Diversity-Oriented Approach to Cyclophanes via Fischer Indolization and Ring-Closing Metathesis: Substrate-Controlled Stereochemical Outcome in RCM

Article abstract of DOI:10.1021/acs.joc.5b01433

Here, we report a new and diversity-oriented approach to macrocyclic cyclophanes by a Grignard reaction, followed by Fischer indolization and ring-closing metathesis (RCM) as key steps. The configuration of the double bond formed during the RCM depends upon the order of synthetic sequence used. Fischer indolization followed by RCM delivers the cis isomer, whereas RCM followed by Fischer indolization gives the trans isomer.

Full text of DOI:10.1021/acs.joc.5b01433

Article
pubs.acs.org/joc
Diversity-Oriented Approach to Cyclophanes via Fischer Indolization
and Ring-Closing Metathesis: Substrate-Controlled Stereochemical
Outcome in RCM
Sambasivarao Kotha,* Ajay Kumar Chinnam, and Mukesh E. Shirbhate
Department of Chemistry, Indian Institute of Technology-Bombay, Powai, India
S
* Supporting Information
ABSTRACT: Here, we report a new and diversity-oriented approach to macrocyclic cyclophanes by a Grignard reaction,
followed by Fischer indolization and ring-closing metathesis (RCM) as key steps. The configuration of the double bond formed
during the RCM depends upon the order of synthetic sequence used. Fischer indolization followed by RCM delivers the cis
isomer, whereas RCM followed by Fischer indolization gives the trans isomer.
INTRODUCTION
■
Ring-closing metathesis (RCM) is a useful tool for assembling
various macrocycles which are commonly found in many
natural products, pharmaceuticals, and supramolecular chem-
istry.1 Among several available methods for the synthesis of
cyclophane derivatives,2 RCM allows a late-stage ring closure
Figure 1. Retrosynthetic route to indole-based cyclophane derivatives.
with substrates containing polar functional groups.3 However, it
is difficult to control the stereochemistry of the olefin during
the macrocyclic formation involving RCM, and generally it
gives a mixture of cis and trans isomers. Few methods are
available to control the stereochemical outcome of the RCM
process, and a limited number of catalysts are accessible for this
purpose.4 However, there have been no reports of substrate-
based selectivity during the RCM process. Here, we have
designed and developed a new strategy for diversity-oriented
synthesis5 of cyclophane derivatives via RCM.6 In this context,
the indole moiety present in the RCM precursor acts as a
conformational control element (CCE)7 to deliver the
cyclophane derivative with predetermined olefinic configura-
tion. When the indole moiety is present in the cyclophane
precursor, the cis isomer was produced. Interestingly, the trans
isomer was formed in the absence of such an inbuilt CCE.
RESULTS AND DISCUSSION
■
Our journey toward the synthesis of cyclophanes begin with
commercially available starting materials. In this regard,
isophthalonitrile 1 was reacted with a Grignard reagent such
as 5-hexenylmagnesium bromide to generate the dione 2
(83%),8b which was then subjected to Fischer indolization in
the presence of 1-methyl-1-phenylhydrazine by using low-
melting mixture conditions9 to give the bis-indole derivative 3.
To this end, the conventional Fischer indolization conditions
(AcOH/HCl) are not useful. Next, the bis-indole derivative 3
was subjected to the RCM protocol in the presence of Grubbs
second-generation (G-II) catalyst to deliver the cyclized
product 4 as a single isomer (Scheme 1). Later, it was
1
identified by H and 13C NMR data. The structure of the
cyclophane 4 was confirmed by single-crystal X-ray diffraction
studies and the configuration of the double bond was found to
be cis.10 Formation of the cyclophane with a trans double bond
generates a strained system when it contains bulky indole rings
on both sides of the olefinic precursor.
We were interested in exploring the possibility of controlling
the configuration of the double bond by changing the reaction
STRATEGY
■
As part of a major program aimed at the development of new
strategies to various macrocycles,8 here we have designed a new
synthetic approach to indole-based cyclophane derivatives via
RCM. The retrosynthetic analysis conceived here involves
nucleophilic addition of a Grignard reagent such as
alkenylmagnesium bromide with 2,6-pyridinedicarbonitrile (or
isophthalonitrile), Fischer indolization, and RCM (Figure 1) as
key steps.
