Regioselective and Stereoselective Pd-Catalyzed Intramolecular Arylation of Furans: Access to Spirooxindoles and 5H-Furo[2,3-c]quinolin-4-ones

Article abstract of DOI:10.1021/acs.joc.6b01774

Herein, we report regio- and stereoselective intramolecular direct arylations of N-(2-bromophenyl)-2-furancarboxamides 1 to produce spirooxindoles 2 and 5H-furo[2,3-c]quinolin-4-ones 3 under different reaction conditions. Specifically, in the presence of

Full text of DOI:10.1021/acs.joc.6b01774

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Article
Regioselective and Stereoselective Pd-catalyzed Intramolecular Arylation
of Furans: Access to Spirooxindoles and 5H-Furo[2,3-c]quinolin-4-ones
Jianchao Liu, Hui Peng, Yongjie Yang, Huanfeng Jiang, and Biaolin Yin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01774 • Publication Date (Web): 23 Sep 2016
Downloaded from http://pubs.acs.org on September 25, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Regioselective and Stereoselective Pd-catalyzed Intramolecular Arylation
of Furans: Access to Spirooxindoles and 5H-Furo[2,3-c]quinolin-4-ones
Jianchao Liu, Hui Peng, Yongjie Yang, Huanfeng Jiang and Biaolin Yin*
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
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical
Engineering, South China University of Technology, Guangzhou 510640, P. R. China 510640
R
R
10 mol % PPh3
5 mol % Pd(PPh3)4
10 mol % PPh3
5 mol % Pd(PPh3)4
Br
R
NR2
O
R1
200 mol % K2CO3
NR2
R1
O
1
200 mol % t-BuOLi
DCE, 80 o
C
O
NR2
R1
O
O
2
1,4-dioxane, 80 o
R1 = aryl
C
O
R1 = aryl, alkyl
22 examples
yields up to 92%
Z/E: 4:1-16:1
2
5 mol % PdCl2
4 examples
yield: 50-68%
Z/E: 1:1.5-1:2.1
10 mol % L3
150 mol % Cs2CO3
30 mol % PivOH
toluene, 100 oC
R
R1
O
NR2
3
O
19 examples
yields up to 82%
Abstract: Herein, we report regio- and stereoselective intramolecular direct arylations of
N-(2-bromophenyl)-2-furancarboxamides to produce spirooxindoles and
1
2
5H-furo[2,3-c]quinolin-4-ones 3 under different reaction conditions. Specifically, in the presence
of Pd(PPh3)4 as a catalyst, PPh3 as a ligand, and K2CO3 as a base, substrates 1 underwent
intramolecular α-arylation, possibly via a Heck insertion pathway, to provide 2, with the Z-isomer
being favored. When the base was t-BuOLi and R1 was an aryl group, the reaction favored E-2,
possibly via an electrophilic palladation pathway. In contrast, in the presence of PdCl2 as a
catalyst, (o-OMePh)3P as a ligand, and PivOH as an additive, substrates 1 underwent
intramolecular β-arylation to provide 3, possibly via a concerted metalation–deprotonation
process.
INTRODUCTION
The synthesis of bi(hetero)aryl compounds, which have interesting bioactivities1 and physical
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 44
1
2
3
4
5
6
7
8
9
properties,2 by means of direct arylation of five-membered heteroaromatic rings (such as furans,
pyrroles, and thiophenes) is an important but challenging task in organic synthesis.3 Three major
reaction pathways involving palladium catalysis have been proposed for this transformation (Scheme
1). One commonly proposed pathway for reaction of π-electron-rich aromatic substrates is electrophilic
aromatic substitution (SEAr),4 whereby an ArPdX intermediate attacks at the most electronegative
position of the heteroaromatic substrate (Scheme 1a). A Heck-type pathway involving β-H elimination5
(Scheme 1b) and a concerted metalation–deprotonation (CMD) process6 have also been suggested
(Scheme 1c). Recently, several groups have reported the regioselective direct arylation of
five-membered heteroaromatic rings by means of elegant methods involving the use of different
reaction conditions to alter the reaction pathway.7 For example, Sharp and co-workers5a
regioselectively arylated 3-furoate and 3-thiophenecarboxylate esters with aryl bromides and could
change the reaction pathway by varying the palladium source and the solvent. Doucet7a reported that
the regioselectivity of the arylation of 2,5-disubstituted furans depended strongly on the base that was
used.
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
Scheme 1. Major Pathways for Direct Arylation of Five-Membered Heteroaromatic Rings
H
PdArX
H
S Ar
E
or
a
Y
Y
Y
PdArX
Ar
Ar
Ar
X
PdX
H
+
H
Pd
Heck
b
Y
or
PdX
Y
or
Ar
Y
X: I, Br
Y: N, O, S
O
Ar
Y
H
O
H
PdArX
or
CMD
c
Y
Y
PdArX
Biomass derived α-substituted furans are readily available and are excellent, widely used building
blocks for the construction of complex molecules.8 Direct arylation is an important tool for
transforming α-substituted furans into other useful compounds (Scheme 2). Intermolecular
ACS Paragon Plus Environment

Page 3 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
arylation of α-monosubstituted furans generally occurs at the unsubstituted α-position.9 Intermolecular
β-arylation of furans occurs only when both of the α-positions are substituted10 or when a 2-
furancarboxamide is used as the substrate; the latter reaction involves chelation-assisted
functionalization of the ortho-C–H bonds, directed by the amide group.11 Intramolecular α-arylation of
α-substituted furans usually leads to opening of the furan ring to form α,β-unsaturated carbonyl
compounds.12 Intramolecular β-arylation of α-furans has also been reported to afford annulated
furans.13
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
Scheme 2. α and β-Arylation of α-Substituted Furans
intermolecular -arylation (ref. 9):
ArX
[Pd]
Ar
R
H
R
O
O
intermolecular -arylation (ref. 10 and 11):
H
Ar
ArX
[Pd]
R'
H
R
O
R'
R
O
O
H
Ar
ArX
[Pd]
CONRR'
O
CONRR'
intramolecular -arylation (ref. 12):
ROC
Br
[Pd]
R
O
intramolecular -arylation (ref. 13):
Br
[Pd]
R
O
R
O
R
This work:
O
NR2
R
R1
O
2
Br
O
[Pd]
R
NR2
R1
1
O
NR2
R1
O
3
O
Although numerous elegant methods for arylation of α-substituted furans have been reported and
used to extend the synthetic applications of furans, tuning the regio- and stereoselectivities of furan
arylation reactions by altering the reaction pathway by means of different reaction conditions has not
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 44
1
2
3
4
5
6
7
8
9
yet been reported. As part of our ongoing work on furan dearomatization and palladium catalysis,14 in
this study, we carried out regio- and stereoselective intramolecular arylation reactions of furans by
using readily available N-(2-bromophenyl)-2-furancarboxamides 1 as the substrates (Scheme 2). These
reactions afforded biologically interesting spirooxindoles 215 or 5H-furo[2,3-c]quinolin-4-ones 316
depending on the reaction conditions, and the reactions probably proceeded by three different
pathways.
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
RESULTS AND DISCUSSION
We used 2-furancarboxamide 1a as the substrate for optimization of the reaction conditions (Table
1). When 1a was treated with Pd(PPh3)4 (5 mol %), PPh3 (10 mol %) and K2CO3 (200 mol %) in
1,4-dioxane at 80 °C under nitrogen for 12 h, α-arylated spirooxindole 2a was obtained in 93% yield as
a 6:1 Z/E mixture (entry 1). The stereochemistry of 2a was assigned by means of NOESY experiments
(see the ESI). The reaction did not occur in the absence of Pd(PPh3)4 (entry 2), and only a trace of 2a
was produced in the absence of a base (entry 3). Screening of a series of other bases revealed that the
base clearly influenced the outcome of the reaction (entries 4–10). Among the weak bases, Na2CO3
gave 2a in a yield (90%) and a Z/E ratio (5.8:1) that were comparable to those observed with K2CO3
(entry 4). The use of Cs2CO3 and DBU led to lower yields and Z/E ratios than K2CO3 (entries 5 and 6).
Li2CO3 gave only a trace of 2a (entry 7). Notably, strong bases (t-BuOLi, t-BuONa, and t-BuOK) gave
2a in low yields but with stereoselectivities opposite to that observed with the weak bases; that is, the
E-isomer was the major isomer (entries 8–10). Among these strong bases, t-BuOLi gave the highest
yield (55%) and the lowest Z/E ratio (1/2.7) (entry 8). On the basis of these results, we used K2CO3 or
t-BuOLi as the base to favor the synthesis of the Z- or E-isomer of 2a, respectively. Solvent screening
demonstrated that DCE was optimal when K2CO3 was the base (entry 12), whereas 1,4-dioxane was
ACS Paragon Plus Environment

