Synthesis of hexadehydrotribenzo[a,e,i][12]annulenes by acetylene insertion into an open-chain precursor

Article abstract of DOI:10.1021/jo202016v

A simple synthesis of a hexadehydrotribenzo[a,e,i][12]annulene by insertion of acetylene into an open-chain diiodo precursor under Sonogashira coupling conditions has been developed and used to prepare a rigid three-armed star connector for testing as a b

Full text of DOI:10.1021/jo202016v

Article
pubs.acs.org/joc
Synthesis of Hexadehydrotribenzo[a,e,i][12]annulenes by Acetylene
Insertion into an Open-Chain Precursor
Miroslav Dudic,† Ivana Císarova,§ and Josef Michl*,†,‡
̌
̌
́
†Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 16610 Prague, Czech Republic, and
‡Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215, United States
§Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 2030, 12840 Prague 2,
Czech Republic
S
* Supporting Information
ABSTRACT: A simple synthesis of a hexadehydrotribenzo-
[a,e,i][12]annulene by insertion of acetylene into an open-
chain diiodo precursor under Sonogashira coupling conditions
has been developed and used to prepare a rigid three-armed
star connector for testing as a building block for a two-
dimensional hexagonal hydrogen-bonding array.
INTRODUCTION
RESULTS
■
■
Hexadehydrotribenzo[a,e,i][12]annulene derivatives and their
multiply fused analogues1,2 have attracted considerable interest,
mainly because they combine a delocalized cyclic π-electron
system with a well-defined rigid triangular geometry.3−5 They
have been recently investigated as optoelectronic materials6−14
and as building blocks in supramolecular chemistry15−24 and
crystal engineering.16,19,25 However, in spite of the availability
of several coupling methods,27−29 such as those by Sonogashira,
Suzuki, Castro-Stevens, and Negishi, the reported syntheses of
these macrocycles generally suffer from low yields and difficult
product isolation.
The drawbacks of the most commonly used procedure, the
trimerization of o-iodoethynylbenzenes, are the usually
relatively poor accessibility of starting materials and the
generally quite low yields (5−64%).9,18,19,21,23,26,30−35 Alkyne
metathesis is a promising approach that affords good yields in
some cases (54−86%) but often requires strictly anaerobic
conditions.36−39 There is only one communication that
describes what would appear to be the simplest synthetic
approach, a direct connection of an o-diiodobenzene with
acetylene under Sonogashira coupling conditions, in yields
varying between 11 and 39%.40 An inspiring approach has been
provided by the Sonogashira coupling of a rod-shaped diiodo
derivative with a bis-ethynyl derivative, which gave the desired
trigonal macrocycles in yields of 25−30%.15,24
Our initial efforts to prepare the hexadehydrotribenzo[a,e,i]-
[12]annulene hexaester 1, a key intermediate for the desired
star connector 2 (Chart 1), followed the most common
literature procedures. These are the trimerization of an o-
iodoethynylbenzene or its phthalimide analogue and the
cyclization of o-diiodobenzene or the corresponding phthali-
mide derivative with acetylene under Sonogashira or Castro-
Stevens coupling conditions. These attempts all yielded
complex mixtures, and neither the desired product nor the
starting materials were isolated in significant yield.
Only the trimerization of o-iodoethynylbenzene 3 under
Sonogashira coupling and high dilution conditions led to the
formation of any trigonal derivative 1, and it was mixed with the
square 4. Most of the reaction products did not pass through a
silica gel column and were presumably of oligomeric or
polymeric nature, and only a 10% yield of 1 and 5% yield of 4
were isolated.
Following this initial discouragement, two synthetic pathways
were developed for the sextuple methyl ester derivative of 1.
The first one was inspired by a published procedure in which a
doubly terminally iodinated rod is coupled with a bis-ethynyl
derivative.15,24 In the second and superior one, 1 was formed by
acetylene insertion into the diiodo derivative 5. An attempt to
replace acetylene with calcium carbide46 failed.
A Classical Route (Scheme 1). Our first successful
synthesis of hexadehydrotribenzo[a,e,i][12]annulenes followed
the classical approach.15,24 It started from o-xylene (6), which
was converted to 1,2-diiodo-4,5-dimethylbenzene (7) by
oxidative iodination47 in 65% yield. Oxidation of 7 by
potassium permanganate in water in the presence of pyridine
led to the corresponding dicarboxylic acid 8 (72%).48 The
We are interested in the use of hexadehydrotribenzo[a,e,i]-
[12]annulenes as 3-fold connectors in the construction of two-
dimensional hydrogen-bonded networks and describe an
alternative approach to this ring system, the insertion of
acetylene into an open chain diiodide. Acetylene has been used
in Sonogashira coupling since the early days,41 and considerable
precedent for the reactions used in our approach exists.42−45
The new ring closure still has an only moderate yield of 57%,
but it uses easily accessible starting materials and permits facile
product isolations.
