Highly Site-Selective Metal-Free C-H Acyloxylation of Stable Enamines

Article abstract of DOI:10.1021/acs.orglett.8b00222

A highly site-selective acyloxylation of stable enamines with PhI(OAc)₂ under metal-free conditions to afford (E)-vinyl acetate derivatives in good to excellent yields is described. Depending on the judicious choice of the solvent system, either the α- or β-site-selective product could be obtained with high selectivity. For the α-site-selective product, the rearranged amide compound is obtained as the major product. This reaction proceeds under mild reaction conditions (room temperature, metal-free, and open-flask) and features a broad substrate scope.

Full text of DOI:10.1021/acs.orglett.8b00222

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly Site-Selective Metal-Free C−H Acyloxylation of Stable
Enamines
Fei Wang,† Wangbing Sun,† Yixin Wang,† Yaojia Jiang,*,† and Teck-Peng Loh*,†,‡,§
†Institute of Advanced Synthesis, Institute of Advanced Materials, School of Chemistry and Molecular Engineering, Jiangsu National
Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing 211816, China
‡Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637616, Singapore
§Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
S
* Supporting Information
ABSTRACT: A highly site-selective acyloxylation of stable
enamines with PhI(OAc)2 under metal-free conditions to
afford (E)-vinyl acetate derivatives in good to excellent yields
is described. Depending on the judicious choice of the solvent
system, either the α- or β-site-selective product could be
obtained with high selectivity. For the α-site-selective product,
the rearranged amide compound is obtained as the major
product. This reaction proceeds under mild reaction conditions (room temperature, metal-free, and open-flask) and features a
broad substrate scope.
namines and their derivatives are useful synthetic building
Our studies commenced with acyloxylation of enaminone 1a
with phenyliodine(III) diacetate (PIDA, 2a) under various
conditions. We were delighted to find that the acyloxylation
product 3a could be obtained, albeit in low yield, using aprotic
solvents (Table 1, entries 1 and 2), together with another
minor product, (Z)-3-(dimethylamino)-3-oxo-1-phenylprop-1-
en-1-yl acetate (4a), the structure of which was confirmed by
single-crystal X-ray diffraction analysis (Figure 1; CCDC no.
1519780). Attempts to improve the selectivity by carrying out
the reaction using different solvents revealed that alcohols led
to a positive effect (Table 1, entries 4−6), while acetic acid gave
the product in only 15% yield, probably because of the stability
problem of 1a under acidic conditions (Table 1, entry 3).
Further screening of the reaction conditions showed that
fluorinated solvents such as hexafluoroisopropanol (HFIP) and
2,2,2-trifluoroethanol (TFE) afforded 3a as the sole product in
59% and 65% yield, respectively. Gratifyingly, the yield of 3a
could be improved to 88% when 1.3 equiv of PIDA was used in
the reaction (Table 1, entry 9). Further reduction of the
amount of PIDA resulted in a decreased yield (Table 1, entry
10). Interestingly, when the solvent system was changed to
acetonitrile, the α-site-selective product could be obtained as
the major product in 34% yield. Furthermore, it was found that
a trace amount of water increased the regioselectivity
dramatically (Table 1, entries 12−15). Finally, the optimized
reaction conditions for the α-acyloxylation of enamines 1a
involve carrying out the reaction with PIDA in the presence of
2.0 equiv of H2O at room temperature.
1
Eblocks since they can function as stable enolates to react
with a wide variety of electrophiles under neutral conditions.
