Direct, facile synthesis of N-acyl-α-amino amides from α-keto esters and ammonia

Article abstract of DOI:10.1039/b808302a

N-Acyl-α-amino amides were prepared, without the necessity of chromatographic purification, in a single step by heating the corresponding α-keto ester in methanolic ammonia. The Royal Society of Chemistry.

Full text of DOI:10.1039/b808302a

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Direct, facile synthesis of N-acyl-a-amino amides from a-keto esters and
ammoniaw
b
Rukundo Ntaganda,a Tamara Milovic,a Jorge Tiburcioz and Avinash N. Thadani*a
Received (in College Park, MD, USA) 16th May 2008, Accepted 17th June 2008
First published as an Advance Article on the web 23rd July 2008
DOI: 10.1039/b808302a
N-Acyl-a-amino amides were prepared, without the necessity of
chromatographic purification, in a single step by heating the
corresponding a-keto ester in methanolic ammonia.
The optimal reaction conditions of reacting 1 with ammonia
(ca. 21 equiv.) in methanol (0.33 M) at 60 1C for 6 h were
subsequently employed when examining the substrate scope of
the reaction (Table 2, vide infra).y The results show that a
variety of a-keto esters (1) successfully reacted under the
aforementioned conditions to afford the desired N-acyl-a-
amino amides 2 in high yields. In particular, electron rich
(entry 5), electron deficient (entries 6 and 7) and ortho-sub-
stituted (entries 2–4) aromatic a-keto esters 1 (R1 = aryl) were
suitable substrates, and furnished 2 in good yields. The reac-
tion conditions were also tolerant of functional groups such as
nitro (entry 6) and halides (entries 4 and 7). In addition, a
heteroaromatic variant of 1 also successfully reacted to pro-
vide 2k in excellent yield (entry 11). A single crystal X-ray
structure of one of the aromatic N-acyl-a-amino amide
products (2a) was also obtained (Fig. 1).13
Amines are an important class of organic compounds with
widespread applications in the pharmaceutical, agrochemical
and fine chemical industries.1 Amino acids and their deriva-
tives, in particular non-natural variants, form an important
subset of amines that are in demand due to their varied use in
biological and medicinal chemistry.2,3 Consequently, any new
methodology that allows for the rapid, cost-effective synthesis
of these compounds from readily available precursors would
be desirable.
As part of an ongoing study into N-unsubstituted imines,4
we found that a-keto esters (1),5 when reacted with ammonia,
readily formed N-acyl-a-amino amides 2 (eqn (1)).6,7 Com-
pound 2 is an important starting material for the synthesis of a
variety of heterocycles including oxazoles,8 thiazoles,9 oxazo-
lones10 and imidazolones.11
Aliphatic a-keto esters, however, reacted more sluggishly
under the conditions listed above. However, elevating the
reaction temperature to 80 1C for 12 h allowed the desired
products 2l–m to be isolated in good yields (entries 12–14). It
should be noted that all the N-acyl-a-amino amide products
(2) were obtained as solids through direct precipitation or
crystallization from the crude reaction mixture, and did not
require any further purification (e.g. column chromatography
or preparative TLC).
ð1Þ
We next sought to determine whether the N-acyl-a-amino
amides could be hydrolyzed to the corresponding a-amino
acids. Towards that end, when compound 2a was heated to
reflux in concentrated hydrochloric acid for 12 h, 2-phenylgly-
cine 3 was obtained in 94% isolated yield after ion-exchange
chromatography (eqn (2)). We anticipate that other unnatural
We initially optimized the formation of 2 (R1 = Ph, R2 = Et)
by varying several reaction parameters (Table 1).12 The results
indicated that the solvent had a profound effect on the overall
isolated yield, with methanol proving to be the solvent of choice
(entries 1–3). In addition, elevated temperatures (entries 4 and 5)
and an excess of ammonia were required to achieve satisfactory
isolated yields within a reasonable period of time. We deter-
mined that the only major by-product of the reaction mixture
was the corresponding a-keto amide (formed through initial
aminolysis of 1a).
Table 1 Optimization studies on the formation of N-acyl-a-amino
amide 2a
a Dept. of Chemistry & Biochemistry, University of Windsor, 401
Sunset Avenue, Windsor, Ontario, Canada N9B 3P4. E-mail:
athadani@uwindsor.ca; Fax: 1 519 973-7098; Tel: 1 519 253-3000
ext. 3556
Departamento de Quımica, Centro de Investigacion y de Estudios
b
´
´
Avanzados, Avenida IPN 2508, Zacatenco 07360, Mexico, D. F.,
Entry
Temperature/1C
Solventa
Yield of 2a (%)b
´
Mexico. E-mail: jtiburcio@cinvestav.mx; Fax: +52 55 50613389;
´
Tel: +52 55 50613721
1
2
3
4
5
a
60
60
60
20
90
b
MeOH
PhCH3
THF
MeOH
MeOH
90
o10
24
w Electronic supplementary information (ESI) available: Optimization
studies, full synthetic and characterization data, and NMR spectra of
2. CCDC reference numbers 688365. For ESI and crystallographic
data in CIF or other electronic format, see DOI: 10.1039/b808302a
z To whom correspondence regarding the crystallographic data
should be addressed.
