Synthesis of indoles by domino reaction of 2-(tosylamino)benzyl alcohols with furfurylamines: Two opposite reactivity modes of the α-carbon of the furan ring in one process

Article abstract of DOI:10.1002/ejoc.201301762

An unusual domino reaction where the same furan α-carbon atom reacts initially as a nucleophile and then as an electrophile is reported. In the presence of acid, N-tosylfurfurylamines react with 2-(tosylamino)benzyl alcohols to afford 2-(2-acylvinyl)indoles. The reaction proceeds by Friedel-Crafts alkylation at the C(2) atom of furan followed by acid-catalyzed intramolecular nucleophilic attack of the ortho-amino group onto the same carbon atom. The replacement of the tosylamino leaving group by phthalimide enables generation of a different type of indole yet allows the ambiphilic nature of C(2) to be retained. Both types of indoles were obtained when N-furfurylbenzamides were employed. Furfurylamines react with 2-(tosylamino)benzyl alcohols affording 2-(2-acylvinyl)indoles by a domino reaction sequence in which the same furan α-carbon atom behaves initially as an electron-rich center and then as an electron deficient one. In addition, substitution of the tosylamino leaving group with a phthalimido group furnishes a change in chemoselectivity. Copyright

Full text of DOI:10.1002/ejoc.201301762

Job/Unit: O31762
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FULL PAPER
DOI: 10.1002/ejoc.201301762
Synthesis of Indoles by Domino Reaction of 2-(Tosylamino)benzyl Alcohols
with Furfurylamines: Two Opposite Reactivity Modes of the α-Carbon of the
Furan Ring in One Process
Maxim G. Uchuskin,*[a] Natalia V. Molodtsova,[a] Sergey A. Lysenko,[b]
Vladimir N. Strel’nikov,[a,c] Igor V. Trushkov,[d] and Alexander V. Butin*[a,b]
Keywords: Oxygen heterocycles / Electrophilic substitution / Nucleophilic substitution / Nitrogen heterocycles
An unusual domino reaction where the same furan α-carbon
atom reacts initially as a nucleophile and then as an electro-
phile is reported. In the presence of acid, N-tosylfurfuryl-
amines react with 2-(tosylamino)benzyl alcohols to afford 2-
(2-acylvinyl)indoles. The reaction proceeds by Friedel–Crafts
lyzed intramolecular nucleophilic attack of the ortho-amino
group onto the same carbon atom. The replacement of the
tosylamino leaving group by phthalimide enables generation
of a different type of indole yet allows the ambiphilic nature
of C(2) to be retained. Both types of indoles were obtained
alkylation at the C(2) atom of furan followed by acid-cata- when N-furfurylbenzamides were employed.
arene reactivity trends.[6] However, due to the low aromatic-
Introduction
ity of the furan ring, they can also react as alkene, 1,3-diene,
1,4-diketone, and enol ether equivalents, to name just a few.
Some of these transformations, being quite different in both
mechanism and reaction products, can be carried out under
similar reaction conditions. For instance, Friedel–Crafts
alkylation of furans is catalyzed by Bronsted or Lewis acids
and usually proceeds with excellent regioselectivity at the
more nucleophilic α-carbon (Scheme 1, panel a). Mean-
while, acid catalysis is also utilized in the Piancatelli reac-
tion[7,8] and related processes[9] where the furan α-carbon
reacts as an electrophile (Scheme 1, panel b). Recognizing
these two different modes of reactivity, under the qualita-
tively same reaction conditions, inspired us to design an
acid-catalyzed domino reaction in which the alkylation step
is combined with Piancatelli-like intramolecular rearrange-
ment. To realize this idea, the nucleophilic moiety of the
alkylating agent should tolerate the internal electrophilic
center. 2-(Tosylamino)benzyl alcohols 1 were selected for
this purpose due to the weakly nucleophilic character of the
tosylamino group. Despite this quality of the tosylamino
moiety, it also was envisioned to be sufficiently reactive in
intramolecular processes such as acid-catalyzed rearrange-
ments of 2-[2-(tosylamino)benzyl]furans.[10] Furthermore, it
was hypothesized that the leaving group at the α-position
of the furan side chain should have moderate nucleo-
fugacity to minimize acid-induced side reactions related to
furfuryl cation generation. Furfuryl alcohols and furfuryl
halides do not satisfy this demand. We considered the tosyl-
amino group as an appropriate substituent because: a) tosyl-
amines are good leaving groups in Bronsted and Lewis acid-
catalyzed reactions;[11] and b) N-tosylfurfurylamine (2) is
relatively stable under acidic conditions; thus, it can be acyl-
In recent years furans have increasingly attracted the at-
tention of researchers from various areas of chemistry. For
industrial chemists, furfural, 5-hydroxymethylfurfural, and
furan-2,5-dicarboxylic acid are among the most important
synthetic platforms produced by biomass processing.[1] The
interest in furans is stimulated by a wide variety of potential
applications in polymer chemistry,[2] the chemistry of mate-
rials,[3] and in medicinal chemistry. Notably, multiple drugs
such as, azimilide, dantrolene, furacin, furosemide, nifura-
tel, ranitidine, and others, contain the furan ring as a key
structural element. To increase the scope of furan utility in
various areas of science and industry, organic chemists have
developed numerous approaches for the transformation of
furans into a broad spectrum of products, from alkanes
which can be utilized as high-quality diesel fuels,[4] to other
heterocyclic systems.[5]
Due to the multifaceted reactivity of furans, these investi-
gations are now experiencing exponential growth. Indeed,
as heteroaromatic compounds, furans demonstrate typical
[a] Department of Chemistry, Perm State University,
Bukireva 15, Perm 614990, Russia
E-mail: maxim_uchuskin@mail.ru
alexander_butin@mail.ru
http://www.psu.ru
[b] Research Institute of Heterocyclic Compounds Chemistry,
Kuban State Technological University,
Moskovskaya 2, Krasnodar 350072, Russia
[c] Institute of Technical Chemistry UB RAS,
Academica Koroleva 3, Perm 614013, Russia
[d] Department of Chemistry, M.V. Lomonosov Moscow State
University,
Leninskie gory 1-3, Moscow 119991, Russia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301762.
Eur. J. Org. Chem. 0000, 0–0
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M. G. Uchuskin, A. V. Butin et al.
FULL PAPER
ated with benzoyl chloride in the presence of AlCl3.[12] The Table 1. Optimization of reaction conditions.[a]
additional advantage of this combination of substrates was
postulated to be that it would enable facile access to useful
indole derivatives 3 (Scheme 1, panel c).[13] Thus, we de-
signed the domino reaction sequence to include Friedel–
Crafts alkylation of furan 2 with 2-(tosylamino)benzyl
alcohols 1 to afford 5-tosylamino-2-[2-(tosylamino)benzyl]-
furans followed by Piancatelli-like intramolecular re-
arrangement and aromatization into 3-aryl(alkyl)-2-(2-acyl-
vinyl)indoles 3. Herein, we report the results of our investi-
gation into this domino reaction inclusive of leaving group
effects observed in dictating the specific furan product
structures formed.
