THF
NH2 OH
NH2 OH
NH2 OH
A survey of the literature showed that there are a large
number of publications on the synthesis of amine–borane
adducts. In sharp contrast, there are only a few reports on
the synthesis of b-amino alcohol boranes. The majority of
these compounds are obtained through the reaction of b-
amino alcohols with borane–etherates or borane–thio-
etherates.13–17
BH3
3a–f
2a–f
1a–f
a: R
b: R
c: R
d: R
e: R
f: R
Me
S
On a different note, b-amino alcohols are usually synthe-
sized either by the direct reduction of free amino acids,18–26
or indirectly from activated amino acid esters27–29 and
amino acid anhydrides.30,31 Reagents employed for the re-
duction of free amino acids are usually metal hydrides,
such as lithium aluminum hydride or lithium borohydride,
in combination with various organic reagents such as tri-
methylchlorosilane, borane–methyl sulfide complex acti-
vated by trimethylborate, or boron trifluoride–diethyl
ether complex. The utilization of sodium borohydride has
also been reported in combination with inorganic com-
pounds such as transition metal complexes, iodine, or sul-
furic acid.
N
H
Scheme 1 b-Amino alcohol N-boranes obtained by the sodium bo-
rohydride–sulfuric acid assisted direct reduction of a-amino acids
As mentioned above, amino alcohol–borane adducts are
relatively stable compounds which are gaining consider-
able attention, especially in asymmetric organic reactions
where they serve as chiral reducing agents. Considering
their increasing importance, we decided to investigate the
scope and limitations of their synthesis further, through
the direct reduction of a-amino acids using sodium boro-
hydride in the presence of sulfuric acid.
While implementing a project aimed toward the synthesis
of optically pure b-amino alcohols, which were intended
for use as organocatalysts in asymmetric reactions, we
To the best of our knowledge, there are no reports on the
direct synthesis of non-cyclic b-amino alcohol N-boranes
from a-amino acids. b-Amino alcohol–borane adducts are
usually synthesized in anhydrous organic solvents from b-
SYNTHESIS 2012, 44, 1057–1062
x
x.
x
x.
2
0
1
2
Advanced online publication: 27.02.2012
DOI: 10.1055/s-0031-1289727; Art ID: T07612SS
© Georg Thieme Verlag Stuttgart · New York

1058
A. Pinaka et al.
PAPER
amino alcohols and borane–ether complexes.13–17 Most of
these boranes exist in cyclic form and are known as ox-
azaborolidines. They are easily hydrolyzed in acidic or al-
kaline aqueous solutions to afford b-amino alcohols and a
mixture of unidentified boron adducts.
Table 1 Yields and Optical Rotations of b-Amino Alcohols 2a–f
and Novel b-Amino Alcohol N-Boranes 3a–f
a-Amino acid
Product Yield Optimized [a]D (c in g/100 mL)
(%)a yield (%)b
(S)-2-phenylglycine 2a
(1a) 3a
33
27
–
53
–57.1 (c 1.0, CHCl3)
–89.3 (c 1.0, CHCl3)
At this point, we emphasize the importance of the work-
up procedure for this direct reduction of a-amino acids.
Following the procedure described by Abiko and
Masamune,26 we obtained the corresponding b-amino al-
cohols and b-amino alcohol N-boranes as 1:1 mixtures.
Only after employing acidic followed by alkaline hydrol-
ysis were we able to obtain exclusively the b-amino alco-
hols in good isolated yields. Nevertheless, our observation
suggests that Abiko’s procedure is of general applicabili-
ty, provided that special care is taken during hydrolysis.
The use of mild alkaline hydrolysis afforded b-amino al-
cohol N-boranes as the major products. This process
might be of industrial importance as these amino alcohol
N-boranes can be easily synthesized in one step, under
mild conditions and in relatively good yields from a-ami-
no acids. They are not flammable and, more importantly,
they are relatively stable in air and aqueous solutions.32
(S)-phenylalanine 2b
26
36
–
67
–21.3 (c 1.0, CHCl3)
–29.5 (c 1.0, CHCl3)
(1b)
3b
(S)-leucine
(1c)
2c
3c
29
28
–
46
+ 4.6 (c 1.3, EtOH)
+45.4 (c 1.3, EtOH)
(S)-isoleucine
(1d)
2d
3d
25
31
–
56
+ 5.2 (c 1.6, EtOH)
+29.4 (c 1.6, EtOH)
(S)-methionine
(1e)
2e
3e
32
44
–
65
–17.2 (c 1.4, EtOH)
+51.1 (c 1.4, EtOH)
(S)-tryptophan
(1f)
2f
3f
34
27
–
42
–16.5 (c 1.0, MeOH)
+25.2 (c 1.0,
MeOH)
a Yields obtained using the experimental conditions described in ref-
erence 26.
b Yields obtained employing the optimized conditions described in
this work.