o10
84
0.33 M 1a. Isolated yield.
ꢀc
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Table 2 Synthesis of N-acyl-a-amino amides 2 from a-keto esters
Entry
R1
Yield (%)a
1
2
3
Ph (1a)
2-CH3C6H4 (1b)
90 (2a)
84 (2b)
88 (2c)
(1c)
4
5
6
7
8
9
10
11
2-BrC6H4 (1d)
3-MeOC6H4 (1e)
3-O2NC6H4 (1f)
4-FC6H4 (1g)
4-MeOC6H4 (1h)
1-Naphthyl (1i)
2-Naphthyl (1j)
84 (2d)
86 (2e)
81 (2f)
92 (2g)
95 (2h)
91 (2i)
91 (2j)
93 (2k)
Scheme 1 Proposed overview of the mechanism for the formation of 2.
incorporation at the amide protons to post-isolation deuter-
ium–hydrogen exchange with adventitious water in the NMR
solvent (DMSO-d6). These results, however, support the for-
mation of enol intermediate 9, with the source of the proton
being ammonia and/or methanol. In addition, further support
for the proposed mechanism comes from the 1H NMR analysis
of the crude reaction mixture upon reaction of 1a under the
standard conditions which showed the presence of a trace
amount of urea (8).15 We attribute the formation of urea to
nucleophilic attack of ammonia on liberated isocyanate (7)
(Scheme 1). Further studies to elucidate the details of the
mechanism are ongoing.
(1k)
CH3 (1l)
(CH3)2CH (1m)
PhCH2 (1n)
12
13
14
a
80 (2l)b
75 (2m)b
80 (2n)b
b
Isolated yield. Reaction conducted at 80 1C for 12 h.
a-amino acids could be synthesized from 2 under analogous
conditions.
ð2Þ
A plausible mechanism for the reaction methodology under
current development is shown in Scheme 1, and is based upon
a proposal originally put forth by Shive and Shive.14
We briefly examined the plausibility of the proposed
mechanism by reacting 1a with deuterated ammonia in deut-
erated methanol under otherwise standard conditions (eqn (3)).
It was determined that there was 498% deuterium incorpora-
tion at the a-position of 2o. We attribute the lower deuterium
In conclusion, we have developed a methodology for the
direct and facile synthesis of a variety of N-acyl-a-amino
amides in one step from a-keto esters. The desired products
are obtained in good to excellent yields through simple pre-
cipitation or recrystallization from the crude reaction mixture,
and do not require any further purification. Preliminary work
towards deducing the mechanism of this transformation was
also presented.
This work was supported through funding from NSERC of
Canada and Kanata Chemical Technologies. We thank
Bhartesh Dhudshia and Jennifer Scott for preparation of
certain a-keto esters.
Fig. 1 X-ray crystal structure of 2a.
ꢀc
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Mullen and J. D. Sutherland, Angew. Chem., Int. Ed., 2007, 46,
8063.
Notes and references
8 For select recent examples, see: (a) T. Morwick, A. Berry, J.
Brickwood, M. Cardozo, K. Catron, M. DeTuri, J. Emeigh, C.
Homon, M. Hrapchak, S. Jacober, S. Jakes, P. Kaplita, T. A.
Kelly, J. Ksiazek, M. Liuzzi, R. Magolda, C. Mao, D. Marshall,
D. McNeil, A. Prokopowicz, III, C. Sarko, E. Scouten, C.
Sledziona, S. Sun, J. Watrous, J. P. Wu and C. L. Cywin, J.
Med. Chem., 2006, 49, 2898; (b) G. I. Elliot, J. R. Fuchs, B. S. J.
Blagg, H. Ishikawa, H. Tao, Z.-Q. Yuan and D. L. Boger, J. Am.
Chem. Soc., 2006, 128, 10589; (c) Y. Hitotsuyanagi, S. Sasaki, Y.
Matsumoto, K. Yamaguchi, H. Itokawa and K. Takeya, J. Am.
Chem. Soc., 2003, 125, 7284.
y General experimental procedure for the synthesis of N-acyl-a-amino
amides: CAUTION: the procedure described below generates pressure in
a closed reaction vessel. The reaction vessel should be placed behind a
blast shield in a well-ventilated fume hood.
To a solution of ammonia in methanol (ca. 7 M in MeOH, 3.0 mL, ca.
21 equiv.) in a Swagelocks 50 mL stainless steel cylinder or an Aces
pressure tube was added the a-keto ester (1.00 mmol). The cylinder
(or tube) was sealed and heated in an oil bath at 60 1C or 80 1C for 6 h
or 12 h. The cylinder (or tube) was then removed, was allowed to cool
to room temperature (1 h), and then cooled further in a ꢁ40 1C bath.
