Intramolecular Palladium-Catalyzed Oxidative Amination of Furans: Synthesis of Functionalized Indoles

Article abstract of DOI:10.1021/acs.joc.8b02470

Unconventional modification of palladium-catalyzed oxidative amination where a furan ring serves as a masked olefin is described. The designed chemical process provides 2-(2-acylvinyl)indole derivatives with up to a 93% yield and excellent E-selectivity. A highly reactive α,β-unsaturated carbonyl moiety of the obtained compounds allows for accessing various heteroaromatic scaffolds through simple synthetic procedures.

Full text of DOI:10.1021/acs.joc.8b02470

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Article
Intramolecular Palladium-Catalyzed Oxidative Amination
of Furans: Synthesis of Functionalized Indoles
Anton S. Makarov, Maxim G. Uchuskin, and Vladimir Gevorgyan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02470 • Publication Date (Web): 22 Oct 2018
Downloaded from http://pubs.acs.org on October 22, 2018
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Intramolecular Palladium-Catalyzed Oxidative Amination of Furans:
Synthesis of Functionalized Indoles
Anton S. Makarov,a Maxim G. Uchuskin,a* and Vladimir Gevorgyanb*
a
Department of Chemistry, Perm State University, Bukireva 15, Perm, 614990, Russian Federation
Fax: (+7)-342-237-16-11; phone: (+7)-342-239-64-01; e-mail: mu@psu.ru
b
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Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, USA
Fax: (+1)-312-355-0836; phone: (+1)-312-355-3579; e-mail: vlad@uic.edu
R2
R2
R1
2) Pd(OAc)2
Benzoquinone
R1
R1
R2
O
1) p-TSA
OH
R3
O
+
R3
3) I2
O
NH
Ts
NH
Ts
N
R3
Ts
24 examples
up to 93%
one-pot
excellent E-selectivity
ABSTRACT
Unconventional modification of palladium-catalyzed oxidative amination where a furan ring
serves as a masked olefin is described. The designed chemical process provides 2-(2-acylvinyl)indole
derivatives with up to a 93% yield and excellent E-selectivity. A highly reactive α,β-unsaturated
carbonyl moiety of the obtained compounds allows for accessing various heteroaromatic scaffolds
through simple synthetic procedures.
Keywords: Furan; Indole; Catalysis; Palladium; Oxidative Amination
INTRODUCTION
Intramolecular transition metal-catalyzed oxidative amination1 has become a powerful practical
instrument being extensively exploited in organic synthesis to provide a wide range of nitrogen-
containing heterocycles, starting from easily accessible substrates.2 Among the variety of possible
products the reaction of an olefin tethered to an amine functionality could end up with under oxidative
amination conditions, the indole derivatives represent an important class of organic compounds due to
their widespread use as active drug components, biologically significant natural products or substrates in
the dye and agricultural industries.3
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Starting from the pioneering works of Hegedus4 (Scheme 1, a) the application of intramolecular
oxidative amination catalyzed by transition metal complexes for the synthesis of substituted indoles has
reached an impressive progress in terms of catalyst loading and conditions applied.5 Thus, recently
Ghorai et al. showed that 2-allylanilines underwent cyclization to form 2-benzylindoles with moderate
to high yields in the presence of 5 mol% of Pd(OAc)2 as a precatalyst and dioxygen as a terminal
oxidant. Moreover, the authors also disclosed a one-pot protocol to obtain 2-benzylindoles starting from
simple anilines and cinnamyl alcohols that reacted to form the intermediate 2-allylanilines under
rhenium catalysis (Scheme 1, b).5d
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The classical version of oxidative amination comprising the interaction of a weakly basic nitrogen
with olefins in the presence of transition metal complexes and terminal oxidants is well-studied.6
Undeniably, the utilization of conceptually new substrates containing masked alkene functionality for
this reaction would greatly expand the scope and practical applicability of oxidative amination as a
method to access important nitrogen-containing heterocycles. To the best of our knowledge, this
possibility has not been explored to date.
Due to low resonance energy,7 furan easily undergoes dearomatization reactions8 under various
conditions, thereby providing structurally diverse compounds. Despite its wide use as a masked 1,4-
dicarbonyl compound,9 furan could also act as an olefin equivalent exhibiting close reactivity to an
isolated carbon-carbon double bond in some transition metal-catalyzed chemical transformations.10 In
consideration of this transformative aspect, we hypothesized that a benzylfuran possessing an amino
group at ortho-position could be an ideal model substrate to study the possibility of intramolecular
oxidative amination. Such a furyl-tethered amine would mimic the substrate for Hegedus indole
synthesis reacting under oxidative amination conditions to furnish an indole core. Moreover, a target
compound would contain a highly reactive enone functionality, which could be employed for further
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modifications (Scheme 1, c).11 Herein, we disclose a new variation of Hegedus indole synthesis via
intramolecular oxidative amination of furans.
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Scheme 1. Classic approaches to indoles via intramolecular oxidative amination and our work
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PdCl2(CH3CN)2
ref. 4d
(a)
(b)
NH2
N
H
R2
R1
R2
5 mol% Pd(OAc)2
10 mol% PPh3, O2
R1
NH2
R3
5 mol% Re2O7
R3
R1
+
NH2 R3
ref. 5d
OH
N
H
R2
(c) This work
R2
R2
R2
Oxidative
Amination
R1
O
OH
Friedel-Crafts
R1
R1
R3
O
R3
+
O
NH
Ts
NH
Ts
N
R3
Ts
RESULTS AND DISCUSSION
In order to check the initial hypothesis, we treated benzylfuran 3a, obtained via Friedel-Crafts
alkylation of 2-methylfuran (2a) with a corresponding benzyl alcohol 1a in the presence of para-
toluenesulfonic acid (p-TSA), with PdCl2 upon heating in acetic acid and observed the formation of a
target functionalized indole 4a as a mixture of Z and E isomers with a moderate yield (Scheme 2).
Scheme 2. Initial observation.
Ph
OH
Ph
Ph
Ph
O
O
5 mol% p-TSA
1 equiv. PdCl2
+
+
AcOH, 110 °C
24 h
DCE, 60 °C
1.5 h
N
N
O
NH
Ts
NH
Ts
Ts
Ts
O
1a
2a
3a
4a
(E)-
38%
4a
(Z)-
17%
Encouraged by this result, we ran an optimization of the reaction conditions with benzylfuran 3a
as a model substrate. The optimization has revealed that a catalytic amount of a Pd(II) source could be
employed so as to reach a complete conversion of the starting benzylfuran 3a. We detected the
formation of the target compound 4a as a composite of geometrical isomers with 36% yield when 5
mol% PdCl2 was added to the mixture of benzylfuran 3a and benzoquinone (BQ) in acetic acid upon
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heating at 110 °C (Table 1, entry 1). Other reoxidants such as CuCl2, Cu(OAc)2, AgCO3, or dioxygen
proved to be less efficient providing lower yields of 4a. Next, we tested PdCl2 complexes with PPh3,
PhCN, and MeCN and discovered that the combined yield of the target isomers could be increased up to
84% with the slight change of the isomeric ratio in favor of E-isomer (entries 2-4). Finally, we found
that Pd(OAc)2 in the amount of 5 mol% enabled to form an indole 4a with 95% analytical yield, yet as a
1:2 Z/E mixture (entry 5). We screened different solvents in attempt to improve Z/E ratio; however, in
all cases the yield of 4a dropped significantly (entries 6-10). By further tuning the reaction parameters,
we eventually determined that the optimal conditions for the formation of indole 4a as a mixture of Z/E
isomers with the highest possible yield could be achieved when the starting benzylfuran 3a was heated
in acetic acid in the presence of 5 mol% of Pd(OAc)2/1 equiv. of BQ at 100 °C for 16 hours (entry 12).
The presence of both Pd(OAc)2 and BQ is required for the reaction to take place (entries 14-16).
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Table 1. Optimization of the reaction conditions.a
Ph
Ph
O
5 mol% Pd(II) catalyst
solvent (0.1 M), temp °C
O
1 equiv. BQ
24 h
N
NH
Ts
Ts
3a
4a
Entry
1
Catalyst
PdCl2
Solvent
AcOH
AcOH
AcOH
AcOH
AcOH
toluene
DMF
temp (°C) Z/E ratiob Yield (%)c
110
110
110
110
110
110
110
110
110
110
100
100
90
1/4
1/6
1/6
1/9
1/2
3/1
5/1
4/1
-
36
42
2
PdCl2(PPh3)2
PdCl2(PhCN)2
PdCl2(CH3CN)2
Pd(OAc)2
3
70
4
84
5
95
6
Pd(OAc)2
62
7
Pd(OAc)2
40
8
Pd(OAc)2
1,4-dioxane
CH3CN
DCE
20
9
Pd(OAc)2
trace
trace
95
10
11
12
13
Pd(OAc)2
-
Pd(OAc)2
AcOH
AcOH
AcOH
1/2
1/2
1/2
d
Pd(OAc)2
95 (93)e
d
Pd(OAc)2
87
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d
14
15
16
-
AcOH
AcOH
AcOH
100
100
100
-
-
-
trace
trace
N/Rg
d,f
Pd(OAc)2
d,f
-
aReactions conditions: a solution of benzylfuran 3a (0.05 mmol), BQ (0.05 mmol) and a catalyst in a
solvent (0.5 mL) were stirred at the indicated temperature for the indicated time. Z/E ratios were
b
c
d
e
determined by NMR. NMR yields with CH2Br2 as an internal standard. Reaction time – 16 h. Isolated
yield is given in parentheses, the reaction was run at 0.2 mmol scale. fNo BQ. g0% conversion of 3a.
The isomeric mixtures of α,β-unsaturated ketones could be selectively converted into E-isomer via
iodine-catalyzed isomerization.12 Indeed, the Z/E-mixture of indole 4a obtained after palladium-
catalyzed reaction of benzylfuran 3a was smoothly transformed into (E)-2-(2-acetylvinyl)indole (E)-4a
with quantitative yield after heating the substrate in acetic acid in the presence of 10 mol% I2. Moreover,
we found that this step could be combined with the previous one without any loss of efficiency (Scheme
3).
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Scheme 3. One-pot synthesis of (E)-4a from 3a
Ph
Ph
O
1) 5 mol% Pd(OAc)2, 1 equiv. BQ
AcOH (0.1 M), 100 oC, 16 h
O
N
Ts
NH
Ts
2) 10 mol% I2,100 °C, 3h
3a
4a
(E)-
93%
Ultimately, we decided to integrate the Friedel-Crafts alkylation step in order to design a
convenient synthetic one-pot protocol toward (E)-2-(2-acylvinyl)indoles 4. The reaction between benzyl
alcohol 1a and 1.5 equivalent of 2-methylfuran (2a) in acetic acid with 4 mol% of p-TSA as a catalyst at
65 °C led to a clean formation of an intermediate benzylfuran 3a with quantitative analytical yield.