Received: July 2, 2015
© XXXX American Chemical Society
A
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compound 2 without any substituents gave the trans isomer.
However, an indole-appended substrate such as 3 gave the cis
isomer on cyclization. We do not anticipate the change in
configuration of the double bond present in 5 during the
Fischer indolization sequence.
Scheme 1. Synthesis of Cyclophane Derivative 4
To understand the scope of the above methodology, the
cyclophane derivative 10 was synthesized along similar lines. In
this regard, isophthalonitrile 1 was treated with the Grignard
reagent derived from 4-bromo-1-butene to deliver the dione 7
(75%), which was then subjected to an RCM sequence.
Unfortunately, the expected ring-closure product 8 was not
formed. Then, the dione 7 was subjected to Fischer indolization
to generate the bis-indole derivative 9, and later this derivative
was reacted with G-II catalyst to give the RCM product 10 as a
cis isomer (Scheme 3); we found that the indole units are
helping the RCM process and the configuration of 10 was
confirmed by single-crystal X-ray diffraction studies.10 Here, in
compound 7 the alkenyl chains are not disposed in a suitable
conformation to facilitate the metathesis process. We
anticipated that by introducing the two indole moieties on
the alkenyl chains (e.g., compound 9), they would be steered
into a suitable conformation which facilitates the RCM
protocol.
To expand the scope this strategy, 2,6-pyridinedicarbonitrile
11 was reacted with a Grignard reagent such as 5-
hexenylmagnesium bromide to generate the Grignard addition
product 12 (96%).8b Later, the dione 12 was subjected to
Fischer indolization in the presence of 1-methyl-1-phenyl-
hydrazine under low-melting mixture conditions to afford the
bis-indole derivative 13, which was subjected to the RCM
protocol in the presence of G-II to deliver the cyclized product
14; its structure was supported by NMR data (Scheme 4).
Finally, the structure of the cyclophane 14 was confirmed by
single-crystal X-ray diffraction studies and the configuration of
the double bond was found to be cis.10
sequence. When the dione 2 was subjected to the RCM
protocol, the configuration of the double bond present in the
cyclophane 5 on the basis of the NMR data was not conclusive.
However, the number of 13C NMR signals of 5 indicated that it
is a single compound.8b The cyclized product 5 was further
subjected to Fischer indolization to give the bis-indole-based
cyclophane derivative 6 (Scheme 2). Later, its structure was
Scheme 2. Synthesis of Cyclophane Derivative 6
To generalize our strategy, the dione 12 was subjected to
RCM to generate the cyclophane derivative 158b as a single
isomer, and then it was subjected to Fischer indolization to
deliver the bis-indole derivative 16 (Scheme 5).
Along similar lines, cyclophane derivative 19 synthesis was
conceived. To this end, 2,6-pyridinedicarbonitrile 11 was
treated with the Grignard reagent derived from 4-bromo-1-
butene to deliver the dione 17 (74%). Next, the dione 17 was
subjected to an RCM sequence and the expected ring-closure
product was not formed. Then, the dione 17 was subjected to
1
identified by H and 13C NMR data, but the spectral data did
not match those of the compound 4 obtained by an earlier
route, which involved Fischer indolization followed by RCM.
The single-crystal X-ray diffraction studies clearly indicated that
the double bond present in 6 is in a trans configuration.10 Thus,
Scheme 3. Synthesis of Cyclophane Derivative 10
B
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Article
oxidation in CH2Cl2 to deliver the dione 22 (71%). Next, dione
22 was subjected to a Fischer indolization sequence with 1-
methyl-1-phenylhydrazine to give the bis-indole product 23
(86%). Then, the bis-indole derivative 23 was treated with G-II
catalyst to deliver the cyclized product 24 in good yield (92%,
Scheme 7).
