Large-scale synthesis of (E)-4-amino-2-methylbut-2-en-1-ol: Key building block for the synthesis of trans-zeatin

Article abstract of DOI:10.14233/ajchem.2014.17644

In this paper a large-scale synthesis of (E)-4-amino-2-methylbut-2-en-1-ol was disclosed and trans-zeatin could be accessed on industrial scale.

Full text of DOI:10.14233/ajchem.2014.17644

Asian Journal of Chemistry; Vol. 26, No. 23 (2014), 8155-8157
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.17644
Large-Scale Synthesis of (E)-4-Amino-2-Methylbut-2-en-1-ol:
Key Building Block for the Synthesis of trans-Zeatin
1
1
1
1
1,*
2
JIANYUN PEI , JIE LI , YAN XIE , JIANGSEN WENG , CHENGSHENG GE and SHUHUA WANG
1
2
College of Chemical and Material Engineering, Quzhou University, Quzhou 324000, P.R. China
Technology Center of Zhejiang Juhua Group, Quzhou 324004, P.R. China
*
Corresponding author: Tel/Fax: +86 570 8015339; E-mail: gechengsheng@qzu.zj.cn
Received: 21 March 2014; Accepted: 19 May 2014; Published online: 15 November 2014;
AJC-16315
In this paper a large-scale synthesis of (E)-4-amino-2-methylbut-2-en-1-ol was disclosed and trans-zeatin could be accessed on industrial
scale.
Keywords: (E)-4-Amino-2-methylbut-2-en-1-ol, trans-Zeatin, Large-scale synthesis.
17.5 mol) in dichloromethane (32 L) was added hexamethylene-
INTRODUCTION
tetramine (2.46 kg, 17.5 mol) at 0 °C, and the mixture was
allowed to warm to room temperature. It was stirred overnight
and filtered. The obtained white solid was dried to give 2 (5.22
kg, 92 % yield). It was directly applied to next step.
(E)-4-Amino-2-methylbut-2-en-1-ol is the structural unit
of natural products such as Cytokinins trans-zeatin and 9-
1
,2
3
2-deoxy-β-D-ribofuran-osyl)-trans-zeatin . Isolated from
(
immature sweet corn (Zea mayes) kernels, trans-zeatin shows
as the most active cytokinin. To our best of knowledge, trans-
zeatin is currently an expensive commercial cytokinin in the
market, which is attributed to the difficulty of affording key
building block (E)-4-amino-2-methylbut-2-en-1-ol on indus-
trial scale. Although numerous procedures for the synthesis
Synthesis of (E)-tert-butyl 4-hydroxy-3-methylbut-2-
enylcarbamate (4): To a solution of 2 (4 kg, 12.4 mol) in
methanol (10 L) was added concentrated hydrochloric acid
(
6 L, 29 mol) carefully, and the mixture was heated to reflux
for 2 h. The resulting solution was cooled down to 0 °C, and
then filtered. The filtrate was concentrated to half of its volume,
cooled down to 0 °C again and filtered. The filtrate was concen-
trated to dryness to give 3 kg of 3 as a colourless oil.
4
-13
,
of (E)-4-amino-2-methylbut-2-en-1-ol have been reported
those experimental procedures are not suitable for scale-up.
Additionally, toxic or expensive reagents were involved in
To a solution of sodium carbonate (4.82 kg, 37.2 mol)
and Boc anhydride (2.7 kg, 12.4 mol) in ethyl acetate (16 L)
and water (24 L) was added dropwise the above obtained 3 (3
kg) in ethyl acetate (4 L) at 0 °C, and then the mixture was
allowed to warm to room temperature. It was stirred overnight
and the water phase was extracted with ethyl acetate. Combined
14
those protocols. Jordis et al. reported an optimized synthesis
of some γ,γ-disubstituted allylamine, however raw material is
expensive and not suitable for commercial purpose. We herein
report a practical large-scale synthesis of (E)-4-amino-2-
methylbut-2-en-1-ol and with this key intermediate, trans-
zeatin could be accessed on industrial scale.
2 4
organic phase was washed with brine and dried over Na SO .
It was evaporated to give 2.7 kg of N-Boc protected derivative
of 3 as a colorless oil.
EXPERIMENTAL
Solvents and reagents were obtained from commercial
To a solution of the above obtained colorless oil in 95 %
ethanol (15 L) was added sodium acetate (1.52 kg, 18.6 mol),
and the reaction mixture was refluxed for 4 h. The resulting
solution was cooled down to room temperature and 20 %
aqueous solution of sodium hydroxide (34 L, 19.6 mol) was
added into the reaction mixture, which was refluxed for 2 h,
and then evaporated. The resulting residue was layered with
ethyl acetate (10 L) and water (10 L), and water phase was
extracted with ethyl acetate (3 × 10 L). The combined organic
1
13
sources without further purification. H and C NMR spectra
were recorded on aVarian 400-MHz spectrometer using CDCl
or DMSO-D as solvent. Melting points were determined on
3
6
WRS-2 melting-point apparatus (Shanghai, China) and unco-
rrected.
Synthesis of 1-[(E)-4-bromo-3-methyl-2-butenyl]-1-
azonia-3,5,7-triaza-tricyclo [3.3.1.1]decane bromide (2): To
a solution of (E)-1,4-dibromo-2-methylbut-2-ene (1) (4 kg,

