Palladium-Catalyzed Formal [4+2] Cycloaddition of Benzoic and Acrylic Acids with 1,3-Dienes via C—H Bond Activation: Efficient Access to 3,4-Dihydroisocoumarin and 5,6-Dihydrocoumalins

Article abstract of DOI:10.1002/cjoc.201800149

We report a palladium-catalyzed formal intermolecular [4+2] cycloaddition of benzoic and acrylic acids with 1,3-dienes including the stock chemicals 1,3-butadiene and isoprene leading to synthetically useful 3,4-dihydroisocoumarins and 5,6-dihydrocoumalins. Stepwise C—H bond cleavage and annulation are likely involved in the reaction pathway. The synthetic potential of the methodology was demonstrated by two short derivatizations and total synthesis of natural product Clausamine B.

Full text of DOI:10.1002/cjoc.201800149

Palladium-Catalyzed Formal [4+2] Cycloaddition of Benzoic and
Acrylic Acids with 1,3-Dienes via C-H Bond Activation: Efficient
Access to 3,4-Dihydroisocoumarin and 5,6-Dihydrocoumalins
Youwen Suna and Guozhu Zhang *,a
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Center for Excel-
lence in Molecular Synthesis, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Ling-
ling Road, Shanghai 200032, P. R. China
We report a palladium-catalyzed formal intermolecular [4+2] cycloaddition of benzoic and acrylic acids with
1,3-dienes including the stock chemicals 1,3-butadiene and isoprene leading to synthetically useful
3,4-dihydroisocoumarins and 5,6-dihydrocoumalins. Stepwise C-H bond cleavage and annulation are likely in-
volved in the reaction pathway. The synthetic potential of the methodology was demonstrated by two short derivat-
izations and total synthesis of natural product Clausamine B.
Keywords Palladium (II) • C-H bond activation • 1,3-diene • cycloaddition • natural product
appreciated by the research community over the past
decades.[3] In this context, Fujiwara–Moritani type/ lac-
tonization reactions of benzoic and acrylic acids with
Introduction
The 3,4-dihydroisocoumarin and 5,6-dihydrocoumalins
structural motifs are common in many pharmaceuticals,
natural products, and organic synthetic intermediates
(Scheme 1). Many of them have a broad spectrum of
biological activities (e.g., antifungal, antiallergenic, an-
ticancer, and antimalarial).[1] Common synthesis meth-
ods use annulation of preformed o-alkenylbenzoic acid
derivatives or o-halobenzoic acids that often require
multistep synthesis.[2] Therefore, the applicable and
simpler methods used to access these valuable molecu-
lar scaffolds from less expensive and more readily
available reagents are highly desired.
alkenes and alkynes have been significantly advanced
[8]
by Miura, [4] Ackermann, [5] Lee, [6] You, [7] Su,
and
others. With proper combination of substrates, catalysts
and oxidants, isocoumarin, 3-benzylidenephthalide,
α-pyrone, butenolide, and phthalide derivatives could be
readily accessed in a highly selective manner (Eqs 1-2).
While 1,3-diene has been frequently utilized in C-H
activation and functionalization,[9] the use of 1,3-diene
as a cyclization partner with benzoic acid en route to
3,4-dihydroisocoumarin and 5,6-dihydrocoumalins is
rare. One such example was reported by the Daugulis
group regarding cobalt-catalyzed 3,4-dihydro- isocou-
marin formation from benzoic acid and functionalized
1,3-dienes (Eq. 3).[10]
The 1,3-dienes and derivatives are readily available
material. Specifically, 1,3-butadiene is a feedstock with
an annual production scale of >10 million tons from
petroleum cracking.[11] The development of efficient
methods for the conversion of 1,3-butadiene to val-
ue-added fine chemicals continues to draw broad re-
search interests due to economic and environmental
benefits.[12] In our continuing efforts for selective di-
functionalization of 1,3-dienes,[13] we envisioned the
feasibility of a Pd-catalyzed C−H activation and cy-
clization between benzoic or acrylic acid and simple
1,3-dienes. Success of this hypothesis would be an al-
ternative approach to prepare 3,4-dihydro- isocoumarin
and 5,6-dihydrocoumalins.