Scheme 4. Synthesis of Cyclophane Derivative 14
Scheme 7. Synthesis of Cyclophane Derivative 24
Scheme 5. Synthesis of Cyclophane Derivative 16
CONCLUSION
■
We have developed a simple synthetic strategy to indole-based
cyclophane derivatives via RCM utilizing G-II catalyst. The
presence of an inbuilt indole moiety next to the aromatic ring
gave the cis isomer during the RCM sequence. However,
without such an inbuilt indole ring, the trans isomer was
obtained during the RCM process. The structures of the five
macrocycles synthesized were confirmed by single-crystal X-ray
diffraction data and clearly indicated that the macrocycle 4 was
endowed with a cis double bond, whereas the macrocycle 6
contains a trans double bond.
Fischer indolization to generate the bis-indole derivative 18,
and later it was subjected to RCM to generate the cyclized
product 19 (Scheme 6) as a cis isomer. The structure of the
cyclophane derivative 19 was confirmed by single-crystal X-ray
diffraction studies.10
To expand the scope of this methodology, we have also
assembled a furan-based cyclophane derivative such as 24. Since
furan derivatives can undergo Diels−Alder chemistry, these
cyclophanes are interesting substrates for further synthetic
manipulation.11 To this end, the 2,5-furandicarboxaldehyde
20,12 prepared by a known method, was treated with a Grignard
reagent such as 5-hexenylmagnesium bromide to generate the
diol 21 (77%). Later, the diol 21 was subjected to MnO2
EXPERIMENTAL SECTION
■
All reactions were performed under an argon or nitrogen atmosphere
using a well-dried reaction flask. All commercial products were used as
received without further purification. All of the solvents used as
reaction media were dried over molecular sieves (4 Å) predried in a
microwave oven, Column chromatography was performed with silica
gel (100−200 mesh) using a mixture of petroleum ether and EtOAc as
eluent. 1H and 13C NMR spectral data were recorded on 400 and 100
MHz or 500 and 126 MHz spectrometers using tetramethylsilane
Scheme 6. Synthesis of Cyclophane Derivative 19
C
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(TMS) as an internal standard and chloroform-d as solvent. Mass
spectral data were recorded on a Q-TOF micromass spectrometer.
High-resolution mass spectroscopy (HRMS) was performed with a
TOF mass spectrometer in positive ESI mode. X-ray diffraction data
for compounds 4, 6, 10, 14, and 19 were collected on a diffractometer
equipped with graphite-monochromated Mo Kα radiation. The
structure was solved by direct methods using shelxs-97 and refined
by full-matrix least squares against F2 using shelxl-97 software. The
melting points recorded are uncorrected.
General Procedure for Grignard Addition Reaction. Mg
turnings and iodine in THF were heated to reflux until the brown
color disappeared. Then, 5-bromo-1-pentene (273 mg, 1.92 mmol)
was added and the mixture was stirred for 30 min. Next,
isophthalonitrile 1 (100 mg, 0.77 mmol) was added and the resulting
mixture was stirred and heated to reflux for 3 h. At the conclusion of
the reaction (TLC monitoring), 2 N HCl was added and the reaction
mixture was stirred for 30 min. The reaction mixture was diluted with
EtOAc (10 mL) and H2O (10 mL), and the reaction mixture was
stirred well and extracted with EtOAc. The organic layer was washed
with brine and dried with Na2SO4. EtOAc was removed under reduced
pressure, and the crude product obtained was purified by column
chromatography to give the dione.
General Procedure for the Preparation of Bis-Indole
Derivatives. In a typical experiment, 1.5 g of an L-(+)-tartaric acid/
N,N′-dimethylurea (30/70) mixture was heated to 70 °C to obtain a
clear melt. To this melt were added 2 mmol of N-methyl-N-
phenylhydrazine and 1 mmol of diketone at 70 °C. At the conclusion
of the reaction (TLC monitoring by mini workup), the reaction
mixture was quenched with water while it was still hot. The reaction
mixture was cooled to room temperature, and the solid was filtered
through a sintered-glass funnel and washed with water (2 × 5 mL).
The crude product was dried under vacuum, and then it was purified
by silica gel column chromatography.
