Synthesis of Functionalized Benzofurans from para-Quinone Methides via Phospha-1,6-Addition/ O-Acylation/Wittig Pathway

Article abstract of DOI:10.1021/acs.orglett.9b03001

An efficient synthesis of functionalized benzofurans is achieved under mild and metal-free conditions from stable para-quinone methides by treatment with phosphine, acyl chloride, and a base. This one-pot phospha-1,6-addition/O-acylation/Wittig reaction i

Full text of DOI:10.1021/acs.orglett.9b03001

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Functionalized Benzofurans from para-Quinone
Methides via Phospha-1,6-Addition/O‑Acylation/Wittig Pathway
Yan-Cheng Liou,† Praneeth Karanam,† Yeong-Jiunn Jang,‡ and Wenwei Lin*,†
†Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei 11677, Taiwan, R.O.C.
‡Chinese Medicine Research and Development Center, China Medical University Hospital, 2, Yuh-Der Road, Taichung 40447,
Taiwan, R.O.C.
S
* Supporting Information
ABSTRACT: An efficient synthesis of functionalized benzofurans is
achieved under mild and metal-free conditions from stable para-quinone
methides by treatment with phosphine, acyl chloride, and a base. This
one-pot phospha-1,6-addition/O-acylation/Wittig reaction is also
demonstrated under catalytic conditions with similar efficacy.
n recent times, p-quinone methides (p-QMs) have been
could further participate in a Wittig reaction. This strategy has
been well-explored by our group in the recent past for the
generation of diverse heterocycles/heteroaromatics.6 Despite
the reactivity of p-QMs, we were surprised to see that the
application of the p-QMs in the phosphine-mediated reactions
has scarcely been explored.5h Therefore, in continuation of our
interest in developing novel strategies for the generation of
phosphorus ylides/phosphonium salts and their application
toward the synthesis of various heterocycles/heteroaromatics
via intramolecular Wittig reactions, we hoped to exploit the
electrophilicity of these p-QMs by subjecting them to tandem
phospha-Michael and intramolecular Wittig reactions. We plan
to start with a stable and well-explored p-QM bearing a
hydroxyl group. The proposed phospha-Michael reaction
would involve 1,6-addition of R3P to p-QM leading to
aromatization of the quinone. The suitably placed hydroxyl
group in the resultant phosphonium zwitterion would then be
acylated with various carbonyl electrophiles to result in
acylated species that would eventually be subjected to
intramolecular Wittig reaction to afford 3-arylbenzofurans,
which are considered as privileged heterocyclic scaffolds.7 In
this context, we report an efficient synthesis of functionalized
benzofurans from the p-QMs bearing an ortho-hydroxy group
through a 1,6-phospha-Michael addition/O-acylation/Wittig
pathway under mild and metal-free conditions.
I
subjected to extensive investigation for their interesting
chemical and biological properties.1,2 A typical reaction of p-
QMs involves rearomatization via nucleophilic addition by a
variety of carbon nucleophiles3 such as malonates, oxindoles,
dicyanoolefins, imines, etc. (Scheme 1). Furthermore, ortho-
Scheme 1. Typical Reactivity Profile of p-QMs (a) and Our
Phospha-Michael/O-Acylation/Wittig Reaction (b)
We initiated our studies by treating the stable p-QM 1a with
PPh3 and PhCOCl, in the presence of Et3N, in THF at room
temperature. The reaction was not fruitful, as no consumption
of starting material was noticed even after 4 h (Table 1, entry
1). We then examined several other phosphines and discovered
that Et2PPh and PBu3 were efficient in promoting our expected
tandem phospha-Michael/O-acylation/Wittig reaction to
deliver the desired benzofuran 3aa in 85% and 95% yields,
hydroxyphenyl substituted p-QMs could also participate in
cycloaddition reactions as a four-atom partner in diverse [4 +
n] cycloadditions with various coupling partners to generate
five-, six-, or seven-membered rings.4 However, to the best of
our knowledge there are a few reports regarding the 1,6-
addition of p-QMs by noncarbon nucleophiles.5
On the other hand, tertiary phosphines, being very good
nucleophiles, could generally add onto a wide variety of
Michael acceptors and the resultant phosphonium zwitterion
could be effectively trapped by a carbonyl electrophile that
Received: August 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03001
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization of the Reaction Conditions for 3aa
Scheme 2. Substrate Scope of Benzofurans 3
b
entry
PR3
base
solvent
t (h)
3aa, yield (%)
c
1
2
3
4
5
6
7
8
9
10
11
12
13
PPh3
PCy3
PEtPh2
PEt2Ph
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DBU
TMG
Et3N
Et3N
Et3N
Et3N
THF
THF
THF
THF
THF
CH2Cl2
Et2O
4
6
6
6
4
7
3
3
3
6
3
4
3
1
3
NR
NR
NR
85
95
−
98
85
98
60
51
95
44
93
98
c
c
ClPh
toluene
toluene
toluene
toluene
toluene
toluene
toluene
d
e
df
,
14
15
dg
,
a
Unless otherwise specified, all the reactions were carried out using 1a
(0.1 mmol), PR3 (1.2 equiv), PhCOCl (1.1 equiv), and base (2.4
b
1
equiv) in anhydrous solvent (0.5 mL) at 30 °C. Determined by H
NMR analysis of crude reaction mixture using 1,3-dinitrobenzene as
an internal standard. NR = no reaction and starting metrials could be
recovered. 1.2 equiv of Et3N was used. 0.5 equiv of Et3N was used.
