Regio- and stereoselective Pd-catalyzed direct arylation of unactivated sp3 C(3)-H bonds of tetrahydrofuran and 1,4-benzodioxane systems

Article abstract of DOI:10.1021/acs.joc.5b00025

An auxiliary-enabled Pd-catalyzed highly regio- and stereoselective sp³ C-H activation and the direct arylation of the C3-position of oxygen heterocycles, such as tetrahydrofuran and 1,4-benzodioxane systems, are reported. An efficient stereoselective construction of cis 2,3-disubstituted tetrahydrofuran derivatives (analogues of norlignans) and cis 2,3-disubstituted 1,4-benzodioxane derivatives (analogues of neolignans) is described. The direct C(sp³)-H arylation of the C3-position of (R)- or (S)- tetrahydrofuran-2-carboxamides furnished the corresponding (2R,3R) and (2S,3S) C3-arylated THF scaffolds as major compounds with very high regio- and diastereoselectivities. The stereochemistry of the products obtained in this work were unambiguously assigned on the basis of the X-ray structure analyses of representative compounds 3b, 3e, 4p, and 7.

Full text of DOI:10.1021/acs.joc.5b00025

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Article
Regio- and Stereoselective Pd-Catalyzed Direct Arylation of Unactivated
sp3 C(3)-H Bonds of Tetrahydrofuran and 1,4-Benzodioxane Systems
Ramarao Parella, and Srinivasarao Arulananda Babu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00025 • Publication Date (Web): 15 Jan 2015
Downloaded from http://pubs.acs.org on January 16, 2015
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Regio- and Stereoselective Pd-Catalyzed Direct Arylation of Unactivated sp C(3)-H Bonds
of Tetrahydrofuran and 1,4-Benzodioxane Systems
Ramarao Parella and Srinivasarao Arulananda Babu*
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Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER)
Mohali, Manauli P.O., Sector 81, SAS Nagar, Mohali, Knowledge City, Punjab 140306, India
sababu@iisermohali.ac.in
ABSTRACT
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An auxiliaryꢀenabled Pdꢀcatalyzed highly regioꢀ and stereoselective sp CꢀH activation and the
direct arylation of the C3ꢀposition of oxygen heterocycles, such as tetrahydrofuran and 1,4ꢀ
benzodioxane systems are reported. An efficient stereoselective construction of cis 2,3ꢀ
disubstituted tetrahydrofuran derivatives (analogues of norlignans) and cis 2,3ꢀdisubstituted 1,4ꢀ
3
benzodioxane derivatives (analogues of neolignans) is described. The direct C(sp )ꢀH arylation
of the C3ꢀposition of (R)ꢀ or (S)ꢀ tetrahydrofuranꢀ2ꢀcarboxamides furnished the corresponding
(2R,3R) and (2S,3S) C3ꢀarylated THF scaffolds as major compounds with very high regioꢀ and
diastereoselectivities. The stereochemistry of the products obtained in this work were
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unambiguously assigned on the basis of the Xꢀray structure analyses of representative
compounds 3b, 3e, 4p and 7.
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INTRODUCTION
Saturated oxygen hetereocycles, especially, tetrahydrofuran (THF) and benzodioxane based
motifs are recurrently encountered in nature (e.g., lignans, annonaceous acetogenins, polyether
ionophores/antibiotics and macrodiolides), pharmaceuticals and bioactive synthetic
1,2
compounds. Several substituted THFꢀ and benzodioxaneꢀbased synthetic molecules and
naturally occurring lignanꢀ, neolignanꢀ and norlignan oxygen hetereocycles were found to exhibit
a wide range of biological activities (e.g., anticancer, antioxidant, antimicrobial, antiꢀ
1ꢀ4
inflammatory and immunosuppressive activities). There exist several naturally occurring THFꢀ
norlignan and benzodioxaneꢀneolignan motifs possessing an aryl group at the C3ꢀposition
1
,2
(
Figure 1) and many of them were found to exhibit various biological activities. For example,
2aꢀc
recently, a family of THFꢀnorlignans, such as metasequirins A, B, E, F, G and H were isolated
and metasequirins E and F were evaluated for cytotoxicity against five human tumor cell lines.
2
a
Further, benzodioxaneꢀneolignan molecules, such as isoamericanol A, americanol A,
isoamericanin A and americanin A were found to show neurotropic and acetylcholine enhancing
2
d,e
activities.
neolignans.
Due to their prevalence in natural products, biological activities and ability to serve as building
The present investigation deals on the synthesis of analogues of norlignans and
1
ꢀ4
blocks in organic chemistry, numerous classical and modern stereoselective synthetic methods
5
including the αꢀCꢀH functionalization have been developed for producing bioactive and
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synthetic tetrahydrofuran and benzodioxane derivatives. In general, majority of the
tetrahydrofuran and benzodioxane derivatives were assembled mainly via the cyclization
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,4
reaction of preꢀdesigned starting materials having the required functional groups.
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Figure 1. Representative examples of lignan natural products.
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The direct functionalization of the unactivated C(sp )ꢀH bonds of organic molecules is known to
be a challenging task in the past decades. However, from the recent past decade, several
exceptional reports appeared on the transition metalꢀcatalyzed direct functionalization of CꢀH
bonds present in organic molecules and indeed, functionalization of organic molecules via the Cꢀ
6
ꢀ15
H activation is emerging as one of the important strategies.
There exist several outstanding
2
reports which are dealing on the direct functionalization of C(sp )ꢀH bonds present in organic
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molecules. On the other hand, the direct functionalization of the unactivated C(sp )ꢀH bonds
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ꢀ15
present in organic molecules is one of the emerging research areas.
Notably, an auxiliaryꢀ
3
enabled, Pdꢀcatalyzed arylation reaction of alkyl C(sp )ꢀH bonds instigated by Daugulis, Yu,
Chen and others is emerging as one of the seminal methods for constructing CꢀC bonds. In this
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line, the direct arylations of C(sp )ꢀH bonds present in the carbocyclic systems, such as
cyclopropane, cyclobutane, mediumꢀsized rings, norbornane framework and acyclic amino acid
1
4,15
derivatives have been successfully demonstrated by various research groups.
Along this line, we envisioned the selective CꢀH functionalization and the direct arylation of the
3
unactivated C(sp )ꢀH bonds present in the THF and 1,4ꢀbenzodioxane systems for assembling
new neolignan/norlignan scaffolds. To the best of our knowledge, there exist only rare papers
dealing on the directing groupꢀenabled, Pdꢀcatalyzed CꢀH functionalization of the unactivated
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C(sp )ꢀH bonds of saturated heterocycles and a literature survey revealed that there is no report
dealing on the Pdꢀcatalyzed direct arylation of the C3ꢀposition of the tetrahydrofuran and
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ꢀ15
3
benzodioxane systems.
With regard to the functionalization of C(sp )ꢀH bonds of saturated
oxygen hetereocycles, there exist only two examples reported by Yu et al., which include the
1
5a
15b
arylation and alkynylation of the C3ꢀposition of a tetrahydropyran derivative (Scheme 1).
3
On the other hand, with regard to the functionalization of the unactivated C(sp )ꢀH bonds of
saturated nitrogen hetereocycles, recently, Bull et al. reported the direct arylation of the C(3)ꢀH
1
5c
bond of a proline derivative. Wu et al. revealed the amination reaction involving the C(3)ꢀH
15d
bond of a proline derivative. Earlier, Chen’s group reported an example of the direct alkylation
1
5e
of the C(3)ꢀH bond of a piperidine derivative.
In continuation of our lab’s interest on the CꢀH activation reactions, herein, we report an
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auxiliaryꢀenabled,
Pdꢀcatalyzed
highly
regioꢀ
and
stereoselective
C(sp )ꢀH
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activation/functionalization of the tetrahydrofuran and 1,4ꢀbenzodioxane systems. This work
demonstrates a new route for the direct arylation of the of C(3)ꢀH position of oxygen
heterocycles, such as tetrahydrofuran and 1,4ꢀbenzodioxane systems and highly stereoselective
construction of novel norlignanꢀtype cis 2,3ꢀdisubstituted tetrahydrofurans and neolignanꢀtype
cis 2,3ꢀdisubstituted 1,4ꢀbenzodioxanes.