Entry Solvent
Acid
T
[°C]
t
[h]
Yield
[%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
benzene
benzene
benzene
benzene
benzene
benzene
benzene
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
CF3CO2H
CF3CO2H
BF3·OEt2
BF3·OEt2
PPA-Et[c]
CF3CO2H
CF3CO2H
Me3SiCl
Me3SiCl
TsOH
20
reflux
0
4
1
0.25
0.5
12
1
48
48
8
0.25
1
2
1
48
11
3
35
25
8
–20
10
19
68
63
55
26
40
52
24
21
14
39
31
64
44
69
40
17
14
52
17
reflux
reflux
40
40
reflux
reflux
reflux
reflux
40
40
reflux
40
Amberlyst 15
PPA-Et[c]
H2SO4
H3PO4
H3PO4
HClO4
HCl
40
40
HCl
reflux 0.166
reflux
reflux
CuSO4·5H2O[d]
CuSO4
4
2
4
Cu(OAc)2·2H2O[d] reflux
[e]
AcOH
AcOH
dioxane
Cu(OTf)2[e]
Yb(OTf)3
HClO4
reflux
reflux 0.166
40 72
0.33
Scheme 1. Examples of nucleophilic and electrophilic reactivity of
α-carbon atom of furan.
[a] All reactions were performed on 2 mmol scale using 1.1 equiv.
of 2. [b] Isolated yields. [c] Ethyl polyphosphate. [d] 200 mol-% of
Lewis acid was used. [e] 10 mol-% of Lewis acid was used.
Results and Discussion
Optimization data revealed that a fine balance of acid
We started this investigation by optimizing reaction con- strength, reaction temperature and solvent polarity is re-
ditions for the synthesis of indole 3a from N-tosylfurfuryl- quired to achieve good yields. In principle, this is not unex-
amine (2) and 2-(tosylamino)benzhydryl alcohol 1a. During pected since both starting compounds have ambiphilic
extensive survey of various acidic conditions (Table 1), we character. Therefore, it is difficult to predict which method
found that good yields could be achieved using CF3CO2H would give the best results for reactions between furfuryl-
in benzene, AcOH/HCl at 40 °C or refluxing CuSO4·5H2O amine 2 and other 2-aminobenzyl alcohols 1. Keeping this
in AcOH (Table 1, Entries 6, 17, and 19, respectively). The in mind, we investigated the reaction scope using the three
use of other strong Bronsted (HClO4, H2SO4, H3PO4) or sets of conditions identified above (Table 2).
Lewis acids (Cu(OTf)2, Yb(OTf)3), in combination with
We found that a broad range of 2-(tosylamino)benzyl
AcOH proved to be much less efficient at inducing the de- alcohols 1 reacted with N-tosylfurfurylamine (2) affording
sired domino reaction. The use of a CF3CO2H/benzene sys- corresponding indoles 3. Overall, indole products were ob-
tem gave much better results than other acids in benzene or tained in reasonable yields using all three procedures for
CF3CO2H in other solvents.
benzhydryl alcohols containing electron-donating substitu-
The structure of 3a was determined by analysis of the ents. Replacement of the aromatic group in the α-position
spectroscopic data. It is worth noting that 3a was obtained with alkyl moieties had no impact on reaction efficiency
3
as a single (E)-isomer as deduced on the basis of J values when the process was initiated with CF3CO2H in benzene
for the olefinic protons.
or CuSO4·5H2O/AcOH (methods B and C, respectively).
2
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Indole Synthesis by Domino Chemistry Using Furfurylamines
Table 2. Scope of benzyl alcohols 1 in domino reaction with N- withdrawing substituent into the indole ring reduces this
tosylfurfurylamine (2).[a]
push-pull character of the alkenes and decelerates cis-trans
isomerization.
N-Tosylfurfurylamine was selected as a reaction compo-
nent due, as noted before, to its good balance of acid sta-
bility and leaving group ability of the tosylamino moiety.
The use of furfuryl derivatives with better leaving groups,
such as furfuryl alcohol and furfuryl chloride, was found to
be unproductive due to their high capacity for oligomeriza-
tion. Consequently, we next turned our attention to the use
of N-furfurylbenzamides 4a–c. The logic of this decision
was supported by previous reports in which benzamide was
employed as a leaving group in alkylations of active meth-
ylene compounds[14a] and Friedel–Crafts reactions[14b]
(Table 3).
We found that reaction of amides 4 with benzhydryl
alcohol 1a proceeded in the presence of HCl in AcOH at
40 °C. However, in every instance, target compound 3a was
formed as a minor product; the major products were indole
derivatives 6 bearing the 4-aroylamino-3-oxobutyl substitu-
ent at the indole C(2). When the reaction between 1a and
4a was performed under refluxing conditions, the yield of
3a was increased and found to coincide with a diminished
yield of 6a (Table 3, Entries 1, 2). On the basis of this obser-
vation, we reasoned that 6 may actually be an intermediate
en route to indole 3. To verify this hypothesis, α-amino-
ketones 6 were treated with HCl in AcOH under the same
reaction conditions used to generate improved yields of 3a.
However, no transformation of 6 into 3a was observed. This
finding suggests that 3 and 6 are likely produced through
different pathways. In contrast, the intermediacy of alkyl-
ated furans 5 was unambiguously demonstrated by their
isolation from the reaction mixture and subsequent conver-
sion into the same 3/6 mixtures previously noted by treat-
ment with the HCl/AcOH system.
Entry 1,3
R1
R2
R3
Ph
Yield [%][b]
A[c]
B[d]
C[e]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
a
b
c
d
e
f
g
h
i
j
k
l
m
n
OMe
OMe
OMe
OMe
OMe
OMe
H
H
Cl
NO2
–OCH2CH2O–
–OCH2CH2O–
–OCH2CH2O–
–OCH2O–
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
H
64
68
64
67
55
62
67
60
17
69
66
61
69
64
65
63
4-MeC6H4 56
4-ClC6H4
4-BrC6H4
Me
Et
70
71
32
30
41
Ph
Me
Ph
Ph
Ph
Me
Et
H
16[f, g]
12[h, g]
61
59
52
42
57
33
31
35
65
62
56
47
[a] All reactions were performed on 2 mmol scale using 1.1 equiv.
of 2. [b] Isolated yields. [c] AcOH/HCl, 40 °C, 24–48 h. [d] Benzene/
CF3CO2H, reflux, 1–2 h. [e] AcOH/CuSO4·5H2O, reflux, 4 h.
[f] trans-Isomer was isolated from the reaction mixture. [g] A small
quantity of unseparated mixture of cis/trans-isomers was also ob-
tained. [h] cis-Isomer was isolated from the reaction mixture.
