One-pot sequence for the decarboxylation of α-amino acids

Article abstract of DOI:10.1055/s-2003-37512

Treatment of an α-amino acid with N-bromosuccinimide in water at pH 5 or in an alcoholic-aqueous ammonium chloride mixture, followed by addition of nickel(II) chloride and sodium borohydride, effected an overall decarboxylation via an intermediate nitrile to afford the corresponding amine in good yield.

Full text of DOI:10.1055/s-2003-37512

542
LETTER
One-pot Sequence for the Decarboxylation of a-Amino Acids
One-pot
S
equence
i
for the
l
D
ecar
l
e
ion of
α
-
Am
s
ino
A
cids Laval, Bernard T. Golding*
School of Natural Sciences - Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 7RU, UK
Fax +44(191)2226929; E-mail: b.t.golding@ncl.ac.uk
Received 24 January 2003
α-amino acids 2a–c in acetophenone, ethylene glycol/p-
Abstract: Treatment of an α-amino acid with N-bromosuccinimide
anisaldehyde (as well as other aromatic aldehydes), cyclo-
hexanol/2-cyclohexen-1-one at elevated temperatures
in water at pH 5 or in an alcoholic-aqueous ammonium chloride
mixture, followed by addition of nickel(II) chloride and sodium
were unsuccessful and the starting material was recov-
ered. This led us to explore the possibility of a ‘one-pot’
combination of two known reactions: oxidative
decarboxylation11 of α-amino acids to nitriles induced by
N-bromosuccinimide,12 reduction of nitriles to amines ef-
fected by sodium borohydride–nickel chloride.13 In this
way, we have developed an efficient method for the decar-
boxylation of a variety of α-amino acids, including 2a–c.
Initially, it was found that oxidative decarboxylation of
the model compound L-ornithine monohydrochloride 3
with N-bromosuccinimide in a phosphate buffer at pH 5
afforded the corresponding nitrile 4 (94%). Subsequent
reduction of nitrile 4 in ethanol with the system nickel
chloride hexahydrate/sodium borohydride afforded pu-
trescine 5 (79%, overall yield 74%) (Scheme 1).
borohydride, effected an overall decarboxylation via an intermedi-
ate nitrile to afford the corresponding amine in good yield.
Key words: α-amino acid, nitrile, amine, decarboxylation
Decarboxylation of α-amino acids is a long-known reac-
tion,1 which leads to amines with a range of applications
from the synthesis of biologically active compounds2 to
the preparation of chiral auxiliaries for asymmetric syn-
thesis.3 The most commonly used method employs ther-
molysis of the amino acid in the presence of catalytic
amount of an aldehyde (e.g. pyridine-4-carboxaldehyde)
or ketone4 (e.g. 2-cyclohexen-1-one5). These methods are
modelled on enzymatic methods for the decarboxylation
of α-amino acids, which utilise a decarboxylase with a
pyridoxal or pyruvoyl cofactor.6 Other non-enzymatic
methods include irradiation with UV light,7 heating in
diphenylmethane solvent8 or thermolysis in a high boiling
solvent in the presence of a peroxide catalyst.9 However,
some unnatural α-amino acids do not undergo decarboxy-
lation under the conditions described and a general non-
thermal procedure is needed. We report herein a new pro-
cedure for the decarboxylation of α-amino acids that is
rather general in scope and gives good yields of amino
compounds.
It was then found that when compound 3 was taken up in
a phosphate buffer solution (pH 5) and a dimethyl forma-
mide solution of N-bromosuccinimide was added drop-
wise at room temperature, decarboxylation started
immediately. When the evolution of CO2 stopped, nick-
el(II) chloride hexahydrate was added, followed by addi-
tion by portions of sodium borohydride. Filtration of the
reaction mixture followed by loading onto an ion ex-
change column afforded, after elution with a gradient of
aqueous hydrochloric acid, putrescine dihydrochloride 5
(71% overall)14a (Scheme 2). Application of this latter
procedure to the decarboxylation of ‘carboxypolyamines’
2a–c furnished the corresponding polyamines 1a–c in
good yields (Table 1, entries 1–3).
During studies of the synthesis of polyamines10 using co-
balt(III) templates, it was necessary to convert precursor
‘carboxypolyamines’ 2a–c into the corresponding
polyamines 1a–c. Several attempts at decarboxylation of
Scheme 1 Two-step decarboxylation of α-amino acid 3. Reagents and conditions: a) Phosphate buffer (pH 5), NBS in CH3CN, r.t.; b)
NiCl2⋅6H2O, NaBH4, EtOH, r.t.
Synlett 2003, No. 4, Print: 12 03 2003.
Art Id.1437-2096,E;2003,0,04,0542,0546,ftx,en;D28903ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
One-pot Sequence for the Decarboxylation of α-Amino Acids
543
Scheme 2 ‘One-pot’ decarboxylation of α-amino acid 3. Reagents and conditions: a) Phosphate buffer (pH 5), NBS in DMF then
NiCl2⋅6H2O, NaBH4, r.t.
Table 1 ‘One-pot’ Decarboxylation of a Series of Natural and non-Natural α-Amino Acids Using the Conditions Given in Ref.14a
Entry
1
Amino acid
Producta
Yield
73%
2a
2b
1a
2
3
62%
69%
1b
1c
6
2c
4
5
L-lysine
77%
68%
L-valine
7
6
7
8
L-isoleucine
81%
76%
59%
8
L-phenylalanine
9a
L-(2R)-threonine
10
11
9
L-glutamic acid
L-asparagine
68%
70%
10
12
13
11
L-methionine
Impureb
Synlett 2003, No. 4, 542–546 ISSN 0936-5214 © Thieme Stuttgart · New York