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Scheme 1. Theme of This Work.
an example reported by Yu et al. (JACS, 2012, 134, 18570)
Pd(TFA) (10 mol%)
H
F
2
Ar
F
Ag CO (2 equiv)
H
2
3
NH
iBu
CF + p-Tol
I
3
O
H
N
O
N
(3 equiv) Ligand (20 mol%)
K2HPO4 (1.2 equiv)
O
Ligand
O
p-Tol
F
O
F
(
1 equiv)
o
55% (cis:trans = 6:1)
hexane, 110 C
an example reported by Yu et al. (JACS, 2013, 135, 3387)
H
Ar
F
[
Pd(allyl)Cl] (5 mol%)
F
2
NH
H
IAd HBF (20 mol%)
O
CF3
4
H
+
O
Br
TIPS
N
61%
O
Cs CO (2 equiv)
F
2
3
O
(2 equiv)
(cis)
F
o
TIPS
(
1 equiv)
ether, 85 C
Bull et al. (OL 2014, 16, 4956)
X
NCbz
NCbz
Pd(OAc) (5 mol %)
2
+
AgOAc (1.8 equiv)
N
N
N
H
N
O
H
O
o
R
110 C
R
(
0.9 equiv)
28-99%
(
1.8 equiv)
this work: direct C(3)-H arylation of THF and benzodioxane systems
auxiliary
O
O
H
H
O
O
N
H
N
O
Ar1
I
H
N
Ar=
N
N
O
Ar
Ar
O
H
Ar
O
Pd(OAc)2
AgOAc
H
Ar1
Ar
O
O
Ar1
3
highly regio- and stereoselective arylation of sp C(3)-H bond
construction of neolignan & norlignan scaffolds
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RESULTS AND DISCUSSION
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To examine the arylation of methylene C(sp )ꢀH bond of oxygen heterocycles, such as
tetrahydrofuran and 1,4ꢀbenzodioxane systems, initially, we prepared the substrate 1a by linking
tetrahydrofuranꢀ2ꢀcarboxylic acid chloride with the Daugulis’s bidentate directing group (8ꢀ
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1
4a,b
aminoquinoline).
Then, to find out the best reaction conditions for achieving the C(3)ꢀH
arylation of substrate 1a, we performed several reactions as shown in Table 1. We found the best
reaction conditions comprising the reaction of substrate 1a, aryl iodide 2a and AgOAc (additive)
in the presence 5 or 10 mol% of the Pd(OAc) catalyst, which afforded the C3ꢀarylated product,
2
cis 2,3ꢀdisubstituted tetrahydrofuran 3a (norlignan analogue) in 70 and 81% yields, respectively
(entries 3 and 4, Table 1). The CꢀH arylation of the substrate 1a with 2a in the presence of
Ag CO as an additive instead of AgOAc also gave the product 3a in 69% yield (entry 5, Table
2
3
1
).
The Pdꢀcatalyzed C(3)ꢀH arylation of substrate 1a with 2a in the presence of various other
additives, such as K CO or KOAc or PhI(OAc) did not give the product 3a (entries 6ꢀ8, Table
2
3
2
1). The CꢀH arylation of substrate 1a in the presence of other palladium catalysts, such as PdCl2
or Pd(TFA) instead of Pd(OAc) did not give satisfactory yields (entries 9 and 10, Table 1).
2
2
However, the CꢀH arylation of 1a in the presence of Pd(CH CN) Cl and Pd(PPh ) instead of
3
2
2
3 4
Pd(OAc) furnished the product 3a in 69 and 30% yields, respectively (entries 11 and 12, Table
2
1
). The Pdꢀcatalyzed CꢀH arylation of 1a with 2a in other solvents, such as MeCN or 1,2ꢀDCE or
tertꢀbutyl alcohol failed to afford the product 3a (entries 13ꢀ15, Table 1). However, the Pdꢀ
catalyzed reaction of 1a with 2a in 1,4ꢀdioxane or tertꢀamyl alcohol gave the product 3a in 46
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and 57% yields, respectively (entries 16 and 17, Table 1). Employing coupling partners 2b or 2c
instead of 2a was ineffective (entry 18, Table 1).
Table 1. Optimization of Reaction Conditions.
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O
X
H
N
O
2
2
H
N
3
PdL (mol%)
2
3
H
+
O
N
O
additive
N
R
(0.55 mmol /
2
2
2
a; X = I, R = OMe
b; X = Br, R = H
c; X = Cl, R = H
2
.2 equiv)
R
solvent (3 mL)
a
1
(
a
3a ; R = OMe
3bb,c; R = H
o
0.25 mmol / 1 equiv)
24 h, 80-110 C
(
1 mmol / 4 equiv)
T ( C) 3a; yield (%)a
o
entry PdL (mol%)
additive (mmol)
AgOAc (0.55)
solvent (3 mL)
2
1
nil
toluene
toluene
toluene
110
0
2
3
Pd(OAc)2 (10)
nil
110
110
<15
70
Pd(OAc) (5)
AgOAc (0.55)
2
4
Pd(OAc) (10)
2
AgOAc (0.55)
toluene
110
81
5
Pd(OAc) (10)
2
Ag CO (0.55)
2
3
toluene
110
69
6
7
8
9
Pd(OAc) (10)
2
K CO (0.55)
2
3
toluene
toluene
toluene
toluene
110
110
110
110
0
Pd(OAc) (10)
KOAc (0.55)
traces
0
2
Pd(OAc) (10)
PhI(OAc) (0.55)
2
2
PdCl (10)
AgOAc (0.55)
AgOAc (0.55)
AgOAc (0.55)
AgOAc (0.55)
AgOAc (0.55)
AgOAc (0.55)
<10
2
10
11
12
13
14
Pd(TFA) (10)
2
toluene
toluene
toluene
110
110
110
80
0
Pd(CH CN) Cl (10)
69
30
0
3
2
2
Pd(PPh ) (10)
3 4
Pd(OAc) (10)
CH CN
3
2
Pd(OAc) (10)
1,2-DCE
80
0
2
tBuOH
0
15
Pd(OAc) (10)
2
AgOAc (0.55)
AgOAc (0.55)
AgOAc (0.55)
AgOAc (0.55)
85
1
6
7
Pd(OAc) (10)
2
1,4-Dioxane
tAmylOH
toluene
100
110
110
46
57
0b,c
1
Pd(OAc) (10)
2
18
Pd(OAc) (10)
2
a
b
The yield corresponds to the reaction of 1a with 2a. The yield corresponds to the reaction of
c
1
a with 2b. The yield corresponds to the reaction of 1a with 2c.
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Table 2. Optimization of Reaction Conditions.
Pd(OAc) (10 mol%)
2
1
a
+
2a
3a
AgOAc
(
1
0.25 mmol /
equiv)
(0.25 -1.0 mmol /
1-4 equiv)
(0.55 mmol / 2.2 equiv)
toluene (3 mL)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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3
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
2
4 h, 110 C
entry
2a (mmol)
2a (equiv)
ratio of
3a: yield (%)
1a : 2a
1
2
3
4
0.25
0.5
1
2
3
4
1 : 1
1 : 3
1 : 3
1 : 4
35
59
68
81
0.75
1.0
Bull's reaction condition
Pd(OAc) (5 mol%)
2
+
2a
3a; 50%
1a
AgOAc
(
1
0.25 mmol /
equiv)
(0.45 mmol /
1.8 equiv)
(
0.45 mmol / 1.8 equiv)
o
neat, 20 h, 110 C
In order to find out how many equivalents of aryl iodide 2a are required for producing the C3ꢀ
arylated product 3a with better yield, we investigated the CꢀH arylation of substrate 1a by
varying the quantity of 2a (Table 2). The Pdꢀcatalyzed CꢀH arylation of substrate 1a with one
equivalent of 2a gave the C3ꢀarylated product 3a in low yield (35%, entry 1, Table 2). Next, the
Pdꢀcatalyzed CꢀH arylation of substrate 1a with two or three equivalents of 2a gave the C3ꢀ
arylated product 3a in 59% and 68% yields, respectively (entries 2 and 3, Table 2). The usage of
four equivalents of 2a gave the C3ꢀarylated product 3a in very good yield (81%, entry 4, Tables
1
and 2). In this line, we have also performed the Pdꢀcatalyzed CꢀH arylation of substrate 1a with
1
5c
1.8 equivalents of 2a by using the Bull’s reaction conditions, which gave the C3ꢀarylated
product 3a in 50% yield (Table 2).
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Scheme 2. Arylation of sp C(3)-H Bond of 1a and Construction of Norlignan-THF
Scaffolds.
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Subsequently, the generality of this bidentate directing groupꢀenabled, Pdꢀcatalyzed direct
arylation of C(3)ꢀH bond of the THF derivative 1a was elaborated using a variety of aryl iodides
3
(
Scheme 2). The direct arylation of the methylene sp C(3)ꢀH bond of the substrate 1a with
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various aryl iodides containing a substituent at the para or meta position (e.g., Ac, Cl and NO2)
afforded the corresponding cis 2,3ꢀdisubstituted tetrahydrofurans 3b-3g in 56ꢀ76% yields.
Similarly, the C3ꢀarylated THF scaffolds 3h and 3i were obtained from the Pdꢀcatalyzed CꢀH
arylation of the substrate 1a by using the corresponding benzodioxaneꢀ or benzodioxoleꢀbased
aryl iodides as the coupling partners. Further, the arylation of the substrate 1a with multi
substituted aryl iodides gave the corresponding products 3j-l in 40ꢀ58% yields. We have also
carried out the Pdꢀcatalyzed direct arylation of the C(3)ꢀposition of the THF derivative 1a with a
variety of hetero aryl iodides, which furnished the corresponding THF scaffolds 3m-3r
possessing heteroaryl groups at the C3ꢀposition in 20ꢀ87% yields.
