Direct Annulation between Aryl Iodides and Epoxides through Palladium/Norbornene Cooperative Catalysis

Article abstract of DOI:10.1002/anie.201712393

Herein we report a direct annulation between aryl iodides and epoxides through palladium/norbornene (Pd/NBE) cooperative catalysis. An iso-propyl ester substituted NBE was found to be most efficient to suppress the formation of multiple-NBE-insertion byproducts and affords the desired 2,3-dihydrobenzofuran derivatives in 44–99 % yields. The reaction is scalable and tolerates a range of functional groups. Asymmetric synthesis is realized using an enantiopure epoxide. Application of this method into a concise synthesis of insecticide fufenozide is demonstrated.

Full text of DOI:10.1002/anie.201712393

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Accepted Article
Title: Direct Annulation between Aryl Iodides and Epoxides via
Palladium/Norbornene Cooperative Catalysis
Authors: Renhe Li and Guangbin Dong
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712393
Angew. Chem. 10.1002/ange.201712393
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10.1002/anie.201712393
Angewandte Chemie International Edition
COMMUNICATION
Direct Annulation between Aryl Iodides and Epoxides via Palladi-
um/Norbornene Cooperative Catalysis
Renhe Li and Guangbin Dong*
Abstract: Herein we report a direct annulation between aryl iodides
and epoxides via palladium/norbornene (Pd/NBE) cooperative
catalysis. An iso-propyl ester-substituted NBE was found most
efficient to suppress formation of multi-NBE-insertion by-products
and afford the desired 2,3-dihydrobenzofuran derivatives in 44−99%
yields. The reaction is scalable, and tolerates a range of functional
groups. Asymmetric synthesis is realized using an enantiopure
epoxide. Application of this method into a concise synthesis of
insecticide fufenozide is demonstrated.
Pd/NBE catalysis, namely Catellani reaction, has recently
emerged as a powerful approach for vicinal bis-functionalization
of arenes.[5] Using simple aryl iodides as substrates, a number of
nucleophiles and electrophiles have been coupled at the ipso
and ortho positions respectively through selective reactions with
the aryl-NBE-palladacycle (ANP) intermediate (Fig. 2).[6-10] In
particular, Lautens and coworkers have developed a suite of
elegant annulation methods through tethering an electrophile
with a nucleophile for synthesis of various benzo-fused rings.[11]
a. examples of known approaches
2,3-Dihydrobenzofuran (DHBF) moiety is frequently found in
pharmaceuticals and agrochemicals (Fig. 1).[1] While a number
of methods are available for its synthesis, only a few can directly
give DHBFs from simple starting materials.[2] For example,
DHBFs can be synthesized via a sequence of ortho-allylation of
phenols and then hydroalkoxylation,[3] in which strong bases
and/or acids are used (Scheme 1a). A (3+2) coupling between
strong acid
or Lewis acid
R'
OH
O
OH
X
R'
R
R
R
R'
NaH
ortho-allylation
hydroalkoxylation
O
OTf
TMS
Me
O
O
Ph
+
Me
Me
CsF, MeCN
low yield
Ph
Ph
benzynes and epoxides appears to be
a more attractive
1
:
1
approach; however, the poor regioselectivity with unsymmetrical
benzynes and the need for more reactive aryl epoxides limited
its application.[4] Hence, a general approach that can synthesize
DHBFs directly from readily available feedstock chemicals
remained to be realized. In this communication, we describe the
development of a simple and direct DHBF synthesis method
through annulation between aryl iodides and terminal epoxides
via palladium/norbornene (NBE) cooperative catalysis (Scheme
1b).
b. this work
R
R
Pd/NBE
catalysis
I
O
O
R'
+
FG
FG
R'
direct annulation
up to 95% yield
FG: functional group
Scheme 1. DHBF Synthesis.
Me
OMe
OMe
Me
HO2C
OH
O
O
R
R
Me
OH
X
O
HO2C
R'
CO2H
Me
Benfur
anti-mitotic
Myrsinoic acid B
methioninase inhibitor
Me
Me
Pd0
OH
O
G
R
Me
O
tBu
A
PdII
OH
N
O
N
H
Me
X
R
O
Me
PdII
O
O
R'
O
O
R
OMe
Cedralin A
anticancer
PdII
H
Fufenozide
larvicidal
R'
O
H
B
F
Figure 1. Bioactive compounds containing DHBFs.