Furthermore, they can also function as latent amino groups
since they can easily be obtained via reduction of the
unsaturated double bond.2 Accordingly, their syntheses have
attracted tremendous attention from synthetic chemists.3 In
recent years, our group4 and other groups5 have developed
efficient methods for the construction of functionalized
enamides via direct sp2 C−H bond functionalization of simple
enamides. Enaminones are another class of enamine derivative
that have attracted the attention of synthetic chemists since
they contain additional functional groups that can be easily
manipulated.6 They are also easy to handle, as they can be
purified by silica gel chromatography. Cabri’s group7 and
others8 reported palladium-catalyzed C−H bond arylation of α-
site enamides (Scheme 1A). Georg’s group9 has elegantly
demonstrated the possibilities of carrying out β-site C−H bond
functionalization of cyclic enamides using transition-metal
catalysts. Acyclic enamides have also been studied in β-site
C−H bond functionalition by Loh,10 Zhao,11 and other
groups12 (Scheme 1B). Dong’s group developed a novel
method for the synthesis of spiro-fused dihydrofuran-3(2H)-
ones that resulted in β-acyloxylation of enaminones as side
products.13 In this paper, we report a metal-free method to
carry out highly site-selective sp2 alkenyl C−H bond
acyloxylation of enaminones. Both α- and β-site-selective
products can be obtained selectively by the judicious choice
of the solvent employed in the reaction. In the case of the α-
site-selective product, the rearranged amide compound is
obtained as the major product. This offers an efficient method
to construct amide bonds.
Received: January 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00222
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Organic Letters
Letter
Scheme 1. Site-Selective sp2 C−H Bond Functionalization
Figure 1. X-ray structure of 4a.
ab
,
Scheme 2. Substrate Scope of β-Acyloxylation
a
Table 1. Optimization of the Reaction Conditions
b
yields (%)
c
entry
solvent
equiv of H2O
1a:2a
3a
4a
1
2
toluene
DCE
AcOH
MeOH
EtOH
IPA
−
−
−
−
−
−
−
−
−
−
−
1.0
2.0
3.0
5.0
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.3
1:0.6
1:2.0
1:2.0
1:2.0
1:2.0
1:2.0
48
45
15
31
45
41
59
65
83
42
19
−
18
20
−
27
45
41
−
−
−
−
34
71
73
70
61
3
4
5
6
7
HFIP
TFE
a
Unless otherwise noted, the reactions were carried out using 1 (0.20
8
mmol) and PIDA (0.30 mmol) in TFE (0.1 M, 2 mL) at room
9
TFE
b
temperature for 0.5−2.0 h in an open flask. Isolated yields are shown.
10
11
12
13
14
15
TFE
c
The reaction was carried out in EtOH.
ACN
ACN
ACN
ACN
ACN
−
−
8
delivering good to excellent yields. To examine the electronic
effect, enaminones with aryl groups bearing electron-donating
and -withdrawing groups were subjected to the optimized
reaction conditions. Substrates with electron-rich and electron-
deficient aryl groups provided the desired products in good
yields (3b−d). A range of halogen substituents (F, Cl, Br, and
I) at the para position of the phenyl groups were also well-
tolerated (3e−h). It is important to note that the bromo and
iodo functionalities could be further employed in many useful
coupling reactions.14 Heterocycles including furan, thiophene,
and pyridine remained intact during the reaction (3i−k). It was
a
Unless otherwise noted, the reactions were performed using 1a (0.1
mmol) and 2a in the solvent (0.1 M, 1 mL) at room temperature in an
b
c
open flask. Yields determined by isolation. IPA = isopropyl alcohol;
HFIP = hexafluoroisopropanol; TFE = 2,2,2-trifluoroethanol.
Encouraged by the above results, we continued to investigate
the substrate scope of β-acyloxylation of enamines (Scheme 2).
In general, the reaction tolerated a broad range of substitutions,
B
DOI: 10.1021/acs.orglett.8b00222
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Organic Letters
Letter
found that the acyloxylation occurred at the β-site of the
enamine with excellent regioselectivity rather than other
reactive C(sp2)−H bonds in the heterocycles. This is consistent
with selectivity based on Mayer’s nucleophilicity constants.15
Naphthalenyl (3l) and alkyl-substituted substrates (3m−o)
could also provide the products as single regioisomers in
moderate to good yields. When the N-substituent was changed
to alkyl and aryl groups, the desired acyloxylation products
were obtained in promising yields of 56% and 70%, respectively
(3p and 3q). On the other hand, dibenzyl substitution (3r) has
a slightly negative influence on the transformation, as the
desired product was obtained in 46% yield. Furthermore, cyclic
amino functional groups were also well-tolerated (3s−v).