Representatively, recrystallization of CꢀH arylated products 3b and 3e formed singleꢀcrystals,
which were subjected to the singleꢀcrystal Xꢀray structure analyses. The Xꢀray structures of the
16
representative compounds 3b and 3e (see SI for the Xꢀray structures of 3b and 3e)
unambiguously confirmed that all these reactions were highly regioꢀ and stereoselective and the
direct CꢀH arylation occurred only at the C3ꢀposition of the substrate 1a and selectively gave the
2
,3ꢀdisubstituted tetrahydrofurans 3a-r having the cis stereochemistry (C2ꢀC3 stereocenters). In
addition, characteristically, the C2 proton of all the compounds (3a-r) appeared as a doublet
chemical shift value range, δ = 4.71ꢀ4.91 ppm) due to its coupling with the C3 proton. The
(
coupling constants (J) of the doublet peaks of the C2 proton of all the compounds 3a-r were
1
calculated from their respective H NMR spectra and found to be in the range of 6.6ꢀ8.2 Hz
(except the compound 3q having a thiophene moiety at the C3ꢀposition, C2H, doublet, J = 6.3
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Hz). Accordingly, the stereochemistry of all the compounds 3a-r were assigned as cis on the
basis of the Xꢀray structure analyses of the compounds 3b and 3e coupled with the similarity in
the NMR spectral pattern of the compounds 3a-r.
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Figure 2. Investigation of C(sp )-H Arylation Reactions Using Other Substrates and
a,b
Auxiliaries.
a
Conditions: Substrate (0.25 mmol), 2a or 1ꢀiodoꢀ4ꢀmethylbenzene (1 mmol, 4 equiv),
o
b
(
Pd(OAc) (5ꢀ10 mol%), AgOAc (0.55 mmol, 2.2 equiv), toluene (3 mL), 24 h and 110 C. See
2
the SI for additional information and individual reaction conditions (Tables 3ꢀ5).
Successively, we investigated the Pdꢀcatalyzed CꢀH arylation of other substrates, such as 1bA,
1bB and 1bC (Figure 2). It is a limitation that the Pdꢀcatalyzed CꢀH arylation reactions of
substrates 1bA, 1bB and 1bC with 2a were not successful (see the SI for additional information
and individual reaction conditions). Furthermore, to find out the other working auxiliaries for
selectively arylating the C(3)ꢀH bond of THF derivatives, we performed the Pdꢀcatalyzed
reactions of substrates 1c-f, 1dA, 1eA and 1fA with 2a (Figure 2) and in these reactions we did
not get any of the corresponding CꢀH arylated THF products. These reactions indicated that 8ꢀ
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14a,b
aminoquinoline (Daugulis’s auxiliary ) is an effective auxiliary as the substrate 1a underwent
the Pdꢀcatalyzed CꢀH arylation smoothly than the other substrates 1c-f, 1dA, 1eA and 1fA.
Furthermore, we focused our attention to further extend the generality of this protocol and we
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decided to investigate the Pdꢀcatalyzed direct CꢀH arylation of the methylene C(sp )ꢀH bond of
1,4ꢀbenzodioxane system (Scheme 3). Along this line, initially, we assembled the substrate 1g by
linking the corresponding 1,4ꢀbenzodioxane carboxylic acid chloride with the Daugulis’s
bidentate directing group (8ꢀaminoquinoline). Then, we performed the reaction of the substrate
1g with phenyl iodide in the presence of AgOAc (2.2 equiv) and 10 mol% of the Pd(OAc)2
catalyst, which successfully gave the C3ꢀarylated product, cis 2,3ꢀdisubstituted 1,4ꢀbenzodioxane
scaffold 4a (neolignan analogue) in 65% yield (Scheme 3). Thenceforth, we capitalized this
success and synthesized of a wide range neolignanꢀtype cis 2,3ꢀdisubstituted 1,4ꢀbenzodioxane
3
scaffolds 4b-q (40ꢀ83%) from the Pdꢀcatalyzed direct arylation of the methylene sp C(3)ꢀH
bond of 1,4ꢀbenzodioxane system 1g by using the corresponding aryl iodides, such as monoꢀ and
disubstituted aryl iodides, benzodioxaneꢀbased aryl iodide and heteroaryl iodides.
In a representative case, the CꢀH arylated product 4p was recrystallized and subjected to the
singleꢀcrystal Xꢀray structure analysis. The Xꢀray structure of the representative compound 4p
1
6
(
see SI for the Xꢀray structure of 4p ) clearly confirmed that the CꢀH arylation of the substrate
1
g was highly regioꢀ and stereoselective and the direct CꢀH arylation occurred only at the C3ꢀ
position of the substrate 1g and selectively gave the 2,3ꢀdisubstituted 1,4ꢀbenzodioxanes 4a-q
with the cis stereochemistry (C2ꢀC3 stereocenters). Characteristically, the C2 and C3 protons in
all the compounds (4a-q) appeared as doublets and the coupling constants (J) of the doublet
1
peaks of C2 and C3 protons of all the compounds 4a-q were calculated from their respective H
18
NMR spectra and found to be in the range of 2.8ꢀ3.1 Hz. Accordingly, the stereochemistry of
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the 2,3ꢀdisubstituted 1,4ꢀbenzodioxanes 4a-q were assigned as cis on the basis of the Xꢀray
structure analysis of the compound 4p coupled with the similarity in their NMR spectral pattern
and the characteristic coupling constant values of the doublet peaks of the C2 protons and C3
protons of all the compounds 4a-q.
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Scheme 3. Arylation of sp C(3)-H Bond of 1g and Construction of Benzodioxane-Neolignan
Motifs.
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Scheme 4. Arylation of sp C(3)-H Bond of 1h,i and Construction of Norlignan-THF
Scaffolds.
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Subsequently, we decided to explore the direct CꢀH arylation of the unactivated sp C(3)ꢀH bond
of chiral tetrahydrofuranꢀ2ꢀcarboxamides and synthesize chiral C3ꢀarylated tetrahydrofuranꢀ2ꢀ
carboxamides. In this regard, we assembled the chiral tetrahydrofuranꢀ2ꢀcarboxamide substrates
3
1
h (Rꢀisomer) and 1i (Sꢀisomer, Scheme 4). Then, we performed the Pdꢀcatalyzed direct C(sp )ꢀ
H arylation of the substrates 1h and 1i with various aryl iodides. These reactions successfully
furnished the corresponding chiral 2,3ꢀdisubstituted tetrahydrofurans 5a-g (2R,3R, major isomer)
and 6a-g (2S,3S, major isomer) in 70ꢀ86% yields. Similarly, the CꢀH arylation of substrates 1h
and 1i with 2ꢀiodothiophene gave the products 5h (2R,3S, major isomer) and 6h (2S,3R, major
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isomer) in 81 and 90% yields, respectively (Scheme 4). The HPLC analyses of the compounds
5
a-h and 6a-h revealed that the CꢀH arylation of the chiral substrates 1h and 1i resulted the
chiral products 5a-h with ee 81 to >99% and 6a-h with ee 83 to >99% and perceptibly, partial
racemizations were observed in most of the reactions under the experimental conditions. The
direct CꢀH arylation of chiral substrates 1h and 1i occurred only at the C3ꢀposition and
selectively gave the chiral 2,3ꢀdisubstituted tetrahydrofurans 5a-h and 6a-h with cis
stereochemistry (C2 and C3 stereocenters). The compounds 5a-h and 6a-h were isolated in pure
form as single diastereomers and characterized by NMR spectral data, mass and HPLC analyses.
The stereochemistry of all the compounds 5a-h and 6a-h (cis isomers) were assigned on the
basis of the Xꢀray structure analyses of the compounds 3b and 3e and deliberations given for
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1
7a
establishing the stereochemistry of the compounds 3a-r.
We also performed the Pdꢀcatalyzed direct arylation of C(3)ꢀH bond of the substrate 1a with
iodobenzene in a gram scale. This reaction gave the C3ꢀarylated product 3b in 70% yield
(Scheme 5). Finally, we have attempted the removal of the bidentate directing group (8ꢀ
aminoquinoline) from the C3ꢀarylated cis 2,3ꢀdisubstituted THF and benzodioxane systems.
Representatively, we carried out the hydrolysis of the carboxamides 3b and 4a. The hydrolysis of
the carboxamides 3b and 4a under the standard hydrolysis reaction conditions (e.g., Con. HCl or
NaOHꢀmediated hydrolysis) failed to afford the corresponding carboxylic acids 7 and 8. Later,
we found that the hydrolysis of carboxamides 3b and 4a in the presence of triflic acid (TfOH)
successfully gave the corresponding carboxylic acids 7 and 8 (Scheme 5). The stereochemistry of
the compound 7 (C2ꢀC3 stereocenters) was unambiguously found to be cis (see SI for the Xꢀray
16
structure of 7) and no significant epimerization was observed under the experimental condition
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employed for hydrolyzing the carboxamide 3b. Additionally, the C2 proton in the compound 7
appeared as a doublet (δ = 4.65 ppm) due to its coupling with the C3 proton similar to its parent
compound 3b (C2H, doublet, δ = 4.78, J = 7.0 Hz). The coupling constant (J) of the doublet peak
of the C2 proton of the compound 7 (cis isomer) was found to be 7.7 Hz similar to its parent
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compound 3b (cis isomer). Likewise, the stereochemistry of the C2ꢀC3 stereocenters of the
compound 8 was assigned as cis based on the coupling constant (J = 3.2 Hz) of the doublet peaks
of the C2/C3 protons, which was found to be in agreement with the literature and its parent
compound 4a (cis isomer), in which the coupling constant (J) of the doublet peaks of the C2/C3
18
protons was 3.1 Hz.