The sodium borohydride–sulfuric acid assisted reduction
procedure was employed initially for the reduction of (S)-
2-phenylglycine (1a). The isolated yield of the expected
b-amino alcohol 2a was lower than that reported by Abiko
and Masamune,26 moreover, an unprecedented product 3a
was also obtained in almost equimolar quantity. The
yields of the isolated products 2a and 3a, after column
chromatography (chloroform–methanol, 1:1), were 33%
and 27%, respectively. The same procedure was em-
ployed subsequently for the reduction of a series of a-ami-
no acids. In all cases, b-amino alcohols 2 and the
corresponding N-boranes 3 were obtained in almost equal
yields (Table 1).
crystal X-ray crystallography (see the Supporting Infor-
mation).
1
The H NMR spectra of b-amino alcohols 2a–f were in
agreement with those reported in the literature,24–26,28,33–35
and were less complicated than those of the corresponding
N-boranes 3a–f. More specifically, in the 1H NMR spectra
of b-amino alcohols 2a–f, three characteristic doublet of
doublets were observed at about 3.5, 3.7 and 4.9 ppm, cor-
responding to the diastereotopic methylene (OCH2) and
methine (NCH) protons of the ABX-system of the amino-
ethanol moiety. In contrast, the corresponding peaks in the
spectra of N-boranes 3a–f appeared closer to each other at
about 3.7 ppm, due to the presence of the borane (BH3)
group. The proton signals of the borane group appeared in
the region between 1.0 and 2.0 ppm. The 13C NMR spectra
of N-boranes 3a–f were analogous to those obtained for b-
amino alcohols 2a–f, with one significant difference:
while the two characteristic aliphatic resonances of b-ami-
no alcohols 2a–f appeared at about 65 (CH2OH) and 57
2.0 ppm (NCH), in the 13C NMR spectra of N-boranes 3a–
f the corresponding carbon signals were much closer to
each other (Figure 1), and in some cases overlapped (phe-
nylglycinol borane, 3a).
To improve the yield of N-borane adduct 3a, several opti-
mization attempts were made regarding both the reaction
conditions and the quantities of reagents utilized. For ex-
ample, the reduction was repeated using a large excess of
sodium borohydride (10-fold excess). However, no sig-
nificant differences in the composition or the isolated
yields of the reaction products was observed. In another
attempt, the reaction mixture was subjected to overnight
reflux directly after the addition of the sulfuric acid–dieth-
yl ether solution. After the standard work-up, no product
3a was isolated at all. The reduction was also carried out
in the absence of sulfuric acid, but in this case the yields
of both products were negligible. In a final attempt, the
work-up procedure was modified; the reaction mixture
was hydrolyzed by the addition of aqueous sodium hy-
droxide solution of low base concentration (4 × 10–2 M)
without the addition of methanol. This resulted in forma-
tion of the corresponding b-amino alcohol N-boranes as
the major products in good yields (Table 1). The b-amino
alcohol N-boranes 3a–f were characterized by means of
NMR spectroscopy (1H, 13C, 13C DEPT, COSY and
HSQC experiments), infrared spectroscopy, high-resolu-
tion mass spectrometry, elemental analysis and single-
The presence of the borane group in compounds 3a–f was
confirmed through the observation of strong absorption
bands in the infrared spectra between 2290–2310 cm–1.
