From 4,5,6,7-tetrahydroindole to functionalized furan-2-one-4,5,6,7- tetrahydroindole-cyclobutene sequence in two steps

Article abstract of DOI:10.1016/j.tet.2011.05.018

Ethyl 3-(4,5,6,7-tetrahydroindol-2-yl)propynoate, readily available from 4,5,6,7-tetrahydroindole and ethyl bromopropynoate, when treated with dichlorodicyanobenzoquinone (DDQ) in methanol affords furan-2-one-4,5,6,7- tetrahydroindole-cyclobutene sequence

Full text of DOI:10.1016/j.tet.2011.05.018

Tetrahedron 67 (2011) 4832e4837
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
From 4,5,6,7-tetrahydroindole to functionalized furan-2-onee
4,5,6,7-tetrahydroindoleecyclobutene sequence in two steps
Lyubov N. Sobenina a, Zinaida V. Stepanova a, Igor’ A. Ushakov a, Al’bina I. Mikhaleva a, Denis N. Tomilin a,
,
Ol’ga N. Kazheva b, Grigorii G. Alexandrovc, Oleg A. Dyachenko b, Boris A. Trofimov a
*
a A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russian Federation
b Institute of Problems of Chemical Physics, Russian Academy of Sciences, 1 Academician N. N. Semenov Str., 142432 Chernogolovka, Russian Federation
c N. S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 31 Leninskii Prosp., 119991 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Ethyl 3-(4,5,6,7-tetrahydroindol-2-yl)propynoate, readily available from 4,5,6,7-tetrahydroindole and
ethyl bromopropynoate, when treated with dichlorodicyanobenzoquinone (DDQ) in methanol affords
furan-2-onee4,5,6,7-tetrahydroindoleecyclobutene sequence in a 52% yield. As kinetic and minor
products, a furan-2-one isomer along with bicycloheptadienone have been either isolated or identified.
The reaction has been shown to proceed via the isolable intermediate the [2þ2]-cycloadduct of ethyl
3-(4,5,6,7-tetrahydroindol-2-yl)propynoate with DDQ. Other alcohols react with the [2þ2]-cycloadduct
in a similar way. The effect of the alcohol structure on the products ratio has been analyzed. All the
intermediates and products are formed as single diastereomer, thus indicating a concerted character of
the rearrangement.
Received 25 February 2011
Received in revised form 13 April 2011
Accepted 5 May 2011
Available online 12 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
view, such as chlorophyll, hemoglobin, vitamin B12, alkaloids and
others, which play a pivotal role in the accumulation of solar
Functionalized multicyclic sequence, which combine funda-
mentally important heterocyclic systems in one molecule represent
rewarding targets for medicinal and material chemistry as well as
methodology of organic synthesis. The functionalized furan-2-
onee4,5,6,7-tetrahydroindole-cyclobutene sequence belongs to
such group of compounds.
energy, oxygen transfer processes, and other life-sustaining
reactions.9
At the present time, the exhaustively substituted cyclobutenes
still remain rare and exotic compounds, albeit, some of them have
been successfully involved as key intermediates in Corey’s brefeldin
A synthesis.10
The furanone moiety is known to be a common structural unit of
numerous pharmaceutically important compounds (anti-AIDS
drugs, such as d4T [1-(2,3-dideoxy-g-D-glyceropent-2-enofur-
The combination of furan-2-one, 4,5,6,7-tetrahydroindole, and
cyclobutene moieties in a one molecule may result in synergism of
properties of these important chemical structures and substantially
expand the fields of application of the newly synthesized func-
tionalized compounds as effective building blocks for organic and
medicinal chemistry.
anosyl)thymine] and AZT {1-[4-azido-5-(hydroxymethyl)tetrahy-
drofuran-2-yl]-5-methyl-pyrimidine-2,4-(1H,3H)-dione},1 vitamin
C,2 tetronic acids, and their thiol analogues3). This fragment occurs
in cardenolides4 (cardioactive steroid lactones), dysidiolidedthe
only known natural inhibitor of a protein phosphatase cdc25A5das
well as in a great variety of other natural molecules, such as ses-
terterpenes6 and pulvinic acid derivatives.7 In strigol and its ana-
logues, the furanone part is primarily responsible for the
germination of seeds.8
However a short-cut to such diversified and multicyclic mole-
cules represents a challenge for organic synthesis.
2. Results and discussion
Here we report on a two-step reaction sequence, which leads to
densely functionalized compounds comprising all the above-
mentioned heterocyclic systems.
The indole and pyrrole scaffolds are also frequently met in many
fundamental compounds, important from the biological point of
For the synthesis, only the available 4,5,6,7-tetrahydroindole 111
and a newly discovered12 though well-elaborated ethynylation of
the pyrrole ring are required. Ethyl 3-(4,5,6,7-tetrahydroindol-2-yl)
propynoate 2 when treated with DDQ in methanol afforded the
* Corresponding author. Tel./fax: þ7 39524193 46; e-mail address: boris_trofimov@
irioch.irk.ru (B.A. Trofimov).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.018

L.N. Sobenina et al. / Tetrahedron 67 (2011) 4832e4837
4833
furan-2-one 3a in 52% yield (Scheme 1). As minor products furan-2-
one 4a and bicycloheptadienone 5a were formed (Scheme 1).
In the beginning of the rearrangement, the 4a/3a isomers ratio
was in favor of isomer 4a and then changes with time in favor of
isomer 3a: 1.7 (15 min), 1.4 (30 min), 1.2 (60 min), 0.8 (90 min), and
0.7 (120 min). Thus, the isomer 4a appears to be a kinetic product
and isomer 3a is a thermodynamic one. This becomes particularly
clear upon the attempted separation of these two isomers. When
the isomers mixture (3a/4a¼1:8) was chromatographed (SiO2 col-
umn, eluent CH2Cl2, 1 h), almost pure (98% purity) isomer 3a was
isolated, the mass of the sample remaining close to the initial one.