Scheme 5. Gram Scale Reaction and Removal of the Directing Group.
In summary, we have shown the bidentate directing groupꢀaided Pdꢀcatalyzed highly regioꢀ and
3
stereoselective sp CꢀH activation and direct arylation of the C(3)ꢀH position of tetrahydrofuran
and 1,4ꢀbenzodioxane systems. The direct CꢀH arylation occurred only at the C3 position of
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racemic tetrahydrofuranꢀ2ꢀcarboxamides and gave the corresponding racemic C3ꢀarylated THF
derivatives with excellent regioꢀ and diastereoselectivities. Similarly, the CꢀH arylation of chiral
(
R)ꢀ or (S)ꢀ tetrahydrofuranꢀ2ꢀcarboxamides resulted the corresponding chiral (2R,3R) and
2S,3S) C3ꢀarylatedꢀTHF scaffolds having cis stereochemistry with excellent regioꢀ and
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(
diastereoselectivities and very good ee. Overall, this protocol has led to the production of a wide
range of cis 2,3ꢀdisubstitutedꢀ THFꢀnorlignan and benzodioxaneꢀneolignan scaffolds with very
high regioꢀ and stereoselectivities.
EXPERIMENTAL SECTION
General. Melting points are uncorrected. FTꢀIR spectra of compounds were recorded as thin
1
13
films or KBr pellets. H and C NMR spectra of all compounds were recorded on 400 MHz and
00 MHz spectrometers respectively (using TMS as an internal standard). HRMS measurements
1
reported in this work were obtained from TOF mass analyzer using electrospray ionization (ESI).
Column chromatography was carried out using silica gel 100ꢀ200 mesh. HPLC analyses were
performed using ODꢀH (0.46 cm IDR, 25 cm length) as a chiral column (eluents, flow rate,
detection method are listed on the HPLC charts). Reactions were performed in anhydrous solvent
under a nitrogen atmosphere. Solutions were dried using anhydrous Na SO . Thin layer
2
4
chromatography analyses were performed on silica gel plates and components were visualized by
observation under iodine. Isolated yields of all the compounds were reported and yields were not
optimized. In all the reactions, purification of the crude reaction mixture by the column
chromatography gave only the major diastereomer (as single compound) in pure form and we did
not isolate any other compound in considerable quantity suitable for characterization.
Procedure for the synthesis of the carboxamides 1a-1i, 1bA-1bC, 1dA, 1eA and 1fA.
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The corresponding carboxylic acid (1.5 mmol) was dissolved in SOCl (4 mmol) and stirred for
2
2
4 h at rt under a nitrogen atmosphere. After this period, the reaction mixture was concentrated
in vacuum and diluted with anhydrous DCM (3 mL) under a nitrogen atmosphere. Then, the
corresponding acid chloride in DCM was added to a separate RB flask containing amine (1
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mmol) and Et N (1.1 mmol) in anhydrous DCM (2 mL) under a nitrogen atmosphere. The
3
reaction mixture was stirred at rt for 10 min and then, the reaction mixture was refluxed for 12 h
under a nitrogen atmosphere. After this period, the reaction mixture was diluted with DCM (5
mL) and washed with water followed by saturated aqueous NaHCO solution. The combined
3
organic layers were dried over anhydrous Na SO , concentrated in vacuum and purification of
2
4
the resulting reaction mixture by column chromatography (EtOAc/hexanes = 30:70) furnished
the corresponding cyclic ether carboxamides 1a-1i, 1bA-1bC, 1dA, 1eA and 1fA.
General procedure for the Pd-catalyzed C-H arylation of the carboxamides 1a-1i, 1bA-
1
bC, 1dA, 1eA and 1fA and preparation of 3a-3r, 4a-4q, 5a-5h and 6a-6h. A mixture of the
corresponding cyclic ether carboxamide 1 (0.25 mmol, 1 equiv), Pd(OAc) (5.6 mg, 10 mol%),
2
ArI (1.0 mmol, 4 equiv) and AgOAc (91.8 mg, 0.55 mmol, 2.2 equiv) in anhydrous toluene (3
o
mL) was heated at 110 C for 24ꢀ48 h under a nitrogen atmosphere. After the reaction period, the
reaction mixture was diluted with EtOAc and concentrated in vacuum and purification of the
resulting reaction mixture by silica gel column chromatography furnished the corresponding CꢀH
arylated cyclic ether carboxamides 3a-3r/4a-4q/5a-5h/6a-6h (see Tables/Schemes for specific
examples).
Procedure for the hydrolysis of the amides 3b and 4a. To a RB flask (capacity 25 mL) molded
with a Liebig condenser (length = 15 cm) sealed at the top and having a J Young air inlet valve at
the side of the RB flask was sequentially added the corresponding carboxamide 3b or 4a (0.25
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mmol) dissolved in a mixture of toluene (3 mL) and water (0.5 mL) and CF SO H (0.5 mL)
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3
using syringes. The air inlet was closed and the reaction mixture was heated at 100 °C and
chilled water was circulated in the outer glass tube of the condenser. After 12 h, the reaction
mixture was transferred from the RB flask into a separating funnel using a syringe, diluted with
EtOAc and extracted with saturated aqueous Na CO solution (20 mL x 2). Then, the combined
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aqueous layers were acidified with 1 N HCl (15 mL x 2) to get pH~2. Then, the aqueous layers
were extracted using EtOAc (10 mL x 2), drying of the combined organic layers over anhydrous
Na SO and evaporation in vacuum gave the corresponding carboxylic acid 7 or 8.
2
4
N-(Quinolin-8-yl)tetrahydrofuran-2-carboxamide (1a): Following the general procedure, 1a
was obtained after purification by column chromatography on silica gel (EtOAc:Hexanes =
o
30:70) as brown colour solid; Yield: 95% (230 mg); mp 85ꢀ87 C; IR (KBr): 3441, 1653, 1554,
ꢀ1
1
1
260, 750 cm ; H NMR (400 MHz, CDCl ): δ 10.94 (br s, 1H), 8.88 (dd, 1H, J = 4.2 Hz, J =
3 1 2
1
.7 Hz), 8.82 (dd, 1H, J = 6.2 Hz, J = 2.8 Hz), 8.17 (dd, 1H, J = 8.3 Hz, J = 1.7 Hz), 7.58ꢀ7.53
1
2
1
2
(m, 2H), 7.47 (dd, 1H, J = 8.3 Hz, J = 4.2 Hz), 4.64 (dd, 1H, J = 8.4 Hz, J = 5.6 Hz), 4.28ꢀ4.23
1 2 1 2
(
m, 1H), 4.08 (dd, 1H, J = 15.2 Hz, J = 7.0 Hz), 2.48ꢀ2.39 (m, 1H), 2.32ꢀ2.25 (m, 1H), 2.04ꢀ
1
2
13
1.98 (m, 2H); C NMR (100 MHz, CDCl ): δ 172.1, 148.6, 138.9, 136.2, 133.9, 128.0, 127.2,
3
+
1
21.9, 121.6, 116.5, 79.2, 69.8, 30.5, 25.6; HRMS (ESI): m/z [M + H] calcd for C H N O :
1
4
15
2
2
2
43.1134; found 243.1154.
N-(Quinolin-8-yl)tetrahydrofuran-3-carboxamide (1bA): Following the general procedure,
1
3
1
bA was obtained after purification by column chromatography on silica gel (EtOAc:Hexanes =
o
0:70) as red colour solid; Yield: 90% (218 mg); mp 80ꢀ82 C; IR (KBr): 3440, 1676, 1527,
ꢀ1 1
385, 791 cm ; H NMR (400 MHz, CDCl ): δ 9.91 (br s, 1H), 8.72 (d, 1H, J = 1.7 Hz), 8.71
3
1
(
dd, 1H, J = 3.1 Hz, J = 1.7 Hz), 8.03 (dd, 1H, J = 8.3 Hz, J = 1.6 Hz), 7.45ꢀ7.38 (m, 2H), 7.34
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(
dd, 1H, J = 8.3 Hz, J = 4.2 Hz), 4.06 (d, 2H, J = 6.9 Hz), 4.02ꢀ3.97 (m, 1H), 3.87ꢀ3.81 (m,
1
2
1
3
1
1
H), 3.27ꢀ3.19 (m, 1H), 2.34ꢀ2.20 (m, 2H); C NMR (100 MHz, CDCl ): δ 172.0, 148.2, 138.2,
3
36.3, 134.3, 127.8, 127.2, 121.7, 121.6, 116.5, 71.0, 68.4, 46.9, 30.7; HRMS (ESI): m/z [M +
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
H] calcd for C H N O : 243.1134; found 243.1158.