However, heating the mixture at elevated temperature further with palladium catalyst/BQ followed by
addition of molecular iodine resulted in the formation of the target indole (E)-4a with 65% yield, the
other component being indole 5a which possessed an oxoalkyl substituent at C-2 of an indole core
(Scheme 4, a). Presumably, by-product 5a was being formed by Brönsted acid-catalyzed rearrangement
of benzylfuran 3a under reaction conditions.13 After some experimentation, we found that the addition of
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sodium acetate equimolar to p-TSA totally prevented the noted side reaction: in that case the target
indole (E)-4a was formed with 91% yield (Scheme 4, b). It should be pointed out that the amount of BQ
should have been equal to the amount of the furan component as otherwise the excess of 2-methylfuran
(2a) either reduced BQ or underwent conjugated addition to BQ14 resulting in lower yield of the target
indole (E)-4a.
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Scheme 4. One-pot synthesis of (E)-4a from 1a
Ph
Ph
OH
Ph
Ph
O
O
2) 5 mol% Pd(OAc)2, 1.5 equiv. BQ
AcOH (0.1 M), 100 oC, 16 h
(a)
O
1) 4 mol% p-TSA
+
AcOH, 65 oC, 1.5 h
3) 10 mol% I2, 100 oC, 3 h
N
N
O
NH
Ts
3a
99% (NMR)
NH
1.5 eq
2a
Ts
(E)-
65%
Ts
5a
29%
Ts
1a
4a
Ph
(b)
Ph
O
1) 4 mol% p-TSA
AcOH (0.1 M), 65 oC, 1.5 h
OH
+
O
NH
Ts
2) 5 mol% Pd(OAc)2, 4% NaOAc
1.5 equiv. BQ, 100 oC, 16 h
3) 10 mol% I2, 100 oC, 3 h
N
1.5 eq
Ts
4a
1a
2a
(E)-
91%
one-pot
With the optimized conditions in hand, we explored the generality of the new one-pot method for
the synthesis of functionalized indoles. First, the scope of the reaction of different benzyl alcohols 1 with
2-methylfuran (2a) was examined (Table 2). Thus, benzyl alcohols possessing various aryl substituents
at α-position reacted smoothly providing corresponding indoles (E)-4a-e (entries 1-5) with high yields
with the exempt of an alcohol 1f which contained sterically hindered 2,5-dimethylphenyl group giving
an indole (E)-4f with 61% yield (entry 6). When we switched to α-methyl substituted benzyl alcohol 1g,
we were able to isolate indole (E)-4g with 16% yield only. Supposedly, alcohol 1g forms relatively less-
stabilized and highly reactive benzylic cation15 undergoing unwanted chemical processes that lowers the
yield of the intermediate benzylfuran. In fact, when we ran this reaction starting from α-
methylbenzylfuran obtained under milder conditions from an alcohol 1g and 2-methylfuran (2a), we
isolated a corresponding indole (E)-4g with 73% yield (entry 7). In contrast, more electron-rich benzyl
alcohol 1h reacted with 2-methylfuran (2a) with the formation of an indole (E)-4h with 85% yield (entry
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8). This result could be explained by higher stabilization of the forming carbenium ion at the Friedel-
Crafts step.
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Other benzyl alcohols possessing different substituent at the aniline ring were also tested. We
found that the presence of methyl or methoxy groups did not change the chemoselectivity of the studied
reaction: the respective indoles (E)-4i-m were formed with 85-89% yield (entries 9-13). 4,5-Difluoro-
and 4-bromo derivatives 1n,o reacted with 2-methylfuran (2a) to form indoles (E)-4n,o with 55% and
45% yield accordingly that could be caused by deactivation properties of halogen substituents (entries
14,15). Finally, indole (E)-4p containing two methoxy groups at the aniline ring and 4-bromophenyl
substituent at α-position was obtained with a 75% yield (entry 16).
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Table 2. Scope of benzyl alcohols.a
R2
R2
1) 4 mol% p-TSA
AcOH (0.1 M), 65 oC, 1.5 h
OH
R1
R1
O
+
O
N
2) 5 mol% Pd(OAc)2, 4 mol% NaOAc
1.5 equiv. BQ, 100 oC, 16 h
3) 10 mol% I2, 100 oC, 3 h
NH
Ts
1a-p
Ts
2a
4a-p
(E)-
Entry
Yield (%)
91 (83)b
Entry
Yield (%)
Product
Product
(E)- (R1 = Me, R2 = H)
4i
86
87
9
1
4a
(E)- (Ph)
(E)- (R1 = OMe, R2 = H)
4j
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11
12
13
14
15
2
3
4
5
6
7
4b
(E)- (4-MeC6H4) 87
(E)- (R1 = H, R2 = Me)
4k
85
86
89
55
45
4c
(E)- (4-MeOC6H4)
85
83
R
Ph
R1
R2
(E)- (R1 =H, R2 = OMe)
4l
4d
(E)- (4-FC6H4)
O
O
N
N
(R1 = R2 = OMe)
4m
(E)-
4e
(E)- (2-MeC6H4) 84
Ts
Ts
(E)- (R1 = R2 = F)
4n
4f
(E)- (2,6-Me C H )
61
6 4
2
(E)- (R1 = H, R2 = Br)
16 (73)c
4o
4g
(E)- (Me)
R
MeO
MeO
MeO
MeO
85d
O
8
16
O
4p
(E)- (4-BrC6H4)
4h
(E)-
75
N
N
Ts
Ts
aReaction conditions: benzyl alcohol 1 (1 equiv.), 2-methylfuran (2a) (1.5 equiv.), stepwise addition of reagents.
c
bReaction was performed at 3 mmol scale of benzyl alcohol 1a and 4.5 mmol 2-methylfuran (2a). Yield of indole
(E)-4g obtained from the corresponding benzylfuran is given in parentheses. dFirst step – 45 min.
Further, we studied the scope of the reaction with regard to the furan component (Table 3). Since
furans other than 2-methylfuran are much less volatile, one equivalent of the furan reaction partner
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might be used, and, as a result, just one equivalent of BQ was needed. 2-Alkylfurans 2b,c possessing n-
butyl and tert-butyl groups reacted with benzyl alcohol 1a to provide corresponding indoles (E)-4q,r
with 84% and 78% yields respectively (entries 1,2). Reaction of 2,3-dimethylfuran (2d) gave indole (E)-
4s with a moderate yield (entry 3), which was possibly caused by a steric hindrance posed by the second
methyl group during an α,β-unsaturated carbonyl side chain forming step (see plausible mechanism,
scheme 5). All tested 2-arylfurans 2e-h were smoothly converted into 2-(2-benzoylvinyl)indoles (E)-4t-
w with up to a 90% yield (entries 4-7). Noticeably, furan 2i possessing an ester group in a side chain
uneventfully reacted with benzyl alcohol 1a producing an indole (E)-4x with high yield (entry 8).
Table 3. Scope of furans.a
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Ph
OH
2
R1
O
R2
R1
1) 4 mol% p-TSA
Ph
R
AcOH (0.1 M), 65 oC, 1.5 h
+
O
2) 5 mol% Pd(OAc)2, 4 mol% NaOAc
1 equiv. BQ, 100 oC, 16 h
3) 10 mol% I2, 100 oC, 3 h
N
NH
Ts
4q-x
(E)-
Ts
1a
2b-i
Entry
Yield (%)
Product
Ph
R
84
78
1
2
4q
(E)- (n-Bu)
O
4r
(E)- (t-Bu)
N
Ts
Ph
3
4sb
(E)-
49
O
N
Ts
4
5
6
7
90
81
76
84
4t
(E)- (Ph)
Ph
R
O
4u
(E)- (4-ClC6H4)
4v
(E)- (4-BrC6H4)
N
Ts
4w
(E)-
(E)-
(naphth-1-yl)
Ph
COOEt
2
8
O
4x
82
N
Ts
aReaction conditions: benzyl alcohol 1a (1 equiv.), furan 2 (1 equiv.),
stepwise addition of reagents. bIndole (E)-4s was obtained from 2,3-
dimethylfuran (2d) and benzyl alcohol 1a.
Mechanistically, the reaction may proceed through three distinct pathways. One possibility may
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include the formation of reactive species containing N-Pd bond (intermediate A, Scheme 5, aza-Heck
path a). Further migratory insertion across a proximal furyl carbon-carbon double bond affords an
intermediate B being in equilibrium with B’. Deprotonation of B’ followed by furan ring opening leads
to enole C which tautomerizes into ketone D. The latter upon β-hydride elimination furnishes reaction
product 4. Alternatively, the reaction could start with coordination of palladium species to the furan ring
followed by aminopalladation (Scheme 5, aza-Wacker path b) or by electrophilic palladation of the
furan ring followed by a nucleophilic addition (Scheme 5, path c) leading to intermediate B/B’.
Scheme 5. Plausible mechanisms.
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Ts
Ts
NH
NH
O
O
path b
3
path a
Pd(OAc)2
HQ
3
aza-Wacker
aza-Heck
AcOH
BQ
Pd0
Ts
N
O
HPdOAc
Ts
Ts
4
NH
N
PdOAc
Ts
N
Pd(OAc)2
HPdOAc
O
O
O
A
A'
E
Ts
Ts
PdOAc
OH
PdOAc
O
N
N
C
D
Ts
N
PdOAc
Ts
N
PdOAc
AcOH
O
O
H
H
B'
B
Ts
Ts
PdOAc
NH
NH
+
PdOAc
+
O
O
A*
A#
Pd(OAc)2
-AcOH
path c
Electrophilic Palladation
Ts
NH
O
3
2-Vinylindoles represent an important class of organic compounds having been utilized as
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building-blocks in synthetic organic chemistry.16 To further highlight the synthetic utility of obtained
products we performed several transformations. Thus, oxidation of an indole (E)-4a with sodium
hypobromite afforded acrylic acid 6 quantitatively. Surprisingly, 6 underwent detosylation followed by
intramolecular nucleophilic substitution instead of electrophilic aromatic substitution in the presence of
PCl5/AlCl3 to provide pyrroloindolone 7 in high yield (Scheme 6).
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Scheme 6. Further transformations of indole (E)-4a.
Ph
Ph
Ph
O
O
18 equiv. NaOH
9 equiv. Br2
1.2 equiv. PCl5
1.2 equiv. AlCl3
OH
1,4-dioxane/H2O
r.t., 24 h
N
Ts
N
Ts
DCM, r.t., 20 h
N
O
4a
(E)-
7
6
79%
98%
Next, cyclopropanation of indole (E)-4u under Corey-Chaykovsky reaction17 conditions provided
cyclopropane 8 with 84% yield. Heating the compound 8 in DCE in the presence of TSA and CuCl2 led
to the formation of indolylfuran 9 with excellent yield (Scheme 7).18
Scheme 7. Further transformations of indole (E)-4u.