Such symmetric and asymmetric absorption bands, attrib-
uted to B–H hydrogen bonds, have been reported in the
literature for various amine–borane adducts.13,16,36 Posi-
tive ion high-resolution mass spectrometry of 3a–f did not
produce valid results since the products undergo hydroly-
sis under the acidic conditions in which the measurements
take place; this observation has previously been reported
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Synthesis of Stable b-Amino Alcohol N-Boranes
1059
Figure 1 13C NMR spectra of b-amino alcohol 2b and the corresponding b-amino alcohol N-borane 3b
in the literature.37 However, fragments corresponding to (Figure 2). In brief, it is worth mentioning that the B–N
[(2M + H)+ – 2BH3 – H2O], observed in the spectra of bond of 1.610(3) Å is within the observed range of B–N
3a–d, strongly suggested that N-boranes 3a–f undergo bonds [1.564(6)–1.658(2) Å].38 The conformation around
self-condensation (formation of substituted aminoethyl– the boron atom is almost tetrahedral with N–B–H bond
aminoethanol adducts) under the conditions employed to angles very close to 109o (see the Supporting Informa-
record the mass spectra.
tion), and unconventional dihydrogen O–H⋅⋅⋅H–B
[H2B⋅⋅⋅H1O¢: 1.81(3) Å] intermolecular contacts appear
in the crystal structure of N-borane 3b.38,39
As regards the reaction mechanism for the formation of b-
amino alcohol N-boranes 3a–f, we propose that it pro-
ceeds in a manner similar to that proposed by Gribble40 for
the reduction of organic acids with sodium borohydride.
Thus, sodium borohydride reacts initially with sulfuric
acid giving borane (BH3), which then reacts with the ami-
no acid affording acyloxyborane–amineborane intermedi-
ate
A
(Scheme 2). This intermediate undergoes
intramolecular transfer of two hydrides from the borane
group to the carbonyl group, giving amineborane–borate
intermediate B, which, under mild work-up conditions
[dilute aqueous sodium hydroxide solution, stirring at
room temperature, (this work)] or forced work-up condi-
tions (concentrated aqueous hydrochloric acid followed
by concentrated alkaline solution) gives amine–boranes
3a–f or b-amino alcohols 2a–f, respectively.
Figure 2 X-ray crystal structure (ORTEP with 30% probability el-
lipsoids) of phenylalaninol N-borane 3b. The intermolecular dihydro-
gen bond H2B⋅⋅⋅H1O¢ is shown. Atoms with prime symbols belong to
the molecule at the symmetry equivalent site (2 – x, 0.5 + y, 2 – z)
In conclusion, the sodium borohydride–sulfuric acid as-
sisted reduction of a-amino acids is an efficient, safe, and
relatively cheap one-pot procedure for the preparation of
novel, chiral b-amino alcohol N-boranes in good yields.
Careful work-up involving mild alkaline hydrolysis at
room temperature was found to be the most appropriate
procedure to obtain the stable b-amino alcohol N-borane
products.
The structures of boranes 3a–f were further established by
elemental analyses, where the measured compositions for
all products were in agreement with the calculated values.
Unambiguous confirmation of the structures was
achieved by X-ray crystallography of borane 3b
© Thieme Stuttgart · New York
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1060
A. Pinaka et al.
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one-step preparation of
β-amino alcohol N-boranes
directly from α-amino acids
OH
O
R
OH
R
N
BH3
NH2
H2
1
3a–f
(2NaBH4 + H2SO4
2BH3 + 2H2 + Na2SO4)
mild alkaline
hydrolysis
H
B
H
H
Na
O
intramolecular
hydride transfer
forced alkaline
hydrolysis
OH
O
R
O
Na
O
B
R
N
R
NH2
NH2
BH3
H
BH3
2a–f
A
B
Scheme 2 Proposed mechanism for the sodium borohydride–sulfuric acid assisted reduction of a-amino acids into b-amino alcohol N-boranes
3a–f
organic solvents were evaporated under vacuum and the remaining
aq soln extracted with CHCl3 (3 × 50 mL). The combined organic
extracts were dried over MgSO4 and evaporated to afford novel b-
amino alcohol N-boranes 3a–f in pure form without the need for fur-
ther purification.
