Synthesis of functionalised β-keto amides by aminoacylation/domino fragmentation of β-enamino amides

Article abstract of DOI:10.3762/bjoc.14.238

Ethylenediamine-derived β-enamino amides are used as equivalents of amide enolate synthons in C-acylation reactions with N-protected amino acids. Domino fragmentation of the obtained intermediates leads to functionalised β-keto amides, bearing a protected amino group in their side chain.

Full text of DOI:10.3762/bjoc.14.238

Synthesis of functionalised β-keto amides by aminoacylation/
domino fragmentation of β-enamino amides
Pavel Yanev and Plamen Angelov*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2602–2606.
Department of Organic Chemistry, University of Plovdiv Paisii
Hilendarski, 24 Tsar Asen Str., 4000 Plovdiv, Bulgaria
doi:10.3762/bjoc.14.238
Received: 14 August 2018
Accepted: 20 September 2018
Published: 10 October 2018
Email:
Plamen Angelov* - angelov@uni-plovdiv.bg
* Corresponding author
Associate Editor: D. Y.-K. Chen
Keywords:
© 2018 Yanev and Angelov; licensee Beilstein-Institut.
License and terms: see end of document.
amino acids; C-acylation; domino reaction; enamines; enaminones;
keto amides; retro-Mannich
Abstract
Ethylenediamine-derived β-enamino amides are used as equivalents of amide enolate synthons in C-acylation reactions with N-pro-
tected amino acids. Domino fragmentation of the obtained intermediates leads to functionalised β-keto amides, bearing a protected
amino group in their side chain.
Introduction
The acylation of amide enolates is one of the main synthetic ap- β-enamino amides as synthetic equivalents of primary and sec-
proaches towards β-keto amides and has found numerous appli- ondary amide enolate synthons in reactions with acid chlorides
cations [1-9]. However, while the generation of tertiary amide [22]. To extend the scope of the methodology, we now have
enolates is straightforward, this is not the case with secondary explored the acylation of these reagents with suitably activated
and primary amides. The NH acidity of the latter compounds amino acids, in order to prepare functionalised β-keto amides,
necessitates either a double deprotonation to ambident 1,3-dian- bearing a protected amino group in their side chain. Keto
ions [10] or proper masking of the amide functionality prior to amides of this type are excellent precursors to various hetero-
deprotonation [11,12]. Consequently, there are very few cyclic systems and are also interesting as building blocks for
published reagents that are synthetically equivalent to primary many biologically active substances [5-9,11,23-33].
or secondary amide enolate synthons. With regard to acylation
reactions, maybe most important among these are some nitriles, Results and Discussion
which can be successfully acylated at the alpha position [13-15] For the purposes of this study we used two β-enamino amides 1
and then hydrated [13,16-20] to reveal a primary amide func- (R1 = H, Ph), that are easily prepared in quantitative yields by
tionality. The dianion of silylated acetamide is another such ex- condensation of Boc-monoprotected ethylenediamine with com-
ample, although with very limited scope [21]. A contribution of mercially available acetoacetamides. As a first step we acylated
ours in this area is the application of ethylenediamine-derived the starting compounds 1 with mixed carbonic anhydrides of
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Beilstein J. Org. Chem. 2018, 14, 2602–2606.
N-protected amino acids, applying a procedure previously de-
veloped by us for closely related analogues [34] (Scheme 1).
Thus, the α-C-acylated intermediates 3a–j (Table 1) and 4
(Table 2) were obtained in good yields and excellent chiral
integrity (er 3c–f ≥ 99:1). The phthaloyl-protected compounds
3k and 3l were obtained in low yields by the mixed carbonic an-
hydride method and after screening various alternative cou-
pling reagents (mixed pivalic anhydrides, T3P, DCC, DIC,
CDI) we were able to improve the yields of 3k,l to 77% and
60%, respectively, only by using the corresponding N-phthaloyl
amino acid chlorides [35,36] as acylating reagents. The in-
creased yield however came at the expense of chiral integrity,
with nearly full racemisation.