Page 5 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
optimal for t-BuOLi (entry 8).
Table 1. Optimization of the α-Arylation of 1aa
8
9
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
Z/Eb
entry
1
base
K2CO3
K2CO3
—
solvent
yield of 2a (%)b
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
93
NR
trace
90
6/1
—
2c
3
—
4
Na2CO3
Cs2CO3
DBU
5.8/1
5/1
5
48
6
35
1/1
7
Li2CO3
trace
53
—
8
t-BuOLi 1,4-dioxane
t-BuONa 1,4-dioxane
1/2.7
1/2.5
1/1.5
4.8/1
12.5/1
2.6/1
2.8/1
1/2
9
45
10
11
12
13
14
15
16
17
18
t-BuOK
K2CO3
1,4-dioxane
toluene
DCE
52
97
K2CO3
98
K2CO3
THF
80
K2CO3
DMF
70
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
toluene
DCE
50
55
1/1.2
1.3/1
1/1.2
THF
60
DMF
37
aReaction conditions, unless otherwise noted: 1a (0.3 mmol), Pd(PPh3)4 (5 mol %), PPh3 (10 mol %), base (200 mol %), solvent
b
1
(3 mL), T = 80 °C, N2 atmosphere, 12 h. NR = no reaction; ND = not detected. Yields and Z/E ratios were determined by H
NMR analysis with mesitylene as an internal standard. cThis reaction was carried out in the absence of Pd(PPh3)4.
To
investigate
the
scope
of
the
reaction,
we
subjected
various
N-(2-bromophenyl)-2-furancarboxamides 1 with different R, R1, and R2 groups to the optimized
reaction conditions (Table 1, entry 12) to synthesize a range of spirooxindoles 2, with the Z-isomer as
the major product (Table 2). The reaction had a broad substrate scope, and in most cases, expected
spirooxindoles 2 were obtained in good to excellent yields (51–92%) and good Z/E selectivities
(4:1–16:1). Specifically, R could be an H atom, an electron-donating group (Me, t-Bu, OMe), or an
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 44
1
2
3
4
5
6
7
8
9
electron-withdrawing group (F). The R1 substituent could be an alkyl group, a phenyl group (either
unsubstituted or with an electron-donating or electron-withdrawing substituent), a thiophenyl group, or
a naphthyl group. Notably, when R1 was Me, the Z/E selectivities were lower (2s–2u) than those
observed with other R1 groups. The R2 substituent could be a small alkyl group (Me, Et) or a slightly
larger alkyl group (i-Pr), but when R2 was H (1v), O-arylation occurred and the corresponding
spirooxindole (2v) could not be isolated.
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
Table 2. Scope of the α-Arylation Reactiona
R
R
10 mol % PPh3
Br
5 mol % Pd(PPh3)4
NR2
200 mol % K2CO3
O
NR2
R1
DCE, 80 o
C
O
1
O
R1
2
O
R
R
R
O
O
O
NEt
NEt
O
Ph
NEt
O
O
Cl
2a, R = H, 91%, 12:1
2f, R = H, 82%, 10:1
2j, R = H, 83%, 14:1
2k, R = 4-Me, 80%,13:1
2b, R = 4-Me, 80%,13:1
2c, R = 4-t-Bu, 82%, 12:1
2d, R = 4-OMe, 75%, 10:1
2e, R = 4-F, 91%, 12:1
2g, R = 4-Me, 72%,16:1
2h, R = 4-OMe, 80%,14:1
2i, R = 5-Me, 70%, 8:1
Cl
O
O
O
NEt
NEt
NEt
O
2m, 87%, 10:1
R
O
O
2n, 85%, 11:1
2l, 80%, 9:1
MeO
CF3
O
NEt
O
O
NEt
O
NEt
S
O
O
2p, R = H, 87%, 13:1
2q, R = 4-Me, 85%,12:1
2o, 86%, 12:1
2r, 92%
O
NR2
O
Me
Me
NH
O
O
2s, R2 = Me, 85%, 4:1b
2t, R2 = Et, 82%, 5:1b
2u, R2 = i-Pr, 51%, 4:1b
2v (ND)
aReaction conditions, unless otherwise noted: 1 (0.3 mmol), DCE (3 mL), T = 80 °C, under N2, 12 h. Yields are isolated yields.
Z/E ratios were determined by 1H NMR analysis. ND = not detected. bT = 90 °C .
When 1a (R1 = Ph) and 1g-1h (R1 = p-Toly) were subjected to the reaction conditions listed in
ACS Paragon Plus Environment

Page 7 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
entry 8 of Table 1, these substrates were transformed to corresponding products 2 in moderate isolated
yields, with the E-isomer being favored (Z/E = 1:1.5–1:2.7, Scheme 3). Notably, when the substrate
was 1s (R1 = Me), the product 2s’ was formed still with the Z-isomer being favored.
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
Scheme 3. Synthesis of E-isomers of 2a and 2g–2ha
aReaction conditions: 1 (0.3 mmol), 1,4-dioxane (3 mL), under N2, 12 h. Yields are isolated yields. Z/E ratios were determined by
1H NMR analysis.
In explanation of the stereoselectivity for the formation of 2 under the two different sets of
reaction conditions, we propose the two paths shown in Scheme 4. The first step is oxidative addition
of Pd(0) to 1 to produce palladium complex 4. In the presence of K2CO3 (path a), 4 undergoes a
Heck-type α-arylation of the furan ring to produce alkyl palladium 5. Alkyl palladium 5 isomerizes
to allylic palladium 6 and then to alkyl palladium 7 and 7′, which undergo β-H elimination to form 2.17
The formation of 7 is favored, owing to the absence of an interaction between the olefinic proton and
the phenyl group, and as a result, Z-2 is the major. In contrast, when R1 is an aryl group and t-BuOLi
is used as the base (path b), deprotonation of the methylene carbon of 4 leads to carbanion 8, which
then undergoes a 1,7-lithium shift to form chelation complexes Z-9 and E-9.18 Complexes 9 undergo
electrophilic palladation to produce 10, and subsequent reductive elimination affords 2. Complex E-9 is
favored over Z-9 owing to the lack of an interaction between the phenyl group and the lithium salt, and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 44
1
2
3
4
5
6
7
8
9
as a result, E-2 is the major product. When R1 is a methyl group, due to low acidity of the proton of the
methylene carbon, the deprotonation of 4s by t-BuOLi to 8s is suppressed, thus 2s’ is formed through
Heck-type insertion still with the Z-isomer as the major product.
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
Scheme 4. Proposed Mechanisms for Formation of 2 under Different Reaction Conditions
Having investigated dearomatizing α-arylation of 1 to form spirooxindoles 2, we next searched for
suitable conditions to achieve intramolecular β-arylation to form β-arylated products 3 by suppressing
α-arylation and enhancing the acidity of the β-H. Addition of a protonic acid, such as pivalic acid
(PivOH), is known to increase the acidity of C–H protons during transformations involving C–H
functionalization.19 Thus, we set out to optimize the reaction conditions for the formation of 3 from
substrate 1a by using PivOH as an additive (Table 3). With Pd(OAc)2 as the catalyst, PCy3·HBF4 as the
ligand, and Cs2CO3 as the base, reaction of 1a at 100 °C in toluene provided 3a and 2a in 58% and
30% yields, respectively (entry 1). In the absence of PivOH, 2a was the only product (85% yield, entry
2). Solvent screening demonstrated that toluene was optimal for the formation of 3a (entries 3–8).
Various ligands were then examined, and the ligand was found to strongly influence the reaction
ACS Paragon Plus Environment

Page 9 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
outcome (entries 9–13). The electron-rich phenyl phosphine ligand (o-OCH3Ph)3P (L3) gave the highest
yield of 3a (78%, entry 10). Finally, different palladium sources were evaluated (entries 14–17), and
PdCl2 was determined to be the best, giving 3a in 86% yield (entry 16).
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
Table 3. Optimization of the Reaction Conditions for the β-Arylation of 1aa
[Pd]/L, Cs2CO3
Br
PivOH
NEt
+
O
NEt
NEt
solvent, 100 o
C
Bn
Bn
Ph
O
O
O
2a
O
O
3a
1a
yield of
3a (%)b
58
yield of
2a (%)b
30
entry
[Pd]
L
solvent
1
2c
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
L1
L1
toluene
toluene
DCE
ND
55
85
L1
32
4
L1
CH3CN
THF
38
35
5
L1
40
42
6
L1
1,4-dioxane
DMA
42
45
7
L1
45
40
8
L1
DMSO
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
30
35
9
L2
ND
78
65
10
11
12
13
14
15
16
17
L3
15
PCy3
PPh3
60
24
46
40
Pd(OAc)2 Binap
50
31
Pd(PPh3)4
Pd2(dba)3
PdCl2
L3
L3
L3
L3
72
23
76
15
86
8
PdBr2
80
12
aReaction conditions, unless otherwise noted: 1 (0.3 mmol), [Pd] (5 mol %), L (10 mol %), Cs2CO3 (150 mol %), PivOH (30
mol % ), solvent (3 mL), under N2, 100 °C, 12 h. L1 = PCy3·HBF4, L2 = (o-CH3Ph)3P, L3 = (o-OCH3Ph)3P. ND = not detected.
bYields were determined by 1H NMR analysis with mesitylene as an internal standard. cNo PivOH was used in this reaction.
We subjected various substrates 1 with different R, R1, and R2 groups to the optimized conditions
(Table 3, entry 16) to evaluate the generality of the β-arylation reaction (Table 4). The substrate scope
was broad, and most of the substrates 1 could be transformed into 5H-furo[2,3-c]quinolin-4-ones 3 in
good yields (70–82%). Specifically, R could be a H atom, an electron-donating group (Me, t-Bu, OMe),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 44
1
2
3
4
5
6
7
8
9
or an electron-withdrawing group (F). The R1 substituent could be an alkyl group, a phenyl group
(either unsubstituted or with an electron-donating or electron-withdrawing substituent), or a thiophenyl
group. The R2 substituent could be a small alkyl group (Me, Et), but when R2 was H (1p) or a larger
alkyl group (i-Pr, 1s), the expected products (3p and 3s, respectively) were not observed.
Table 4. Substrate Scope of the β-Arylationa
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
R
R
5 mol % PdCl2, 10 mol % L3
150 mol % Cs2CO3, 30 mol % PivOH
Br
NR2
R
NR2
toluene, 100 o
C
R1
O
O
R1
3
O
1
O
R
R
Cl
NEt
NEt
NEt
O
O
O
Ph
O
O
O
3i, R = H, 80%
3a, R = H, 82%
3e, R = H, 75%
3j, R = 4-CH3, 75%
3k, R = 4-OCH3, 70%
3l, R = 5-CH3, 78%
3m, R = 4-F, 81%
3b, R = 4-CH3, 80%
3c, R = 5-CH3, 78%
3d, R = 4-t-Bu, 80%
3f, R = 4-CH3, 73%
3g, R = 5-CH3, 80%
3h, R = 4-OCH3, 70%
Et
NEt
O
N
NEt
O
O
R2
O
S
O
O
3p, R2 = H, ND
3q, R2 = CH3, 70%
3r R2 = C2H5, 75%
3s, R2 = i-Pr, ND
3o, 82%
3n, 82%
aReaction conditions: 1 (0.3 mmol), toluene (3 mL), under N2, 12 h. Yields are isolated yields.
Scheme 5. Proposed Mechanism for the Formation of 3
A mechanism for the formation of 3 is proposed in Scheme 5. Oxidative addition of Pd(0) to 1
ACS Paragon Plus Environment

