Facile [2+2] cycloaddition of DDQ to an alkyne: Synthesis of pyrrolyl- and indolylbicyclo[4.2.0]octadienes from C -ethynylpyrroles or C -ethynylindoles

Article abstract of DOI:10.1055/s-0029-1217133

C-Ethynylpyrroles or -indoles, which can be prepared by cross-coupling of pyrroles or indoles with haloalkynes on active surfaces, undergo [2+2]-cycloaddition reactions with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to give 2-pyrrolyl- or 3-indolylbicyclooctadienes in almost quantitative yields. The adducts are charge-transfer complexes that are paramagnetic in the solid state, and therefore represent a new family of densely functionalized pyrrole and indole derivatives potentially useful as pharmaceutical candidates, highly potent building blocks, or precursors of advanced materials. The reaction contributes to the practical and basic chemistry of pyrroles, indoles, alkynes, and quinones. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1217133

470
PAPER
Facile [2+2] Cycloaddition of DDQ to an Alkyne: Synthesis of Pyrrolyl- and
Indolylbicyclo[4.2.0]octadienes from C-Ethynylpyrroles or C-Ethynylindoles
C
ycloaddition of
o
D
D
Q
to an
A
r
cetylen
i
ic Moie
s
ty A. Trofimov,* Lyubov’ N. Sobenina, Zinaida V. Stepanova, Igor’ A. Ushakov, Lidiya M. Sinegovskaya,
Tamara I. Vakul’skaya, Al’bina I. Mikhaleva
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky St., Irkutsk 664033,
Russian Federation
Fax +7(3952)419346; E-mail: boris_trofimov@irioch.irk.ru
Received 23 September 2009; revised 7 October 2009
able as a result of the discovery of techniques for the ethy-
Abstract: C-Ethynylpyrroles or -indoles, which can be prepared by
nylation of the pyrrole nucleus by electrophilic
cross-coupling of pyrroles or indoles with haloalkynes on active
surfaces, undergo [2+2]-cycloaddition reactions with 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone to give 2-pyrrolyl- or 3-indolylbicy-
haloalkynes on alumina5 or other active surfaces.6 Note
that these functionalized ethynylpyrroles and -indoles are
clooctadienes in almost quantitative yields. The adducts are charge- not accessible by common synthetic approaches, includ-
ing Sonogashira couplings.7 In particular, this new meth-
transfer complexes that are paramagnetic in the solid state, and
therefore represent a new family of densely functionalized pyrrole
od permits the preparation of 2-acyl- and 2-
and indole derivatives potentially useful as pharmaceutical candi-
(alkoxycarbonyl)ethynyl-4,5,6,7-tetrahydroindoles from
dates, highly potent building blocks, or precursors of advanced ma-
readily available 4,5,6,7-tetrahydroindole.8 These com-
terials. The reaction contributes to the practical and basic chemistry
pounds, because of their possible aromatization, may be
suitable as intermediates for the synthesis of 2-functional-
ized indoles.9
of pyrroles, indoles, alkynes, and quinones.
Key words: pyrroles, indoles, cycloadditions, alkynes, polycycles
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is a
particularly effective reagent for aromatization, and it is
often the reagent of choice for the dehydrogenation of
both simple and complex hydroaromatic compounds.10
Some fully aromatic derivatives have been obtained in
high yields by dehydrogenation of the corresponding tet-
rahydro heteroaromatic compounds by using DDQ.11 It is
known that treatment of dimethyl (4,7-dihydro-1H-indol-
2-yl)fumarate with DDQ in benzene at room temperature
for one hour gives the expected indole in 94% yield.12
Consequently, we were intrigued by the possibility of ap-
plying this method to the synthesis of indoles with alkyne
substituents, starting with the 2-ethynyl-4,5,6,7-tetrahy-
droindoles 1a–d.
Pyrroles and benzopyrroles (indoles) are among the most
important heterocyclic systems in that they occur widely
in nature as constituents of the frameworks of natural
products and because many synthetic variants of these
compounds have significant pharmaceutical effects.1
Considerable attention has therefore been devoted to the
development of efficient methods for derivatizing the pyr-
role nucleus. Among the most useful pyrrole building
blocks are those containing alkyne moieties. Because of
the rich chemistry of the alkyne function, alkynylpyrroles
are widely used in syntheses of pyrrole-containing struc-
tures.2 Of particular interest are 2-ethynylpyrroles, owing
to their usefulness in the total syntheses of polyfunctional
complex molecules containing the indole skeleton.3 Be-
cause indole skeletons are present in many drugs and nat-
ural products, the search for new methods for preparing
indoles with various substitution patterns has recently
been the object of several research programs.4
To our surprise, however, the anticipated aromatization
did not occur under analogous conditions; instead, [2+2]
cycloaddition at the triple bond occurred to afford 1:1 ad-
ducts, the bicyclo[4.2.0]octadienes 2a–d, in 81–93% iso-
lated yields (Table 1).
Although methods for the preparation of 3-substituted in-
doles are well developed, the syntheses of 2-substituted
indole derivatives is less well elaborated. A new, reliable,
and robust method for preparing 2-functionalized indoles,
particularly 2-ethynylindoles, could make a considerable
contribution to the chemistry and pharmacology of in-
doles.
The adducts, which were bright or deep cherry in color,
began to precipitate immediately on mixing the reactants.
The adducts were stable in the solid state for months, but
decomposed within hours in solution in benzene or di-
methyl sulfoxide.
