Behaviour of enaminomalonates and enamidomalonates under various reductive conditions: a novel synthetic approach to N-acetyl-N-aryl β-amino acids

Article abstract of DOI:10.1016/j.tetlet.2008.02.078

The behaviour of enaminomalonates and their deprotection to amines under various reductive conditions is described. A new synthetic approach to N-aryl-N-acetyl-β-amino acids using heterogeneous catalytic hydrogenation has been discovered.

Full text of DOI:10.1016/j.tetlet.2008.02.078

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2631–2633
Behaviour of enaminomalonates and enamidomalonates under
various reductive conditions: a novel synthetic approach to
N-acetyl-N-aryl b-amino acids
*
´ˇ
ˇ
´
´
Tomas Solcan, Pavol Jakubec , Nadezˇda Pronayova, Viktor Milata
Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of Technology, Radlinske´ho Street 9, SK-812 37 Bratislava, Slovakia
Received 11 November 2007; revised 29 January 2008; accepted 15 February 2008
Available online 19 February 2008
Abstract
The behaviour of enaminomalonates and their deprotection to amines under various reductive conditions is described. A new
synthetic approach to N-aryl-N-acetyl-b-amino acids using heterogeneous catalytic hydrogenation has been discovered.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Reduction; b-Amino acid; Enaminoester; Deprotection
EWG1
EWG2
Recently, racemic and enantiomerically enriched b-
amino acids and their derivatives have gained much atten-
tion within the chemical community for being versatile
tools for synthetic chemists.1 Enantiomerically enriched
b-amino carboxylic acids occur in natural substances such
as alkaloids and antibiotics.2 Both the free form of these b-
amino carboxylic acids and their derivatives show interest-
ing pharmacological effects and can also be employed in
the synthesis of modified peptides.1,2
EWG1
EWG2
R1NH2
AlkO
R1HN
R1HN
1
2
Reduction
EWG1
EWG2
3
Alkoxymethylene compounds 1 (Scheme 1) are tricentric
electrophilic enol ethers suitable for the synthesis of various
types of heterocycle.3
Scheme 1.
are presented results from screening various conditions for
the reduction of enaminonitriles and enaminoesters 2.
There are a few examples reported in the literature for
the selective reduction of double bonds as in specific
systems 2. These involve high pressure catalytic hydro-
genation (1000 psi) or a combination of borane and sodium
borohydride reduction.6–8 Model studies were carried out
on the easily synthesized aminomalonate system 2a, avail-
able from aniline 4 and enol ether 1a (Alk = Me, Et,
R1 = Ph, EWG1 = EWG2 = COOMe, Scheme 2).9
The reaction of amines with alkoxymethylene com-
pounds 1 is used for the protection of the amino group,
especially in amino sugar chemistry.4,5 Replacement of
the alkoxy group with amines yields aminomethylene
derivatives 2, which are potential precursors of b-amino
acids 3 (Scheme 1). Such a chemoselective reduction of
the double bond in 2 would provide a general synthetic
route to b-amino acid derivatives from the easily available
alkoxymethylene compounds 1 in two simple steps. Herein
NaBH4/I2 was employed as a reductive system on sub-
strate 2a, but only produced an equimolar mixture of
aniline 4 and dimethylmethylmalonate 5 (Scheme 2).10
*
Corresponding author. Tel./fax: +421 2 52968560.
E-mail address: pavol.jakubec@zoznam.sk (P. Jakubec).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.078