Page 11 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
produces palladium complex 4. Nucleophilic attack of 4 by pivalate anion produces ArPd(OPiv)
complex 10, which forms a CMD transition state (11) via activation of the β-C–H bond of the furan
ring. After a release of PivOH, 11 is transformed into biarylpalladium species 12, which is
subsequently converted to complex 13. Complex 13 then undergoes reductive elimination to give 3 and
regenerate Pd(0).
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
When N-benzyl-2-furancarboxamide 1ab was subjected to the optimized reaction conditions for
the α- and β-arylations, the substrate was transform into [5.6]spirooxindole 2w (60% yield, 12:1 Z/E
mixture) and seven-membered lactam 3t (56% yield), respectively (Scheme 6).
Scheme 6. Synthesis of 2w and 3t
5 mol % PdCl2
10 mol % PPh3
10 mol % L3
150 mol % Cs2CO3
Br
5 mol % Pd(PPh3)4
O
200 mol % K2CO3
N
N
Ph
30 mol % PivOH
toluene, 100 oC
O
DCE, 80 o
C
O
n-Bu
O
Ph
N
n-Bu
Ph
O
n-Bu
O
2w, 60%, 12/1
1ab
3t, 56%
CONCLUSION
In summary, we achieved regioselective Pd-catalyzed intramolecular direct arylation of the furan
rings of N-(2-bromophenyl)-2-furancarboxamides using different reaction conditions to efficiently
synthesize biologically interesting spirooxindoles and 5H-furo[2,3-c]quinolin-4-ones. Interestingly,
when R1 of 1 was an aryl group, Z and E favored spirooxindoles can be formed using K2CO3 and
t-BuOLi as the base, respectively. We propose three possible pathways for these
transformations—namely, Heck insertion, electrophilic palladation, and CMD—indicating the
versatility of this Pd-catalyzed direct arylation for the transformation of furans. In particular, the
dearomatizing intramolecular α-arylation that occurred without opening of the furan ring is of great
significance for extending the synthetic applications of furan derivatives.
EXPERIMENTAL SECTION
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 44
1
2
3
4
5
General Information. IR spectra were recorded with FT-IR as a thin film or using KBr pellets and are
6
7
1
expressed in cm-1. H (400 MHz) and 13C (100 MHz) NMR spectra were recorded using CDCl3 as a
8
9
solvent. Chemical shifts are reported in ppm downfield to tetramethylsilane. Coupling constants are
reported and expressed in Hz; splitting patterns are designated as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), dd (double doublet), dt (double triplet), dq (double quartet), br (broad). Mass
spectra were obtained from high resolution ESI mass spectrometer. All reactions were carried out using
freshly distilled and dry solvents. Column chromatography was performed over silica gel (100-200
Mesh) using petroleum ether and ethyl acetate as the eluent. The structures of S1, S2, S3, S4, S5, S6,
S7 are shown in the Supporting Information.
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
General procedure for the preparation of 1
Method A
Synthesis of S2: To a solution of 5-substitued-benzoylfuran-2-carboxylate (S1) (10 mmol) in
MeOH (20 mL) was added NaBH4 (418.0 mg, 11 mmol) in portions at 0 oC. After stirring at the same
temperature for 1 h, H2O (30 mL) was added to quench the reaction. Removal of MeOH under reduced
pressure provided the aqueous layer which was extracted with EtOAc (10 mL×3). The combined
organic layers were washed with saturated brine, dried over Na2SO4, concentrated under reduced
pressure, providing a colorless liquid.
To the solution of the above-made liquid in CH2Cl2 (40 mL) was added CF3COOH (2.5 g, 22 mmol)
o
then Et3SiH (2.55 g, 22 mmol) in portions at 0 C. The reaction was stirred for 30 minutes, then H2O
(20 mL) was added to quench the reaction. The resulting mixture was extracted with CH2Cl2 (10
mL×3), and the combined organic layers were washed with saturated brine, dried over sodium sulfate,
concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel
ACS Paragon Plus Environment

Page 13 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(using petroleum ether/ethyl acetate = 30:1 as the eluent) to give product S2 (S2a-S2g).
Methyl 5-benzylfuran-2-carboxylate (S2a). Colorless oil (1.85 g, 86% over 2 steps); IR (film) 2951,
1726, 1496, 1308, 1019, 797 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.31 (m, 2H), 7.30 – 7.27 (m,
3H), 7.12 (d, J = 3.3 Hz, 1H), 6.09 (d, J = 3.3 Hz, 1H), 4.06 (s, 2H), 3.89 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 159.6, 159.2, 143.4, 136.6, 128.8, 128.6, 126.9, 119.2, 108.9, 51.7, 34.7; HRMS (ESI) m/z
calcd for C13H12NaO3 [M + Na]+: 239.0679; Found: 239.0689.
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
Methyl 5-(4-methylbenzyl)furan-2-carboxylate (S2b). Colorless oil (2.07 g, 90% over 2 steps); IR
1
(film) 2951, 1726, 1595, 1436, 1201, 1020, 927 cm-1; H NMR (400 MHz, CDCl3) δ 7.15 – 7.09 (m,
4H), 7.07 (d, J = 3.4 Hz, 1H), 6.04 (d, J = 3.4 Hz, 1H), 3.97 (s, 2H), 3.84 (s, 3H), 2.31 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 160.0, 159.2, 143.3, 136.4, 133.6, 129.3, 128.7, 119.2, 108.7, 51.7, 34.3,
21.0; HRMS (ESI) m/z calcd for C14H14NaO3 [M + Na]+: 253.0835; Found: 253.0845.
Methyl 5-(4-chlorobenzyl)furan-2-carboxylate (S2c). Colorless oil (2.12 g, 85% over 2 steps); IR (film)
2952, 1725, 1592, 1435, 1201, 1016, 927 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.4 Hz, 2H),
7.17 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 3.4 Hz, 1H), 6.08 (d, J = 3.4 Hz, 1H), 4.00 (s, 2H), 3.87 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 159.3, 158.9, 143.5, 135.1, 132.8, 130.1, 128.8, 119.3, 109.0, 51.9, 34.0;
HRMS (ESI) m/z calcd for C13H11ClNaO3 [M + Na]+: 273.0298; Found: 273.0298.
Methyl 5-(4-methoxybenzyl)furan-2-carboxylate (S2d). Colorless oil (2.16 g, 88% over 2 steps); IR
1
(film) 2951, 1725, 1604, 1437, 1249, 1027 cm-1; H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.6 Hz,
2H), 7.08 (d, J = 3.4 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.04 (d, J = 3.4 Hz, 1H), 3.97 (s, 2H), 3.86 (s,
3H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.1, 159.2, 158.5, 143.3, 129.8, 128.7, 119.2, 114.1,
108.6, 55.2, 51.7, 33.9; HRMS (ESI) m/z calcd for C14H14NaO4 [M + Na]+: 269.0784; Found:
269.0793.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 44
1
2
3
4
5
Ethyl 5-(2-methylbenzyl)furan-2-carboxylate (S2e). Colorless oil (2.09 g, using ethyl-2-furoate as the
6
7
1
start material, 86% over 2 steps); IR (film) 2980, 1720, 1456, 1206, 965 cm-1; H NMR (400 MHz,
8
9
CDCl3) δ 7.22 – 7.17 (m, 4H), 7.09 (d, J = 3.2 Hz, 1H), 5.94 (d, J = 3.2 Hz, 1H), 4.37 (q, J = 7.1 Hz,
2H), 4.05 (s, 2H), 2.31 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 158.9,
143.6, 136.5, 134.9, 130.4, 129.7, 127.2, 126.2, 119.0, 108.7, 60.7, 32.6, 19.3, 14.3; HRMS (ESI) m/z
calcd for C15H16NaO3 [M + Na]+: 267.0992; Found: 267.1000.
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
Methyl 5-(thiophen-2-ylmethyl)furan-2-carboxylate (S2f). Colorless oil (1.89 g, 85% over 2 steps); IR
1
(film) 2952, 1725, 1434, 1203, 1022, 927 cm-1; H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 5.1, 1H),
7.09 (d, J = 3.4 Hz, 1H), 6.93 (dd, J = 5.1, 3.5 Hz, 1H), 6.89 (d, J = 3.4, 1H), 6.17 (d, J = 3.4 Hz, 1H),
4.22 (s, 2H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.1, 158.4, 143.5, 138.4, 127.0, 126.2,
124.5, 119.2, 108.9, 51.7, 28.9; HRMS (ESI) m/z calcd for C11H10O3NaS [M + Na]+: 245.0243; Found:
245.0251.
Methyl 5-(naphthalen-2-ylmethyl)furan-2-carboxylate (S2g). Colorless solid (2.39 g, 90% over 2 steps),
o
mp: 68.6 – 69.5 C; IR (film) 2951, 1724, 1595, 1434, 1203, 809 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.82 – 7.72 (m, 3H), 7.67 (s, 1H), 7.49 – 7.40 (m, 2H), 7.34 (dd, J = 8.4, 1.1 Hz, 1H), 7.09 (d, J = 3.4
Hz, 1H), 6.07 (d, J = 3.3 Hz, 1H), 4.17 (s, 2H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.5,
159.2, 143.5, 134.1, 133.5, 132.4, 128.4, 127.6, 127.6, 127.4, 127.0, 126.2, 125.8, 119.3, 109.1, 51.8,
34.9; HRMS (ESI) m/z calcd for C17H14NaO3 [M + Na]+: 289.0835; Found: 289.0838.
Synthesis of 1: To the solution of S2 (5 mmol) in THF (5 mL) was added aqueous NaOH (2 N, 10 mL)
slowly. The reaction was stirred at room temperature until the disappearance of S2 according to the
TLC. The organic solvent was removed under reduced pressure, then aqueous HCl (2 N) was added
slowly to acidify the aqueous solution (pH = 2). The resulting mixture was extracted with EtOAc (10
ACS Paragon Plus Environment