1,3-Bis(3-(but-3-en-1-yl)-1-methyl-1H-indol-2-yl)benzene (3): pale
yellow oil, 76% (150 mg, starting with 120 mg of 1,1′-(1,3-
phenylene)bis(hex-5-en-1-one) (2)); Rf = 0.60 (petroleum ether/
EtOAc 95/5); IR (neat) νmax 3774, 2919, 2850, 1734, 1641, 1467,
̃
1363, 1244, 1047 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.50−2.51 (m,
4H), 2.98−2.99 (m, 4H), 3.73 (s, 6H), 5.00−5.11 (m, 4H), 5.92−5.95
(m, 2H), 7.27−7.29 (m, 2H), 7.36−7.39 (m, 2H), 7.45−7.46 (m, 2H),
7.55−7.57 (m, 3H), 7.69−7.78 (m, 3H); 13C NMR (100.6 MHz,
CDCl3) δ 24.5, 31.0, 35.4, 109.6, 113.4, 114.7, 119.3, 119.4, 122.0,
127.7, 128.6, 130.4, 132.5, 132.7, 137.4, 138.8; HRMS (Q-Tof) m/z
calcd 445.2638 for C32H33N2 [M + H]+, found 445.2638.
1,1′-(1,3-Phenylene)bis(pent-4-en-1-one) (7): semisolid, 77% (436
(E)-5,11-Dimethyl-5,11,16,17,20,21-hexahydro-6,10-(metheno)-
cyclotrideca[1,2-b:8,7-b′]diindole (6): white solid, 48% (24 mg,
starting with 30 mg of dione 5); mp 269−270 °C; Rf = 0.80
mg, starting with 300 mg of isophthalonitrile 1 + 4-pentenymagnesium
bromide); Rf = 0.70 (petroleum ether/EtOAc 80/20); IR (neat) νmax
̃
3634, 3463, 2986, 2086, 1890, 1742, 1447, 1374, 1242, 1047 cm−1; 1H
NMR (400 MHz, CDCl3) δ 2.47−2.53 (m, 4H), 3.10 (t, J = 4.60 Hz,
4H), 4.99−5.11 (m, 4H), 5.84−5.94 (m, 2H), 7.56 (t, J = 7.76 Hz
1H), 8.14 (dd, J1 = 1.76 Hz, J2 = 7.76 Hz 2H), 8.51 (t, J = 1.51 Hz,
1H); 13C NMR (100.6 MHz, CDCl3) δ 28.1, 38.0, 115.7, 127.6, 129.2,
132.3, 137.1, 137.4, 198.8; HRMS (Q-Tof) m/z calcd 243.1380 for
C16H19O2 [M + H]+, found 243.1370.
(petroleum ether/EtOAc 90/10); IR (neat) νmax 2923, 2853, 1656,
̃
1
1601, 1468, 1363, 1220, 1020 cm−1; H NMR (500 MHz, CDCl3) δ
2.48 (q, J = 5.92 Hz, 4H), 2.88 (t, J = 6.00 Hz, 4H), 3.72 (s, 6H), 5.47
(t, J = 4.08 Hz, 2H), 7.15−7.19 (m, 2H), 7.28−7.32 (m, 2H), 7.35−
7.44 (m, 4H), 7.57 (t, J = 7.60 Hz, 2H), 7.66 (d, J = 7.84 Hz, 2H); 13C
NMR (125.6 MHz, CDCl3) δ 25.3, 31.5, 32.8, 109.6, 113.4, 119.3,
119.4, 122.0, 127.9, 128.9, 131.6, 131.9, 134.6, 137.4, 137.8; HRMS
(Q-Tof) m/z calcd 417.2325 for C30H29N2 [M + H]+, found 417.2325.