The Swagelocks cylinder (or pressure tube) was opened and the
contents were transferred to a small Erlenmeyer flask (50 mL). A
steady stream of air was blown over the reaction mixture until some
precipitation was observed. The reaction mixture was then heated
slightly to redissolve all solid matter, and allowed to stand at room
temperature for 2 h. The precipitated product was filtered off through
a sintered glass funnel, and washed with ice-cold methanol (ca. 5 mL).
9 M. J. Thompson, W. Heal and B. Chen, Tetrahedron Lett., 2006,
47, 2361.
10 For select recent examples, see: (a) B. Iliev, A. Linden, R. Kunz
and H. Heimgartner, Tetrahedron, 2006, 62, 1079; (b) B. Iliev, A.
Linden and H. Heimgartner, Helv. Chim. Acta, 2006, 89, 153;
(c) W.-Q. Jiang, S. P. G. Costa and H. L. S. Maia, Org. Biomol.
Chem., 2003, 1, 3804.
11 For select recent examples, see: (a) M. Sedla
´
k, P. Drabina, R.
Keder, J. Hanusek, I. Cısarova and A. Ruzicka, J. Organomet.
1 (a) G. R. Maxwell, Synthetic Nitrogen Products, Kluwer Aca-
demic/Plenum, New York, 2004; (b) S. A. Lawrence, Amines
Synthesis, Properties, and Application, Cambridge University Press,
Cambridge, 2004.
2 (a) W. C. Chan, A. Higton and J. S. Davies, in Amino Acids,
Peptides, and Proteins, ed. J. S. Davies, Royal Society of Chemistry,
2006, vol. 35, p. 1; (b) Amino Acids: Chemistry, Biology and Medicine,
ed. G. Lubec and G. A. Rosenthal, Springer, New York, 1992.
3 For recent reviews on the asymmetric synthesis of a-amino acids,
´
´
Chem., 2006, 691, 2623; (b) K. W. Gillman, M. A. Higgins,
G. S. Poindexter, M. Browning, W. J. Clarke, S. Flowers, J. E.
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Mattson, A. Ortiz, S. Rassnick, J. W. Russell and I.
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´
nometallics, 2006, 25, 901.
12 See ESIw for detailed optimization studies.
see: (a) C. Najera and J. M. Sansano, Chem. Rev., 2007, 107, 4584;
´
13 Crystal data, 2a: C15H14N2O2, M = 254.28, monoclinic, space
group C2/c, a = 18.101(4) A, b = 7.1667(14) A, c = 20.677(4) A,
b = 101.16(3)1, V = 2631.6(9) A3, Z = 8, T = 293(2) K, m(Mo-
(b) H. Vogt and S. Brase, Org. Biomol. Chem., 2007, 5, 406.
4 B. Dhudshia, J. Tiburcio and A. N. Thadani, Chem. Commun.,
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¨
Ka) = 0.087 mmꢁ1, 7631 reflections collected, 2245 unique (Rint
=
5 (a) H. Shimizu and M. Murakami, Chem. Commun., 2007, 2855;
(b) J. M. Domagala, Tetrahedron Lett., 1980, 21, 4997; (c) J. A.
Westbrook and S. E. Schaus, in Science of Synthesis, ed. J. Panek,
Georg Thieme Verlag, Stuttgart, 2006, vol. 20b, p. 1091.
6 A similar transformation of a-keto acids (1, R2 = H) has been
previously reported to furnish N-acylamino acids albeit in low
yields and with restricted substrate scope (R1 = alkyl), see: (a) H.
Yanagawa, Y. Makino, K. Sato, M. Nishizawa and F. Egami,
Origins Life, 1984, 14, 163; (b) F. Egami, Y. Makino, K. Sato, N.
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0.0527), F2 refinement, R1 = 0.0446, wR2 = 0.1161, (1649
reflections, I 4 2s(I)). Goodness-of-fit = 1.067. Data were
collected on a Nonius Kappa CCD instrument and solutions
performed using the SHELXTL 5.03 Program Library, Siemens
Analytical Instrument Division, Madison, WI, USA, 1997. CCDC
688365.
14 (a) W. Shive and G. W. Shive, J. Am. Chem. Soc., 1946, 68, 117;
(b) B. M. Adger, U. C. Dyer, I. C. Lennon, P. D. Tiffin and S. E.
Ward, Tetrahedron Lett., 1997, 38, 2153.
15 An alternative by-product, methyl carbamate, which could have
been formed via nucleophilic attack of methanol on liberated
isocyanate was not detected by 1H NMR spectroscopy in the crude
reaction mixture.
7 For recent, unrelated synthesis of a-amino amides, see: (a) S. C.
Pan and B. List, Angew. Chem., Int. Ed., 2008, 47, 3622; (b) L. B.
ꢀc
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4054 | Chem. Commun., 2008, 4052–4054