Page 15 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
mL×3), the combined organic layers were washed with saturated brine, dried over Na2SO4,
concentrated under reduced pressure, providing a white solid (S3).
8
9
To a round-bottom 50 mL flask equipped with a condenser pipe and a drying tube was added the
above-obtained solid (S3) then SOCl2 (20 mL). The mixture was heated to reflux for 3 hours. The
excessive SOCl2 was removed under reduced pressure. Dry CH2Cl2 (5 mL) was added to the residue to
form a clear solution. The solution was slowly added to a mixture of 2-bromoaniline (S4, 5.5 mmol),
triethylamine (1.01 g, 10 mmol) and CH2Cl2 (5 mL) at 0 oC. After the addition, the solution was stirring
at room temperature for 30 minutes, and then H2O (30 mL) was added. The resulting mixture was
extracted with EtOAc (10 mL×3), the combined organic layers were washed with brine, dried over
Na2SO4, concentrated under reduced pressure, The residue was purified by flash chromatography on a
silica gel (using PE/ EtOAc = 12:1 as the eluent) to give product 1 (1a-q, 1u-y, 1ab).
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
5-Benzyl-N-(2-bromophenyl)-N-ethylfuran-2-carboxamide (1a). Colorless oil (1.21 g, 63% over 4
steps); IR (film) 2977, 2932, 1720, 1640, 1211, 969 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J =
7.9, 1.2 Hz, 1H), 7.35 – 7.30 (m, 1H), 7.29 – 7.27 (m, 2H), 7.26 – 7.24 (m, 1H), 7.24 – 7.22 (m, 1H),
7.22 – 7.18 (m, 1H), 7.07 (d, J = 7.1 Hz, 2H), 6.05 (br, 1H), 5.84 (br, 1H), 4.28 – 4.16 (m, 1H), 3.78 (s,
2H), 3.55 – 3.45 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.7, 157.2, 146.4,
141.4, 137.0, 133.7, 131.1, 129.5, 128.7, 128.5, 128.2, 126.6, 124.2, 117.4, 108.1, 44.4, 34.4, 12.7;
HRMS (ESI) m/z calcd for C20H19BrNO2 [M + H]+: 384.0594 ; Found: 384.0608.
5-Benzyl-N-(2-bromo-4-methylphenyl)-N-ethylfuran-2-carboxamide (1b). Colorless oil (1.31 g, 66%
over 4 steps); IR (film) 2975, 1722, 1641, 1522, 1448, 1210, 969 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.42 (s, 1H), 7.29 – 7.17 (m, 3H), 7.12 – 7.03 (m, 4H), 5.93 (br, 1H), 5.81 (br, 1H), 4.23 – 4.12 (m, 1H),
3.80 (s, 2H), 3.51 – 3.37 (m, 1H), 2.34 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 44
1
2
3
4
5
6
7
8
9
158.8, 157.1, 146.4, 139.9, 138.6, 137.1, 134.1, 130.7, 128.9, 128.7, 128.5, 126.6, 123.8, 117.2, 108.1,
44.4, 34.5, 20.9, 12.6; HRMS (ESI) m/z calcd for C21H21BrNO2 [M + H]+: 398.0750; Found: 398.0757.
5-Benzyl-N-(2-bromo-4-tert-butylphenyl)-N-ethylfuran-2-carboxamide (1c). Colorless oil (1.32 g, 60%
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
over 4 steps); IR (film) 2926, 1743, 1688, 1643, 1464, 1212, 1024, 967 cm-1; H NMR (400 MHz,
CDCl3) δ 7.63 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.29 – 7.25 (m, 2H), 7.24 – 7.13 (m, 2H), 7.08 (d, J =
7.2 Hz, 2H), 5.93 (br, 1H), 5.78 (br, 1H), 4.25 – 4.15(m, 1H), 3.76 (s, 2H), 3.52 – 3.42 (m, 1H), 1.31 (s,
9H), 1.22 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.7, 157.2, 153.4, 146.3, 138.6, 137.1,
130.7, 130.5, 128.7, 128.5, 126.6, 125.3, 123.8, 117.2, 108.1, 44.4, 34.8, 34.4, 31.2, 12.7; HRMS (ESI)
m/z calcd for C24H26BrNNaO2 [M + Na]+: 462.1039; Found: 462.1039.
5-Benzyl-N-(2-bromo-4-methoxyphenyl)-N-ethylfuran-2-carboxamide (1d). Colorless oil, (1.34 g, 65%
over 4 steps); IR (film) 2934, 1721, 1640, 1216, 970 cm-1; H NMR (400 MHz, CDCl3) δ 7.49 – 7.43
1
(m, 1H), 7.29 – 7.23 (m, 2H), 7.22 – 7.17 (m, 1H), 7.06 (d, J = 7.2 Hz, 2H), 6.78 – 6.72 (m, 2H), 6.09
(br, 1H), 5.85 (br, 1H), 4.21 – 4.10 (m, 1H), 3.79 (s, 2H), 3.74 (s, 3H), 3.58 – 3.45 (m, 1H), 1.22 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.5, 158.7, 157.2, 146.3, 142.0, 137.1, 133.8, 128.7,
128.5, 126.6, 117.4, 116.6, 115.4, 114.5, 108.2, 55.7, 44.6, 34.5, 12.7; HRMS (ESI) m/z calcd for
C21H21BrNO3 [M + H]+: 414.0699 ; Found: 414.0705.
5-Benzyl-N-(2-bromo-4-fluorophenyl)-N-ethylfuran-2-carboxamide (1e). Colorless oil (1.1 g, 55% over
4 steps); IR (film) 2930, 1719, 1639, 1451, 1264, 967 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.21
(m, 4H), 7.18 – 7.13 (m, 1H), 7.02 (d, J = 6.7 Hz, 2H), 6.97 (t, J = 8.0 Hz, 1H), 6.28 (br, 1H), 5.91 (br,
1H), 4.22 – 4.11 (m, 1H), 3.75 (s, 2H), 3.51 – 3.40 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 161.4 (d, JC-F = 253.4 Hz), 158.7, 157.2, 146.5, 137.6 (d, JC-F = 4.0 Hz), 136.9, 131.7
(d, JC-F = 9.1 Hz), 128.6, 128.5, 126.7, 124.6 (d, JC-F = 10.2 Hz), 120.7 (d, JC-F = 25.2 Hz), 117.8, 115.2
ACS Paragon Plus Environment