1,3-Bis(3-allyl-1-methyl-1H-indol-2-yl)benzene (9): pale yellow oil,
78% (80 mg, starting with 60 mg of 1,1′-(1,3-phenylene)bis(pent-4-
1,1′-(Pyridine-2,6-diyl)bis(pent-4-en-1-one) (17): pale yellow oil,
74% (242 mg, starting with 200 mg of 2,6-pyridinedicarbonitrile 11 +
4-pentenymagnesium bromide); Rf = 0.70 (petroleum ether/EtOAc
90/10); IR (neat) νmax
̃
3684, 3619, 3019, 2976, 2927, 2400, 1729,
en-1-one) (7)); Rf = 0.70 (petroleum ether/EtOAc 90/10); IR (neat)
1688, 1601, 1519, 1423, 1221, 1046 cm−1; 1H NMR (400 MHz,
CDCl3) δ 2.52 (q, J = 7.24 Hz, 4H), 3.37 (t, J = 7.29 Hz, 4H), 5.00−
5.12 (m, 4H), 5.87−5.97 (m, 2H), 7.98 (t, J = 7.92 Hz, 1H), 8.19 (d, J
= 7.80 Hz, 2H); 13C NMR (100.6 MHz, CDCl3) δ 28.2, 37.0, 115.4,
125.9, 137.5, 138.2, 152.6, 200.7; HRMS (Q-Tof) m/z calcd 266.1151
for C15H17NNaO2 [M + Na]+, found 266.1157.
ν
̃
2920, 1712, 1467, 1427, 1365, 1223, 1092 cm−1; H NMR (500
1
max
MHz, CDCl3) δ 3.52−3.53 (m, 4H), 3.69 (s, 6H), 5.00−5.06 (m, 4H),
6.00−6.07 (m, 2H), 7.15−7.19 (m, 2H), 7.27−7.31 (m, 2H), 7.38 (d, J
= 8.16 Hz, 2H), 7.45−7.49 (m, 3H), 7.62 (t, J = 7.61 Hz, 1H), 7.66 (d,
J = 7.90 Hz, 2H); 13C NMR (100.6 MHz, CDCl3) δ 29.4, 31.2, 109.6,
111.1, 114.9, 119.5, 122.1, 127.9, 128.6, 130.3, 132.2, 132.5, 137.6,
137.7, 137.9; HRMS (Q-Tof) m/z calcd 417.2325 for C30H29N2 [M +
H]+, found 417.2323.
1,1′-(Furan-2,5-diyl)bis(hex-5-en-1-ol) (21): pale yellow oil, 77%
(300 mg, starting with 200 mg of 2,5-furandicarboxaldehyde 20 + 5-
hexenylmagnesium bromide); Rf = 0.60 (petroleum ether/EtOAc 80/
2,6-Bis(3-(but-3-en-1-yl)-1-methyl-1H-indol-2-yl)pyridine (13):
pale yellow oil, 89% (101 mg, starting with 70 mg of 1,1′-(pyridine-
2,6-diyl)bis(hex-5-en-1-one) (12)); Rf = 0.70 (petroleum ether/
20); IR (neat) νmax 3524, 3022, 2946, 2835, 1638, 1463, 1365, 1286,
̃
1047 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.31−1.39 (m, 2H), 1.40−
1.57 (m, 2H) 1.76−1.86 (m, 4H), 2.02−2.10 (m, 4H), 2.84 (bs, 2H),
4.58 (t, J = 6.56 Hz, 2H) 4.92−5.01 (m, 4H), 5.72−5.82 (m, 2H), 6.10
(s, 2H); 13C NMR (100.6 MHz, CDCl3) δ 24.9, 33.5, 34.8, 34.8, 67.6,
106.4, 106.4, 114.9, 138.6, 156.1, 156.2; HRMS (Q-Tof) m/z calcd
287.1618 for C16H24NaO3 [M + Na]+, found 287.1618.
EtOAc 90/10); IR (neat) νmax 2984, 2941, 2878, 1522, 1424, 1216,
̃
1046 cm−1; 1H NMR (500 MHz, CDCl3) δ 2.49 (q, J = 7.55 Hz, 4H),
3.03 (t, J = 7.75 Hz, 4H), 3.82 (s, 6H), 4.96−5.08 (m, 4H), 5.87−5.95
(m, 2H), 7.21 (t, J = 7.05 Hz, 2H), 7.32−7.35 (m, 2H), 7.41 (d, J =
8.25 Hz, 2H), 7.54 (d, J = 7.75 Hz, 2H), 7.74 (d, J = 7.89 Hz, 2H),
7.94 (t, J = 7.80 Hz, 1H); 13C NMR (125.6 MHz, CDCl3) δ 24.6, 31.5,
35.4, 109.7, 114.7, 115.1, 119.4, 119.6, 122.7, 124.0, 127.6, 136.0,
136.6, 137.9, 138.7, 151.9; HRMS (Q-Tof) m/z calcd 468.2410 for
C31H31N3Na [M + Na]+, found 468.2414.
