Recyclization of (2-aminophenyl)bis(5-tert-butyl-2-furyl)methanes into indole derivatives: Unusual dependence on substituent at nitrogen atom

Article abstract of DOI:10.1055/s-2008-1067248

The recyclization of (2-aminophenyl)bis(5-tert-butyl-2-furyl)methanes under acidic conditions was studied. It was found that the extent of reaction of these substrates depends on the substituent at the nitrogen atom of the aniline moiety. N-Tosyl derivatives were converted into the corresponding 3-(5-tert-butyl-2-furyl)-2-(4,4-dimethyl-3-oxopentyl)-1-tosyl-1H-indoles. Indole formation was followed by furan ring opening in the case of N-unsubstituted substrates leading to 3-(5,5-dimethyl-1,4-dioxohexyl)-2-(4,4-dimethyl-3- oxopentyl)-1H-indoles. The same products were obtained from N-acetyl derivatives. However, the behavior of the N-benzoyl analogues depends on the reaction conditions: at room temperature 1-benzoyl-3-(5-tert-butyl-2-furyl)-1H- indoles were formed, but debenzoylation and furan ring opening proceed with heating. These data and results of control experiments showed that the reaction mechanism consists of three successive steps: recyclization itself, deacylation of the resulting N-acylindole, and furan ring opening in N-unsubstituted 3-(2-furyl)indoles. The last step can be realized for N-unsubstituted indoles only, but the furan ring is stable for N-acylindoles. This was explained by transformation of N-unsubstituted 1H-indoles under the reaction conditions into 3H-indole tautomers. These tautomers can be considered as 2,5-dialkylfurans, which have much lower stability against acids than 2-aryl-5-alkylfurans. This tautomerization is impossible for N-acylindoles. The high acidic stability of 2-(5-tert-butyl-2-furyl)indoles supports this conclusion. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067248

PAPER
2943
Recyclization of (2-Aminophenyl)bis(5-tert-butyl-2-furyl)methanes into Indole
Derivatives: Unusual Dependence on Substituent at Nitrogen Atom
R
ecyclization of (2
l
-Amin
e
oaryl)bis(5
x
-
tert-butyl-2-
a
f
uryl)meth
n
a
nes der V. Butin,*a Sergey K. Smirnov,a Fatima A. Tsiunchik,a Maxim G. Uchuskin,a Igor V. Trushkovb
a
Research Institute of Heterocyclic Compounds Chemistry, Kuban State University of Technology,
Moskovskaya st. 2, Krasnodar 350072, Russian Federation
Fax +7(861)2596592; E-mail: alexander_butin@mail.ru; av_butin@yahoo.com
Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russian Federation
b
Received 20 May 2008; revised 11 June 2008
the nature of the substituents on the nitrogen atom of the
2-aminoaryl moiety. The recyclization leads to either
N-substituted 3-furylindoles or N-unsubstituted triketo-
indoles, which were formed by protolytic opening of the
Abstract: The recyclization of (2-aminophenyl)bis(5-tert-butyl-2-
furyl)methanes under acidic conditions was studied. It was found
that the extent of reaction of these substrates depends on the substit-
uent at the nitrogen atom of the aniline moiety. N-Tosyl derivatives
were converted into the corresponding 3-(5-tert-butyl-2-furyl)-2- furan ring. Here we describe the full details of this inves-
(4,4-dimethyl-3-oxopentyl)-1-tosyl-1H-indoles. Indole formation
was followed by furan ring opening in the case of N-unsubstituted
tigation.
The starting (2-aminophenyl)bis(2-furyl)methanes were
substrates leading to 3-(5,5-dimethyl-1,4-dioxohexyl)-2-(4,4-dime-
prepared from commercially available 2-nitrobenzalde-
hydes 1a–d and easily synthesized 2-tert-butylfuran (2)9
by the reaction sequence shown in Scheme 1. The per-
chloric acid catalyzed condensation of 2-nitrobenzalde-
hydes 1a–d with 2-tert-butylfuran (2) in 1,4-dioxane
afforded (2-nitrophenyl)bis(2-furyl)methanes 3a–d. Re-
duction of the nitro group with hydrazine hydrate/Raney
nickel in refluxing ethanol yields amines 4a–d (Scheme 1,
thyl-3-oxopentyl)-1H-indoles. The same products were obtained
from N-acetyl derivatives. However, the behavior of the N-benzoyl
analogues depends on the reaction conditions: at room temperature
1-benzoyl-3-(5-tert-butyl-2-furyl)-1H-indoles were formed, but de-
benzoylation and furan ring opening proceed with heating. These
data and results of control experiments showed that the reaction
mechanism consists of three successive steps: recyclization itself,
deacylation of the resulting N-acylindole, and furan ring opening in
N-unsubstituted 3-(2-furyl)indoles. The last step can be realized for
N-unsubstituted indoles only, but the furan ring is stable for N- Table 1). Amides 5a–d and 6a–d were synthesized by, re-
acylindoles. This was explained by transformation of N-unsubsti-
tuted 1H-indoles under the reaction conditions into 3H-indole tau-
tomers. These tautomers can be considered as 2,5-dialkylfurans,
treatment of aniline 4b with the corresponding benzoyl
which have much lower stability against acids than 2-aryl-5-alkyl-
furans. This tautomerization is impossible for N-acylindoles. The
spectively, tosylation and acetylation of anilines 4a–d
(Scheme 2, Table 1). Benzanilides 7a,b were obtained by
chlorides in pyridine (Scheme 3).
high acidic stability of 2-(5-tert-butyl-2-furyl)indoles supports this
conclusion.
R1
R2
NO2
HClO4
+
Key words: furans, ring opening, ring closure, fused ring system,
indole, triketoindole
1,4-dioxane
O
CHO
1a–d
2
R1
R2
Heterocyclic compounds have attracted great attention of
organic chemists for many years due to both their broad
spectrum of chemical reactivity and their different phar-
macological activity. Indoles and furans are among the
most studied heterocycles. At the same time, there is a
very short list of publications dealing with the
preparation1 and biological properties2 of 3-(2-furyl)in-
doles. Recently, we have developed a new method for the
synthesis of 3-(2-furyl)indoles by the acid-catalyzed recy-
clization of (2-aminophenyl)bis(2-furyl)methanes.3 This
recyclization is a general approach to various benzannu-
lated heterocycles. Earlier we used it for the synthesis of
benzofurans,4 indoles,5 isoquinolines,6 isocoumarins7 and
isochromenes.8 However, during this investigation we
found that the direction of the recyclization depends on
R1
R2
NH2
NO2
NH2NH2
O
O
Raney nickel
O
O
3a–d
4a–d
Scheme 1 Synthesis of compounds 3 and 4
The behavior of compounds 4–7 in the recyclization ex-
periments differed significantly. When tosylamides 5a–d
were heated at reflux in ethanol saturated with hydrogen
chloride, the reaction products were 3-(2-furyl)-1-tosyl-
indoles 8a–d (Scheme 4, Table 2). Acetamides 6a–d un-
der these reaction conditions gave predominantly the
products of oligomerization. However, recyclization of
acetamides 6a–d at room temperature also yielded substi-
tuted indoles. In this case, the reactions proceeded very
SYNTHESIS 2008, No. 18, pp 2943–2952
x
x.
x
x
.
2
0
0
8
Advanced online publication: 04.09.2008
DOI: 10.1055/s-2008-1067248; Art ID: Z11808SS
© Georg Thieme Verlag Stuttgart · New York

2944
A. V. Butin et al.
PAPER
Ts
Table 1 Yields of Compounds 3–6
R1
R2
NH
R1
R2
NH2
Compd R1
R2
Yield (%)
TsCl
Py
O
O
3–6
3
4
5
6
a
b
c
H
H
92
94
90
88
86
83
89
81
58
61
65
68
53
57
58
62
O
O
Ac2O
OMe
OMe
Ac
OCH2O
OCH2CH2O
4a–d
5a–d
R1
NH
d
R2
O
tion conditions we found that triketoindoles 9a–d were
formed from acetamides 6a–d in moderate yields by the
treatment with hydrochloric acid in acetic acid at room
temperature for 1–2 days.
