Recyclable Hypervalent-Iodine-Mediated Dehydrogenative α,β′-Bifunctionalization of β-Keto Esters under Metal-Free Conditions

Article abstract of DOI:10.1002/chem.201502450

We have developed a method for recyclable hypervalent-iodine-mediated direct dehydrogenative α,β′- bifunctionalization of β-ketoesters and β-diketones under metal-free conditions, which affords a straightforward way to synthesize benzo-fused 2,3-dihydrofurans. This efficient, mild method, which has a wide substrate scope and good functional-group tolerance, was used for the multistep synthesis of the protected aglycone of a naturally occurring phenolic glycoside. A mechanism involving Michael addition to an enone intermediate and subsequent oxidative cyclization is proposed.

Full text of DOI:10.1002/chem.201502450

DOI: 10.1002/chem.201502450
Full Paper
&
Organic Synthesis
Recyclable Hypervalent-Iodine-Mediated Dehydrogenative a,b’-
Bifunctionalization of b-Keto Esters Under Metal-Free Conditions
Ya-Nan Duan, Li-Qian Cui, Lin-Hong Zuo, and Chi Zhang*[a]
Abstract: We have developed a method for recyclable
hypervalent-iodine-mediated direct dehydrogenative a,b’-
bifunctionalization of b-ketoesters and b-diketones under
metal-free conditions, which affords a straightforward way
to synthesize benzo-fused 2,3-dihydrofurans. This efficient,
mild method, which has a wide substrate scope and good
functional-group tolerance, was used for the multistep syn-
thesis of the protected aglycone of a naturally occurring
phenolic glycoside. A mechanism involving Michael addition
to an enone intermediate and subsequent oxidative
cyclization is proposed.
Introduction
bond. Dehydrogenative b-functionalization of saturated car-
bonyl compounds usually requires a transition-metal catalyst,
such as palladium[4] or nickel,[5] and metal-free examples are
rare.[6] In addition, regioselective coupling at the b-position is
a challenge, especially for carbonyl compounds with multiple
reactive sites. Not surprisingly, there are few reports on the de-
hydrogenative b’-functionalization of b-keto esters. In 2012,
Pihko et al. reported the first oxidative coupling of a-substitut-
ed b-keto esters at the b’-position with indoles or other elec-
tron-rich arenes (Scheme 2a);[7] the a-positions of the sub-
strates remained untouched. We wondered whether we could
access a,b’-bifunctionalized products by one-step, metal-free
dehydrogenative bifunctionalization of b-keto esters. To our
knowledge, this reaction, which could be used to efficiently
construct complex organic molecules, remains unexplored.
2,3-Dihydrofurans are widely present in biologically active
natural products[8] and are also useful building blocks in
organic synthesis.[9] Numerous synthetic methods have been
developed,[10] most of which start from unsaturated carbonyl
compounds or alkenes. To our knowledge, 2,3-dihydrofurans
have never been synthesized by metal-free dehydrogenative
bifunctionalization of saturated b-keto esters. Herein, as part of
our ongoing work on oxidation reactions induced by hyper-
valent iodine reagents[11] and on the reactivity of AIBX (5-tri-
methylammonio-1,3-dioxo-1,3-dihydro 1l5benzo[d][1,2]iodoxol-
1-ol anion), a reagent developed by our group,[11i] we report
the construction of 2,3-dihydrofurans by AIBX-mediated dehy-
drogenative a,b’-bifunctionalization of saturated b-keto esters
(Scheme 2b).