Reaction was performed at 50 °C. Reaction was carried out on 0.3
c
d
e
f
g
mmol scale in toluene (0.75 mL).
respectively (entries 4 and 5). Encouraged by these results,
different solvents (entries 6−9) were screened. It was
delightful to find that Et2O and toluene were most suitable
to furnish the benzofuran 3aa in 98% yield. Bases such as DBU
and TMG were also tested (entries 10 and 11), and they could
not enhance the yield of 3aa. After the effect of other
parameters such as molar equivalents of Et3N, reaction
concentration, and temperature was examined, the optimal
conditions were selected to be 0.3 mmol of 1a, 1.2 equiv of
PBu3, 1.1 equiv of PhCOCl (2a), and 1.2 equiv of Et3N in 0.75
mL of toluene at 30 °C.
With the optimal conditions for the formation of benzofuran
3aa established, the substrate scope was then evaluated
(Scheme 2). First, various acyl chlorides 2a−2l were subjected
to a reaction with the p-QM 1a. It was interesting to note that
all the aromatic acyl chlorides, irrespective of their electronic
nature, afforded the desired benzofurans 3aa−3al in good to
excellent yields. Also, the positional effect of the substituents in
the aromatic acyl chlorides did not influence the yield of the
products. However, the aromatic acyl chlorides 2f and 2g
bearing p-CN and p-NO2 substitutions respectively resulted in
comparatively lower yields of the products 3af and 3ag even
after longer reaction times due to their poor solubility.
Delightfully, aliphatic acyl chloride such as n-butyl chloride
(2j) and heteroaromatic acyl chloride such as 2-thienyl
chloride (2k) were also applicable in the reaction to provide
the products 3aj and 3ak in good yields. Furthermore,
cinnamoyl chloride (2l) also participated in the reaction,
albeit providing a moderate yield of the benzofuran 3al. Next,
the scope of the differently substituted p-QMs was evaluated
a
Unless otherwise specified, all the reactions were carried out using 1
(0.3 mmol), PBu3 (1.2 equiv), R2COCl (1.1 equiv), and Et3N (1.2
equiv) in dry toluene (0.75 mL) at 30 °C under argon atmosphere.
b
c
Isolated yield. Rection was performed on the 1 mmol scale under
optimized reaction conditions.
and the data revealed that all the p-QMs generated diverse
benzofurans in good to excellent yields irrespective of the
nature and position of the substitution. Moreover, a naphthol
derived p-QM 1h was also subjected to our standard
conditions to generate naphtho(2,3-b)furan 3ha in 67%
yield. To demonstrate the synthetic utility of the protocol, a
1.0 mmol scale reaction was also carried out with the substrate
1a and 2a to result in 3aa in 93% yield.