O
6a–d
On the basis of this data, we concluded that triketoindoles
9 were formed as a result of complex multistep processes
that consist of recyclization itself, N-deacetylation, and
protolytic furan ring opening in the formed 3-(2-furyl)-
1H-indoles. Conversely, the tosylamides rearranged with
retention of the amide moiety even under prolonged
refluxing with the same reagents. The resulting 3-(5-tert-
butyl-2-furyl)-1-tosylindoles were stable to the acid-cata-
lyzed furan ring opening, which was easily realized for N-
unsubstituted indoles. These results are in a full agree-
ment with our previous experiments, wherein we have
found5 that N-acetyl derivatives were easily deacetylated
under similar reaction conditions, but the corresponding
tosylamides afforded N-tosylindoles.
Scheme 2 Synthesis of compounds 5 and 6
R
O
NH2
MeO
MeO
NH
MeO
MeO
ArCOCl
Py
O
O
O
O
7a R = Me (87%)
7b R = NO2 (61%)
4b
Table 2 Yields of Compounds 8 and 9
Scheme 3 Synthesis of compounds 7
Compd R1
R2
Yield (%)
Ts
8, 9
8
9
Ts
N
R1
R2
NH
R1
R2
HCl
a
b
c
H
H
59
62
61
65
42
51
56
49
O
EtOH
O
OMe
OMe
O
O
OCH2O
OCH2CH2O
d
5a–d
8a–d
To prove this supposition, we studied the recyclization of
some other model compounds. Firstly, we synthesized {2-
[(acetyl)(methyl)amino]phenyl}bis(2-furyl)methane 10b
by treatment of acetamide 6b with sodium hydride fol-
lowed by alkylation with methyl iodide (Scheme 6). We
Scheme 4 Synthesis of indoles 8
slowly (ca. 7 days were needed for full conversion of
amide) and afforded N-unsubstituted triketoindoles 9a–d
(Scheme 5, Table 2). During the optimization of the reac-
Ac
H
R1
R2
N
R1
R2
NH
MeO
MeO
NH2
O
HCl
HCl
AcOH
EtOH
O
O
O
O
O
O
4b
6a–d
9a–d
Scheme 5 Synthesis of triketoindoles 9
Synthesis 2008, No. 18, 2943–2952 © Thieme Stuttgart · New York

PAPER
Recyclization of (2-Aminophenyl)bis(5-tert-butyl-2-furyl)methanes
2945
Ac
Me
Ac
MeO
MeO
N
Me
N
MeO
MeO
MeO
MeO
NH
HCl
MeI
O
NaH, THF
O
EtOH
O
O
O
O
O
10b
11b
6b
Scheme 6 Synthesis of compound 10b
Ts
Ts
indole 9b on treatment with ethanolic hydrogen chloride
(Scheme 7). This data is in accordance with the following
mechanism of transformations of compounds 6 in ethan-
olic hydrogen chloride: the first step is recyclization itself;
deacetylation of the formed indole yields N-unsubstituted
indoles that are able to participate in the second furan ring
opening.
MeO
MeO
MeO
MeO
N
N
O
O
HCl
O
O
EtOH
O
8b
This mechanism is also supported by the results of the re-
cyclization of benzamides 7a,b induced by hydrochloric
acid in acetic acid. When these reactions were performed
at room temperature for one day, amides 7a,b gave rise to
the corresponding 1-benzoyl-3-(2-furyl)indoles 13a,b
(Scheme 8), however, with heating the main product of
recyclization was triketoindole 9b. Moreover, heating N-
benzoylindole 13a at 45 °C for 16 hours led to its deben-
zoylation followed by acid-catalyzed furan ring opening
(Scheme 8).
KOH
MeOH
H
H
MeO
MeO
MeO
N
N
O
O
MeO
HCl
EtOH
O
O
O
12b (61%)
9b (56%)
To summarize, treatment of N-unsubstituted (2-amino-
phenyl)bis(2-furyl)methanes with acid afforded N-unsub-
stituted 3-(2-furyl)indoles that were unstable under these
reaction conditions and transformed into the correspond-
ing triketoindoles by acid-catalyzed furan ring opening.
Due to fast deacetylation, N-acetyl derivatives also
formed N-unsubstituted indoles followed by furan ring
opening leading to the corresponding triketoindoles. N-
Tosylanilines yielded N-tosylindoles that were stable to
the above reaction conditions to both detosylation and fu-
ran ring opening. N-Benzoylanilines showed intermediate
behavior; at room temperature we isolated N-benzoyl-3-
(2-furyl)indoles that underwent both debenzoylation and
ring opening on heating. Taking all data together, we can
conclude that the furan ring opening proceeds efficiently
Scheme 7 Synthesis of triketoindole 9b from N-unsubstituted
indole 12b
found that 10b was isolated unchanged after prolonged re-
flux of an ethanolic solution saturated with hydrogen
chloride. We failed also to isolate the targeted triketone
11b after keeping this compound in a mixture of acetic
acid and hydrochloric acid at room temperature. A com-
plex mixture of unidentified products was formed in the
latter reaction. On the other hand, under the same reaction
conditions, amine 4b was, indeed, transformed into the
corresponding triketoindoles 9b (Scheme 5). Then, we
synthesized N-unsubstituted indole 12b by detosylation
of N-tosylindole 8b and found that 12b yielded triketo-
R
R
O
O
H
MeO
MeO
N
MeO
MeO
NH
MeO
MeO
N
O
HCl
HCl
O
AcOH
45 °C
AcOH
r.t.
O
O
O
O
O
7a,b
13a R = Me (55%)
13b R = NO2 (52%)
9b
Scheme 8 Synthesis of indoles 13 and triketoindole 9b from benzanilides 7
Synthesis 2008, No. 18, 2943–2952 © Thieme Stuttgart · New York

2946
A. V. Butin et al.
PAPER
for N-unsubstituted 3-(2-furyl)indoles, but does not pro- of 15 yielded 5-tert-butyl-2-[2-(2-nitro-4,5-dimethoxy-
ceed for N-acylindoles. It is known that 2-alkyl-5-aryl- phenyl)-1-oxoethyl]furan 16. Its reduction by iron/acetic
furans are relatively stable to treatment with acids, but acid mixture gave 2-(2-furyl)indole 17. In full agreement
2,5-dialkylfurans hydrolyze easily under the same reac- with our supposition, compound 17 failed form any prod-
tion conditions. This is why the furan ring did not open in uct of furan ring opening at reflux with ethanolic hydro-
N-acyl-3-(2-furyl)indoles. However, more basic N-un- gen chloride for several hours (Scheme 11).
substituted 3-(2-furyl)-1H-indoles can be reversibly pro-
tonated at C3 with formation of the tautomeric 3-(2-
furyl)-3H-indoles. In this tautomer, there is no conjuga-
tion between furan and indole moieties. Therefore, it can
be considered as an example of a 2,5-dialkylfuran, which
hydrolyze under these reaction conditions (Scheme 9).
MeO
MeO
Si-PPA
HNO3
AcOH
+
O
MeO
MeO
COOH
O
14
2
O
15
H
H
R1
R2
R1
R2
+N
N
NO2
MeO
MeO
– H+
+ H+
O
O
H
H+
MeO
MeO
N
Fe
AcOH
H
O
O
O
O
O
17
H+
12
16
H
H
MeO
MeO
R1
R2
O
R1
R2
N
N
N
O
O
H+
H
O
O
O
Scheme 11 Synthesis of 2-(2-furyl)-1H-indole 17
O
9
Herein we studied the direction of acid-catalyzed
recyclization of (2-aminophenyl)bis(5-tert-butyl-2-fur-
yl)methane as a function of substituent at the nitrogen
atom. It was found that rearrangement of bis(2-furyl)[2-
(tosylamino)phenyl]methanes afforded the corresponding
3-(2-furyl)-2-(3-oxoalkyl)-1-tosylindoles, which are very
interesting as potent biologically active agents. Converse-
ly, [2-(acetylamino)phenyl]bis(2-furyl)methanes recy-
clized into 3-(1,4-dioxoalkyl)-2-(3-oxoalkyl)-1H-indoles,
which were also formed from N-unsubstituted substrates.