1
Signals for the indole protons were absent from the H
NMR spectra of the adducts 2a–d, but the signals for the
four methylene groups of the cyclohexano moiety and the
signals for the pyrrole H-3 atom remained. The NH,H-3
coupling constants were in the range 1.7–2.0 Hz, which
are typical values for 2,4,5-trisubstituted pyrroles.5a,13 In
the 13C NMR spectra, the signals of the acetylenic carbons
(81.8–87.9 ppm) disappeared, and cyclobutene sp3 signals
(53.8–52.2 ppm) were observed. Analysis of heteronucle-
2-Ethynylpyrroles and 3-ethynylindoles bearing electron-
withdrawing substituents (acyl or alkoxycarbonyl groups)
adjacent to the triple bond have now became readily avail-
SYNTHESIS 2010, No. 3, pp 0470–0476
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Advanced online publication: 20.11.2009
DOI: 10.1055/s-0029-1217133; Art ID: Z20209SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cycloaddition of DDQ to an Acetylenic Moiety
471
photochemical; in this case, the [2+2] cycloaddition was
as efficient as that observed in daylight.
Table 1 Reactions of 2-Ethynyl-4,5,6,7-tetrahydroindoles 1a–d
with DDQ
O
This new reaction was found to be general in character.
Apart from 2-ethynyl-4,5,6,7-tetrahydroindoles 1a–d,
other substituted 2-ethynylpyrroles, e.g. pyrroles 3a–c
(R1 = Ph, 4-ClC6H4, 4-MeOC6H4), also reacted with DDQ
by the same [2+2]-cycloaddition path (Table 2), although
the process took longer (one hour) or required the pres-
ence of a polar solvent (acetone, acetonitrile, or acetone–
benzene). This shows the importance of donation of elec-
trons from the pyrrole moiety to the alkyne group. (As a
result of the inductive effect, the tetrahydroindolyl group
releases electrons more readily than do the arylpyrrolyl
substituents in 3a–c.)
NC
NC
Cl
Cl
O
Cl
NC
O
Cl
N
R1
O
N
R1
benzene
r.t., 5–10 min
O
CN
R2
O
R2
1a–d
2a–d
Pyrrole
R1
R2
Yield (%)
1a
1b
1c
1d
H
OEt
OEt
OEt
Ph
87
93
81
88
Me
Bn
H
Table 2 Reactions of 2-Ethynylpyrroles 3a–c with DDQ
O
O
Cl
NC
NC
Cl
Cl
NC
R1
Cl
N
H
R1
O
ar single quantum coherence (HSQC) and heteronuclear
multiple bond correlation (HMBC) two-dimensional (2D)
spectra permitted the unambiguous assignment of the 13C
chemical shifts of the pyrrole skeleton and the direct C-3–
O
CN
N
O
O
R2
H
3a–c
R2
acetone–benzene or
MeCN, r.t., 5–10 min
4a–c
H-3 couplings. No C≡C stretching vibration absorption Pyrrole
R1
Ph
R2
Ph
Yield (%)
band (which should appear at 2175–2184 cm–1)6b was de-
3a
82
76
92
tected in the IR spectra of any of the adducts 2a–d.
3b
4-ClC6H4
Ph
4-O2NC6H4
With regard to whether the chlorine-substituted C=C bond
or the cyano-substituted C=C bond of DDQ is involved in
3c
4-MeOC6H4
the cycloaddition, a comparison of the 13C NMR spectra
of the adducts with that of DDQ14 unambiguously favored
The structures of the adducts 4a-c were confirmed by their
NMR spectra, which showed that the C-3 and C-4 carbons
and the corresponding H-3 and H-4 protons of the pyrrole
remained intact. The H-3 and the H-4 protons appeared as
a doublet of doublets with typical couplings (4JH-3,NH ≈ 2.4
Hz, 3JH-3, H-4 ≈ 4.2 Hz, and 4JH-4,NH ≈ 2.6 Hz). Direct C-3–
H-3 and C-4–H-4 couplings were observed in 2D HSQC
spectra. All these values are typical of a 2,5-disubstituted
pyrrole moiety. The large difference (up to 22 ppm) be-
tween the 13C chemical shifts of the CN-substituted car-
bons in the tetrahydroindoles 2a–d and those of the 5-
aryl-substituted series 4a–c is the result of intramolecular
charge transfer (CT) from the arylpyrrole moiety (by the
through-conjugation mechanism) to the dicyanocy-
clobutene moiety of the molecule; this was confirmed by
the presence of large red shifts (up to 70 nm) and the hy-
pochromic effect of the CT band in the UV/visible (UV/
Vis) spectra of compounds 2a–d and 4a–c (Figure 1).
This long-range charge transfer is also manifested in the
13C NMR downfield shifts (1–3 ppm) of the most remote
structures 2a–d. Indeed, the chemical shifts of the olefinic
carbons C-3 and C-4 of the quinone ring (d = 142.9–144.0
ppm and d = 140.1–141.1 ppm, respectively) were similar
to those of the chlorine-substituted carbons (d = 141.0
ppm) in DDQ, and were significantly different from those
associated with carbon atoms bound to cyano groups (d =
125.1 ppm).
In general, DDQ is a powerful oxidizing agent. In addi-
tion, it has proved to be a versatile reagent for various or-
ganic transformations, including diene condensation.15 It
has not, however, been reported to participate in any
[2+2]-cycloaddition reaction with an alkyne moiety.
Moreover, it has been used to oxidize phenylalkynes to
the corresponding enynes, which retain intact triple
bonds.16 Furthermore, no other [2+2]-cycloaddition reac-
tion at the triple bond of an ethynylpyrrole has been re-
ported.