Transformations of carbonyl compounds play a pivotal role in
organic synthesis. The partially positively charged carbonyl
carbon atom usually acts as an electrophile,[1] whereas the
a carbon atom always acts as a nucleophile (Scheme 1a,b);[2]
Scheme 1. Functionalization of carbonyl compounds.
therefore, different functional groups can be installed at the
two positions. Recently, catalytic functionalization at the usual-
ly unreactive b-carbon atom of saturated carbonyl compounds
has attracted attention (Scheme 1c)[3] as a method for directly
and efficiently converting the b-CÀH bond to a CÀC or CÀX
Results and Discussion
[a] Y.-N. Duan, L.-Q. Cui, L.-H. Zuo, C. Zhang
State Key Laboratory of Elemento-Organic Chemistry
Collaborative Innovation Center of Chemical Science and Engineering
Nankai University, Tianjin 300071 (P. R. China)
E-mail: zhangchi@nankai.edu.cn
First, we optimized the reaction conditions (Table 1). Reaction
of tert-butyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate (1)
with dimedone (2, 2.5 equiv) and AIBX (2.5 equiv) in a homoge-
nous solution of diglyme and water at 408C afforded desired
product 3a in 82% yield within 3 h (Table 1, entry 1). The cis
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502450.
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role of AcOH in reactions with a decreased dime-
done load. A homogenous solution of CH3CN and
water was the best reaction medium (entries 3–12),
giving 3a in 93% yield (entry 7). Compared with
AcOH (pKa =4.7), CF3CO2H (pKa =À0.25) and NH4Cl
(pKa =9.24) gave only moderate yields of 3a (en-
tries 13 and 14). The amount of AcOH could be re-
duced to 1.0 equivalent with almost no decrease in
the yield of 3a (entry 15), but the yield dropped
slightly when the amount was further reduced to
0.5 equivalents (entry 16). Use of 2-iodoxybenzoic
acid, the parent of AIBX, as the oxidant sharply de-
creased the yield of 3a (22%), which highlighted
the different reactivities of these two reagents
(entry 17). Dess–Martin reagent, another hypervalent iodine(V)
agent, was also inferior to AIBX in this reaction (entry 18). Nei-
ther phenyliodine(III) diacetate (PIDA) nor phenyliodine(III) bis-
(trifluoroacetate) (PIFA) were able to afford the desired dihy-
drofuran product (entries 19 and 20). Other oxidants, such as
2,3-dichloro-5,6-dicyano-1,4-benzoquinone and cerium ammo-
nium nitrate, were inferior to AIBX (entries 21 and 22). Our op-
timization experiments indicated
Scheme 2. Regioselective b’- and a,b’-functionalization of b-keto esters.
relationship between H9 and the ester group was confirmed
by X-ray crystallography (Figure 1).[12] Reducing the amount of
dimedone to 1.5 equivalents decreased the yield of 3a and re-
sulted in the formation of an undesired product of homocou-
pling of 1 in 8% yield (entry 2). However, the addition of AcOH
(1.5 equiv) suppressed the homocoupling reaction and 3a was
obtained in 82% yield (entry 3), which indicated the crucial
that an oxidative system consist-
Table 1. Optimization of reaction conditions.
ing of 2.5 equiv of AIBX and
1.0 equiv of AcOH in 1:3 (v/v)
CH3CN/water at 408C was opti-
mal (entry 15).
We next investigated the gen-
erality of the reaction by using
various b-keto esters and a b-di-
Entry
2 [equiv]
Additive [equiv]
Solvent
t [h]
Yield [%][a]
ketone as substrates (Scheme 3).