O
O
O
MeO
O
OH
O
H
HO
OH
O
O
O
HN
HO
Me
H
H
Me
HO
OMe
clausamine B
agrimonolide
withanolide E
O
H
MeO
H
O
O
OH
HO
O
O
HO
HN
O
O
H
OH
H3C
H
O
COOH
talumarin A
longipedlactone C
claulamine A
Figure 1 Representative natural products.
Due to their broad availability and versatile reactivity,
the use of carboxylic acids as directing groups for C-H
functionalization has been increasingly recognized and
*
E-mail: Email address; Tel.: telephone number ((optional)); Fax: fax number ((optional))
Received ((will be filled in by the editorial staff)); accepted ((will be filled in by the editorial staff)); published online XXXX, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.2013xxxxx or from the author. ((Please delete
if not appropriate.)).
Dedicated to Professor Xiyan Lu on the Occasion of his 90th birthday
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201800149
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PdSO4 was the best catalyst of those tested,[14] and a
55% yield was observed (Table 1, entry 5). Further at-
tempts with other solvents used for Pd(II)-catalyzed
C−H functionalization reactions led to low reactivities
(Table 1, entries 6-7). The optimal temperature was
110°C—higher temperatures resulted in a lower yield
(Table 1, entry 8). Notably, increasing the ratio of acid
over diene improved the yields (Table 1, entries 9-10).
Finally, we emphasize that oxidants other than
Cu(OAc)2 performed less efficiently (Table 1, en-
tries11-12).
Previous work
:
O
O
O
Pd, Rh, Ru
oxidant
R3
R1
OH
OH
R1
R2
(1)
(2)
+
R2
H
O
R1
O
O
R1
O
Pd, Ru, Rh, Ir
O
R1
R4
R1
+
+
R4
oxidant
H
R4
R4 = Ar, COOEt
O
O
Co (10 mol%)
O
OH
(3)
+
Cu(OAc)2 (2 equiv.)
2 examples
This work:
O
O
H
Table 1 Optimization of the reaction conditions for the palla-
dium (II)-catalyzed [4+2] cycloaddition.
PdSO4 (10 mol%)
Cu(OAc)2 (2 equiv.)
O
OH
R2
R1
R1
(4)
+
R2
DMF, 110 oC, 24h
benzoic
acrylic acids
2 = H, alkyl, aryl
35 examples
yield: 24%- 95%
R
Herein, we report a palladium(II)-catalyzed formal [4+2]
cycloaddition of benzoic and acrylic acids with
1,3-dienes. Under these optimized conditions, benzoic,
or acrylic acids reacted efficiently with a broad range of
1,3-dienes including 1,3-butadiene and isoprene via a
tandem ortho C-H bond activation and annulation (Eq.
4). The synthetic potential of this method was demon-
strated in the total synthesis of natural product Clausa-
mine B in just five steps.
En-
trya
Catalyst
solvent Temp
(°C)
oxidant
Yield
(3a)
[%]b
1
Pd(OAc)2
Pd(TFA)2
PdCl2
DMF
DMF
DMF
110
110
110
110
110
110
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Ag2O
26
30
2
3
27
4
(PPh3)2PdCl2 DMF
35
5
PdSO4
PdSO4
PdSO4
PdSO4
PdSO4
PdSO4
PdSO4
PdSO4
DMF
Tol
55
Experimental
6
trace
30
In a glovebox, in a 10 mL tube with seal, anhydrous
palladium(II) sulfate (4.1 mg, 0.02 mmol), benzoic acid
(73.3 mg, 0.6 mmol), (E)-buta-1,3-dien-1-ylbenzene (2b)
(26 mg, 0.2 mmol), copper acetate (72.4 mg, 0.4 mmol)
were added in subsequently, then DMF (2 mL) was
added. The tightly sealed tube was put in an oil bath and
heated at 110 oC with stirring for 24 hours. After the full
consumption of diene, the reaction mixture was diluted
with ethyl acetate and the resulting suspension was fil-
tered through a pad of silica gel using ethyl acetate as
eluent. The filtrate was added to water (100 mL) and
then extracted with ethyl acetate (100 mL x 3). The
combined organic solution solution were washed with
brine and dried with anhydrous sodium sulfate. Then
filtered, evaporated in vacuum. The residue was purified
by chromatography using petroleum ether/ethyl acetate
(5/1) as eluent to give the desired product.