The [2+2] cycloaddition of DDQ to the triple bond of 2-
ethynyl-4,5,6,7-tetrahydroindoles 1a–d is therefore the
first example of such a reaction of an alkyne with DDQ.
C
para carbons of the aryl substituents in the adducts 4a–c
compared with those of the starting alkynes 3a–c.5d
Most cycloaddition reactions of benzoquinones with
alkynes are photochemical, leading to either an adduct at
the carbonyl group17 or at the double bond,18 depending
on the structure of the quinone. Monitoring of the reaction
of 2-ethynyl-4,5,6,7-tetrahydroindoles 1a–d with DDQ
The 3-ethynylindoles 5a and 5b reacted similarly with
DDQ, undergoing [2+2] cycloaddition to give the corre-
sponding cycloadducts 6a and 6b in 84 and 87% yields,
respectively. These reactions proceeded as smoothly as
those of the 2-ethynylpyrroles 3a–c, and were complete in
1
by H NMR in darkness proved that the reaction is not
Synthesis 2010, No. 3, 470–476 © Thieme Stuttgart · New York

472
B. A. Trofimov et al.
PAPER
Figure 1 CT bands in the UV/Vis spectra of the cycloadducts: 1, 2a;
2, 2b; 3, 2c; 4, 2d; 5, 4a; 6, 4b; 7, 4c
Figure 2 UV/Vis spectra of a mixture of pyrrole 1a (0.025 mM) and
DDQ (0.025 mM) in benzene at r.t.; 1, DDQ; 2, pyrrole 1a; 3, after 2
min; 4, after 10 min; 5, after 25 min; 6, after 60 min
Table 3 Reaction of 3-Ethynylindoles 5a and 5b with DDQ
Cl
Cl
O
O
O
NC
NC
Cl
Cl
Ph
O
CN
NC
Ph
O
O
R
N
H
acetone–benzene or
MeCN, r.t., 5–10 min
R
N
H
5a,b
6a,b
Indole
5a
R
Yield (%)
H
87
84
Figure 3 UV/Vis spectra of a mixture of pyrrole 1a (0.025 mM) and
DDQ (0.025 mM) in MeCN at –30 °C to r.t.
5b
Me
case giving the radical cation 7a and the radical anion 7b
(Scheme 1).
5–10 min in acetone–benzene or acetonitrile at room tem-
perature (Table 3).
Thus, UV/Vis monitoring of the course of the cycloaddi-
tion reaction shows that the starting alkynes 1a–d are
transformed rapidly on contact with DDQ to give the
cycloadducts 2a–d, a major feature of which is strong
intramolecular charge transfer. At a low temperature
(–30 °C), the intermediate radical cation possibly became
discernible (1082 nm). Note that for adducts 4a–c, which
are derived from 2-ethynyl-5-arylpyrroles, the CT band
was significantly red-shifted (up to 70 nm) with a simul-
taneous hypochromic effect (Dlog e = 0.53), indicating
deep charge transfer with participation of the aryl substit-
uents (Figure 1). This is accompanied by downfield shifts
of Cpara carbons of the aryl groups (see above) and a pro-
nounced shielding of the CN-substituted carbons.
Reactions of quinones often proceed with electron trans-
fer and can therefore be monitored by UV19 or ESR19a,c,20
spectroscopy. Indeed, our experimental results from these
techniques could be tentatively rationalized as providing
evidence for electron transfer in the cycloaddition reac-
tion. When monitored by UV/Vis spectroscopy
(Figure 2), two sharp and intense peaks at 330 and 381
nm, along with a broad absorption band in the region 400–
600 nm were observed immediately after mixing reactant
1a with DDQ in benzene. After 60 minutes, the intensity
of the band at 330 nm decreased whereas the intensities of
the band at 381 nm and the broad absorption in the region
400–600 nm increased, and a peak at 477 nm appeared.
The final spectrum corresponded to that of the adduct 2a,
the isosbestic point at 431 nm indicating the conversion
1a + DDQ → 2a.
In MeCN at about –30 °C, an absorption band at 1082 nm
(which disappeared at room temperature) was observed
(Figure 3).
According to Polyakov,19a this band can be assigned to a
radical cation species, in this case, possibly 7a. It is
known that CT-complexes or ion-radical pairs such as 7
dissociate in polar solvents such as acetonitrile, in this
In the ESR spectrum of a 1:1 (molar) mixture of pyrrole
1a and DDQ in benzene at room temperature, two overlap
signals (g-factors 2.0052 and 2.0048, respectively) with
no hyperfine structure were observed. On the basis of the
value of the g-factor, the first signal was assigned to the
DDQ radical anion. To check this assignment, the reaction
was monitored at a low temperature. An ampoule contain-
ing the reaction mixture under argon was frozen in liquid
nitrogen and then placed in the ESR spectrometer. In the
spectrum, a signal with hyperfine structure (five lines,
Synthesis 2010, No. 3, 470–476 © Thieme Stuttgart · New York

PAPER
Cycloaddition of DDQ to an Acetylenic Moiety
473
O
O
O
NC
NC
Cl
Cl
NC
NC
Cl
Cl
O
1a +
N
H
OEt
O
7
O
NC
NC
Cl
Cl
O
+
N
2a
H
OEt
O
7a
7b
Scheme 1
recorded on a Bruker ELEXSYS E580 spectrometer. The reactions
were monitored by TLC on Silufol UV254 plates (CH2Cl2) and by 1H
NMR (CDCl3).
aN = 0.58 G, g = 2.0052), attributable to the DDQ radical
anion21 was registered. This was consistent with the tenta-
tive mechanism involving electron transfer from the ethy-
nylpyrrole moiety to DDQ to form an ion-radical pair
consisting of a DDQ radical anion and an ethynylpyrrole
radical cation, the latter being undetectable by the ESR
technique that was used because of its lower stability.