O
Ph
Ph
Ph
1.2 equiv. (CH3)3SO+ I-
1.2 equiv. NaH
O
25 mol% TSA
1.2 equiv. CuCl2.2H2O
Cl
THF/DMF
r.t., 3 h
DCE, 80 °C
24 h
N
Ts
N
Ts
N
Ts
O
Cl
Cl
8
84%
4u
(E)-
9
98%
Finally, reduction of cyclopropane 8 with sodium borohydride followed by treatment with TSA
upon heating produced diene 10 with a high yield.19 Diene 10 underwent spontaneous cyclization to
form dihydrocarbazole 11 when stored on light. Heating diene 10 neat on sunlight led to a full
conversion within 8 hours to produce compound 11 with quantitative analytical yield. Dihydrocarbazole
11 seemed to be pretty sensitive to air: it was rapidly oxidized into its unsaturated analogue 12.20 In
order to convert a compound 11 into carbazole 12 in full, the mixture containing both heterocycles has
been dissolved in toluene and treated with DDQ (Scheme 8).
Scheme 8. Synthesis of carbazole 12.
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O
Ph
Ph
1) 2 equiv. NaBH4
Cl
Cl
EtOH/1,4-dioxane, r.t., 1 h
5
6
7
8
2) 10 mol% p-TSA
DCE, 70 °C, 30 min
N
Ts
N
Ts
10
87%
8
9
10
11
12
13
14
15
16
17
Sunlight, air
neat, 80 °C, 8 h
1.2 equiv. DDQ
Cl
Cl
10
toluene, r.t.
6 h
N
Ts
N
Ts
11
12
99%
99% (NMR)
CONCLUSION
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In conclusion, we have showed that substituted furans can act as masked olefins under oxidative
amination conditions. The synthetic protocol based on described reaction affords densely functionalized
2-(2-acylvinyl)indole derivatives with good-to-excellent yields and excellent E-selectivity from easily
accessible starting materials. We have also demonstrated efficient transformations of the obtained indole
products into a diverse range of heterocyclic scaffolds.
EXPERIMENTAL SECTION
General Information
1H and 13C NMR spectra were recorded with a «Bruker Avance III HD 400» (400 MHz for 1H and
100 MHz for 13C NMR) and Bruker Avance DRX-500 (500 MHz for 1H and 125 MHz for 13C NMR) or
1
DPX-400 (400 MHz for H and 100 MHz for 13C NMR) spectrometers at room temperature; the
chemical shifts (δ) were measured in ppm with respect to the solvent (CDCl3, 1Н: δ = 7.26 ppm, 13C: δ =
1
13
77.16 ppm; [D6] DMSO, Н: δ = 2.50 ppm, C: δ = 39.52 ppm). Coupling constants (J) are given in
Hertz. Splitting patterns of an apparent multiplets associated with an averaged coupling constants were
designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets) and br
13
(broadened). All C spectra were recorded with broadband proton decoupling. HRMS analysis was
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performed on Micromass 70 VSE mass spectrometer. Anhydrous solvents purchased from Aldrich were
additionally purified on PureSolv PS-400-4 by Innovative Technology, Inc. purification system and/or
stored over calcium hydride. All starting materials were purchased from Strem Chemicals, Aldrich, TCI
America, Oakwood Chemical, AK Sci., Alfa Aesar, Enamine, Combi-blocks or synthesized via known
literature procedures. Palladium(II) chloride and palladium(II)acetate were purchased from Aldrich.
Column chromatography was carried out employing Silicycle Silica-P flash silica gel (40-63 μm).
Precoated silica gel plates F-254 were used for thin-layer analytical chromatography. Data sets for X-
Ray diffraction were collected with a «New Xcalibur, Ruby» diffractometer at room temperature.
General procedure for the synthesis of 2-(N-tosylamino)benzyl alcohols 1a-g13
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To a solution of 2-(N-tosylamino)benzaldehyde13 (413 mg, 1.5 mmol) in THF (8.0 mL) was added
a solution of RMgBr (3.3 mmol, 2.2 equiv.) dropwise at -78 °C under argon. The resulting mixture was
allowed to warm up to room temperature, and saturated NH4Cl (5 mL) was added. The organic layer
was separated, and the water layer was washed with ethyl acetate (2 × 10 mL). The combined organic
solutions were dried over Na2SO4, and the solvents were evaporated. The resulted crude product was
purified by column chromatography (petroleum ether/ethyl acetate, 30:1 to 10:1) to give alcohols 1a-g.
N-{2-[Hydroxy(phenyl)methyl]phenyl}-4-methylbenzenesulfonamide (1a)21:
1
Colorless oil; 509 mg, 96% yield; H NMR (400 MHz, CDCl3) δ = 7.99 (br s, 1H, NH), 7.50–7.45 (m,
3H, HAr), 7.31–7.13 (m, 8H, HAr), 7.04–7.00 (m, 1H, HAr), 6.94–6.92 (m, 1H, HAr), 5.69 (br s, 1H, CH),
13
2.76 (br s, 1H, OH), 2.38 (s, 3H, Me) ppm; C{1H} NMR (100 MHz, CDCl3) δ = 143.7, 141.3, 136.9,
136.0, 133.4, 129.7 (2C), 129.2, 129.1, 128.8 (2C), 128.0, 127.4 (2C), 126.5 (2C), 124.7, 122.3, 74.9,
21.6 ppm.
N-{2-[Hydroxy(4-methylphenyl)methyl]phenyl}-4-methylbenzenesulfonamide (1b)13:
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Colorless oil; 523 mg, 95% yield; H NMR (500 MHz, CDCl3) δ = 8.07 (br s, 1H, NH), 7.48–7.46 (m,
4
5
6
3H, HAr), 7.22–7.19 (m, 1H, HAr), 7.14–7.09 (m, 4H, HAr), 7.02–6.99 (m, 3H, HAr), 6.92–6.90 (m, 1H,
7
8
9
3
3
HAr), 5.60 (d, J = 3.2 Hz, 1H, CH), 2.81 (d, J = 3.2 Hz, 1H, OH), 2.38 (s, 3H, Me), 2.36 (s, 3H, Me)
ppm; 13C{1H} NMR (125 MHz, CDCl3) δ = 143.7, 138.2, 137.7, 136.7, 135.9, 133.3, 129.6 (2C), 129.4
(2C), 129.1, 129.0, 127.3 (2C), 126.4 (2C), 124.6, 122.1, 74.7, 21.6, 21.3 ppm.
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N-{2-[Hydroxy(4-methoxyphenyl)methyl]phenyl}-4-methylbenzenesulfonamide (1c)13:
1
Colorless oil; 512 mg, 89% yield; H NMR (500 MHz, CDCl3) δ = 8.18 (br s, 1H, NH), 7.45–7.47 (m,
3H, HAr), 7.21–7.18 (m, 1H, HAr), 7.13–7.11 (m, 2H, HAr), 7.05–6.98 (m, 3H, HAr), 6.91–6.89 (m, 1H,
HAr), 6.80–6.78 (m, 2H, HAr), 5.59 (br s, 1H, CH), 3.79 (s, 3H, OMe), 3.11 (br s, 1H, OH), 2.36 (s, 3H,
Me) ppm; C{1H} NMR (125 MHz, CDCl3) δ = 159.3, 143.7, 136.6, 135.9, 133.3 (2C), 129.6 (2C),
13
129.0, 128.9, 127.7 (2C), 127.2 (2C), 124.6, 121.9, 114.0 (2C), 74.4, 55.4, 21.6 ppm.
N-{2-[(4-Fluorophenyl)(hydroxy)methyl]phenyl}-4-methylbenzenesulfonamide (1d)13:
Colorless oil; 468 mg, 84% yield; 1H NMR (500 MHz, CDCl3) δ = 8.06 (s, 1H, NH), 7.48–7.46 (m, 1H,
HAr), 7.44–7.42 (m, 2H, HAr), 7.24–7.21 (m, 1H, HAr), 7.13–7.08 (m, 4H, HAr), 7.05–7.02 (m, 1H, HAr),
6.94–6.90 (m, 3H, HAr), 5.71 (s, 1H, CH), 3.10 (br s, 1H, OH), 2.37 (s, 3H, Me) ppm; C{1H} NMR
13
(125 MHz, CDCl3) δ = 162.4 (d, J = 246.3 Hz), 143.9, 137.0, 136.5, 135.9, 133.2, 129.7 (2C), 129.3,
129.2, 128.0 (d, J = 8.1 Hz, 2C), 127.2 (2C), 124.8, 122.2, 115.4 (d, J = 21.6 Hz, 2C), 74.3, 21.6 ppm.
N-{2-[Hydroxy(2-methylphenyl)methyl]phenyl}-4-methylbenzenesulfonamide (1e):
1
Colorless oil; 502 mg, 91% yield; H NMR (500 MHz, CDCl3) δ = 8.16 (br s, 1H, NH), 7.66–7.64 (m,
2H, HAr), 7.44–7.42 (m, 1H, HAr), 7.39–7.38 (m, 1H, HAr), 7.24–7.21 (m, 5H, HAr), 7.12–7.10 (m, 1H,
3
3
HAr), 6.97–6.94 (m, 1H, HAr), 6.58–6.56 (m, 1H, HAr), 5.73 (d, J = 4.0 Hz, 1H, CH), 2.96 (d, J = 4.0
Hz, 1H, OH), 2.39 (s, 3H, Me), 1.78 (s, 3H, Me) ppm; C{1H} NMR (125 MHz, CDCl3) δ = 144.0,
13
139.1, 137.0, 136.1, 135.5, 133.9, 130.6, 129.8 (2C), 129.0, 128.4, 128.1, 127.3 (2C), 126.5, 126.4,
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125.6, 123.9, 70.7, 21.6, 18.8 ppm; HRMS (ESI/TOF): m/z calcd. for C21H21NO3SNa [M+Na]+
390.1134; found 390.1132.
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N-{2-[(2,6-Dimethylphenyl)(hydroxy)methyl]phenyl}-4-methylbenzenesulfonamide (1f):
1
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Colorless oil; 452 mg, 79% yield; H NMR (400 MHz, CDCl3) δ = 9.11 (br s, 1H, NH), 7.68–7.66 (m,
2H, HAr), 7.64–7.61 (m, 1H, HAr), 7.24–7.21 (m, 3H, HAr), 7.15–7.11 (m, 1H, HAr), 7.02–7.00 (m, 2H,
HAr), 6.91–6.87 (m, 1H, HAr), 6.44–6.42 (m, 1H, HAr), 5.82 (br s, 1H, CH), 2.75 (br s, 1H, OH), 2.38 (s,
3H, Me), 2.00 (s, 6H, Me) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 143.8, 137.6, 137.3 (2C), 137.0,
136.5, 131.0, 129.8 (2C), 129.5 (2C), 128.9, 128.3, 127.5, 127.1 (2C), 124.9, 123.6, 71.4, 21.6, 20.7
(2C) ppm; HRMS (ESI/TOF): m/z calcd. for C22H23NO3SNa [M+Na]+ 404.1291; found 404.1291.