Received: June 13, 2011
Published: November 22, 2011
© 2011 American Chemical Society
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Chart 1
Scheme 1
addition of pyridine greatly improved the yield since it allowed
the portion of 7 that sublimed into the condenser to be flushed
back into the reaction vessel. The diacid 8 was esterified with
methanol in the presence of thionyl chloride in 86% yield, and
Sonogashira coupling of the diester 949 with ethynyltrimethyl-
silane (1.05 equiv) followed by deprotection with tetrabutyl-
ammonium fluoride afforded the monoiodomonoethynyl
compound 3 in a statistical mixture, from which it was isolated
in a 34% yield.
Scheme 2
The last step in the synthesis of the doubly iodinated rod 10
was the coupling of 3 with excess 9, which proceeded in a yield
of 37%, limited by the formation of the byproduct 5, which was
isolated in a 16% yield. The bis-ethynyl derivative 11 was
prepared in 72% yield by the reaction of 9 with an excess of
ethynyltrimethylsilane followed by deprotection (Scheme 2).
Under high dilution conditions, the Sonogashira coupling of 10
with 11 afforded the desired macrocycle 1 in 32% yield.
A New Route (Scheme 3). The open-chain side product 5
is nearly identical with the full desired annulene, except for only
one missing acetylene link, and its formation therefore
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molecules are packed in columns similarly as in certain other
compounds of this type26 (Figure S1, Supporting Information).
The straightforward procedure of Scheme 3 suffers from the
low yield in which the precursor 5 is formed to start with. A
search for the best conditions for its preparation by Sonogashira
coupling of 11 with a large excess of 9 (Scheme 4) produced a
yield of 51%. This value is affected by the formation of the
square derivative 4, which was isolated in a ∼10% yield and less
than 90% purity, and whose structure was confirmed only by
Scheme 3
1
high resolution mass spectrometry and H and 13C NMR
spectroscopy.
suggested an alternative path to 1. Indeed, introduction of
anhydrous gaseous acetylene into a solution of 5 in the
presence of tetrakis(triphenylphosphine)palladium(0) and
copper(I) iodide produced 1 in 57% yield. The exact
dimensions of the annulene 1 were determined by single-
crystal X-ray diffraction (Figure S1, Supporting Information).
Interestingly, we were only able to grow suitable crystals from
THF in the presence of metal triflates such as silver triflate,
even though the salt was not incorporated in the crystal. The
The transformation of 1 into the desired rigid star connector
2 was performed in four steps (Scheme 5). Methyl ester
hydrolysis, anhydride formation, and subsequent glycine tert-
butyl ester insertion afforded the tri-tert-butyl derivative 12 in a
51% overall yield. After the removal of tert-butyl groups with
trifluoroacetic acid the final product 2 was isolated in 90% yield.
The use of the cheaper glycine methyl ester instead of tert-
butyl ester is unsatisfactory due to difficulties with selectivity in
the final hydrolysis step. Several methods that we expected to
Scheme 4
Scheme 5
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Scheme 6
preferentially remove the methyl ester group in the presence of
a phthalimide moiety (NaOH/H2O at 20 or 60 °C, LiI50 in
EtOAc or THF, AlCl3,51 and HCl52) were tested on a model,
methyl 2-(5,6-diiodo-1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-
acetate, and yielded either the starting methyl ester or a
mixture of the desired material with products in which the
phthalimide rings were partially hydrolyzed.
the hexadehydrotribenzo[12]annulene ring system. Although 5
is presently accessible in an only modest yield, its preparation
and the isolation of all intermediates and of the final products
require no difficult separations. We conclude that this method
may well represent a superior general approach to the
preparation of hexadehydrotribenzo[a,e,i][12]annulenes.
EXPERIMENTAL SECTION
■
DISCUSSION
■
All chemicals were of standard commercial quality. Solvents were
dried, distilled, and degassed before use. NMR spectra were recorded
at 400 and 500 MHz at 25 °C in DMSO-d6 and CDCl3. H NMR
After the common methods for the formation of
hexadehydrotribenzo[a,e,i][12]annulene failed, we looked for
alternatives. We first turned to the published path15,24 in which
a rodlike diiodide is connected with a bis-ethynyl derivative
under Sonogashira coupling conditions, and this indeed led to
the goal (Scheme 2). However, the low-yield access to the
intermediates 3 and 10, due to competing reactions and
difficult isolations, makes this route less than ideal.