N-Benzoyl analogues had intermediate reactivity. When
these reactions were performed at room temperature, 1-
benzoyl-3-(2-furyl)-2-(3-oxoalkyl)indoles were formed,
but under moderate heating debenzoylation followed by
furan ring opening proceeded. The obtained results can be
explained by transformation of N-acetyl- and N-unsubsti-
tuted (2-aminophenyl)bis(2-furyl)methanes into N-un-
substituted indoles. Their protonation at C3 yielded the
corresponding tautomeric 3-(2-furyl)-3H-indoles that un-
derwent acid-catalyzed furan ring opening. This ring
opening did not occur under same reaction conditions for
1-acyl-3-(2-furyl)indoles. The significant reactivity dif-
ference against acids is explained by the fact that the be-
havior of 3-(2-furyl-5-tert-butyl)-3H-indoles is typical for
other 2,5-dialkylfurans, but 1-acyl-3-(2-furyl)indoles
have much higher stability toward acids, which is typical
for 2-alkyl-5-arylfurans. This explanation is in a full
agreement with results of investigations of reactivity for
specially designed model compounds, in particular, N-un-
substituted 2-(2-furyl)indoles and 3-(2-furyl)indoles. In
Scheme 9
According to the proposed mechanism, 2-(2-furyl)-1H-in-
doles must be stable to the furan ring opening process un-
der the same reaction conditions. Indeed, protonation of 2-
(2-furyl)-1H-indoles at C3 leads to unreactive intermedi-
ates as the substituent in the furan ring has an electron-
withdrawing nature (Scheme 10).
H
N
+N
– H+
O
O
R
R
H
H
H+
H
H
H
O
N
R
O
Scheme 10
To prove this conclusion, we synthesized 2-(5-tert-butyl-
2-furyl)-5,6-dimethoxy-1H-indole (17) as a model com-
pound by the reaction sequence shown in Scheme 11. Tri-
methylsilyl polyphosphate (PPSE)10 catalyzed acylation
of 2-tert-butylfuran (2) with 3,4-dimethoxyphenylacetic
acid (14) afforded 2-acyl-5-tert-butylfuran 15. Nitration
Synthesis 2008, No. 18, 2943–2952 © Thieme Stuttgart · New York

PAPER
Recyclization of (2-Aminophenyl)bis(5-tert-butyl-2-furyl)methanes
2947
tered off and the filtrate was evaporated under reduced pressure.
The residue was dissolved in CH2Cl2–hexane and filtered through a
pad of silica gel (5–40 mm) and evaporated under reduced pressure
to dryness. Compounds 4a,c were obtained as light-yellow oils and
used without additional purification.
accordance to the proposed mechanism, N-unsubstituted
2-(2-furyl)indoles were stable to furan ring opening under
the studied reaction conditions, but N-unsubstituted 3-(2-
furyl)indoles were converted easily into the correspond-
ing polycarbonyl compounds by furan ring opening. The
synthesized triketoindoles are good precursors for synthe-
sis of different indole derivatives with broad range of
physiological activity.
(2-Amino-4,5-dimethoxyphenyl)bis(5-tert-butyl-2-furyl)meth-
ane (4b)
White solid; yield: 4.78 g (83%); mp 119 °C (CH2Cl2–hexane).
IR (KBr): 3388, 3212, 2960, 1524, 1464, 1288, 1264, 1224, 1212,
1184, 1172, 1128, 1016, 784, 760 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.26 (s, 18 H, t-Bu), 3.16 (br s, 2
H, NH2), 3.68 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 5.36 (s, 1 H,
CH), 5.89 (s, 4 H, HFur), 6.32 (s, 1 H, HAr), 6.44 (s, 1 H, HAr).
1
Melting points are uncorrected. H NMR and 13C NMR spectra
were recorded in CDCl3 or DMSO-d6 on a Bruker AC 200 and
Bruker AM 300 spectrometers with TMS as internal standard; cou-
pling constants given to the nearest 0.1 Hz. Mass spectra were re-
corded on a Kratos MS-30 instrument with 70 eV electron impact
ionization at 200 °C. IR spectra were measured as KBr plates on
InfraLUM FT-02 and InfraLUM FT-801 instruments. Column
chromatography was performed using silica gel KSK manufactured
by LTD Sorbpolymer.
Anal. Calcd for C25H33NO4: C, 72.96; H, 8.08; N, 3.40. Found: C,
73.07; H, 8.16; N, 3.49.
[2-Amino-4,5-(ethylenedioxy)phenyl]bis(5-tert-butyl-2-fur-
yl)methane (4d)
Colorless prisms; yield: 4.64 g (81%); mp 126–127 °C (CH2Cl2–
hexane).
Bis(5-tert-butyl-2-furyl)(2-nitrophenyl)methanes 3a–d; Gener-
al Procedure
IR (KBr): 3456, 3376, 2964, 1516, 1460, 1328, 1204, 1188, 1124,
1072, 1012, 792, 772 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.26 (s, 18 H, t-Bu), 3.15 (br s, 2
H, NH2), 4.15–4.17 (m, 2 H, CH2), 4.19–4.21 (m, 2 H, CH2), 5.33
(s, 1 H, CH), 5.87 (s, 4 H, HFur), 6.25 (s, 1 H, HAr), 6.41 (s, 1 H, HAr).
To a soln of 2-nitrobenzaldehyde 1 (30 mmol) and 2-tert-butylfuran
2 (9.3 g, 75 mmol) in 1,4-dioxane (25 mL) was added 70% HClO4
(1 mL). The mixture was stirred at 65–70 °C until all the starting
compound had been consumed (TLC monitoring), then poured into
H2O, neutralized with NaHCO3, and left overnight at r.t. The prod-
uct was extracted with CH2Cl2 (2 × 100 mL). The organic layer was
separated, washed with H2O (2 × 50 mL), dried (anhyd Na2SO4),
and evaporated under reduced pressure. The residue was dissolved
in hexane and the resultant soln was filtered through a pad of silica
gel (5–40 mm) and evaporated under reduced pressure to dryness.
Compounds 3a,b were obtained as light-yellow oils and used with-
out additional purification.
Anal. Calcd for C25H31NO4: C, 73.32; H, 7.63; N, 3.42. Found: C,
73.24; H, 7.75; N, 3.39.
Bis(5-tert-butyl-2-furyl)[2-(tosylamino)phenyl]methanes 5a–d;
General Procedure
TsCl (1.06 g, 5.6 mmol) was added to a soln of 4 (4 mmol) in pyri-
dine (7 mL) at r.t. and the mixture was left for 40 min. Then, it was
poured into excess H2O and the precipitate was filtered off, washed
with H2O, and dried. Recrystallization (CH2Cl2–hexane, 1:6) af-
forded product 5.
Bis(5-tert-butyl-2-furyl)[4,5-(methylenedioxy)-2-nitrophe-
nyl]methane (3c)
Pale green prisms; yield: 11.48 g (90%); mp 99–100 °C (CH2Cl2–
hexane).
Bis(5-tert-butyl-2-furyl)[2-(tosylamino)phenyl]methane (5a)
White solid; yield: 1.17 g (58%); mp 129–131 °C.
IR (KBr): 2968, 1525, 1482, 1330, 1260, 1122, 1038, 1017, 932,
785 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (s, 18 H, t-Bu), 5.87 (d,
J = 3.1 Hz, 2 H, HFur), 5.93 (d, J = 3.1 Hz, 2 H, HFur), 6.08 (s, 2 H,
CH2), 6.29 (s, 1 H, CH), 6.79 (s, 1 H, HAr), 7.49 (s, 1 H, HAr).
IR (KBr): 3284, 2968, 1599, 1549, 1491, 1391, 1340, 1166, 1126,
1011, 905, 833, 779, 671 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.25 (s, 18 H, t-Bu), 2.41 (s, 3 H,
CH3), 4.94 (s, 1 H, CH), 5.73 (d, J = 3.1 Hz, 2 H, HFur), 5.85 (d,
J = 3.1 Hz, 2 H, HFur), 6.77 (br s, 1 H, NH), 6.86–6.90 (m, 1 H, HAr),
7.07–7.13 (m, 1 H, HAr), 7.20–7.27 (m, 3 H, HAr, HTs), 7.49–7.53
(m, 1 H, HAr), 7.64 (d, J = 8.2 Hz, 2 H, HTs).