These results can be rationalized by competitive proton-
However, much lower yields were obtained using the ation of 5 at either the amide group or C(5) of the furan
AcOH/HCl system (method A) (Table 2, Entries 5, 6, 12, ring (Scheme 2). Protonation of the amide group
13). Similarly, removal of the electron-donating alkoxy (Scheme 2, path a) significantly increases its nucleofugacity
group in 1, as in 2-(tosylamino)benzhydryl alcohol (1g), (cation A) affording carbocation B by amide elimination.
had no significant influence on the reaction yield when Nucleophilic attack by the 2-tosylamino group onto the
methods B and C, but not A, were applied (Table 2, Entry C(2) atom of the furan followed by opening of the spiro-
7). In contrast, the combination of both effects (as in 1h) dihydrofuran ring in C establishes indole 3. Protonation of
dramatically decreased the reaction efficiency (Table 2, En- furanyl C(5) (Scheme 2, path b) produces cation D, thus en-
try 8). When primary benzyl alcohol 1n was utilized, indole abling generation of spiro-intermediate E. Rearrangement
3n was formed in moderate yield regardless of which reac- of E is completed by furan ring scission and tautomeri-
tion conditions were employed (Table 2, Entry 14). This ob- zation to F. It is has to be noted that, in this pathway, the
servation can be explained by the low stability of a primary furan C(2) also exhibits two opposite modes of reactivity
carbocation that leads to its oligomerization and, as a re- being a nucleophile in the alkylation step leading to inter-
sult, significant tarring of the reaction. Electron-with- mediate 5 and then serving as an electrophile in its reaction
drawing substituents situated para- to the tosylamino group with the 2-tosylamino group leading to intermediate E.[15]
reduce substrate nucleophilicity resulting in reduced prod-
Finally, the reaction of 1a with N-furfurylphthalimide 9
uct generation (Table 2, Entries 9, 10). Moreover, in these was investigated. In this case 4-phthalimido-3-oxobutylind-
cases, both cis- and trans-isomers of indoles 3 were ob- ole 10 was isolated exclusively (Scheme 3). This reaction is
tained. Isomeric product mixtures can be attributed to the likely to proceed through a mechanism analogous to that
fact that indoles 3 are push-pull alkenes and undergo a rela- described for formation of 6. The formation of 3 in trace
tively fast cis-trans isomerization due to their capacity to amounts is possibly related to the much lower rate of pro-
assume a zwitterionic form. Introduction of an electron- tonation of phthalimide O atoms relative to furan ring pro-
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M. G. Uchuskin, A. V. Butin et al.
FULL PAPER
Table 3. Reaction of N-furfurylbenzamides 4 with benzhydryl alcohol 1a.[a]
Entry
4,6
Ar
T [°C]
t
Yield [%][b]
3a
6
1
2
3
4
5
6
a
a
b
b
c
c
Ph
Ph
40
reflux
40
reflux
40
2 d
10 min
2d
10 min
2d
12
16
6
9
12
9
62
48
63
44
50
45
4-O2NC6H4
4-O2NC6H4
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
reflux
10 min
[a] All reactions were performed on 2 mmol scale using 1.1 equiv. of 4 in 15 mL of solvent. [b] Isolated yields.
tonation encountered in generating intermediates like 5.
Again, the furan C(2) reacts initially as a nucleophile, and
then as an electrophile.
Scheme 3. Reaction of 1a with N-furfurylphthalimide 9.
This result was quite unexpected given the better leaving
group ability of phthalimide relative to benzamides. More-
over, the clear-cut dependence of the 3a/6 ratio on the na-
ture of substituents on 4 could be expected at the first
glance. In all likelihood, these results can be explained by a
change in the 5-to-3 rate-limiting step that occurs with a
change of N-protecting group. Namely, the electron-donat-
ing para-methoxy substituent in 4c accelerates protonation
of the amide oxygen affording very stable cation A
(Scheme 2, path a). However, the high stability of this cat-
ion significantly decelerates amide elimination that fur-
nishes cation B. Oppositely, para-nitrobenzamide and
phthalimide are better leaving groups than the unsubsti-
tuted benzamide. However, in these cases, protonation of
the amide oxygen producing cation A is quite inefficient.
As a result, formation of 3 is decelerated and protonation
of the furan ring leading to cation D (Scheme 2, path b)
and then to 6 (or 10) predominates.
Scheme 2. Possible mechanisms for generation of indoles 3 and 6.
4
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Indole Synthesis by Domino Chemistry Using Furfurylamines
chromatography on silica gel using CH2Cl2/hexane (1:5) mixture as
an eluent and recrystallized from a mixture of CHCl2/hexane.
Conclusions
In conclusion, we have developed a domino reaction of
N-tosylfurfurylamine with 2-tosylaminobenzyl alcohols af-
fording 2-(2-acetylvinyl)indoles. The specific feature of this
reaction is related to the unusual behaviour of the α-carbon
of the furan, which reacts initially as a nucleophile in the
Friedel–Crafts alkylation and then as an electrophile in the
Piancatelli-like rearrangement, which is accompanied by
aromatization of the rearranged product.
Such ambiphilic behaviour is typical for isocyanides but
quite unusual for aromatic carbon atoms. Furans are the
most appropriate substrates to realize this dual reactivity
due to the known ambiphilic properties of the furan ring.
Further efforts to unveil other examples of analogous ambi-
philic reactivity of aromatic carbons are currently un-
derway.
Method B: A mixture of 2-(tosylamino)benzyl alcohol 1 (2 mmol),
N-tosylfurfurylamine (2) (2.2 mmol), CF3CO2H (1 mL) and benz-
ene (20 mL) was refluxed for 1–2 h (TLC control). Then reaction
mixture was poured into cold water (100 mL) and NaHCO3 was
added until neutral reaction. The resulting mixture was extracted
with ethyl acetate (3ϫ 30 mL). The combined organic fractions
were dried with Na2SO4 and concentrated under reduced pressure.
Products were purified by column chromatography on silica gel
using CH2Cl2/hexane (1:5) mixture as an eluent and recrystallized
from a mixture of CH2Cl2/hexane.
Method C: A mixture of 2-(tosylamino)benzyl alcohol 1 (2 mmol),
N-tosylfurfurylamine (2) (2.2 mmol), CuSO4·5H2O (1 g, 4 mmol)
and AcOH (15 mL) was refluxed for 4 h (TLC control). Then the
reaction mixture was treated as described in Method A.
Method D: A mixture of 2-(tosylamino)benzhydryl alcohol 1a
Substitution of the tosylamino group in the furan side (2 mmol), N-benzoylfurfurylamine 4 (2.2 mmol), HCl (2.5 mL) and
AcOH (15 mL) was refluxed for 10 min (TLC control). Then the
reaction mixture was poured into cold water (100 mL) and
NaHCO3 was added until neutral reaction. The precipitate formed
was filtered. The product was purified by column chromatography
on silica gel using CH2Cl2/hexane (1:5) mixture as an eluent and
recrystallized from a mixture of CHCl2/hexane.
chain by the phthalimide moiety changes chemoselectivity
of the reaction; 2-(4-phthalimido-3-oxobutyl)-indole was
exclusively formed in this case. At the same time, the α-
carbon in the furan demonstrates the same ambiphilic be-
haviour. N-furfurylbenzamides represent the intermediate
case producing both types of products. Control experiments
suggested two independent pathways for the formation of
these indole derivatives.
(3E)-4-[5,6-Dimethoxy-1-(4-methylphenyl)sulfonyl-3-phenyl-1H-
indol-2-yl]but-3-en-2-one (3a): Yellow solid. Rf = 0.55 (acetone/
1
petroleum ether, 1:1), m.p. 176–177 °C. H NMR (600 MHz, [D6]-
3
DMSO): δ = 8.00 (d, J = 16.4 Hz, 1 H, CH=), 7.71 (s, 1 H, Ind),
7.65–7.62 (m, 2 H, Ar), 7.53–7.48 (m, 2 H, Ar), 7.47–7.43 (m, 1 H,
Ar), 7.38–7.31 (m, 4 H, Ar), 6.60 (s, 1 H, Ind), 5.91 (d, 3J =
16.4 Hz, 1 H, CH=), 3.93 (s, 3 H, CH3O), 3.65 (s, 3 H, CH3O),
2.30 (s, 3 H, CH3), 2.20 (s, 3 H, CH3) ppm. 13C NMR (150 MHz,
[D6]DMSO): δ = 197.1, 149.7, 148.0, 145.6, 133.4, 132.0, 131.7,
131.4, 130.2 (2 C), 130.1, 130.0, 129.4 (2 C), 129.3 (2 C), 129.2,
128.4, 126.5 (2 C), 123.2, 101.1, 98.7, 56.0, 55.5, 27.0, 21.0 ppm.