When we noticed the facile formation of the byproduct 3 in
the coupling of 7 with 8, we decided to attempt a ring closure
of 5 to 1 by direct coupling with acetylene, which promised to
simplify the reaction sequence and improve the yield. This
attempt was successful and afforded 1 in a 57% yield, thus
opening a new route to hexadehydrotribenzo[a,e,i][12]-
annulenes.
A comparison with the overall yields of other methods used
for the preparation of 1 unequivocally showed the benefit of the
new insertion procedure. While the overall yields of
trimerization of 3 and of the alternative route via 10 are only
3% and 4%, respectively, the use of the new insertion procedure
affords 1 from 9 in an overall yield of 21% (Scheme 6).
Since model reactions with tert-butyl and methyl phthalimi-
doacetates showed that the tert-butyl group but not the methyl
group can be easily removed selectively without disturbing the
imide, the next task was the preparation of the tert-butyl triester
12, which was straightforward. The triester was finally
hydrolyzed to the triacid 2, which is extremely insoluble. We
attribute this to the formation of an extensive hydrogen bond
network and take it to be a promising indication for our future
attempts to form a monolayer hydrogen bonded network on a
surface.
1
spectra were referenced to TMS. 13C NMR with total decoupling of
protons was referenced against the solvent (DMSO, → 31.5 ppm and
CDCl3, → 77.0 ppm). IR spectra were measured in KBr matrix.
X-ray Diffraction of 1. Initial attempts at crystallization of 1 gave
powders, but a suitable single crystal grew upon slow evaporation of a
solution of 1 (5 mg, 0.0077 mmol) and silver trifluoromethanesulfo-
nate (2 mg, 0.0077 mmol) in tetrahydrofuran-d8 (0.5 mL) in an NMR
tube. Monoclinic, P21/c (No. 14), a = 26.5365(6) Å, b = 32.7390(8) Å,
c = 17.4054(4)Å, β = 98.3440(10)°, V = 14961.4(6) Å3, Z = 16,
Dx = 1.152 Mg m−3. A yellow crystal of dimensions 0.43 × 0.19 × 0.19
mm was mounted into a Lindemann capillary and measured at a
diffractometer by monochromatized Mo Kα radiation (λ = 0.71073 Å)
at 150(2) K. A multiscan absorption correction was applied during
data reduction (μ = 0.09 mm−1). A total of 121763 measured
reflections was obtained (θmax= 26°), of which 29370 were unique
(Rint = 0.037) and 13952 met the I > 2σ(I) criterion. The structure was
solved by direct methods (SHELXS53) and refined by full matrix least-
squares based on F2 (SHELXL9753). Hydrogen atoms were fixed into
idealized positions (riding model) and assigned temperature factors of
either Hiso(H) = 1.2Ueq (pivot atom) or Hiso(H) = 1.5Ueq (pivot atom)
for the methyl moiety. The refinement converged (Δ/σmax = 0.002) to
R = 0.054 for the observed reflections and wR(F2) = 0. 167, GOF =
0.89 for 1753 parameters,and all 29370 reflections. The final difference
map displayed no peaks of chemical significance (Δρmax = 0.45, Δρmin
= −0.22 e.Å−3). The contributions of disordered tetrahydrofuran
molecules were removed from the diffraction data with the PLATON/
SQUEEZE (PLATON54) procedure to improve the precision of the
main part of the structure.53,54
4,5-Diiodophthalic Acid (8). A mixture of 1,2-diiodo-4,5-
dimethylbenzene (7)47 (10 g, 27.9 mmol), potassium permanganate
(53 g, 335 mmol), pyridine (80 mL), and water (120 mL) was refluxed
for 48 h. The hot mixture was filtered through a paper filter. The solid
residue was washed with a hot aqueous potassium hydroxide solution
(1 M, 200 mL), and the filtrate was acidified with concentrated
hydrochloric acid to pH 1−2. The suspension was filtered off and
washed with concentrated hydrochloric acid (2 × 30 mL), water (2 ×
30 mL), and toluene (2 × 30 mL). The resulting solid was dried for
5 h at 0.2 Torr and 80 °C. The product was obtained as a white powder
CONCLUSION
■
In developing a synthetic method for the key intermediate 1
needed for the preparation of the rigid trigonal star connector
2, we found that the coupling of 10 and 11 under high dilution
conditions, analogous to published syntheses, is successful. In
the course of this work, we discovered that the insertion of
acetylene into 5 represents a shorter and superior approach to
1
(8.9 g). Yield: 72%. Mp: >300 °C (ethanol). H NMR (400 MHz,
DMSO-d6): δ 8.17 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ 166.6,
138.2, 133.1, 112.3. IR (KBr) 3422, 3084, 2937, 2909, 2633, 2603,
2533, 2496, 2478, 2442, 2366, 2343, 2073, 2034, 2003, 1906, 1722,
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1699, 1667, 1648, 1587, 1540, 1489, 1460, 1386, 1311, 1258, 1223,
1146, 1101, 1078, 909, 886, 849, 821, 791, 778, 755, 700, 680, 655,
613, 570, 480, 447 cm−1. UV−vis (methanol): λmax (ε) 241 (3.9 × 104)
nm (M−1 cm−1). HRMS (EI+) for (C8H4I2O4−H2O): calcd 399.8093,
found 399.8098. Anal. Calcd for C8H4I2O4: C, 22.93; H, 0.96; I, 60.73.