Anal. Calcd for C24H27NO6: C, 67.75; H, 6.40; N, 3.29. Found: C,
67.91; H, 6.54; N, 3.38.
Bis(5-tert-butyl-2-furyl)[4,5-(ethylenedioxy)-2-nitrophe-
nyl]methane (3d)
Pale green prisms; yield: 11.60 g (88%); mp 123–124 °C (CH2Cl2–
hexane).
Anal. Calcd for C30H35NO4S: C, 71.26; H, 6.98; N, 2.77. Found: C,
71.35; H, 6.95; N, 2.80.
Bis(5-tert-butyl-2-furyl)[4,5-dimethoxy-2-(tosylamino)phe-
nyl]methane (5b)
White solid; yield: 1.38 g (61%); mp 117–119 °C.
IR (KBr): 2961, 1521, 1320, 1299, 1268, 1188, 1067, 1014, 899,
784 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.25 (s, 18 H, t-Bu), 4.29 (s, 4 H,
CH2), 5.85 (d, J = 3.1 Hz, 2 H, HFur), 5.89 (d, J = 3.1 Hz, 2 H, HFur),
6.29 (s, 1 H, CH), 6.79 (s, 1 H, HAr), 7.63 (s, 1 H, HAr).
IR (KBr): 3282, 2959, 1600, 1513, 1462, 1387, 1342, 1207, 1161,
1091, 1008, 904, 784, 678 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.25 (s, 18 H, t-Bu), 2.42 (s, 3 H,
CH3), 3.68 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 4.79 (s, 1 H, CH),
5.67 (d, J = 3.1 Hz, 2 H, HFur), 5.83 (d, J = 3.1 Hz, 2 H, HFur), 6.42
(s, 1 H, HAr), 6.58 (br s, 1 H, NH), 7.02 (s, 1 H, HAr), 7.27 (d, J = 8.2
Hz, 2 H, HTs), 7.63 (d, J = 8.2 Hz, 2 H, HTs).
Anal. Calcd for C25H29NO6: C, 68.32; H, 6.65; N, 3.19. Found: C,
68.37; H, 6.72; N, 3.24.
(2-Aminophenyl)bis(5-tert-butyl-2-furyl)methanes 4a–d; Gen-
eral Procedure
To a soln of 3 (14 mmol) in EtOH (60 mL) was added active Raney
nickel (4 g) and hydrazine hydrate (5 mL) and the mixture refluxed
for 1 h. When the reaction was complete (TLC), the nickel was fil-
Anal. Calcd for C32H39NO6S: C, 67.94; H, 6.95; N, 2.48. Found: C,
68.05; H, 7.01; N, 2.45.
Synthesis 2008, No. 18, 2943–2952 © Thieme Stuttgart · New York

2948
A. V. Butin et al.
PAPER
Bis(5-tert-butyl-2-furyl)[4,5-(methylenedioxy)-2-(tosylami-
no)phenyl]methane (5c)
Anal. Calcd for C26H31NO5: C, 71.37; H, 7.14; N, 3.20. Found: C,
71.50; H, 7.21; N, 3.17.
White solid; yield: 1.43 g (65%); mp 144–145 °C.
[2-(Acetylamino)-4,5-(ethylenedioxy)phenyl]bis(5-tert-butyl-2-
furyl)methane (6a)
Colorless needles; yield: 3.64 g (62%); mp 202 °C.
IR (KBr): 3282, 2968, 1511, 1482, 1408, 1358, 1156, 1041, 941,
895, 781, 674 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.24 (s, 18 H, t-Bu), 2.42 (s, 3 H,
CH3), 4.78 (s, 1 H, CH), 5.68 (d, J = 3.1 Hz, 2 H, HFur), 5.83 (d,
J = 3.1 Hz, 2 H, HFur), 5.94 (s, 2 H, CH2), 6.37 (s, 1 H, HAr), 6.57 (br
s, 1 H, NH), 7.01 (s, 1 H, HAr), 7.29 (d, J = 8.1 Hz, 2 H, HTs), 7.68
(d, J = 8.1 Hz, 2 H, HTs).
IR (KBr): 3261, 2966, 1660, 1530, 1279, 1191, 1126, 1067, 1018,
784 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23 (s, 18 H, t-Bu), 1.98 (s, 3 H,
CH3), 4.21 (s, 4 H, CH2CH2), 5.30 (s, 1 H, CH), 5.86–5.89 (m, 4 H,
H
Fur), 6.57 (s, 1 H, HAr), 7.23 (br s, 1 H, NH), 7.28 (s, 1 H, HAr).
Anal. Calcd for C31H35NO6S: C, 67.74; H, 6.42; N, 2.55. Found: C,
67.87; H, 6.48; N, 2.51.
Anal. Calcd for C27H33NO5: C, 71.82; H, 7.37; N, 3.10. Found: C,
71.79; H, 7.41; N, 3.12.
Bis(5-tert-butyl-2-furyl)[4,5-(ethylenedioxy)-2-(tosylami-
no)phenyl]methane (5d)
White solid; yield: 1.53 g, (68%), mp 188–189 °C.
[2-(Benzoylamino)-4,5-dimethoxyphenyl]bis(5-tert-butyl-2-fur-
yl)methanes 7a,b; General Procedure
Substituted benzoyl chloride (12 mmol) was added to soln of 4 (7.3
mmol) in pyridine (12 mL). The mixture was left at r.t. for 1 h (for
7a) or was refluxed for 20 min (for 7b). Then, it was poured into ex-
cess H2O; the precipitate was filtered off, washed with H2O, dried,
and recrystallized (CH2Cl2–hexane).
IR (KBr): 3281, 2966, 1507, 1426, 1332, 1305, 1166, 1067, 1015,
914, 780, 667 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (s, 18 H, t-Bu), 2.42 (s, 3 H,
CH3), 4.17–4.24 (m, 4 H, CH2CH2), 4.78 (s, 1 H, CH), 5.69 (d,
J = 3.0 Hz, 2 H, HFur), 5.83 (d, J = 3.0 Hz, 2 H, HFur), 6.42 (s, 1 H,
HAr), 6.52 (br s, 1 H, NH), 7.00 (s, 1 H, HAr), 7.27 (d, J = 8.1 Hz, 2
H, HTs), 7.66 (d, J = 8.1 Hz, 2 H, HTs).
Bis(5-tert-butyl-2-furyl)[2-(4-methylbenzoylamino)-4,5-
dimethoxyphenyl]methane (7a)
White solid; yield: 3.36 g (87%); mp 149–151 °C.
IR (KBr): 3245, 2959, 1647, 1522, 1214, 1090, 1009, 778 cm–1.
Anal. Calcd for C32H37NO6S: C, 68.18; H, 6.62; N, 2.48. Found: C,
68.40; H, 6.74; N, 2.61.
1H NMR (300 MHz, CDCl3): d = 1.24 (s, 18 H, t-Bu), 2.41 (s, 3 H,
CH3), 3.77 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 5.48 (s, 1 H, CH),
5.90 (s, 4 H, HFur), 6.52 (s, 1 H, HAr), 7.20 (d, J = 8.0 Hz, 2 H, HBz),
7.56 (d, J = 8.0 Hz, 2 H, HBz), 7.71 (s, 1 H, HAr), 7.95 (s, 1 H, NH).
[2-(Acetylamino)phenyl]bis(5-tert-butyl-2-furyl)methanes 6a–
d; General Procedure
A mixture of 4 (13 mmol) in Ac2O (2.5 mL) was left at 55–60°C for
15 min. Then, it was poured into excess H2O; the precipitate was fil-
tered off, washed with H2O, and dried. Recrystallization (CH2Cl2–
hexane, 1:8) afforded compound 6.
Anal. Calcd for C33H39NO5: C, 74.83; H, 7.42; N, 2.64. Found: C,
74.91; H, 7.39; N, 2.69.
[2-(Acetylamino)phenyl]bis(5-tert-butyl-2-furyl)methane (6a)
White solid; yield: 2.71 g (53%); mp 135–136 °C.