All solvents were dried and purified according to standard proce-
dures. Reaction products were isolated as chromatographically pure
materials. All the amino acids were purchased from commercial
suppliers and used without any further purification. TLC was car-
ried out on silica gel plates (Merck Kieselgel F254) and visualization
was accomplished by UV light or by spraying with phosphomolyb-
dic acid followed by heating. Flash column chromatography was
carried out on SiO2 (silica gel 60, 70–230 mesh, ASTM). 1H NMR
and 13C NMR spectra were recorded on a Bruker Avance 500 MHz
(125 MHz for 13C) spectrometer. Chemical shifts are reported in
ppm downfield from Me4Si, using the residual solvent signal as the
internal standard. Coupling constants (J) are reported in Hz. The as-
signment of signals in the 13C NMR spectra was verified using
DEPT experiments. Infrared spectra were recorded on a Nicolet
6700 Fourier transform spectrometer. Bands are reported in wave-
numbers (cm–1) with the following relative intensities: br (broad),
s (strong 67–100%), m (medium 33–67%), or w (weak <33%).
HRMS spectra were obtained using the electrospray ionization
(ESI) method. Absorption spectra were obtained on a JASCO V-
560 spectrophotometer. The molar extinction coefficients are given
in L mol–1 cm–1. Elemental analyses were obtained using a Perkin-
Elmer 2400 CHN elemental analyzer. Optical rotation measure-
ments were performed on a Perkin-Elmer 241 polarimeter and cal-
culated from the equation [a]D = (ameasured × 100)/c × l; where l is the
path length of the cell, and c the concentration of the solution (g/100
mL). Crystallographic data have been deposited at the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK, and copies can be obtained on request, free of charge, by
quoting the publication citation and the deposition number CCDC
857109 (3b).
b-Amino Alcohols 2a–f; General Procedure
To obtain b-amino alcohols 2a–f as the major products, an identical
procedure to that described for the synthesis of compounds 3a–f
was adopted initially. On completion of the reaction, hydrolysis was
achieved by the addition of aq HCl (10 mL, 3 M). The resulting
mixture was stirred vigorously for 2 h at r.t. after which, aq NaOH
soln (15 mL, 5 M) was added and the work-up procedure described
for the synthesis of compounds 3a–f was followed to afford b-ami-
no alcohols 2a–f as the major products in yields of up to 70%.
(2S)-(–)-2-Amino-2-phenylethanol N-Borane (3a)
The reaction of (S)-2-phenylglycine (2.26 g, 15.0 mmol) with
NaBH4 (2.28 g, 60 mmol) following the above general procedure
furnished 3a (1.21 g, 53%) as a wax-like product.
[a]D20 –89.3 (c 1.0, CHCl3).
IR (neat): 3227 (m, OH), 3143 (w, NH), 2942 (w), 2317 (s, BH),
2274 (s, BH), 1582 (m), 1454 (m), 1162 (s, N→B), 1062 (s), 758
(s), 697 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 7.35–7.21 (m, 5 H, phenyl), 4.92
(s, 1 H, NH), 4.03 (dd, J1 = 11.4 Hz, J2 = 2.8 Hz, 1 H, OCH2), 3.91
(br s, 1 H, NH), 3.84 (m, 1 H, NCH), 3.69 (dd, J1 = 11.4 Hz, J2 = 2.6
Hz, 1 H, OCH2), 3.29 (s, 1 H, OH), 1.51 (br s, 3 H, BH3).
13C NMR (125 MHz, DMSO-d6): d = 139.6 (C-3), 128.93 (C-5, C-
5¢), 128.89 (C-6), 128.4 (C-4, C-4¢), 64.6 (C-1), 64.5 (C-2).
HRMS (ESI): m/z calcd for C16H21N2O [(2M + H)+ – 2BH3 – H2O]:
b-Amino Alcohol N-Boranes 3a–f; General Procedure
To a three-necked, round-bottomed flask containing NaBH4 (2.28 g,
60 mmol) and anhydrous THF (30 mL) under argon was added the
appropriate a-amino acid (15 mmol) with stirring. The flask was
immersed in an ice–H2O bath (0 °C) and a soln of concd H2SO4 (1.5
mL, 28.6 mmol) in Et2O (5.0 mL) was added at such a rate that the
temperature was maintained below 20 °C. The mixture was then
stirred vigorously at r.t. under an Ar atm for ca. 20 h. After comple-
tion of the reaction, the flask was again immersed in an ice-H2O
bath (0 °C) and an aq NaOH soln (100 mL, 4 × 10–2 M) was added
slowly, in order to maintain the temperature of the mixture below
40 °C. The resulting mixture was stirred vigorously for 3 h at r.t.
CAUTION: the full experimental procedure was performed inside
a fume-hood in order to safely vent dangerous emissions (H2). The
257.1648; found: 257.1677.
