Amino Acid Decarboxylation

542
LETTER
One-pot Sequence for the Decarboxylation of a-Amino Acids
One-pot Sequence for the D
Gi ecarboxylation of α-Am
lleino Acidss 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-
in water at pH 5 or in an alcoholic-aqueous ammonium chloride
mixture, followed by addition of nickel(II) chloride and sodium
hexanol/2-cyclohexen-1-one at elevated temperatures
borohydride, effected an overall decarboxylation via an intermedi-
were unsuccessful and the starting material was recov-
ate nitrile to afford the corresponding amine in good yield.
ered. This led us to explore the possibility of a ‘one-pot’
Key words: α-amino acid, nitrile, amine, decarboxylation
combination of two known reactions: oxidative
decarboxylation11 of α-amino acids to nitriles induced by
N-bromosuccinimide,12 reduction of nitriles to amines ef-
Decarboxylation of α-amino acids is a long-known reac-
fected by sodium borohydride–nickel chloride.13 In this
tion,1 which leads to amines with a range of applications
way, we have developed an efficient method for the decar-
from the synthesis of biologically active compounds2 to
boxylation of a variety of α-amino acids, including 2a–c.
the preparation of chiral auxiliaries for asymmetric syn-
Initially, it was found that oxidative decarboxylation of
thesis.3 The most commonly used method employs ther-
the model compound L-ornithine monohydrochloride 3
molysis of the amino acid in the presence of catalytic
with N-bromosuccinimide in a phosphate buffer at pH 5
amount of an aldehyde (e.g. pyridine-4-carboxaldehyde)
afforded the corresponding nitrile 4 (94%). Subsequent
or ketone4 (e.g. 2-cyclohexen-1-one5). These methods are
reduction of nitrile 4 in ethanol with the system nickel
modelled on enzymatic methods for the decarboxylation
chloride hexahydrate/sodium borohydride afforded pu-
of α-amino acids, which utilise a decarboxylase with a
trescine 5 (79%, overall yield 74%) (Scheme 1).
pyridoxal or pyruvoyl cofactor.6 Other non-enzymatic
It was then found that when compound 3 was taken up in
methods include irradiation with UV light,7 heating in
a phosphate buffer solution (pH 5) and a dimethyl forma-
diphenylmethane solvent8 or thermolysis in a high boiling
mide solution of N-bromosuccinimide was added drop-
solvent in the presence of a peroxide catalyst.9 However,
wise at room temperature, decarboxylation started
some unnatural α-amino acids do not undergo decarboxy-
immediately. When the evolution of CO stopped, nick-
2
lation under the conditions described and a general non-
el(II) chloride hexahydrate was added, followed by addi-
thermal procedure is needed. We report herein a new pro-
tion by portions of sodium borohydride. Filtration of the
cedure for the decarboxylation of α-amino acids that is
reaction mixture followed by loading onto an ion ex-
rather general in scope and gives good yields of amino
change column afforded, after elution with a gradient of
compounds.
aqueous hydrochloric acid, putrescine dihydrochloride 5
During studies of the synthesis of polyamines10 using co-
(71% overall)14a (Scheme 2). Application of this latter
balt(III) templates, it was necessary to convert precursor
procedure to the decarboxylation of ‘carboxypolyamines’
‘carboxypolyamines’ 2a–c into the corresponding
2a–c furnished the corresponding polyamines 1a–c in
polyamines 1a–c. Several attempts at decarboxylation of
good yields (Table 1, entries 1–3).
Scheme 1
Two-step decarboxylation of α-amino acid 3. Reagents and conditions: a) Phosphate buffer (pH 5), NBS in CH3CN, r.t.; b)
NiCl ⋅
2 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

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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
NiCl ⋅
2 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
Amino acid
Producta
Yield
1
73%
2a
1a
2
62%
2b
1b
3
69%
2c
1c
4
L-lysine
77%
6
5
L-valine
68%
7
6
L-isoleucine
81%
8
7
L-phenylalanine
76%
9a
8
L-(2R)-threonine
59%
10
9
L-glutamic acid
68%
11
10
L-asparagine
70%
12
11
L-methionine
Impureb
13
Synlett 2003, No. 4, 542 – 546
ISSN 0936-5214
© Thieme Stuttgart · New York