Substrates with small ester
groups, ethyl and benzyl, afford-
ed the corresponding products
3b and 3c (85 and 83%, respec-
tively). b-Keto esters with elec-
tron-donating or -withdrawing
groups on the phenyl ring were
smoothly bifunctionalized by
the AIBX-mediated reaction, af-
fording the expected products
in good to excellent yields (3d–
l), which suggests that the elec-
tronic properties of the phenyl
ring had little influence on the
reaction. The halogen atoms on
the phenyl rings can serve as
handles for increasing molecular
complexity by means of well-de-
1
2
3
4
5
6
7
8
2.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
None
None
diglyme
diglyme
diglyme
1,4-dioxane
THF
3
3
1.1
2
3
1.5
1.3
1.3
1.3
2.5
7
82
66 (8)
82
85
83
86
93
89
87
AcOH (1.5)
AcOH (1.5)
AcOH (1.5)
AcOH (1.5)
AcOH (1.5)
AcOH (1.5)
AcOH (1.5)
AcOH (1.5)
AcOH (1.5)
AcOH (1.5)
CF3CO2H (1.5)
NH4Cl (1.5)
AcOH (1.0)
AcOH (0.5)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
glyme
MeCN
tBuOH
acetone
DMSO
EtOAc
H2O alone
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
benzene
MeCN
9
10
11
12
13
14
15
16
17[c]
18[d]
19[e]
20[g]
21[h]
22[i]
80
31[b]
36[b]
60
3
1.5
2.5
2
2.5
2.5
2
58 (34)
92
86
22
38
ND[f]
ND[f]
ND[f]
ND[f]
2
0.5
1.5
5
veloped
transition-metal-cata-
[a] Isolated yields; yields in parentheses are for the homocoupling product. [b] With 33% recovery of 1. [c] 2-Io-
doxybenzoic acid was used as oxidant with the isolation of the corresponding a-hydroxylation product, tert-
butyl 2-hydroxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, in 9% yield. [d] Dess–Martin reagent was used as
oxidant; a-hydroxylation product, tert-butyl 2-hydroxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate, was isolated
in 22% yield. [e] PIDA was used as the oxidant; 1 was recovered in 12% yield with 12% a-hydroxylation prod-
uct. [f] Not detected. [g] PIFA was used as the oxidant; 1 was recovered in 42% yield with 54% a-hydroxylation
product. [h] 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone was used as oxidant; 1 was recovered in 35% yield.
[i] Cerium ammonium nitrate was used as the oxidant; 1 was recovered in 50% yield. PIDA=phenyliodine(III)
diacetate; PIFA=phenyliodine(III) bis(trifluoroacetate).
lyzed coupling reactions. Note
that the clean formation of 3k
and 3l (90 and 85%, respective-
ly) shows that the ortho methyl
and bromo substituents did not
sterically hinder the coupling re-
action. Substrates with a naph-
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tion of 3,5-di(methoxymethoxy)phenol, an electron-rich
phenol, with the b-diketone 2-acetyl-2,3-dihydro-1H-inden-1-
one afforded the desired dihydrofuran framework, providing
access to a 5a,10b-dihydro-6H-indeno[2,1-b]benzofuran-6-one
moiety.
Because AIBX is highly water soluble (0.38m), it can be
regenerated (92%) after the reaction by 1) removal of the
organic components by extraction with EtOAc, 2) evaporation
of the aqueous phase to give reduced AIBX, and 3) oxidation
of the reduced AIBX with dimethyl dioxirane.[11i]
To investigate the reaction mechanism, we performed the
following control experiments. When enone A, the product of
dehydrogenation of 1, was synthesized[13] and subjected to the
standard reaction conditions (amount of AIBX used was
Figure 1. Crystal structure of 3a with 50% ellipsoid probability.
thalene ring and a thiophene
moiety, both of which are readi-
ly oxidizable, were compatible
with the reaction conditions,
providing 3m and 3n (72 and
78%, respectively). 2-Acetyl-2,3-
dihydro-1H-inden-1-one, a b-di-
ketone, afforded 3o (67%).
We also investigated reactions
of other activated methylene
compounds with b-keto ester
1 and the reaction of an elec-
tron-rich phenol with the b-dike-
tone
2-acetyl-2,3-dihydro-1H-
inden-1-one (Scheme 4). When
dimedone was replaced with cy-
clohexane-1,3-dione, 4a was ob-
tained in 85% yield. Reaction of
acetoacetone (2 equiv), an acy-
clic b-diketone, afforded desired
product 4b (80%). Unexpected-
ly, uncyclized product 4c (75%)
was obtained from the reaction
of benzoylacetone. This out-
come suggests stepwise forma-
tion of the CÀC and CÀO bonds,
with the CÀC bond forming
before the CÀO bond. Reaction
of 1 and 6,6-dimethyldihydro-
2H-pyran-2,4(3H)dione afforded
constitutional isomers 4d and
4d’ (75% total yield), which in-
dicated that both enol forms
from ketone and ester moiety in
6,6-dimethyldihydro-2H-pyran-
2,4(3H)dione were involved in
the formation of the CÀO bond.