1
4
15
2
2
N-(Quinolin-8-yl)tetrahydro-2H-pyran-4-carboxamide (1bB): Following the general
procedure, 1bB was obtained after purification by column chromatography on neutral alumina
o
(EtOAc:Hexanes = 40:60) as brown colour solid. Yield: 88% (225 mg); mp 141ꢀ143 C; IR
ꢀ1 1
(KBr): 3352, 1682, 1528, 1280, 792 cm ; H NMR (400 MHz, CDCl ): δ 9.98 (br s, 1H), 8.82
3
(dd, 1H, J = 4.2 Hz, J = 1.6 Hz), 8.80 (dd, 1H, J = 7.1 Hz, J = 1.8 Hz), 8.19 (d, 1H, J = 8.3
1 2 1 2
Hz), 7.58ꢀ7.51 (m, 2H), 7.49 (dd, 1H, J = 8.3 Hz, J = 4.2 Hz), 4.14 (t, 1H, J = 3.0 Hz), 4.11 (t,
1
2
1H, J = 3.0 Hz), 3.55 (dt, 2H, J = 11.0 Hz, J = 3.5 Hz), 2.80ꢀ2.72 (m, 1H), 2.09ꢀ1.96 (m, 4H);
1
2
13
C NMR (100 MHz, CDCl ): δ 172.9, 148.2, 138.4, 136.5, 134.3. 128.0, 127.4, 121.7, 121.6,
3
+
1
2
16.5, 67.3, 43.6, 29.3; HRMS (ESI): m/z [M + H] calcd for C H N O : 257.1290; found
15 17
2
2
57.1290.
N-(Quinolin-8-yl)chroman-3-carboxamide (1bC): Following the general procedure, 1bC was
obtained after purification by column chromatography on neutral alumina (EtOAc:Hexanes =
3
7
0:70) as yellow colour liquid. Yield: 85% (258 mg); IR (DCM): 3343, 1682, 1528, 1228, 1068,
ꢀ1 1
52 cm ; H NMR (400 MHz, CDCl ): δ 10.17 (br s, 1H), 8.82ꢀ8.79 (m, 2H), 8.19 (d, 1H, J =
3
8.2 Hz), 7.59ꢀ7.54 (m, 2H), 7.48 (dd, 1H, J = 8.2 Hz, J = 4.2 Hz), 7.17 (t, 2H, J = 8.0 Hz), 6.93
1
2
(dd, 2H, J = 12.2 Hz, J = 8.0 Hz), 4.66ꢀ4.62 (m, 1H), 4.30 (t, 1H, J = 10.4 Hz), 3.37 (dd, 1H, J
1
2
1
1
3
=
15.3 Hz, J = 10.0 Hz), 3.27ꢀ3.15 (m, 2H); C NMR (100 MHz, CDCl ): δ 170.5, 154.0, 148.3,
2 3
1
38.4, 136.4, 134.1, 129.9, 127.9, 127.6, 127.4, 121.9, 121.7, 120.8, 120.5, 116.8, 116.7, 67.4,
+
4
1.3, 28.6; HRMS (ESI): m/z [M + H] calcd for C H N O : 305.1290; found 305.1286.
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N-(2-(Dimethylamino)ethyl)tetrahydrofuran-2-carboxamide (1c): Following the general
procedure, 1c was obtained after purification by column chromatography on silica gel (MeOH:
EtOAc = 10:90) as dark brown colour liquid; Yield: 40% (75 mg); IR (DCM): 3433, 1637, 1528,
10
11
12
13
14
15
16
17
18
19
20
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38
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ1 1
1
260, 749 cm ; H NMR (400 MHz, CDCl ): δ 7.07 (br s, 1H), 4.36 (dd, 1H, J = 8.3 Hz, J =
3 1 2
5.8 Hz), 3.99ꢀ3.86 (m, 2H), 3.41ꢀ3.29 (m, 2H), 2.41 (dt, 2H, J = 6.3 Hz, J = 1.5 Hz), 2.33ꢀ2.26
1
2
1
3
(
m, 1H), 2.24 (s, 6H), 2.10ꢀ2.02 (m, 1H), 1.95ꢀ1.83 (m, 2H); C NMR (100 MHz, CDCl ): δ
3
+
1
73.3, 78.5, 69.4, 58.1, 45.3, 36.4, 30.2, 25.5; HRMS (ESI): m/z [M + H] calcd for C H N O :
9
19
2
2
187.1447; found 187.1459.
N-(Pyridin-2-ylmethyl)tetrahydrofuran-2-carboxamide (1d): Following the general
procedure, 1d was obtained after purification by column chromatography on silica gel
(EtOAc:Hexanes = 60:40) as dark brown colour liquid; Yield: 71% (146 mg); IR (DCM): 3396,
ꢀ1 1
1
1
650, 1530, 1075, 758 cm ; H NMR (400 MHz, CDCl ): δ 8.46 (d, 1H, J = 4.5 Hz), 7.68 (br s,
3
H), 7.58 (t, 1H, J = 7.6 Hz), 7.18 (d, 1H, J = 7.6 Hz), 7.12 (t, 1H, J = 5.9 Hz), 4.56ꢀ4.40 (m,
2H), 4.35 (dd, 1H, J = 8.3 Hz, J = 6.1 Hz), 3.95ꢀ3.90 (m, 1H), 3.85ꢀ3.79 (m, 1H), 2.27ꢀ2.18 (m,
1
2
13
1
1
H), 2.06ꢀ1.96 (m, 1H), 1.88ꢀ1.78 (m, 2H); C NMR (100 MHz, CDCl ): δ 173.4, 156.7, 149.1,
3
+
36.7, 122.3, 121.8, 78.5, 69.4, 43.9, 30.2, 25.4; HRMS (ESI): m/z [M + H] calcd for
C H N O : 207.1133; found 207.1132.
11
15
2
2
N-((Tetrahydrofuran-2-yl)methyl)picolinamide (1dA): Following the general procedure, 1dA
was obtained after purification by column chromatography on silica gel (EtOAc:Hexanes =
4
7
0:60) as dark brown colour liquid; Yield: 80% (165 mg); IR (DCM): 3480, 1668, 1590, 1077,
ꢀ1 1
51 cm ; H NMR (400 MHz, CDCl ): δ 8.57ꢀ8.55 (m, 1H), 8.36 (br s, 1H), 8.19 (d, 1H, J = 7.8
3
Hz), 7.84 (dt, 1H, J = 7.7 Hz, J = 1.7 Hz), 7.44ꢀ7.40 (m, 1H), 4.13ꢀ4.07 (m, 1H), 3.95ꢀ3.90 (m,
1
2
1
H), 3.82ꢀ3.71 (m, 2H), 3.47ꢀ3.41 (m, 1H), 2.07ꢀ1.99 (m, 1H), 1.95ꢀ1.87 (m, 2H), 1.68ꢀ1.59 (m,
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13
1
H); C NMR (100 MHz, CDCl ): δ 164.4, 149.8, 148.1, 137.3, 126.1, 122.2, 77.8, 68.3, 43.2,
3
+
2
8.8, 25.9; HRMS (ESI): m/z [M + H] calcd for C H N O : 207.1134; found 207.1157.
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N-(2-(Methylthio)phenyl)tetrahydrofuran-2-carboxamide (1e): Following the general
procedure, 1e was obtained after purification by column chromatography on silica gel
(EtOAc:Hexanes = 30:70) as yellow colour liquid; Yield: 81% (192 mg); IR (DCM): 3441,
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1 1
1
685, 1523, 1275, 750 cm ; H NMR (400 MHz, CDCl ): δ 9.57 (br s, 1H), 8.36 (dd, 1H, J =
3 1
8
.2 Hz, J = 1.3 Hz), 7.47 (dd, 1H, J = 7.6 Hz, J = 1.3 Hz), 7.32ꢀ7.28 (m, 1H), 7.09 (dt, 1H, J =
2
1
2
1
7.6 Hz, J = 1.3 Hz), 4.54 (dd, 1H, J = 8.5 Hz, J = 5.4 Hz), 4.17ꢀ4.12 (m, 1H), 4.01 (dd, 1H, J =
2
1
2
1
13
1
5.2 Hz, J = 7.0 Hz), 2.41 (s, 3H), 2.39ꢀ2.33 (m, 1H), 2.26ꢀ2.18 (m, 1H), 2.02ꢀ1.93 (m, 2H); C
2
NMR (100 MHz, CDCl ): δ 171.7, 137.5, 132.4, 128.6, 126.0, 124.5, 120.3, 79.0, 69.8, 30.4,
3
+
25.6, 18.5; HRMS (ESI): m/z [M + Na] calcd for C H NNaO S: 260.0721; found 260.0734.
12
15
2
N-(2-(Methylthio)phenyl)tetrahydrofuran-3-carboxamide (1eA): Following the general
procedure, 1eA was obtained after purification by column chromatography on silica gel
o
(
EtOAc:Hexanes = 40:60) as colourless solid. Yield: 70% (65 mg); mp 64ꢀ66 C; IR (KBr):
ꢀ1
1
3
437, 1661, 1471, 1554, 1261, 750 cm ; H NMR (400 MHz, CDCl ): δ 8.49 (br s, 1H), 8.26 (d,
3
1H, J = 8.2 Hz), 7.46 (d, 1H, J = 7.2 Hz), 7.28 (t, 1H, J = 8.2 Hz), 7.08 (t, 1H, J = 7.2 Hz), 4.09ꢀ
3
.97 (m, 3H), 3.87 (dd, 1H, J = 15.4 Hz, J = 7.5 Hz), 3.17ꢀ3.11 (m, 1H), 2.39 (s, 3H), 2.29 (dd,
1 2
1
3
2
H, J = 14.0 Hz, J = 7.0 Hz); C NMR (100 MHz, CDCl ): δ 172.0, 137.9, 132.4, 128.6, 125.8,
1
2
3
+
124.6, 121.0, 70.9, 68.2, 46.8, 30.5, 18.7; HRMS (ESI): m/z [M + H] calcd for C H NO S:
1
2
16
2
2
38.0902; found 238.0908.