544
G. Laval, B. T. Golding
LETTER
Table 1 ‘One-pot’ Decarboxylation of a Series of Natural and non-Natural α-Amino Acids Using the Conditions Given in Ref.14a (continued)
Entry
12
Amino acid
Producta
Yield
73%
15
14
13
14
61%
67%
17
19
16
18
a Products were isolated as their hydrochloride salts.
b See text.
A series of natural and non-natural α-amino acids were re- selected amino acids (Table 2, entries 1 and 2). When the
acted under the conditions described (Table 1). As expect- reaction with L-phenylalanine was performed in slightly
ed, when L-lysine monohydrochloride was employed as wet methanol saturated with ammonium chloride, the de-
substrate, 1,5-diaminopentane dihydrochloride (6) was carboxylation did not reach completion and amine 9a was
obtained (77%). Decarboxylation of L-valine, L-(2S)-iso- obtained only in low yield (Table 2, entry 3). Presumably,
leucine and L-phenylalanine afforded isobutylamine (7), the low conversion of this reaction is due to an insufficient
(2S)-methyl-1-aminobutane (8), and 2-phenylethylamine amount of the oxidizing species H2O+Br in the reaction
(9a) as their monohydrochloride salts in 68%, 81% and mixture. However, when the volume of saturated aqueous
76% yields, respectively (Table 1, entries 5–7).
ammonium chloride was raised to 5%, the reaction pro-
ceeded very well in methanol, ethanol and dimethyl for-
mamide (Table 2, entries 4–6).
To explore the effect of a functional group in the side
chain of the amino acid, we attempted reactions on L-
(2R)-threonine, L-glutamic acid, L-asparagine and L-me- The best results were obtained in ethanol–5% saturated
thionine, respectively. Decarboxylation proceeded well aqueous ammonium chloride and this solvent was chosen
with L-threonine, L-glutamic acid and L-asparagine af- to conduct decarboxylation of L-(2S)-isoleucine and L-
fording (2R)-hydroxypropylamine (10), 4-aminobutyric (2R)-threonine (Table 2, entries 7 and 8, for a typical pro-
acid (11) and 3-aminopropionamide (12) as their mono cedure see ref.14b). The advantage of an alcoholic solvent
hydrochloride salts in moderate to good yields (Table 1, was the ease of extraction of the product from the reaction
entries 8–10). For L-methionine, which is the only amino mixture. However, for amino acids poorly soluble in or-
acid investigated that did not undergo decarboxylation in ganic solvents, the procedure of ref.14a (cf. Table 1) is pre-
satisfactory yield, an unidentified by-product was ob- ferred. The method described has been extended to the
tained in addition to 3-methylthiopropyl-1-amine (13) preparation of a specifically labeled amine. Thus, treat-
(Table 1, entry 11).
ment of L-phenylalanine with NBS in EtOD–5% D2O sat-
urated with ND4Cl, followed by reduction with NaBD4–
NiCl2, gave [1-2H2]2-phenylethylamine 9b in good yield
(Table 2, entry 9).
Application of the method described to non-proteinogenic
α-amino acids proved efficient for the preparation of the
corresponding amino alcohol. Thus, the non-natural race-
mic γ-hydroxy-α-amino acids 14, 16, 18,10 were success- In conclusion, we have reported two efficient one-pot pro-
fully decarboxylated yielding the corresponding γ-amino cedures for the decarboxylation of α-amino acids to the
alcohols as their monohydrochloride salts 15,15 17, 19, re- corresponding amines. The procedures involve a se-
spectively, in good yields (Table 1, entries 12–14).
quence of oxidative decarboxylation and reduction and
works well on a variety of natural and non-natural α-ami-
no acids. The reactions can be performed either in buff-
ered aqueous solution at pH 5 or in an organic solvent
containing 5% saturated aqueous ammonium chloride.
Kinetic studies of the oxidative decarboxylation of α-ami-
no acids with N-bromosuccinimide12 have shown that a
pH value of 5 was critical for directing the reaction to-
wards the corresponding nitrile rather than the aldehyde.
Although phosphate buffer proved to be an efficient reac-
tion medium for achieving our conversions, the use of
aqueous ammonium chloride was more practical and
yielded the desired compounds in slightly better yields on
Acknowledgement
We thank the EPSRC for support.
Synlett 2003, No. 4, 542–546 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
One-pot Sequence for the Decarboxylation of α-Amino Acids
545
Table 2 Variation of the Experimental Conditions for the Decarboxylation of α-Amino Acids
Entry Substrate
Conditions
Producta
9a
Yield
(Conversionb)
1
2
3
4
5
6
7
8
9
L-Phenylalanine
H2O, NH4Cl, NBS in DMF then NiCl2⋅6H2O,
NaBH4
82%
(100%)
L-(2S)-isoLeucine H2O, NH4Cl, NBS in DMF then NiCl2⋅6H2O,
9a
85%
(100%)
NaBH4
L-Phenylalanine
L-Phenylalanine
L-Phenylalanine
L-Phenylalanine
wet MeOH, NH4Cl
NBS in DMF then NiCl2⋅6H2O, NaBH4
9ac
9ac
9ac
9a
30%
(41%)
MeOH–H2O (95:5), NH4Cl, NBS in DMF then
NiCl2⋅6H2O, NaBH4
65%
(79%)
EtOH–H2O (95:5), NH4Cl, NBS in DMF then
NiCl2⋅6H2O, NaBH4
71%
(89%)
DMF–H2O (95:5), NH4Cl, NBS in DMF then
NiCl2⋅6H2O, NaBH4
65%
(68%)
L-(2S)-isoLeucine EtOH–H2O (95:5), NH4Cl, NBS in DMF then
NiCl2⋅6H2O, NaBH4
8c
73%
(87%)
L-(2R)-Threonine EtOH–H2O (95:5), NH4Cl, NBS in DMF then
NiCl2⋅6H2O, NaBH4
10
55%
(82%)
L-Phenylalanine
EtOD–D2O (95:5), ND4Cl, NBS in DMF then
NiCl2, NaBD4
68%
(75%)
9b
a Isolated as the hydrochloride salt.
b Based on the amount of starting material recovered.
c The product was isolated as the free amine after reduction of the volume of the reaction mixture and extraction with diethyl ether from a
basic aqueous solution.
(10) Laval, G.; Clegg, W.; Crane, C. G.; Hammershøi, A.;
References
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was taken up in a pH 5 phosphate buffer (prepared from 100
mL of a 0.1 M solution of citric acid and 100 mL of a 0.2 M
solution of disodium hydrogen orthophosphate
dodecahydrate) (90 mL). To the stirred amino acid solution
was added NBS (10.3 g, 57.9 mmol) in DMF (20 mL) at r.t.,
where upon CO2 gas was evolved immediately. After 30
min, nickel(II) dichloride hexahydrate (22.9 g, 96.5 mmol)
was dissolved into the reaction mixture and NaBH4 (5.84 g,
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154 mmol) was added in portions with vigorous stirring.
Addition of the latter was exothermic and hydrogen gas was
(8) Kametani, T.; Takano, S.; Hibino, S.; Takeshita, M.
vigorously evolved. After 20 min at r.t., the reaction mixture
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(500 mL). The light green filtrate was loaded on a column
(25 cm × 2 cm) of Dowex 50WX8-200 ion exchange resin,
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Synlett 2003, No. 4, 542–546 ISSN 0936-5214 © Thieme Stuttgart · New York