Obviously, the formation of furan-2-ones 3 and 4 represents
a typical domino process (Scheme 5), triggered by the addition of
methanol to the carbonyl group adjacent to the position 3 of the
cyclobutene ring. The hemiacetal A attacks by its hydroxyl group the
opposite carbonyl function (at carbon atom C5) and in hemiacetal B,
thus formed, the cleavage of the C4eC5 bond occurs. This is
accompanied by the simultaneous proton transfer from hydroxyl to
anionic carbon atom C4 to finally give the labile (kinetic) isomer 4.
Cl
Cl
O
O
O
Br
(DDQ)
NC CN
MeOH, (ii)
OEt
O
N
H
N
H
(i)
OEt
2
1
O
Cl
OMe
Cl
MeO
NC
O
NC
Cl
CN
Cl
O
+
N
H
+
O
Cl
N
H
O
N
H
OMe
CN
OEt
O
O
CN
OEt
CN
OEt
O
4a
O
5a
3a
(i) K2CO3, rt, 1 h;
(ii) rt, 32 h
Scheme 1.
Apparently, the [2þ2]-cycloadduct of ethyl 3-(4,5,6,7-tetrahy-
droindol-2-yl)propynoate 2 with DDQ 6 is the intermediate of this
reaction (Scheme 2).
OH
O
7 Cl
MeO
NC
N
Cl
NC
8
6
MeOH
Cl
Cl
3
4
5
N
H
O
H
O
CN
OEt
CN
O
O
OEt
6
A
Cl
Cl
O
Cl
Cl
Cl
Cl
O
O
O
MeO
NC
N
Cl
Cl
O H
NC
MeO
NC
N
8
NC CN
MeOH
N
H
O
O
2
3
O
4
CN
OEt
H
O
6
H
CN
H
4
CN
O
O
O
OEt
OEt
B
Scheme 2.
Cl
Cl
O
CN
O
Recently, we have shown13 that the cycloadducts of the type 6
(the cycloadducts 8) can be isolated in almost quantitative yields
when 2-ethynylpyrroles 2,7 are allowed to contact with DDQ in
aprotic solvent (benzene, acetone) at room temperature (Scheme 3).
MeO
Cl
8
NC
8
3
O
O
3
4
N
H
4
Cl
N
H
H
OMe
CN
OEt
CN
O
3
OEt
Scheme 5.
R2
R1
R2
R1
O
Cl
Cl
Cl
Cl
NC
The latter (as follows from experiment) rearranges to the more
stable (thermodynamic) isomer 3. Although this rearrangement
might be rationalized as proceeding via the cleavage of the C3eC8
and C4-H bonds and the concerted formation of the C4eC8 and
C3-H bonds, the activation energy of such a process (if not con-
certed) is expected to be high. Meanwhile, the alternative pathway
for the formation of 3 can also be envisaged. Indeed, if methanol
attacks another carbonyl group of compound 6, followed by a sim-
ilar sequence of steps as shown in Scheme 5, compound 3 will be
formed directly (Scheme 6). However, initially as shown above
product 4 is formed in a larger quantity than its isomer 3. If the
fragmentation B/4 is reversible, the isomerization 4/3 could be
understood without admitting the concerted process (Scheme 5).
O
O
O
N
H
N
H
O
NC CN
R3
CN
R3
O
6,8
2,7
benzene or acetone,
rt, 5-10 min
7,8: R1 = Ph, 4-ClC6H4, 4-MeOC6H4, R2 = H;
R1-R2 = (CH2)4; R3 = Ph, 4-NO2C6H4
Scheme 3.
Upon ethanolysis the cycloadducts 8 rearranged mostly to
bicycloheptadienones, but furan-2-ones of the type 3 were identi-
fied by 1H NMR only (though in case of tetrahydroindole derivative
2 this compound was isolated in a larger quantitative yield that
made it possible to grow a single crystal for X-ray analysis), while
furan-2-ones of the type 4 were not detected at all.14
Here it has been revealed that the [2þ2]-cycloadduct 6 upon
action of methanol (rt, 24 h or 55e56 ꢀC, 15 min) did rearrange to
the furan-2-one 3a as a major product, the minor ones being iso-
meric furan-2-one 4a and bicycloheptadienone 5a. (Scheme 4)
Cl
O
O
Cl
MeOH
NC
NC
8
Cl
OMe
OH
Cl
3
4
5
1
N
H
N
H
2
O
CN
CN
OEt
O
O
R3
6
O
Cl
Cl
O
Cl
O
NC
Cl
Cl
NC
NC
MeOH
O
3
5
N
H
3a + 4a + 5a
O
Cl
OMe
4
N
H
H
O
N
H
CN
OEt
OMe
O
CN
OEt
6
O
CN
OEt
O
Scheme 4.
Scheme 6.

