One-pot stepwise approach to β-enaminoketoesters through "masked" 1,3-aza-dipoles

Article abstract of DOI:10.1021/ol501930f

t-BuOK-mediated rearrangement of 1,3-ketoesters with 2-(azidomethyl) aromatics in a two-step, one-pot telescoped sequence affords β-enaminoketoesters in moderate to good yields. A novel pathway is proposed in which the umpolung of the azide is achieved from electrophilicity to nucleophilicity via deprotonation and undergoes nucleophilic attack onto the 1,3-ketoester.

Full text of DOI:10.1021/ol501930f

Letter
pubs.acs.org/OrgLett
One-Pot Stepwise Approach to β‑Enaminoketoesters through
“Masked” 1,3-Aza-Dipoles
Zhi-ming Yan, Na Wu,* Dong Liang, Heng-shan Wang, and Ying-ming Pan*
Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of
Chemistry & Chemical Engineering of Guangxi Normal University, Guilin 541004, People’s Republic of China
S
* Supporting Information
ABSTRACT: t-BuOK-mediated rearrangement of 1,3-ketoesters
with 2-(azidomethyl) aromatics in a two-step, one-pot telescoped
sequence affords β-enaminoketoesters in moderate to good yields. A
novel pathway is proposed in which the umpolung of the azide is
achieved from electrophilicity to nucleophilicity via deprotonation and undergoes nucleophilic attack onto the 1,3-ketoester.
β-Enaminoketoester, a versatile building block to construct a
variety of molecules,1 has been used to react with hydrazine to
afford pyrazole2 and also to synthesize chiral β-amino acid by
asymmetric hydrogenation.3 Tandem Blaise-acylation is known
to proceed to β-enaminoketoesters via Reformatsky reaction
with nitrile;2a 1,3-ketoester condensation with Me2NCH(OMe)2
also affords the desired product.4 Herein we are interested in
discovering a two-step, one-pot protocol to synthesize β-
enaminoketoesters via “masked” 1,3-aza-dipoles.
Scheme 1. Rearrangements of 1,3-Ketoesters with Benzyl
Azide Compared with Aldehyde Amidation with Benzyl Azide
To our best knowledge, azide is a common 1,3-dipole for
Huisgen cycloaddition5 with alkynes and electron-deficient
alkenes to yield substituted 1,2,3-triazoles6 and dihydro-
triazoles.7 Azides show ambiphilicity under various conditions:
they are nucleophilic under acidic conditions when applied in
Schmidt8 and Boyer reactions9 and electrophilic under basic
conditions and utilized in the direct electrophilic azidation of
basic enolate to approach an α-amino acid10 and Regitz diazo
transfer.11 Recently, Manetsch12 reported an unusual case, in
which the umpolung of the azide is achieved from electrophilicity
to nucleophilicity via deprotonation of the benzylic proton,
leading to nucleophlic attack of the outermost nitrogen atom of
benzyl azides onto an aromatic aldehyde (Scheme 1). Intrigued
by Manetsch’s work, herein we disclose our results in base-
mediated rearrangements of 1,3-ketoesters with benzyl azides in
moderate to good yields.
First, bases were screened for α-C deprotonation of benzyl
azide. When mild inorganic bases and amine were employed, no
reaction occurred (Table 1, entries 1−3). Luckily, strong bases
resulted in formation of 3a in satisfying yields under heating
conditions (Table 1, entries 4 and 5). The equivalents of base
also had a significant effect on product yield (Table 1, entries 6−
9). The reaction could proceed successfully in DMF (Table 1,
entry 5), but other solvents including DMSO, THF, toluene,
EtOH, and CH2Cl2 gave low yields (Table 1, entries 10−14).
With the optimized reaction conditions, the two-step, one-pot
telescoped sequence works well using both benzyl chloride and
bromide (Table 2, 3b−3f). Alkyl ketoesters (including primary,
secondary, and tertiary substituents) afforded (E)-β-enamino-
ketoesters as sole isomers in good yields (Table 2, 3b−3k). The
sole E isomer of 3d was further confirmed by X-ray diffraction
analysis (Figure 1 and Supporting Information). Mild electron-
deficient (Table 2, 3h), electron-donating (Table 2, 3g, 3i), and
halogen-substituted (Table 2, 3j, 3k) benzyl azides were
tolerated, giving rise to the desired products in good yields.
However, benzyl azides with strong electron-withdrawing
substituents did not work (p-NO2, p-CO2Et). On the other
hand, aliphatic azides (n-hexyl azide and cyclohexyl azide)
decomposed under the condition. 1,3-Ketoesters bearing
benzoyl groups were also employed (Table 2, 3l−3p). Aromatic
ketoesters were found to transform to 3 (E/Z mixtures) more
slowly (36 h), during which trace amounts of 2-benzoyl-3-phenyl
acrylates were detected (ESI-MS) as byproducts.
On the basis of our experiment results, a putative mechanism is
proposed (Scheme 2). Deprotonation of benzyl azide first
generates a highly reactive species 4, the outermost nitrogen