Table 2: Yields of compounds 4 and 11 (R2 = R3 = H), obtained ac-
cording to Scheme 1 and Scheme 6.
compound 4/11 R1
n
PG
Yield 4 (%) Yield 11 (%)
a
b
c
d
e
f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
1
2
2
3
4
2
3
4
1
2
3
4
COOEt 90
COOEt 75
95
93
74
71
68
90
60
73
60
58
60
55
Cbz
Cbz
Cbz
Troc
Troc
Troc
Cbz
Cbz
Cbz
Cbz
88
85
75
57
77
65
95
82
70
73
g
h
i
j
H
k
l
H
H
targeted β-keto amides. In the course of these experiments the
two series of compounds showed markedly different behaviour.
Domino fragmentation of α-aminoacyl
intermediates 3 to N-protected
γ-amino-β-ketoamides 5
Initially we tried a procedure developed earlier by us for
simpler β-keto amides (30 min in neat TFA, then aqueous
NaOAc) [22]. In contrast to the preparation of non-function-
alised β-keto amides, here these conditions led to satisfactory
yields of keto amides 5 only for substrates 3 with R3 ≠ H (3g–l),
while in all other cases (3a–f, R3 = H) gave significant amounts
of pyrrolin-4-ones 6 as competing side products (Scheme 2).
Scheme 1: Preparation of α-C-acylated β-enamino amides 3 and 4.
Reagents and conditions: 2, NMM, EtOCOCl, CH2Cl2, 0 °C, 5 min;
then 1 and DMAP (0.2 equiv) in CH2Cl2, 0 °C to rt, 1 h.
Table 1: Yields of compounds 3 and 5 (R1 = Ph, n = 0), obtained ac-
cording to Scheme 1 and Scheme 2.
Compound 3/5 R2
R3
PG
Yield 3
Yield 5
(%)
(%)
a
b
c
d
e
f
H
H
H
H
H
H
H
COOEt 88
Troc 75
COOEt 86
Troc 65
COOEt 85
Troc 60
57
52
45
62
70
54
95
90
85
90
H
CH3
CH3
CH2Ph
CH2Ph
H
g
h
i
CH3 COOEt 80
CH3 Troc 80
H
H
Ph COOEt 70
COC6H4CO 94
j
H
k
l
CH3
COC6H4CO 45 (77)a 87
Scheme 2: Domino fragmentation of 3 to β-keto amides 5 with
competing cyclisation to pyrrolin-4-ones 6. Reagents and conditions:
TFA (neat, 5 min, rt), then 3 M aqueous NaOAc.
CH2Ph COC6H4CO 18 (60)a 85
aYields from acylation reaction with the corresponding acid chlorides.
The relative amount of the side products 6 depended on the
deprotection conditions and mainly on the duration of the expo-
sure of 3 to acid. Given enough time, the treatment in neat or
diluted TFA led to a complete transformation of 3a–f into 6
After the series of α-aminoacyl (3) and ω-aminoacyl (4) inter-
mediates were successfully prepared, we proceeded with the
removal of the Boc protection group from the ethylenediamine
moiety in order to trigger the domino fragmentation to the
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Beilstein J. Org. Chem. 2018, 14, 2602–2606.
without formation of the desired β-keto amides 5a–f at all. On
the contrary – when the deprotection was carried out for 5 min
in neat TFA, the pyrrolinones 6 were the minor product and the
β-keto amides 5a–f were obtained in higher, although still mod-
erate, yields (Table 1). These results indicated that the acidic
conditions required for the Boc deprotection favoured the
unwanted side process (Scheme 3) and the aza-Michael/retro-
Mannich sequence only takes place after the addition of NaOAc
(Scheme 4).
Scheme 5: Reactivity of analogues 9, lacking the auxiliary amino
group [34].