Bis(5-tert-butyl-2-furyl)[2-(4-nitrobenzoylamino)-4,5-
dimethoxyphenyl]methane (7b)
White solid; yield: 2.49 g (61%); mp 199–200 °C.
IR (KBr): 3232, 2965, 1640, 1554, 1014, 783, 755 cm–1.
IR (KBr): 3247, 2963, 1651, 1527, 1346, 1218, 1091, 1013, 864,
777 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.22 (s, 18 H, t-Bu), 1.99 (s, 3 H,
CH3), 5.42 (s, 1 H, CH), 5.88–5.91 (m, 4 H, HFur), 7.07–7.10 (m, 2
H, HAr), 7.27–7.30 (m, 1 H, HAr), 7.47 (br s, 1 H, NH), 7.83–7.85
(m, 1 H, HAr).
1H NMR (300 MHz, CDCl3): d = 1.21 (s, 18 H, t-Bu), 3.81 (s, 3 H,
OCH3), 3.94 (s, 3 H, OCH3), 5.45 (s, 1 H, CH), 5.91 (d, J = 3.1 Hz,
2 H, HFur), 5.93 (d, J = 3.1 Hz, 2 H, HFur), 6.63 (s, 1 H, HAr), 7.74 (s,
1 H, HAr), 7.79 (d, J = 8.5 Hz, 2 H, HBz), 8.08 (s, 1 H, NH), 8.24 (d,
J = 8.5 Hz, 2 H, HBz).
Anal. Calcd for C25H31NO3: C, 76.30; H, 7.94; N, 3.56. Found: C,
76.46; H, 7.85; N, 3.60.
[2-(Acetylamino)-4,5-dimethoxyphenyl]bis(5-tert-butyl-2-fur-
yl)methane (6b)
Anal. Calcd for C32H36N2O7: C, 68.56; H, 6.47; N, 5.00. Found: C,
68.80; H, 6.61; N, 5.09.
White solid; yield: 3.36 g (57%); mp 122 °C.
1-[3-(5-tert-Butyl-2-furyl)-1-tosyl-1H-indol-2-yl]-4,4-dimethyl-
pentan-3-ones 8a–d; General Procedure
IR (KBr): 3294, 2968, 1658, 1533, 1257, 1208, 1103, 1014, 785
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23 (s, 18 H, t-Bu), 2.02 (s, 3 H,
CH3), 3.74 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 5.36 (s, 1 H, CH),
5.87–5.90 (m, 4 H, HFur), 6.55 (s, 1 H, HAr), 7.28 (br s, 1 H, NH),
7.37 (s, 1 H, HAr).
Ethanolic HCl (25 mL) [prepared by saturation of EtOH (200 g)
with HCl gas (100 g)] was added to a soln of 5 (4 mmol) in EtOH
(20 mL). The mixture was refluxed until all the starting compound
had been consumed (TLC monitoring). The mixture was poured
into H2O and the precipitate obtained was filtered off, washed with
H2O, and dried. Recrystallization (CH2Cl2–hexane, 1:3) afforded 8.
Anal. Calcd for C27H35NO5: C, 71.50; H, 7.78; N, 3.09. Found: C,
71.70; H, 7.69; N, 3.02.
1-[3-(5-tert-Butyl-2-furyl)-1-tosyl-1H-indol-2-yl]-4,4-dimethyl-
pentan-3-one (8a)
White solid; yield: 1.19 g (59%); mp 108–109 °C.
[2-(Acetylamino)-4,5-(methylenedioxy)phenyl]bis(5-tert-butyl-
2-furyl)methane (6c)
White solid; yield: 3.29 g (58%); mp 181–182 °C.
IR (KBr): 3247, 2963, 1650, 1534, 1480, 1243, 1043, 780 cm–1.
IR (KBr): 2966, 1703, 1523, 1450, 1371, 1346, 1172, 1086, 976,
819, 728, 663 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.21 (s, 9 H, t-Bu), 1.33 (s, 9 H, t-
Bu), 2.34 (s, 3 H, CH3), 3.05–3.13 (m, 2 H, CH2), 3.40–3.48 (m, 2
H, CH2), 6.09 (d, J = 3.2 Hz, 1 H, HFur), 6.44 (d, J = 3.2 Hz, 1 H,
1H NMR (300 MHz, CDCl3): d = 1.23 (s, 18 H, t-Bu), 2.01 (s, 3 H,
CH3), 5.33 (s, 1 H, CH), 5.86–5.90 (m, 4 H, HFur), 5.92 (s, 2 H, CH2),
6.52 (s, 1 H, HAr), 7.23 (s, 1 H, HAr), 7.27 (br s, 1 H, NH).
Synthesis 2008, No. 18, 2943–2952 © Thieme Stuttgart · New York

PAPER
Recyclization of (2-Aminophenyl)bis(5-tert-butyl-2-furyl)methanes
2949
HFur), 7.20 (d, J = 8.2 Hz, 2 H, HTs), 7.30–7.35 (m, 2 H, HAr), 7.66
(d, J = 8.2 Hz, 2 H, HTs), 7.79–7.83 (m, 1 H, HAr), 8.27–8.31 (m, 1
H, HAr).
13C NMR (50 MHz, CDCl3): d = 21.6, 22.4, 26.6 (3 C), 29.1 (3 C),
32.7, 37.8, 44.1, 103.7, 108.7, 113.5, 115.0, 120.3, 124.0, 124.7,
126.4 (2 C), 128.1, 130.0 (2 C), 136.0, 136.7 (2 C), 145.0, 145.8,
163.8, 214.9.
MS (EI, 70 eV): m/z (%) = 505 (5) [M+], 352 (16), 351 (84), 337
(19), 336 (100), 266 (24), 250 (18), 236 (43), 91 (32), 57 (54), 43
(33).
(d, J = 3.2 Hz, 1 H, HFur), 7.19 (d, J = 8.1 Hz, 2 H, HTs), 7.26 (s, 1
H, HInd), 7.64 (d, J = 8.1 Hz, 2 H, HTs), 7.83 (s, 1 H, HInd).
13C NMR (50 MHz, CDCl3): d = 21.6, 22.5, 26.6 (3 C), 29.0 (3 C),
32.8, 37.7, 44.1, 64.4, 64.6, 103.7, 103.9, 107.5, 108.4, 113.2,
122.4, 126.5 (2 C), 130.0 (2 C), 131.4, 136.0 (2 C), 141.6, 142.1,
144.9, 145.9, 163.6, 215.0.
MS (EI, 70 eV): m/z (%) = 563 (2) [M+], 410 (14), 409 (62), 395
(12), 394 (48), 310 (20), 294 (23), 149 (23), 91 (72), 57 (44), 43
(100).
Anal. Calcd for C32H37NO6S: C, 68.18; H, 6.62; N, 2.48. Found: C,
68.23; H, 6.70; N, 2.49.
Anal. Calcd for C30H35NO4S: C, 71.26; H, 6.98; N, 2.77. Found: C,
71.43; H, 6.93; N, 2.74.
1-[2-(4,4-Dimethyl-3-oxopentyl)-1H-indol-3-yl]-5,5-dimethyl-
hexane-1,4-diones 9a–d; General Procedure
1-[3-(5-tert-Butyl-2-furyl)-5,6-dimethoxy-1-tosyl-1H-indol-2-
yl]-4,4-dimethylpentan-3-one (8b)
White solid; yield: 1.40 g (62%); mp 138–139 °C.
A suspension of 6 (4.5 mmol) in ethanolic HCl (50 mL) [prepared
by saturation of EtOH (200 g) with HCl gas (100 g)] was left at r.t.
until all the starting compound had been consumed (TLC monitor-
ing). The mixture was poured into H2O and neutralized with
NaHCO3; the precipitate was filtered off, washed with H2O, and
dried. Compounds 9 were isolated by column chromatography (sil-
ica gel, 50–160 mm, hexane–acetone–CH2Cl2, 15:5:3) as a white
solid.