4834
L.N. Sobenina et al. / Tetrahedron 67 (2011) 4832e4837
The structure of furan-2-one of type 3 was previously un-
passed through the silica gel column (eluent CH2Cl2), the complete
rearrangement 9/10 took place. Evidently, in this case, the in-
termediate hemiacetal C rearranges via the cleavage of the C3eC8
bond with simultaneous proton transfer from hydroxyl group to C3
anionic atom to deliver the open-chained ester 9. The latter is
further transformed to its cyclic isomer 10 via the proton abstrac-
tion from the position 3 (under the action of iso-propanol as a base)
followed by the nucleophilic attack at the opposite CeCl bond to
release chlorine anion as a good fugitive group.
ambiguously established by a single crystal X-ray analysis.14 Here,
all the spectral data (1H, 13C NMR, HMBC, HSQC) for isomer 3a are in
agreement with those determined for the tricyclic compounds of
the type 3. For isomer 4a, in the 13C NMR spectra signals of the
carbon atoms C3 and C4 in the cyclobutene ring (49.1 and
35.8 ppm) and those of the two carbonyl carbons at 162.0 and
160.4 ppm were observed. In the 1H NMR spectrum of furanone 4a
the proton of the cyclobutene ring appeared at 4.30 ppm and dis-
played long range correlations (2D HMBC) with the carbon atoms at
49.1, 104.7, 105.3, 114.1 (CN), and 144.8 (C2 of pyrrole ring). The
NOEs between this proton and the protons of the OCH3 (3.45 ppm)
and OCH2 groups were observed in the 2D NOESY spectrum.
The structure of bicycloheptadienone 5a including its relative
stereochemistry and preferred conformation in crystal state has
been determined by its single crystal X-ray analysis (Fig. 1). Also,
the 1H and 13C NMR spectra entirely support the structure of
bicycloheptadienone 5a.
i-Pr
O
H
O
7
Cl
8
NC
i-PrOH
3
6
5
6 Cl
4
N
H
O
CN
OEt
O
C
i-Pr
O
i-Pr
O
O
NC
Cl
O
NC
Cl
Cl
N
H
N
H
-HCl
O
O
CN
OEt
CN
OEt
O
O
9
10
Scheme 8.
tert-Butanol did not react with [2þ2]-cycloadduct 6 under
even harsher conditions (reflux, 2 h). In this case, instead of the
expected products, a new unstable furan-2-onee4,5,6,7-tetrahy-
droindoleecyclobutene 11 with hydroxy group in place of tert-
butoxy substituent has been isolated in 24% yield that may result
from similar reactions with trace water (Scheme 9). Such an as-
sumption is supported by the isolation of the same cyclic hemi-
acetal from the reaction of cycloadduct 6 with water in dioxane
(reflux, 2 h).
O
Cl
Cl
CN
O
H2O
N
H
6
t-BuOH
OH
CN
O
Fig. 1. X-ray crystal structure of bicycloheptadienone 5a.
OEt
11
Scheme 9.
In the transformation depicted by Schemes 1e9, the free NH-
indole function plays obviously an important if not a key role
since the N-methyl- (12a) and N-benzyl- (12b) protected conge-
ners of [2þ2]-cycloadducts do not form furan-2-ones, only the
bicycloheptadienones 13a,b being isolated in moderate yields
(Scheme 10). This implies a hydrogen bonding effect with the
participation of NH and carbonyl functions that may fix favorable
conformations and facilitate the proton transfers. Apart from
bicycloheptadienones 13a,b, the reaction mixtures contained also
their precursors 14a,b. The latter is transformed on SiO2 to bicy-
cloheptadienones 13a,b.
Similarly, [2þ2]-cycloadduct 6 reacted with ethanol and n-
propanol (Scheme 7), though as preliminary reported,14 with eth-
anol the 3b/5b ratio was almost the same. The yields of compounds
3c and 5c, the products of rearrangements of cycloadduct 6 in
n-propanol (55e56 ꢀC, 2 h), were 55% and 2%, correspondingly.
The isomer 4c was detected in the initial stage of the reaction only
(1H NMR).
Cl
O
OR
O
RO
NC
Cl
Cl
Cl
CN
NC
ROH
Cl
O
6
+
+
O
N
H
N
H
O
N
H
O
OR
CN
OEt
CN
OEt
4b,c
O
CN
OEt
O
O
3. Conclusion
3b,c
5b,c
R = Et (b), n-Pr (c)
Scheme 7.
OEt
OEt
Cl
Cl
O
NC
O
O
Cl
Cl
O
NC
Cl
NC
EtOH
+
N
R
N
R
N
R
O
O
CN
OEt
CN
OEt
O
CN
OEt
O
O
14a,b
12a,b
13a,b
The reaction of [2þ2]-cycloadduct 6 with iso-propanol (rt, 7
days or 55e56 ꢀS, 2 h) led to the mixture of open-chained ester 9
and bicycloheptadienone 10 (Scheme 8). The ester 9 appeared to be
the precursor of its cyclic isomer: when their 1:1 mixture was
R = Me (a), Bn (b)
Scheme 10.

L.N. Sobenina et al. / Tetrahedron 67 (2011) 4832e4837
4835
An efficient two-step methodology for the diastereoselective syn-
thesis of the polyfunctionalized linked-tricyclic systems comprising
4,5,6,7-tetrahydroindole, alkoxycarbonyldicyanocyclobutene, and
dichloroalkoxyfuran-2-one moieties has been developed. The
methodology includes the transition metal-free coupling of now
readily available 4,5,6,7-tetrahydroindole and ethyl bromopropy-
noate followed by the three component domino reaction between
ethyl 3-(4,5,6,7-tetrahydroindol-2-yl)propynoate, dichlorodicyano-
benzoquinone, and alcohols under mild conditions (20e56 ꢀC). Apart
from the major compounds, furan-2-onee4,5,6,7-tetrahydroindolee
cyclobutenes, as minor products, bicycloheptadienones and their
precursors have been isolated. As the pivotal intermediate of the
methodology, [2þ2]-cycloadduct of 2-ethynyl-4,5,6,7-tetrahy-
droindole and DDQ, is isolable which further undergoes the domino
type alcoholysis and rearrangements. All the isolated and identified
products represent single diastereomers thus indicating the con-
certed character of the cleavage and formation of the CeC- and CeH-
bonds involved into the domino reactions.
mixture of furanones 3a (41%) and 4a (59%). This mixture was
passed through column with SiO2 (le60 cm, eluentdCH2Cl2) to
afford 0.025 g of furanone 3a, the purity is 96%, the impurity is
furanone 4a. The residue after removing methanol (0.061 g) con-
taining furanone 3a (39%), furanone 4a (36%), and bicyclohepta-
dienone 5a was fractionated by silica column chromatography
(eluentdCH2Cl2) to afford compounds 3a (0.035 g) and 5a (0.006 g,
6%). The total yield of furanone 3a is 0.060 g (56%).