8
156 Pei et al.
Asian J. Chem.
phase was washed with saturated solution of sodium bicarbonate
and brine, dried over Na SO . The filtrate was concentrated to
give 2.5 kg of 4. H NMR (400 MHz, CDCl ) δ: 1.41 (s, 9H),
.66 (s, 3H), 3.70-3.76 (m, 2H), 3.97 (s, 2H), 5.43 (t, J = 8Hz,
solvent optimization such as chloroform (85 % yield), toluene
(60 % yield) and dichloroethane (80 % yield) was explored.
Thus far, dichloromethane gave best yield. Interestingly, we
only obtained one isomer 2, and another isomer 2' was not
detected.
2
4
1
3
1
1
1
9
H). H NMR spectral data were consistent with described .
Synthesis of (E)-4-amino-2-methylbut-2-en-1-ol (5): To
N
a solution of 2.5 kg of 4 in dichloromethane (3.5 L) was added
trifluoroacetic acid (1.4 kg, 12.4 mol). The mixture was stirred
for 2 h and then neutralized with sodium hydroxide, concen-
trated. The residue was distilled over high vaccum (0.01 mmHg)
Hexamethylenetetramine
Cl
Br
Br
Br
CH Cl2
2
N
N
N
1
2
1
x
at 60 °C to give 751 g of 5 as a colourless oil in 60 % yield. H
NMR (400 MHz, CDCl ) δ: 1.63 (s, 3H), 3.30 (t, J = 8 Hz, 2H),
Hexamethylenetetramine
3
N
Cl
1
.95 (s, 2H), 5.49 (t, J = 8 Hz, 1H). H NMR spectral data
CH Cl2
2
Br
3
N
N
N
7
were consistent with described .
2'
Synthesis of trans-zeatin: To a solution of 6-chloropurine
656 g, 4.25 mol) and triethylamine (516 g, 5.1 mol) in butyl
Scheme-I: Regioselective amination via 1 and hexamethylenetetramine
(
alcohol (1.8 L) was added 5 (430 g, 4.25 mol). The reaction
mixture was heated to reflux for 4 h, and cooled down to room
temperature slowly. The solvent was evaporated and the residue
was twice recrystallized with water and ethanol to give 661 g
Using delepine reaction condition compound 2 was
converted to compound 3, which was subjected to N-Boc-
protection, subsequent acetoxylation and hydroxylation to give
compound 4. De-protection of compound 4 with trifluoroacetic
acid and distillation under vacuum gave (E)-4-amino-2-
methylbut-2-en-1-ol (5) in 60 % overall yield (Scheme-II).
of trans-zeatine as a white solid in 71 % yield with 99 % HPLC
1
purity. m.p. 208-209 °C. H NMR (400 MHz, DMSO-d
6
) δ:
1.64 (s, 3H), 3.33 (s, 2H), 4.09 (br, 1H), 4.73 (br, 1H), 5.51 (t,
J = 8 Hz, 1H), 7.70 (br, 1H), 8.06 (s, 1H), 8.16 (s, 1H), 12.84
1
br, 1H). H NMR spectral data were consistent with described .
7
(
OH
1
. Tea, BuOH
HN
2. 6-Chloro-9H-purine
NH2
HO
RESULTS AND DISCUSSION
N
N
71 % yield
1
Recently Madhusudhan et al. discovered that hexa-
5
N
H
N