N-(2-Methylquinolin-8-yl)tetrahydrofuran-2-carboxamide (1f): Following the general
procedure, 1f was obtained after purification by column chromatography on silica gel
o
(
EtOAc:Hexanes = 30:70) as brown colour solid; Yield: 85% (217 mg); mp 83ꢀ85 C; IR (KBr):
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1
3
440, 1603, 1573, 1260, 757 cm ; H NMR (400 MHz, CDCl ): δ 10.99 (br s, 1H), 8.76 (dd, 1H,
3
J = 5.5 Hz, J = 3.4 Hz), 8.03 (d, 1H, J = 8.4 Hz), 7.48ꢀ7.47 (m, 2H), 7.32 (d, 1H, J = 8.4 Hz),
1
2
4
.64 (dd, 1H, J = 8.4 Hz, J = 5.3 Hz), 4.29ꢀ4.24 (m, 1H), 4.12ꢀ4.07 (m, 1H), 2.77 (s, 3H), 2.44ꢀ
1 2
10
11
12
13
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35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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55
56
57
58
59
60
13
2
.37 (m, 1H), 2.33ꢀ2.25 (m, 1H), 2.04ꢀ1.97 (m, 2H); C NMR (100 MHz, CDCl ): δ 172.1,
3
157.4, 138.3, 136.2, 133.3, 126.2, 126.1, 122.4, 121.7, 116.4, 79.2, 69.7, 30.5, 25.5, 25.4; HRMS
+
(
ESI): m/z [M + H] calcd for C H N O : 257.1290; found 257.1298.
1
5
17
2
2
N-(2-Methylquinolin-8-yl)tetrahydrofuran-3-carboxamide (1fA): Following the general
procedure, 1fA was obtained after purification by column chromatography on silica gel
(
EtOAc:Hexanes = 40:60) as brown colour liquid. Yield: 90% (230 mg); IR (DCM): 3342, 1683,
ꢀ1 1
1
530, 1384, 763 cm ; H NMR (400 MHz, CDCl ): δ 10.05 (br s, 1H), 8.75ꢀ8.71 (m, 1H), 8.01
3
(d, 1H, J = 8.4 Hz), 7.45 (d, 2H, J = 4.2 Hz), 7.31 (d, 1H, J = 8.4 Hz), 4.17ꢀ4.05 (m, 3H), 3.93
13
(
dd, 1H, J = 15.2 Hz, J = 7.7 Hz), 3.41ꢀ3.27 (m, 1H), 2.75 (s, 3H), 2.43ꢀ2.27 (m, 2H); C NMR
1
2
(
100 MHz, CDCl ): δ 171.9, 157.3, 137.7, 136.4, 133.7, 126.3, 126.0, 122.5, 121.5, 116.5, 71.1,
3
+
6
2
8.5, 47.0, 30.7, 25.3; HRMS (ESI): m/z [M + H] calcd for C H N O : 257.1290; found
1
5
17
2
2
57.1281.
N-(Quinolin-8-yl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxamide (1g): Following the
general procedure, 1g was obtained after purification by column chromatography on silica gel
o
(
EtOAc:Hexanes = 30:70) as brown colour solid; Yield: 84% (257 mg); mp 121ꢀ123 C; IR
ꢀ1 1
(KBr): 3440, 1682, 1491, 1274, 750 cm ; H NMR (400 MHz, CDCl ): δ 10.98 (br s, 1H), 8.84
3
(
dd, 1H, J = 4.2 Hz, J = 1.6 Hz), 8.81 (t, 1H, J = 4.4 Hz), 8.17 (dd, 1H, J = 8.3 Hz, J = 1.6 Hz),
1 2 1 2
7
3
1
.57 (d, 2H, J = 4.3 Hz), 7.47 (dd, 1H, J = 8.3 Hz, J = 4.2 Hz), 7.27ꢀ7.24 (m, 1H), 7.01ꢀ6.92 (m,
1 2
H), 4.97 (dd, 1H, J = 7.0 Hz, J = 2.7 Hz), 4.69 (dd, 1H, J = 11.4 Hz, J = 2.7 Hz), 4.44 (dd,
1
2
1
2
13
H, J = 11.4 Hz, J = 7.0 Hz); C NMR (100 MHz, CDCl ): δ 165.7, 148.7, 143.4, 141.8, 138.7,
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
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6
1
36.2, 133.5, 127.9, 127.1, 122.5, 122.5, 122.0, 121.8, 117.7, 117.7, 116.9, 73.8, 65.3 ; HRMS
+
(ESI): m/z [M + H] calcd for C H N O : 307.1083; found 307.1094.
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(R)-N-(Quinolin-8-yl)tetrahydrofuran-2-carboxamide (1h): Following the general procedure,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
h was obtained after purification by column chromatography on silica gel (EtOAc:Hexanes =
2
5
30:70) as dark brown colour liquid; Yield: 90% (218 mg); ee 99%; ([α] D = ꢀ101.1 (c 0.05,
ꢀ1 1
DCM); IR (DCM): 3377, 2964, 1276, 1263, 847 cm ; H NMR (400 MHz, CDCl ): δ 10.93 (br
3
s, 1H), 8.86 (dd, 1H, J = 4.2 Hz, J = 1.7 Hz), 8.81 (dd, 1H, J = 6.6 Hz, J = 2.3 Hz), 8.14 (dd,
1
2
1
2
1H, J = 8.3 Hz, J = 1.7 Hz), 7.56ꢀ7.50 (m, 2H), 7.44 (dd, 1H, J = 8.3 Hz, J = 4.2 Hz) 4.63 (dd,
1
2
1
2
1
2
H, J = 8.4 Hz, J = 5.6 Hz), 4.26ꢀ4.21 (m, 1H), 4.06 (dd, 1H, J = 15.2 Hz, J = 7.0 Hz), 2.44ꢀ
1 2 1 2
1
3
.37 (m, 1H), 2.31ꢀ2.23 (m, 1H), 2.02ꢀ1.94 (m, 2H); C NMR (100 MHz, CDCl ): δ 172.1,
3
148.6, 138.9, 136.2, 133.9, 128.0, 127.2, 121.9, 121.6, 116.5, 79.2, 69.8, 30.5, 25.6; HRMS
+
(ESI): m/z [M + H] calcd for C H N O : 243.1134; found 243.1138.
1
4
15
2
2
(S)-N-(Quinolin-8-yl)tetrahydrofuran-2-carboxamide (1i): Following the general procedure,
1i was obtained after purification by column chromatography on silica gel (EtOAc:Hexanes =
25
3
0:70) as dark brown colour liquid; Yield: 88% (213 mg); ee 99%; ([α] D = +111.1 (c 0.05,
ꢀ1
1
DCM); IR (DCM): 3334, 1683, 1578, 1530, 1067, 750 cm ; H NMR (400 MHz, CDCl ): δ
3
1
8
0.93 (br s, 1H), 8.87 (dd, 1H, J = 4.2 Hz, J = 1.7 Hz), 8.81 (dd, 1H, J = 6.3 Hz, J = 2.7 Hz),
1 2 1 2
.16 (dd, 1H, J = 8.3 Hz, J = 1.7 Hz), 7.58ꢀ7.53 (m, 2H), 7.46 (dd, 1H, J = 8.3 Hz, J = 4.2 Hz)
1
2
1
2
4.64 (dd, 1H, J = 8.4 Hz, J = 5.6 Hz), 4.28ꢀ4.22 (m, 1H), 4.08 (dd, 1H, J = 15.2 Hz, J = 7.0
1
2
1
2
1
3
Hz), 2.48ꢀ2.38 (m, 1H), 2.32ꢀ2.24 (m, 1H), 2.04ꢀ1.97 (m, 2H); C NMR (100 MHz, CDCl ): δ
3
1
72.1, 148.6, 138.9, 136.2, 133.9, 128.0, 127.2, 122.0, 121.6, 116.5, 79.2, 69.8, 30.5, 25.6;
+
HRMS (ESI): m/z [M + H] calcd for C H N O : 243.1134; found 243.1130.
1
4
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(
2R*,3R*)-3-(4-Methoxyphenyl)-N-(quinolin-8-yl)tetrahydrofuran-2-carboxamide
(3a):
Following the general procedure, 3a was obtained after purification by column chromatography
on silica gel (EtOAc:Hexanes = 40:60) as brown colour viscous liquid; Yield: 81% (71 mg); IR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ1 1
(
DCM): 3341, 1683, 1489, 1326, 791 cm ; H NMR (400 MHz, CDCl ): δ 10.59 (br s, 1H), 8.87
3
(dd, 1H, J = 4.2 Hz, J = 1.7 Hz), 8.48 (dd, 1H, J = 7.2 Hz, J = 1.7 Hz), 8.12 (dd, 1H, J = 8.3
1
2
1
2
1
Hz, J = 1.7 Hz), 7.47ꢀ7.40 (m, 3H), 7.21 (d, 2H, J = 8.8 Hz), 6.68 (d, 2H, J = 8.8 Hz), 4.74 (d,
2
1
H, J = 7.0 Hz), 4.63ꢀ4.57 (m, 1H), 4.21ꢀ4.15 (m, 1H), 3.90ꢀ3.85 (m, 1H), 3.62 (s, 3H), 2.58ꢀ
1
3
2.53 (m, 1H), 2.31ꢀ2.26 (m, 1H); C NMR (100 MHz, CDCl ): δ 168.6, 158.2, 148.5, 138.8,
3
1
36.1, 133.6, 132.5, 128.9, 127.9, 127.1, 121.7, 121.5, 116.6, 113.6, 83.9, 68.7, 55.0, 47.2, 33.7;
+
HRMS (ESI): m/z [M + H] calcd for C H N O : 349.1552; found 349.1563.