R
R
PdII
O PdII
R'
C
[*]
R. Li, Prof. Dr. G. Dong
Department of Chemistry
University of Chicago
R
E
Chicago, Illinois 60637, United States
E-mail: gbdong@uchicago.edu
R
PdII
R'
D
ANP
Supporting information for this article is given via a link at the end of
the document
PdII
O
ligands on Pd are
omitted for clarity
O
R'
Figure 2. Proposed catalytic circle.
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10.1002/anie.201712393
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COMMUNICATION
Despite the successful cyclization with highly strained 2H-
azirines (44-48 kcal/mol),[11g] the use of simple epoxides as the
coupling partner in Pd/NBE catalysis has not been reported. The
challenge is three-fold. First, activation of epoxides typically
requires acids or Lewis acids,[12] while the Pd/NBE catalysis
operates under slightly basic conditions. Second, the alkoxide
generated from epoxide ring opening (step E, Fig. 2) is an
excellent hydride donor and can lead to ipso reduction via β-
hydrogen elimination.[7f,8a,9b] Third, coupling with oxygen
nucleophiles with β-hydrogen has not been reported previously
for Pd/NBE catalysis, likely due to the difficulty of the C−O bond
reductive elimination versus β-hydrogen elimination (steps G
and H, Fig. 2).
of less polar solvents (entries 2 and 3) or other mono-dentate
phosphines (entries 6 and 7) gave no annulation product. An
improved yield (74%) was obtained using 5 mol% Buchwald’s
Ruphos-Pd-G4 precatalyst.[14] While regular NBE (N1) provided
the desired annulation product (entry 9), multi-NBE insertion
became the major side reaction, as the ANP intermediate is
known to react further with additional NBE when the electrophile
is not reactive enough.[15] Thus, we hypothesized that use of a
less reactive NBE, such as those with a substitution at the C2
position, would hinder the multi-NBE insertion pathway. To our
delight, the isopropyl ester-derived NBE (N4) was found to be
most efficient for this transformation.[16] NBEs with less sterically
hindered ester groups (N2 and N3) gave lower yields, while
bulky t-butyl-ester substituted one (N5) significantly diminished
the reactivity. Interestingly, the CF3-substiutted NBE (N8) still
afforded the desired product albeit in a lower yield. It is
noteworthy that, while most prior Pd/NBE catalyzed reactions
require a high loading or excess NBE, only 20 mol% N4 was
found sufficient in this reaction. NaOAc proved to be an optimal
base (entries 10 and 11). While 4 equiv of epoxide 2a was used
due to its volatility, reducing the loading to 2 equiv still provided
DHBF 3aa in 57% yield (entry 12).
Table 1. Control experiments for annulation with epoxides.
Me
OMs
Pd
(±) N4
(20 mol%)
Me
I
RuPhos-Pd-G4 (5 mol%)
NaOAc (150 mol%)
O
O
RuPhos
Me
nBu
+
nBu
N
DMF (0.1 M), 120 o
C
H
3aa
1a
2a
"standard condition"
RuPhos-Pd-G4
Yield [%][a]
Entry
Change from the standard condition
Table 2. Substrates scope with aryl iodides.[a]
1
2
none
74
Me
Me
toluene instead of DMF
dioxane instead of DMF
no RuPhos-Pd-G4
Pd(OAc)2 + RuPhos
Pd(OAc)2 + PPh3
Pd(OAc)2 + P(2-furyl)3
no N4
0
(±) N4 (20 mol%)
I
O
R1
O
RuPhos-Pd-G4 (10 mol%)
+
nBu
R1
nBu
3
0
NaOAc (150 mol%)
DMF (0.1 M), 120 o
C
2a
1a-p
3aa-3pa
4
0
Me
Me
Me
Et
5
41
O
O
O
nBu
nBu
nBu
6
0
3aa, 76%[b]
3ba, 79%[b]
3ca, 55%[b]
7
0
OTBS
CO2Me
Me
O
MeO
8
0
see below
0
O
O
nBu
nBu
nBu
nBu
nBu
9
other NBEs
3ea, 50%[c]
3da, 65%
3fa, 74%
Me
O
Me
O
10
11
12
no NaOAc
Me
O
F
KOAc instead of NaOAc
2.0 equiv of 2a
trace
57
nBu
nBu
F
Cl
3ga, 73%
3ha, 44%
3ia, 48%
Me
O
Me
O
Me
O
OMe
nBu
nBu
nBu
nBu
Me2N
MeN
MeO2C
3ja, 95%
3ka, 86%
3la, 81%
O
O
N
Me
O
O
O
nBu
Me
HO
Me 3ma, 61%
3na, 87%
3oa, 55%
Me
O
O
H
H
[a] The reaction was run with 0.1 mmol 1a and 0.4 mmol 2a in 1 mL DMF for
24h. [b] Yields are determined by 1H NMR analysis using 1,3,5-
trimethoxybenzene as the internal standard.
