Sequential C-H functionalization reactions for the enantioselective synthesis of highly functionalized 2,3-dihydrobenzofurans

Article abstract of DOI:10.1021/ja401731d

The enantioselective synthesis of 2,3-dihydrobenzofurans was achieved by using two sequential C-H functionalization reactions, a rhodium-catalyzed enantioselective intermolecular C-H insertion followed by a palladium-catalyzed C-H activation/C-O cyclization. Further diversification of the 2,3-dihydrobenzofuran structures was possible by a subsequent palladium-catalyzed intermolecular Heck-type sp² C-H functionalization.

Full text of DOI:10.1021/ja401731d

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Communication
Sequential C–H Functionalization Reactions for the Enantioselective
Synthesis of Highly Functionalized 2,3-Dihydrofurans
Hengbin Wang, Gang Li, Keary M Engle, Jin-Quan Yu, and Huw Madoc Lynn Davies
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja401731d • Publication Date (Web): 20 Apr 2013
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Sequential C–H Functionalization Reactions for the Enanti-
oselective Synthesis of Highly Functionalized 2,3-
Dihydrobenzofurans
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Hengbin Wang,a Gang Li,b Keary M. Engle,b Jin-Quan Yub* and Huw M. L. Daviesa*
aDepartment of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
bThe Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037
KEYWORDS: C-H Functionalization, Rhodium, Palladium, Carbenoid, and Dihydrofuran
Supporting Information Placeholder
carboxylates (eq 1).8 Even though the approach has been used
in the synthesis of complex natural products,3 it suffers from
ABSTRACT: The enantioselective synthesis of 2,3-
dihydrofurans was achieved by using two sequential C–H
the necessity to synthesize the poly-substituted aromatic sub-
functionalization reactions, a rhodium-catalyzed enantioselec-
strates for the intramolecular reactions. Furthermore, it often
tive intermolecular C–H insertion, followed by a palladium-
requires the use of both a chiral catalyst and an auxiliary to
catalyzed C–H activation/C–O cyclization. Further diversifica-
achieve acceptable levels of asymmetric induction.
CO2Me
CO2Me
tion of the 2,3-dihydrofuran structures was possible by a sub-
sequent palladium-catalyzed intermolecular Heck-type sp2 C–
N2
R2
R1
Rh(II)
H functionalization.
R1
(1)
O
R2
O
In this paper we describe an alternative approach to synthe-
size 2-arylbenzofuran-2-carboxylates, which begins by an
intermolecular C–H insertion followed by an intramolecular
C–H oxidation (Scheme 1). The major advantage of this new
approach is the range of 2,3-dihydrobenzofurans that can be
generated with high levels of asymmetric induction (93-99%
ee), using a single chiral catalyst and without the need for a
chiral auxiliary.
C–H Functionalization methodologies offer new strategies
for the synthesis of complex natural products1 and in recent
years, a number of elegant synthetic applications have been
described.2,3 Two distinct types of metal-catalyzed C–H func-
tionalization processes are becoming broadly effective. One of
these is the C–H insertion by a metal bound carbene, nitrene or
oxo intermediate4 and the other is “C–H activation” initiated
by C–H insertion by a metal complex.5 We have begun a pro-
gram to explore opportunities to combine C–H functionaliza-
tion methodologies to achieve the streamlined synthesis of
advanced structural features present in natural products and
pharmaceuticals. In this paper we describe an enantioselective
approach to dihydrobenzofurans, which utilizes up to three C–
H functionalization reactions in sequence.
Scheme 1. Sequential C–H functionalization approach to
2,3-dihydrobenzofurans
CO2Me
N2
MeO2C
R2
R2
1. Rh(II)
H
H
R1
R1
+
OH
2. H+/H2O
H
H
OTBS
CO2Me
3. Pd(II)/ Pd(IV)
R1
R2
O
This program arose from independent studies by the Davies
group on enantioselective intermolecular benzylic C–H inser-
tion9 and Yu’s group on C–H activation/C–O cyclization.5b
For the benzylic C–H insertion to be useful in this context, it
would be necessary to demonstrate that the enantioselective
reaction is still feasible with electron rich aryldiazoacetates
and benzyl silyl ethers because these are the types of function-
ality that tend to be present in the biologically relevant dihy-
drobenzofurans.6 The palladium catalyzed C–H activation/C–
O cyclization reaction has been conducted on relatively simple
tertiary and secondary alcohols.5b It has not been demonstrated
to be feasible with secondary benzylic alcohols nor β-hydroxyl
esters. With the substrates required for this study, benzyl alco-
hol oxidation, dehydration and retro-aldol reactions are poten-
Figure 1. Complementary C–H Functionalization Methods.
Dihydrofurans are common subunits in a wide range of nat-
ural products and pharmaceuticals.6 Therefore, the develop-
ment of new methodologies for constructing this structural
motif has been an important field in chemical research.7 The
Davies group developed an enantioselective intramolecular C–
H insertion approach for the synthesis of 2-arylbenzofuran-2-
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tial competing reactions with the desired C—H activation/C— Table 1. Rhodium Catalyzed C—H Insertion
Page 2 of 4
1
O cyclization reaction.