21 21
2
3
(2R*,3R*)-3-Phenyl-N-(quinolin-8-yl)tetrahydrofuran-2-carboxamide (3b): Following the
general procedure, 3b was obtained after purification by column chromatography on silica gel
o
(
(
(
EtOAc:Hexanes = 40:60) as brown colour solid; Yield: 73% (58 mg); mp 102ꢀ104 C; IR
ꢀ1 1
DCM): 3441, 1642, 1527, 1275, 750 cm ; H NMR (400 MHz, CDCl ): δ 10.60 (br s, 1H), 8.88
3
dd, 1H, J = 4.2 Hz, J = 1.7 Hz), 8.45 (dd, 1H, J = 7.4 Hz, J = 1.7 Hz), 8.12 (dd, 1H, J = 8.3
1
2
1
2
1
Hz, J = 1.7 Hz), 7.47ꢀ7.39 (m, 3H), 7.31ꢀ7.29 (m, 2H), 7.15 (t, 2H, J = 7.3 Hz), 7.05 (t, 1H, J =
2
7
2
.3 Hz), 4.78 (d, 1H, J = 7.0 Hz), 4.65ꢀ4.59 (m, 1H), 4.24ꢀ4.18 (m, 1H), 3.94ꢀ3.89 (m, 1H),
13
.64ꢀ2.55 (m, 1H), 2.37ꢀ2.29 (m, 1H); C NMR (100 MHz, CDCl ): δ 168.4, 148.5, 140.5,
3
138.8, 136.1, 133.6, 128.2, 127.9, 127.9, 127.1, 126.7, 121.7, 121.5, 116.6, 83.9, 68.7, 48.0,
+
3
3.7; HRMS (ESI): m/z [M + H] calcd for C H N O : 319.1447; found 319.1460.
2
0
19
2
2
(
2R*,3R*)-3-(4-Acetylphenyl)-N-(quinolin-8-yl)tetrahydrofuran-2-carboxamide
(3c):
Following the general procedure, 3c was obtained after purification by column chromatography
on silica gel (EtOAc:Hexanes = 50:50) as yellow colour solid; Yield: 72% (65 mg); mp 117ꢀ119
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o
ꢀ1 1
C; IR (KBr): 3424, 1678, 1528, 1274, 749 cm ; H NMR (400 MHz, CDCl ): δ 10.62 (br s,
3
1
H), 8.88 (dd, 1H, J = 4.2 Hz, J = 1.6 Hz), 8.42 (dd, 1H, J = 7.6 Hz, J = 1.6 Hz), 8.12 (dd, 1H,
1 2 1 2
J = 8.3 Hz, J = 1.6 Hz), 7.73 (d, 2H, J = 8.3 Hz), 7.47ꢀ7.39 (m, 3H), 7.38 (d, 2H, J = 8.3 Hz),
1
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
4
.79 (d, 1H, J = 7.0 Hz), 4.65ꢀ4.59 (m, 1H), 4.24ꢀ4.18 (m, 1H), 3.99ꢀ3.94 (m, 1H), 2.65ꢀ2.57 (m,
1
3
1H), 2.42 (s, 3H), 2.34ꢀ2.25 (m, 1H); C NMR (100 MHz, CDCl ): δ 197.7, 168.0, 148.6, 146.4,
3
1
38.7, 136.2, 135.5, 133.4, 128.4, 128.2, 127.9, 127.1, 122.0, 121.6, 116.6, 83.8, 68.7, 47.8, 33.6,
+
2
6.5; HRMS (ESI): m/z [M + H] calcd for C H N O : 361.1552; found 361.1568.
2
2
21
2
3
(2R*,3R*)-3-(4-Chlorophenyl)-N-(quinolin-8-yl)tetrahydrofuran-2-carboxamide
(3d):
Following the general procedure, 3d was obtained after purification by column chromatography
o
on silica gel (EtOAc:Hexanes = 30:70) as colourless solid; Yield: 62% (55 mg); mp 143ꢀ145 C;
ꢀ1 1
IR (DCM): 3339, 1682, 1528, 1057, 757 cm ; H NMR (400 MHz, CDCl ): δ 10.61 (br s, 1H),
3
8
.88 (dd, 1H, J = 4.2 Hz, J = 1.7 Hz), 8.47 (dd, 1H, J = 7.3 Hz, J = 1.7 Hz), 8.13 (dd, 1H, J =
1 2 1 2 1
8
.3 Hz, J = 1.7 Hz), 7.49ꢀ7.41 (m, 3H), 7.22 (d, 2H, J = 8.6 Hz), 7.11 (d, 2H, J = 8.6 Hz), 4.75
2
(d, 1H, J = 7.0 Hz), 4.61ꢀ4.55 (m, 1H), 4.22ꢀ4.16 (m, 1H), 3.91ꢀ3.86 (m, 1H), 2.62ꢀ2.53 (m, 1H),
13
2
.29ꢀ2.21 (m, 1H); C NMR (100 MHz, CDCl ): δ 168.1, 148.5, 139.2, 138.8, 136.2, 133.5,
3
132.5, 129.3, 128.4, 127.9, 127.1, 121.9, 121.5, 116.2, 83.7, 68.6, 47.3, 33.7; HRMS (ESI): m/z
+
[
M + H] calcd for C H ClN O : 353.1057; found 353.1070.
2
0
18
2
2
(2R*,3R*)-3-(4-Cyanophenyl)-N-(quinolin-8-yl)tetrahydrofuran-2-carboxamide
(3e):
Following the general procedure, 3e was obtained after purification by column chromatography
o
on silica gel (EtOAc:Hexanes = 50:50) as colourless solid; Yield: 76% (65 mg); mp 200ꢀ202 C;
ꢀ1 1
IR (KBr): 3431, 1636, 1531, 1275, 749 cm ; H NMR (400 MHz, CDCl ): δ 10.60 (br s, 1H),
3
8
.88 (dd, 1H, J = 4.2 Hz, J = 1.7 Hz), 8.41 (dd, 1H, J = 7.6 Hz, J = 1.7 Hz), 8.16 (dd, 1H, J =
1 2 1 2 1
8
.3 Hz, J = 1.7 Hz), 7.52ꢀ7.49 (m, 1H), 7.46 (dd, 1H, J = 8.3 Hz, J = 4.0 Hz), 7.44ꢀ7.38 (m,
2
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H), 4.78 (d, 1H, J = 7.0 Hz), 4.64ꢀ4.58 (m, 1H), 4.25ꢀ4.19 (m, 1H), 3.97ꢀ3.92 (m, 1H), 2.68ꢀ
1
3
.59 (m, 1H), 2.32ꢀ2.23 (m, 1H); C NMR (100 MHz, CDCl ): δ 167.6, 148.6, 146.4, 138.7,
3
36.3, 133.2, 132.0, 128.8, 127.9, 127.1, 122.2, 121.6, 118.8, 116.6, 110.5, 83.7, 68.6, 47.8,
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43
44
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
3.4; HRMS (ESI): m/z [M + H] calcd for C H N O : 344.1399; found 344.1408.
2
1
18
3
2
(2R*,3R*)-3-(4-Nitrophenyl)-N-(quinolin-8-yl)tetrahydrofuran-2-carboxamide
(3f):
Following the general procedure, 3f was obtained after purification by column chromatography
on silica gel (EtOAc:Hexanes = 50:50) as brown colour solid; Yield: 56% (51 mg); mp 160ꢀ162
o
ꢀ1 1
C; IR (KBr): 3396, 1664, 1596, 1076, 750 cm ; H NMR (400 MHz, CDCl ): δ 10.64 (br s,
3
1
H), 8.88 (dd, 1H, J = 4.2 Hz, J = 1.7 Hz), 8.41 (dd, 1H, J = 7.6 Hz, J = 1.7 Hz), 8.13 (dd, 1H,
1 2 1 2
J = 8.3 Hz, J = 1.7 Hz), 8.00 (d, 2H, J = 8.8 Hz), 7.49ꢀ7.39 (m, 5H), 4.80 (d, 1H, J = 7.0 Hz),
1
2
4.65ꢀ4.60 (m, 1H), 4.25ꢀ4.19 (m, 1H), 4.03ꢀ3.98 (m, 1H), 2.69ꢀ2.60 (m, 1H), 2.32ꢀ2.24 (m, 1H);
13
C NMR (100 MHz, CDCl ): δ 167.6, 148.6, 146.7, 138.7, 136.3, 133.2, 128.8, 127.9, 127.1,
3
+
1
23.5, 122.2, 121.7, 116.6, 83.7, 68.6, 47.6, 33.5; HRMS (ESI): m/z [M + H] calcd for
C H N O : 364.1297; found 364.1309.
