Enamine-based domino strategy for C-acylation/deacetylation of acetoacetamides: A practical synthesis of -keto amides

Article abstract of DOI:10.1055/s-0029-1219836

A practical three-step route for C-acylation/deacetylation of acetoacetamides is described. Initial enamination of the acetoacetamides with Boc-monoprotected ethylenediamine provides β-enamino amides, which are acylated at the -carbon with excellent selectivity. The C-acylated derivatives undergo domino fragmentation in acidic media to give the corresponding β-keto amides accompanied by 2-methyl-4,5-dihydro-1H-imidazole. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219836

LETTER
1273
Enamine-Based Domino Strategy for C-Acylation/Deacetylation of
Acetoacetamides: A Practical Synthesis of b-Keto Amides
A
P
ractica
l
Sy
l
nthesis
a
of
b
-Keto
mmides en Angelov*
University of Plovdiv, Department of Organic Chemistry, 24 Tsar Asen Str., 4000 Plovdiv, Bulgaria
E-mail: angelov@uni-plovdiv.bg
Received 16 February 2010
acetoacetamides with monoprotected ethylenediamine
would both provide excellent starting material for a-C-
acylation and set the scene for a domino-like sequence of
intramolecular Michael addition and retro-Mannich frag-
Abstract: A practical three-step route for C-acylation/deacetyla-
tion of acetoacetamides is described. Initial enamination of the ace-
toacetamides with Boc-monoprotected ethylenediamine provides b-
enamino amides, which are acylated at the a-carbon with excellent
selectivity. The C-acylated derivatives undergo domino fragmenta- mentation. The required Boc-monoprotected ethylenedi-
tion in acidic media to give the corresponding b-keto amides ac-
companied by 2-methyl-4,5-dihydro-1H-imidazole.
amine was easily prepared in 75% yield by reacting di-
tert-butyl dicarbonate with excess of ethylenediamine.18
This material was then reacted with acetoacetamides 1
(Scheme 1, i) to provide the corresponding b-enamino
amides 2 in quantitative yields.19 The acylation of the
enamino amides 2 with acid chlorides (Scheme 1, ii,
Key words: b-keto amide, enaminone, C-acylation, domino reac-
tion, 1,3-dicarbonyl
b-Keto amides are widely used in the synthesis of various Table 1) was carried out in the presence of equimolar
heterocyclic compounds.1 In addition to that, many bio- amount of triethylamine and was greatly facilitated by
logically active compounds contain b-keto amide frag- DMAP catalysis (0.2 equiv catalyst). The reactions were
ments in their structure.2 As a consequence, considerable carried out in dichloromethane for one hour at room tem-
efforts have been directed towards the development of perature and the C-acylated products 3 were obtained in
synthetic methodologies giving access to this class of high yields (75–95%).20
compounds. Depending on the retrosynthetic disconnec-
BocHN
tion, the methods for b-keto amide synthesis can be divid-
BocHN
ed into three main categories: a) acylation of amide
enolates3 or their synthetic equivalents,4 including asym-
metric acylations,5 b) addition of ketone enolates to
isocyanates6 or Passerini condensation followed by reduc-
tion,7 and, c) coupling of amines and b-keto acids8 or their
synthetic equivalents, such as b-keto esters,9 b-keto
O
O
NH
O
O
NH
O
i
ii
NHR1
NHR1
NHR1
R2
1
2
thioesters,10
2,2-difluoro-4-alkoxy-1,3,2-dioxaborin-
3
anes,11 ketene dimers12 and acylketenes obtained in situ
from 1,3-dioxin-4-ones13 or acylated Meldrum’s ac-
ids.2b,c,14
Scheme 1 Reagents and conditions: (i) BocNHCH2CH2NH2,
Na2SO4, CH2Cl2 or MeOH, 24 h, r.t.; (ii) DMAP (0.2 equiv), Et3N,
R2COCl, CH2Cl2, 1 h, r.t.