N-[2-(1-Hydroxyethyl)phenyl]-4-methylbenzenesulfonamide (1g)13:
1
Colorless oil; 415 mg, 95% yield; H NMR (500 MHz, CDCl3) δ = 8.42 (br s, 1H, NH), 7.70–7.68 (m,
2H, HAr), 7.44–7.42 (m, 1H, HAr), 7.23–7.17 (m, 3H, HAr), 7.09–7.07 (m, 1H, HAr), 7.05–7.03 (m, 1H,
HAr), 4.84 (q, 3J = 6.6 Hz, 1H, CH), 2.37 (s, 3H, Me), 1.36 (d, 3J = 6.6 Hz, 3H, Me) ppm; 13C{1H} NMR
(125 MHz, CDCl3) δ = 143.9, 137.1, 135.9, 134.2, 129.8 (2C), 128.7, 127.3 (2C), 127.1, 124.8, 122.0,
69.9, 23.0, 21.7 ppm.
General procedure for the synthesis of 2-(N-tosylamino)benzyl alcohols 1h-p22
To a solution of the appropriate 2-aminobenzoic acid (3.5 mmol) in H2O/THF (2:1 v/v) (30 mL)
was added triethylamine (1.05 g, 1.47 mL, 10.5 mmol) at room temperature followed by p-
toluenesulfonyl chloride (810 mg, 4.2 mmol) at 0 °C. The resulting mixture was stirred at room
temperature for 6 h. On completion, THF was removed and the aqueous solution was washed with
diethyl ether (30 mL). The diethyl ether layer was discarded while the aqueous layer was acidified with
hydrochloric acid (2 M, pH ca. 2) and extracted with ethyl acetate (3 × 15 mL). The combined organic
layers were washed with brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure.
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The resulting solid was dried under vacuum overnight and used directly for the next step. The obtained
solid was dissolved in CH2Cl2 (35 mL) and cooled to 0 °C under a nitrogen atmosphere. The solution
was then treated with N,O-dimethylhydroxylamine·HCl (DMHA) (401 mg, 4.2 mmol) followed by N-
methylmorpholine (NMM) (1.15 mL, 10.5 mmol). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide)
hydrochloride (EDC·HCl) (805 mg, 4.2 mmol) was then added portion-wise over a 15 min period. The
reaction mixture was allowed to stir for further 3 h at 0 °C and an additional 15 h at room temperature.
On completion, the reaction mixture was treated with saturated NaHCO3 solution (30 mL). The organic
and aqueous phases were separated and the aqueous phase was extracted with ethyl acetate (3 × 5 mL).
The combined organic layers were washed with 10% citric acid solution (20 mL) followed by brine (30
mL), dried over Na2SO2 and concentrated under reduced pressure. The solid product was washed with a
mixture of 5% ethyl acetate/n-hexane solution and the resulting Weinreb amide was dried under vacuum
overnight. The resulted amide was dissolved in anhydrous THF (25 mL) followed by the addition of the
respective R2MgBr (0.5 M, 1 M or 2 M THF solution, 7 mmol) at room temperature under a nitrogen
atmosphere. The resulting mixture was then stirred for 18 h at room temperature. On completion, the
reaction mixture was treated with saturated NH4Cl or 2 M aqueous HCl solution (15 mL) and the
resulting mixture was stirred at room temperature for 15 min before ethyl acetate (50 mL) was added.
The phases were separated and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The
combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated under
reduced pressure to afford a solid or oil, which was then dried under vacuum. The crude product formed
after the third step was dissolved in MeOH (35 mL), cooled to 0 °C followed by portionwise addition of
NaBH4 (265 mg, 7 mmol). The reaction mixture was allowed to stir for further 1 h at 0 °C and an
additional 2 h at room temperature. Upon completion, the reaction mixture was treated with saturated
NH4Cl, stirred for 15 min before ethyl acetate (20 mL) was added. The phases were separated and the
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aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed
with brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure. The target benzyl
alcohols 1h-p were purified then by column chromatography (petroleum ether/ethyl acetate, 30:1 to
10:1). Yields refer to the overall yields over 4 steps.
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N-[2-(1-Hydroxyethyl)-4,5-dimethoxyphenyl]-4-methylbenzenesulfonamide (1h)21:
1
Colorless oil; 898 mg, 73% yield; H NMR (400 MHz, CDCl3) δ = 7.67 (br s, 1H, NH), 7.61–7.59 (m,
3
2H, HAr), 7.22–7.20 (m, 2H, HAr), 6.70 (s, 1H, HAr), 6.68 (s, 1H, HAr), 4.83 (q, J = 6.4 Hz, 1H, CH),
3.81 (s, 3H, OMe), 3.68 (s, 3H, OMe), 2.63 (br s, 1H, OH), 2.37 (s, 3H, Me), 1.27 (d, 3J = 6.4 Hz, 3H,
13
Me) ppm; C{1H} NMR (100 MHz, CDCl3) δ = 148.4, 147.2, 143.9, 136.6, 130.4, 129.7 (2C), 127.5
(2C), 127.3, 109.7, 108.7, 67.6, 56.2, 56.0, 23.0, 21.6 ppm.
N-{2-[Hydroxy(phenyl)methyl]-4-methylphenyl}-4-methylbenzenesulfonamide (1i):
Colorless oil; 887 mg, 69% yield; 1H NMR (500 MHz, CDCl3) δ = 8.02 (s, 1H, NH), 7.46–7.44 (m, 2H,
HAr), 7.29–7.27 (m, 4H, HAr), 7.12–7.14 (m, 4H, HAr), 6.81 (br d, 3J = 7.8 Hz, 1H, HAr), 6.77 (d, J = 7.8
Hz, 1H, HAr), 5.60 (s, 1H, CH), 2.88 (s, 1H, OH), 2.37 (s, 3H, Me), 2.26 (s, 3H, Me) ppm; C{1H}
13
NMR (125 MHz, CDCl3) δ = 143.7, 141.4, 139.2, 136.6, 135.7, 130.5, 129.6 (2C), 129.1, 128.7 (2C),
127.8, 127.3 (2C), 126.4 (2C), 125.4, 122.8, 74.5, 21.6, 21.3 ppm; HRMS (ESI/TOF): m/z calcd. for
C21H21NO3SNa [M+Na]+ 390.1134; found 390.1135.
N-{2-[Hydroxy(phenyl)methyl]-4-methoxyphenyl}-4-methylbenzenesulfonamide (1j):
Colorless oil; 980 mg, 73% yield; 1H NMR (500 MHz, CDCl3) δ = 8.14 (s, 1H, NH), 7.46–7.44 (m, 2H,
HAr), 7.30 – 7.28 (m, 3H, HAr), 7.16–7.12 (m, 4H, HAr), 7.07 (d, 4J = 2.5 Hz, 1H, HAr), 6.78 (d, 3J = 8.5
Hz, 1H, HAr), 6.51 (dd, 3J = 8.5, 4J = 2.5 Hz, 1H, HAr), 5.61 (d, 3J = 3.2 Hz, 1H, CH), 3.73 (s, 3H, OMe),
3
13
2.75 (d, J = 3.2 Hz, 1H, OH), 2.37 (s, 3H, Me) ppm; C{1H} NMR (125 MHz, CDCl3) δ = 160.1,
143.8, 141.5, 137.2, 136.5, 130.2, 129.7 (2C), 128.7 (2C), 127.8, 127.4 (2C), 126.4 (2C), 125.0, 109.9,
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107.2, 74.6, 55.5, 21.7 ppm; HRMS (ESI/TOF): m/z calcd. for C21H21NO4SNa [M+Na]+ 406.1083;
found 406.1075.
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N-{2-[Hydroxy(phenyl)methyl]-5-methylphenyl}-4-methylbenzenesulfonamide (1k):
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Colorless oil; 952 mg, 74% yield; H NMR (500 MHz, CDCl3) δ = 7.76 (s, 1H, NH), 7.48 – 7.46 (m,
2H, HAr), 7.30 – 7.28 (m, 3H, HAr), 7.26 (d, 3J = 8.2 Hz, 1H, HAr), 7.15 – 7.13 (m, 4H, HAr), 7.00 (br d,
3J = 8.2 Hz, 1H, HAr), 6.75 (br s, 1H, HAr), 5.65 (s, 1H, CH), 2.98 (br s, 1H, OH), 2.38 (s, 3H, Me), 2.21
(s, 3H, Me) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ = 143.7, 141.4, 136.6, 135.0, 134.3, 132.9, 129.8,
129.7 (2C), 129.5, 128.6 (2C), 127.8, 127.3 (2C), 126.4 (2C), 123.1, 74.2, 21.6, 21.0 ppm; HRMS
(ESI/TOF): m/z calcd. for C21H21NO3SNa [M+Na]+ 390.1134; found 390.1126.
N-{2-[Hydroxy(phenyl)methyl]-5-methoxyphenyl}-4-methylbenzenesulfonamide (1l):
Colorless oil; 953 mg, 71% yield; 1H NMR (500 MHz, CDCl3) δ = 7.48–7.46 (m, 2H, HAr), 7.41 (s, 1H,
NH), 7.29–7.22 (m, 3H, HAr), 7.16–7.11 (m, 4H, HAr), 7.11 (d, 3J = 8.8 Hz, 1H, HAr), 6.67 (dd, 3J = 8.8,
4J = 2.8 Hz, 1H, HAr), 6.47 (d, J = 2.8 Hz, 1H, HAr), 5.59 (s, 1H, CH), 3.63 (s, 3H, OMe), 3.21 (br s,
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1H, OH), 2.37 (s, 3H, Me) ppm; C{1H} NMR (125 MHz, CDCl3) δ = 157.6, 143.8, 141.4, 138.6,
136.5, 129.7 (2C), 128.6 (2C), 127.8, 127.6, 127.4 (2C), 126.5 (2C), 126.4, 114.8, 113.4, 73.1, 55.4,
21.6 ppm; HRMS (ESI/TOF): m/z calcd. for C21H21NO4SNa [M+Na]+ 406.1083; found 406.1081.
N-{2-[Hydroxy(phenyl)methyl]-4,5-dimethoxyphenyl}-4-methylbenzenesulfonamide (1m)13,21
:
Colorless oil; 1223 mg, 81% yield; 1H NMR (500 MHz, CDCl3) δ = 7.52–7.50 (m, 2H, HAr), 7.31–7.27
(m, 4H, HAr+NH), 7.20–7.18 (m, 2H, HAr), 7.14–7.12 (m, 2H, HAr), 6.82 (s, 1H, HAr), 6.44 (s, 1H, HAr),
5.61 (d, 3J = 3.5 Hz, 1H, CH), 3.74 (s, 3H, OMe), 3.67 (s, 3H, OMe), 2.72 (br s, 1H, OH), 2.40 (s, 3H,
Me) ppm; C{1H} NMR (125 MHz, CDCl3) δ = 148.8, 147.0, 143.9, 141.7, 136.5, 129.7 (2C), 128.9
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(2C), 128.7 (2C), 127.9, 127.5 (2C), 126.5 (2C), 111.7, 108.8, 73.1, 56.1 (2C), 21.7 ppm.