Page 17 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
(d, JC-F = 22.2 Hz), 108.3, 44.5, 34.5, 12.6; HRMS (ESI) m/z calcd for C20H18BrFNO2 [M + H]+:
402.0499; Found: 402.0511.
7
8
9
N-(2-Bromophenyl)-N-ethyl-5-(4-methylbenzyl)furan-2-carboxamide (1f). Colorless oil (1.23 g, 62%
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
over 4 steps); IR (film) 2976, 1641, 1480, 1211, 1023, 969 cm-1; H NMR (400 MHz, CDCl3) δ 7.63
(dd, J = 7.9, 1.3 Hz, 1H), 7.35 – 7.30 (m, 1H), 7.26 – 7.18 (m, 2H), 7.08 (d, J = 7.9 Hz, 2H), 6.97 (d, J
= 7.8 Hz, 2H), 6.03 (d, J = 2.2 Hz, 1H), 5.82 (d, J = 2.2 Hz, 1H), 4.26 – 4.18 (m, 1H), 3.74 (s, 2H),
3.56 – 3.47 (m, 1H), 2.33 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 157.6,
146.3, 141.4, 136.1, 133.9, 133.7, 131.1, 129.4, 129.1, 128.6, 128.2, 124.2, 117.4, 107.9, 44.4, 34.0,
21.0, 12.7; HRMS (ESI) m/z calcd for C21H21BrNO2 [M + H]+: 398.0750 ; Found: 398.0762.
N-(2-Bromo-4-methylphenyl)-N-ethyl-5-(4-methylbenzyl)furan-2-carboxamide (1g). Colorless oil (1.33
g, 65% over 4 steps); IR (film) 2975, 1642, 1446, 1210, 969 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.43
(s, 1H), 7.10 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 7.8 Hz, 2H), 6.96 (d, J = 7.8 Hz, 2H), 5.91 (br, 1H), 5.78
(br, 1H), 4.25 – 4.12 (m, 1H), 3.76 (s, 2H), 3.50 – 3.41 (m, 1H), 2.35 (s, 3H), 2.31 (s, 3H), 1.20 (t, J =
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.9, 157.5, 146.2, 139.9, 138.7, 136.1, 134.1, 134.0,
130.7, 129.1, 128.9, 128.6, 123.8, 117.2, 107.9, 44.4, 34.1, 21.0, 20.8, 12.6; HRMS (ESI) m/z calcd for
C22H23BrNO2 [M + H]+: 412.0907 ; Found: 412.0920.
N-(2-Bromo-4-methoxyphenyl)-N-ethyl-5-(4-methylbenzyl)furan-2-carboxamide (1h). Colorless oil
(1.45 g, 68% over 4 steps); IR (film) 2931, 1642, 1473, 1216, 970 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.49 (d, J = 9.6 Hz, 1H), 7.08 (d, J = 7.8 Hz, 2H), 6.98 (d, J = 7.8 Hz, 2H), 6.84 – 6.76 (m, 2H), 6.10
(br, 1H), 5.85 (br, 1H), 4.21 – 4.12 (m, 1H), 3.77 (s, 2H), 3.77 (s, 3H), 3.58 – 3.49 (m, 1H), 2.33 (s, 3H),
1.25 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.5, 158.7, 157.6, 146.2, 142.1, 136.1, 134.0,
133.8, 129.2, 128.6, 117.4, 116.6, 115.4, 114.5, 107.9, 55.7, 44.6, 34.1, 21.0, 12.7; HRMS (ESI) m/z
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 44
1
2
3
4
5
calcd for C22H23BrNO3 [M + H]+: 428.0856 ; Found: 428.0869.
6
7
8
9
N-(2-Bromo-5-methylphenyl)-N-ethyl-5-(4-methylbenzyl)furan-2-carboxamide (1i). Colorless oil (1.34
g, 65% over 4 steps); IR (film) 2976, 1643, 1472, 1211, 969 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.47
(d, J = 8.1 Hz, 1H), 7.08 – 7.02 (m, 3H), 7.00 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 7.8 Hz, 2H), 5.97 (br,
1H), 5.80 (br, 1H), 4.20 – 4.10 (m, 1H), 3.74 (s, 2H), 3.54 – 3.44 (m, 1H), 2.30 (s, 3H), 2.28 (s, 3H),
1.21 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.7, 157.5, 146.3, 141.1, 138.5, 136.1, 134.0,
133.2, 131.6, 130.3, 129.1, 128.6, 120.6, 117.3, 107.9, 44.5, 34.1, 21.0, 20.8, 12.7; HRMS (ESI) m/z
calcd for C22H22BrNNaO2 [M + Na]+: 434.0726; Found: 434.0728.
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
N-(2-Bromophenyl)-5-(4-chlorobenzyl)-N-ethylfuran-2-carboxamide (1j). Colorless oil (1.25 g, 60%
over 4 steps); IR (film) 2976, 1743, 1641, 1482, 1210, 968 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.58 (d,
J = 7.9 Hz, 1H), 7.31 – 7.26 (m, 1H), 7.25 – 7.14 (m, 4H), 6.97 (d, J = 8.0 Hz, 2H), 6.05 (br, 1H), 5.84
(br, 1H), 4.28 – 4.09 (m, 1H), 3.73 (s, 2H), 3.55– 3.42 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 158.7, 156.4, 146.6, 141.3, 135.5, 133.7, 132.5, 131.1, 130.0, 129.5, 128.6, 128.2,
124.1, 117.3, 108.3, 44.5, 33.8, 12.6; HRMS (ESI) m/z calcd for C20H18BrClNO2 [M + H]+: 418.0204;
Found: 418.0212.
N-(2-Bromo-4-methylphenyl)-5-(4-chlorobenzyl)-N-ethylfuran-2-carboxamide (1k). Colorless oil (1.24
g, 58% over 4 steps); IR (film) 2927, 1643, 1495, 1272, 1210, 966 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.41 (s, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.08 (br, 2H), 6.99 (d, J = 8.2 Hz, 2H), 5.95 (br, 1H), 5.83 (br,
1H), 4.22 – 4.10 (m, 1H), 3.77 (s, 2H), 3.52 – 3.37 (m, 1H), 2.35 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.8, 156.3, 146.6, 139.9, 138.6, 135.6, 134.1, 132.4, 130.6, 130.0, 128.9,
128.6, 123.7, 117.1, 108.3, 44.5, 33.8, 20.8, 12.6; HRMS (ESI) m/z calcd for C21H20BrClNO2 [M + H]+:
432.0360; Found: 432.0373.
ACS Paragon Plus Environment

Page 19 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N-(2-Bromo-4-methylphenyl)-N-ethyl-5-(4-methoxybenzyl)furan-2-carboxamide (1l). Colorless oil
(1.32 g, 62% over 4 steps); IR (film) 2931, 1641, 1397, 969 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.46
(s, 1H), 7.12 (br, 2H), 7.01 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 5.93 (br, 1H), 5.80 (br, 1H),
4.25 – 4.15 (m, 1H), 3.80 (s, 3H), 3.76 (s, 2H), 3.52 – 3.43 (m, 1H), 2.37 (s, 3H), 1.22 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 158.9, 158.4, 157.7, 146.3, 139.9, 138.6, 134.1, 130.7, 129.7,
129.2, 128.9, 123.8, 117.2, 113.9, 107.9, 55.2, 44.4, 33.6, 20.8, 12.6; HRMS (ESI) m/z calcd for
C22H23BrNO3 [M + H]+: 428.0856 ; Found: 428.0862.
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
N-(2-Bromophenyl)-N-ethyl-5-(2-methylbenzyl)furan-2-carboxamide (1m). Colorless oil (1.29 g, 65%
1
over 4 steps); IR (film) 2975, 1642, 1474, 1211, 969 cm-1; H NMR (400 MHz, CDCl3) δ 7.63 (d, J =
7.9 Hz, 1H), 7.34 – 7.30 (m, 1H), 7.26 – 7.20 (m, 2H), 7.15 – 7.11 (m, 3H), 6.98 (d, J = 6.6 Hz, 1H),
5.98 (br, 1H), 5.71 (br, 1H), 4.27 – 4.17 (m, 1H), 3.78 (s, 2H), 3.58 – 3.48 (m, 1H), 2.19 (s, 3H), 1.24 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 156.9, 146.2, 141.4, 136.4, 135.2, 133.7, 131.1,
130.3, 129.7, 129.5, 128.2, 126.9, 126.1, 124.2, 117.4, 108.1, 44.4, 32.2, 19.4, 12.7; HRMS (ESI) m/z
calcd for C21H21BrNO2 [M + H]+: 398.0750; Found: 398.0757.
N-(2-Bromophenyl)-5-(2-chlorobenzyl)-N-ethylfuran-2-carboxamide (1n). Colorless oil (1.27 g, 61%
1
over 4 steps); IR (film) 2929, 1701, 1472, 1270, 1025, 967 cm-1; H NMR (400 MHz, CDCl3) δ 7.60
(dd, J = 7.9, 1.0 Hz, 1H), 7.35 – 7.28 (m, 2H), 7.25 – 7.15 (m, 4H), 7.04 – 7.01 (m, 1H), 6.08 (br, 1H),
5.87 (br, 1H), 4.26 – 4.16 (m, 1H), 3.90 (s, 2H), 3.56 – 3.46 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 158.7, 155.4, 146.5, 141.4, 134.9, 133.9, 133.7, 131.1, 130.8, 129.4, 128.2, 128.1,
126.9, 126.9, 124.1, 117.4, 108.7, 44.4, 31.9, 12.6; HRMS (ESI) m/z calcd for C20H17BrClNNaO2 [M +
Na]+: 440.0023; Found: 440.0024.
N-(2-Bromo-4-methylphenyl)-N-ethyl-5-(thiophen-2-ylmethyl)furan-2-carboxamide (1o). Colorless oil
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 44
1
2
3
4
5
6
7
8
9
(1.1 g, 55% over 4 steps); IR (film) 2927, 1743, 1642, 1391, 1271, 968 cm-1; H NMR (400 MHz,
CDCl3) δ 7.47 (s, 1H), 7.16 (dd, J = 5.1, 0.7 Hz, 1H), 7.13 (s, 2H), 6.94 – 6.91 (m, 1H), 6.76 (s, 1H),
5.92 (br, 2H), 4.29 – 4.11 (m, 1H), 4.03 (s, 2H), 3.54 – 3.45 (m, 1H), 2.38 (s, 3H), 1.22 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 156.0, 146.4, 140.0, 138.9, 138.6, 134.1, 130.7, 129.1,
126.8, 125.9, 124.2, 123.7, 117.1, 108.1, 44.4, 28.7, 20.9, 12.6; HRMS (ESI) m/z calcd for
C19H18BrNNaO2S [M + Na]+: 426.0134; Found: 426.0146.
1
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
N-(2-Bromophenyl)-N-ethyl-5-(naphthalen-2-ylmethyl)furan-2-carboxamide (1p). Colorless oil (1.15 g,
53% over 4 steps); IR (film) 2975, 1744, 1688, 1473, 1212, 966 cm-1; H NMR (400 MHz, CDCl3) δ
1
7.81 – 7.70 (m, 3H), 7.49 –7.42(m, 4H), 7.17 (t, J = 9.1 Hz, 3H), 7.04 – 7.01 (m, 1H), 6.11 (br, 1H),
5.87 (br, 1H), 4.22 – 4.12 (m, 1H), 3.91 (s, 2H), 3.54 – 3.44 (m, 1H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 158.8, 157.0, 146.6, 141.3, 134.5, 133.6, 133.5, 132.3, 130.9, 129.3, 128.1, 127.6,
127.6, 127.2, 127.1, 126.1, 125.6, 124.1, 117.5, 108.4, 99.9, 44.5, 34.7, 12.7; HRMS (ESI) m/z calcd
for C24H21BrNO2 [M + H]+: 434.0750; Found: 434.0761.
N-(2-Bromo-4-methylphenyl)-N-ethyl-5-(naphthalen-2-ylmethyl)furan-2-carboxamide (1q). Colorless
oil (1.20 g, 54% over 4 steps); IR (film) 2974, 1641, 1448, 1211, 967 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.82 – 7.69 (m, 3H), 7.54 – 7.40 (m, 3H), 7.32 (s, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.07 (d, J = 7.9 Hz,
1H), 7.02 (d, J = 8.0 Hz, 1H), 5.99 (br, 1H), 5.86 (br, 1H), 4.22 – 4.12 (m, 1H), 3.97 (s, 2H), 3.49 –
3.40 (m, 1H), 2.22 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 156.9, 146.5, 139.9,
138.6, 134.6, 134.0, 133.5, 132.3, 130.6, 128.9, 128.1, 127.6, 127.6 127.1, 127.1, 126.1, 125.6, 123.7,
117.2, 108.4, 99.9, 44.4, 34.6, 20.7, 12.6; HRMS (ESI) m/z calcd for C25H23BrNO2 [M + H]+: 448.0907;
Found: 448.0914.
5-Benzyl-N-(2-bromo-5-methylphenyl)-N-ethylfuran-2-carboxamide (1u). Colorless oil (1.24 g, 62%
ACS Paragon Plus Environment