Found C, 23.02; H, 1.06; I, 60.53.
(ethanol). 1H NMR (400 MHz, CDCl3): δ 8.23 (s, 2H), 7.89 (s, 2H),
3.92 (s, 12H). 13CNMR (100 MHz, CDCl3): δ 166.6, 165.8, 139.32,
133.0, 132.5, 132.0, 131.7, 103.4, 95.7, 53.0). IR (KBr): 3425, 3011,
2957, 2926, 2852, 1728, 1589, 1538, 1437, 1384, 1313, 1278, 1280,
1240, 1193, 1133, 1084, 1051, 999, 962, 929, 902, 889, 829, 806, 786,
774, 741, 724, 703, 694, 645, 631, 566, 543, 514, 456 cm−1. UV−vis
(dichloromethane): λmax (ε) 256 (3.1 × 104), 317 (2.2 × 104) nm
(M−1 cm−1). HRMS (EI+) calcd for (C22H16I2O8): 661.8935, found
661.8945. Anal. Calcd for C22H16I2O8: C, 39.90; H, 2.44; I, 38.33.
Found: C, 40.19; H, 2.58; I, 38.13.
4,5-Diiodophthalic Acid Dimethyl Ester (9). To a solution of
4,5-diiodophthalic acid (8) (9.7 g, 22.3 mmol) in methanol (100 mL)
was added thionyl chloride (13.6 mL, 0.185 mol) dropwise. The
mixture was stirred at rt overnight. The suspension was neutralized by
an aqueous potassium carbonate solution (5%, 300 mL) and extracted
with dichloromethane (2 × 200 mL). The combined organic phases
were dried over magnesium sulfate. The product was obtained as a
4,5-Diethynylphthalic Acid Dimethyl Ester (11). A two-
necked flask was charged with 4,5-diiodophthalic acid dimethyl ester
(9) (3 g, 6.72 mmol), bis(triphenylphosphine)palladium(II) dichloride
(0.472 g, 0.67 mmol), copper(I) iodide (0.128 g, 0.67 mmol), and
triphenylphosphine (176 mg, 0.67 mmol) under inert atmosphere.
After three successive vacuum/argon cycles, tetrahydrofuran (40 mL,
anhydrous, degassed) and triethylamine (40 mL, anhydrous, degassed)
were added. After 15 min of stirring at rt, ethynyltrimethylsilane (2.1 mL,
14.8 mmol, degassed) was added, and the mixture was stirred for
24 h at rt. The volatiles were evaporated under reduced pressure, and
the residue was dissolved in tetrahydrofuran (50 mL). Tetrabutyl-
ammonium fluoride was added as a 1 M tetrahydrofuran solution
(16.3 mL, 16.3 mmol) at −15 °C. The mixture was stirred for 30 min
at −15 °C, quenched with water (30 mL), extracted with
dichloromethane (2 × 20 mL), and dried over magnesium sulfate.
The crude product was purified by column chromatography (silica gel,
acetone−petroleum ether 1:4) to yield a white solid (1.2 g). Yield:
1
white solid (8.9 g). Yield: 86%. Mp = 123−124 °C (methanol). H
NMR (400 MHz, CDCl3): δ 8.17 (s, 2H), 3.90 (s, 6H). 13C NMR
(100 MHz, CDCl3): δ 165.3, 139.2, 132.2, 111.6, 52.9. IR (KBr) 3073,
3052, 1732, 1571, 1528, 1483, 1430, 1336, 1282, 1223, 1212, 1198,
1187, 1131, 1078, 973, 905, 897, 854, 817, 776, 738, 692, 666, 592,
572, 488, 431 cm−1. UV−vis (dichloromethane): λmax (ε) 242 (2.2 ×
104) nm (M−1 cm−1). HRMS (EI+) for (C10H8I2O4): calcd 445.8512,
found 445.8505. Anal. Calcd. for C10H8I2O4: C, 26.93; H, 1.81; I,
56.91. Found: C, 26.92; H, 1.82; I, 57.01.
4-Ethynyl-5-iodophthalic Acid Dimethyl Ester (3). A two-
necked flask was charged with 4,5-diiodophthalic acid dimethyl ester
(9) (2 g, 4.48 mmol), bis(triphenylphosphine)palladium(II) dichloride
(0.158 g, 0.22 mmol), copper(I) iodide (0.086 g, 0.45 mmol), and
triphenylphosphine (0.118 g, 0.45 mmol) under an inert atmosphere.