[Separately, both the reactants (pyrrole 1a and DDQ) are
nonparamagnetic in benzene].
2-Ethynylpyrroles 1a–d and 3a–c and 3-ethynylindoles 5a and 5b
were prepared from pyrroles or indoles and haloalkynes by the
methods described in the literature.5,6
Ethyl 3,4-Dichloro-1,6-dicyano-2,5-dioxo-8-(4,5,6,7-tetrahy-
dro-1H-indol-2-yl)bicyclo[4.2.0]octa-3,7-diene-7-carboxylate
(2a)
A soln of indole 1a (0.109 g, 0.5 mmol) and DDQ (0.114 g, 0.5
mmol) in anhyd benzene (20 mL) was stirred at r.t. for 5 min. The
benzene was evaporated (~5 min) and the residue was filtered on a
short silica gel column (5 g) with elution by CH2Cl2 to give a cherry-
colored solid; yield: 0.193 g (87%); mp 207–208 °C.
In the solid state, adducts 2a–d, 4a–c, 6a, and 6b are all
paramagnetic (~1018 spin/g), as exemplified by the ESR
spectrum of adduct 2a, in which two overlap singlets
(g1 = 2.0052, DH1 = 8.7 G; g2 = 2.0042, DH2 = 2.9 G) are
observed. This paramagnetism vanishes on dissolving the
adducts in, for example, benzene. It may be assumed that
the paramagnetism of the solid sample results from elec-
tron transfer in associated molecules. In the future, we
plan to study this phenomenon, which is of interest in re-
lation to advanced materials science, in more depth.
IR (KBr): 2246 (nCN), 1716, 1694 (nC=O), 1634, 1565, 1546, 1518
(nC=C), 1288, 1048 (nC–O), 798 cm–1 (nC–Cl).
1H NMR (400.13 MHz, CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H, CH3),
1.75 (m, 2 H, CH2-6), 1.82 (m, 2 H, CH2-5), 2.54 (m, 2 H, CH2-4),
2.68 (m, 2 H, CH2-7), 4.30 (m, 2 H, OCH2), 6.73 (d, J = 1.7 Hz, 1
H, H-3), 10.65 (br s, 1 H, NH).
13C NMR (101.6 MHz, CDCl3): d = 14.1, 22.4, 22.7, 23.0, 23.8,
52.5, 53.5, 62.4, 108.6, 111.3, 111.8, 119.4, 120.6, 125.0, 141.1,
142.4, 143.5, 144.0, 161.8, 174.7, 176.4.
In summary, the simple and efficient [2+2]-cycloaddition
reaction of DDQ with 2-ethynylpyrroles or 3-ethynylin-
doles with electron-withdrawing substituents at the triple
bond gives densely functionalized pyrrolyl- and indolyl-
substituted bicyclo[4.2.0]octadienes in almost quantita-
tive isolated yields. This reaction is likely to attract grow-
ing attention because of the widespread research
efforts2,3,22 in the area of pyrroles and indoles with acety-
lenic substituents. The cycloadducts that were obtained
are paramagnetic in the solid state and represent a novel
class of functionalized pyrroles, indoles, and cy-
clobutenes that have a considerable potential as pharma-
ceutical candidates, synthetic building blocks, and
precursors for advanced materials.
UV/Vis (MeCN): lmax (log e) = sh. 267 (3.99), 285 (4.09), 369
(4.33), 459 nm (3.77).
Anal. Calcd for C21H15Cl2N3O4: C, 56.77; H, 3.40; Cl, 15.96; N,
9.46. Found: C, 56.48; H, 3.40; Cl, 15.65; N, 9.50.
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-diene-7-car-
boxylate (2b)
A soln of indole 1b (0.116 g, 0.5 mmol) and DDQ (0.114 g, 0.5
mmol) in anhyd benzene (20 mL) was stirred at r.t. for 5 min while
the mixture thickened. The precipitate was filtered off and washed
with Et2O (5 mL) to give a cherry-colored solid; yield: 0.109 g. The
benzene and Et2O were evaporated, and the residue was filtered on
a short silica gel column (5 g) with elution by CH2Cl2 to give a fur-
ther crop of the product; yield: 0.104 g; total yield: 0.213 g (93%);
mp 163–164 °C.
IR spectra were recorded on a Bruker Vertex 70 spectrometer (400–
4000 cm–1, KBr pellets). The UV/Vis spectra were recorded on a
Perkin-Elmer Lambda 35 spectrophotometer (MeCN, 4 × 10–4 to
7 × 10–4 mol/L, d = 0.1 cm; reaction mixtures in soln were exam-
ined at a concentration 0.025 mM in benzene at 25 °C or MeCN at
–30 °C. The 1H (400.13 MHz) and 13C NMR (101.6 MHz) spectra
were recorded on a Bruker DPX-400 instrument. Concerted 1H–1H
2D homonuclear experiments (COSY and NOESY) and 1H–13C 2D
heteronuclear experiments (HSQC and HMBC) were used to assign
the carbon and proton resonances in all cases. CW ESR spectra were
IR (KBr): 2250 (nCN), 1715, 1678 (nC=O), 1620, 1565, 1543, 1502
(nC=C), 1270, 1055 (nC–O), 809 cm–1 (nC–Cl).