methylenetetramine, a bulky amine, could be applied to large-
scale synthesis of (Z)-4-chlorobut-2-en-1-amine hydrochloride
starting from (Z)-1,4-dichlorobut-2-ene. The substitution of
5
trans-Zeatin
Scheme-III: scale-up synthesis of trans-zeatin
(
Z)-1,4-dichlorobut-2-ene with hexamethylenetetramine in
Furthermore, (E)-4-amino-2-methylbut-2-en-1-ol (5) was
dichloromethane under refluxing gave mono-amination salt
in nearly quantitative yield, and the formed salt has very low
solubility in reaction solvent, which prevented the further
substitution. Different from (Z)-1,4-dichlorobut-2-ene, (E)-1,4-
dibromo-2-methylbut-2-ene has more reactive bromide group
and methyl group marks E-1,4-dibromo-2-methylbut-2-ene as
an un-symmetric unit, which results in regio-selective
amination involved. Initially, we refluxed (E)-1,4-dibromo-2-
methylbut-2-ene and hexamethylenetetramine in dichloro-
methane (Scheme-I). Unfortunately, we obtained a complex
mixture. Further, the reaction mixture was stirred at ambient
temperature.A white solid 2 was obtained in 92 % yield. Further
coupled with 6-chloropurine to give > 99 % purity of trans-
zeatin in 71 % yield after twice recrystallization (Scheme-
III).
Eventually, trans-zeatin was prepared in 39 % overall yield
starting from trans-1,4-dibromo-2-methylbut-2-ene and
hexamethylenetetramine.
In conclusion, we developed an efficient large-scale
preparative method for (E)-4-hydroxy-3-methylbut-2-enyl.
trans-Zeatin could be accessed on industrial scale, based on
readily available starting material, operational simplicity and
good yield.
–
+
N
Cl
+
+
Hexamethylenetetramine
Br
CH Cl2
Conc. HCl
NH Cl
3
Br
Br
Br
N
N
MeOH, reflux
2
92 % yield
N
1
2
3
1
. Boc O, Na CO
2 2 3
TFA, CH Cl
2. AcONa, Ethanol
N HBoc
2
2
HO
NH2
HO
Distillation
steps, 60 % overal yield
3. NaOH
5
4
5
Scheme-II: Large-scale synthetic route of (E)-4-amino-2-methylbut-2-en-1-ol

Vol. 26, No. 23 (2014)
ACKNOWLEDGEMENTS
Large-Scale Synthesis of (E)-4-Amino-2-Methylbut-2-en-1-ol 8157
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7
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2
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Parker, Aust. J. Chem., 31, 1291 (1978).
S. D. Robert, U.S. Patent 3960923 (1973).
This research work was financially supported by Foun-
dation of Provincial Education Department of Zhejiang of P.R.
China (Grant No.Y201224719) and National Natural Science
Foundation of China (No. 21472110).
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