Similar results were observed for
the reaction of 1 and coumarin,
which afforded 4e and 4e’
(57% total yield). Notably, reac-
Scheme 3. Substrate scope. [a] 2.0 equiv of dimedone. [b] 8 mL of 1:1 (v/v) CH3CN/H2O.
Scheme 4. Reactions of activated methylene compounds. [a] 2.0 equiv acetoacetone; product of homocoupling of
1 was isolated in 8% yield. [b] 2.0 equiv of 2-acetyl-2,3-dihydro-1H-inden-1-one reacted with 3,5-di(methoxy
methoxy)phenol.
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outlined in Scheme 6. First, de-
hydrogenation of
1
affords
enone A, which undergoes Mi-
chael addition with dimedone
to produce adduct B. In the
presence of AcOH, fully enolized
intermediate B reacts with resid-
ual AIBX to form complex C. Re-
moval of a water molecule from
C to generate complex D and
subsequent collapse of D result
in the formation of benzo-fused
dihydrofuran 3a accompanied
by liberation of an iodine(III)
species, AIBA.
To investigate the utility of
this method, we synthesized the
protected aglycone of natural
product I called in its original
report (Figure 2), a phenolic gly-
coside isolated from Kaempferia
parviflora[14] (Scheme 7).
Scheme 5. Mechanistic experiments.
Knoevenagel condensation of
aldehyde 5 with malonic acid
and subsequent catalytic hydro-
genation and intramolecular
Friedel–Crafts acylation fur-
nished 5-hydroxy-6-methoxy-1-
indanone 8 (80% over three
steps). Treatment of
8 with
acetic anhydride in the presence
of aqueous HClO4 at room tem-
perature resulted in double ace-
tylation of 8 to provide b-dike-
tone 9 (63%), a 2-acetyl-2,3-di-
hydro-1H-inden-1-one
deriva-
tive. The key dehydrogenative
a,b’-bifunctionalization of 9 af-
forded desired coupling prod-
ucts 10 and 11 (41% combined
yield). Partial deacetylation of 10
under acidic conditions generat-
ed 11. Compound 12 was pro-
duced by deprotection of the
acetyl
and
methoxymethyl
Scheme 6. Proposed mechanism of AIBX-mediated a,b’-bifunctionalization of a b-keto ester.
groups of 10 and 11. Subse-
quent benzoylation of 12 pro-
vided 13 (62%), the structure of
1 equiv less than the usual amount of 2.5 equiv), 3a was ob-
tained (69%, Scheme 5), which suggests that A is an inter-
mediate. Enone A reacted with dimedone to yield Michael
adduct B (88% yield) under the standard reaction conditions,
except for the absence of AIBX (Scheme 5b). When B was
treated with 1.5 equivalents of AIBX (Scheme 5c), 3a was ob-
tained (67%), which indicates the intermediacy of B.
On the basis of the above-described results and our previ-
ous work on AIBX-mediated dehydrogenation reactions of
cyclic b-dicarbonyl compounds,[11i] we propose the mechanism
Figure 2. Phenolic glycoside natural product I.
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dimedone (42 mg, 0.3 mmol) in 1:3
(v/v) CH3CN/water (5.3 mL). The re-
action mixture was heated to 408C
with stirring and monitored by TLC
analysis. After 1 was consumed, the
reaction mixture was allowed to
cool to room temperature and ex-
tracted with EtOAc (3”50 mL). The
combined organic layers were
washed with brine and dried over
anhydrous MgSO4. The solvent was
evaporated, and the residue was
purified by column chromatogra-
phy to afford 3a in 92% yield
(68 mg).