Method B. A solution of cycloadduct 6 (0.111 g, 0.25 mmol) in
methanol (20 mL) was stirred at room temperature for 24 h. The
formed crystals were filtered off and dried to give the mixture
(0.020 g) of furanones 3a (14%) and 4a (86%). After passing this
mixture through column with SiO2 (eluentdCH2Cl2) furanone 3a
(0.018 g, the purity is 96%, the impurity is furanone 4a) was iso-
lated. The residue after removing methanol (0.084 g) containing
furanones 3a (17%), 4a (39%), and bicycloheptadienone 5a (37%)
was passed through SiO2 (eluentdCH2Cl2) and furanone 3a
(0.044 g, the purity is 95%, the impurity is furanone 4a) and bicy-
cloheptadienone 5a (0.07 g, 7%) were isolated. The total yield of
furanone 3a is 0.062 g (58%).
The methodology elaborated opens an exceptionally concise and
synthetically attractive atom and step economic route to novel
promising families of building blocks for drug design.
4.1.3. Ethyl 3,4-dicyano-4-(3,4-dichloro-2-methoxy-5-oxo-2,5-dihy-
drofuran-2-yl)-2-(4,5,6,7-tetrahydro-1H-indol-2-yl)cyclobut-1-ene-
carboxylate (3a). Yield 52e58%; yellow plates, mp 209e210 ꢀC;
[Found: C, 55.74; H, 4.12; Cl, 14.53; N, 8.89. C22H19Cl2N3O5 requires
C, 55.48; H, 4.02; Cl, 14.89; N, 8.82%]; Rf (30% Et2O/n-hexane) 0.86;
nmax (KBr) 3320 (NH), 2247 (CN), 1806 (CO), 1689 (CO), 1624 cmꢁ1
(C]C); dO (400.13 MHz, CDCl3) 10.71 (1H, br s, NH), 6.60 (1H, d, J
2.0 Hz, H3), 4.33 (1H, s, CHeSN), 4.24 (2H, m, CH2C]O), 3.40 (3H, s,
CH3O), 2.67 (2H, m, CH27), 2.53 (2H, m, CH24), 1.82 (2H, m, CH25), 1.74
(2H, m, CH26), 1.35 (3H, t, J 7.1 Hz, CH3); dc (101.6 MHz, CDCl3) 162.0,
160.6, 147.9, 144.6, 140.1, 125.1, 123.0, 121.7, 117.2, 113.9, 113.8, 105.7,
104.9, 61.8, 52.4, 50.3, 34.3, 23.4, 23.0, 22.5, 22.4, 14.2.
4. Experimental section
4.1. General information
IR spectra were obtained in KBr pellets. 1O and 13S NMR spectra
were recorded at 400.13 MHz and 101.6 MHz, respectively. The
concerted application of 1He1H 2D homonuclear experiments COSY
and NOESY and also 1He13C 2D heteronuclear experiments HSQC
and HMBC were used for the distinction of the carbon and proton
resonances in all cases. The X-ray diffraction study of 5a was carried
out with using a Bruker SMART APEX2 CCD diffractometer at room
temperature (Mo Ka radiation). Crystalline structure of compound
5a was solved by direct methods followed by Fourier synthesis using
SHELXS-97.15 All non-hydrogen atoms were refined using aniso-
tropic full-matrix approximation using SHELXL-97.15 The coordinates
of the hydrogen atoms were calculated from geometric conditions.
Atom coordinates, bond lengths, and angle values were deposited at
Cambridge Crystallographic Data Centre (CCDC). These data are
available via www.ccdc.cam.uk/conts/retrieving.html (or from CCDC,
12 Union Road, Cambridge CB2 1EZ, UK; fax: þ44 (0) 1223 336 033;
or deposit@ccdc.cam.ac.uk). Any request to the CCDC for data should
quote the full literature citation and CCDC reference number 805575.
4.1.4. Ethyl 3,4-dicyano-3-(3,4-dichloro-2-methoxy-5-oxo-2,5-dihy-
drofuran-2-yl)-2-(4,5,6,7-tetrahydro-1H-indol-2-yl)cyclobut-1-ene-
carboxylate (4a). dO (400.13 MHz, CDCl3) 10.71 (1H, br s, NH), 6.68
(1H, s, H3), 4.30 (1H, s, CHeSN), 4.24 (2H, m, CH2C]O), 3.45 (3H, s,
CH3O), 2.67 (2H, m, CH27), 2.53 (2H, m, CH24), 1.82 (2H, m, CH25), 1.74
(2H, m, CH26), 1.35 (3H, t, J 7.1 Hz, CH3); dC (101.6 MHz, CDCl3) 162.2,
160.8, 148.0, 144.8, 140.3, 125.7, 123.3, 121.9, 117.6, 114.1, 113.9, 105.3,
104.7, 62.0, 52.5, 49.1, 35.8, 23.6, 23.2, 22.7, 22.6, 14.4.