7
CH3CN 110
8
DMF
DMF
DMF
DMF
DMF
140
110
110
110
110
34
9c
10d
11
12
52
60
N.D.
trace
BQ
aUnless otherwise noted, reaction conditions were, 1,3-diene (0.2
mmol), 1a (2 equiv.), palladium salt (5 mol %), oxidant (2
equiv.), heated in solvent (0.2 M) at 110 °C for 24 h; bNMR yield
c
using diethyl phthalate as internal standard; 1/2 ratio was 1/1;
d1/2 ratio was 3/1
The substrate scope of the reaction was investigated
using the optimized conditions (Table 1, entry 10) (Ta-
bles 2, 3). In general, the use of unsubstituted, para-,
and ortho-substituted benzoic acids afforded
3,4-dihydroisocoumarins as single products. Benzoic
acids with electron-donating groups (EDGs such as
alkoxy, alkyl) and electron-withdrawing group (EWG
such as Ac) gave comparable yields. Interestingly, the
reaction of 3-ethylbenzoic acid provided mostly 3d in-
dicating that C−H cleavage on the benzoic acid ring
selectively occurred at the less hindered ortho site,
while 3f and 3g were obtained in 1/1 ratio. The reaction
can be extended to other aromatic acids. For instance,
1-naphthoic acid reacted to afford 3k in 60% yield. We
were pleased to find that the reaction of
1-cyclohexene-1-carboxylic acid proceeded efficiently
under standard conditions to afford a bicyclic product
3m in 63% yield. The cyclopent-1-enecarboxylic acid
Results and Discussion
We began our studies by exploring the reaction of ben-
zoic acid with (E)-buta-1,3-dien-1-ylbenzene; the rep-
resentative data are summarized in Table 1. When the
reaction was performed in the presence of Pd(OAc)2 (5
mol%) and Cu(OAc)2 (2.0 equiv.) in DMF at 110°C for
12 h, the envisioned [4+2] annulation product
(E)-3-styrylisochroman-1-one 3a was obtained in 26%
yield (Table 1, entry 1). The reactions were catalyzed by
many other Pd salts including Pd(TFA)2, PdCl2,
(PPh3)2PdCl2, etc., and these provided comparable re-
sults (Table 1, entries 2-5). To our surprise, an unusual
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pent-1-enecarboxylic acid (3ae). Dienes with aliphatic
substitution were coupling partners as well—the corre-
sponding products were obtained in moderate yields
(3af-3ah). Finally, 1,2-disubstituted 1,3-diene was ap-
plicable to the current reaction conditions indicating this
protocol tolerated extra steric congestion (3ai).
also reacted to provide the desired product 3n albeit in
relatively low yield. We also found that a naturally oc-
curring citronellic acid was compatible under current
reaction conditions, giving product 3o in 80% yield.
Besides the cyclic acrylic acid, other α-substituted
acrylic acids with various combination of
β-substitutions were suitable substrates as well leading
to products 3p-3s from low to excellent yields.
Table 3 Scope studies: different dienes a, b
Table 2 Scope studies: different carboxylic acid.a, b
aUnless otherwise noted, the reaction was carried out under these
optimized conditions (Table 1, entry 10). bisolated yield. cratio of
diene and acid is 1:1.
O
Cu(II)
O
O
Pd(0)
Cu(I)
Ph
O
H
OH
Pd(II)
athe reactions were carried out under these optimized conditions
(Table 1, entry 10). bisolated yield.
O
Pd(II)
Ph
AcOH
O
D
We note that the α-substitution is crucial to the success
of this chemistry—neither cinnamic acid nor acrylic
acid provides any product at all. In these two cases, the
starting material remains intact suggesting that the rigid
conformation is maintained by the α-substitution and is
essential for the C-H activation. In addition, strongly
electron withdrawing groups such as CF3O and NO2,
either decreased the product yield (3ai) or shut down the
reaction.