After evaluation of the substrate scope, we also wished to
examine the effectiveness of our protocol by employing
catalytic phosphine. We have earlier reported a mild synthesis
of functionalized furans utilizing catalytic amounts of
phosphine oxide and Et3N. We demonstrated that TESCl
can promote the activation of the phosphine oxide 4, while
phenylsilane reduces the activated phosphine oxide to generate
free phosphine.8 Following our reported procedure, we carried
out the reaction of 1a with 2a in the presence of a catalytic
amount of 4 (10 mol %), TESCl (20 mol %), PhSiH3 (1.6
equiv), and Et3N in THF at 50 °C (Scheme 3). After 29 h, the
B
DOI: 10.1021/acs.orglett.9b03001
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis of Benzofurans 3 under Catalytic
Conditions
Scheme 5. Plausible Mechanism for the Formation of 3
a b
,
the desired benzofurans 3. The formation of intermediate C
from 1 via zwitterion A justifies the utility of only 1.2 equiv of
Et3N in promoting an O-acylation as well as a Wittig reaction.
Alternatively, phosphonium salt B from PBu3 and PhCOCl
reacts with p-QM 1 to form 5 in the presence of Et3N. Further
1,6-addition of PBu3 to 5 followed by proton trasfer and
intramolecular Wittig reaction leads to benzofuran 3 via ylide
D.
In conclusion, we have efficiently exploited the reactivity of
p-QMs to generate a series of benzofurans by employing a one-
pot sequential phospha-1,6-addition/O-acylation/Wittig reac-
tion. All the products have been obtained in good to excellent
yields under mild and metal-free conditions in short reaction
times. Further, we have also demonstrated the efficacy of our
protocol by employing catalytic phosphine. Further studies to
synthesize other heterocycles from p-QMs are currently
underway in our laboratory.
a
Unless otherwise specified, all the reactions were carried out using 1a
(0.3 mmol), 4 (10 mol %), TESCl (20 mol %), PhSiH3 (1.6 equiv),
R2COCl (1.1 equiv), and Et3N (1.2 equiv) in anhydrous THF (0.75
b
mL) at 50 °C under an argon atmosphere. Isolated yield.
desired benzofuran 3aa could be isolated in 92% yield.
Encouraged by the result, two other acyl chlorides 2b and 2i,
having an EWG and an EDG respectively, were tested under
the same conditions. Delightfully, the catalytic protocol
worked well in each case affording the corresponding products
in excellent yields (3ab, CCDC 1943703).
Several control experiments have been carried out to
understand the reaction pathway. Unfortunately, our efforts
to isolate the intermediates failed, but the formation of
intermediate A was confirmed by HRMS analysis of the
reaction of p-QM 1 and PBu3. Also, we have been able to
observe the formation of phosphonium salt 6 (CCDC
1952659) which is devoid of an acyl group. We believe that
this might be formed from the intermediate C.9 However,
reversing the addition sequence like PBu3 and PhCOCl to p-
QM 1 in the presence of Et3N also provided the benzofuran 3
in similar yields. It indicates p-QM 1 exhibits more affinity
toward PBu3 irrespective of the addition sequence which
makes our reaction conditions more convenient. We have also
carried out the reaction with p-QM 1a and PhCOCl in the
presence of Et3N in CH2Cl2. The acylation of p-QM 5 was
observed with a 96% yield within 0.5 h. Compound 5 further
afforded the desired product 3aa in 98% yield by using the 1.2
equiv of PBu3 without a base (Scheme 4).
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.9b03001.
Experimental procedures, characterization data, and
spectra of all compounds (PDF)
Accession Codes
CCDC 1943703 and 1952659 contain 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
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 4. Synthesis of Benzofuran via Compound 5
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wenweilin@ntnu.edu.tw.
ORCID
Praneeth Karanam: 0000-0003-3982-3525
Wenwei Lin: 0000-0002-1121-072X
Notes
A tentative mechanism as depicted in Scheme 5 could be
considered for the formation of benzofurans 3. The addition of
phosphine and PhCOCl to the p-QM 1 results in the
formation of O-acylated phosphonium salt species C, via the
zwitterionic species A which is equilibrium with p-QM 1. The
catalytic amount of PBu3 would form phosphonium salt B with
an acyl chloride to accelerate the O-acylation reaction.10
Deprotonation of C by Et3N generates reactive phosphorus
ylide D which upon intramolecular Wittig reaction furnishes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Ministry of Science and Technology of
the Republic of China (MOST 107-2628-M-003-001-MY3)
for financial support.
C
DOI: 10.1021/acs.orglett.9b03001
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Organic Letters
Letter
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DOI: 10.1021/acs.orglett.9b03001
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