4.1.5. 6-Ethyl 2-methyl 3-chloro-1,5-dicyano-4-oxo-7-(4,5,6,7-tetra-
hydro-1H-indol-2-yl)bicyclo[3.2.0]hepta-2,6-diene-2,6-dicarboxylate
(5a). Yield 4e7%; red needles, mp 239e240 ꢀC; [Found: C, 59.72; H,
4.27; Cl, 8.00; N, 9.28. C22H18ClN3O5 requires C, 60.07; H, 4.12; Cl,
8.06; N, 9.55%]; Rf (30% Et2O/n-hexane) 0.83; nmax (KBr) 3346 (NH),
2248 (CN), 1756, 1724, 1684 (CO), 1615 cmꢁ1 (C]C); dH
(400.13 MHz, CDCl3) 10.89 (1H, br s, NH), 6.97 (1H, d, J 1.9 Hz, H3),
4.31 (2H, q, J 7.1 Hz, CH2O), 4.02 (3H, s, OCH3), 2.68 (2H, m, CH27),
2.55 (2H, m, CH24), 1.82 (2H, m, CH25), 1.75 (2H, m, CH26), 1.38 (3H, t, J
7.1 Hz, CH3); dC (101.6 MHz, CDCl3) 182.9, 162.8, 161.0, 148.2, 143.9,
142.3, 142.0, 124.1, 121.6, 119.2, 112.0, 111.3, 105.8, 62.3, 53.9, 52.1,
47.4, 23.8, 23.3, 22.9, 22.6, 14.3.
4.1.1. Reaction of ethyl 3-(4,5,6,7-tetrahydroindol-2-yl)propynoate
(2) with DDQ in methanol. A solution of ethyl 3-(4,5,6,7-tetrahy-
droindol-2-yl)propynoate (2) (0.109g, 0.5 mmol)inmethanol (20 mL)
was added to a solution of DDQ (0.114 g, 0.5 mmol) in methanol
(10 mL). The reaction mixture was allowed to stand at room tem-
perature for 32 h. The formed crystals were filtered off and dried to
give 0.037 g of the mixture of furanones 3a (12%) and 4a (88%). After
passing this mixture through column with SiO2 (eluentdCH2Cl2),
furanone 3a (0.035 g, the purity is 95%, the impurity is furanone 4a)
was isolated. The residue after removal of methanol (0.207 g) con-
taining furanone 3a(35%), furanone4a(39%), bicycloheptadienone 5a
(19%), and cycloadduct 6 (7%) was passed through SiO2 (CH2Cl2) and
furanone 3a (0.084 g) and bicycloheptadienone 5a (0.010 g, 4%) were
isolated. The total yield of furanone 3a is 0.119 g (52%).
4.1.6. Reaction of ethyl 3,4-dichloro-1,6-dicyano-2,5-dioxo-8-
(4,5,6,7-tetrahydro-1H-indol-2-yl)bicyclo[4.2.0]octa-3,7-diene-7-car-
boxylate (6) with n-propanol. Method A. The solution of cyclo-
adduct 6 (0.200 g, 0.45 mmol) in n-propanol (20 mL) was left at
room temperature for 7 days. The formed crystals were filtered off
and dried to give 0.063 g of mixture of furanone 3c (73%) and
bicycloheptadienone 5c (27%). After passing the crystals through
column with SiO2 (eluentdhexane/ether, from 4:1 to 1:1) furanone
3c (0.036 g, the purity is 93%, the impurity is bicycloheptadienone
5c) was isolated. The residue after removing n-propanol (0.141 g)
4.1.2. Reaction of ethyl 3,4-dichloro-1,6-dicyano-2,5-dioxo-8-(4,5,6,
7-tetrahydro-1H-indol-2-yl)bicyclo[4.2.0]octa-3,7-diene-7-carboxyl-
ate (6) with methanol. Method A. A solution of cycloadduct 6
(0.100 g, 0.23 mmol) in MeOH (20 mL) was heated to reflux for
15 min and allowed to stand at room temperature for 24 h. Then the
formed crystals were filtered off and dried to give 0.027 g of the

4836
L.N. Sobenina et al. / Tetrahedron 67 (2011) 4832e4837
containing furanone 3c (79%), furanone 4c (9%), and bicyclo-
heptadienone 5c (12%) was passed through SiO2 (hexane/ether,
from 4:1 to 1:1) and furanone 3c (0.101 g) was isolated. The total
yield of furanone 3c is 0.134 g (59%).
Method B. The solution of cycloadduct 6 (0.100 g, 0.23 mmol) in
n-propanol (10 mL) was heated (55e56 ꢀC) for 2 h. The reaction
mixture was diluted with brine (100 mL) and extracted with diethyl
ether (5ꢂ40 mL). The ether extracts were washed with water and
dried over Na2SO4. The residue after removing solvent (0.112 g)
containing furanones 3c (68%), 4c (16%), and bicycloheptadienone
5c (16%) was passed through SiO2 (eluentdhexane/CH2Cl2, from
4:1 to 1:1) to give furanone 3c (0.063 g, 55%). Bicycloheptadienone
5c was isolated only as single crystals together with furanone 3c.
CH27), 2.53 (2H, m, CH24), 1.82 (2H, m, CH26), 1.74 (2H, m, CH25), 1.42
(3H, d, J 6.3 Hz, CH3 of i-Pr), 1.35 (3H, d, J 6.2 Hz, CH3 of i-Pr),1.32 (3H,
t, J 7.1 Hz, CH3); dC (101.6 MHz, CDCl3) 188.5, 162.2, 161.7, 143.8, 139.3,
138.1, 127.8, 122.8, 121.8, 116.6,115.2,114.3,111.1, 73.9, 61.8, 52.4, 38.4,
23.6, 23.3, 22.8, 22.7, 21.7, 21.6, 14.4.