OPdL3
O
H
A
O
PdL2
O
Ph
O
AcOH
C
PdL2
B
Ph
Scheme 1 Proposed catalytic cycle
We then turned our attention to the variations on
1,3-diene partners. Feedstock 1,3-butadiene and iso-
prene were successfully engaged in this 4+2 cycloaddi-
According to previous studies and our observations, we
propose a stepwise reaction mechanism (Scheme 1).
First, heating the palladium catalyst with acid is likely
to form a palladium acetate complex A. This can then
undergo the well-known cyclometallation with ortho
C-H bond to give palladacycle B and liberating one
equivalent of acid.[6] Migratory insertion of the
1,3-diene 2a with B can then occur to give a new pal-
ladacycle C containing a π-allylpalladium species in an
equilibrium form.[9e] An inner sphere C–C
bond-forming reductive elimination of favored D pro-
vides the lactone 3a and the palladium(0) species.[9f]
tion
with
citronellic
acid
and
(E)-2-methyl-3-phenylacrylic acid to give the desired
products in moderate yields (3t-3v). Benzene on
(E)-buta-1,3-dien-1-ylbenzene could be freely function-
alized with fluoro and methoxy groups without impact-
ing the efficiency (3w-3z). An even better substrate for
this chemistry was buta-1,3-diene- 1,1-diyldibenzene
because these reactions with four representative acids
proceeded cleanly to provide the products in over 90%
yields (3aa-3ad); moreover, a moderate 65% yield was
achieved from the reaction with challenging cyclo-
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These then undergo oxidation by Cu(OAc)2 to regener-
ate palladium(II) to initiate a new catalytic cycle.
and acrylic acids to form 3,4-dihydroisocoumarin and
5,6-dihydrocoumalins in moderate to excellent yields.
The synthetic potential of this protocol was demon-
strated via several easy derivatizations of the products
and was further showcased in the short synthesis of nat-
ural product Clausamine B.
This series of 6-allyl-5,6-dihydro-2H-pyran-2-ones are
synthetically versatile building blocks due to the pres-
ence of several different functional groups for further
elaborations (Scheme 2). For example, reduction of the
ketone in 2a produced the corresponding hemiacetal 4a
in 80% yield as a single diastereomer. Treatment of 4a
with BF3-Et2O followed by Zn(Me)2 provided tetrasub-
stituted dihydropyran 5a.[15] An SN2’ addition of organo
copper(I) reagent with 3a, 3u at the terminal carbon of
the double bond resulting in the ring opening and formal
1,4 difunctionalization of the original 1,3-butadiene.[16]
Acknowledgement
We are grateful to NSFC-21772218, 21421091,
XDB20000000, the “Thousand Plan” Youth program,
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, and the Chi-
nese Academy of Sciences.
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Scheme 2 Synthetic utilities of lactone products.
The total synthesis of Clausamine B was pursued to
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Scheme 3 Total synthesis of Clausamine B
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Entry for the Table of Contents
Page No.
O
O
H
PdSO4 (10 mol%)
O
Cu(OAc)2 (2 equiv.)
OH
R2
R1
R1
+
R2
DMF, 110 oC, 24h
benzoic
acrylic acids
R2 = H, alkyl, aryl
35 examples
yield: 24%- 95%
O
O
Palladium-Catalyzed [4+2] Cyclo-
addition of Benzoic and Acrylic
Acids with 1,3-Dienes via C-H
Bond Activation: Efficient Access
to 3,4-Dihydroisocoumarin and
5,6- Dihydrocoumalins
O
O
OH
NH
standard conditions
48%
O
N
H
Clausamine B
Text for Table of Contents: We report a palladium-catalyzed formal intermolecular
[4+2] cycloaddition of benzoic and acrylic acids with 1,3-dienes including the stock
chemicals 1,3-butadiene and isoprene leading to synthetically useful
3,4-dihydroisocoumarin and 5,6-dihydrocoumalins. Stepwise C-H bond cleavage and
annulation are likely involved in the reaction pathway. The synthetic potential of the
methodology was demonstrated by two short derivatizations and total synthesis of nat-
ural product Clausamine B.
Youwen Sun; Guozhu Zhang*
This article is protected by copyright. All rights reserved.