20
18
3
4
(2R*,3R*)-3-(3-Nitrophenyl)-N-(quinolin-8-yl)tetrahydrofuran-2-carboxamide
(3g):
Following the general procedure, 3g was obtained after purification by column chromatography
on silica gel (EtOAc:Hexanes = 50:50) as brown colour solid; Yield: 75% (68 mg); mp 109ꢀ111
o
ꢀ1 1
C; IR (KBr): 3441, 1684, 1528, 1259, 791 cm ; H NMR (400 MHz, CDCl ): δ 10.57 (br s,
3
1H), 8.84 (dd, 1H, J = 4.2 Hz, J = 1.7 Hz), 8.37 (dd, 1H, J = 7.6 Hz, J = 1.7 Hz), 8.17 (t, 1H, J
1
2
1
2
=
1.7 Hz), 8.11 (dd, 1H, J = 8.3 Hz, J = 1.7 Hz), 7.87ꢀ7.84 (m, 1H), 7.60 (d, 1H, J = 7.7 Hz),
1 2
7
4
.47ꢀ7.42 (m, 2H), 7.38 (t, 1H, J = 8.0 Hz), 7.26 (t, 1H, J = 8.0 Hz), 4.78 (d, 1H, J = 6.8 Hz),
.70ꢀ4.64 (m, 1H), 4.26ꢀ4.20 (m, 1H), 4.03ꢀ3.98 (m, 1H), 2.70ꢀ2.61 (m, 1H), 2.36ꢀ2.28 (m, 1H);
13
C NMR (100 MHz, CDCl ): δ 167.6, 148.7, 148.0, 142.8, 138.6, 136.1, 134.4, 133.2, 129.0,
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27.8, 126.9, 122.7, 122.1, 121.9, 121.7, 116.5, 83.7, 68.6, 47.5, 33.3; HRMS (ESI): m/z [M +
+
H] calcd for C H N O : 364.1297; found 364.1310.
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(2R*,3R*)-3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-N-(quinolin-8-yl)tetrahydrofuran-2-
0
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carboxamide (3h): Following the general procedure, 3h was obtained after purification by
column chromatography on silica gel (EtOAc:Hexanes = 40:60) as colourless liquid; Yield: 53%
ꢀ1 1
(50 mg); IR (DCM): 3440, 1677, 1528, 1282, 749 cm ; H NMR (400 MHz, CDCl ): δ 10.55 (br
3
s, 1H), 8.88 (dd, 1H, J = 4.2 Hz, J = 1.7 Hz), 8.52 (dd, 1H, J = 6.9 Hz, J = 1.7 Hz), 8.11 (dd,
1
2
1
2
1H, J = 8.2 Hz, J = 1.7 Hz), 7.46ꢀ7.42 (m, 3H), 6.80 (d, 1H, J = 2.0 Hz ), 6.75 (dd, 1H, J = 8.3
1
2
1
Hz, J = 2.0 Hz), 6.60 (d, 1H, J = 8.3 Hz), 4.71 (d, 1H, J = 6.8 Hz), 4.60ꢀ4.55 (m, 1H), 4.20ꢀ4.14
2
1
3
(m, 1H), 4.09ꢀ3.94 (m, 4H), 3.82ꢀ3.78 (m, 1H), 2.58ꢀ2.49 (m, 1H), 2.30ꢀ2.22 (m, 1H); C NMR
(100 MHz, CDCl ): δ 168.6, 148.5, 143.0, 142.2, 138.8, 136.0, 133.7, 127.9, 127.1, 121.6, 121.4,
3
+
1
20.9, 116.9, 116.8, 116.6, 83.8, 68.6, 64.1, 47.3, 33.6; HRMS (ESI): m/z [M + H] calcd for
C H N O : 377.1501; found 377.1508.
22 21
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4
(
2R*,3R*)-3-(Benzo[d][1,3]dioxol-5-yl)-N-(quinolin-8-yl)tetrahydrofuran-2-carboxamide
3i): Following the general procedure, 3i was obtained after purification by column
(
chromatography on silica gel (EtOAc:Hexanes = 40:60) as brown colour liquid; Yield: 46% (42
ꢀ1 1
mg); IR (DCM): 3432, 1637, 1528, 1269, 749 cm ; H NMR (400 MHz, CDCl ): δ 10.57 (br s,
3
1
H), 8.88 (dd, 1H, J = 4.2 Hz, J = 1.7 Hz), 8.51 (dd, 1H, J = 7.1 Hz, J = 1.7 Hz), 8.13 (dd, 1H,
1 2 1 2
J = 8.3 Hz, J = 1.7 Hz), 7.47ꢀ7.42 (m, 3H), 6.79 (d, 1H, J = 1.7 Hz), 6.75 (dd, 1H, J = 8.0 Hz,
1
2
1
J2 = 1.7 Hz), 6.57 (d, 1H, J = 8.0 Hz), 5.76 (d, 1H, J = 1.5 Hz), 5.66 (d, 1H, J = 1.5 Hz), 4.71 (d,
1
H, J = 6.8 Hz), 4.61ꢀ4.55 (m, 1H), 4.21ꢀ4.15 (m, 1H), 3.86ꢀ3.81 (m, 1H), 2.60ꢀ2.51 (m, 1H),
1
3
2
.30ꢀ2.22 (m, 1H); C NMR (100 MHz, CDCl ): δ 168.4, 148.5, 147.4, 146.1, 138.8, 136.1,
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+
3.7; HRMS (ESI): m/z [M + H] calcd for C H N O : 363.1345; found 363.1352.
21 19
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(
2R*,3R*)-3-(4-Bromo-3-fluorophenyl)-N-(quinolin-8-yl)tetrahydrofuran-2-carboxamide
3j): Following the general procedure, 3j was obtained after purification by column
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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50
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56
57
58
59
60
(
chromatography on silica gel (EtOAc:Hexanes = 40:60) as brown colour solid; Yield: 58% (60
o
ꢀ1 1
mg); mp 99ꢀ101 C; IR (KBr): 3339, 1686, 1530, 1325, 751 cm ; H NMR (400 MHz, CDCl ): δ
3
1
0.58 (br s, 1H), 8.88 (dd, 1H, J = 4.2 Hz, J = 1.7 Hz), 8.47 (dd, 1H, J = 7.4 Hz, J = 1.7 Hz),
1 2 1 2
8.13 (dd, 1H, J = 8.3 Hz, J = 1.7 Hz), 7.50ꢀ7.42 (m, 3H), 7.30ꢀ7.26 (m, 1H), 7.08 (dd, 1H, J =
1
2
1
9
.8 Hz, J = 2.1 Hz), 6.95 (dd, 1H, J = 8.3 Hz, J = 2.1 Hz), 4.74 (d, 1H, J = 6.8 Hz), 4.60ꢀ4.54
2 1 2
1
3
(
m, 1H), 4.22ꢀ4.15 (m, 1H), 3.88ꢀ3.84 (m, 1H), 2.63ꢀ2.54 (m, 1H), 2.27ꢀ2.18 (m, 1H); C NMR
(100 MHz, CDCl ): δ 167.8, 158.7 (d, J = 245.6 Hz), 148.6, 142.6 (d, JCꢀF = 6.4 Hz), 138.7,
3
CꢀF
1
36.2, 133.3, 133.1, 127.9, 127.1, 125.0 (d, JCꢀF = 3.0 Hz), 122.1, 121.6, 116.7, 116.0 (d, JCꢀF =
+
2
2.2 Hz), 107.0 (d, JCꢀF = 20.7 Hz), 83.6, 68.4, 47.2, 33.5; HRMS (ESI): m/z [M + H] calcd for
C H BrFN O : 415.0457; found 415.0465.
20
17
2
2
(2R*,3R*)-N-(Quinolin-8-yl)-3-(3,4,5-trimethoxyphenyl)tetrahydrofuran-2-carboxamide
(3k): Following the general procedure, 3k was obtained after purification by column
chromatography on silica gel (EtOAc:Hexanes = 60:40) as brown colour solid; Yield: 54% (55
o
ꢀ1 1
mg); mp 89ꢀ91 C; IR (DCM): 3441, 1681, 1590, 1127, 750 cm ; H NMR (400 MHz, CDCl ): δ
3
10.53 (br s, 1H), 8.82 (dd, 1H, J = 4.2 Hz, J = 1.5 Hz), 8.55 (dd, 1H, J = 6.8 Hz, J = 2.2 Hz),
1
2
1
2
8
.11 (dd, 1H, J = 8.3 Hz, J = 1.5 Hz), 7.47ꢀ7.40 (m, 3H), 6.49 (s, 2H), 4.73 (d, 1H, J = 6.6 Hz),
1 2
4
.61ꢀ4.55 (m, 1H), 4.22ꢀ4.16 (m, 1H), 3.85ꢀ3.81 (m, 1H), 3.63 (s, 6H), 3.44 (s, 3H), 2.62ꢀ2.53
1
3
(
m, 1H), 2.32ꢀ2.24 (m, 1H); C NMR (100 MHz, CDCl ): δ 168.4, 152.8, 148.3, 138.6, 136.5,
3
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