Besides enaminones, enaminolates were explored to extend the
potential application of this methodology. Delightfully, the
reactions proceeded smoothly and gave the desired products in
moderate to good yields with both acyclic and cyclic enamines
(3w−y). The reactio ngave the β-acyloxylation product in 68%
yield when the N,N-unsubstituted enamine 1z was examined in
TFE (3z).
Functional groups including heterocycle, triple bond, and
double bond were all well-tolerated and led to the
corresponding products in 53%−78% yield (4h−n). It is
worth noting that diene compounds play a pivotal role in
organic synthesis. Therefore, various conjugated alkenyl groups
were explored, and the corresponding conjugated vinyl
acyloxylated amides were obtained under the established
conditions. When different aminol groups were installed on
the enamine, the reaction proceeded smoothly to give the
desired products in good to excellent yields (4q−u).
Importantly, when enamines with different amino acids as the
N-substituents were explored under the reaction conditions,
amides with an amino acid residue were formed in promising
yields (4t, 4u).
According to the obtained results, we proposed the possible
reaction pathway shown in Scheme 4. Initially, enaminone 1
Scheme 4. Proposed Pathway for Acyloxylation of
Enaminones
Next, we explored the α-acyloxylation of enamines to afford
the rearranged products (Scheme 3). Substrates with both
electron-rich and electron-deficient aryl groups provided the
desired products in promising yields (4a−g). Neither the
electronic properties of the substituents nor their position on
the phenyl group had a significant effect on the reaction.
a b
,
Scheme 3. Substrate Scope of α-Acyloxylation
may react with PIDA to generate iodonium intermediate A.
There are two possible pathways by which the −OAc anion may
attack A. First, A may be attacked by the OAc anion at the β-
site of the enamine to give intermediate B (path a)11c with
release of iodobenzene and acetate anion. Cation intermediate
B then is pronated to afford the β-acyloxylation product 3. On
the other hand, if −OAc attacks the α-site of the enamine,
intermediate C is probably obtained (path b) and consequently
undergoes elimination to give D. Finally, the amide product 4
can be obtained by rearrangement of α-acyloxylation
intermediate D through protonation intermediate E.16
To better understand the mechanism, several control and
isotopic labeling experiments were investigated (Scheme 5).
First, we carried out the reaction using 18O-labeled water
(Scheme 5a). The result showed that 18O was not incorporated
into the product, supporting the possible intramolecular acyl
transfer pathway. A D2O exchange experiment was then
performed under standard reaction conditions, and the D-
labeled product was detected (Scheme 5b). Considering that
the role of water may be to liberate small amounts of AcOH to
protonate intermediate D, we also employed a small amount of
AcOD to test the reaction (Scheme 5c). As expected, the D-
labeled product 4a″ was observed. In the meantime, the
deuterium-free product 4a was examined with 2.0 equiv of
D2O, and there was no H/D exchange product (Scheme 5d).
These obtained results provide evidence that the possible
protonation step is involved to generate intermediate E. When
isolated product 3a was used as the substrate under the
standard reaction conditions, there was no rearranged product
4a, but the known amide 6a was obtained in 36% yield.17 This
ruled out the possibility of the conversion of product 3a into 4a
(Scheme 4).
a
Unless otherwise noted, the reactions were carried out using 1 (0.20
mmol) and PIDA (0.40 mmol) in CH3CN (0.1 M, 2 mL) at room
temperature for 0.5−2.0 h in an open flask. Isolated yields are shown.
b
C
DOI: 10.1021/acs.orglett.8b00222
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Letter
Scheme 5. Mechanism Study
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge funding from the National
Natural Science Foundation of China (21502089), the Jiangsu
Province Funds Surface Project (BK 20161541), and the
Starting Funding of Research (39837107) from Nanjing Tech
University. We also thank the Jiangsu National Synergetic
Innovation Center for Advanced Materials for financial support
through a SICAM Fellowship. Dr. Li Yongxing (NTU) is
thanked for single-crystal X-ray diffraction analysis.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00222.
Experimental procedures and characterization data for
new compounds (PDF)
Accession Codes
CCDC 1519780 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, U.K.; fax: +44 1223 336033.
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Notes
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D
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