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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
Amino acid
Producta
Yield
73%
12
14
15
13
61%
16
17
14
67%
18
19
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 H O+Br in the reaction
2
(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-
To explore the effect of a functional group in the side
ceeded very well in methanol, ethanol and dimethyl for-
chain of the amino acid, we attempted reactions on
mamide (Table 2, entries 4–6).
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% D O sat-
2
Application of the method described to non-proteinogenic
urated with ND Cl, followed by reduction with NaBD –
4
4
α-amino acids proved efficient for the preparation of the
NiCl , gave [1-2H ]2-phenylethylamine 9b in good yield
2
2
corresponding amino alcohol. Thus, the non-natural race-
(Table 2, entry 9).
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
Kinetic studies of the oxidative decarboxylation of α-ami-
works well on a variety of natural and non-natural α-ami-
no acids with N-bromosuccinimide12 have shown that a
no acids. The reactions can be performed either in buff-
pH value of 5 was critical for directing the reaction to-
ered aqueous solution at pH 5 or in an organic solvent
wards the corresponding nitrile rather than the aldehyde.
containing 5% saturated aqueous ammonium chloride.
Although phosphate buffer proved to be an efficient reac-
tion medium for achieving our conversions, the use of
Acknowledgement
aqueous ammonium chloride was more practical and
yielded the desired compounds in slightly better yields on
We thank the EPSRC for support.
Synlett 2003, No. 4, 542 – 546
ISSN 0936-5214
© Thieme Stuttgart · New York