General Procedure for the Preparation of Oxidation. To a
solution of dialcohol derivative 21 (50 mg) in CH2Cl2 (10 mL) was
added MnO2 (4 equiv) oxidizing agent at room temperature, and the
reaction mixture was heated at reflux overnight. At the conclusion of
the reaction (TLC monitoring), the crude reaction mixture was filtered
through a Celite pad (washed with CH2Cl2) and concentrated under
reduced pressure. The crude product was purified by column
chromatography (silica gel; EtOAc/petroleum ether, 10%) to diketone
derivative 22.
(E)-5,11-Dimethyl-5,11,16,17,20,21-hexahydro-6,10-(azeno)-
cyclotrideca[1,2-b:8,7-b′]diindole (16): white solid, 44% (59 mg,
starting with 80 mg of dione 15); mp 248−250 °C; Rf = 0.40
(petroleum ether/EtOAc 90/10); IR (neat) νmax 3004, 2969, 2924,
̃
1
1714, 1422, 1364, 1223, 1093 cm−1; H NMR (500 MHz, CDCl3) δ
2.26−2.29 (m, 4H), 3.02−3.09 (m, 4H), 3.84 (s, 6H), 5.15 (s, 2H),
7.14−7.21 (m, 2H), 7.29−7.36 (m, 2H), 7.38−7.48 (m, 4H), 7.68−
7.71 (m, 2H), 7.87−7.95 (m, 1H); 13C NMR (125.6 MHz, CDCl3) δ
24.2, 31.8, 32.9, 109.7, 116.6, 119.4, 119.6, 122.6, 122.9, 127.9, 130.7,
135.8, 136.6, 138.0, 151.9; HRMS (Q-Tof) m/z calcd 418.2278 for
C29H28N3 [M + H]+, found 418.2275.
1,1′-(Furan-2,5-diyl)bis(hex-5-en-1-one) (22): pale yellow oil, 71%
(140 mg, starting with 200 mg of furan diol 21); Rf = 0.50 (petroleum
ether/EtOAc 80/20); IR (neat) νmax 3162, 3021, 2943, 2627, 2410,
̃
2293, 2254, 1637, 1376, 1230, 1039 cm−1; 1H NMR (400 MHz,
CDCl3) δ 1.80−1.87 (m, 4H), 2.14 (q, J = 7.16 Hz, 4H) 2.90 (t, J =
7.40 Hz, 4H), 4.97−5.06 (m, 4H), 5.74−5.84 (m, 2H), 7.18 (s, 2H);
13C NMR (100.6 MHz, CDCl3) δ 23.0, 33.2, 38.0, 115.7, 117.1, 137.9,
153.6, 190.3; HRMS (Q-Tof) m/z calcd 283.1305 for C16H20NaO3 [M
+ Na]+, found 283.1304.
2,6-Bis(3-allyl-1-methyl-1H-indol-2-yl)pyridine (18): pale yellow
oil, 65% (103 mg, starting with 80 mg of 1,1′-(pyridine-2,6-
diyl)bis(pent-4-en-1-one) (17)); Rf = 0.70 (petroleum ether/EtOAc
D
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Article
90/10); IR (neat) νmax
̃
3854, 2949, 2844, 2349, 2261, 1651, 1459,
1H NMR (500 MHz, CDCl3) δ 3.39 (d, J = 13.80 Hz, 2H), 3.83 (s,
1022 cm−1; H NMR (400 MHz, CDCl3) δ 3.64−3.65 (m, 4H), 3.85
(s, 6H), 5.07−5.12 (m, 4H), 6.07−6.17 (m, 2H), 7.14−7.18 (m, 2H),
7.28−7.33 (m, 2H), 7.39 (d, J = 8.20 Hz, 2H), 7.53 (d, J = 7.81 Hz,
2H), 7.67 (d, J = 7.88 Hz, 2H), 7.90 (t, J = 5.32 Hz, 1H); 13C NMR
(100.6 MHz, CDCl3) δ 29.5, 31.7, 109.7, 112.6, 115.2, 119.5, 119.8,
122.8, 123.9, 127.7, 136.3, 136.6, 137.7, 137.9, 151.5; HRMS (Q-Tof)
m/z calcd 440.2097 for C29H27N3Na [M + Na]+, found 440.2095.