4.1.11. 6-Ethyl 2-isopropyl 3-chloro-1,5-dicyano-4-oxo-7-(4,5,6,7-
tetrahydro-1H-indol-2-yl)bicyclo[3.2.0]hepta-2,6-diene-2,6-di-
carboxylate (10). Yield 23e33%; red needles, mp 223e224 ꢀC;
[Found: C, 61.32; H, 4.56; Cl, 7.84; N, 9.28. C24H22ClN3O5 requires: C,
61.61; H, 4.74; Cl, 7.58; N, 8.98%]; Rf (30% Et2O/n-hexane) 0.83; nmax
(KBr) 3423 (NH), 2248 (CN), 1759, 1709, 1684 (CO), 1613 cmꢁ1 (C]
C); dO (400.13 MHz, CDCl3) 10.84 (1H, br s, NH), 7.02 (1H, d, J 1.9 Hz,
H3), 5.32 (1H, m, CH(CH3)2), 4.31 (2H, q, J 7.1 Hz, CH2O), 2.68 (2H, m,
CH27), 2.55 (2H, m, CH24), 1.82 (2H, m, CH25), 1.75 (2H, m, CH26), 1.43
(3H, d, J 6.4 Hz, CHCH3), 1.38 (3H, d, J 6.4 Hz, CHCH3), 1.37 (3H, t, J
7.1 Hz, CH3); dC (101.6 MHz, CDCl3) 182.9, 162.7, 160.1, 148.2, 144.6,
141.7, 141.5, 123.8, 121.5, 119.3, 111.9, 111.2, 105.8, 72.7, 62.1, 52.0,
47.4, 23.8, 23.2, 22.7, 22.6, 21.7 (2Nf), 14.2.
4.1.7. Ethyl
3,4-dicyano-4-(3,4-dichloro-2-n-propoxy-5-oxo-2,5-
dihydrofuran-2-yl)-2-(4,5,6,7-tetrahydro-1H-indol-2-yl)cyclobut-1-
enecarboxylate (3c). Yield 55e59%; yellow needles, mp 169e170 ꢀC;
[Found: C, 56.78; H, 4.34; Cl, 13.86; N, 8.56. C24H23Cl2N3O5 requires
C, 57.15; H, 4.60; Cl, 14.06; N, 8.33%]; Rf (30% Et2O/n-hexane) 0.85;
nmax (KBr) 3321 (NH), 2255 (CN), 1807 (CO), 1682 (CO), 1625 cmꢁ1
(C]C); dO (400.13 MHz, CDCl3) 10.71 (1H, br s, NH), 6.60 (1H, d,
J 1.8 Hz, H3), 4.32 (1H, s, CHeSN), 4.22 (2H, m, CH2C]O), 3.46 (2H,
m, OCH2 of Pr), 2.67 (2H, m, CH27), 2.53 (2H, m, CH24), 1.83 (2H, m,
CH2),1.74 (4H, m, CH25,6),1.35 (3H, t, J 7.3 Hz, CH3), 0.99 (3H, t, J 7.3 Hz,
CH3 of Pr); dC (101.6 MHz, CDCl3) 162.1, 160.8, 148.4, 144.7, 140.1,
124.9, 123.1, 121.9, 117.3, 114.1, 113.9, 106.0, 104.7, 67.3, 61.9, 50.6,
34.5, 23.6, 23.2, 22.6, 22.5, 22.4, 14.3, 10.3.
4.1.12. Reaction of ethyl 3,4-dichloro-1,6-dicyano-2,5-dioxo-8-
(4,5,6,7-tetrahydro-1H-indol-2-yl)bicyclo[4.2.0]octa-3,7-diene-7-car-
boxylate (6) with tert-butanol. A solution of cycloadduct 6 (0.100 g,
0.23 mmol) in t-BuOH (20 mL) was heated to reflux for 2 h and the
solvent was removed at vacuo. The residue (0.098 g), containing
only hydroxyfuranone 11 (1H NMR) was dissolved in ethanol and
left to stand at room temperature for 24 h. The formed white
crystals were filtered off and washed with cold ethanol to give
0.025 g (24%) of hydroxyfuranone 11.