CO2Me
MeO2C
2
3
4
5
6
7
8
9
R2
To test the feasibility of the proposed synthetic approach,
the reaction of aryldiazoacetate 1 and TBS ether 2 was evalu-
ated (Scheme 2). As previously demonstrated, the best chiral
dirhodium complex for this reaction is Rh2(PTTL)4. The C—H
insertion product 3 was isolated in good yield and with excel-
lent levels of enantioselectivity (95% ee) and diastereoselec-
tivity (>97:3 dr). Before the C—H activation/C—O cycliza-
tion could be conducted, the TBS group would need to be re-
moved. A variety of conditions were examined but the best
result for the formation of the alcohol 4 was achieved using
HCl in ethanol. With 4 in hand, dihydrofuran 5 could be
formed employing the reaction conditions developed by the
Yu group.5b The reaction gave good regiocontrol, favoring ring
closure at the para position to the methoxy group, and did not
result in any epimerization or racemization. Minor side-
reactions were the retro-aldol reaction (~10%) and aromatiza-
tion of the product to the benzofuran (trace amounts were ob-
served).
1 mol %
Rh2(R-PTTL)4
R2
H
N2
+
R1
R1
H
OTBS
DMB, 50 °C
OTBS
6
7
8a–k
2 equiv
1 equiv
OMe
MeO2C
MeO2C
MeO2C
MeO
OMe
MeO
MeO
OTBS
OTBS
OTBS
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8a, 76% yield
>97:3 dr, 93% ee
8b, 58% yield
>97:3 dr, 95% ee
8c, 86% yield
>97:3 dr, 96% ee
Br
CF3
MeO2C
MeO2C
MeO2C
MeO
MeO
MeO
MeO
OTBS
OTBS
OTBS
8d, 86% yield
> 97:3 dr, 98% ee
8e, 92% yield
>97:3 dr, 97% ee
8f, 86% yielda
>97:3 dr, 97% ee
OMe
OMe
MeO2C
MeO2C
MeO2C
Me
Me
MeO
MeO
MeO
MeO
OMe
Scheme 2. Exploratory study of the sequential C—H func-
tionalization approach to dihydrobenzofurans
OTBS
OTBS
OTBS
8g, 74% yielda
>97:3 dr, 97% ee
8h, 77% yielda
8i, 92% yield
94:6 dr, 99% ee
OMe
CO2Me
>97:3 dr, 97% ee
MeO2C
OMe
OMe
1 mol %
Rh2(R-PTTL)4
MeO
MeO
N2
+
H
OMe
H
DMB, 50 °C
MeO2C
OTBS
MeO2C
H
H
OTBS
2
1 equiv
Me
1
2 equiv
3
70% yield, >97:3 dr, 95% ee
OTBS
OTBS
8j, 77% yield
>97:3 dr, 98% ee
8k, 76% yield
>97:3 dr, 96% ee
CO2Me
10 mol %
Pd(OAc)2
OMe
OMe
MeO
MeO2C
H
OMe
OMe
MeO
HCl
EtOH
Li2CO3
PhI(OAc)2
100 °C, 24 h
O
a2,2-dimethylbutane (DMB)/α,α,α-trifluorotoluene (v/v = 3/1)
was used as solvent.
OH
5
57% isolated yield
4
80% yield
13:1 ratio of regioisomer
94% ee
To test the substrate scope of this approach to 2,3-
dihydrobenzofurans, a variety of aryldiazoacetates 6 and TBS
protected benzyl alcohols 7 were subjected to the Rh2(R-
PTTL)4-catalyzed C—H insertion reaction conditions. The
emphasis was placed on methoxy-substituted substrates, in
order to evaluate if the C—H insertion with a highly electron
deficient carbenoid would be compatible with the electron rich
aromatic rings. As shown in Table 1, the products 8a-k were
obtained with high levels of diastereoselectivity (>97:3 dr) and
enantioselectivity (93-99% ee). Using the same deprotection
condition as for compound 3, the alcohols 9a-k required for
the C—H activation/C—O cyclization were readily prepared
from the silyl ethers 8a-k (eq 2).
Table 2. Palladium Catalyzed Cyclization
10 mol % Pd(OAc)2
1.5 equiv Li2CO3
CO2Me
MeO2C
R2
R2
R1
R1
1.5 equiv PhI(OAC)2
C6F6, 100 °C, 24 h
O
OH
H
10a-k
9a-k
CO2Me
CO2Me
CO2Me
OMe
MeO
MeO
MeO
OMe
O
O
O
10a
56% yield, 13:1 rr, 93% ee
10b
41% yield, 14:1 rr, 93% ee
10c
63% yield, 14:1 rr, 97% ee
CO2Me
CO2Me
MeO
CO2Me
MeO
MeO
CF3
Br
O
O
O
MeO
10fb
47% yield, >30:1 rr, 97% ee
MeO2C
MeO2C
R2
10d
61% yield, 15:1 rr, 99% ee
10e
61% yield, 15:1 rr, 98% ee
R2
conc. HCl, EtOH
0 °C - r.t.
