A simple route to β-aminomethylketones

Article abstract of DOI:10.1016/j.tetlet.2004.09.122

A simple procedure leading to β-aminomethylketones has been developed. The procedure involves base-catalyzed Michael-type addition of sodium t-butyl acetoacetate to N-Boc imines generated in situ followed by hydrolysis and decarboxylation of the adducts.

Full text of DOI:10.1016/j.tetlet.2004.09.122

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8505–8506
A simple route to b-aminomethylketones
Stefan Zawadzki* and Andrzej Zwierzak
_
´ ´
Institute of Organic Chemistry, Technical University (Politechnika), Zeromskiego 116, 90-924 Łodz, Poland
Received 28 July 2004; revised 8 September 2004; accepted 16 September 2004
Available online 5 October 2004
Abstract—A simple procedure leading to b-aminomethylketones has been developed. The procedure involves base-catalyzed
Michael-type addition of sodium t-butyl acetoacetate to N-Boc imines generated in situ followed by hydrolysis and decarboxylation
of the adducts.
Ó 2004 Elsevier Ltd. All rights reserved.
b-Aminoketones are of interest in view of their biologi-
cal activity and application as building blocks in the
preparation of many nitrogen-containing heterocyclic
compounds.1 While b-aminoketones substituted at
nitrogen are easily accessible by Mannich reactions,1a
for compounds with a free amino function only a few
methods are available. The hitherto reported procedures
include: synthesis via phthalimido derivatives,2 addition
of ammonia to a,b-unsaturated ketones,3 addition of
alkylmagnesium reagents to benzoylacetonitrile,4 reduc-
tion of diimines with LiAIH4 followed by hydrolysis,5
hydrolysis of tetrahydropyrimidines,6 reduction of
isoxazoles,7 and decomposition of b-isothiocyanatoke-
tones by heating with concd HCl.8 In the last few years
substantial progress has been made with the enantiose-
lective versions of Mannich-type reactions leading to
various N-substituted b-aminoketones.9,10
analytically pure b-aminomethylketone hydrochlorides
5 in high yields.11
Similar addition/decarboxylation of methyl acetoacetate
to N-benzoyl glyoxylic imines, leading to protected b-
aminoketones has been reported previously.12
The following typical experimental procedure was used.
Sodium hydride (0.24g, 10mmol) was added with stir-
ring to a solution of a-amidoalkyl-p-tolyl sulfone 113
(5mmol) in THF (30mL) for ca. 10min. Then, t-butyl
acetoacetate 2 (0.79g, 5mmol) dissolved in THF
(10mL) was slowly added dropwise. The resulting mix-
ture was stirred at room temperature for 2h, cooled to
10°C, and quenched with satd aq NH4Cl (25mL). The
organic layer was separated and the aqueous phase
extracted with ether (10mL). The combined organics
were dried over MgSO4 and evaporated to give pure
(1H NMR) adducts 4 as colourless, syrupy oils. The
crude adducts 4 were treated with 10% aq HCl
(15mL) and refluxed with efficient stirring for 2h
(Scheme 1). Water and an excess of HCl were then evap-
orated, the residue dissolved in water (20mL), heated
over ca. 10min with a small amount of powdered acti-
vated charcoal (Fluka), filtered and evaporated to dry-
ness to give b-aminomethylketone hydrochlorides 5a–g
as oily liquids. Compound 5a–g thus prepared were ana-
lytically pure. Some of them crystallized slowly and
could then be recrystallized from EtOH–ether. Yields
and mps of 5a–g are compiled in the Table 1.
In the course of our studies on potential applications of
a-amidoalkyl-p-tolyl sulfones 1 as N-Boc imine equiva-
lents 3, we found that sodium hydride can be used for
base-induced elimination of p-toluenesulfonic acid from
1. Michael-type addition of sodium t-butyl acetoacetate
to N-Boc imines 3 thus generated affords (after quench-
ing with aq NH4Cl) the corresponding adducts 4 in
almost quantitative yields and spectroscopic purity.
The crude adducts 4 on reflux with 10% aq HCl undergo
easy deprotection followed by decarboxylation to give
The outlined procedure for the synthesis of b-amino-
Keywords: a-Amidoalkyl-p-tolyl sulfones; N-Boc imines; t-Butyl aceto-
acetate; Decarboxylation.
methylketones represents
a simple and economic
*
approach to these compounds from easily available
starting materials.
Corresponding author. Tel.: +48 42 6313143; fax: +48 42 6365530;
e-mail: zawadzsp@mail.p.lodz.pl
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.122