Experimental Section
1
General Remarks: H and 13C NMR spectra were recorded with a
Bruker Avance-600 (600 MHz for 1H and 150 MHz for 13C NMR)
and Agilent 400-MR DD2 (400 MHz for H and 100 MHz for 13C
1
NMR) spectrometers at room temperature; the chemical shifts (δ)
were measured in ppm with respect to the solvent (CDCl3, 1H: δ =
7.26 ppm, 13C: δ = 77.2 ppm; [D6]DMSO, H: δ = 2.50 ppm, 13C:
1
IR (KBr): ν = 1668, 1608, 1546, 1489, 1368, 1317, 1292, 1244, 1227,
˜
1163, 1028, 766 cm–1. MS (EI, 70 eV): m/z (%) = 475 (100) [M]+,
320 (70), 278 (98), 263 (64), 247 (82), 234 (25), 219 (28), 91 (40),
76 (76), 43 (68). C27H25NO5S (475.56): calcd. C 68.19, H, 5.30, N,
2.95, S, 6.74; found C, 68.29, H, 5.29, N, 3.04, S, 6.64.
δ = 39.5 ppm). Coupling constants (J) are given in Hertz. Splitting
patterns of an apparent multiplet associated with an averaged cou-
pling constants were designed as s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet), dd (doublet of doublets) and br (broad-
ened). IR spectra were measured as KBr plates using Prestige-21
FT-IR and Perkin–Elmer FT-IR Spectrum Two spectrophotome-
ters. Mass spectra were recorded with a Kratos MS-30 instrument
using 70 eV electron impact ionization at 200 °C. Elemental analy-
ses were performed with a Fisons EA-1108 CHNS elemental ana-
lyser instrument. High resolution mass spectra were measured with
a Bruker microTOF II instrument. Melting points are uncorrected.
Column chromatography was performed using silica gel KSK (50–
160 μm, LTD Sorbpolymer). All the reactions were carried out
using freshly distilled and dry solvents from solvent stills. Starting
2-(tosylamino)benzhydryl and 2-(tosylamino)benzyl alcohols
1a–n, N-furfuryl-4-methylbenzenesulfonamide (2), and N-furfuryl-
(3E)-4-[5,6-Dimethoxy-3-(4-methylphenyl)-1-(4-methylphenyl)sulf-
onyl-1H-indol-2-yl]but-3-en-2-one (3b): Beige solid. Rf = 0.56 (acet-
one/petroleum ether, 1:1), m.p. 157–158 °C. 1H NMR (600 MHz,
3
[D6]DMSO): δ = 7.98 (d, J = 16.4 Hz, 1 H, CH=), 7.70 (s, 1 H,
Ind), 7.65–7.58 (m, 2 H, Ar), 7.37–7.33 (m, 2 H, Ar), 7.32–7.28 (m,
3
2 H, Ar), 7.25–7.18 (m, 2 H, Ar), 6.60 (s, 1 H, Ind), 5.97 (d, J =
16.4 Hz, 1 H, CH=), 3.92 (s, 3 H, CH3O), 3.66 (s, 3 H, CH3O),
2.37 (s, 3 H, CH3), 2.31 (s, 3 H, CH3), 2.21 (s, 3 H, CH3) ppm. 13
C
NMR (150 MHz, [D6]DMSO): δ = 197.1, 149.6, 148.0, 145.5,
137.8, 133.3, 131.8, 131.5, 130.1 (2 C), 129.9, 129.8, 129.7 (2 C),
129.4, 129.3 (2 C), 128.8, 126.4 (2 C), 123.4, 101.2, 98.8, 55.9, 55.5,
26.9, 21.0, 20.8 ppm. IR (KBr): ν = 1663, 1483, 1368, 1321, 1290,
˜
benzamides
4 were synthesized according to published pro-
1242, 1225, 1190, 1159, 1047, 1007, 856, 787 cm–1. MS (EI, 70 eV):
m/z (%) = 489 (100) [M]+, 334 (60), 292 (98), 276 (46), 261 (42),
233 (29), 166 (17), 139 (14), 118 (19), 91 (21), 76 (30), 57 (21), 43
(59). C28H27NO5S (489.58): calcd. C 68.69, H, 5.56, N, 2.86, S,
6.55; found C, 68.86, H, 5.42, N, 2.77, S, 6.29.
cedures.[10b,12,16,17]
General Procedure for the Synthesis of Indoles 3a–n, 6a–c, 10
Method A: A mixture of 2-(tosylamino)benzyl alcohol 1 (2 mmol),
N-protected furfurylamine 2, 4, or 9 (2.2 mmol), HCl (2.5 mL) and
AcOH (15 mL) was stirred at 35–40 °C for 24–48 h (TLC control).
Then the reaction mixture was poured into cold water (100 mL)
and NaHCO3 was added until neutral reaction. The precipitate
formed was filtered. The product was purified by column
(3E)-4-[3-(4-Chlorophenyl)-5,6-dimethoxy-1-(4-methylphenyl)sulf-
onyl-1H-indol-2-yl]but-3-en-2-one (3c): Yellow solid. Rf = 0.57
(acetone/petroleum ether, 1:1), m.p. 201–202 °C. 1H NMR
(600 MHz, [D6]DMSO): δ = 7.98 (d, 3J = 16.4 Hz, 1 H, CH=), 7.70
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O31762
/KAP1
Date: 20-02-14 10:59:28
Pages: 9
M. G. Uchuskin, A. V. Butin et al.
(s, 1 H, Ind), 7.66–7.62 (m, 2 H, Ar), 7.57–7.53 (m, 2 H, Ar), 7.40– H, Ar), 7.53–7.49 (m, 3 H, Ar), 7.48–7.43 (m, 1 H, Ar), 7.38–7.33
FULL PAPER
3
7.33 (m, 4 H, Ar), 6.64 (s, 1 H, Ind), 5.91 (d, J = 16.4 Hz, 1 H,
(m, 4 H, Ar), 7.32–7.28 (m, 1 H, Ar), 7.28–7.25 (m, 1 H, Ar), 5.97
CH=), 3.92 (s, 3 H, CH3O), 3.68 (s, 3 H, CH3O), 2.31 (s, 3 H,
(d, 3J = 16.5 Hz, 1 H, CH=), 2.30 (s, 3 H, CH3), 2.23 (s, 3 H,
CH3), 2.23 (s, 3 H, CH3) ppm. 13C NMR (150 MHz, [D6]DMSO): CH3) ppm. 13C NMR (150 MHz, [D6]DMSO): δ = 197.2, 145.8,
δ = 197.1, 149.7, 148.0, 145.6, 133.9, 133.0, 131.6, 131.4 (2 C),
136.5, 133.7, 132.2, 131.7, 131.6, 131.5, 130.3 (2 C), 130.1, 129.6 (2
131.2, 130.8, 130.5, 130.1 (2 C), 130.0, 129.2 (2 C), 127.3, 126.4 (2 C), 129.1 (2 C), 128.4, 127.6, 126.9, 126.5 (2 C), 124.9, 120.5, 115.0,
C), 122.9, 101.1, 98.6, 55.9, 55.6, 27.0, 21.0 ppm. IR (KBr): ν = 27.1, 21.0 ppm. IR (KBr): ν = 1674, 1447, 1379, 1250, 1171, 1088,
˜
1674, 1497, 1379, 1304, 1254, 1200, 1096, 1022, 854, 791 cm–1. MS
(EI, 70 eV): m/z (%) = 511/509 (33/100) [M]+, 356/354 (18/36), 312
˜
976, 750 cm–1. MS (EI, 70 eV): m/z (%) = 415 (35) [M]+, 276 (100),
260 (55), 218 (55), 118 (25), 91 (30), 76 (45), 43 (43). C25H21NO3S
(32), 281 (30), 277 (32), 91 (35), 43 (15). C27H24ClNO5S (510.00): (415.50): calcd. C 72.27, H, 5.09, N, 3.37, S, 7.72; found C, 72.45,
calcd. C 63.59, H, 4.74, N, 2.75, S, 6.29; found C, 63.54, H, 4.78, H, 4.95, N, 3.38, S, 7.63.