1H NMR (400.13 MHz, CDCl3): d = 1.33 (t, J = 7.1 Hz, 3 H, CH3),
1.71 (m, 2 H, CH2-5), 1.84 (m, 2 H, CH2-6), 2.51 (m, 2 H, CH2-4),
2.58 (m, 2 H, CH2-7), 3.59 (s, 3 H, NMe), 4.25 (q, J = 7.1 Hz, 2 H,
OCH2), 6.83 (s, 1 H, H-3).
Synthesis 2010, No. 3, 470–476 © Thieme Stuttgart · New York

474
B. A. Trofimov et al.
PAPER
13C NMR (101.6 MHz, CDCl3): d = 14.0, 22.4, 22.8, 22.8, 23.1,
33.7, 52.7, 53.1, 62.1, 111.8, 111.9, 112.1, 121.0, 123.0, 124.1,
140.3, 142.0, 143.2, 145.3, 159.7, 175.5, 177.2.
IR (KBr): 2257 (nCN), 1713, 1631 (nC=O), 1597, 1581, 1542,
1494, 1455 (nC=C), 803 cm–1 (nC–Cl).
1H NMR (400.13 MHz, CDCl3): d = 6.93 (dd, 3J = 4.4 Hz, 4J = 2.8
Hz, 1 H, H-4), 7.27 (dd, 3J = 4.4 Hz, 4J = 2.5 Hz, 1 H, H-3), 7.44 (m,
1 H, CH-4 Ph), 7.50 (m, 2 H, CH-3,5 Ph), 7.56 (m, 2 H, CH-3,5
COPh), 7.65 (m, 1 H, CH-4 COPh), 7.76 (m, 2 H, CH-2,6 Ph), 7.87
(m, 2 H, CH-2,6 COPh), 12.62 (br s, 1 H, NH).
13C NMR (101.6 MHz, CDCl3): d = 29.7, 31.0, 111.6, 113.1, 114.0,
118.3, 124.2, 124.4, 125.8, 128.1, 129.1, 129.2, 129.4, 129.6, 130.3,
133.6, 136.1, 143.4, 143.6, 143.8, 175.0, 176.2, 187.8.
UV/Vis (MeCN): lmax (log e) = sh. 267 (3.96), 285 (4.01), 368
(4.23), 463 nm (3.71).
Anal. Calcd for C22H17Cl2N3O4: C, 57.66; H, 3.74; Cl, 15.47; N,
9.17. Found: C, 57.73; H, 3.94; Cl, 15.84; N, 8.82.
Ethyl 8-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3,4-dichlo-
ro-1,6-dicyano-2,5-dioxobicyclo[4.2.0]octa-3,7-diene-7-carbox-
ylate (2c)
A soln of indole 1c (0.154 g, 0.5 mmol) and DDQ (0.114 g, 0.5
mmol) in anhyd benzene (20 mL) was stirred at r.t. for 5 min. The
benzene was then evaporated and the residue was filtered on a short
silica gel column (5 g) with elution by CH2Cl2 to give a cherry-
colored solid; yield: 0.216 g (81%); mp 181–182 °C.
UV/Vis (MeCN): lmax (log e) = 278 (4.43), 412 (4.14), 494 nm
(4.19).
Anal. Calcd for C27H13Cl2N3O3: C, 65.08; H, 2.63; Cl, 14.23; N,
8.43. Found: C, 64.81; H, 2.82; Cl, 13.97; N, 8.13.
7-Benzoyl-3,4-dichloro-8-[5-(4-chlorophenyl)-1H-pyrrol-2-yl]-
2,5-dioxobicyclo[4.2.0]octa-3,7-diene-1,6-dicarbonitrile (4b)
A soln of DDQ (0.114 g, 0.5 mmol) in anhyd benzene (10 mL) was
added to a soln of pyrrole 3b (0.153 g, 0.5 mmol) in anhyd acetone
(10 mL), and the mixture was stirred at r.t. for 5 min. The solvents
were removed to give a dark-cherry-colored lustrous powder that
was washed with Et2O (5 mL); yield: 0.202 g (76%); mp >300 °C.
IR (KBr): 2251 (nCN), 1713 (nC=O), 1623, sh. 1592, 1565, 1543,
1502 (nC=C), 1270, 1055 (nC–O), 809 cm–1 (nC–Cl).
1H NMR (400.13 MHz, CDCl3): d = 1.34 (t, J = 7.1 Hz, 3 H, CH3),
1.76 (m, 2 H, CH2-5), 1.85 (m, 2 H, CH2-6), 2.59 (m, 4 H, CH2-4,7),
4.28 (m, 2 H, OCH2), 5.14 (d, J = 16.8 Hz, 1 H, CH2Ph), 5.77 (d,
J = 16.8 Hz, 1 H, CH2Ph), 6.48 (m, 2 H, CH-2,6 Ph), 6.96 (s, 1 H,
H-3), 7.18 (m, 3 H, CH-3,4,5 Ph).
13C NMR (101.6 MHz, CDCl3): d = 14.1, 22.5, 22.9, 22.9, 23.0,
48.0, 52.2, 52.7, 62.1, 111.8, 111.9, 112.3, 122.1, 122.2, 124.2,
125.2, 127.8, 129.1, 136.8, 140.1, 141.9, 142.9, 145.4, 160.2, 174.8,
176.6.
IR (KBr): 2260 (nCN), 1712, 1630 (nC=O), 1597, 1582, 1543,
1493, 1472 (nC=C), 803 cm–1 (nC–Cl).