After three successive vacuum/argon cycles, tetrahydrofuran (20 mL,
anhydrous, freeze−pump−thaw degassed) and triethylamine (15 mL,
anhydrous, degassed) were added. After 15 min of stirring at rt,
ethynyltrimethylsilane (0.665 mL, 4.71 mmol, degassed) was added,
and the reaction mixture was stirred for 48 h at rt. The volatiles were
evaporated under reduced pressure, and the residue was dissolved in
tetrahydrofuran (20 mL). Tetrabutylammonium fluoride was added as
a 1 M tetrahydrofuran solution (4.6 mL, 4.6 mmol) at −15 °C, and the
mixture was stirred for 30 min at −15 °C. The reaction mixture was
quenched with water (30 mL), extracted with dichloromethane (2 ×
30 mL), and dried over magnesium sulfate. The crude mixture was
purified by column chromatography (silica gel, acetone−petroleum
ether 1:9). The product was obtained as a white solid (513 mg). Yield:
34% over two steps. Mp: 99−101 °C (ethanol). 1H NMR (400 MHz,
CDCl3): δ 8.18 (s, 1H), 7.81 (s, 1H), 3.91 (s, 3H), 3.90 (s, 3H) 3.55
(s, 1H). 13C NMR (100 MHz, CDCl3): δ 166.6, 165.9, 139.1, 133.2,
132.4, 131.9, 131.5, 103.5, 84.1, 83.7, 53.0, 52.9. IR (KBr) 3441, 3267,
3084, 3060, 3005, 2955, 2901, 2845, 2720, 2547, 2261, 2114, 1792,
1732, 1636, 1589, 1534, 1507, 1498, 1434, 1389, 1361, 1292, 1254,
1229, 1202, 1133, 1083, 993, 970, 918, 893, 821, 789, 764, 700, 681,
658, 608, 589, 526, 462, 424 cm−1. UV−vis (dichloromethane): λmax
(ε) 241 (3.0 × 104) 268 (1.3 × 104) nm (M−1 cm−1). HRMS (ESI) for
(C12H9IO4Na): calcd 366.94377, found 366.94375. Anal. Calcd for
C12H9IO4: C, 41.89; H, 2.64; I, 36.88. Found: C, 41.78; H, 2.75; I,
36.59.
1
72% over two steps. Mp: 99−100 °C. H NMR (400 MHz, CDCl3):
δ 7.84 (s, 2H), 3.90 (s, 6H), 3.48 (s, 2H). 13C NMR (100 MHz,
CDCl3): δ 166.5,133.2,131.59,127.86,84.23,80.22,52.8. IR (KBr):
3268, 3244, 2104, 1730, 1715, 1604, 1540, 1489, 1436, 1380, 1298,
1269, 1255, 1242, 1214, 1193, 1148, 1131, 1030, 967, 929, 907, 895,
833, 790, 771, 737, 726, 686, 660, 544, 507, 451, 422 cm−1. UV−vis
(dichloromethane): λmax (ε) 239 (6.4 × 104), 279 (2.0 × 104) nm
(M−1 cm−1). HRMS (EI+), calcd for (C14H10O4): 242.0579, found
242.0584. Anal. Calcd for C14H10O4: C, 69.42; H, 4.16. Found: C,
69.42; H, 4.28.
Note: The purification should be carried out under inert
atmosphere to avoid decomposition of 11.
Tetramethyl 5,5′-(4,5-Bis(methoxycarbonyl)-1,2-
phenylene)bis(ethyne-2,1-diyl)bis (4-iodophthalate) (5). A
two-necked flask was charged with 4,5-diiodophthalic acid dimethyl
ester (9) (10 g, 22.3 mmol), 4,5-diethynylphthalic acid dimethyl ester
(11, 0.6 g, 2.48 mmol), tetrakis(triphenylphosphine)palladium(0)
(0.29 g, 0.248 mmol), and copper(I) iodide (0.047 g, 0.248 mmol)
under inert atmosphere. After three successive vacuum/argon cycles,
tetrahydrofuran (40 mL, anhydrous, degassed) and triethylamine (40 mL,
anhydrous, degassed) were added. The mixture was stirred for 72 h
at rt under inert atmosphere, quenched with an aqueous ammonium
chloride (10%; 50 mL), extracted with dichloromethane (2 × 50 mL),
and dried over magnesium sulfate. The crude product was purified by
column chromatography (silica gel, acetone−petroleum ether 1:4 and
1:2), affording the principal product 5 as a white solid (1.1 g, 51%)
and the byproduct 4 (0.053 g; ∼10%), which was only ∼90% pure
Note: The purification should be carried out under inert
atmosphere to avoid decomposition of 3.