2,5-Bis(3-(but-3-en-1-yl)-1-methyl-1H-indol-2-yl)furan (23): pale
yellow oil, 86% (143 mg, starting with 100 mg of 1,1′-(furan-2,5-
diyl)bis(hex-5-en-1-one) (22)); Rf = 0.70 (petroleum ether/EtOAc
1
6H), 3.99 (t, J = 11.51 Hz, 2H), 5.74 (dd, J1 = 4.75 Hz, J2 = 6.15 Hz,
2H), 7.18−7.21 (m, 2H), 7.28−7.33 (m, 2H), 7.36 (d, J = 8.20 Hz,
2H), 7.43 (d, J = 7.85 Hz, 2H), 7.77 (d, J = 7.91 Hz, 2H); 7.93, (t, J =
7.81 Hz, 1H); 13C NMR (125.6 MHz, CDCl3) δ 23.4, 31.9, 109.9,
116.6, 119.3, 119.8, 121.7, 122.9, 127.0, 128.3, 136.2, 137.1, 138.3,
151.3; HRMS (Q-Tof) m/z calcd 390.1970 for C27H24N3 [M + H]+,
found 390.1980.
(Z)-5,10-Dimethyl-5,10,15,16,19,20-hexahydro-6,9-
epoxycyclododeca[1,2-b:8,7-b′]diindole (24): white solid, 92% (43
mg, starting with 50 mg of 2,5-bis(3-(but-3-en-1-yl)-1-methyl-1H-
indol-2-yl)furan (23)); mp 268−271 °C; Rf = 0.30 (petroleum ether/
90/10); IR (neat) νmax 3054, 2928, 2854, 2291, 2253, 1639, 1467,
̃
1368, 1238, 1035 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.48−2.52 (m,
4H), 3.04−3.07 (m, 4H), 3.87 (s, 6H), 4.99−5.13 (m, 4H), 5.92−6.00
(m, 2H), 6.75 (d, J = 6.65 Hz, 2H), 7.20 (t, J = 7.10 Hz, 2H), 7.33 (t, J
= 8.00 Hz, 2H), 7.38 (t, J = 6.21 Hz, 2H), 7.69 (t, J = 7.76 Hz, 2H);
13C NMR (100.6 MHz, CDCl3) δ 24.7, 31.6, 35.4, 109.6, 112.2, 114.9,
EtOAc 90/10); IR (neat) νmax 3054, 2935, 2861, 2345, 1650, 1464,
̃
1265 cm−1; 1H NMR (500 MHz, CDCl3) δ 2.56−2.61 (m, 4H), 3.00−
3.04 (m, 4H), 3.85 (s, 6H), 5.87−5.93 (m, 2H), 6.67 (s, 2H), 7.17−
7.20 (m, 2H), 7.28−7.32 (m, 2H), 7.35 (d, J = 8.20 Hz, 2H), 7.71 (d, J
= 7.90 Hz, 2H); 13C NMR (125.6 MHz, CDCl3) δ 27.5 30.1, 31.5,
109.7, 111.7, 116.2, 119.3, 119.7, 122.8, 127.4, 127.5, 131.1, 138.2,
147.3; HRMS (Q-Tof) m/z calcd 407.2123 for C28H27N2O [M + H]+,
found 407.2141.
115.9, 119.5, 119.6, 122.8, 127.4, 127.6, 137.8, 138.7, 146.6; HRMS
(Q-Tof) m/z calcd 435.2431 for C30H31N2O [M + H]+, found
435.2438.