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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
Yield
(Conversionb)
1
L-Phenylalanine
H
⋅
2O, NH4Cl, NBS in DMF then NiCl2 6H2O,
9a
82%
NaBH
(100%)
4
2
L-(2S)-isoLeucine
H
⋅
2O, NH4Cl, NBS in DMF then NiCl2 6H2O,
9a
85%
NaBH
(100%)
4
3
L-Phenylalanine
wet MeOH, NH4Cl
9ac
30%
NBS in DMF then NiCl ⋅6H O, NaBH
(41%)
2
2
4
4
L-Phenylalanine
MeOH–H2O (95:5), NH4Cl, NBS in DMF then
9ac
65%
NiCl ⋅6H O, NaBH
(79%)
2
2
4
5
L-Phenylalanine
EtOH–H2O (95:5), NH4Cl, NBS in DMF then
9ac
71%
NiCl ⋅6H O, NaBH
(89%)
2
2
4
6
L-Phenylalanine
DMF–H2O (95:5), NH4Cl, NBS in DMF then
9a
65%
NiCl ⋅6H O, NaBH
(68%)
2
2
4
7
L-(2S)-isoLeucine
EtOH–H2O (95:5), NH4Cl, NBS in DMF then
8c
73%
NiCl ⋅6H O, NaBH
(87%)
2
2
4
8
L-(2R)-Threonine
EtOH–H2O (95:5), NH4Cl, NBS in DMF then
10
55%
NiCl ⋅
2 6H2O, NaBH4
(82%)
9
L-Phenylalanine
EtOD–D O (95:5), ND Cl, NBS in DMF then
68%
2
4
NiCl2, NaBD4
(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.
References
(10) Laval, G.; Clegg, W.; Crane, C. G.; Hammershøi, A.;
Sargeson, A. M.; Golding, B. T. Chem. Commun. 2002,
(1) Curtius, T.; Lederer, A. Chem. Ber. 1886, 19, 2462.
1874.
(2) See for example: (a) Pasini, A.; Zunio, F. Angew. Chem.,
(11) (a) Gowda, B. T.; Mahadevappa, D. S. J. Chem. Soc., Perkin
Int. Ed. Engl. 1987, 26, 615. (b) Miyadera, T.; Sugimura,
Trans. 2 1983, 323. (b) For the oxidative decarboxylation
Y.; Hashimoto, T.; Tanaka, T.; Iino, K.; Shibata, T.;
of N-protected amino acids see for example: Boto, A.;
Sugawara, S. J. Antibiotics 1983, 36, 1034.
Hernandez, R.; De Leon, Y.; Suarez, E. J. Org. Chem. 2001,
(3) See for example: Martens, J. Top. Curr. Chem. 1984, 125,
66, 7796.
165.
(12) Gopalakrishnan, G.; Hogg, J. L. J. Org. Chem. 1985, 50,
(4) Chatelus, G. Bull. Soc. Chim. Fr. 1964, 2533.
1206.
(5) (a) Hashimoto, M.; Eda, Y.; Osanai, Y.; Iwai, T.; Aoki, S.
(13) Satoh, T.; Suzuki, S. Tetrahedron Lett. 1969, 4555.
Chem. Lett. 1986, 6, 893. (b) Wallbaum, S.; Mehler, T.;
(14) Typical Procedures. (a) L-Asparagine (2.90 g, 19.3 mmol)
Martens, J. Synth. Commun. 1994, 24, 1381.
was taken up in a pH 5 phosphate buffer (prepared from 100
(6) (a) Boeker, E. A.; Snell, E. E. In The Enzymes, 3rd ed. Vol.
mL of a 0.1 M solution of citric acid and 100 mL of a 0.2 M
6; Boyer, P. D., Ed.; Academic Press: New York, 1972, 217–
solution of disodium hydrogen orthophosphate
254. (b) Werle, E. Angew. Chem. 1951, 63, 550. (c) Gale,
dodecahydrate) (90 mL). To the stirred amino acid solution
E. F. Adv. Enzymol. 1946, 6, 1.
was added NBS (10.3 g, 57.9 mmol) in DMF (20 mL) at r.t.,
(7) (a) Nakai, H.; Kanaoka, Y. Synthesis 1982, 141.
where upon CO gas was evolved immediately. After 30
2
(b) Flemming, K. Strahlentherapie 1964, 123, 457.
min, nickel(II) dichloride hexahydrate (22.9 g, 96.5 mmol)
(c) Photochemical decarboxylation of N-arenesulfonyl
was dissolved into the reaction mixture and NaBH4 (5.84 g,
amino acids: Papageorgiou, G.; Corrie, J. E. T. Tetrahedron
154 mmol) was added in portions with vigorous stirring.
1999, 237.
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
Synthesis 1972, 475.
was filtered through Celite® and diluted with distilled H O
2
(9) (a) Rossen, K.; Simpson, P. M.; Wells, K. Synth. Commun.
(500 mL). The light green filtrate was loaded on a column
1993, 23, 1071. (b) Kanao, S.; Shinozuka, S. J. Pharm. Soc.
(25 cm × 2 cm) of Dowex 50WX8-200 ion exchange resin,
Jpn. 1947, 67, 218.
the column was washed well with H2O (400 mL) and the
Synlett 2003, No. 4, 542 – 546
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546
G. Laval, B. T. Golding
LETTER
amine was eluted with a concentration gradient of
latter was exothermic and hydrogen was vigorously evolved.
ammonium hydroxide. Removal of the solvent under
After 30 min at r.t., the reaction was filtered through
reduced pressure afforded the amine, which was treated with
Celite®, and the ethanol was removed. The liquid residue
1.0 M HCl to give 3-aminopropionamide (12) as its
was taken up in water (20 mL) and basified to pH 10 with aq
hydrochloride (1.68 g, 13.5 mmol). (b) L-Phenylalanine
1.0 M NaOH. The aq solution was extracted with Et O (2 ×
2
(400 mg, 2.42 mmol) was taken up in a mixture of EtOH (40
30 mL). The combined organic extracts were washed with a
mL), H O (2 mL) and a sat. aq solution of NH Cl (1.5 mL).
sat. aq solution of NaHCO (20 mL) and dried over MgSO .
2
4
3
4
To the stirred amino acid solution was added NBS (1.07 g,
Removal of the solvent afforded 2-phenylethylamine (9a)
6.05 mmol) in DMF (5 mL) at r.t., whereupon CO was
(208 mg, 71%) as a colourless oil.
2
evolved immediately. After 20 min, nickel(II) dichloride
(15) Amino alcohol 15 is a building block for the synthesis of the
hexahydrate (2.30 g, 9.68 mmol) was dissolved into the
antidepressant fluoxetine: Hilborn, J. W.; Lu, Z.-H.; Jurgens,
reaction mixture and NaBH (915 mg, 24.2 mmol) was
A. R.; Fang, Q. K.; Byers, P.; Wald, S. A.; Senanayake, C.
4
added in portions with vigorous stirring. Addition of the
H. Tetrahedron Lett. 2001, 8919.
Synlett 2003, No. 4, 542 – 546
ISSN 0936-5214
© Thieme Stuttgart · New York

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