N-{4,5-Difluoro-2-[hydroxy(phenyl)methyl]phenyl}-4-methylbenzenesulfonamide (1n)13:
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Colorless oil; 859 mg, 63% yield; H NMR (500 MHz, CDCl3) δ = 7.48–7.44 (m, 2H, HAr), 7.32–7.22
(m, 4H, HAr), 7.20–7.14 (m, 2H, HAr), 7.11–7.06 (m, 2H, HAr), 6.66 (dd, 3JH-F = 10.8 Hz, 4JH-F = 8.5 Hz,
1H, HAr), 5.53 (s, 1H, CH), 2.39 (s, 3H, Me) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ = 149.6 (dd, 1J =
249.4 Hz, 2J = 13.2 Hz), 147.2 (dd, 1J = 247.1, 2J = 12.7 Hz), 144.4, 140.5, 135.9, 131.9 (d, 3J = 6.5 Hz),
131.1 (br s), 129.9 (2C), 128.9 (2C), 128.3, 127.2 (2C), 126.4 (2C), 117.7 (d, 2J = 19.1 Hz), 112.3 (d, 2J
= 21.0 Hz), 73.3, 21.6 ppm.
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N-{4-Bromo-2-[hydroxy(phenyl)methyl]phenyl}-4-methylbenzenesulfonamide (1o):
Colorless oil; 1029 mg, 68% yield; 1H NMR (500 MHz, CDCl3) δ = 8.24 (s, 1H, HAr), 7.63 (d, 4J = 1.7
Hz, 1H, HAr), 7.44–7.42 (m, 2H, HAr), 7.31–7.29 (m, 3H, HAr), 7.15–7.10 (m, 5H, HAr), 6.77 (d, 3J = 8.2
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Hz, 1H, HAr), 5.62 (d, J = 3.4 Hz, 1H, CH), 3.03 (d, J = 3.4 Hz, 1H, OH), 2.38 (s, 3H, Me) ppm;
13C{1H} NMR (125 MHz, CDCl3) δ = 144.1, 140.6, 137.3, 136.1, 131.5, 130.5, 129.8 (2C), 128.9 (2C),
128.2, 127.3 (2C), 127.2, 126.3 (2C), 124.3, 122.7, 74.6, 21.7 ppm; HRMS (ESI/TOF): m/z calcd. for
C20H18BrNO3SNa [M+Na]+ 454.0083; found 454.0085.
N-{2-[(4-Bromophenyl)(hydroxy)methyl]-4,5-dimethoxyphenyl}-4-methylbenzenesulfonamide
(1p)11c:
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Colorless oil; 896 mg, 52% yield; H NMR (400 MHz, CDCl3) δ = 7.47–7.45 (m, 2H, HAr), 7.37–7.35
(m, 2H, HAr), 7.23 (br s, 1H, NH), 7.19–7.17 (m, 2H, HAr), 7.03–7.01 (m, 2H, HAr), 6.77 (s, 1H, HAr),
6.48 (s, 1H, HAr), 5.73 (br s, 1H, CH), 3.71 (s, 3H, OMe), 3.71 (s, 3H, OMe), 2.98 (br s, 1H, OH), 2.41
(s, 3H, Me) ppm; C{1H} NMR (100 MHz, CDCl3) δ = 149.0, 147.2, 144.0, 141.2, 136.3, 131.5 (2C),
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129.7 (2C), 128.9, 128.0 (2C), 127.9, 127.4 (2C), 121.5, 112.1, 108.7, 72.4, 56.2, 56.0, 21.6 ppm.
General procedure for the synthesis of benzylfurans 3a,g11d
To a solution of an appropriate benzyl alcohol 1a or 1g (2.0 mmol) and 2-methylfuran (2a) (3
mmol, 265 µL, 1.5 equiv.) in 1,2-DCE (10 mL) was added p-TSA (17 mg, 0.1 mmol). The resulting
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mixture was stirred for 1.5 h at 60 °C. Upon completion, the reaction mixture was concentrated under
reduced pressure. The target benzylfurans 3 were further purified by column chromatography
(petroleum ether/ethyl acetate, 20:1).
4-Methyl-N-{2-[(5-methylfuran-2-yl)(phenyl)methyl]phenyl}benzenesulfonamide (3a)11d:
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Colorless oil; 818 mg, 98% yield; H NMR (400 MHz, CDCl3) δ = 7.62–7.60 (m, 2H, HAr), 7.51–7.49
(m, 1H, HAr), 7.29–7.24 (m, 6H, HAr), 7.14–7.10 (m, 1H, HAr), 6.85–6.83 (m, 2H, HAr), 6.80–6.78 (m,
1H, HAr), 6.31 (br s, 1H, NH), 5.88 (d, 3J = 2.9 Hz, 1H, HFur), 5.63 (d, 3J = 2.9 Hz, 1H, HFur), 4.95 (br s,
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1H, CH), 2.46 (s, 3H, Me), 2.27 (s, 3H, Me) ppm; C{1H} NMR (100 MHz, CDCl3) δ = 152.5, 152.4,
143.9, 140.0, 137.2, 135.7, 134.4, 129.9 (2C), 129.7, 128.9 (2C), 128.8 (2C), 128.0, 127.4, 127.3 (2C),
126.5, 125.7, 110.1, 106.3, 46.2, 21.7, 13.7 ppm.
4-Methyl-N-{2-[1-(5-methylfuran-2-yl)ethyl]phenyl}benzenesulfonamide (3g)11d:
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Colorless oil; 590 mg, 83% yield; H NMR (400 MHz, CDCl3) δ = 7.61–7.59 (m, 2H, HAr), 7.40–7.38
(m, 1H, HAr), 7.24–7.14 (m, 5H, HAr), 6.77 (br s, 1H, NH), 5.83 (d, 3J = 3.0 Hz, 1H, HFur), 5.79 (d, 3J =
3.0 Hz, 1H, HFur), 3.86 (q, 3J = 7.2 Hz, 1H, CH), 2.39 (s, 3H, Me), 2.21 (s, 3H, Me), 1.32 (d, 3J = 7.2 Hz,
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3H, Me) ppm; C{1H} NMR (100 MHz, CDCl3) δ = 155.7, 151.6, 143.8, 137.2, 137.0, 134.3, 129.7
(2C), 127.8, 127.6, 127.4 (2C), 126.7, 125.2, 106.2, 106.0, 34.0, 21.6, 18.4, 13.6 ppm.
General procedure for the synthesis of indoles 4a-p
In a 3 mL Wheaton microreactor vial equipped with a Teflon pressure cap, a mixture of an
appropriate benzyl alcohol 1 (0.2 mmol), 2-methylfuran (2a) (27 µL, 0.3 mmol, 1.5 equiv.), p-TSA ( 1.4
mg, 4 mol%) and acetic acid (2 mL) was stirred at 65 °C for 1.5 h. After that, Pd(OAc)2 (2.3 mg, 5
mol%), benzoquinone (33 mg, 0.3 mmol, 1.5 equiv.) and NaOAc (0.7 mg, 4 mol%) was added, and the
reaction mixture was stirred for an additional 16 h at 100 °C. Next, I2 (5 mg, 10 mol%) was added, and
the resulting mixture was stirred further for 3 h at 100 °C. Upon completion, the reaction mixture was
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filtered through a pad of silica, the solvent was evaporated, and the residue was subjected to column
chromatography (petroleum ether/ethyl acetate, 30:1 to 10:1) to afford a target indole derivative.
Procedure for the gram-scale synthesis of indole 4a
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In a 100 mL RBF equipped with a rubber septum, a mixture of benzyl alcohol 1a (1059 mg, 3
mmol), 2-methylfuran (2a) (405 µL, 4.5 mmol, 1.5 equiv.), p-TSA ( 21 mg, 4 mol%) and acetic acid (30
mL) was stirred at 65 °C for 1.5 h. After that, Pd(OAc)2 (69 mg, 5 mol%), benzoquinone (990 mg, 4.5
mmol, 1.5 equiv.) and NaOAc (20 mg, 4 mol%) was added, and the reaction mixture was stirred for an
additional 16 h at 100 °C. Next, I2 (150 mg, 10 mol%) was added, and the resulting mixture was stirred
further for 3 h at 100 °C. Upon completion, the reaction mixture was filtered through a pad of silica, the
solvent was evaporated, and the residue was subjected to column chromatography (petroleum ether/ethyl
acetate, 15:1) to afford indole 4a as pale yellow oil (1035 mg, 83%).
(E)-4-(3-Phenyl-1-tosyl-1H-indol-2-yl)but-3-en-2-one (4a)11c,d
:
Pale yellow oil; 76 mg, 91% yield; 1H NMR (500 MHz, CDCl3) δ = 8.30–8.28 (m, 1H, HAr), 8.13 (d, 3J
= 16.5 Hz, 1H, CH), 7.61–7.59 (m, 2H, HAr), 7.45–7.37 (m, 4H, HAr), 7.30–7.22 (m, 4H, HAr), 7.19–7.17
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(m, 2H, HAr), 6.06 (d, J = 16.5 Hz, 1H, CH), 2.34 (s, 3H, Me), 2.31 (s, 3H, Me) ppm; C{1H} NMR
(125 MHz, CDCl3) δ = 198.3, 145.4, 137.6, 135.0, 132.6, 132.6, 132.4, 131.7, 131.1, 129.9 (2C), 129.7
(2C), 129.2 (2C), 128.8, 128.4, 126.8 (3C), 124.6, 120.9, 115.7, 27.1, 21.7 ppm; HRMS (ESI/TOF): m/z
calcd. for C25H22NO3S [M+H]+ 416.1315; found 416.1315.
(E)-4-[3-(4-Methylphenyl)-1-tosyl-1H-indol-2-yl]but-3-en-2-one (4b):
Pale yellow oil; 75 mg, 87% yield; 1H NMR (500 MHz, CDCl3) δ = 8.29–8.27 (m, 1H, HAr), 8.13 (d, 3J
= 16.5 Hz, 1H, CH), 7.60–7.58 (m, 2H, HAr), 7.42–7.39 (m, 1H, HAr), 7.30–7.28 (m, 1H, HAr), 7.24–7.21
(m, 3H, HAr), 7.18–7.14 (m, 4H, HAr), 6.11 (d, 3J = 16.5 Hz, 1H, CH), 2.40 (s, 3H, Me), 2.33 (s, 6H, Me)
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ppm; C{1H} NMR (125 MHz, CDCl3) δ = 198.5, 145.3, 138.3, 137.6, 135.0, 132.9, 132.5, 131.5,
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131.2, 129.9 (2C), 129.8 (2C), 129.6 (2C), 129.3, 129.1, 126.8 (3C), 124.6, 121.0, 115.7, 27.0, 21.7,
21.5 ppm; HRMS (ESI/TOF): m/z calcd. for C26H24NO3S [M+H]+ 430.1471; found 430.1472.