2632
T. Solcˇan et al. / Tetrahedron Letters 49 (2008) 2631–2633
COOMe
COOMe
COOMe
O
Na
PhN
COOMe
COOMe
i or ii
i
COOMe
COOMe
11a
ii
PhNH2
PhHN
+
COOMe
2a
PhN
2a
4
5
9
iii
Scheme 2. Reagents and conditions: (i) NaBH4, I2, THF, 0 °C, 30 min,
60%; (ii) Pd/C, H2, 4 h, rt, 73%.
R
PhN
COOMe
COOMe
10a, b
R= Me, Et
Decreasing the reaction temperature to À50 °C reduced the
reaction rate but gave the same products.
Our subsequent approach employed catalytic hydro-
genation. We screened various conditions, modifying the
usual parameters (temperature, pressure, reaction time,
and type of catalyst). The major products from this screen
were again aniline 4 and dimethylmethylmalonate 5
(Scheme 2). However, these conditions can be useful for
the deprotection of amines protected as alkylidenemalo-
nates. Alternatively, the reduction system can be used for
the indirect methylation of malonates using aniline, ortho-
formate and a reducing reagent.
Next, we turned our attention to the use of complex
hydrides. Reduction with sodium borohydride under vari-
ous conditions failed to produce the desired product 3a.
Even employing Na(CN)BH3 as previously reported did
not solve the problem, as 2a was inert under various condi-
tions (AcOH, rt or MeOH, reflux). These results prompted
us to activate substrate 2a with Lewis acids. Unfortunately,
such modifications led to very complex reaction mixtures.
Therefore, in a subsequent screen, we turned our attention
towards more reactive complex hydrides. Using a large
excess of lithium aluminium hydride in the reduction of
2a led, as expected, to over reduction producing mainly
the unsaturated amino alcohol 6a. This structure was con-
firmed by analytical methods, and further transformation
to 7a and 8a, via hydrogenation using a standard catalyst
(Pd/C, Scheme 3). Interestingly, under very mild condi-
tions, the saturated amino alcohol 7a as well as amine 8a
was isolated.
Scheme 5. Reagents and conditions: (i) Na, xylene, reflux, 24 h, 95%; (ii)
acetic anhydride, DMF, rt, 0.5 h, 72%; (iii) RBr, THF, rt, 45–60%.
In the next step, we turned our attention to reduction
using metals under various conditions. The chemoselective
reduction of conjugated double bonds has been reported
with elemental magnesium (Mg, MeOH, rt) or with zinc
(Zn, AcOH, rt).11 However, the application of such reduc-
tive agents to 2a led to very complex reaction mixtures.
The use of sodium in xylene produced the sodium salt 9
as the major product (95% yield). This structure was
confirmed by the subsequent N-alkylation and acylation
of 9a leading to the known compounds 10a and 11a
(Scheme 5).12
The results described so far show the complexity of ena-
minomalonates as substrates for high yielding chemoselec-
tive reduction of their double bond. We therefore decided
to use the more stable N-acylated 11a for further study.13
This would produce the more stable N-acylated reduced
product 12a (Scheme 6). Using enamidomalonate 11a we
searched for suitable reducing conditions. Catalytic hydro-
genation of 11a performed under very mild reaction condi-
tions produced the desired N-acylated b-amino ester 12a in
excellent yield (Scheme 6, Table 1, entry 2a).
Consequently, this transformation was generalized for
more complex substrates. Thus, enamidomalonates 11b–d
were prepared under mild conditions in good yields using
sodium hydride for the generation of the sodium salt
followed by acylation (Scheme 6, Table 1).14 Chemoselec-
tive catalytic reduction of enamidomalonates 11b–d under
mild reaction conditions produced the b-amino esters
These results prompted us to modify the reaction condi-
tions to synthesize the desired amino ester. By changing the
reaction parameters (the amount of LAH, reaction time)
an 18% yield of 3a was isolated from the complex reaction
mixture (Scheme 4). This low yield led to further reduction
systems being investigated.
O
O
EWG1
EWG2
EWG1
EWG2
i, ii
iii
2a-d
N
N
R1
R1
11a-d
12a-d
i
ii
PhHN
OH
PhHN
R
2a
Scheme 6. Reagents and conditions: (i) NaH, THF; (ii) Ac2O, 0.5 h,
reflux; (iii) H2, Pd/C, rt, 0.5–3 h.
6a
7a R = OH
8a R = H
Table 1
Scheme 3. Reagents and conditions: (i) LAH (excess), THF, rt, 24 h, 52%;
(ii) H2, Pd/C, rt, 24 h, 7a 30%, 8a 24%.
Reduction of enamidomalonates with H2/Pd/C
Entry
EWG1
EWG2
R1
Yield 11
Yield 12
2a
2b
2c
2d
a
COOMe
COOMe
COOMe
COOMe
COOMe
CN
COOMe
COOMe
Ph
Ph
97
91
42
96
94
COOMe
COOMe
66a,b
91
i
2-Naphthyl
4-Tolyl
PhHN
PhHN
COOMe
COOMe
92
2a
3a
Employing Na in xylene for the generation of the Na-salt.
Z-Isomer only.
b
Scheme 4. Reagents and conditions: (i) LAH, THF, 0 °C, 1 h, 18%.