N, 2.77, S, 6.39.
(3E)-4-[3-Methyl-1-(4-methylphenyl)sulfonyl-1H-indol-2-yl]but-3-en-
(3E)-4-[3-(4-Bromophenyl)-5,6-dimethoxy-1-(4-methylphenyl)sulf-
onyl-1H-indol-2-yl]but-3-en-2-one (3d): Yellow solid. Rf = 0.56 m.p. 141–142 °C. H NMR (400 MHz, CDCl3): δ = 8.24–8.16 (m,
(acetone/petroleum ether, 1:1), m.p. 215–216 °C. 1H NMR 1 H, Ar), 8.14 (d, 3J = 16.6 Hz, 1 H, CH=), 7.54–7.47 (m, 2 H,
(600 MHz, [D6]DMSO): δ = 7.97 (d, 3J = 16.4 Hz, 1 H, CH=), Ar), 7.45–7.41 (m, 1 H, Ar), 7.40–7.34 (m, 1 H, Ar), 7.31–7.22 (m,
7.72–7.67 (m, 3 H, Ar + Ind), 7.66–7.62 (m, 2 H, Ar), 7.38–7.33
1 H, Ar), 7.15–7.07 (m, 2 H, Ar), 6.33 (d, 3J = 16.6 Hz, 1 H, CH=),
2-one (3h): Cream solid. Rf = 0.57 (acetone/petroleum ether, 1:1),
1
(m, 2 H, Ar), 7.33–7.29 (m, 2 H, Ar), 6.64 (s, 1 H, Ind), 5.91 (d, 2.48 (s, 3 H, CH3), 2.29 (s, 3 H, CH3), 2.28 (s, 3 H, CH3) ppm. 13
C
3J = 16.4 Hz, 1 H, CH=), 3.92 (s, 3 H, CH3O), 3.68 (s, 3 H, CH3O),
NMR (100 MHz, CDCl3): δ = 198.8, 145.1, 137.4, 134.8, 134.4,
131.8, 131.7, 131.6, 129.7 (2 C), 126.7, 126.6 (2 C), 124.3, 124.0,
2.31 (s, 3 H, CH3), 2.23 (s, 3 H, CH3) ppm. 13C NMR (150 MHz,
[D6]DMSO): δ = 197.1, 149.7, 148.0, 145.6, 133.4, 132.2 (2 C), 120.0, 115.6, 26.5, 21.6, 11.1 ppm. IR (KBr): ν = 1661, 1450, 1367,
˜
131.7 (2 C), 131.6, 131.3, 131.2, 130.6, 130.1 (2 C), 130.0, 127.3, 1256, 1171, 1124, 1086, 974, 758 cm–1. MS (EI, 70 eV): m/z (%) =
126.5 (2 C), 122.8, 121.7, 101.1, 98.6, 56.0, 55.6, 27.0, 21.0 ppm.
353 (35) [M]+, 198 (100), 182 (45), 156 (56), 91 (52), 77 (25), 43
IR (KBr): ν = 1674, 1557, 1495, 1377, 1256, 1094, 1020, 845, (28). C20H19NO3S (353.43): calcd. C 67.97, H, 5.42, N, 3.96, S,
˜
793 cm–1. MS (EI, 70 eV): m/z (%) = 555/553 (100/100) [M]+, 400/ 9.07; found C, 67.92, H, 5.45, N, 3.85, S, 8.95.
398 (27/27), 341 (12), 277 (22), 234 (14), 43 (28). C27H24BrNO5S
(3E)-4-[5-Chloro-1-(4-methylphenyl)sulfonyl-3-phenyl-1H-indol-2-yl-
(554.45): calcd. C 58.49, H, 4.36, N, 2.53, S, 5.78; found C, 58.56,
]but-3-en-2-one (3i): Cream solid. Rf = 0.65 (acetone/petroleum
H, 4.42, N, 2.47, S, 5.79.
ether, 1:1), m.p. 202–203 °C. 1H NMR (400 MHz, CDCl3): δ = 8.22
(3E)-4-[5,6-Dimethoxy-3-methyl-1-(4-methylphenyl)sulfonyl-1H-
indol-2-yl]but-3-en-2-one (3e): Yellow solid. Rf = 0.54 (acetone/pe-
(d, 3J = 8.9 Hz, 1 H, Ind), 8.08 (d, 3J = 16.5 Hz, 1 H, CH=), 7.64–
4
3
7.55 (m, 2 H, Ar), 7.47–7.39 (m, 3 H, Ar), 7.35 (dd, J = 2.1, J =
3
troleum ether, 1:1), m.p. 166–167 °C. 1H NMR (600 MHz, [D6]- 8.9 Hz, 1 H, Ind), 7.25–7.17 (m, 5 H, Ar), 6.05 (d, J = 16.5 Hz, 1
3
DMSO): δ = 8.03 (d, J = 16.3 Hz, 1 H, CH=), 7.63 (s, 1 H, Ind),
H, CH=), 2.35 (s, 3 H, CH3), 2.30 (s, 3 H, CH3) ppm. 13C NMR
7.55–7.51 (m, 2 H, Ar), 7.31–7.27 (m, 2 H, Ar), 7.09 (s, 1 H, Ind), (100 MHz, CDCl3): δ = 198.0, 145.7, 135.8, 134.8, 133.2, 132.9,
3
6.42 (d, J = 16.3 Hz, 1 H, CH=), 3.90 (s, 3 H, CH3O), 3.80 (s, 3
132.2, 132.0, 131.8, 130.5, 130.0 (2 C), 129.6 (2 C), 129.3 (2 C),
H, CH3O), 2.38 (s, 3 H, CH3), 2.29 (s, 3 H, CH3), 2.28 (s, 3 H, 128.7, 127.6, 126.9, 126.8 (2 C), 120.3, 116.8, 27.2, 21.8 ppm. IR
CH3) ppm. 13C NMR (150 MHz, [D6]DMSO): δ = 197.3, 149.4,
147.6, 145.3, 133.5, 132.3, 131.1, 130.1, 130.0 (2 C), 128.8, 126.3 (2
C), 125.2, 124.3, 101.8, 98.5, 55.8, 55.7, 27.6, 20.9, 11.1 ppm. IR
(KBr): ν = 1676, 1445, 1377, 1248, 1188, 1088, 978, 811, 770 cm–1.