(E)-4-[3-(4-Methoxyphenyl)-1-tosyl-1H-indol-2-yl]but-3-en-2-one (4c):
Pale yellow oil; 76 mg, 85% yield; 1H NMR (500 MHz, CDCl3) δ = 8.29–8.27 (m, 1H, HAr), 8.13 (d, 3J
= 16.5 Hz, 1H, CH), 7.60–7.58 (m, 2H, HAr), 7.42–7.39 (m, 1H, HAr), 7.30–7.28 (m, 1H, HAr), 7.25–7.22
(m, 1H, HAr), 7.19–7.16 (m, 4H, HAr), 6.97–6.95 (m, 2H, HAr), 6.13 (d, 3J = 16.5 Hz, 1H, CH), 3.85 (s,
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3H, OMe), 2.33 (s, 6H, Me) ppm; C{1H} NMR (125 MHz, CDCl3) δ = 198.5, 159.7, 145.3, 137.6,
135.0, 132.9, 132.3, 131.5, 131.3, 130.9 (2C), 129.9 (2C), 128.8, 126.8 (3C), 124.6, 124.3, 121.0, 115.8,
114.7 (2C), 55.4, 27.0, 21.7 ppm; HRMS (ESI/TOF): m/z calcd. for C26H24NO4S [M+H]+ 446.1421;
found 446.1418.
(E)-4-[3-(4-Fluorophenyl)-1-tosyl-1H-indol-2-yl]but-3-en-2-one (4d):
Pale yellow oil; 72 mg, 83% yield; 1H NMR (500 MHz, CDCl3) δ = 8.30–8.28 (m, 1H, HAr), 8.12 (d, 3J
= 16.5 Hz, 1H, CH), 7.62–7.60 (m, 2H, HAr), 7.43–7.41 (m, 1H, HAr), 7.26–7.23 (m, 4H, HAr), 7.19–7.17
(m, 2H, HAr), 7.15–7.12 (m, 2H, HAr), 6.04 (d, 3J = 16.5 Hz, 1H, CH), 2.34 (s, 3H, Me), 2.33 (s, 3H, Me)
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ppm; C{1H} NMR (125 MHz, CDCl3) δ = 198.2, 162.7 (d, JC-F = 248.1 Hz), 145.5, 137.5, 135.0,
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132.7, 132.5, 131.8, 131.6 (d, JC-F = 8.1 Hz, 2C), 130.9, 129.9 (2C), 128.3, 127.5, 126.9, 126.8 (2C),
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124.7, 120.7, 116.4 (d, JC-F = 21.6 Hz, 2C), 115.7, 27.1, 21.7 ppm; HRMS (ESI/TOF): m/z calcd. for
C25H21FNO3S [M+H]+ 434.1221; found 434.1219.
(E)-4-[3-(2-Methylphenyl)-1-tosyl-1H-indol-2-yl]but-3-en-2-one (4e):
Pale yellow oil; 72 mg, 84% yield; 1H NMR (500 MHz, CDCl3) δ = 8.30–8.28 (m, 1H, HAr), 8.17 (d, 3J
= 16.6 Hz, 1H, CH), 7.57–7.55 (m, 2H, HAr), 7.43–7.40 (m, 1H, HAr), 7.34–7.27 (m, 2H, HAr), 7.25–7.20
(m, 2H, HAr), 7.17–7.15 (m, 2H, HAr), 7.04–7.02 (m, 2H, HAr), 5.80 (d, 3J = 16.6 Hz, 1H, CH), 2.33 (s,
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137.8, 136.6, 134.8, 132.9, 131.8 (2C), 131.4, 131.0, 130.8, 129.8 (2C), 129.7, 129.2, 128.9, 127.0,
126.7 (2C), 126.6, 124.8, 121.0, 116.1, 26.8, 21.7, 19.5 ppm; HRMS (ESI/TOF): m/z calcd. for
C26H24NO3S [M+H]+ 430.1471; found 430.1473.
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(E)-4-[3-(2,6-Dimethylphenyl)-1-tosyl-1H-indol-2-yl]but-3-en-2-one (4f):
Pale yellow oil; 54 mg, 61% yield; 1H NMR (500 MHz, CDCl3) δ = 8.32–8.30 (m, 1H, HAr), 8.21 (d, 3J
= 16.6 Hz, 1H, HAr), 7.53–7.51 (m, 2H, HAr), 7.44–7.41 (m, 1H, HAr), 7.23–7.20 (m, 2H, HAr), 7.14–7.12
(m, 2H, HAr), 7.11–7.09 (m, 2H, HAr), 6.96–6.94 (m, 1H, HAr), 5.68 (d, 3J = 16.6 Hz, 1H, CH), 2.32 (s,
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3H, Me), 2.28 (s, 3H, Me), 1.72 (s, 6H, Me) ppm; C{1H} NMR (125 MHz, CDCl3) δ = 198.7, 145.3,
138.4, 136.5, 134.7, 133.1 (2C), 131.4, 131.1, 130.9, 129.8, 129.7 (2C), 129.0, 128.8, 128.1 (2C), 127.2,
126.6 (2C), 125.0, 120.7, 116.5, 26.7, 21.7, 19.8 (2C) ppm; HRMS (ESI/TOF): m/z calcd. for
C27H26NO3S [M+H]+ 444.1628; found 444.1631.
(E)-4-(3-Methyl-1-tosyl-1H-indol-2-yl)but-3-en-2-one (4g)11c:
Pale yellow oil; 12 mg, 16% yield; 1H NMR (400 MHz, CDCl3) δ = 8.22–8.20 (m, 1H, HAr), 8.15 (d, 3J
= 16.6 Hz, 1H, CH), 7.53–7.51 (m, 2H, HAr), 7.45–7.43 (m, 1H, HAr), 7.40–7.37 (m, 1H, HAr), 7.29–7.26
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(m, 1H, HAr), 7.12–7.10 (m, 2H, HAr), 6.34 (d, J = 16.6 Hz, 1H, CH), 2.49 (s, 3H, Me), 2.30 (s, 3H,
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Me), 2.29 (s, 3H, Me). ppm; C{1H} NMR (100 MHz, CDCl3) δ = 198.8, 145.1, 137.4, 134.8, 134.4,
131.8, 131.7, 131.6, 129.8 (2C), 126.7, 126.6 (2C), 124.3, 124.0, 120.0, 115.6, 26.5, 21.6, 11.1 ppm.
(E)-4-(5,6-Dimethoxy-3-methyl-1-tosyl-1H-indol-2-yl)but-3-en-2-one (4h)11c,d
:
Pale yellow oil; 70 mg, 85% yield; 1H NMR (400 MHz, CDCl3) δ = 8.13 (d, 3J = 16.6 Hz, 1H, CH), 7.74
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(s, 1H, HAr), 7.46–7.44 (m, 2H, HAr), 7.11–7.09 (m, 2H, HAr), 6.78 (s, 1H, HAr), 6.27 (d, J = 16.6 Hz,
1H, HAr), 4.00 (s, 3H, OMe), 3.89 (s, 3H, OMe), 2.46 (s, 3H, Me), 2.29 (s, 3H, Me), 2.25 (s, 3H, Me)
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ppm; C{1H} NMR (100 MHz, CDCl3) δ = 198.9, 149.8, 148.0, 145.1, 134.6, 134.6, 132.3, 130.7,
130.0, 129.7 (2C), 126.5 (2C), 125.1, 124.6, 100.8, 99.2, 56.5, 56.2, 26.4, 21.6, 11.5 ppm.
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7.18–7.16 (m, 2H, HAr), 7.04 (br s, 1H, HAr), 6.04 (d, 3J = 16.5 Hz, 1H, CH), 2.35 (s, 3H, Me), 2.34 (s,
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3H, Me), 2.31 (s, 3H, Me) ppm; C{1H} NMR (125 MHz, CDCl3) δ = 198.4, 145.2, 135.9, 134.9,
134.5, 132.8, 132.6, 132.3, 131.8, 131.3, 129.8 (2C), 129.7 (2C), 129.2 (2C), 128.9, 128.4 (2C), 126.8
(2C), 120.6, 115.5, 27.0, 21.7, 21.3 ppm; HRMS (ESI/TOF): m/z calcd. for C26H24NO3S [M+H]+
430.1471; found 430.1470.
(E)-4-(5-Methoxy-3-phenyl-1-tosyl-1H-indol-2-yl)but-3-en-2-one (4j):
Pale yellow oil; 78 mg, 87% yield; 1H NMR (500 MHz, CDCl3) δ = 8.17 (d, 3J = 9.2 Hz, 1H, HAr), 8.09
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(d, J = 16.5 Hz, 1H, CH), 7.56–7.54 (m, 2H, HAr), 7.45–7.38 (m, 3H, HAr), 7.25–7.23 (m, 2H, HAr),
7.17–7.15 (m, 2H, HAr), 7.02 (dd, 3J = 9.2, 4J = 2.5 Hz, 1H, HAr), 6.66 (d, 4J = 2.5 Hz, 1H, HAr), 6.03 (d,
3J = 16.5 Hz, 1H, CH), 3.73 (s, 3H, OMe), 2.34 (s, 3H, Me), 2.31 (s, 3H, Me) ppm; 13C{1H} NMR (125
MHz, CDCl3) δ = 198.5, 157.4, 145.3, 134.7, 132.7, 132.5, 132.4, 132.3, 132.2, 129.8 (2C), 129.6 (2C),
129.3 (2C), 129.2, 128.5, 126.8 (2C), 122.5, 116.9, 116.2, 102.6, 55.7, 27.0, 21.7 ppm; HRMS
(ESI/TOF): m/z calcd. for C26H24NO4S [M+H]+ 446.1421; found 446.1416.
(E)-4-(6-Methyl-3-phenyl-1-tosyl-1H-indol-2-yl)but-3-en-2-one (4k):
Pale yellow oil; 73 mg, 85% yield; 1H NMR (500 MHz, CDCl3) δ = 8.11 (d, 3J = 16.5 Hz, 1H, CH), 8.10
(br s, 1H, HAr), 7.60–7.58 (m, 2H, HAr), 7.44–7.38 (m, 3H, HAr), 7.26–7.24 (m, 2H, HAr), 7.19–7.15 (m,
3H, HAr), 7.07 (d, 3J = 8.0 Hz, 1H, HAr), 6.03 (d, 3J = 16.5 Hz, 1H, CH), 2.52 (s, 3H, Me), 2.35 (s, 3H,
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Me), 2.30 (s, 3H, Me) ppm; C{1H} NMR (125 MHz, CDCl3) δ = 198.4, 145.3, 138.1, 137.4, 135.1,
132.8, 132.6, 132.0, 131.0, 129.9 (2C), 129.7 (2C), 129.2 (2C), 129.1, 129.0, 128.4, 126.8 (2C), 126.2,
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120.5, 115.8, 27.1, 22.4, 21.8 ppm; HRMS (ESI/TOF): m/z calcd. for C26H24NO3S [M+H]+ 430.1471;
found 430.1470.