1
judging by H NMR (400 MHz, CDCl3), δ 7.90 (s, 8H), 3.91 (s,
Tetramethyl 4,4′-Ethyne-1,2-diylbis(5-iodobenzene-1,2-di-
carboxylate) (10). A two-necked flask was charged with 4,5-
diiodophthalic acid dimethyl ester (9) (3.85 g, 8.6 mmol), 4-
ethynyl-5-iodophthalic acid dimethyl ester (3) (0.655 g; 1.9 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.19 mmol), and
copper(I) iodide (0.73 g, 0.38 mmol) under inert atmosphere. After
three successive vacuum/argon cycles, tetrahydrofuran (40 mL,
anhydrous, degassed) and triethylamine (20 mL, anhydrous, degassed)
were added under inert atmosphere, and the mixture was stirred
overnight at rt and 2 h at 40 °C. Aqueous ammonium chloride (10%,
40 mL) was added to the reaction mixture, which was then extracted
with dichloromethane (2 × 20 mL). Combined organic phases were
dried over magnesium sulfate. The crude mixture was purified by
column chromatography (silica gel, acetone−petroleum ether 1:4).
The principal product 10 (461 mg, 37% yield) and the byproduct 5
(277 mg, 16% yield) were isolated as white solids. Mp: 203−204 °C
24H), and 13C NMR (150 MHz, CDCl3), δ 166.7, 132.9, 131.9, 127.8,
92.4, 53.1, and whose identity was secured by HRMS (ESI+), calcd for
(C48H32O16Na): 887.15826, found 887.15755. 5. Mp: 194−195 °C
1
(methanol). H NMR (400 MHz, CDCl3): δ 8.20 (s, 2H), 8.00 (s,
2H), 7.90 (s, 2H), 3.95 (s, 6H), 3.92(s, 6H), 3.87 (s, 6H). 13C NMR
(150 MHz, CDCl3): δ 166.5, 166.3, 166.0, 139.1, 133.18, 133.0, 132.7,
132.0, 131.9, 131.3, 127.3, 103.9, 96.5, 92.4, 53.1, 53.0. IR (KBr):
3441, 2952, 2217, 1729, 1629, 1600, 1586, 1539, 1499, 1435, 1403,
1376, 1353, 1320, 1288, 1254, 1193, 1130, 1081, 1040, 993, 965, 939,
906, 894, 838, 826, 804, 788, 773, 755, 727, 706, 684, 676, 592, 542,
531, 460 cm−1. UV−vis (dichloromethane)( λmax (ε) 262 (6.0 × 104),
302 (4.9 × 104) nm (M−1 cm−1). HRMS (EI+): calcd for
(C34H24I2O12) 877.9357, found 877.9388. Anal. Calcd for
C34H24I2O12: C, 46.49; H, 2.75; I, 28.9. Found: C, 46.31; H, 2.72; I,
28.67.
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Hexamethyl 5,6,11,12,17,18-Hexadehydrotribenzo[a,e,i]-
[12]annulene-2,3,8,9,14,15-hexacarboxylate (1). Method A.
A two-necked flask was charged with 11 (0.376 g, 1.55 mmol), 10
(1.03 g, 1.55 mmol), tetrakis(triphenylphosphine)palladium(0) (0.18
g, 0.155 mmol), and copper(I) iodide (0.03 g, 0.155 mmol) under
inert atmosphere. After three successive vacuum/argon cycles,
tetrahydrofuran (150 mL, anhydrous, degassed) and triethylamine
(150 mL, anhydrous, degassed) were added. The reaction mixture was
stirred for 48 h at rt under an inert atmosphere, quenched with an
aqueous ammonium chloride solution (10%; 100 mL), and extracted
with dichloromethane (2 × 100 mL). The combined organic phases
were dried over magnesium sulfate. The crude product was purified by
column chromatography (silica gel, dichloromethane−acetone 30:1)
and obtained as a light yellow solid (0.32 g, yield 32%).
2,2′,2″-(1,3,8,10,15,17-Hexaoxo-5,6,12,13,19,20-hexadehy-
dro-8,10,15,17-tetrahydro-1H-cyclododeca[1,12-f:4,5-f′:8,9-f″]-
triisoindole-2,9,16(3H)-triyl)triacetic Acid (2). A mixture of 12
(70 mg, 0.082 mmol) and trifluoroacetic acid (7 mL; freshly distilled)
in dry tetrahydrofuran (20 mL) was stirred at rt for 48 h in an inert
atmosphere. The volatiles were removed under reduced pressure, and
the residue was triturated with methyl alcohol. The product was dried
at 0.2 Torr at 80 °C for 5 h and obtained as a yellow solid (51 mg).