UV/Vis (CHCl3): lmax (e) = 220 (2560), 258 nm (133).
Anal. Calcd for C8H14BNO: C, 63.63; H, 9.34; N, 9.28. Found: C,
63.44; H, 9.19; N, 9.54.
(2S)-(–)-2-Amino-3-phenylpropan-1-ol N-Borane (3b)
The reaction of (S)-phenylalanine (2.47 g, 15.0 mmol) with NaBH4
(2.28 g, 60 mmol) following the above general procedure furnished
3b (1.67 g, 67%) as a wax-like product.
[a]D20 –29.5 (c 1.0, CHCl3).
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Synthesis of Stable b-Amino Alcohol N-Boranes
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IR (neat): 3273 (m, OH), 3115 (m, NH), 2936 (m), 2353 (s, BH),
2261 (s, BH), 1602 (s), 1299 (s), 1163 (s, N→B), 1044 (s), 699 (s),
747 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 7.37–7.15 (m, 5 H, phenyl), 4.22
(br s, 1 H, NH), 3.87 (dd, J1 = 11.5 Hz, J2 = 2.3 Hz, 2 H, OCH, NH),
3.57 (dd, J1 = 11.5 Hz, J2 = 5.3 Hz, 1 H, OCH), 3.04 (m, 1 H, CH2-
phenyl), 3.01 (s, 2 H, NCH, OH), 2.79 (m, 1 H, CH2-phenyl), 1.49
(br s, 3 H, BH3).
13C NMR (125 MHz, CDCl3): d = 136.5 (C-7), 129.4 (C-6, C-6¢),
129.1 (C-4), 127.3 (C-5, C-5¢), 60.7 (C-1), 59.5 (C-2), 35.6 (C-3).
HRMS (ESI): m/z calcd for C18H25N2O [(2M + H)+ – 2BH3 – H2O]:
285.1961; found 285.1969.
(2S)-(+)-2-Amino-4-methylsulfanylbutan-1-ol N-Borane (3e)
The reaction of (S)-methionine (2.24 g, 15.0 mmol) with NaBH4
(2.28 g, 60 mmol) following the above general procedure furnished
3e (1.45 g, 65%) as a colorless viscous oil.
[a]D20 +51.1 (c 1.4, EtOH).
IR (neat): 3225 (m, OH), 3142 (w, NH), 2915 (m), 2860 (w), 2316
(s, BH), 2273 (s, BH), 1585 (m), 1427 (m), 1163 (s, N→B), 1077
(s), 1039 (s), 997 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 4.36 and 4.20 (2 × s, 2 H, NH2),
3.89 (dd, J1 = 11.5 Hz, J2 = 4.9 Hz, 1 H, OCH2), 3.62 (dd, J1 = 11.5
Hz, J2 = 6.3 Hz, 1 H, OCH2), 2.99 (s, 1 H, OH), 2.97 (m, 1 H, NCH),
2.54 (m, 2 H, SCH2), 2.00 and 1.76 (2 × m, 2 H, CH2CH2S), 2.09 (s,
3 H, SCH3), 1.36 (br s, 3 H, BH3).
13C NMR (125 MHz, CDCl3): d = 61.6 (C-1), 57.9 (C-2), 30.9 (C-
3), 28.3 (C-4), 15.8 (C-5).
HRMS (ESI): m/z calcd for C5H14NOS [(M + H)+ – BH3]: 136.0791;
UV/Vis (CHCl3): lmax (e) = 220 (2032), 258 nm (208).
Anal. Calcd for C9H16BNO: C, 65.50; H, 9.77; N, 8.49. Found: C,
65.31; H, 9.47; N, 8.12.
(2S)-(+)-2-Amino-4-methylpentan-1-ol N-Borane (3c)
The reaction of (S)-leucine (1.96 g, 15.0 mmol) with NaBH4 (2.28
g, 60 mmol) following the above general procedure furnished 3c
(0.91 g, 46%) as a colorless viscous oil.
found 136.0795.
UV/Vis (CHCl3): lmax (e) = 227 (560), 260 nm (88).
Anal. Calcd for C5H16BNOS: C, 40.28; H, 10.81; N, 9.39. Found:
C, 40.40; H, 10.66; N, 9.24.
[a]D20 +45.4 (c 1.3, EtOH).