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(E)-4-(6-Methoxy-3-phenyl-1-tosyl-1H-indol-2-yl)but-3-en-2-one (4l):
Pale yellow oil; 77 mg, 86% yield; 1H NMR (500 MHz, CDCl3) δ = 8.10 (d, 3J = 16.5 Hz, 1H, CH), 7.82
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(d, J = 2.0 Hz, 1H, HAr), 7.60–7.58 (m, 2H, HAr), 7.44–7.36 (m, 3H, HAr), 7.25–7.23 (m, 2H, HAr),
7.19–7.17 (m, 2H, HAr), 7.15 (d, 3J = 8.6 Hz, 1H, HAr), 6.86 (dd, 3J = 8.6 Hz, 4J = 2.0 Hz, 1H, HAr), 6.02
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(d, J = 16.5 Hz, 1H, CH), 3.93 (s, 3H, Me), 2.35 (s, 3H, Me), 2.29 (s, 3H, Me) ppm; C{1H} NMR
(125 MHz, CDCl3) δ = 198.4, 159.7, 145.4, 139.1, 135.0, 132.8, 132.6, 131.2, 130.5, 129.9 (2C), 129.7
(2C), 129.5, 129.2 (2C), 128.5, 126.8 (2C), 125.1, 121.6, 114.2, 99.7, 56.0, 27.0, 21.8 ppm; HRMS
(ESI/TOF): m/z calcd. for C26H24NO4S [M+H]+ 446.1421; found 446.1414.
(E)-4-(5,6-Dimethoxy-3-phenyl-1-tosyl-1H-indol-2-yl)but-3-en-2-one (4m)11c,d
:
Pale yellow oil; 85 mg, 89% yield; 1H NMR (400 MHz, CDCl3) δ = 8.10 (d, 3J = 16.4 Hz, 1H, CH), 7.87
(s, 1H, HAr), 7.58–7.56 (m, 2H, HAr), 7.49–7.40 (m, 3H, HAr), 7.28–7.25 (m, 2H, HAr), 7.20–7.18 (m,
2H, HAr), 6.64 (s, 1H, HAr), 6.02 (d, 3J = 16.5 Hz, 1H, CH), 4.06 (s, 3H, OMe), 3.80 (s, 3H, OMe), 2.37
(s, 3H, Me), 2.30 (s, 3H, Me) ppm; C{1H} NMR (100 MHz, CDCl3) δ = 198.5, 150.0, 148.2, 145.3,
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134.7, 132.7 (2C), 132.6, 130.7, 130.5, 130.0, 129.8 (2C), 129.6 (2C), 129.3 (2C), 128.5, 126.7 (2C),
124.4, 101.3, 99.2, 56.6, 56.2, 27.0, 21.7 ppm; HRMS (ESI/TOF): m/z calcd. for C27H26NO5S [M+H]+
476.1526; found 476.1534.
(E)-4-(5,6-Difluoro-3-phenyl-1-tosyl-1H-indol-2-yl)but-3-en-2-one (4n):
Pale yellow oil; 50 mg, 55% yield; 1H NMR (500 MHz, CDCl3) δ = 8.17–8.14 (m, 1H, HAr), 8.06 (d, 3J
= 16.5 Hz, 1H, CH), 7.60–7.58 (m, 2H, HAr), 7.46–7.39 (m, 3H, HAr), 7.23–7.21 (m, 4H, HAr), 7.05–7.02
(m, 1H, HAr), 6.03 (d, J = 16.5 Hz, 1H, CH), 2.37 (s, 3H, Me), 2.29 (s, 3H, Me) ppm; C{1H} NMR
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(125 MHz, CDCl3) δ = 198.1, 150.2 (dd, 1JC-F = 248.3 Hz, 2JC-F = 14.8 Hz), 149.1 (dd, 1JC-F = 246.0 Hz,
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(2C), 128.8, 127.8, 126.9 (2C), 107.8 (d, JC-F = 20.0 Hz), 104.9 (d, JC-F = 24.7 Hz), 27.2, 21.8 ppm;
HRMS (ESI/TOF): m/z calcd. for C25H20F2NO3S [M+H]+ 452.1126; found 452.1125.
(E)-4-(6-Bromo-3-phenyl-1-tosyl-1H-indol-2-yl)but-3-en-2-one (4o):
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Pale yellow oil; 45 mg, 45% yield; 1H NMR (500 MHz, CDCl3) δ = 8.49 (d, 4J = 1.6 Hz, 1H, HAr), 8.07
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(d, 3J = 16.5 Hz, 1H, CH), 7.63–7.61 (m, 2H, HAr), 7.45–7.39 (m, 3H, HAr), 7.36 (dd, J = 8.4 Hz, 4J =
1.6 Hz, 1H, HAr), 7.24–7.22 (m, 4H, HAr), 7.15 (d, 3J = 8.4 Hz, 1H, HAr), 6.03 (d, 3J = 16.5 Hz, 1H, CH),
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2.37 (s, 3H, Me), 2.29 (s, 3H, Me) ppm; C{1H} NMR (125 MHz, CDCl3) δ = 198.1, 145.8, 138.1,
134.9, 133.0, 132.0, 131.9, 131.8, 130.1 (2C), 129.8, 129.7 (2C), 129.3 (2C), 128.7, 128.0 (2C), 126.9
(2C), 122.0, 120.7, 118.6, 27.2, 21.8 ppm; HRMS (ESI/TOF): m/z calcd. for C25H21BrNO3S [M+H]+
494.0420; found 494.0419.
(E)-4-[3-(4-Bromophenyl)-5,6-dimethoxy-1-tosyl-1H-indol-2-yl]but-3-en-2-one (4p):
Pale yellow oil; 83 mg, 75% yield; 1H NMR (400 MHz, CDCl3) δ = 8.05 (d, 3J = 16.5 Hz, 1H, CH), 7.84
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(s, 1H, HAr), 7.58–7.53 (m, 4H, HAr), 7.18–7.12 (m, 4H, HAr), 6.57 (s, 1H, HAr), 6.00 (d, J = 16.5 Hz,
1H, HAr), 4.02 (s, 3H, OMe), 3.78 (s, 3H, OMe), 2.34 (s, 3H, Me), 2.29 (s, 3H, Me) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ = 198.0, 150.2, 148.5, 145.4, 135.0, 132.6 (2C), 132.5, 132.3, 131.8, 131.3 (2C),
131.1, 130.6, 129.9 (2C), 128.0, 126.7 (2C), 124.0, 122.7, 101.2, 99.4, 56.6, 56.3, 27.0, 21.7 ppm;
HRMS (ESI/TOF): m/z calcd. for C27H25BrNO5S [M+H]+ 554.0631; found 554.0622.
Alternative Synthesis of (E)-4-(3-methyl-1-tosyl-1H-indol-2-yl)but-3-en-2-one (4g)
In a 3 mL Wheaton microreactor vial, equipped with a Teflon pressure cap, a mixture of
benzylfuran 3b (71 mg, 0.2 mmol), Pd(OAc)2 (2.3 mg, 5 mol%), benzoquinone (22 mg, 0.2 mmol, 1.0
equiv.) and acetic acid (2 mL) was stirred at 100 °C for 16 h. After that, I2 (5 mg, 10 mol%) was added,
and the resulting mixture was stirred further for 3 h at 100 °C. Upon completion, the reaction mixture
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was filtered through a pad of silica, the solvent was evaporated, and the residue was subjected to a
column chromatography (petroleum ether/ethyl acetate, 20:1) to afford target indole 4g as a pale yellow
oil (52 mg, 73%).
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General procedure for the synthesis of indoles 4q-x
In a 3 mL Wheaton microreactor vial equipped with a Teflon pressure cap, a mixture of benzyl
alcohol 1a (71 mg, 0.2 mmol), furan 2 (0.2 mmol, 1.0 equiv.), p-TSA ( 1.4 mg, 4 mol%) and acetic acid
(2 mL) was stirred at 65 °C for 1.5 h. After that, Pd(OAc)2 (2.3 mg, 5 mol%), benzoquinone (22 mg, 0.2
mmol, 1.0 equiv.) and NaOAc (0.7 mg, 4 mol%) was added, and the reaction mixture was stirred for an
additional 16 h at 100 °C. Next, I2 (5 mg, 10 mol%) was added, and the resulting mixture was stirred
further for 3 h at 100 °C. Upon completion, the reaction mixture was filtered through a pad of silica, the
solvent was evaporated, and the residue was subjected to column chromatography (petroleum ether/ethyl
acetate, 30:1 to 10:1) to afford a target indole derivative.
(E)-1-(3-Phenyl-1-tosyl-1H-indol-2-yl)hept-1-en-3-one (4q):
Pale yellow oil; 77 mg, 84% yield; 1H NMR (500 MHz, CDCl3) δ = 8.30–8.28 (m, 1H, HAr), 8.10 (d, 3J
= 16.4 Hz, 1H, HAr), 7.62–7.60 (m, 2H, HAr), 7.45–7.37 (m, 4H, HAr), 7.31–7.22 (m, 4H, HAr), 7.18–7.16
(m, 2H, HAr), 6.09 (d, 3J = 16.4 Hz, 1H, CH), 2.53 (t, 3J = 7.4 Hz, 2H, CH2), 2.34 (s, 3H, Me), 1.58–1.52
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(m, 2H, CH2), 1.36–1.28 (m, 2H, CH2), 0.91 (t, J = 7.3 Hz, 3H, Me) ppm; C{1H} NMR (125 MHz,
CDCl3) δ = 200.5, 145.3, 137.6, 135.1, 132.6, 132.0, 131.9, 131.2, 131.0, 129.9 (2C), 129.8 (2C), 129.2
(2C), 128.5, 128.3, 126.9 (2C), 126.7, 124.6, 120.8, 115.7, 40.4, 26.7, 22.5, 21.8, 14.0 ppm; HRMS
(ESI/TOF): m/z calcd. for C28H28NO3S [M+H]+ 458.1784; found 458.1783.