Yield: 90%. 1H NMR (400 MHz, DMSO-d6): δ 7.99 (s, 6H), 4.32 (s,
6H). IR (KBr): 3474, 3068, 2993, 2945, 2539, 2360, 2216, 1783, 1719,
1614, 1477, 1424, 1391, 1311, 1200, 1179, 1149, 1122, 1037, 1011,
935, 816, 754, 737, 677, 617, 559, 526, 481, 457, 418 cm−1. HRMS
(ESI+), calcd for (C36H15O12N3Na): 704.05448, found 704.05479.
Note: Additional analytical characterization was prevented by the
extremely low solubility of 2.
Method B. A two-necked flask was charged with 5 (0.63 g; 0.717
mmol), tetrakis(triphenylphosphine)palladium (0) (0.083 g, 0.0717
mmol), and copper(I) iodide (0.014 g, 0.0717 mmol). After three
successive vacuum/argon cycles, tetrahydrofuran (130 mL, anhydrous,
degassed), toluene (130 mL, anhydrous, degassed), and triethylamine
(130 mL, anhydrous, degassed) were added. Dried acetylene gas was
bubbled into the solution for 3 min. The reaction mixture was stirred
at 40 °C for 18 h under an inert atmosphere, quenched with aqueous
ammonium chloride (10%; 100 mL), extracted with dichloromethane
(2 × 50 mL), and dried over magnesium sulfate. The crude product
was purified by column chromatography (silica gel, dichloromethane−
acetone 40:1 and 30:1) to afford a yellow solid (0.265 g). Yield: 57%.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H, 13C NMR spectra of all new compounds and a
packing view of a crystal of 1. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: michl@eefus.colorado.edu.
■
1
Mp: 275−276 °C (dichloromethane−diethyl ether). H NMR (400
MHz, CDCl3): δ 7.68 (s, 6H), 3.92 (s, 18H). 13C NMR (100 MHz,
CDCl3): δ 166.3, 132.7, 132.3, 128.3, 93.9, 52.9. IR (KBr): 3438, 3073,
3027, 3004, 2954, 2853, 2361, 2213, 2065, 1730, 1635, 1600, 1558,
1538, 1499, 1435, 1387, 1325, 1286, 1258, 1194, 1129, 1057, 1021,
969, 912, 846, 803, 787, 779, 743, 728, 667, 565, 479. UV−vis
(dichloromethane): λmax (ε) 249 (1.8 × 104), 311 (1.72 × 105), 346
(1.0 × 104), 361 (1.4 × 104) nm (M−1 cm−1). HRMS (EI+), calcd for
(C36H24O12): 648.1278, found 648.1278. Anal. Calcd for C36H24O12:
C, 66.67; H, 3.73. Found: C, 66.29; H, 3.75.
ACKNOWLEDGMENTS
■
This project was supported by funding from the European
Research Council under the European Community’s Seventh
Framework Programme (FP7/2007-2013)/ERC grant agree-
ment no. 227756 and by the Ministry of Education, Youth and
Sports of the Czech Republic (Project No. MSM0021620857).
REFERENCES
■
Tri-tert-butyl 2,2′,2″-(1,3,8,10,15,17-Hexaoxo-5,6,12,13,19,20-
hexadehydro-8,10,15,17-tetrahydro-1H-cyclododeca[1,12-f :4,5-
f ′:8,9-f ″]triisoindole-2,9,16(3H)-triyl)triacetate (12). Potassium
hydroxide (377 mg, 6.7 mmol) and 1 (162 mg, 0.25 mmol) were
refluxed for 48 h in a mixture of tetrahydrofuran (15 mL), methyl
alcohol (15 mL), and water (15 mL). The reaction mixture was
extracted with dichloromethane (2 × 10 mL), and the organic phase
was washed with aqueous potassium hydroxide (20 mL, 20%). The
combined aqueous phases were acidified with concentrated hydro-
chloric acid to pH 1−2 and evaporated under reduced pressure. The
residue was dried for 5 h by azeotropic distillation with toluene (2 ×
20 mL) under reduced pressure (0.2 Torr) at 80 °C, suspended into
toluene (70 mL, anhydrous), and acetanhydride (50 mL; freshly
distilled) was added. The apparatus was equipped with a Dean−Stark
trap, and the mixture was refluxed for 48 h. Toluene and acetanhydride
were removed under reduced pressure and the residue was dried at 0.2
Torr at 80 °C for 5 h. Glycine tert-butyl ester hydrochloride (139 mg,
0.82 mmol), N,N-diisopropylethylamine (0.31 mL, 1.75 mmol), and
toluene (100 mL, anhydrous) were added. The apparatus was
equipped with a Dean−Stark trap, and the mixture was refluxed for 48 h.