1H NMR (400.13 MHz, CDCl3): d = 6.90 (dd, 3J = 4.1 Hz, 4J = 2.4
Hz, 1 H, H-4), 7.27 (dd, 3J = 4.1 Hz, 4J = 2.4 Hz, 1 H, H-3), 7.46 (m,
2 H, CH-3,5 Ph), 7.57 (m, 2 H, CH-3,5 COPh), 7.67 (m, 3 H, CH-
2,6 Ph, CH-4 COPh), 7.87 (m, 2 H, CH-2,6 COPh), 12.63 (br s, 1 H,
NH).
UV/Vis (MeCN): lmax (log e) = sh. 267 (3.96), 285 (4.01), 368
(4.23), 462 nm (3.71).
Anal. Calcd for C28H21Cl2N3O4: C, 62.93; H, 3.96; Cl, 13.27; N,
7.86. Found: C, 62.75; H, 3.92; Cl, 13.55; N, 7.53.
13C NMR (101.6 MHz, C6D6): d = 30.0, 30.2, 112.3, 113.5, 113.8,
119.4, 123.5, 124.5, 126.7, 129.0, 129.8, 133.6, 135.8, 136.4, 140.7,
140.8, 143.3, 144.3, 174.3, 176.1, 187.3.
7-Benzoyl-3,4-dichloro-2,5-dioxo-8-(4,5,6,7-tetrahydro-1H-in-
dol-2-yl)bicyclo[4.2.0]octa-3,7-diene-1,6-dicarbonitrile (2d)
A soln of indole 1d (0.125 g, 1 mmol) and DDQ (0.114 g, 0.5 mmol)
in anhyd benzene (20 mL) was stirred at r.t. for 5 min. The benzene
was then evaporated and the residue was filtered on a short silica gel
column (5 g) with elution by CH2Cl2 to give a cherry-colored solid;
yield: 0.209 g (88%); mp >210 °C (dec.).
UV/Vis (MeCN): lmax (log e) = 282 (4.50), 412 (4.17), 491 nm
(4.24).
Anal. Calcd for C27H12Cl3N3O3: C, 60.87; H, 2.27; Cl, 19.96; N,
7.89. Found: C, 60.96; H, 2.36; Cl, 19.78; N, 7.59.
3,4-Dichloro-7-[5-(4-methoxyphenyl)-1H-pyrrol-2-yl]-8-(4-ni-
trobenzoyl)-2,5-dioxobicyclo[4.2.0]octa-3,7-diene-1,6-dicarbo-
nitrile (4c)
A soln of DDQ (0.114 g, 0. 5 mmol) in benzene (10 mL) was added
to a soln of pyrrole 3c (0.173 g, 0. 5 mmol) in acetone (10 mL), and
the mixture was stirred at r.t. for 5 min. The solvents were removed.
to give a dark cherry-colored lustrous powder that was washed with
Et2O (5 mL); yield: 0.263 g (92%); mp >300 °C.
IR (KBr): 2251 (nCN), sh. 1717, 1708, 1639 (nC=O), 1598, 1583,
1556, 1530, 1454 (nC=C), 803 cm–1 (nC–Cl).
1H NMR (400.13 MHz, CDCl3): d = 1.78 (m, 2 H, CH2-5), 1.86 (m,
2 H, CH2-6), 2.61 (m, 2 H, CH2-4), 2.78 (m, 2 H, CH2-7), 6.92 (d,
J = 1.7 Hz, 1 H, H-3), 7.53 (m, 2 H, CH-3,5 Ph), 7.61 (m, 1 H, CH-
4 Ph), 7.77 (m, 2 H, CH-2,6 Ph), 11.80 (br s, 1 H, NH).
13C NMR (101.6 MHz, CDCl3): d = 22.3, 22.9, 23.0, 24.1, 52.5,
53.8, 111.8, 113.3, 115.5, 121.2, 122.8, 127.9, 127.9, 129.0, 133.2,
136.3, 140.6, 143.2, 143.6, 144.3, 174.9, 176.4, 187.3.
IR (KBr): 2248 (nCN), 1725, 1713, 1629 (nC=O), 1603, 1575,
1545, 1493 (nC=C), 1529, 1344 (nNO2), 1436 (dOCH), 1261, 1026
(nC–O), 803 cm–1 (nC–Cl).
UV/Vis (MeCN): lmax (log e) = 272 (4.19), 408 (4.12), 480 nm
1H NMR (400.13 MHz, CDCl3): d = 3.87 (s, 3 H, MeO), 6.93 (dd,
3J = 4.0 Hz, 4J = 2.4 Hz, 1 H, H-4), 7.03 (d, J = 8.6 Hz, 2 H, CH-3,5
4-MeOC6H4), 7.34 (dd, 3J = 4.0 Hz, 4J = 2.4 Hz, 1 H, H-3), 7.73 (d,
J = 8.6 Hz, 2 H, CH-2,6 4-MeOC6H4), 7.96 (d, J = 8.4 Hz, 2 H, CH-
3,5 4-NO2C6H4), 8.40 (d, J = 8.4 Hz, 2 H, CH-2,6 4-NO2C6H4),
12.57 (br s, 1 H, NH).
13C NMR (101.6 MHz, C6D6): d = 29.7, 54.6, 112.2, 113.7, 113.9,
114.7, 114.9, 115.4, 121.3, 123.7, 124.5, 124.7, 140.8, 141.1, 143.0,
143.1, 143.6, 149.9, 161.6, 173.8, 173.9, 175.6, 185.2.
(3.96).