Page 21 of 44
The Journal of Organic Chemistry
1
2
3
4
5
1
over 4 steps); IR (film) 2964, 1642, 1452, 1269, 970 cm-1; H NMR (400 MHz, CDCl3) δ 7.48 (d, J =
6
7
8
9
8.1 Hz, 1H), 7.29 – 7.25 (m, 2H), 7.24 – 7.19 (m, 1H), 7.08 (d, J = 7.1 Hz, 2H), 7.06 (s, 1H), 7.02 (d, J
= 8.2 Hz, 1H), 6.01 (br, 1H), 5.84 (br, 1H), 4.22 – 4.12 (m, 1H), 3.81 (s, 2H), 3.57 – 3.47 (m, 1H), 2.30
(s, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 157.1, 146.3, 139.9, 138.6,
137.1, 134.1, 130.7, 128.9, 128.7, 128.4, 126.5, 123.7, 117.2, 108.1, 44.4, 34.5, 20.8, 12.6; HRMS (ESI)
m/z calcd for C21H20BrNNaO2 [M + Na]+: 420.0570; Found: 420.0572.
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
N-(2-Bromo-4-methylphenyl)-5-(2-chlorobenzyl)-N-ethylfuran-2-carboxamide(1v). Colorless oil (1.29
g, 60% over 4 steps); IR (film) 2928, 1700, 1643, 1390, 1210, 824 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.42 (s, 1H), 7.36 – 7.30 (m, 1H), 7.19 – 7.14 (m, 2H), 7.10 (s, 2H), 7.04 – 7.01 (m, 1H), 6.00 (br, 1H),
5.86 (br, 1H), 4.23 – 4.13 (m, 1H), 3.93 (s, 2H), 3.52 – 3.42 (m, 1H), 2.35 (s, 3H), 1.21 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 155.3, 146.5, 139.9, 138.6, 134.9, 134.1, 133.8, 130.7,
130.6, 129.4, 128.9, 128.1, 126.9, 123.7, 117.2, 108.7, 44.4, 32.0, 20.8, 12.6; HRMS (ESI) m/z calcd
for C21H19BrClNNaO2 [M + Na]+: 454.0180; Found: 454.0181.
N-(2-Bromo-5-methylphenyl)-5-(2-chlorobenzyl)-N-ethylfuran-2-carboxamide (1w). Colorless oil (1.39
g, 66% over 4 steps); IR (film) 2967, 1701, 1642, 1472, 1211, 968 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.45 (d, J = 8.1 Hz, 1H), 7.35 – 7.30 (m, 1H), 7.21 – 7.13 (m, 2H), 7.08 – 6.96 (m, 3H), 6.05 (br, 1H),
5.87 (br, 1H), 4.21 – 4.11 (m, 1H), 3.92 (s, 2H), 3.57 – 3.47 (m, 1H), 2.29 (s, 3H), 1.23 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 158.6, 155.3, 146.5, 141.0, 138.5, 134.9, 133.9, 133.2, 131.5,
130.7, 130.3, 129.4, 128.1, 126.9, 120.6, 117.3, 108.7, 44.5, 32.0, 20.8, 12.7; HRMS (ESI) m/z calcd
for C21H19BrClNNaO2 [M + Na]+: 454.0180; Found: 454.0183.
N-(2-Bromo-4-methoxyphenyl)-5-(2-chlorobenzyl)-N-ethylfuran-2-carboxamide (1x). Colorless oil
(1.36 g, 61% over 4 steps); IR (film) 2931, 1700, 1391, 1219, 969 cm-1; 1H NMR (400 MHz, CDCl3) δ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 44
1
2
3
4
5
6
7
8
9
7.37 – 7.29 (m, 1H), 7.21 – 7.15 (m, 2H), 7.14 – 7.09 (m, 2H), 7.05 – 7.01 (m, 1H), 6.83 (dd, J = 8.7,
1.9 Hz, 1H), 5.99 (br, 1H), 5.87 (br, 1H), 4.25 – 4.11 (m, 1H), 3.95 (s, 2H), 3.81 (d, J = 2.3 Hz, 3H),
3.49 –3.36 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.6, 158.9, 155.4, 146.5,
134.9, 133.9, 133.8, 131.4, 130.7, 129.4, 128.1, 126.9, 124.6, 118.6, 117.2, 113.9, 108.7, 55.7, 44.4,
32.0, 12.6; HRMS (ESI) m/z calcd for C21H19BrClNNaO3 [M + Na]+: 470.0129; Found: 470.0129.
N-(2-Bromo-4-fluorophenyl)-N-ethyl-5-(4-methylbenzyl)furan-2-carboxamide (1y). Colorless oil (1.03
g, 50% over 4 steps); IR (film) 2976, 1744, 1643, 1425, 1182, 976 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.49 (dd, J = 8.8, 5.7 Hz, 1H), 7.06 (d, J = 7.9 Hz, 2H), 6.96 (dd, J = 8.7, 2.9 Hz, 1H), 6.94 – 6.89 (m,
3H), 6.36 (d, J = 3.1 Hz, 1H), 5.89 (d, J = 3.1 Hz, 1H), 4.18 – 4.08 (m, 1H), 3.69 (s, 2H), 3.55 – 3.45
(m, 1H), 2.31 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.7 (d, JC-F = 250.6
Hz), 158.5, 157.6, 146.3, 142.7 (d, JC-F = 9.9 Hz), 136.2, 134.1 (d, JC-F = 8.9 Hz), 133.9, 129.2, 128.5,
118.7, 118.3 (d, JC-F = 22.7 Hz), 117.9, 116.6 (d, JC-F = 22.1 Hz), 108.1, 44.6, 34.1, 21.0, 12.7; HRMS
(ESI) m/z calcd for C21H19BrFNO2 [M + Na]+: 438.0475; Found: 438.0472.
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
5-Benzyl-N-(2-bromobenzyl)-N-butylfuran-2-carboxamide (1ab). Colorless oil (1.06 g, 50% over 4
1
steps); IR (film) 2926, 1684, 1626, 1425, 1202, 965 cm-1; H NMR (400 MHz, CDCl3) δ 7.53 (d, J =
7.1 Hz, 1H), 7.28 – 6.81 (m, 9H), 6.04 (br, 1H), 4.81 (s, 2H), 4.09 – 3.68 (m, 2H), 3.45 (s, 2H), 1.69 –
1.57 (m, 2H), 1.39 – 1.11 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.3,
156.8, 147.0, 137.0, 136.8, 136.7, 132.7, 128.7, 128.6, 128.4, 127.7, 126.7, 122.4, 118.0, 108.2, 47.7,
47.6, 34.7, 29.6, 20.1, 13.9; HRMS (ESI) m/z calcd for C23H24BrNNaO2 [M + Na]+: 448.0883; Found:
448.0882.
Method B
To a solution of 2-substitued furan S5 (6 mmol) in anhydrous THF (6 mL), at -10 oC under nitrogen
ACS Paragon Plus Environment