(E)-4,4-Dimethyl-1-(3-phenyl-1-tosyl-1H-indol-2-yl)pent-1-en-3-one (4r):
Pale yellow oil; 71 mg, 78% yield; 1H NMR (400 MHz, CDCl3) δ = 8.35–8.32 (m, 1H, HAr), 8.13 (d, 3J
= 15.7 Hz, 1H, CH), 7.68–7.66 (m, 2H, HAr), 7.47–7.36 (m, 4H, HAr), 7.32–7.29 (m, 3H, HAr), 7.26–7.22
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(m, 1H, HAr), 7.19–7.17 (m, 2H, HAr), 6.50 (d, 3J = 15.7 Hz, 1H, CH), 2.34 (s, 3H, Me), 0.94 (s, 9H, Me)
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ppm; C{1H} NMR (100 MHz, CDCl3) δ = 203.3, 145.1, 137.7, 135.7, 133.3, 132.8, 130.8, 130.8,
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130.0 (2C), 129.8 (2C), 129.2 (2C), 128.1, 128.0, 127.4, 127.1 (2C), 126.6, 124.4, 120.7, 115.7, 43.0,
26.0 (3C), 21.7 ppm; HRMS (ESI/TOF): m/z calcd. for C28H28NO3S [M+H]+ 458.1784; found 458.1787.
(E)-3-Methyl-4-(3-phenyl-1-tosyl-1H-indol-2-yl)but-3-en-2-one (4s):
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Pale yellow oil; 42 mg, 49% yield; 1H NMR (500 MHz, CDCl3) δ = 8.34–8.32 (m, 1H, HAr), 7.92 (s, 1H,
CH), 7.54–7.52 (m, 3H, HAr), 7.44–7.41 (m, 1H, HAr), 7.39–7.36 (m, 2H, HAr), 7.32–7.26 (m, 4H, HAr),
7.14–7.12 (m, 2H, HAr), 2.54 (s, 3H, Me), 2.31 (s, 3H, Me), 0.98 (s, 3H, Me) ppm; 13C{1H} NMR (125
MHz, CDCl3) δ = 202.0, 145.2, 142.8, 136.4, 136.0, 132.7, 131.9, 130.3 (2C), 129.8 (2C), 129.6, 129.0
(2C), 127.5 (2C), 127.4, 125.6, 124.6, 123.9, 122.8, 120.2, 114.7, 27.4, 21.8, 21.1 ppm; HRMS
(ESI/TOF): m/z calcd. for C26H24NO3S [M+H]+ 430.1471; found 430.1472.
(E)-1-Phenyl-3-(3-phenyl-1-tosyl-1H-indol-2-yl)prop-2-en-1-one (4t):
Pale yellow oil; 86 mg, 90% yield; 1H NMR (500 MHz, CDCl3) δ = 8.36–8.34 (m, 1H, HAr), 8.30 (d, 3J
= 15.8 Hz, 1H, CH), 7.69–7.67 (m, 2H, HAr), 7.64–7.62 (m, 2H, HAr), 7.54–7.49 (m, 3H, HAr), 7.47–7.43
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15.8 Hz, 1H, HAr), 2.33 (s, 3H, Me) ppm; C{1H} NMR (125 MHz, CDCl3) δ = 189.6, 145.2, 137.9,
137.8, 135.2, 133.1, 132.9, 132.6, 132.4, 130.9, 130.1 (2C), 129.9 (2C), 129.4 (2C), 128.8, 128.6 (2C),
128.5 (2C), 128.3, 128.1, 127.0 (2C), 126.9, 124.6, 120.8, 115.8, 21.7 ppm; HRMS (ESI/TOF): m/z
calcd. for C30H24NO3S [M+H]+ 478.1471; found 478.1470.
(E)-1-(4-Chlorophenyl)-3-(3-phenyl-1-tosyl-1H-indol-2-yl)prop-2-en-1-one (4u):
Pale yellow oil; 83 mg, 81% yield; 1H NMR (500 MHz, CDCl3) δ = 8.36–8.34 (m, 1H, HAr), 8.30 (d, 3J
= 15.8 Hz, 1H, CH), 7.68–7.66 (m, 2H, HAr), 7.57–7.55 (m, 2H, HAr), 7.53–7.42 (m, 4H, HAr), 7.37–7.32
(m, 5H, HAr), 7.28–7.24 (m, 1H, HAr), 7.18–7.16 (m, 2H, HAr), 6.96 (d, 3J = 15.8 Hz, 1H, CH), 2.33 (s,
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3H, Me) ppm; C{1H} NMR (125 MHz, CDCl3) δ = 188.3, 145.3, 139.4, 138.0, 136.3, 135.4, 133.2,
132.8, 132.6, 130.9, 130.1 (2C), 129.9 (2C), 129.8 (2C), 129.4 (2C), 129.2, 128.9 (2C), 128.3, 127.5,
127.1, 127.0 (2C), 124.6, 120.9, 115.9, 21.7 ppm; HRMS (ESI/TOF): m/z calcd. for C30H23ClNO3S
[M+H]+ 512.1082; found 512.1085.
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(E)-1-(4-Bromophenyl)-3-(3-phenyl-1-tosyl-1H-indol-2-yl)prop-2-en-1-one (4v):
Pale yellow oil; 85 mg, 76% yield; 1H NMR (500 MHz, CDCl3) δ = 8.35–8.33 (m, 1H, HAr), 8.30 (d, 3J
= 15.8 Hz, 1H, HAr), 7.67–7.65 (m, 2H, HAr), 7.54–7.43 (m, 8H, HAr), 7.36–7.32 (m, 3H, HAr), 7.28–7.25
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(m, 1H, HAr), 7.18–7.16 (m, 2H, HAr), 6.94 (d, J = 15.8 Hz, 1H, HAr), 2.33 (s, 3H, Me) ppm; C{1H}
NMR (125 MHz, CDCl3) δ = 188.5, 145.3, 137.9, 136.7, 135.2, 133.2, 132.9, 132.5, 131.9 (2C), 130.9,
130.1 (2C), 130.0 (2C), 129.9 (2C), 129.4 (2C), 129.3, 128.4, 128.1, 127.4, 127.0 (3C), 124.6, 120.9,
115.9, 21.8 ppm; HRMS (ESI/TOF): m/z calcd. for C30H23BrNO3S [M+H]+ 556.0577; found 556.0579.
(E)-1-(Naphthalen-1-yl)-3-(3-phenyl-1-tosyl-1H-indol-2-yl)prop-2-en-1-one (4w):
Pale yellow oil; 89 mg, 84% yield; 1H NMR (500 MHz, CDCl3) δ = 8.34–8.31 (m, 2H, HAr), 8.17 (d, 3J
= 16.0 Hz, 1H, CH), 7.99–7.97 (m, 1H, HAr), 7.90–7.88 (m, 1H, HAr), 7.59–7.57 (m, 2H, HAr), 7.56–7.42
(m, 8H, HAr), 7.38–7.36 (m, 2H, HAr), 7.35–7.33 (m, 1H, HAr), 7.27–7.24 (m, 1H, HAr), 7.13–7.11 (m,
2H, HAr), 6.76 (d, 3J = 16.0 Hz, 1H, CH), 2.31 (s, 3H, Me) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ =
194.5, 145.2, 137.7, 136.3, 135.2, 134.0, 133.9, 132.9, 132.3, 132.2, 132.1, 130.8, 130.6, 130.0 (2C),
129.9 (2C), 129.3 (2C), 128.7, 128.6, 128.4, 127.7, 127.6, 126.9 (3C), 126.5, 125.8, 124.5, 124.5, 120.9,
115.6, 21.7 ppm; HRMS (ESI/TOF): m/z calcd. for C34H26NO3S [M+H]+ 528.1628; found 528.1628.
(E)-Ethyl 4-oxo-6-(3-phenyl-1-tosyl-1H-indol-2-yl)hex-5-enoate (4x):
Pale yellow oil; 82 mg, 82% yield; 1H NMR (500 MHz, CDCl3) δ = 8.31–8.29 (m, 1H, HAr), 8.18 (d, 3J
= 16.4 Hz, 1H, HAr), 7.63–7.61 (m, 2H, HAr), 7.45–7.37 (m, 4H, HAr), 7.30–7.22 (m, 4H, HAr), 7.19–7.17
(m, 2H, HAr), 6.12 (d, 3J = 16.4 Hz, 1H, HAr), 4.15 (q, 3J = 7.1 Hz, 2H, OCH2), 2.88 (t, 3J = 6.7 Hz, 2H,
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CH2), 2.61 (t, J = 6.7 Hz, 2H, CH2), 2.34 (s, 3H, Me), 1.26 (t, 3J = 7.1 Hz, 3H, Me) ppm; 13C{1H} NMR
(125 MHz, CDCl3) δ = 197.7, 172.8, 145.2, 137.5, 134.9, 132.3, 131.6, 131.1, 130.8, 129.9, 129.8 (2С),
129.6 (2С), 129.1 (2С), 128.7, 128.3, 126.8 (2С), 126.7, 124.5, 120.8, 115.6, 60.6, 34.9, 28.1, 21.6, 14.2
ppm; HRMS (ESI/TOF): m/z calcd. for C29H28NO5S [M+H]+ 502.1683; found 502.1680.
Synthesis of (E)-3-(1-tosyl-3-phenyl-1H-indol-2-yl)prop-2-enoic acid (6)
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To a solution of NaOH (720 mg, 18.0 mmol, 18 equiv.) in H20 (50 mL) was added Br2 (465 µL,
9.0 mmol, 9 equiv.) dropwise at 0 °C. The resulting pale yellow solution was stirred at the same
temperature for 0.5 h. Then, a solution of indole 4a (414 mg, 1.0 mmol, 1 equiv.) in 1,4-dioxane (10
mL) was added dropwise over a period of ca. 5 min keeping the temperature at around 0 °C. The
reaction was allowed to warm to room temperature and stirred for 24 h. Upon completion, the aqueous
solution was washed with diethyl ether (20 mL). The diethyl ether layer was discarded while the
aqueous layer was acidified with hydrochloric acid (2 M, pH ca. 2) and extracted with CH2Cl2 (2 × 30
mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and
concentrated under reduced pressure to afford acrylic acid 6 as a white solid with high NMR purity. If
needed, the acid 6 could be recrystallized from acetone.
(E)-3-(1-Tosyl-3-phenyl-1H-indol-2-yl)prop-2-enoic acid (6):
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White solid; Mp = 218−219 °C; 409 mg, 98% yield; H NMR (400 MHz, DMSO) δ = 12.49 (br s, 1H,
3
OH), 8.19–8.17 (m, 1H, HAr), 8.07 (d, J = 16.1 Hz, 1H, CH), 7.66–7.64 (m, 2H, HAr), 7.52–7.43 (m,
3
4H, HAr), 7.37–7.33 (m, 4H, HAr), 7.31–7.27 (m, 1H, HAr), 7.24–7.22 (m, 1H, HAr), 5.73 (d, J = 16.1
Hz, 1H, CH), 2.30 (s, 3H, Me) ppm; 13C{1H} NMR (100 MHz, DMSO) δ = 166.4, 145.6, 136.3, 133.9,
132.2, 131.7, 131.2, 130.1 (2C), 130.0, 129.5 (2C), 129.0 (2C), 128.2, 127.3, 126.7, 126.3 (2C), 124.7,
124.6, 120.3, 114.9, 20.9 ppm; HRMS (ESI/TOF): m/z calcd. for C24H19NO4SNa [M+Na]+ 440.0927;
found 440.0926.
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