˜
MS (EI, 70 eV): m/z (%) = 451/449 (33/91) [M]+, 296/294 (35/80),
280/278 (7/22), 252/250 (35/75), 217 (100), 91 (72), 65 (20), 43 (38).
C25H20ClNO3S (449.95): calcd. C 66.73, H, 4.48, N, 3.11, S, 7.13;
found C, 66.96, H, 4.57, N, 3.16, S, 6.92.
(KBr): ν = 1659, 1555, 1354, 1285, 1244, 1165, 1005, 853 cm–1. MS
˜
(EI, 70 eV): m/z (%) = 413 (92) [M]+, 258 (100), 243 (18), 215 (95),
201 (60), 185 (21), 91 (20), 65 (18), 43 (47). C22H23NO5S (413.49):
calcd. C 63.90, H, 5.61, N, 3.39, S, 7.75; found C, 64.21, H, 5.53,
N, 3.36, S, 7.51.
(3Z)-4-[1-(4-Methylphenyl)sulfonyl-5-nitro-3-phenyl-1H-indol-2-
yl]but-3-en-2-one (3j): Pale yellow solid. Rf = 0.63 (acetone/petro-
leum ether, 1:1), m.p. 181–182 °C. 1H NMR (400 MHz, [D6]-
3
4
3
(3E)-4-[3-Ethyl-5,6-dimethoxy-1-(4-methylphenyl)sulfonyl-1H-indol-
2-yl]but-3-en-2-one (3f): Yellow solid. Rf = 0.51 (acetone/petroleum
DMSO): δ = 8.32 (d, J = 9.2 Hz, 1 H, Ind), 8.25 (dd, J = 2.2, J
4
= 9.2 Hz, 1 H, Ind), 8.13 (d, J = 2.2 Hz, 1 H, Ind), 7.95–7.90 (m,
ether, 1:1), m.p. 204–205 °C. 1H NMR (600 MHz, [D6]DMSO): δ
2 H, Ar), 7.53–7.45 (m, 3 H, Ar), 7.44–7.32 (m, 4 H, Ar), 7.18 (d,
3
3
= 7.97 (d, J = 16.4 Hz, 1 H, CH=), 7.61 (s, 1 H, Ind), 7.53–7.48 3J = 12.0 Hz, 1 H, CH=), 6.49 (d, J = 12.0 Hz, 1 H, CH=), 2.33
(m, 2 H, Ar), 7.31–7.27 (m, 2 H, Ar), 7.06 (s, 1 H, Ind), 6.36 (d, (s, 3 H, CH3), 1.39 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]-
3J = 16.4 Hz, 1 H, CH=), 3.89 (s, 3 H, CH3O), 3.79 (s, 3 H, CH3O),
DMSO): δ = 198.1, 146.3, 144.1, 138.0, 134.8, 134.7, 133.8, 130.8,
130.3 (2 C), 129.7 (2 C), 129.0 (2 C), 128.9, 127.9, 127.3 (2 C),
3
2.73 (q, J = 7.5 Hz, 2 H, CH2), 2.39 (s, 3 H, CH3), 2.27 (s, 3 H,
3
CH3), 1.09 (t, J = 7.5 Hz, 3 H, CH3) ppm. 13C NMR (150 MHz, 126.4, 123.1, 120.3, 115.5, 114.8, 28.6, 21.1 ppm. IR (KBr): ν =
˜
[D6]DMSO): δ = 197.4, 149.4, 147.7, 145.3, 133.2, 132.5, 131.5,
131.4, 129.9 (2 C), 129.7, 128.2, 126.3 (2 C) 123.4, 101.6, 98.8, 55.9,
1698, 1521, 1342, 1239, 1167, 1087, 1021, 929, 750 cm–1. MS (EI,
70 eV): m/z (%) = 460 (100) [M]+, 417 (22), 305 (95), 289 (60), 261
(88), 246 (90), 228 (75), 216 (70), 190 (20), 155 (31), 91 (88), 65
55.8, 27.5, 21.0, 17.8, 14.1 ppm. IR (KBr): ν = 1657, 1545, 1491,
˜
1358, 1319, 1250, 1167, 1009, 964, 845, 785 cm–1. MS (EI, 70 eV): (18), 43 (24). C25H20N2O5S (460.50): calcd. C 65.20, H, 4.38, N,
m/z (%) = 427 (42) [M]+, 398 (20), 272 (100), 230 (22), 77 (15), 43 6.08, S, 6.96; found C, 65.27, H, 4.42, N, 5.93, S, 6.73.
(32). C23H25NO5S (427.51): calcd. C 64.62, H, 5.89, N, 3.28, S,
(3E)-4-[6-(4-Methylphenyl)sulfonyl-8-phenyl-2,3-dihydro-6H-[1,4]-
7.50; found C, 64.83, H, 5.72, N, 3.38, S, 7.53.
dioxino[2,3-f]indol-7-yl]but-3-en-2-one (3k): Pale yellow solid. Rf =
(3E)-4-[1-(4-Methylphenyl)sulfonyl-3-phenyl-1H-indol-2-yl]but-3-en-
0.59 (acetone/petroleum ether, 1:1), m.p. 233–234 °C. 1H NMR
2-one (3g): White solid. Rf = 0.62 (acetone/petroleum ether, 1:1),
(600 MHz, [D6]DMSO): δ = 7.96 (d, 3J = 16.4 Hz, 1 H, CH=),
1
m.p. 146–147 °C. H NMR (600 MHz, [D6]DMSO): δ = 8.22–8.15 7.63–7.58 (m, 3 H, Ar), 7.51–7.41 (m, 3 H, Ar), 7.40–7.36 (m, 2 H,
(m, 1 H, Ar), 8.03 (d, 3J = 16.5 Hz, 1 H, CH=), 7.69–7.64 (m, 2
Ar), 7.31–7.27 (m, 2 H, Ar), 6.59 (s, 1 H, Ar), 5.92 (d, 3J = 16.4 Hz,
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31762
/KAP1
Date: 20-02-14 10:59:28
Pages: 9
Indole Synthesis by Domino Chemistry Using Furfurylamines
1 H, CH=), 4.32–4.29 (m, 2 H, CH2), 4.25–4.22 (m, 2 H, CH2),
2.32 (s, 3 H, CH3), 2.20 (s, 3 H, CH3) ppm. 13C NMR (150 MHz,
[D6]DMSO): δ = 197.1, 145.6, 143.9, 142.3, 133.5, 131.7, 131.6,
131.5, 130.8, 130.7, 130.2 (2 C), 129.3 (2 C), 129.1 (2 C), 128.4,
(s, 3 H, CH3O), 3.23–3.09 (m, 2 H, CH2), 3.02–2.92 (m, 2 H, CH2),
2.29 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
205.3, 166.4, 147.7, 147.4, 145.3, 134.7, 134.0, 133.8, 132.3, 131.4,
130.2 (2 C), 129.8, 129.5 (2 C), 128.9 (2 C), 128.4 (2 C), 127.8,
128.2, 126.4 (2 C), 124.4, 106.7, 103.4, 64.3, 63.9, 27.0, 21.1 ppm. 127.3 (2 C), 126.2 (2 C), 124.2, 122.7, 100.9, 99.2, 56.0, 55.5, 48.8,
IR (KBr): ν = 1672, 1555, 1460, 1368, 1335, 1244, 1163, 1069, 847,
40.6, 21.0, 20.9 ppm. IR (KBr): ν = 3399, 1711, 1655, 1526, 1489,
˜
˜
700 cm–1. MS (EI, 70 eV): m/z (%) = 473 (100) [M]+, 319 (35), 276
1369, 1225, 1163, 1024, 714 cm–1. MS (EI, 70 eV): m/z (%) = 596
(45), 220 (31), 91 (40), 43 (34). C27H23NO5S (473.54): calcd. C (28) [M]+, 441 (100), 423 (20), 320 (18), 279 (25), 266 (31), 234 (15),
68.48, H, 4.90, N, 2.96, S, 6.77; found C, 68.39, H, 4.92, N, 2.93,
S, 6.76.