Page 23 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
atmosphere, was added a solution of n-BuLi (2.1 mL, 1.6 M in hexane, 3.3 mmol). The solution was
stirred for 1 h at the same temperature and then a solution of S6 (3 mmol) in anhydrous THF (2 mL)
was added. The reaction mixture was stirred for 30 minutes, then was quenched with saturated aq.
NH4Cl (4 mL). The organic solvent was evaporated under reduced pressure and the aqueous layer was
extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with saturated brine,
dried over sodium sulfate, concentrated under reduced pressure to provide the crude product (S7)
which was submitted to the next step without further purification.
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
The mixture of above-made crude product S7, R2I (10 mmol), K2CO3 (1.2g, 9 mmol) and CH3CN
o
(5 mL) was stirred at 80 C under nitrogen atmosphere for 8 h. The reaction mixture was filtered and
concentrated. The residue was purified by flash chromatography on a silica gel (using petroleum
ether/ethyl acetate = 12:1 as the eluent) to give product 1 (1r-t, 1z, and 1aa).
N-(2-Bromo-4-(trifluoromethyl)phenyl)-N-ethyl-5-methylfuran-2-carboxamide (1r). Colorless oil (0.63
g, 56% over 2 steps); IR (film) 2934, 1744, 1647, 1425, 1216, 960 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.81 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 6.19 (br, 1H), 5.87 (br, 1H), 4.25 – 4.16
(m, 1H), 3.60 – 3.51 (m, 1H), 2.08 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
158.5, 155.1, 145.6, 142.4, 134.3, 130.9 (d, JC-F = 33.6 Hz), 128.6, 128.1 (q, JC-F = 4.0 Hz), 125.8 (q,
JC-F = 3.6 Hz), 123.2 (q, JC-F = 273.4 Hz), 118.1, 107.7, 44.5, 13.4, 12.8; HRMS (ESI) m/z calcd for
C15H14BrF3NO2 [M + H]+: 376.0155; Found: 376.0164.
N-(2-Bromophenyl)-5-ethyl-N-methylfuran-2-carboxamide (1s). Colorless oil (0.54 g, 58% over 2
steps); IR (film) 2974, 1644, 1424, 1215, 946 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.69 – 7.64 (m, 1H),
7.41 – 7.32 (m, 1H), 7.31 – 7.22 (m, 2H), 6.03 (br, 1H), 5.84 (br, 1H), 3.34 (s, 3H), 2.46 (q, J = 7.3 Hz,
2H), 1.02 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.4, 159.3, 145.5, 143.3, 133.7, 130.1,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 44
1
2
3
4
5
6
7
129.6, 128.7, 123.5, 117.4, 106.1, 36.9, 21.3, 11.6; HRMS (ESI) m/z calcd for C14H14BrNNaO2 [M +
Na]+: 330.0100; Found: 330.0099
8
9
N-(2-Bromophenyl)-N,5-diethylfuran-2-carboxamide (1t). Colorless oil (0.58 g, 60% over 2 steps); 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
(film) 2976, 1642, 1471, 1211, 949 cm-1; H NMR (400 MHz, CDCl3) δ 7.73 – 7.61 (m, 1H), 7.38 –
7.31 (m, 1H), 7.27 – 7.21 (m, 2H), 5.97 (br, 1H), 5.83 (br, 1H), 4.26 – 4.16 (m, 1H), 3.54 – 3.44 (m,
1H), 2.46 (q, J = 7.2 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 160.3, 158.8, 145.7, 141.6, 133.7, 131.2, 129.5, 128.3, 124.3, 117.3, 106.0, 44.4, 21.3, 12.7,
11.6; HRMS (ESI) m/z calcd for C15H16BrNNaO2 [M + Na]+: 344.0257; Found: 344.0255.
N-(2-Bromophenyl)-N-ethyl-5-methylfuran-2-carboxamide (1z). Colorless oil (0.46 g, 50% over 2
steps); IR (film) 2975, 1701, 1642, 1445, 1215, 961 cm-1; H NMR (400 MHz, CDCl3) δ 7.68 (d, J =
1
8.0 Hz, 1H), 7.41 – 7.34 (m, 1H), 7.31 – 7.24 (m, 2H), 5.80 (br, 1H), 5.68 (br, 1H), 4.27 – 4.17 (m, 1H),
3.55 – 3.47 (m, 1H), 2.17 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 154.9,
145.5, 141.4, 133.8, 131.3, 129.6, 128.4, 124.3, 117.1, 107.6, 44.3, 13.6, 12.7; HRMS (ESI) m/z calcd
for C14H14BrNNaO2 [M + Na]+: 330.0100; Found: 330.0099.
N-(2-Bromophenyl)-5-ethyl-N-isopropylfuran-2-carboxamide (1aa). Colorless oil (0.42 g, 42% over 2
steps); IR (film) 2976, 1642, 1471, 1211, 949 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.9 Hz,
1H), 7.39 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.30 – 7.23 (m, 1H), 5.86 (br, 1H), 5.81 (br, 1H),
4.98 – 4.85 (m, 1H), 2.47 (q, J = 7.3 Hz, 2H), 1.38 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 1.04 (t,
J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.1, 158.8, 146.1, 139.5, 133.7, 131.6, 129.5, 127.9,
126.3, 116.9, 105.9, 49.6, 21.9, 21.3, 19.1, 11.6; HRMS (ESI) m/z calcd for C16H18BrNNaO2 [M + Na]+:
358.0413; Found: 358.0418.
General procedure for the preparation of 2 (Z-isomer as the major)
ACS Paragon Plus Environment

Page 25 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
To the mixture of K2CO3 (83 mg, 0.6 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol, 5 mol %), and PPh3 (8
mg, 0.03 mmol, 10 mol %) in a Schlenk flask was added a solution of 1 (0.3 mmol) in DCE (3 mL)
under nitrogen atmosphere. The reaction was stirred at 80 oC for 12 h. H2O (5 mL) was added to the
reaction and the resulting mixture was extracted with ethyl acetate (3× 5 mL). The combined organic
extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was
purified by flash chromatography on a silica gel (using petroleum ether/ethyl acetate = 15:1 as the
eluent) to give product 2 (Z-isomer as the major).
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
(Z)-5-Benzylidene-1'-ethyl-5H-spiro[furan-2,3'-indolin]-2'-one (2a). Colorless oil (82.7 mg, 91%, Z/E
= 12/1); IR (film) 2925, 1730, 1650, 1368, 1214, 1023 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J =
7.4 Hz, 2H), 7.45 – 7.38 (m, 1H), 7.29 – 7.24 (m, 3H), 7.14 – 7.07 (m, 2H), 6.95 (d, J = 7.9 Hz, 1H),
6.66 (d, J = 5.7 Hz, 1H), 6.08 (d, J = 5.7 Hz, 1H), 5.60 (s, 1H), 3.93 – 3.71 (m, 2H), 1.37 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 172.1, 158.9, 142.9, 135.9, 130.9, 130.8, 130.5, 128.3, 128.2,
126.5, 125.7, 125.4, 123.2, 108.9, 101.1, 92.8, 35.3, 12.7; HRMS (ESI) m/z calcd for C20H18NO2 [M +
H]+: 304.1332; Found: 304.1339.
(Z)-5-Benzylidene-1'-ethyl-5'-methyl-5H-spiro[furan-2,3'-indolin]-2'-one (2b). Yellow solid (76 mg,
80%, Z/E = 13/1), mp: 157.1 – 157.6 oC; IR (film) 2979, 2930, 1726, 1653, 1449, 1218, 1006 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.5 Hz, 2H), 7.26 – 7.20 (m, 2H), 7.18 – 7.14 (m, 1H), 7.11 –
7.06 (m, 1H), 7.04 (s, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 5.6 Hz, 1H), 6.04 (d, J = 5.6 Hz, 1H),
5.55 (s, 1H), 3.85 – 3.69 (m, 2H), 2.29 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
172.0, 159.1, 140.4, 135.9, 132.9, 131.1, 131.0, 130.4, 128.3, 128.2, 126.5, 126.2, 125.7, 108.6, 101.0,
93.0, 35.3, 20.9, 12.7; HRMS (ESI) m/z calcd for C21H20NO2 [M + H]+: 318.1489; Found: 318.1500.
(Z)-5-Benzylidene-5'-tert-butyl-1'-ethyl-5H-spiro[furan-2,3'-indolin]-2'-one (2c). Colorless oil (88.3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 44
1
2
3
4
5
6
7
8
9
mg, 82%, Z/E = 12/1); IR (film) 2979, 1724, 1610, 1449, 1217, 933 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.59 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.25 – 7.19 (m, 3H), 7.12 – 7.06 (m, 1H), 6.85 (d, J
= 8.2 Hz, 1H), 6.63 (d, J = 5.6 Hz, 1H), 6.05 (d, J = 5.6 Hz, 1H), 5.57 (s, 1H), 3.83 – 3.73 (m, 2H),
1.32 (t, J = 7.2 Hz, 3H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.1, 159.1, 146.6, 140.5, 135.9,
131.1, 130.5, 128.2, 128.1, 127.5, 126.2, 125.6, 122.5, 108.4, 100.9, 93.1, 35.2, 34.6, 31.5, 12.7;
HRMS (ESI) m/z calcd for C24H25NNaO2 [M + Na]+: 382.1777; Found: 382.1786.
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
(Z)-5-Benzylidene-1'-ethyl-5'-methoxy-5H-spiro[furan-2,3'-indolin]-2'-one (2d). Colorless oil (74.9 mg,
1
75%, Z/E = 10/1); IR (film) 2977, 1728, 1458, 1218, 967 cm-1; H NMR (400 MHz, CDCl3) δ 7.59 –
7.51 (m, 2H), 7.25 – 7.19 (m, 2H), 7.13 (d, J = 8.2 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.60 (d, J = 5.6 Hz,
1H), 6.57 – 6.51 (m, 1H), 6.48 (s, 1H), 6.01 (d, J = 5.6, 1H), 5.53 (s, 1H), 3.84 (s, 3H), 3.81 – 3.70 (m,
2H), 1.32 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.6, 162.3, 158.9, 144.4, 135.9, 130.9,
130.4, 128.2, 128.2, 126.4, 125.6, 118.3, 106.6, 100.9, 97.1, 92.7, 55.7, 35.3, 12.7; HRMS (ESI) m/z
calcd for C21H20NO3 [M + H]+: 334.1438; Found: 334.1450.
(Z)-5-Benzylidene-1'-ethyl-5'-fluoro-5H-spiro[furan-2,3'-indolin]-2'-one (2e). Colorless oil (87.6 mg,
1
91%, Z/E = 12/1); IR (film) 2981, 1728, 1654, 1455, 1213, 933 cm-1; H NMR (400 MHz, CDCl3) δ
7.61 (d, J = 7.8 Hz, 2H), 7.32 – 7.25 (m, 2H), 7.17 – 7.06 (m, 2H), 7.01 (d, J = 7.2 Hz, 1H), 6.86 (dd, J
= 8.3, 3.1 Hz, 1H), 6.68 (d, J = 5.5 Hz, 1H), 6.07 (d, J = 5.5 Hz, 1H), 5.62 (s, 1H), 3.90 – 3.66 (m, 2H),
1.35 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.9, 159.1 (d, JC-F = 243.4 Hz), 158.7, 138.7,
135.6, 130.9, 130.3, 128.3, 128.2, 128.1 (d, JC-F = 7.6 Hz), 125.9, 117.2 (d, JC-F = 23.7 Hz), 113.4 (d,
JC-F = 24.9 Hz), 109.5 (d, JC-F = 7.7 Hz), 101.6, 92.6, 35.4, 12.6; HRMS (ESI) m/z calcd for
C20H17FNO2 [M + H]+: 322.1238; Found: 322.1249.
(Z)-1'-Ethyl-5-(4-methylbenzylidene)-5H-spiro[furan-2,3'-indolin]-2'-one (2f). Colorless oil (77.9 mg,
ACS Paragon Plus Environment