IR (neat): 3231 (m, OH), 3150 (w, NH), 2956 (s), 2871 (m), 2320
(s, BH), 2272 (s, BH), 1586 (m), 1467 (m), 1165 (s, N→B), 1039
(s), 756 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 4.24 (s, 1 H, NH2), 3.82 (dd,
J1 = 11.3 Hz, J2 = 3.8 Hz, 2 H, OCH2), 3.49 (m, 1 H, NCH), 3.23 (br
s, 1 H, OH), 2.79 (s, 1 H, NH2), 1.53 (m, 3 H, CH2CH), 1.25 (br s,
3 H, BH3), 0.84 [d, J = 5.6 Hz, 6 H, (CH3)2C].
13C NMR (125 MHz, CDCl3): d = 61.8 (C-1), 57.1 (C-2), 39.1 (C-
3), 25.1 (C-4), 23.2 (C-5), 22.6 (C-5¢).
HRMS (ESI): m/z calcd for C12H29N2O [(2M + H)+ – 2BH3 – H2O]:
(2S)-(+)-2-Amino-3-(1H-indol-2-yl)-propan-1-ol N-Borane (3f)
The reaction of (S)-tryptophan (3.1 g, 15.0 mmol) with NaBH4 (2.28
g, 60 mmol) following the above general procedure furnished 3f
(1.28 g, 42%) as a colorless viscous oil.
[a]D20 +25.2 (c 1.0, MeOH).
IR (neat): 3360 (s, OH), 3252 (s, NH), 3146 (m, NH), 2954 (w),
2332 (s, BH), 2307 (s, BH), 1596 (m), 1454 (m), 1162 (s, N→B),
1027 (s), 749 (s) cm–1.
1H NMR (500 MHz, CD3OD): d = 7.58 (d, J = 7.6 Hz, 1 H, ArH),
7.31 (d, J = 7.9 Hz, 1 H, ArH), 7.12–6.92 (m, 3 H, ArH), 4.58 (s, 4
H, NH, NH2, OH), 3.71 (dd, J1 = 10.7 Hz, J2 = 4.5 Hz, 1 H, OCH2),
3.48 (dd, J1 = 5.8 Hz, J2 = 14.2 Hz, 1 H, OCH2), 3.19 (dd, J1 = 14.2
Hz, J2 = 7.6 Hz, 1 H, OCH2), 2.96 (m, 1 H, NCH), 2.95 (m, 2 H,
CH2), 1.52 (br s, 3 H, BH3).
13C NMR (125 MHz, CD3OD): d = 137.2 (C-4), 127.8 (C-11),
123.6 (C-6), 121.6 (C-8), 118.9 (C-7), 118.5 (C-9), 111.4 (C-10),
110.3 (C-5), 61.2 (C-1), 59.5 (C-2), 24.9 (C-3).
HRMS (ESI): m/z calcd for C11H17N2O [(M + 3H)+ – BH3]:
193.1324; found 193.1330.
217.2274; found: 217.2284.
UV/Vis (CHCl3): lmax (e) = 226 (287), 258 nm (49).
Anal. Calcd for C6H18BNO: C, 55.00; H, 13.85; N, 10.69. Found C,
55.48; H, 14.00; N, 10.73.
(2S,3S)-(+)-2-Amino-3-methylpentan-1-ol N-Borane (3d)
The reaction of (S)-isoleucine (1.96 g, 15.0 mmol) with NaBH4
(2.28 g, 60 mmol) following the above general procedure furnished
3d (1.09 g, 56%) as a colorless viscous oil.
[a]D20 +29.4 (c 1.6, EtOH).
UV/Vis (MeOH): lmax (e) = 224 (26580), 280 nm (681).
IR (neat): 3238 (m, OH, NH), 2962 (s), 2933 (m), 2877 (w), 2318
(s, BH), 2272 (s, BH), 1586 (m), 1461 (m), 1163 (s, N→B), 1033
(s), 997 (s), 962 (m), 864 (w) cm–1.
Anal. Calcd for C11H17BN2O: C, 64.74; H, 8.40; N, 13.73. Found:
C, 64.53; H, 8.26; N, 13.58.