atom of which undergoes nucleophilic attack onto the carbonyl
carbon of ketone 2. Intramolecular proton shift gives the
nucleophilic carbanion 6 in situ, followed by an intramolecular
Mannich reaction via a six-membered chairlike transition state to
yield triazenide 7. Then, proton shift affords an electron-
intensive oxide 8, followed by elimination of molecular nitrogen
Received: July 3, 2014
Published: July 23, 2014
© 2014 American Chemical Society
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Table 1. Optimization of 1,3-Ketoesters Rearrangement with
Benzyl Azide
Table 2. t-BuOK-Mediated 1,3-Ketoester Rearrangements
with Benzyl Azides
a
a
b
entry
base (equiv)
solvent
t (°C)
yield (%)
1
2
3
4
5
6
7
8
9
Cs2CO3 (2)
K2CO3 (2)
Et3N (2)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
THF
70
70
70
70
70
70
70
70
70
70
70
70
70
70
rt
nr
nr
nr
KOH (2)
81
88
85
68
trace
nr
t-BuOK (2)
t-BuOK (4)
t-BuOK (1)
t-BuOK (0.5)
t-BuOK (0.1)
t-BuOK (2)
t-BuOK (2)
t-BuOK (2)
t-BuOK (2)
t-BuOK (2)
t-BuOK (2)
t-BuOK (2)
t-BuOK (2)
c
10
trace
7
11
12
13
14
15
16
17
toluene
EtOH
DCM
DMF
DMF
DMF
nr
nr
26
14
35
77
50
90
a
Reaction conditions: 1a (1 mmol) and sodium azide (1.1 mmol)
were dissolved in solvent (3 mL) and stirred at 70 °C overnight,
followed by treatment with base and 2a (0.5 mmol), and stirring
continued at 70 °C (except for entries 15−17) in a sealed tube for 12
b
h. The equivalent of base is based on 2a. Isolated yield. nr = no
c
reaction. DMSO is not versatile for all substrates and works only for
particular substrates; see Table 2.
leading to β-amino ketoesters 9. One equivalent of ammonia
gas,13 which was detected by wet litmus paper, is lost under
heating condition, leading to 2-acyl-substituted acrylate deriva-
tive 10. [3 + 2] Cycloaddition of 10 with a second equivalent of
azide yields a “masked” 1,3-aza-dipole, namely, substituted
triazole 11, which is unstable and releases N214 in situ to generate
a zwitterionic species 12. Finally, 1,2-proton shift and imine-
enamine tautomerization affords β-enaminoketoesters 3. The
sole E selectivity of 3a−3k could be explained by intramolecular
H-bonding between the imine and enol group4d,e in 13, while the
pool Z/E selectivity of 3l−3p could possibly be explained by
steric hindrance between benzoyl substituents and imine, leading
to rotation of ketoester’s α-C−β-C σ bond to a partial Z isomer
during the tautomerization process.
a
Reaction procedure: 1a (1 mmol) and sodium azide (1.1 mmol) were
dissolved in DMF (3 mL) and stirred at 70 °C overnight, followed by
treatment with t-BuOK (1 mmol) and 2a (0.5 mmol), and stirrring
continued at 70 °C in a sealed tube for 12−36 h. In DMSO (3 mL).
b
To further illustrate the envisioned mechanism, we employed
a mild sterically hindered azide 3-(azidomethyl)-1,1′-biphenyl15
and the more bulky 1-(azidomethyl)naphthalene for the
rearrangement but isolated only 2-acetyl-3-aromatic acrylates
(Scheme 3, 10q, 10r) as the sole product with no β-
enaminoketoesters detected (Scheme 3).
This could be explained by prohibition of [3 + 2] cycloaddition
because of steric hindrance at the β-position of substituted
acrylates 10. On the other hand, 10b obtained from an aldol
condensation protocol16 could also react with the benzyl azide to
afford β-enaminoketoester 3b, which illustrates that 10 is likely a
key intermediate in the proposed pathway of t-BuOK-mediated
rearrangement of 1,3-ketoesters with benzyl azides. To further
exclude the possibility that the deprotonated benzylic azide loses
molecular nitrogen to form benzylideneamide in situ and
undergoes Mannich reaction by enolate of the 1,3-ketoester, a
Figure 1. X-ray crystal structure of 3d.
control experiment was conducted wherein the azide was stirred
with t-BuOK at 70 °C for 10 min, and then 1,3-ketoester was
added to the mixture. Interestingly, most of the azide
decomposed, with the product formed in trace amounts.
In conclusion, 1,3-ketoesters have been used to rearrange with
benzyl azides to afford β-enaminoketoesters in moderate to good
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Letter
Notes
Scheme 2. Possible Reaction Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank the Ministry of Education of China
(IRT1225), the National Natural Science Foundation of China
(21362002, 41206077, and 81260472), Guangxi Natural Science
Foundation of China (2012GXNSFAA053027 and
2011GXNSFD018010), Guangxi Scientific Research and Tech-
nology Development Program (1355004-3), and Bagui Scholar
Program of Guangxi for financial support.
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*E-mail: panym2013@hotmail.com.
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