H
O
3pa, 59%[c]
dr 1:1
nBu
To address the aforementioned challenges, we propose that
1) use of polar aprotic solvents would promote SN2-type ring
opening of epoxides; and 2) use of a sterically hindered
phosphine ligand, such as Buchwald’s ligands, would inhibit β-
hydrogen elimination and promote the C−O reductive
elimination.[13] Indeed, after a careful survey of the reaction
parameters, the desired DHBF product 3aa was observed with
RuPhos/DMF as the ligand/solvent combination (Table 1). Use
[a] All reactions were run with 0.3 mmol 1a-p and 1.2 mmol 2a in 3mL DMF
for 24h. Isolated yields are reported. [b] 5.0 mol% of RuPhos-Pd-G4 was used.
[c] 20 mol% of RuPhos-Pd-G4 was used.
With the optimal reaction conditions in hand, the scope of the
aryl iodides was examined first (Table 2). To our delight,
substrates with electron-donating and -withdrawing groups all
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10.1002/anie.201712393
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COMMUNICATION
Me
Me
O
worked well giving the direct annulation products in moderate to
excellent yields. One important feature of this transformation is
that a variety of functional groups, including alkyl, TBS-silyl
protected benzyl alcohol, methyl ester, methoxy, fluoride,
chloride, amide, Weinreb amide and free tertiary alcohol, were
all tolerated (3ba-3ma). It is worthy to mention that aryl chloride
(3ia), which is reactive under the Pd/RuPhos conditions,
survived in this reaction.[14] Notably, polyaryl iodide (3na) and
heteroaryl iodide (3oa) were also suitable substrates.
Furthermore, more complex estrone-derived substrate (3pa) is
competent in this transformation, giving the desired DHBF in
59% yield. Altogether, this method exhibits excellent
chemoselectivity.
N4
(20 mol%)
(±)
I
RuPhos-Pd-G4 (10 mol%)
O
nBu
+
nBu
(1)
(2)
NaOAc (150 mol%)
DMF, 120 oC
MeO2C
MeO2C
1j
3ja
2a
1.23 g, 99%
1.38 g (5.0 mmol)
Me
I
Me
(±) N4 (20 mol%)
RuPhos-Pd-G 4 (4 mol%)
O
O
nBu
+
nBu
NaOAc (150 mol%)
DMF, 120 oC
1a
2a
3aa
1.22 g, 80%
1.75 g (8.0 mmol)
Me
O
Me
N4
(20 mol%)
(±)
RuPhos-Pd-G4 (10 mol%)
I
O
+
(3)
NaOAc (150 mol%)
DMF, 120 oC
OPh
2h
OPh
(S)-
99% ee
1a
3ah*
89%, 99% ee
0.3 mmol scale
Next, the scope of epoxides was explored (Table 3).[17] Direct
annulation with simple ethylene oxide, propyl oxide and other 2-
alkyloxiranes occurred smoothly (3ab-3ae). Epoxides containing
phenyl, ether or ester moieties all delivered the products in good
to excellent yields (3ag-3al). Note that benzyl ether (3ag) and
furan (3aj) are compatible under the reaction conditions.