Page 27 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
82%, Z/E = 10/1); IR (film) 2927, 1725, 1655, 1475, 1214, 933 cm-1; H NMR (400 MHz, CDCl3) δ
7.46 (d, J = 7.4 Hz, 2H), 7.41 –7.32 (m, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.08 – 7.01 (m, 3H), 6.91 (d, J =
7.8 Hz, 1H), 6.63 (d, J = 5.7 Hz, 1H), 6.00 (d, J = 5.7 Hz, 1H), 5.53 (s, 1H), 3.89 – 3.65 (m, 2H), 2.28
(s, 3H), 1.33 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.2, 158.4, 142.9, 135.4, 132.9,
130.8, 130.5, 130.3, 128.9, 128.2, 126.7, 125.4, 123.1, 108.8, 101.1, 92.7, 35.3, 21.2, 12.7; HRMS (ESI)
m/z calcd for C21H20NO2 [M + H]+: 318.1487; Found: 318.1497.
1
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
(Z)-1'-Ethyl-5'-methyl-5-(4-methylbenzylidene)-5H-spiro[furan-2,3'-indolin]-2'-one (2g). Colorless oil
(71.5 mg, 72%, Z/E = 16/1); IR (film) 2979, 1724, 1655, 1449, 1217, 933 cm-1; H NMR (400 MHz,
1
CDCl3) δ 7.51 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.9 Hz, 1H), 7.13 – 7.05 (m, 3H), 6.83 (d, J = 7.9 Hz,
1H), 6.64 (d, J = 5.7 Hz, 1H), 6.04 (d, J = 5.7 Hz, 1H), 5.57 (s, 1H), 3.91 – 3.70 (m, 2H), 2.33 (s, 3H),
2.32 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.1, 158.5, 140.4, 135.4, 133.0,
132.9, 130.9, 130.6, 130.4, 128.9, 128.2, 126.7, 126.2, 108.6, 100.9, 92.9, 35.3, 21.2, 20.9, 12.7;
HRMS (ESI) m/z calcd for C22H22NO2 [M + H]+: 332.1645; Found: 332.1655.
(Z)-1'-Ethyl-5'-methoxy-5-(4-methylbenzylidene)-5H-spiro[furan-2,3'-indolin]-2'-one (2h). Colorless
oil (83.3 mg, 80%, Z/E = 14/1); IR (film) 2934, 1728, 1618, 1459, 1218, 966 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.46 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 8.1 Hz, 2H), 6.58 (d, J = 5.6
Hz, 1H), 6.53 (d, J = 8.2, 1H), 6.47 (s, 1H), 5.97 (d, J = 5.6 Hz, 1H), 5.50 (s, 1H), 3.83 (s, 3H), 3.81 –
3.70 (m, 2H), 2.28 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.7, 162.3, 158.3,
144.4, 135.3, 133.1, 130.5, 130.4, 128.9, 128.2, 126.4, 118.5, 106.5, 100.9, 97.1, 92.6, 55.7, 35.3, 21.2,
12.7; HRMS (ESI) m/z calcd for C22H22NO3 [M + H]+: 348.1594; Found: 348.1603.
(Z)-1'-Ethyl-6'-methyl-5-(4-methylbenzylidene)-5H-spiro[furan-2,3'-indolin]-2'-one (2i). Colorless oil,
(69.5 mg, 70%, Z/E = 8/1); IR (film) 3854, 3740, 3433, 2358, 1775, 1728, 1618, 1505, 1459, 1370,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 44
1
2
3
4
5
6
7
8
9
1274, 1218, 1171, 1099, 1043, 966, 832, 753, 638, 582, 518, 465 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.46 (d, J = 7.7 Hz, 2H), 7.09 (d, J = 7.5 Hz, 1H), 7.03 (d, J = 7.7 Hz, 2H), 6.86 (d, J = 7.5 Hz, 1H),
6.72 (s, 1H), 6.59 (d, J = 5.6 Hz, 1H), 5.98 (d, J = 5.6 Hz, 1H), 5.51 (s, 1H), 3.86 – 3.68 (m, 2H), 2.40
(s, 3H), 2.27 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.4, 158.4, 143.0,
141.3, 135.3, 133.0, 130.4, 130.4, 128.8, 128.1, 125.2, 123.7, 123.6, 109.7, 100.9, 92.6, 35.2, 22.0, 21.2,
12.7; HRMS (ESI) m/z calcd for C22H21NNaO2 [M + Na]+: 354.1464; Found: 354.1470.
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
(Z)-5-(4-Chlorobenzylidene)-1'-ethyl-5H-spiro[furan-2,3'-indolin]-2'-one (2j). Colorless oil (83.9 mg,
83%, Z/E = 14/1); IR (film) 2980, 1725, 1654, 1480, 1272, 1096, 934 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.49 (d, J = 8.6 Hz, 2H), 7.41 – 7.36 (m, 1H), 7.23 – 7.16 (m, 3H), 7.10 – 7.04 (m, 1H), 6.92 (d, J =
7.9 Hz, 1H), 6.62 (d, J = 5.7 Hz, 1H), 6.07 (d, J = 5.7 Hz, 1H), 5.51 (s, 1H), 3.86 – 3.74 (m, 2H), 1.33
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.9, 159.3, 142.9, 134.4, 131.4, 131.0, 130.9,
130.3, 129.4, 128.3, 126.3, 125.4, 123.2, 108.9, 99.9, 92.9, 35.3, 12.7; HRMS (ESI) m/z calcd for
C20H17ClNO2 [M + H]+: 338.0942; Found: 338.0951.
(Z)-5-(4-Chlorobenzylidene)-1'-ethyl-5'-methyl-5H-spiro[furan-2,3'-indolin]-2'-one (2k). Colorless oil
(84.2 mg, 80%, Z/E = 13/1); IR (film) 2979, 1722, 1653, 1456, 1272, 934; 1H NMR (400 MHz, CDCl3)
δ 7.50 (d, J = 8.4 Hz, 2H), 7.21 – 7.15 (m, 3H), 7.03 (s, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 5.7
Hz, 1H), 6.07 (d, J = 5.7 Hz, 1H), 5.51 (s, 1H), 3.84 – 3.69 (m, 2H), 2.30 (s, 3H), 1.32 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 171.8, 159.4, 140.4, 134.4, 133.0, 131.6, 131.2, 130.9, 130.2,
129.4, 128.3, 126.2, 126.1, 108.7, 99.9, 93.1, 35.3, 20.9, 12.7; HRMS (ESI) m/z calcd for C21H19ClNO2
[M + H]+: 352.1099; Found: 352.1107.
(Z)-1'-Ethyl-5-(4-methoxybenzylidene)-5'-methyl-5H-spiro[furan-2,3'-indolin]-2'-one (2l). Colorless oil
(83.3 mg, 80%, Z/E = 9/1); IR (film) 2933, 1722, 1453, 1251, 931 cm-1; 1H NMR (400 MHz, CDCl3) δ
ACS Paragon Plus Environment

Page 29 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7.55 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 7.9 Hz, 1H), 7.07 (s, 1H), 6.87 – 6.75 (m, 3H), 6.63 (d, J = 5.7 Hz,
1H), 6.00 (d, J = 5.7 Hz, 1H), 5.54 (s, 1H), 3.84 – 3.74 (m, 2H), 3.79 (s, 3H), 2.32 (s, 3H), 1.35 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.2, 157.7, 157.6, 140.4, 132.9, 130.9, 130.3, 129.9,
129.5, 128.8, 126.8, 126.2, 113.7, 108.6, 100.5, 92.8, 55.2, 35.3, 20.9, 12.7; HRMS (ESI) m/z calcd for
C22H22NO3 [M + H]+: 348.1594; Found: 348.1606.
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
(Z)-1'-Ethyl-5-(2-methylbenzylidene)-5H-spiro[furan-2,3'-indolin]-2'-one (2m). Colorless oil (82.7 mg,
87%, Z/E = 10/1); IR (film) 2931, 1724, 1473, 1214, 933 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.93 (d,
J = 7.7 Hz, 1H), 7.39 – 7.31 (m, 1H), 7.25 – 7.20 (m, 1H), 7.12 – 6.97 (m, 4H), 6.89 (d, J = 7.8 Hz,
1H), 6.66 (d, J = 5.6 Hz, 1H), 6.03 (d, J = 5.6 Hz, 1H), 5.66 (s, 1H), 3.82 – 3.73 (m, 2H), 2.35 (s, 3H),
1.31 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.1, 158.9, 142.9, 134.9, 134.2, 130.8, 130.8,
130.7, 129.8, 128.7, 126.6, 125.9, 125.8, 125.4, 123.1, 108.8, 97.9, 92.6, 35.3, 20.3, 12.7; HRMS (ESI)
m/z calcd for C21H20NO2 [M + H]+: 318.1489; Found: 318.1497.
(Z)-5-(2-Chlorobenzylidene)-1'-ethyl-5H-spiro[furan-2,3'-indolin]-2'-one (2n). Colorless oil (85.9 mg,
1
85%, Z/E = 11/1); IR (film) 2980, 1777, 1654, 1480, 1215, 934 cm-1; H NMR (400 MHz, CDCl3) δ
8.09 (d, J = 7.9 Hz, 1H), 7.44 – 7.38 (m, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 7.17 –
7.07 (m, 2H), 7.06 – 7.02 (m, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.73 (d, J = 5.5 Hz, 1H), 6.14 (d, J = 5.5
Hz, 1H), 6.03 (s, 1H), 3.91 – 3.76 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
171.7, 160.2, 142.9, 133.4, 131.9, 131.7, 130.9, 130.7, 129.8, 129.1, 126.6, 126.5, 126.1, 125.4, 123.2,
108.9, 96.5, 92.9, 35.3, 12.6; HRMS (ESI) m/z calcd for C20H16ClNNaO2 [M + Na]+: 360.0762; Found:
360.0768.
(Z)-1'-Ethyl-5'-methyl-5-(thiophen-2-ylmethylene)-5H-spiro[furan-2,3'-indolin]-2'-one (2o). Colorless
1
oil (83.3 mg, 86%, Z/E = 12/1); IR (film) 2978, 1726, 1461, 1218, 936 cm-1; H NMR (400 MHz,
ACS Paragon Plus Environment