It can be hypothesized that in acidic media the ammonium
species 7, resulting from the deprotection of 3 followed by pro- Higher enantiomeric ratios for compounds 5 (87:13–80:20)
tonation, exists predominantly as an imino tautomer, stabilised were obtained with TFA/CH2Cl2 (1:4) and 15 min deprotection
by intramolecular H-bonding. Such a tautomer would be time, without any change in the yields indicated in Table 1. Ex-
susceptible to favourable 5-exo-trig process, leading eventually periments with more dilute TFA required longer deprotection
to the pyrrolin-4-ones 6. This hypothesis is strongly supported time, which in turn gave advantage to the unwanted cyclisation
by the behaviour of analogues 9 in which the auxiliary amino to pyrrolinones 6 and lowered the yields of compounds 5. Only
group is absent (Scheme 5). Under identical conditions (neat the phthaloyl-protected derivative 3k gave the corresponding
TFA, rt) compounds 9 do not react even after 12 hours. A reac- keto amide 5k in both, high yield and good er (95:5) when the
tion occurs only upon heating in TFA solution, but then the Boc-deprotection was performed in 1:9 TFA/CH2Cl2 for
cyclisation mode is completely different and leads to enam- 30 min.
inotetramic derivatives 10 instead of pyrrolin-4-ones 6 [34].
Domino fragmentation of ω-aminoacyl
Another drawback caused by the acidic deprotection conditions
intermediates 4 to N-protected
ω-amino-β-ketoamides 11
The longer chain in compounds 4 precludes the favourable
5-exo-trig process discussed earlier (Scheme 3) and according-
ly there was no competing formation of cyclic side products. A
different type of unwanted cyclisation occurred with the GABA
was the loss of chiral integrity. When the deprotection of 3 was
performed in neat TFA for 5 min, the keto amides 5c–f were
obtained in poor enantiomeric excess and the concomitantly
formed pyrrolinones 6c–f were fully racemic. This again is in
sharp contrast to analogues 9, which cyclise to 10 with excel-
lent retention of configuration [34].
Scheme 3: Proposed mechanism for the formation of side products 6.
Scheme 4: Proposed mechanism for the formation of the target β-keto amides 5.
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Beilstein J. Org. Chem. 2018, 14, 2602–2606.
derivatives 4b,c,f,j (n = 2) but here the competing process was tives and imposes the requirement for tertiary-substituted
slower and could be effectively avoided by limiting the depro- nitrogen in the aminoacyl moiety. There is no such limitation
tection time to 5 min in neat TFA. In this way a series of for the ω-amino derivatives.
ω-amino-β-keto amides 11 with variable chain lengths and
N-protection groups was successfully obtained (Scheme 6,
Supporting Information
Table 2).
Supporting Information File 1
Full experimental details and analytical data.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-238-S1.pdf]
Supporting Information File 2
HPLC data and processed NMR spectra.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-238-S2.pdf]
Scheme 6: Domino fragmentation of compounds 4 (R2 = R3 = H) to
N-protected ω-amino-β-keto amides 11.
Acknowledgements
This research was funded by the Bulgarian National Science
Minor amounts of the enol tautomer (1–10%) were present in Fund (Grant DN09/15-2016) and the Royal Society of Chem-
the CDCl3 solutions of all β-keto amides 5 and 11. Along with istry, UK (Grant RF17-6592). The authors are grateful to the
that, the 1H NMR spectra of the GABA-derivatives 11b,c,f,j Faculty of Biology, Department of Plant Physiology and Molec-
(n = 2) in CDCl3 indicated a ring–chain tautomeric equilibrium ular Biology and Dr Mladen Naydenov for carrying out high
with 55–75% share of the open chain form. Although an estima- resolution mass spectral measurements on equipment provided
tion of the tautomeric ratio was possible through a comparison under the EC FP7/REGPOT-2009-1/BioSupport project.
of selected peak areas, the partial overlap and broadening of
ORCID® iDs
Plamen Angelov - https://orcid.org/0000-0002-3625-9933
other signals prevented a full and unequivocal assignment. To
circumvent this issue, we chose to lock the chain form by
reducing the keto group in 11 with NaBH4 (Scheme 7). The
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