4.1.8. 6-Ethyl 2-n-propyl 3-chloro-1,5-dicyano-4-oxo-7-(4,5,6,7-tet-
rahydro-1H-indol-2-yl)bicyclo[3.2.0]hepta-2,6-diene-2,6-dicarbox-
ylate (5c). Yield 2%; red prisms, mp 220e221 ꢀC; Rf (30% Et2O/n-
hexane) 0.84; nmax (KBr) 3318 (NH), 2255 (CN), 1754, 1720, 1682
(CO),1622 cmꢁ1 (C]C); dO (400.13 MHz, CDCl3) 10.86 (1H, br s, NH),
7.00 (1H, d, J 1.9 Hz, H3), 4.37 (2H, q, J 6.2 Hz, OCH2), 4.31 (2H, t, J
7.1 Hz, OCH2), 2.67 (2H, m, CH27), 2.54 (2H, m, CH24), 1.82 (4H, m,
CH25,6), 1.73 (2H, m, CH2), 1.38 (3H, t, J 6.2 Hz, CH3), 1.02 (3H, t, J
7.1 Hz, CH3).
4.1.13. Ethyl 3,4-dicyano-4-(3,4-dichloro-2-hydroxy-5-oxo-2,5-dihy-
drofuran-2-yl)-2-(4,5,6,7-tetrahydroindol-2-yl)cyclobut-1-enecabox-
ylate (11). Yield 24%; white prisms, mp 133e134 ꢀC; [Found: C,
54.18; H, 3.98; Cl, 14.98; N, 8.79. C21H17Cl2N3O5 requires C, 54.56; H,
3.71; Cl, 15.34; N, 9.09%]; nmax (KBr) 3463 (OH), 3329 (NH), 2256
(CN), 2203 (CN), 1805 (CO), 1682 (CO), 1630 cmꢁ1 (C]C);
dO (400.13 MHz, CDCl3) 10.63 (1H, br s, NH), 6.59 (1H, s, H3), 4.40
(1H, s, CHCN), 4.31 (1H, br s, OH), 4.22 (4H, m, 2OCH2), 2.66 (2H, m,
CH27), 2.52 (2H, m, CH24), 1.80 (2H, m, CH25), 1.73 (2H, m, CH26), 1.34
(3H, t, J 7.3 Hz, CH3); dC (101.6 MHz, CDCl3) 162.3, 161.7, 150.0, 144.2,
139.8, 123.7, 122.6, 121.8, 117.1, 114.4, 114.3, 107.0, 104.0, 61.9, 50.7,
34.3, 23.4, 23.0, 22.5, 22.4, 14.1.
4.1.9. Reaction of ethyl 3,4-dichloro-1,6-dicyano-2,5-dioxo-8-
(4,5,6,7-tetrahydro-1H-indol-2-yl)bicyclo[4.2.0]octa-3,7-diene-7-car-
boxylate (6) with iso-propanol. Method A. A solution of cycloadduct
6 (0.100 g, 0.23 mmol) in iso-propanol (20 mL) was allowed to stand
at room temperature for 7 days. Then iso-propanol was removed
and the residue (0.109 g) containing bicycloheptadienone 10 and its
precursor 9 was passed through SiO2 (CH2Cl2) to afford compounds
9 (0.038 g, 33%) and 10 (0.023 g, 22%).
Method B. The solution of cycloadduct 6 (0.100 g, 0.23 mmol) in
iso-propanol (10 mL) was heated (55e56 ꢀS) for 2 h and allowed to
stand at room temperature for 60 h. The formed crystals of the
mixture of compounds 9 and 10 (0.027 g, the ratio 9/10, 1:1) were
filtered off and passed through column with SiO2 (eluentdCH2Cl2) to
afford bicycloheptadienone 10 (0.021 g). After removal of iso-prop-
anol (0.072 g), the residue was fractionated by column chromatog-
raphy (SiO2, le30 cm, eluentdCH2Cl2) and the mixture (0.020 g) of
compounds 9 and 10 (the ratio 9/10, 3:1) was isolated. Repeated
fractionation of this mixture gave 0.014 g of bicycloheptadienone 10.
The total yield of bicycloheptadienone 10 is 0.035 g (33%).
4.1.14. Reaction of ethyl 3,4-dichloro-1,6-dicyano-2,5-dioxo-8-(1-
methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)bicyclo[4.2.0]-octa-3,7-di-
ene-7-carboxylate (12a) with ethanol. The solution of cycloadduct
12a (0.100 g, 0.22 mmol) in EtOH (20 mL) was allowed to stand at
room temperature for 24 h. Then the solution was poured into brine
(100 mL) and extracted with diethyl ether (5ꢂ20 mL). The ether
extracts were washed with water and dried over Na2SO4. After
removing diethyl ether, the residue (0.084 g) containing bicyclo-
heptadienone 13a and intermediate 14a (the ratio 13a/14a,1:2) was
passed through SiO2 (eluentdCH2Cl2) to give 0.044 g (43%) of
bicycloheptadienone 13a.
4.1.15. Diethyl 7-(1-methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-chloro-
1,5-dicyano-4-oxobicyclo[3.2.0]hepta-2,6-diene-2,6-dicarboxylate
(13a). Yield 43%; red needles, mp 158e160 ꢀC; [Found: C, 61.32; H,
4.58; Cl, 7.75; N, 8.64. C24H22ClN3O5 requires C, 61.61; H, 4.74; Cl,
7.58; N, 8.98%]; Rf (30% Et2O/n-hexane) 0.76; nmax (KBr) 2244, 2199
(CN), 1758, 1724, 1702 (CO), 1625 cmꢁ1 (C]C); dO (400.13 MHz,
CDCl3) 6.93 (1H, s, H3), 4.33 (4H, m, 2OCH2), 3.49 (3H, s, NMe), 2.53
(4H, m, CH24,7), 1.85 (2H, m, CH25), 1.71 (2H, m, CH26), 1.38 (3H, t, J
7.3 Hz, CH3), 1.35 (3H, t, J 7.3 Hz, CH3); dC (101.6 MHz, CDCl3) 182.8,
160.2, 160.1, 146.4, 145.0, 144.0, 141.6, 123.4, 122.5, 119.6, 112.6, 111.5,
109.6, 63.6, 61.9, 51.9, 48.5, 33.6, 23.1, 23.0, 22.9, 22.5, 14.2, 13.9.