C-Acylation/deacetylation is a well-established approach
for the synthesis of b-diketones and b-keto esters from
acetylacetone and acetoacetic esters, respectively,15 but to
the best of the author’s knowledge it has never been ap-
plied to acetoacetamides, despite their general availabili-
ty. The methodology presented in this letter may be
regarded as an enamine-assisted variation of the C-acyla-
tion/deacetylation approach, which applied to acetoaceta-
mides turns them into synthetic equivalents of amide
enolates. The idea for the present investigation originated
from two earlier observations; the selective and high-
yielding a-C-acylation of b-enamino amides16 and the
retro-Mannich reactions of some 1,1-disubstituted tet-
rahydroisoquinolines.17 Putting these two pieces of infor-
mation together, it was envisaged that enamination of
The final stage of the synthesis was a Boc-deprotection of
3 with TFA, which triggered the expected domino se-
quence of intramolecular Michael addition followed by
retro-Mannich fragmentation (Scheme 2). Thus, the b-
keto amides 6 were obtained in excellent yields with ac-
companying formation of 2-methyl-4,5-dihydro-1H-
imidazole (5).21 Although this co-product is of no practi-
cal interest here, the approach may prove useful for the
preparation of other 2-substituted dihydroimidazoles,
considering the mild reaction conditions. The intermedi-
ate 4 was not isolated. It appears to be rather unstable and
at this stage it is not clear whether the domino process
takes place in the acidic solution or during the aqueous
workup.
In conclusion, a practical and straightforward synthesis of
b-keto amides has been disclosed. It does not require an
inert atmosphere22 and in most cases can be done without
SYNLETT 2010, No. 8, pp 1273–1275
Advanced online publication: 16.04.2010
DOI: 10.1055/s-0029-1219836; Art ID: G06610ST
x
x.
x
x.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

1274
P. Angelov
LETTER
BocHN
O
O
NH
O
NH
O
NHR1
NHR1
TFA
N
NH
NHR1
NHR1
N
+
HO
R2
H
R2
O
R2
O
O
R2
6
4
5
3
Scheme 2
(2) (a) Moya, P.; Castillo, M.; Primo-Yufera, E.; Couillaud, F.;
Martinez-Manez, R.; Garcera, M.-D.; Miranda, M. A.;
Primo, J.; Martinez-Pardo, R. J. Org. Chem. 1997, 62, 8544.
(b) Cantin, A.; Moya, P.; Castillo, M.; Primo, J.; Miranda,
M. A.; Primo-Yufera, E. Eur. J. Org. Chem. 1999, 221.
(c) Moya, P.; Cantin, A.; Castillo, M.-A.; Primo, J.; Miranda,
M. A.; Primo-Yufera, E. J. Org. Chem. 1998, 63, 8530.
(d) Muzaffar, A.; Brossi, A. J. Nat. Prod. 1990, 53, 1021.
(3) Yip, K.-T.; Li, J.-H.; Lee, O.-Y.; Yang, D. Org. Lett. 2005,
7, 5717.
(4) (a) Kuzma, P. C.; Brown, L. E.; Harris, T. M. J. Org. Chem.
1984, 49, 2015. (b) Chen, Y.; Sieburth, S. McN. Synthesis
2002, 2191. (c) Gotor, V.; Liz, R.; Testera, A. M.
Tetrahedron 2004, 60, 607.
(5) (a) Evans, D. A.; Ennis, M. D.; Le, T. J. Am. Chem. Soc.
1984, 106, 1154. (b) Kashima, C.; Fukuchi, I.; Takahashi,
K.; Hosomi, A. Tetrahedron 1996, 52, 10335.
(6) (a) Hendi, S. B.; Hendi, M. S.; Wolfe, J. F. Synth. Commun.
1987, 17, 13. (b) Groß, A. G.; Deppe, H.; Schober, A.
Tetrahedron Lett. 2003, 44, 3939.