220 (24), 188 (25), 162 (40), 105 (90), 91 (55), 65 (30), 43 (28).
C34H32N2O6S (596.69): calcd. C 68.44, H, 5.41, N, 4.69, S, 5.37;
found C, 68.51, H, 5.58, N, 4.66, S, 5.05.
(3E)-4-[8-Methyl-6-(4-methylphenyl)sulfonyl-2,3-dihydro-6H-[1,4]di-
oxino[2,3-f]indol-7-yl]but-3-en-2-one (3l): Beige solid. Rf = 0.57
(acetone/petroleum ether, 1:1), m.p. 186–187 °C. 1H NMR
(600 MHz, [D6]DMSO): δ = 7.98 (d, 3J = 16.4 Hz, 1 H, CH=), 7.52
N-{4-[5,6-Dimethoxy-1-(4-methylphenyl)sulfonyl-3-phenyl-1H-indol-
2-yl]-2-oxobutyl}-4-nitrobenzamide (6b): Beige solid. Rf = 0.50
(acetone/petroleum ether, 1:1), m.p. 171–172 °C. 1H NMR
3
(s, 1 H, Ind), 7.51–7.48 (m, 2 H, Ar), 7.34–7.29 (m, 2 H, Ar), 7.06 (400 MHz, [D6]DMSO): δ = 9.14 (t, J = 5.7 Hz, 1 H, NH), 8.37–
(s, 1 H, Ind), 6.42 (d, 3J = 16.4 Hz, 1 H, CH=), 4.32–4.29 (m, 2 H,
8.29 (m, 2 H, Ar), 8.11–8.04 (m, 2 H, Ar), 7.69–7.67 (m, 2 H, Ar),
CH2), 4.27–4.24 (m, 2 H, CH2), 2.37 (s, 3 H, CH3), 2.28 (s, 3 H, 7.66 (s, 1 H, Ind), 7.50–7.46 (m, 3 H, Ar), 7.44–7.39 (m, 1 H, Ar),
3
CH3), 2.22 (s, 3 H, CH3) ppm. 13C NMR (150 MHz, [D6]DMSO): 7.38–7.32 (m, 3 H, Ar), 6.68 (s, 1 H, Ind), 4.17 (d, J = 5.7 Hz, 2
δ = 197.3, 145.3, 143.7, 141.9, 133.6, 132.1, 131.3, 130.8, 130.1 (2
C), 129.6, 126.2 (2 C), 125.3, 124.3, 107.0, 103.1, 64.3, 63.8, 27.6,
H, CH2N), 3.86 (s, 3 H, CH3O), 3.66 (s, 3 H, CH3O), 3.22–3.10
(m, 2 H, CH2), 3.04–2.90 (m, 2 H, CH2), 2.30 (s, 3 H, CH3) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 204.8, 164.9, 149.2, 147.7,
147.4, 145.3, 139.4, 134.7, 134.0, 132.3, 130.2 (2 C), 129.8, 129.5 (2
21.0, 10.8 ppm. IR (KBr): ν = 1668, 1566, 1477, 1360, 1331, 1250,
˜
1171, 1146, 1063, 887, 814 cm–1. MS (EI, 70 eV): m/z (%) = 411
(100) [M]+, 256 (92), 213 (53), 185 (15), 157 (30), 91 (18), 43 (17). C), 129.0 (2 C), 128.8 (2 C), 127.8, 126.3 (2 C), 124.3, 123.7 (2 C),
C22H21NO5S (411.47): calcd. C 64.22, H, 5.14, N, 3.40, S, 7.79;
found C, 64.05, H, 4.97, N, 3.39, S, 7.71.
122.7, 100.9, 99.2, 56.0, 55.5, 48.9, 40.7, 21.0, 20.9 ppm. IR (KBr):
ν = 3362, 1711, 1663, 1522, 1486, 1343, 1303, 1157, 1089, 1024,
˜
845, 717 cm–1. HRMS (ESI) calcd. for C34H31N3O8S+ [M]+
641.1832, found 641.1826.
(3E)-4-[8-Ethyl-6-(4-methylphenyl)sulfonyl-2,3-dihydro-6H-[1,4]-
dioxino[2,3-f]indol-7-yl]but-3-en-2-one (3m): Beige solid. Rf = 0.58
(acetone/petroleum ether, 1:1), m.p. 136–137 °C. 1H NMR
(600 MHz, [D6]DMSO): δ = 7.93 (d, 3J = 16.4 Hz, 1 H, CH=), 7.50
N-{4-[5,6-Dimethoxy-1-(4-methylphenyl)sulfonyl-3-phenyl-1H-indol-
2-yl]-2-oxobutyl}-3,4-dimethoxybenzamide (6c): Beige solid. Rf =
(s, 1 H, Ind), 7.49–7.47 (m, 2 H, Ar), 7.33–7.27 (m, 2 H, Ar), 7.06 0.40 (acetone/petroleum ether, 1:1), m.p. 183–184 °C. 1H NMR
(s, 1 H, Ind), 6.35 (d, 3J = 16.4 Hz, 1 H, CH=), 4.31–4.28 (m, 2 H,
(600 MHz, [D6]DMSO): δ = 8.66 (t, J = 5.6 Hz, 1 H, NH), 7.71–
3
3
CH2), 4.27–4.24 (m, 2 H, CH2), 2.66 (q, J = 7.5 Hz, 2 H, CH2), 7.67 (m, 2 H, Ar), 7.66 (s, 1 H, Ind), 7.51–7.47 (m, 3 H, Ar), 7.46
3
4
2.38 (s, 3 H, CH3), 2.27 (s, 3 H, CH3), 1.06 (t, J = 7.5 Hz, 3 H, (d, J = 1.9 Hz, 1 H, Ar), 7.44–7.39 (m, 1 H, Ar), 7.37–7.31 (m, 4
CH3) ppm. 13C NMR (150 MHz, [D6]DMSO): δ = 197.4, 145.3,
H, Ar), 7.03 (d, J = 8.5 Hz, 1 H, Ar), 6.68 (s, 1 H, Ind), 4.07 (d,
3
143.6, 141.9, 133.4, 132.3, 131.7, 130.5, 130.4, 130.0 (2 C), 129.0, 3J = 5.6 Hz, 2 H, CH2N), 3.86 (s, 3 H, CH3O), 3.81 (s, 3 H, CH3O),
126.3 (2 C), 124.4, 107.0, 103.4, 64.3, 63.8, 27.5, 21.0, 17.8, 3.80 (s, 3 H, CH3O), 3.66 (s, 3 H, CH3O), 3.20–3.11 (m, 2 H, CH2),
14.1 ppm. IR (KBr): ν = 1676, 1483, 1375, 1263, 1198, 1094, 939,
3.00–2.90 (m, 2 H, CH2), 2.30 (s, 3 H, CH3) ppm. 13C NMR
˜
876, 700 cm–1. MS (EI, 70 eV): m/z (%) = 425 (100) [M]+, 396 (60), (150 MHz, [D6]DMSO): δ = 205.5, 166.0, 151.4, 148.3, 147.7,
270 (95), 227 (42), 190 (20), 43 (29). C23H23NO5S (425.50): calcd.