IR (KBr): 2961, 1701, 1489, 1365, 1307, 1157, 1059, 1013, 848,
783 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.20 (s, 9 H, t-Bu), 1.34 (s, 9 H, t-
Bu), 2.35 (s, 3 H, CH3), 2.99–3.07 (m, 2 H, CH2), 3.33–3.41 (m, 2
H, CH2), 3.93 (s, 3 H, OCH3), 4.00 (s, 3 H, OCH3), 6.09 (d, J = 3.2
Hz, 1 H, HFur), 6.39 (d, J = 3.2 Hz, 1 H, HFur), 7.19 (d, J = 8.2 Hz, 2
H, HTs), 7.35 (s, 1 H, HInd), 7.60 (d, J = 8.2 Hz, 2 H, HTs), 7.88 (s, 1
H, HInd).
1-[2-(4,4-Dimethyl-3-oxopentyl)-1H-indol-3-yl]-5,5-dimethyl-
hexane-1,4-dione (9a)
13C NMR (50 MHz, CDCl3): d = 21.6, 22.4, 26.5 (3 C), 29.1 (3 C),
32.7, 37.6, 44.1, 56.0, 56.4, 99.0, 102.1, 103.7, 108.2, 113.7, 121.2,
126.2 (2 C), 130.0 (2 C), 130.9, 135.0, 135.9, 144.9, 146.1, 147.4,
147.8, 163.5, 214.9.
MS (EI, 70 eV): m/z (%) = 565 (3) [M+], 412 (29), 411 (100), 397
(23), 396 (81), 326 (12), 313 (15), 312 (70), 297 (14), 296 (33), 92
(18), 91 (34), 57 (53).
White solid; yield: 0.70 g (42%); mp 135–136 °C.
IR (KBr): 3333, 2966, 1697, 1634, 1451, 1181, 1083, 994, 744
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.09 (s, 9 H, t-Bu), 1.24 (s, 9 H, t-
Bu), 2.99–3.06 (m, 4 H, CH2), 3.30–3.34 (m, 2 H, CH2), 3.37–3.41
(m, 2 H, CH2), 7.20–7.23 (m, 2 H, HInd), 7.34–7.37 (m, 1 H, HInd),
7.94–7.96 (m, 1 H, HInd), 9.27 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 22.4, 26.5 (3 C), 26.8 (3 C), 30.9,
36.1, 37.1, 44.2, 44.3, 111.5, 113.6, 120.9, 121.9, 122.4, 126.2,
134.8, 147.5, 195.6, 214.8, 217.4.
MS (EI, 70 eV): m/z (%) = 369 (19) [M+], 312 (35), 284 (55), 256
(15), 242 (19), 212 (17), 184 (23), 172 (33), 170 (32), 144 (29), 142
(38), 141 (100), 130 (29), 113 (70), 57 (76), 43 (34).
Anal. Calcd for C32H39NO6S: C, 67.94; H, 6.95; N, 2.48. Found: C,
68.16; H, 7.11; N, 2.51.
1-[3-(5-tert-Butyl-2-furyl)-5,6-(methylenedioxy)-1-tosyl-1H-
indol-2-yl]-4,4-dimethylpentan-3-one (8c)
White solid; yield: 1.34 g (61%); mp 104–105 °C.
IR (KBr): 2967, 1701, 1460, 1368, 1174, 1040, 666 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.20 (s, 9 H, t-Bu), 1.31 (s, 9 H, t-
Bu), 2.36 (s, 3 H, CH3), 3.01–3.09 (m, 2 H, CH2), 3.32–3.40 (m, 2
H, CH2), 6.01 (s, 2 H, CH2), 6.07 (d, J = 3.2 Hz, 1 H, HFur), 6.35 (d,
J = 3.2 Hz, 1 H, HFur), 7.19 (s, 1 H, HInd), 7.21 (d, J = 8.2 Hz, 2 H,
HTs), 7.63 (d, J = 8.2 Hz, 2 H, HTs), 7.82 (s, 1 H, HInd).
Anal. Calcd for C23H31NO3: C, 74.76; H, 8.46; N, 3.79. Found: C,
74.85; H, 8.51; N, 3.75.
1-[2-(4,4-Dimethyl-3-oxopentyl)-5,6-dimethoxy-1H-indol-3-yl]-
5,5-dimethylhexane-1,4-dione (9b)
White solid; yield: 0.98 g (51%); mp 148 °C.
13C NMR (50 MHz, CDCl3): d = 21.6, 22.5, 26.6 (3 C), 29.1 (3 C),
32.7, 37.8, 44.1, 96.8, 99.4, 101.4, 103.6, 108.4, 113.8, 122.4, 126.4
(2 C), 130.0 (2 C), 131.3, 135.5, 135.9, 145.0, 145.4, 145.8, 146.3,
163.7, 215.0.
MS (EI, 70 eV): m/z (%) = 549 (2) [M+], 396 (27), 395 (100), 381
(21), 380 (63), 310 (12), 296 (49), 281 (23), 280 (50), 91 (35), 57
(28), 43 (35).
IR (KBr): 3344, 2969, 1702, 1693, 1625, 1480, 1462, 1127, 1015,
856, 817, 756 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.09 (s, 9 H, t-Bu), 1.23 (s, 9 H, t-
Bu), 2.97–3.06 (m, 4 H, CH2), 3.21–3.26 (m, 2 H, CH2), 3.33–3.38
(m, 2 H, CH2), 3.91 (s, 3 H, OCH3), 3.96 (s, 3 H, OCH3), 6.86 (s, 1
H, HInd), 7.46 (s, 1 H, HInd), 9.07 (br s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 22.3, 26.4 (3 C), 26.7 (3 C), 30.8,
36.2, 36.6, 44.1 (2 C), 56.1, 56.5, 94.6, 103.5, 113.5, 119.1, 128.9,
145.5, 146.2, 146.9, 195.3, 215.2, 217.8.
Anal. Calcd for C31H35NO6S: C, 67.74; H, 6.42; N, 2.55. Found: C,
67.86; H, 6.50; N, 2.53.
MS (EI, 70 eV): m/z (%) = 429 (36) [M+], 344 (14), 288 (13), 272
(10), 244 (12), 204 (16), 190 (15), 141 (85), 113 (48), 58 (100), 57
(54).
1-[3-(5-tert-Butyl-2-furyl)-5,6-(ethylenedioxy)-1-tosyl-1H-
indol-2-yl]-4,4-dimethylpentan-3-one (8d)
White solid; yield: 1.46 g (65%), mp 86–87 °C.
Anal. Calcd for C25H35NO5: C, 69.90; H, 8.21; N, 3.26. Found: C,
69.96; H, 8.05; N, 3.11.
IR (KBr): 2965, 1703, 1584, 1462, 1365, 1330, 1161, 1068, 662
cm–1.
1H NMR (200 MHz, CDCl3): d = 1.20 (s, 9 H, t-Bu), 1.31 (s, 9 H, t-
Bu), 2.33 (s, 3 H, CH3), 3.02–3.09 (m, 2 H, CH2), 3.35–3.42 (m, 2
H, CH2), 4.29 (s, 4 H, CH2CH2), 6.06 (d, J = 3.2 Hz, 1 H, HFur), 6.38
1-[2-(4,4-Dimethyl-3-oxopentyl)-5,6-(methylenedioxy)-1H-
indol-3-yl]-5,5-dimethylhexane-1,4-dione (9c)
White solid; yield: 1.04 g (56%); mp 122 °C.
Synthesis 2008, No. 18, 2943–2952 © Thieme Stuttgart · New York

2950
A. V. Butin et al.
PAPER
1-[3-(5-tert-Butyl-2-furyl)-5,6-dimethoxy-1H-indol-2-yl]-4,4-
IR (KBr): 3359, 2969, 1697, 1643, 1461, 1036, 946, 833 cm–1.
dimethylpentan-3-one (12b)
1H NMR (300 MHz, CDCl3): d = 1.09 (s, 9 H, t-Bu), 1.23 (s, 9 H, t-
Bu), 2.95–3.04 (m, 4 H, CH2), 3.17–3.22 (m, 2 H, CH2), 3.29–3.34
(m, 2 H, CH2), 5.95 (s, 2 H, CH2), 6.80 (s, 1 H, HInd), 7.40 (s, 1 H,
HInd), 9.05 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 22.6, 26.4 (3 C), 26.8 (3 C), 30.8,
36.1, 36.6, 44.1, 44.2, 92.3, 100.3, 100.9, 113.9, 120.2, 129.5,
144.4, 144.6, 145.5, 195.1, 215.2, 217.5.