Acknowledgements
This work was financially sup-
ported by The National Natural
Science Foundation of China
(21172110,
21421062) and the Tianjin Natu-
ral Science Foundation
21472094,
and
Scheme 7. Synthesis of the aglycone of I. a) malonic acid (1.5 equiv), piperidine, pyridine, reflux, 98%; b) H2, Pd/
C, EtOAc/methanol, 94%; c) TfOH, 08C–RT, 87%; d) HClO4, acetic anhydride, CCl4, 63%; e) AIBX (2.5 equiv),
Cl2CHCO2H (1 equiv), 3,5-di(methoxymethoxy)phenol, CH3CN/H2O, 41% (combined yield); f) 3n HCl (20 equiv),
MeOH, reflux, 81%; g) BzCl (6 equiv), Et3N (6 equiv), THF, 62%; h) mCPBA (16.2 equiv), NaHCO3 (32.4 equiv),
CH2Cl2, 41%. mCPBA=meta-chloroperbenzoic acid.
(09JCYBJC05900). We thank Mr.
Z.-L. Dong for assistance with the
preparation of several substrates.
which was confirmed by X-ray crystallography.[15] Finally, Bayer–
Villiger oxidation of 13 afforded 14 (41%); note that the ben-
Keywords: AIBX
functionalization · metal-free synthesis · reaction mechanism
·
carbonyl groups
·
dehydrogenative
zoyloxy group was essential for this oxidation step. Thus,
a straightforward multistep synthesis of the protected agly-
cone of I was accomplished in an overall yield of 4.3% by
means of our a,b’-bifunctionalization method as the key step.
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Conclusion
In summary, we have developed a method for a,b’-bifunction-
alization of b-keto esters by direct, metal-free dehydrogenative
functionalization of two CÀH bonds mediated by AIBX. The
synthetic potential of this method was demonstrated by the
rapid construction of 2,3-dihydrofurans from various b-dicar-
bonyl compounds and activated methylene compounds or
electron-rich phenol nucleophiles. The method was used to
synthesize the protected aglycone of a natural product. Mech-
anistic studies revealed that the reaction involved enone A,
which underwent Michael addition and subsequent oxidative
intramolecular cyclization to give the desired product. Efforts
to improve our understanding of the mechanism of the
reaction and its applications to natural product synthesis are
ongoing.
Experimental Section
Typical procedure for AIBX-mediated dehydrogenative a,b’-
bifunctionalization of b-keto esters
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[12] X-ray diffraction data were collected on a Bruker SMART-1000 CCD dif-
fractometer. Crystal data for 3a (C22H24O5): Mr =368.41; colorless; T=
293 K, 0.30”0.10”0.10 mm3; monoclinic; space group P2; l=
0.71073 Š; a=6.1369(12), b=30.737(6), c=10.545(2) Š; a=90.00, b=
92.98(3), g=90.008; V=1986.5(7) Š3; Z=4; 1calcd =1.232 gcmÀ3
0.087 mmÀ1
unique reflections=4565; R1 =0.0451, wR2 =0.0835.
; m=
;
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CCDC 900957 contains the supplementary crystallographic data for this
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b=71.65 (3), g=65.53(3)8; V=1520.5(5) Š3; Z=2; 1calcd =1.430 gcmÀ3
m=0.104 mmÀ1
reflections collected/unique=14144/6835; R(int)=
;
;
0.0406, R1 =0.0430, wR2 =0.1021 (I>2sI); GOF=1.022. CCDC 1055772
contain the supplementary crystallographic data for this paper. These
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graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Received: June 25, 2015
Published online on July 27, 2015
Chem. Eur. J. 2015, 21, 13052 – 13057
www.chemeurj.org
13057
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