Table 1 Isolated Yields of Compounds 3 and 6 Obtained According
to Scheme 1 and Scheme 2
Compd R1
R2
Yield (%)
3
6
a
b
c
d
e
f
Ph
i-Pr
77
90
75
95
89
75
93
85
80
88
93
90
95
96
90
97
95
80
Ph
i-Bu
Bn
Ph
Ph
Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
H
i-Bu
Bn
g
h
i
Ph
n-C9H19
CH2CH2Ph
(7) Neo, A. G.; Delgado, J.; Polo, C.; Marcaccini, S.; Marcos,
C. F. Tetrahedron Lett. 2005, 46, 23.
H
(8) Dekhane, M.; Douglas, K. T.; Gilbert, P. Tetrahedron Lett.
1996, 37, 1883.
chromatographic purification. Work to extend this meth-
odology to other 1,3-dicarbonyl compounds is currently in
progress and the results will be reported in due course.
(9) (a) Witzeman, J. S.; Nottingham, W. D. J. Org. Chem. 1991,
56, 1713. (b) Kibler, C. J.; Weissberger, A. Org. Synth.,
Coll. Vol. III; Wiley: New York, 1955, 108. (c) Hoffman,
R. V.; Huizenga, D. J. J. Org. Chem. 1991, 56, 6435.
(d) Cossy, J.; Thellend, A. Synthesis 1989, 753.
(10) Kim, H.-O.; Olsen, R. K.; Choi, O.-S. J. Org. Chem. 1987,
52, 4531.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(11) (a) Stefane, B.; Polanc, S. Synlett 2004, 698. (b) Stefane,
B.; Polanc, S. Tetrahedron 2007, 63, 10902.
Acknowledgment
(12) (a) Sung, K.; Wu, S.-Y. Synth. Commun. 2001, 31, 3069.
(b) Williams, J. W.; Krynitsky, J. A. Org. Synth., Coll. Vol.
III; Wiley: New York, 1955, 10.
(13) (a) Sato, M.; Ogasawara, H.; Komatsu, S.; Kato, T. Chem.
Pharm. Bull. 1984, 32, 3848. (b) Clemens, R. J.; Hyatt, J. A.
J. Org. Chem. 1985, 50, 2431. (c) Ramana, C. V.; Mondal,
M. A.; Puranik, V. G.; Gurjar, M. K. Tetrahedron Lett. 2006,
47, 4061.
Funding from the Bulgarian Ministry of Education and Science
(DO-02-195) and from the University of Plovdiv (MU-18-08 and
ISH-2-08) is gratefully acknowledged.
References and Notes
(1) (a) Zhou, C.-Y.; Che, C.-M. J. Am. Chem. Soc. 2007, 129,
5828. (b) Kumar, K.; Sai, S.; Gilbert, T. M.; Klumpp, D. A.
J. Org. Chem. 2007, 72, 9761. (c) Bagley, M. C.;
Chapaneri, K.; Dale, J. W.; Xiong, X.; Bower, J. J. Org.
Chem. 2005, 70, 1389. (d) Lieby-Muller, F.; Constantieux,
T.; Rodriguez, J. J. Am. Chem. Soc. 2005, 127, 17176.
(e) Szczepankiewicz, B. G.; Heathcock, C. H. J. Org. Chem.
1994, 59, 3512. (f) Messeri, T.; Pentassuglia, G.; Di Fabio,
R. Tetrahedron Lett. 2001, 42, 3227. (g) Cerreti, A.;
D’Annibale, A.; Trogolo, C.; Umani, F. Tetrahedron Lett.
2000, 41, 3261.
(14) Xu, F.; Armstrong, J. D. III.; Zhou, J. X.; Simmons, B.;
Hughes, D.; Ge, Z.; Grabowski, E. J. J. J. Am. Chem. Soc.
2004, 126, 13002.
(15) (a) Straley, J. M.; Adams, A. C. Org. Synth., Coll. Vol. IV;
Wiley: New York, 415. (b) Hao, W.; Zhang, Y.; Ying, T.;
Lu, P. Synth. Commun. 1996, 26, 2421. (c) Gukhman,
E. V.; Reutov, V. A. Russ. J. Gen. Chem. 1999, 69, 1608.
(d) Renault, O.; Guillon, J.; Dallemagne, P.; Rault, S.