General Procedure for RCM Reaction. A solution of the bis-
indole-alkene derivative 3 (0.36 mmol) in dry CH2Cl2 (50 mL) was
degassed with nitrogen for 15 min. Then, G-II catalyst (7.5 mol %)
was added and the reaction mixture was stirred at room temperature
for 24 h. At the conclusion of the reaction (TLC monitoring), the
solvent was removed under reduced pressure and the crude product
was purified by silica gel column chromatography (5% EtOAc/
petroleum ether) to give the RCM compound 4 as a colorless solid.
(Z)-5,11-Dimethyl-5,11,16,17,20,21-hexahydro-6,10-(metheno)-
cyclotrideca[1,2-b:8,7-b′]diindole (4): white solid, 98% (55 mg,
starting with 60 mg of 1,3-bis(3-(but-3-en-1-yl)-1-methyl-1H-indol-2-
yl)benzene (3)); mp 263−265 °C; Rf = 0.60 (petroleum ether/EtOAc
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01433.
■
S
1H and 13C NMR spectra for all new compounds and X-
ray crystallographic data and refinement parameters for
4, 6, 10, 14, and 19 (PDF)
X-ray crystallographic data for 4, 6, 10, 14, and 19 (ZIP)
AUTHOR INFORMATION
Corresponding Author
*S.R.K.: fax, 022-2572 7152; e-mail, srk@chem.iitb.ac.in.
Notes
90/10); IR (neat) νmax 3621, 3018, 2926, 2853, 1733, 1602, 1466,
̃
■
1
1216, 1046 cm−1; H NMR (500 MHz, CDCl3) δ 2.63 (s, 4H), 3.05
(bs, 4H), 3.77 (s, 6H), 5.89 (bs, 2H), 7.18−7.22 (m, 2H), 7.28−7.32
(m, 2H), 7.39−7.42 (m, 4H), 7.62 (t, J = 7.68 Hz, 1H), 7.72 (d, J =
7.89 Hz, 2H), 7.80 (t, J = 1.31 Hz, 1H); 13C NMR (125.6 MHz,
CDCl3) δ 27.7, 30.5, 31.4, 109.7, 114.3, 119.3, 119.5, 122.2, 127.7,
128.3, 129.6, 130.7, 132.2, 132.7, 137.3, 137.8; HRMS (Q-Tof) m/z
calcd 417.2325 for C30H29N2 [M + H]+, found 417.2329.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(Z)-5,11-Dimethyl-5,11,16,19-tetrahydro-6,10-(metheno)-
cyclotrideca[1,2-b:8,7-b′]diindole (10): white solid, 83% (13 mg,
starting with 17 mg of 1,3-bis(3-allyl-1-methyl-1H-indol-2-yl)benzene
(9)); mp 268−271 °C; Rf = 0.60 (petroleum ether/EtOAc 85/15); IR
We thank the Department of Science and Technology (DST),
New Delhi, India, for financial support and the Sophisticated
Analytical Instrument Facility (SAIF), IIT-Bombay, for record-
ing spectral data. S.K. thanks the Department of Science and
Technology for the award of a J. C. Bose fellowship. A.K.C.
thanks the University Grants Commission, New Delhi, India,
for the award of a research fellowship. M.E.S. thanks the IIT-
Bombay for the award of a research fellowship.
(neat) νmax
2984, 2935, 1697, 1652, 1422, 1371, 1239, 1023 cm−1; 1H
̃
NMR (500 MHz, CDCl3) δ 3.40 (d, J = 14.55 Hz, 2H), 3.77−3.82 (m,
2H), 3.90 (s, 6H), 5.82 (s, 2H), 7.20 (t, J = 7.70 Hz, 2H), 7.30 (t, J =
7.40 Hz, 2H), 7.40 (d, J = 8.15 Hz, 2H), 7.47 (dd, J1 = 1.45 Hz, J2 =
7.60 Hz, 2H), 7.62 (t, J = 7.61 Hz, 1H), 7.73 (d, J = 7.85 Hz, 2H), 8.14
(s, 1H); 13C NMR (125.6 MHz, CDCl3) δ 23.5, 31.3, 109.7, 113.6,
118.6, 119.7, 122.2, 127.3, 128.3, 128.7, 131.8, 137.1, 137.3, 138.9;
HRMS (Q-Tof) m/z calcd 389.2018 for C28H25N2 [M + H]+, found
389.2009.
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