8506
S. Zawadzki, A. Zwierzak / Tetrahedron Letters 45 (2004) 8505–8506
1938, 60, 407–409; (c) Barry, J. E.; Finkelstein, M.; Ross,
Ts
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O
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NaH (2eq.), THF, R.T., 2 h
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2785–2789.
Boc
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OBu-t
94-99%
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1
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O
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3
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O
O
9. Enders, D.; Oberbo¨rsch, S. Synlett 2002, 471–473, and
references cited therein.
O
R
OBu-t
Boc
10% aq. HCl, reflux, 2 h
65-95%
10. Enders, D.; Oberbo¨rsch, S.; Adam, J. Synlett 2000, 644–
646.
11. Selected spectroscopic data for compounds 5a–g. Com-
NH3 Cl
R
N
H
5
4
1
pound 5a: H NMR (250MHz, D2O): 2.25 (3H, s, CH3),
Scheme 1.
3.02 (2H, t, J = 6.1Hz, CH2), 3.22 (2H, br t, J = 6.1Hz,
CH2). 13C NMR (63MHz, D2O): 28.2, 32.9, 37.7, 209.5.
MS/CI: 88 (MK), 71 (MKÀNH3). Compound 5b: 1H
NMR (250MHz, D2O): 1.31 (3H, d, J = 6.7Hz, CH3),
2.23 (3H, s, CH3), 2.93 (1H, dd, J = 8.2, 19.0Hz, CH2),
3.01 (1H, dd, J = 4.7, 19.0Hz, CH2), 3.60–3.81 (1H, m,
CH). 13C NMR (63MHz, D2O): 20.3, 32.2, 46.2, 48.7,
214.1. MS/CI: 102 (MK), 85 (MKÀNH3). Compound 5c:
1H NMR (250MHz, D2O): 0.96 (3H, t, J = 7.5Hz, CH3–
CH2), 1.68 (2H, dq, J = 7.5Hz, CH3–CH2), 2.25 (3H, s,
CH3), 2.90 (1H, dd, J = 8.6, 19.2Hz, CH2), 3.09 (1H, dd,
J = 4.0, 19.2Hz, CH2), 3.50–3.65 (1H, m, CH). 13C NMR
(63MHz, D2O): 7.4, 23.4, 28.3, 41.9, 47.1, 209.7. MS/CI:
116 (MK), 99 (MKÀNH3). Compound 5d: 1H NMR
(250MHz, D2O): 0.92 (3H, t, J = 7.2Hz, CH3–CH2–CH2),
1.37 (2H, 6 hex, J = 7.2Hz, CH3–CH2CH2), 1.53–1.70
(2H, m, CH3–CH2–CH2), 2.24 (3H, s, CH3), 2.90 (1H, dd,
J = 8.4, 19.2Hz, COCH2), 3.08 (1H, dd, J = 4.0, 19.2Hz,
COCH2), 3.55–3.70 (1H, m, CH). 13C NMR (63MHz,
D2O): 11.7, 16.3, 28.5, 32.3, 42.7, 45.6, 209.3. MS/CI: 130
(MK), 113 (MKÀNH3). Compound 5e: 1H NMR
(250MHz, D2O): 0.96, 0.98 (6H, 2d, J = 6.6Hz,
(CH3)2CH), 1.98 (1H, 8 lines, J = 6.6Hz, (CH3)2CH),
2.25 (3H, s, CH3), 2.87 (1H, dd, J = 9.4, 19.3Hz, CH2),
3.09 (1H, dd, J = 3.1, 19.3Hz, CH2), 3.45–3.56 (1H, m,
CH). 13C NMR (63MHz, D2O): 15.5, 16.0, 28.0, 28.3,
39.9, 50.7, 209.7. MS/CI: 130 (MK), 113 (MKÀNH3).
Compound 5f: 1H NMR (250MHz, D2O): 2.24 (3H, s,
CH3), 3.39 (2H, d, J = 6.9Hz, CH2), 7.46 (5H, br s, C6H5),
CH signal hidden under D2O. 13C NMR (63MHz, D2O):
28.0, 44.1, 49.0, 125.4, 127.7, 127.8, 133,7, 208.5. MS/CI:
164 (MK), 147 (MKÀNH3). Compound 5g: 1H NMR
(250MHz, D2O): 2.24 (3H, s, CH3CO), 3.37 (2H, d,
J = 7.0Hz, CH2), 3.85 (3H, s, OCH3), 4.77 (1H, t,
J = 7.0Hz, CH), 7.00–7.48 (4H, m, C6H4). 13C NMR
(63MHz, D2O): 27.9, 44.0, 48.5, 53.7, 112.9, 113.2, 126.2,
127.1, 127.5, 208.6. MS/CI: 194 (MK), 177 (MKÀNH3).
12. Ben-Ishai, D.; Altman, J.; Bernstein, Z.; Peled, N.
Tetrahedron 1978, 34, 467–473, and references cited
therein.
Table 1. b-Aminomethylketone hydrochlorides 5a
Entry
R
Yield (%)b
Mp (°C)
a
b
c
d
e
f
H
Me
86
95
75
77
82
66
65
Oil
131–133 (129–130)c
73–75c
Oil
Et
Pr
i-Pr
Ph
Oil
Oil
140–143c
g
p-MeO–C6H4
a All compounds were fully characterized by analytical and spectro-
scopic methods.
b Yields of crude, analytically pure products.
c Crystallized from EtOH–Et2O. Literature8 mp is given in parentheses.
References and notes
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