546
G. Laval, B. T. Golding
LETTER
amine was eluted with a concentration gradient of
latter was exothermic and hydrogen was vigorously evolved.
After 30 min at r.t., the reaction was filtered through
Celite®, and the ethanol was removed. The liquid residue
was taken up in water (20 mL) and basified to pH 10 with aq
1.0 M NaOH. The aq solution was extracted with Et2O (2 ×
30 mL). The combined organic extracts were washed with a
sat. aq solution of NaHCO3 (20 mL) and dried over MgSO4.
Removal of the solvent afforded 2-phenylethylamine (9a)
(208 mg, 71%) as a colourless oil.
ammonium hydroxide. Removal of the solvent under
reduced pressure afforded the amine, which was treated with
1.0 M HCl to give 3-aminopropionamide (12) as its
hydrochloride (1.68 g, 13.5 mmol). (b) L-Phenylalanine
(400 mg, 2.42 mmol) was taken up in a mixture of EtOH (40
mL), H2O (2 mL) and a sat. aq solution of NH4Cl (1.5 mL).
To the stirred amino acid solution was added NBS (1.07 g,
6.05 mmol) in DMF (5 mL) at r.t., whereupon CO2 was
evolved immediately. After 20 min, nickel(II) dichloride
hexahydrate (2.30 g, 9.68 mmol) was dissolved into the
reaction mixture and NaBH4 (915 mg, 24.2 mmol) was
added in portions with vigorous stirring. Addition of the
(15) Amino alcohol 15 is a building block for the synthesis of the
antidepressant fluoxetine: Hilborn, J. W.; Lu, Z.-H.; Jurgens,
A. R.; Fang, Q. K.; Byers, P.; Wald, S. A.; Senanayake, C.
H. Tetrahedron Lett. 2001, 8919.
Synlett 2003, No. 4, 542–546 ISSN 0936-5214 © Thieme Stuttgart · New York