Anal. Calcd for C25H15Cl2N3O3: C, 63.04; H, 3.17; Cl, 14.89; N,
8.82. Found: C, 63.37; H, 3.26; Cl, 15.02; N, 8.89.
7-Benzoyl-3,4-dichloro-2,5-dioxo-8-(5-phenyl-1H-pyrrol-2-
yl)bicyclo[4.2.0]octa-3,7-diene-1,6-dicarbonitrile (4a)
A soln of DDQ (0.114 g, 0.5 mmol) in anhyd MeCN (10 mL) was
added to a soln of pyrrole 3a (0.136 g, 0.5 mmol) in anhyd MeCN
(10 mL), and the mixture was stirred at r.t. for 5 min. The solvent
was then evaporated and the residue was filtered on a short silica gel
column (5 g) with elution by CH2Cl2 to give a deep cherry-colored
solid; yield: 0.204 g (82%); mp 215–216 °C.
UV/Vis (MeCN): lmax (log e) = 278 (4.34), 447 (3.93), 530 nm
(4.13).
Anal. Calcd for C28H14Cl2N4O6: C, 58.66; H, 2.46; Cl, 12.37; N,
9.77. Found: C, 58.96; H, 2.36; Cl, 12.54; N, 9.59.
Synthesis 2010, No. 3, 470–476 © Thieme Stuttgart · New York

PAPER
Cycloaddition of DDQ to an Acetylenic Moiety
475
7-Benzoyl-3,4-dichloro-8-(1H-indol-3-yl)-2,5-dioxobicy-
clo[4.2.0]octa-3,7-diene-1,6-dicarbonitrile (6a)
A soln of DDQ (0.114 g, 0.5 mmol) in anhyd benzene (10 mL) was
added to a soln of indole 5a (0.123 g, 0.5 mmol) in anhyd acetone
(10 mL), and the mixture was stirred at r.t. for 5 min. The solvents
were removed to give a lustrous red powder that was washed with
Et2O (5 mL); yield: 0.205 g (87%); mp >300 °C.
Matsumoto, S.; Ogura, K. Heterocycles 2001, 55, 231.
(d) Matsumoto, S.; Kobayashi, T.; Ogura, K. Heterocycles
2005, 66, 319. (e) Hayes, M. E.; Shinokubo, H.; Danheiser,
R. L. Org. Lett. 2005, 7, 3917. (f) Nakamura, I.; Sato, T.;
Terada, M.; Yamamoto, Y. Org. Lett. 2007, 9, 4081.
(3) (a) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.;
Gonzalez, J. M. Adv. Synth. Catal. 2005, 347, 526.
(b) Barluenga, J.; Vazquez-Villa, H.; Merino, I.; Ballesteros,
A.; Gonzalez, J. M. Chem. Eur. J. 2006, 12, 5790. (c)Zhao,
J.; Hughes, C. O.; Toste, F. D. J. Am. Chem. Soc. 2006, 128,
7436. (d) Asao, N.; Aikawa, H. J. Org. Chem. 2006, 71,
5249.
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Chem. Soc. 2002, 124, 15168. (b) Coleman, C. M.; O’Shea,
D. F. J. Am. Chem. Soc. 2003, 125, 4054. (c) Campos, K.;
Woo, J. C. S.; Lee, S.; Tillyer, R. D. Org. Lett. 2004, 6, 79.
(d) Amjad, M.; Knight, D. W. Tetrahedron Lett. 2004, 45,
539. (e) Yue, D.; Larock, R. C. Org. Lett. 2004, 6, 1037.
(f) Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis 2004,
610.
IR (KBr): 3391 (nNH), 2247 (nCN), 1712, 1699, sh. 1628 (nC=O),
1607, 1598, 1580, 1557, 1496 (nC=C), 806 cm–1 (nC–Cl).
1H NMR (400.13 MHz, acetone-d6): d = 6.83 (m, 1 H, H-7), 6.94
(m, 1 H, H-6), 7.15 (m, 1 H, H-5), 7.40 (m, 2 H, CH-3 Ph), 7.55 (m,
2 H, CH-4 Ph, H-2), 7.95 (m, 2 H, CH-2 Ph), 8.07 (m, 1 H, H-4),
11.53 (br s, 1 H, NH).
13C NMR (101.6 MHz, acetone-d6): d = 53.9, 54.3, 106.6, 112.7,
113.1, 113.4, 120.5, 121.8, 123.8, 123.9, 125.9, 129.1, 129.2, 133.4,
134.5, 136.0, 137.0, 139.7, 142.0, 144.0, 176.6, 177.9, 187.6.
UV/Vis (MeCN): lmax (log e) = sh. 262 (4.72), 273 (4.73), 375
(4.21), 437 nm (3.77).
Anal. Calcd for C25H11Cl2N3O3: C, 63.58; H, 2.35; Cl, 15.01; N,
8.90. Found: C, 63.76; H, 2.36; Cl, 14.78; N, 8.59.
(5) (a) Trofimov, B. A.; Stepanova, Z. V.; Sobenina, L. N.;
Mikhaleva, A. I.; Ushakov, I. A. Tetrahedron Lett. 2004, 45,
6513. (b) Stepanova, Z. V.; Sobenina, L. N.; Mikhaleva, A.
I.; Ushakov, I. A.; Elokhina, V. N.; Voronov, V. K.;
Trofimov, B. A. Synthesis 2004, 2736. (c) Sobenina, L. N.;
Demenev, A. P.; Mikhaleva, A. I.; Ushakov, I. A.;
Vasil’tsov, A. M.; Ivanov, A. V.; Trofimov, B. A.
Tetrahedron Lett. 2006, 47, 7139. (d) Trofimov, B. A.;
Sobenina, L. N.; Stepanova, Z. V.; Demenev, A. P.;
Mikhaleva, A. I.; Ushakov, I. A.; Vakul’skaya, T. I.;
Petrova, O. V. Russ. J. Org. Chem. (Engl. Transl.) 2006, 42,
1348. (e) Trofimov, B. A.; Sobenina, L. N.; Stepanova, Z.