C 64.92, H, 5.45, N, 3.29, S, 7.54; found C, 64.95, H, 5.47, N, 3.39,
S, 7.41.
147.4, 145.2, 134.8, 134.0, 132.2, 130.1 (2 C), 129.8, 129.4 (2 C),
128.9 (2 C), 127.7, 126.2 (2 C), 126.0, 124.2, 122.7, 120.5, 110.9,
110.7, 101.0, 99.3, 56.0, 55.6, 55.5, 55.4, 48.8, 40.6, 21.0, 20.9 ppm.
IR (KBr): ν = 3433, 1722, 1657, 1599, 1468, 1358, 1263, 1223, 1155,
˜
(3E)-4-[5-(4-Methylphenyl)sulfonyl-5H-[1,3]dioxolo[4,5-f]indol-6-yl]-
but-3-en-2-one (3n): Beige solid. Rf = 0.57 (acetone/petroleum ether,
1018, 852, 766 cm–1. HRMS (ESI) calcd. for C36H36N2O8S+ [M]+
656.2192, found 656.2187.
1
1:1), m.p. 206–207 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.11
3
(d, J = 16.1 Hz, 1 H, CH=), 7.66–7.61 (m, 2 H, Ar), 7.60 (s, 1 H,
2-{4-[5,6-Dimethoxy-1-(4-methylphenyl)sulfonyl-3-phenyl-1H-
indol-2-yl]-2-oxobutyl}isoindole-1,3(2H)-dione (10): Method A. Pale
Ind), 7.40–7.36 (m, 2 H, Ar), 7.35 (s, 1 H, Ind), 7.06 (s, 1 H, Ind),
3
6.75 (d, J = 16.1 Hz, 1 H, CH=), 6.10 (s, 2 H, OCH2O), 2.34 (s, yellow solid. Rf = 0.52 (acetone/petroleum ether, 1:1), m.p. 186–
1
3 H, CH3), 2.31 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]- 187 °C. H NMR (400 MHz, [D6]DMSO): δ = 7.96–7.89 (m, 2 H,
DMSO): δ = 197.2, 147.7, 145.8, 145.7, 134.8, 133.9, 132.9, 131.2,
130.3 (2 C), 127.8, 126.3 (2 C), 123.7, 113.6, 101.8, 99.9, 95.9, 27.6,
Ar), 7.88–7.81 (m, 2 H, Ar), 7.74–7.67 (m, 2 H, Ar), 7.66 (s, 1 H,
Ind) 7.54–7.45 (m, 2 H, Ar), 7.44–7.31 (m, 5 H, Ar), 6.69 (s, 1 H,
Ind), 4.60 (s, 2 H, CH2N), 3.87 (s, 3 H, CH3O), 3.66 (s, 3 H, CH3O),
3.23–3.13 (m, 2 H, CH2), 3.12–3.02 (m, 2 H, CH2), 2.29 (s, 3 H,
CH3) ppm. 13C NMR (150 MHz, DMSO): δ = 202.2, 167.4 (2 C),
147.8, 147.4, 145.3, 134.8 (2 C), 134.4, 133.9, 132.2, 131.5 (2 C),
130.2 (2 C), 129.8, 129.5 (2 C), 129.0 (2 C), 127.8, 126.3 (2 C),
124.4, 123.3 (2 C), 122.7, 100.9, 99.2, 56.0, 55.5, 46.3, 40.7, 21.0,
21.0 ppm. IR (KBr): ν = 1656, 1528, 1455, 1364, 1314, 1238, 1163,
˜
1084, 1035, 945, 799 cm–1. MS (EI, 70 eV): m/z (%) = 383 (41)
[M]+, 228 (100), 213 (12), 198 (15), 186 (18), 91 (35), 43 (25).
C20H17NO5S (383.42): calcd. C 62.65, H, 4.47, N, 3.65, S, 8.36;
found C, 62.64, H, 4.62, N, 3.67, S, 8.15.
N-{4-[5,6-Dimethoxy-1-(4-methylphenyl)sulfonyl-3-phenyl-1H-indol-
2-yl]-2-oxobutyl}benzamide (6a): Beige solid. Rf = 0.52 (acetone/
20.8 ppm. IR (KBr): ν = 1713, 1487, 1431, 1362, 1304, 1231, 1190,
˜
1159, 1090, 1028, 997, 847, 760 cm–1. C35H30N2O7S (622.69): calcd.
C 67.51, H, 4.86, N, 4.50, S, 5.15; found C, 67.27, H, 4.70, N, 4.30,
S, 5.29.
1
petroleum ether, 1:1), m.p. 139–140 °C. H NMR (400 MHz, [D6]-
DMSO): δ = 8.80 (t, 3J = 5.7 Hz, 1 H, NH), 7.90–7.84 (m, 2 H,
Ar), 7.72–7.67 (m, 2 H, Ar), 7.66 (s, 1 H, Ind), 7.57–7.45 (m, 5 H,
Ar), 7.44–7.38 (m, 1 H, Ar), 7.37–7.32 (m, 4 H, Ar), 6.68 (s, 1 H,
Supporting Information (see footnote on the first page of this arti-
3
1
Ind), 4.11 (d, J = 5.7 Hz, 2 H, CH2N), 3.86 (s, 3 H, CH3O), 3.66
cle): H and 13C NMR spectra of 3a–n, 6a–c and 10.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Job/Unit: O31762
/KAP1
Date: 20-02-14 10:59:28
Pages: 9
M. G. Uchuskin, A. V. Butin et al.
FULL PAPER
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Acknowledgments
Financial support was provided by the Russian Foundation for
Basic Research (grant number 13-03-00463) and the Ministry of
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Received: November 23, 2013
Published Online: ᭿
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31762
/KAP1
Date: 20-02-14 10:59:28
Pages: 9
Indole Synthesis by Domino Chemistry Using Furfurylamines
Domino Reactions
M. G. Uchuskin,* N. V. Molodtsova,
S. A. Lysenko, V. N. Strel’nikov,
I. V. Trushkov, A. V. Butin* ............... 1–9
Synthesis of Indoles by Domino Reaction
of 2-(Tosylamino)benzyl Alcohols with
Furfurylamines: Two Opposite Reactivity
Modes of the α-Carbon of the Furan Ring
in One Process
Furfurylamines react with 2-(tosylamino)-
benzyl alcohols affording 2-(2-acylvinyl)-
indoles by a domino reaction sequence in
which the same furan α-carbon atom be-
haves initially as an electron-rich center
and then as an electron deficient one. In
addition, substitution of the tosylamino
leaving group with a phthalimido group
furnishes a change in chemoselectivity.
Keywords: Oxygen heterocycles / Electro-
philic substitution / Nucleophilic substi-
tution / Nitrogen heterocycles
Eur. J. Org. Chem. 0000, 0–0
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9