MS (EI, 70 eV): m/z (%) = 413 (62) [M+], 328 (30), 272 (24), 256
(15), 188 (18), 174 (37), 149 (12), 142 (20), 141 (100), 113 (76), 57
(75), 43 (44).
Compound 8b (1.13 g, 2 mmol) was added to soln of KOH (5.6 g,
100 mmol) in MeOH (23 mL) and the mixture was refluxed for 4 h.
When the reaction was complete (TLC), the mixture was poured
into H2O (200 mL) and the product was extracted with CH2Cl2 (4 ×
50 mL). The combined organic layers were washed with H2O (3 ×
100 mL) and dried (anhyd Na2SO4). The solvent was evaporated un-
der reduced pressure and the residue was recrystallized (CH2Cl2–
hexane, 1:10) to give a white solid; yield: 0.50 g (61%); mp 140–
141 °C.
IR (KBr): 3356, 2964, 1704, 1488, 1456, 1336, 1220, 1200, 1188,
1132, 1008 cm–1.
Anal. Calcd for C24H31NO5: C, 69.71; H, 7.56; N, 3.39. Found: C,
69.86; H, 7.51; N, 3.46.
1H NMR (300 MHz, CDCl3): d = 1.12 (s, 9 H, t-Bu), 1.39 (s, 9 H, t-
Bu), 2.96–3.00 (m, 2 H, CH2), 3.19–3.23 (m, 2 H, CH2), 3.90 (s, 3
H, OCH3), 3.95 (s, 3 H, OCH3), 6.08 (d, J = 3.1 Hz, 1 H, HFur), 6.27
(d, J = 3.1 Hz, 1 H, HFur), 6.83 (s, 1 H, HInd), 7.36 (s, 1 H, HInd), 8.53
(br s, 1 H, NH).
1-[2-(4,4-Dimethyl-3-oxopentyl)-5,6-(ethylenedioxy)-1H-indol-
3-yl]-5,5-dimethylhexane-1,4-dione (9d)
White solid; yield: 0.94 g, (49%); mp 142–143 °C.
13C NMR (75 MHz, CDCl3): d = 21.3, 26.5 (3 C), 29.2 (3 C), 32.7,
36.9, 44.2, 56.2, 56.3, 94.4, 101.9, 103.2, 104.1, 104.9, 118.8,
129.4, 134.2, 145.1, 146.7, 149.1, 161.8, 217.4.
IR (KBr): 3341, 2969, 1699, 1689, 1624, 1459, 1338, 1161, 1063,
1010, 934, 878 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.07 (s, 9 H, t-Bu), 1.22 (s, 9 H, t-
Bu), 2.94–3.01 (m, 4 H, CH2), 3.18–3.23 (m, 2 H, CH2), 3.28–3.33
(m, 2 H, CH2), 4.26 (s, 4 H, CH2CH2), 6.80 (s, 1 H, HInd), 7.38
(s, 1 H, HInd), 9.07 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 22.5, 26.5 (3 C), 26.8 (3 C), 30.7,
36.0, 36.7, 44.1, 44.2, 64.3, 64.6, 98.8, 108.1, 113.0, 120.6, 129.9,
140.3, 140.8, 147.2, 195.1, 214.9, 217.5.
MS (EI, 70 eV): m/z (%) = 427 (32) [M+], 342 (20), 242 (10), 202
(18), 188 (17), 149 (14), 142 (16), 141 (100), 113 (46), 57 (48), 43
(40).
MS (EI, 70 eV): m/z (%) = 411 (100) [M+], 396 (42), 57 (70).
Anal. Calcd for C25H33NO4: C, 72.96; H, 8.08; N, 3.40. Found: C,
73.01; H, 8.09; N, 3.42.
1-[3-(5-tert-Butyl-2-furyl)-5,6-dimethoxy-1-(4-methylbenzoyl)-
1H-indol-2-yl]-4,4-dimethylpentan-3-one (13a); Typical Proce-
dure
To a soln of 7a (0.9 g, 1.7 mmol) in AcOH (30 mL) was added 35%
HCl with cooling. The mixture was stirred at 30°C for 7 h, then it
was poured into excess H2O and NaHCO3 was added until the pH
was neutral. The product was extracted with CH2Cl2 (3 × 50 mL).
The combined organic extracts were dried (Na2SO4), filtered, and
evaporated. The residue was purified by column chromatography
(silica gel 50/160, acetone–CH2Cl2–hexane, 5:3:20) to give a white
solid; yield: 0.49 g (55%); mp 112–113 °C.
Anal. Calcd for C25H33NO5: C, 70.23; H, 7.78; N, 3.28. Found: C,
70.36; H, 7.71; N, 3.30.
1-[2-(4,4-Dimethyl-3-oxopentyl)-5,6-dimethoxy-1H-indol-3-yl]-
5,5-dimethylhexane-1,4-dione (9b)
From 4b
IR (KBr): 2959, 1692, 1488, 1366, 1320, 1299, 1160, 1103, 829,
781, 747 cm–1.
35% HCl (7 mL) was added to a cooled soln (10–12 °C) of 4b (1.0
g, 2.4 mmol) in AcOH (25 mL). The mixture was left at r.t. for 24
h. When the reaction was complete (TLC), the mixture was poured
into H2O, neutralized with NaHCO3, and extracted with CH2Cl2 (3
× 50 mL). The extract was dried (anhyd Na2SO4) and evaporated to
dryness. Compound 9b was isolated as described above; yield: 0.44
g (43%).
1H NMR (300 MHz, CDCl3): d = 1.12 (s, 9 H, t-Bu), 1.38 (s, 9 H, t-
Bu), 2.46 (s, 3 H, CH3), 2.97–3.02 (m, 2 H, CH2), 3.20–3.25 (m, 2
H, CH2), 3.56 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 6.13 (d, J = 3.1
Hz, 1 H, HFur), 6.40 (s, 1 H, HInd), 6.46 (d, J = 3.1 Hz, 1 H, HFur),
7.31 (d, J = 7.8 Hz, 2 H, HBz), 7.42 (s, 1 H, HInd), 7.65 (d, J = 7.8 Hz,
2 H, HBz).
13C NMR (75 MHz, CDCl3): d = 21.8, 22.4, 26.5 (3 C), 29.2 (3 C),
32.8, 36.9, 44.1, 55.7, 56.1, 98.3, 101.9, 103.7, 107.4, 111.7, 120.2,
129.5 (2 C), 130.2 (2 C), 130.6, 132.5, 135.7, 144.1, 146.4, 146.6,
146.9, 163.2, 169.4, 214.7.
{2-[(Acetyl)(methyl)amino]-4,5-dimethoxyphenyl}bis(5-tert-
butyl-2-furyl)methane (10b)
NaH (0.24 g, 60% dispersion in mineral oil) was added at 15 °C to
soln of 6b (2.27 g, 5 mmol) in THF (25 mL). The mixture was
stirred for 15 min and MeI (0.5 mL, 6.25 mmol) was added to the
resulting suspension. Mixture was stirred at r.t. for 40 min (TLC),
then filtered and evaporated to dryness. Residue was dissolved in
EtOAc– petroleum ether (2:1) and filtered through a pad of silica
gel (5–40 mm). Solvents were evaporated to ca. 40 mL. The result-
ing soln was left until the product 10b crystallized as a white solid;
yield: 2.24 g (96%); mp 171–172 °C.
MS (EI, 70 eV): m/z (%) = 529 (9) [M+], 119 (100), 91 (37), 57 (20).
Anal. Calcd for C33H39NO5: C, 74.83; H, 7.42; N, 2.64. Found: C,
75.14; H, 7.47; N, 2.69.
1-[3-(5-tert-Butyl-2-furyl)-5,6-dimethoxy-1-(4-nitrobenzoyl)-
1H-indol-2-yl]-4,4-dimethylpentan-3-one (13b)
Following the typical procedure for 13a but the mixture was stirred
at 30°C for 1.5 h. Then it was poured into excess H2O and NaHCO3
was added until the pH was neutral. The product was filtered off and
recrystallized (aq EtOH) to give a pale-yellow solid; yield: 0.50 g
(52%); mp 145 °C.