Tetrahedron Lett. 2000, 41, 681. (e) Katritzky, A. R.;
Wang, Z.; Wang, M.; Wilkerson, C. R.; Hall, C. D.;
Akhmedov, N. G. J. Org. Chem. 2004, 69, 6617. (f) Zou,
X.; Jia, X.; Wang, X.; Xie, G. Synth. Commun. 2007, 37,
1617.
(16) Venkov, A. P.; Angelov, P. A. Synthesis 2003, 2221.
Synlett 2010, No. 8, 1273–1275 © Thieme Stuttgart · New York

LETTER
A Practical Synthesis of b-Keto Amides
1275
(17) Venkov, A. P.; Angelov, P. A. Synth. Commun. 2003, 33,
3025.
(18) Kofoed, T.; Hansen, H. F.; Ørum, H.; Koch, T. J. Peptide
Sci. 2001, 7, 402.
was washed with 5% aq solution of AcOH (15 mL) and then
with sat. aq NaHCO3 (15 mL). The organic phase was dried
over Na2SO4 and the solvent was distilled off. The residue
crystallized upon trituration with Et2O or Et2O–PE (1:1) to
give the corresponding product 3 in 50–90% yield.
Additional 10–30% were isolated from the ethereal
washings after column chromatography on silica gel with
Et2O as the eluent [increasing polarity to Et2O–MeOH (10:1)
for products 3 with R1 = H].
(19) Preparation of b-Enamino Amides 2: The corresponding
acetoacetamide 1 (5 mmol) was added to a solution of Boc-
monoprotected ethylenediamine (5 mmol) in CH2Cl2 (20
mL) or MeOH (20 mL) for acetoacetamide 1h (1, R1 = H)
and the reaction mixture was stirred over anhyd Na2SO4 for
24 h at r.t. After that, the sulfate was filtered off and the
solvent was removed by distillation. The residue was
triturated with small amount of Et2O to give practically clean
b-enamino amide in nearly quantitative yield (93–98%).
Compound 2a (2, R1 = Ph) has moderate solubility in CH2Cl2
and crystallizes out of the reaction mixture, so special care
must be taken to wash it thoroughly off the drying agent. The
b-enamino amides 2 are air-stable and can be stored safely at
r.t., but they easily decompose on silica gel.
(20) Preparation of a-Acyl-b-enamino Amides 3; General
Procedure: The corresponding acid chloride (1 mmol) was
slowly added to a magnetically stirred solution of enamino
amide 2 (1 mmol), DMAP (0.2 mmol, 25 mg) and Et3N (1
mmol, 0.14 mL) in CH2Cl2 (20 mL). The reaction mixture
was stirred for 1 h at r.t. and after that was transferred to a
separating funnel with additional 20 mL of CH2Cl2, where it
(21) Preparation of b-Keto Amides 6; General Procedure: The
corresponding intermediate 3 (200 mg) was dissolved in
TFA (2 mL), the solution was stirred for 40 min at r.t. and
the reaction was quenched with aq solution of MeCOONa (3
mol/L, 20 mL). The resulting mixture was stirred for 20 min
at r.t. and then extracted with CH2Cl2 [3 × 20 mL (5 × 20 mL
for 6h and 10 × 20 mL for 6c and 6i)]. In the case of 6i the
aqueous phase was saturated with NaCl prior to extraction.
The combined organic layers were washed with sat. aq
NaHCO3 (15 mL) and dried over Na2SO4. The solvent was
distilled off to afford practically clean b-keto amides. In
some cases enol tautomer was registered immediately after
isolation, but it gradually converted to the keto form.
(22) All reactions were carried out in untreated CH2Cl2 and open
to air.
Synlett 2010, No. 8, 1273–1275 © Thieme Stuttgart · New York

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