V.; Ushakov, I. A.; Petrova, O. V.; Tarasova, O. A.;
Volkova, K. A.; Mikhaleva, A. I. Synthesis 2007, 447.
(f) Trofimov, B. A.; Sobenina, L. N.; Demenev, A. P.;
Stepanova, Z. V.; Petrova, O. V.; Ushakov, I. A.; Mikhaleva,
A. I. Tetrahedron Lett. 2007, 48, 4661.
7-Benzoyl-3,4-dichloro-8-(2-methyl-1H-indol-3-yl)-2,5-dioxobi-
cyclo[4.2.0]octa-3,7-diene-1,6-dicarbonitrile (6b)
A soln of DDQ (0.114 g, 0.5 mmol) in anhyd benzene (10 mL) was
added to a soln of indole 5b (0.130 g, 0.5 mmol) in anhyd acetone
(10 mL), and the mixture was stirred at r.t. for 5 min. The solvents
were removed to give a lustrous red solid that was washed with Et2O
(5 mL); yield: 0.204 g (84%); mp >300 °C.
IR (KBr): 3372 (nNH), 2262, sh. 2254 (nCN), 1602, 1574, 1568,
1523, 1485, 1457 (nC=C), 1729, 1717, sh. 1625 (nC=O), 795 cm–1
(nC–Cl).
1H NMR (400.13 MHz, acetone-d6): d = 2.28 (s, 3 H, Me), 7.08,
7.15 (m, 2 H, H-5,6), 7.31 (m, 1 H, H-7), 7.40 (m, 2 H, CH-3 Ph),
7.53 (m, 1 H, CH-4 Ph), 7.61 (m, 1 H, H-4), 7.91 (m, 2 H, CH-2 Ph),
11.11 (br s, 1 H, NH).
13C NMR (101.6 MHz, acetone-d6): d = 13.7, 54.7, 56.4, 105.0,
112.2, 113.3, 114.3, 120.1, 122.2, 123.6, 126.5, 129.4, 129.4, 132.0,
135.1, 135.9, 136.4, 139.4, 142.0, 143.4, 147.9, 177.3, 177.6, 188.4.
(6) (a) Trofimov, B. A.; Sobenina, L. N.; Stepanova, Z. V.;
Vakul’skaya, T. I.; Kazheva, O. N.; Aleksandrov, G. G.;
Dyachenko, O. A.; Mikhaleva, A. I. Tetrahedron 2008, 64,
5541. (b) Trofimov, B. A.; Sobenina, L. N.; Stepanova, Z.
V.; Petrova, O. V.; Ushakov, I. A.; Mikhaleva, A. I.
Tetrahedron Lett. 2008, 49, 3946.
UV/Vis (MeCN): lmax (log e) = sh. 262 (4.35), 273 (4.36), 380
(3.70), 453 nm (3.62).
(7) Passarela, D.; Lesma, G.; Deleo, M.; Martinelli, M.; Silvani,
Anal. Calcd for C26H13Cl2N3O3: C, 64.21; H, 2.69; Cl, 14.58; N,
8.64. Found: C, 63.96; H, 2.56; Cl, 14.78; N, 8.59.
A. J. Chem. Soc., Perkin Trans. 1 1999, 2669.
(8) (a) Trofimov, B. A.; Mikhaleva, A. I. N-Vinylpyrroles;
Nauka: Novosibirsk, 1984. (b) Trofimov, B. A. Adv.
Heterocycl. Chem. 1990, 51, 177. (c) Trofimov, B. A.;
Mikhaleva, A. I.; Schmidt, E. Yu.; Ryapolov, O. A.;
Platonov, V. B. RU 2297410, 2006.
(9) (a) Lim, S.; Jabin, I.; Revial, G. Tetrahedron Lett. 1999, 40,
4177. (b) Trofimov, B. A.; Mikhaleva, A. I.; Schmidt, E.
Yu.; Ryapolov, O. A.; Platonov, V. B. RU 2307830, 2006.
(c) Trofimov, B. A.; Mikhaleva, A. I.; Schmidt, E. Yu.;
Ryapolov, O. A.; Platonov, V. B. RU 2345066, 2007.
(10) Bharate, S. B. Synlett 2006, 496.
(11) Begouin, A.; Hesse, S. In Proceedings of ECSOC-10 [on
CD-ROM], The Tenth International Electronic Conference
on Synthetic Organic Chemistry, November 1–30, 2006;
Seijas, J. A.; Tato, M. P. V., Eds.; MDPI: Basel, 2006, a007;
also available online at http://193.144.75.244/congresos/
ecsoc/10/GOS/a007/a007.pdf).
(12) Cavdar, H.; Saracoglu, N. J. Org. Chem. 2006, 71, 7793.
(13) (a) Sobenina, L. N.; Drichkov, V. N.; Mikhaleva, A. I.;
Petrova, O. V.; Ushakov, I. A.; Trofimov, B. A. Tetrahedron
2005, 61, 4841. (b) Trofimov, B. A.; Petrova, O. V.;
Sobenina, L. N.; Drichkov, V. N.; Mikhaleva, A. I.;
Acknowledgment
The work was carried out under financial support of leading scien-
tific schools by the President of the Russian Federation (Grant NSh-
263.2008.3), the Russian Foundation of Basic Research (Grant No
09-03-00064a).
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Synthesis 2010, No. 3, 470–476 © Thieme Stuttgart · New York