R1
R1
(2)
OTBS
OH
9a-k
CO2Me
CO2Me
CO2Me
Me
MeO
MeO
MeO
OMe
MeO
8a-k
78-89% yield
OMe
O
O
O
Me
10ia,b,c
45% yield, >30:1 rr, 99% ee
OMe
10g
43% yield, >30:1 rr, 97% ee
Me
10h
40% yield, > 30:1 rr, 99% ee
A variety of conditions were explored for conducting the
palladium catalyzed C—H activation/C—O cyclization
(see supporting materials for details). The optimized condi-
tions were palladium acetate (10 mol %) as catalyst, phenylio-
donium diacateate as the terminal oxidant, and lithium car-
bonate or disodium phosphate as base (Table 2). Typical reac-
tion time and temperature were 24 h at 100 °C but slightly
more vigorous conditions were required for the less electronic
rich substrates. Under these conditions the alcohols 9a-k cy-
clized to the corresponding dihydrofurans 10a-k. In cases
CO2Me
CO2Me
O
O
10ja,b,d
44% yield, >30:1 rr, 98% ee
10ka,b,d,e
39% yield, 97% ee
a20 mol % of Pd(OAc)2 was used. Na2HPO4 was used as base.
cReaction time was 48 h. dReaction time was 72 h. eReaction tem-
perature was 120 °C.
b
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where a mixture of regioisomers could have been formed, the
least sterically congested product (10a-j) is strongly favored.
1
AUTHOR INFORMATION
C—H functionalization onto an electron rich aromatic ring is
favored. Cyclization to a position para to a methoxy group is
favored, as illustrated for substrates 9a-h, which gave the di-
hydrobenzofurans 10a-h within 24 h. However, in the case of
9f-h, containing two methoxy groups in the ring undergoing
C—H oxidation, a significant amount of aromatized benzofu-
ran side-products were observed in the crude reaction mix-
tures. Substrates 9i-k lacking a methoxy group in the ring un-
dergoing C—H oxidations required more vigorous reaction
conditions to form the dihydrofurans 10i-k. The carboxylic
acid derived from 10g was crystalline and its absolute configu-
ration was unambiguously assigned by X-ray crystallog-
raphy.10 The absolute configuration of the other dihydrofurans
is assumed to be the same by analogy. Even though the yields
of the dihydrobenzofurans are relatively modest (39-63%),
these reactions illustrate the synthetic potential of C—H func-
tionalization. Yet the dihydrobenzofurans are produced in 93-
99% ee without any observable epimerization.
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9
Corresponding Author
* hmdavie@emory.edu
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manu-
script.
Funding Sources
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This work was supported by NSF under the CCI Center for Selec-
tive C-H Functionalization, CHE-1205646.
ACKNOWLEDGMENT
We thank Dr. John Bacsa for the X-ray crystallographic structure
determination.
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Scheme 3. Heck-type C—H Functionalization
H
CO2H
CO2Me
2N NaOH
MeO
MeO
MeOH
OMe
OMe
OMe
OMe
O
O
5
11
81% yield
2 equiv.
CO2Et
CO2Et
20 mol% Pd(OAc)2
20 mol% Ac-Ile-OH
2 equiv KHCO3
CO2H
MeO
t-AmylOH, 1 atm O2
100 °C, 48 h
OMe
OMe
O
12
46% isolated yield
60% conversion
In conclusion, this paper illustrates the potential of C—H
functionalization for the streamlined synthesis of complex
targets. Dihydrofurans were synthesized in a highly regio-,
diastereo- and enantioselective manner by a synthetic se-
quence involving three distinct C—H functionalization steps.
As selective C—H functionalization methodologies continue
to develop, it is expected that they will have a great impact on
the strategies used for the synthesis of complex targets, fine
chemicals, natural products and potential therapeutic agents.
Controlling site selectivity in multiple C—H functionalization
steps will be critical to bring this synthetic potential to frui-
tion, and this study demonstrates that such levels of control are
becoming achievable.
ASSOCIATED CONTENT
Full experimental data, X-ray crystallographic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
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(8) (a) Davies, H. M. L.; Grazini, M. V. A.; Aouad, E. Org. Lett.
2001, 3, 1475-1477; (b) Saito, H.; Oishi, H.; Kitagaki, S.;
Nakamura, S.; Anada, M.; Hashimoto, S. Org. Lett. 2002, 4,
3887-3890; (c) Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org.
Lett. 2006, 8, 3437-3440.
(9) Davies, H. M. L.; Hedley, S. J.; Bohall, B. R. J. Org. Chem.
2005, 70, 10737-10742.
(10) The crystal structure has been deposited at the Cambridge Crys-
tallographic Data Centre, and the deposition number CCDC
921156 has been allocated.
CO2Me
OTBS
H
CO2Me
H
Triple C-H
OMe
OMe
CO2Me
OMe
OMe
+
N2
H
MeO
Functionalization
H
O
TOC graphic
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