IR (KBr): 2964, 1664, 1516, 1460, 1368, 1252, 1196, 1128, 1016,
796, 784 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.17 (s, 9 H, t-Bu), 1.21 (s, 9 H, t-
Bu), 1.84 (s, 3 H, CH3), 3.18 (s, 3 H, NCH3), 3.80 (s, 3 H, OCH3),
3.85 (s, 3 H, OCH3), 5.36 (s, 1 H, CH), 5.81–5.90 (m, 4 H, HFur),
6.60 (s, 1 H, HAr), 6.91 (s, 1 H, HAr).
IR (KBr): 2963, 1685, 1526, 1490, 1307, 1189, 1160, 1104, 1013,
868, 790 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.09 (s, 9 H, t-Bu), 1.39 (s, 9 H, t-
Bu), 2.92–2.97 (m, 2 H, CH2), 3.18–3.23 (m, 2 H, CH2), 3.57 (s, 3
Anal. Calcd for C28H37NO5: C, 71.92; H, 7.98; N, 3.00. Found: C,
72.01; H, 8.06; N, 2.97.
Synthesis 2008, No. 18, 2943–2952 © Thieme Stuttgart · New York

PAPER
Recyclization of (2-Aminophenyl)bis(5-tert-butyl-2-furyl)methanes
2951
H, OCH3), 3.94 (s, 3 H, OCH3), 6.16 (d, J = 3.2 Hz, 1 H, HFur), 6.43
(s, 1 H, HInd), 6.49 (d, J = 3.2 Hz, 1 H, HFur), 7.41 (s, 1 H, HInd), 7.95
(d, J = 8.5 Hz, 2 H, HBz), 8.36 (d, J = 8.5 Hz, 2 H, HBz).
13C NMR (75 MHz, CDCl3): d = 29.1 (3 C), 32.7, 56.0, 56.1, 94.1,
97.7, 101.9, 104.0, 104.6, 121.7, 128.5, 130.3, 145.2, 146.0, 147.0,
163.2.
MS (EI, 70 eV): m/z (%) = 560 (11) [M+], 150 (17), 104 (17), 57
(100).
MS (EI, 70 eV): m/z (%) = 299 (39) [M+], 285 (31), 284 (100), 269
(12), 241 (11), 240 (23), 226 (13), 155 (12), 142 (18), 101 (23), 89
(17), 82 (15), 59 (47), 43 (35).
Anal. Calcd for C32H36N2O7: C, 68.56; H, 6.47; N, 5.00. Found: C,
68.52; H, 6.50; N, 4.97.
Anal. Calcd for C18H21NO3: C, 72.22; H, 7.07; N, 4.68. Found: C,
72.31; H, 7.04; N 4.72.
1-(5-tert-Butyl-2-furyl)-2-(3,4-dimethoxyphenyl)ethan-1-one
(15)
Acknowledgment
Homoveratric acid (14) (4 g, 20 mmol) and 2-tert-butylfuran (2)
(2.73 g, 22 mmol) were added to soln of PPSE in CHCl3 (50 mL).
The mixture was refluxed with stirring for 40 min (TLC), then
poured into H2O (300 mL), stirred, and extracted with CH2Cl2
(3 × 40 mL). The combined extracts were dried (Na2SO4), filtered,
and evaporated to dryness under reduced pressure. The obtained oil
was dissolved in hexane, the soln was filtered through a pad of silica
gel and left until crystallization of the product as colorless needles;
yield: 2.90 g (48%); mp 75–76 °C.
Financial support was provided by the Russian Foundation of
Basic Research (grant 07-03-00352) and Bayer HealthCare AG
(Germany).
References
(1) (a) Gabrielyan, G. E.; Papayan, G. L. Arm. Khim. Zh. 1973,
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2,001,007,434, 2001; Chem. Abstr. 2001, 134, 131549.
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IR (KBr): 1668, 1589, 1513, 1465, 1358, 1268, 1233, 1157, 1046,
1026, 955, 859, 810, 782, 710 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.34 (s, 9 H, t-Bu), 3.85 (s, 3 H,
OCH3), 3.89 (s, 3 H, OCH3), 4.01 (s, 2 H, CH2), 6.14 (d, J = 3.5 Hz,
1 H, HFur), 6.81 (d, J = 8.6 Hz, 1 H, HAr), 6.86 (s, 1 H, HAr), 6.87 (d,
J = 8.6 Hz, 1 H, HAr), 7.13 (d, J = 3.5 Hz, 1 H, HFur).
Anal. Calcd for C18H22O4: C, 71.50; H, 7.33. Found: C, 71.61; H,
7.39.
1-(5-tert-Butyl-2-furyl)-2-(3,4-dimethoxy-2-nitrophenyl)ethan-
1-one (16)
Fuming HNO3 (4.8 mL) was added dropwise to a soln of a ketone
15 (7 g, 23 mmol) in AcOH (60 mL) at 0 °C. The mixture was main-
tained at 0 °C for 10 min and at r.t. for 20 min. Then it was poured
into ice and the residue that separated was filtered off and washed
with aq NaHCO3 soln until pH 7 was reached. Recrystallization
(hexane) afforded 16 as pale-yellow needles; yield: 6.50 g (81%);
mp 119–120 °C.
IR (KBr): 1667, 1582, 1525, 1466, 1330, 1275, 1234, 1071, 1051,
1013, 953, 876, 795 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.36 (s, 9 H, t-Bu), 3.97 (s, 6 H,
OCH3), 4.54 (s, 2 H, CH2), 6.20 (d, J = 3.5 Hz, 1 H, HFur), 6.77 (s, 1
H, HAr), 7.21 (d, J = 3.5 Hz, 1 H, HFur), 7.75 (s, 1 H, HAr).
Anal. Calcd for C18H21NO6: C, 62.24; H, 6.09; N, 4.03. Found: C,
62.35; H, 6.18; N, 4.09.
2-(5-tert-Butyl-2-furyl)-5,6-dimethoxy-1H-indole (17)
The mixture of ketone 16 (1.04 g, 3 mmol), Fe (3 g), AcOH (1 mL),
EtOAc (10 mL), and H2O (10 mL) was refluxed for 10–20 min
(TLC). The mixture was cooled and neutralized with NaHCO3; iron
was filtered off. The organic layer was separated from the obtained
mixture, the aqueous layer was extracted with EtOAc (3 × 50 mL).
The combined organic fractions were dried (Na2SO4) and evaporat-
ed to dryness. Compound 17 was isolated by column chromatogra-
phy (silica gel, 5–40 mm, hexane–CH2Cl2, 10:1) as a white solid;
yield: 0.52 g (58%); mp 156 °C.
(4) Butin, A. V.; Gutnov, A. V.; Abaev, V. T.; Krapivin, G. D.
Molecules 1999, 4, 52.
(5) (a) Butin, A. V.; Smirnov, S. K.; Stroganova, T. A.
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Tetrahedron 2007, 63, 9437. (b) Butin, A. V.; Dmitriev, A.
S.; Kostyukova, O. N.; Abaev, V. T.; Trushkov, I. V.
Synthesis 2007, 2208.
IR (KBr): 3364, 2964, 1458, 1326, 1250, 1217, 1132, 1030, 1009,
851, 782, 543 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.34 (s, 9 H, t-Bu), 3.89 (s, 3 H,
OCH3), 3.92 (s, 3 H, OCH3), 6.04 (d, J = 2.7 Hz, 1 H, HFur), 6.40 (d,
J = 2.7 Hz, 1 H, HFur), 6.58 (s, 1 H, HInd), 6.87 (s, 1 H, HInd), 7.03 (s,
1 H, HInd), 8.34 (br s, 1 H, NH).
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43, 1195. (b) Butin, A. V.; Dmitriev, A. S.; Uchuskin, M. G.;
Abaev, V. T.; Trushkov, I. V. Synth. Commun. 2008, 38,
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Synthesis 2008, No. 18, 2943–2952 © Thieme Stuttgart · New York

2952
A. V. Butin et al.
PAPER
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Synthesis 2008, No. 18, 2943–2952 © Thieme Stuttgart · New York