4.1.10. (Z)-Ethyl 3,4-dicyano-4-(2,3-dichloro-4-isopropoxy-4-oxobut-
2-enoyl)-2-(4,5,6,7-tetrahydroindol-2-yl)cyclobut-1-enecarboxylate
(9). Yield 33%; yellow prisms, mp 172e173 ꢀC; [Found: C, 56.78; H,
4.31; Cl, 14.41; N, 8.69. C24H23Cl2N3O5 requires C, 57.15; H, 4.60; Cl,
14.06; N, 8.33%]; Rf (30% Et2O/n-hexane) 0.84; nmax (KBr) 3327 (NH),
2252, 2203 (CN), 1725,1691 (CO), 1633 cmꢁ1 (C]C); dO (400.13 MHz,
CDCl3) 10.59 (1H, br s, NH), 6.58 (1H, d, J 2.0 Hz, H3), 5.19 (1H, m,
CH(CH3)2), 4.42 (1H, s, CHeSN), 4.27 (2H, m, CH2C]O), 2.67 (2H, m,

L.N. Sobenina et al. / Tetrahedron 67 (2011) 4832e4837
4837
cycles 2004, 63, 519e527; (c) Rajaram, A. R.; Pu, L. Org. Lett. 2006, 8,
2019e2021; (d) Zografos, A. I.; Georgiadis, D. Synthesis 2006, 3157e3188.
4. Lichtenthaler, F. W.; Cuny, E.; Sakanaka, O. Angew. Chem., Int. Ed. 2005, 44,
4944e4948.
5. (a) Gunasekera, S. P.; McCarthy, P. J.; Kelly-Borges, M. J. Am. Chem. Soc.
1996, 118, 8759e8760; (b) Corey, E. J.; Roberts, B. E. J. Am. Chem. Soc. 1997,
119, 12425e12431; (c) Takahashi, M.; Dodo, K.; Sugimoto, Y.; Aoyagi, Y.;
Yamada, Y.; Hasimoto, Y.; Shirai, R. Bioorg. Med. Chem. Lett. 2000, 10,
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Bhargava, A.; Muller, O.; Lieb, F.; Waldmann, H. J. Am. Chem. Soc. 2002,
124, 13171e13178.
4.1.16. Reaction of ethyl 3,4-dichloro-1,6-dicyano-2,5-dioxo-8-(1-
benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)bicyclo[4.2.0]octa-3,7-di-
ene-7-carboxylate (12b) with ethanol. Cycloadduct 12b (0.100 g,
0.19 mmol) was heated to reflux in EtOH (20 mL) for 2 min and
allowed to cool to room temperature. Then the solution was poured
into brine (100 mL) and extracted with diethyl ether (5ꢂ20 mL).
The ether extracts were washed with water and dried over Na2SO4.
After removing diethyl ether the residue (0.096 g) containing
bicycloheptadienone 13b and compound 14b (the ratio 13b/14b,
1:1.5) was passed through SiO2 (eluentdCH2Cl2) to give 0.027 g
(26%) of bicycloheptadienone 13b.
6. (a) Soriente, A.; Crispino, A.; De Rosa, M.; De Rosa, S.; Scettri, A.; Scognamiglio,
G.; Villano, R.; Sodano, G. Eur. J. Org. Chem. 2000, 947e953; (b) Basabe, P.;
Delgado, S.; Marcos, I. S.; Diez, D.; Diego, A.; De Roman, M.; Urones, J. G. J. Org.
Chem. 2005, 70, 9480e9485.
4.1.17. Diethyl 7-(1-benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-chloro-
1,5-dicyano-4-oxobicyclo[3.2.0]hepta-2,6-diene-2,6-dicarboxylate
(13b). Yield 26%; red prisms, mp 135e136 ꢀC; [Found: C, 65.92; H,
4.59; Cl, 6.21; N, 7.44. C30H26ClN3O5 requires C, 66.24; H, 4.82; Cl,
6.52; N, 7.72%]; Rf (30% Et2O/n-hexane) 0.78; nmax (KBr) 2244, 2199
(CN), 1753, 1724, 1704 (CO), 1625 cmꢁ1 (C]C); dO (400.13 MHz,
CDCl3) 7.12 (3H, m, CH3,4,5 Ph), 7.02 (1H, s, H3), 6.45 (2H, m, CH2,6),
5.59 (1H, d, J 16.8 Hz, CH2Ph), 5.04 (1H, d, J 16.8 Hz, CH2Ph), 4.34
(4H, m, 2OCH2), 2.60 (4H, m, CH24,7), 1.78 (4H, m, CH25,6), 1.38 (3H, t, J
7.3 Hz, CH3), 1.35 (3H, t, J 7.3 Hz, CH3); dC (101.6 MHz, CDCl3) 182.3,
160.5, 159.7, 146.6, 144.4, 143.5, 140.8, 137.3, 128.8, 127.9, 125.3,
122.8, 122.5, 120.4, 112.4, 111.7, 111.3, 63.3, 62.1, 49.1, 48.7, 48.2, 23.1,
23.0, 22.9, 22.6, 14.2, 14.0.
7. (a) Mangnus, E. M.; Stommen, P. L. A.; Zwanenburg, B. J. Plant Growth Regul.
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O. A.; Platonov, V. B. Patent RF No RU 2,297,410, 2006.
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I. A. Tetrahedron Lett. 2004, 45, 6513e6516; (b) Stepanova, Z. V.; Sobenina, L.
N.; Mikhaleva, A. I.; Ushakov, I. A.; Elokhina, V. N.; Voronov, V. K.; Trofimov,
B. A. Synthesis 2004, 2736e2743; (c) Sobenina, L. N.; Demenev, A. P.; Mi-
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Volkova, K. A.; Mikhaleva, A. I. Synthesis 2007, 447e451; (f) Trofimov, B. A.;
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Acknowledgements
This work was carried out under financial support of the leading
scientific schools by the President of the Russian Federation (Grant
NSh-3230.2010.3), the Russian Foundation of Basic Research (Grant
No. 09-03-00064a), and Integration Projects Nos. 93, 5.9.
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