1H NMR (500 MHz, CDCl3): d = 4.32 and 3.70 (2 × s, 2 H, NH2),
3.90 (dd, J1 = 11.6 Hz, J2 = 3.4 Hz, 1 H, OCH2), 3.62 (dd, J1 = 11.6
Hz, J2 = 3.4 Hz, 1 H, OCH2), 2.84 (s, 1 H, OH), 2.67 (m, 1 H, NCH),
1.90 (m, 1 H, CH), 1.41 and 1.18 (2 × m, 2 H, CH2CH3), 1.63 (br s,
3 H, BH3), 0.91 (d, J = 7.3 Hz, 3 H, CH3CH), 0.86 (t, J = 7.3 Hz, 3
H, CH3CH2).
13C NMR (125 MHz, CDCl3): d = 62.7 (C-1), 59.6 (C-2), 34.1 (C-
3), 26.4 (C-4), 14.4 (C-6), 11.6 (C-5).
HRMS (ESI): m/z calcd for C12H29N2O [(2M + H)+ – 2BH3 – H2O]:
217.2274; found 217.2281.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
We thank NCSR Demokritos and the National Technical University
of Athens for financial support. A.P. is grateful to the NCSR Demo-
kritos for a PhD fellowship. The Foundation for Education and Eu-
ropean Culture is also acknowledged for providing a scholarship to
G.C.V. Mrs. E. Yannakopoulou (Institute of Physical Chemistry,
NCSR Demokritos) and Dr. L. Leontiadis (Institute of Radioiso-
topes & Radiodiagnostic Products, NCSR Demokritos) are grateful-
ly acknowledged for carrying out elemental analysis measurements
and for obtaining the HRMS spectra, respectively.
UV/Vis (CHCl3): lmax (e) = 226 (280), 252 nm (54).
Anal. Calcd for C6H18BNO: C, 55.00; H, 13.85; N, 10.69. Found: C,
55.16; H, 14.20; N, 10.36.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1057–1062

1062
A. Pinaka et al.
PAPER
(22) Lane, C. F.; Myatt, H. L.; Daniels, J.; Hopps, H. B. J. Org.
Chem. 1974, 39, 3052.
(23) Gage, J. R.; Evans, D. A. Org. Synth. Coll. Vol. 8; Wiley:
Chichester, 1993, 528.
(24) Demir, A. S.; Akhmedov, M. I.; Şeşenoglu, Turk. J. Chem.
1999, 23, 123.
(25) McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M.
J. Org. Chem. 1993, 58, 3568.
(26) Abiko, A.; Masamune, S. Tetrahedron Lett. 1992, 33, 5517.
(27) Karrer, P.; Portmann, P.; Suter, M. Helv. Chim. Acta 1948,
31, 1617.
(28) Seki, H.; Koga, K.; Matsuo, H.; Ohki, S.; Matsuo, I.;
Yamada, S. Chem. Pharm. Bull. 1965, 13, 995.
(29) Delair, P.; Einhorn, C.; Einhorn, J.; Luche, J. L. J. Org.
Chem. 1994, 59, 4680.
(30) Fehrentz, J. A.; Califano, J. C.; Amblard, M.; Loffet, A.;
Martinez, J. Tetrahedron Lett. 1994, 35, 569.
(31) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez,
J. Tetrahedron Lett. 1991, 32, 923.
(32) The reduction of (R,S)-N-acetyl-phenylalanine and (R,S)-N-
benzoyl-alanine with three equivalents of diborane,
affording the corresponding stable aminoboranes, has been
reported, see: Yonemitsu, O.; Hamada, T.; Kanaoka, Y.
Chem. Pharm. Bull. 1969, 17, 2075.
References
(1) White, S. S.; Kelly, H. C. J. Am. Chem. Soc. 1968, 90, 2009.
(2) Itsuno, S.; Wakasugi, T.; Ito, K.; Hirao, A.; Nakahama, S.
Bull. Chem. Soc. Jpn. 1985, 58, 1669.
(3) Leontjev, A. E.; Vasiljeva, L. L.; Pivnitsky, K. K. Russ.
Chem. Bull., Int. Ed. 2004, 53, 703.
(4) (a) Salunkhe, A. M.; Burkhardt, E. R. Tetrahedron Lett.
1997, 38, 1523. (b) Huang, K.; Merced, F. G.; Ortiz-
Marciales, M.; Meléndez, H. J.; Correa, W.; De Jesús, M.