T. Solcˇan et al. / Tetrahedron Letters 49 (2008) 2631–2633
2633
O
O
References and notes
COOMe
i
PhN
NHPh
COOMe
11a
1. Enantioselective Synthesis of b-Amino Acids; Juaristi, E., Ed.; Wiley-
VCH: New York, 1997.
2. Liu, M.; Sibi, P. Tetrahedron 2002, 58, 7991.
3. Milata, V. Aldrichim. Acta 2001, 34, 20.
13
Scheme 7. Reagents and conditions: (i) EtMgBr, THF, 0 °C?rt, 16 h,
82%.
´
´
4. Aliaz, M.; Giron, J.; Hidalgo, F. J.; de la Maza, M. P.; Millan, F.;
Zamora, R.; Vique, E. Synthesis 1989, 544.
´
5. Gomez-Sanchez, A.; Borrachero, P.; Bellanato, J. Carbohydr. Res.
12b–d. Our synthetic approach tolerated different aryl sub-
stituents on nitrogen. Moreover, it was possible to reduce
the N-acetyl substrate 11 with two different electron-with-
drawing substituents. Starting with Z-configured substrates
11b we obtained amino ester 12b in racemic form. This
result is very promising for the development of an asym-
metric version of the reduction. The procedure is very
attractive due to its ease (room temperature, only slightly
higher pressure, short reaction time), simple work up and
good to excellent yields.15
Finally, we investigated the reactivity of 11a towards
nucleophiles for the selective deprotection of N-acylated
amines protected with alkylidenemalonates. Chemoselec-
tive deprotection of 11a was achieved using ethylmagne-
sium bromide in a very good yield under mild reaction
conditions, yielding N-acetylaniline 13 (Scheme 7).
In conclusion, the behaviour of aminomalonates and
amidomalonates under various reductive conditions has
been examined. A new approach for the deprotection of
amines protected with an alkylidene malonate group, and
a new synthetic approach to N-acylated b-amino esters
are described. Our current efforts in this area are directed
towards the extension of the strategy to an asymmetric
reduction using chiral catalysts and/or using chiral
substrates.
1984, 135, 101.
6. Mellino, D. G.; Cvetovich, R. J.; Ryan, K.; Sletzinger, M. J. Org.
Chem. 1986, 51, 1498.
7. Melilo, D. G.; Shinkai, I.; Liu, T.; Ryan, K.; Sletzinger, M.
Tetrahedron Lett. 1980, 21, 2783.
8. Cohen, S. G.; Sprinzak, Y.; Khedouri, E. J. Am. Chem. Soc. 1961, 83,
4225.
ˇ
´
9. Cernuchova, P.; Vo-Thanh, G.; Milata, V.; Loupy, A. Heterocycles
2004, 64, 177.
10. McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org.
Chem. 1993, 58, 3568.
11. Profitt, J. A.; Watt, D. S. J. Org. Chem. 1975, 40, 127.
12. (a) Shvo, Y.; Shanan-Aditi, H. J. Am. Chem. Soc. 1969, 91, 6683; (b)
Ouali, S.; Vaultier, M.; Carrie, R. Bull. Soc. Chim. Fr. 1985, 5, 809.
13. Sibi, M. P.; Asano, Y. J. Am. Chem. Soc. 2001, 123, 9708.
14. Momose, T.; Tanaka, T.; Yokota, T.; Nagamoto, N.; Yamada, K.
Chem. Pharm. Bull. 1978, 26, 2224.
15. Typical procedure: 11a (1.8 mmol, 500 mg) was dissolved in MeOH
(15 mL) and 10% Pd/C (100 mg) was added. The resulting suspension
was vigorously stirred in a Paar-apparatus (rt, 2.5 atm) until complete
consumption of the starting material (TLC monitoring, typically
2 h). The catalyst was filtered off and washed with MeOH (10 mL).
The filtrate was concentrated in vacuo and dried to produce the title
compound 12a (460 mg, 91%) as an off-white solid. 1H NMR (CDCl3,
300 MHz): 1.83 (s, 3H, CH3CO), 3.66 (s, 6H, CH3O), 3.81 (t,
1H, J = 7.6 Hz, CHCH2), 4.26 (d, 2H, J = 7.6 Hz, CHCH2), 7.14–
7.18 (m, 2H, H-Ph), 7.30–7.43 (m, 3H, H-Ph); 13C NMR (CDCl3,
75 MHz): 22.6 (CH3CO), 48.1 (CHCH2), 50.0 (CHCH2), 52.5
(2 Â CH3O), 127.8, 128.0, 129.6, 142.4 (C-Ar), 167.9 (2 Â C@O),
170.7 (C@O).