Finally, the synthetic utility of this method is demonstrated in a
concise synthesis of fufenozide (Scheme 2),[18] which is an
effective insect growth regulator showing high insecticidal
activities towards plutella, xylostella and mythimna.[19] Starting
from the commercially available aryl iodide 1q and propyl oxide
2c, their direct annulation provided the key DHBF intermediate
(3qc) in 85% yield. Subsequent hydrolysis and peptide coupling
with hydrazine 5 accomplished the synthesis of fufenozide in an
excellent yield.
Table 3. Substrates scope with epoxides.[a]
Me
Me
N4
(±)
(20 mol%)
I
O
O
RuPhos-Pd-G4 (10 mol%)
R2
R2
+
NaOAc (150 mol%)
DMF (0.1 M), 120 oC
O
Me
Me
O
Me
O
1a
2b-l
3ab-3al
RuPhos-Pd-G4 (10 mol%)
I
O
NaOH (10%)
OMe
N4 (20 mol%)
OMe
Me
100 oC, 3 h
94%
Me
Me
Me
NaOAc (150 mol%)
DMF, 120 oC, 3 h
3qc
1q
O
O
O
85%
Me
Et
Me
Me
O
3ab, 75%[b]
3ac, 72%[b]
3ad, 68%[b]
1. (COCl)2, DMF (cat.)
Me
Me
O
tBu
O
OH
Me
N
O
N
Me
2.
Me
O
Me
Me
H
Me
tBu
O
4
O
N
O
Fufenozide
insecticide
H2N
Me
C8H17
5
O
Ph
OBn
Et3N
3ae, 66%[b]
3af, 82%
3ag, 90%
88%
Me
O
Me
Scheme 2. Synthesis of insecticide fufenozide.
O
OPh
O
Cl
X-ray
structure
3ah, 90%
3ai, 84%
In summary, a direct annulation between aryl iodides and
epoxides is developed via Pd/NBE cooperative catalysis. A
variety of 2,3-dihydrobenzofuran derivatives have been obtained
in moderate to excellent yields. The use of easily available
reactants, high chemo-selectivity and scalability should make
this method attractive for practical applications.
Me
O
Me
Me
O
O
O
O
O
O
OtBu
Me
3aj, 73%
3ak, 46%
3al, 85%
[a] All reactions were run with 0.3 mmol 1a and 1.2 mmol epoxide in 3mL
DMF for 24h. Isolated yields are reported. [b] 5.0 mol% of RuPhos-Pd-G4 was
used.
Acknowledgements
Financial supports from the University of Chicago and Eli Lilly
are acknowledged. We thank Mr. Ki-young Yoon for X-ray
structures. We also thank Mr. Zhe Dong for preliminary
investigation and donation of substrates. Mr. Dr. Ziqiang Rong is
thanked for checking the experiments.
The reaction is scalable. On a gram scale, DHBF 3ja was
obtained in 99% yield (Eq 1). In addition, using 1.75 g of aryl
iodide 1a (8.0 mmol), DHBF 3aa was isolated in 80% yield with
only 4.0 mol% [Pd] (Eq 2). Moreover, when an enantiopure
epoxide (S)-2h was used, the annulation reaction proceeded
with stereo-retention and afforded chiral DHBF 3ah* in 99% ee
with 89% yield (Eq 3). Given the wide availability of enantiopure
epoxides, this transformation is anticipated to be useful for
building chiral complex target molecules with DHBF moieties.
Keywords: annulation • catalysis • epoxides • palladium •
norbornene
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COMMUNICATION
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10.1002/anie.201712393
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Renhe Li and Guangbin Dong*
Page No. – Page No.
Direct Annulation between Aryl
Iodides and Epoxides via Palladi-
um/Norbornene Cooperative
Catalysis
A simple and direct annulation between readily available aryl iodides and epoxides
is enabled by palladium/norbornene (Pd/NBE) cooperative catalysis. This approach
offers a practical synthesis of various 2,3-dihydrobenzofuran derivatives.
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