J. Org. Chem. 2008, 73, 4017.
(5) Uyeda, C.; Biscoe, M.; LePlae, P.; Breslow, R. Tetrahedron
Lett. 2006, 47, 127.
(6) Graham, T. W.; Tsang, C.-W.; Chen, X.; Guo, R.; Jia, W.;
Lu, S.-M.; Sui-Seng, C.; Ewart, C. B.; Lough, A.; Amoroso,
D.; Abdur-Rashid, K. Angew. Chem. Int. Ed. 2010, 49, 8708.
(7) Blaquiere, N.; Diallo-Garcia, S.; Gorelsky, S. I.; Black, D.
A.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 14034.
(8) Bowden, M. E.; Brown, I. W. M.; Gainsford, G. J.; Wong, H.
Inorg. Chim. Acta 2008, 361, 2147.
(9) (a) Scheideman, M.; Wang, G.; Vedejs, E. J. Am. Chem. Soc.
2008, 130, 8669. (b) Jaska, C. A.; Temple, K.; Lough, A. J.;
Manners, I. J. Am. Chem. Soc. 2003, 125, 9424.
(10) Framer, E.; Vaultier, M. Heteroat. Chem. 2000, 11, 218.
(11) Dallanegra, R.; Chaplin, A. B.; Weller, A. S. Angew. Chem.
Int. Ed. 2009, 48, 6875.
(33) Poindexter, G. S.; Meyers, A. I. Tetrahedron Lett. 1977, 18,
3527.
(12) Spielman, J.; Harder, S. J. Am. Chem. Soc. 2009, 131, 5064.
(13) Mancilla, T.; Santiesteban, F.; Contreras, R.; Klaébé, A.
Tetrahedron Lett. 1982, 23, 1561.
(34) Suhartono, M.; Weidlich, M.; Stein, T.; Karas, M.; Dürner,
G.; Göbel, M. W. Eur. J. Org. Chem. 2008, 1608.
(35) Repke, D. B.; Ferguson, W. J. J. Heterocycl. Chem. 1976,
13, 775.
(36) Contreras, R.; Santiesteban, F.; Paz-Sandoval, M. A.
Tetrahedron 1984, 40, 3829.
(37) Dietrich, B. L.; Goldberg, K. I.; Heinekey, D. M.; Autrey, T.;
Linehan, J. C. Inorg. Chem. 2008, 47, 8583.
(38) Aldridge, S.; Downs, J. D.; Tang, Y. C.; Parson, S.; Clarke,
C. M.; Johnstone, D. L. R.; Robertson, E. H.; Rankin, W. H.
D.; Wann, A. D. J. Am. Chem. Soc. 2009, 131, 2231.
(39) Fanfrlik, J.; Lepsik, M.; Horinek, D.; Havlas, Z.; Hobza, P.
ChemPhysChem 2006, 7, 1100.
(40) (a) Gribble, G. W. Chem. Soc. Rev. 1998, 27, 395.
(b) Brown, H. C.; Subba Rao, B. C. J. Am. Chem. Soc. 1960,
82, 681.
(14) Tlahuext, H.; Santiesteban, F.; Garcia-Báez, F.; Contreras,
R. Tetrahedron: Asymmetry 1994, 5, 1579.
(15) Kelly, H. C.; Edwards, J. O. Inorg. Chem. 1963, 2, 39.
(16) Santiesteban, F.; Mancilla, T.; Klaébé, A.; Contreras, R.
Tetrahedron Lett. 1983, 24, 759.
(17) Ferey, V.; Toupet, L.; Le Gall, T.; Mioskowski, C. Angew.
Chem., Int. Ed. Engl. 1996, 35, 430.
(18) Meyers, A. I.; Dickman, D. A.; Bailey, T. R. J. Am. Chem.
Soc. 1985, 107, 7974.
(19) Dickman, D. A.; Meyers, A. I.; Smith, G. A.; Gawley, R. E.
Org. Synth. Coll. Vol. 7; Wiley: New York, 1990, 530.
(20) Nicolás, E.; Russell, K. C.; Hruby, V. J. J. Org. Chem. 1993,
58, 766.
(21) Giannis, A.; Sandhoff, K. Angew. Chem., Int. Ed. Engl.
1989, 28, 218.
Synthesis 2012, 44, 1057–1062
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