Toluene was removed under reduced pressure and the crude product
was purified by column chromatography (silica gel, dichloromethane−
acetone 80:1; 60:1; 40:1), affording a yellow solid (0.108 g). Yield: 51%
(1) Staab, H. A.; Graf, F. Tetrahedron Lett. 1966, 7, 751.
(2) Campbell, D.; Eglinton, G.; Henderson, W.; Raphael, R. A. Chem.
Commun. 1966, 87.
(3) Jones, C. S.; O’Connor, M. J.; Haley, M. M. In Acetylene
Chemistry; Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.; Wiley-
VCH: Weinheim, 2005; p 303.
(4) Bunz, U. H. F.; Rubin, Y.; Tobe, Y. Chem. Soc. Rev. 1999, 28, 107.
(5) Spitler, E. L.; Johnson, C. A. II; Haley, M. M. Chem. Rev. 2006,
106, 5344.
(6) Pak, J. J.; Weakley, T. J. R.; Haley, M. M. J. Am. Chem. Soc. 1999,
121, 8182.
(7) Sarkar, A.; Pak, J. J.; Rayfield, G. W.; Haley, M. M. J. Mater. Chem.
2001, 11, 2943.
(8) Marsden, J. A.; Miller, J. J.; Haley, M. M. Angew. Chem., Int. Ed.
2004, 43, 1694.
(9) Sonoda, M.; Sakai, Y.; Yoshimura, T.; Tobe, Y.; Kamada, K.
Chem. Lett. 2004, 33, 972.
(10) Marsden, J. A.; Miller, J. J.; Shirtcliff, L. D.; Haley, M. M. J. Am.
Chem. Soc. 2005, 127, 2464.
(11) Haley, M. M. Pure Appl. Chem. 2008, 80, 519.
(12) Kivala, M.; Diederich, F. Pure Appl. Chem. 2008, 80, 411.
(13) Bhaskar, A.; Guda, R.; Haley, M. M.; Goodson, T. III. J. Am.
Chem. Soc. 2006, 128, 13972.
(14) Hisaki, I.; Sonoda, M.; Tobe, Y. Eur. J. Org. Chem. 2006, 4, 833.
(15) Enozawa, H.; Hasegawa, M.; Takamatsu, D.; Fukui, K.; Iyoda,
M. Org. Lett. 2006, 8, 1917.
(16) Seo, S. H.; Jones, T. V.; Seyler, H.; Peters, J. O.; Kim, T. H.;
Chang, J. Y.; Tew, G. N. J. Am. Chem. Soc. 2006, 128, 9264.
(17) Seo, S. H.; Chang, J. Y.; Tew, G. N. Angew. Chem., Int. Ed. 2006,
45, 7526.
1
over three steps. Mp: > 300 °C dec. H NMR (400 MHz, CDCl3): δ
7.84 (s, 6H), 4.34 (s, 6H); 1.48 (s, 27H). 13C NMR (100 MHz,
CDCl3): δ 165.8, 165.7, 132.1, 131.7, 127.3, 95.4, 83.2, 40.0, 28.0. IR
(KBr): 3441, 2980, 2938, 1783, 1743, 1722, 1477, 1455, 1421, 1393,
1371, 1307, 1235, 1159, 1118, 1035, 1010, 933, 908, 848, 815, 769,
752, 737, 628, 616, 574, 551, 522, 481, 458, 437 cm−1.UV−vis λmax
(ε): 216 (3.1 × 104), 296 (1.08 × 105), 345 (5.9 × 104), 350 (5.5 ×
104) nm (M−1 cm−1). HRMS (APCI), calcd for (C48H39O12N3):
849.25392, found 849.25360. Anal. Calcd for C48H39O12N3: C, 67.84;
H, 4.63; N, 4.94. Found: C, 67.46; H, 4.73; N, 4.58.
(18) Tahara, K.; Furukawa, S.; Uji-I, H.; Uchino, T.; Ichikawa, T.;
Zhang, J.; Mamdouh, W.; Sonoda, M.; De Schryver, F. C.; De Feyter,
S.; Tobe, Y. J. Am. Chem. Soc. 2006, 128, 16613.
73
dx.doi.org/10.1021/jo202016v | J. Org. Chem. 2012, 77, 68−74

The Journal of Organic Chemistry
Article
(19) Hisaki, I.; Sakamoto, Y.; Shigemitsu, H.; Tohnai, N.; Miyata, M.;
Seki, S.; Saeki, A.; Tagawa, S. Chem.Eur. J. 2008, 14, 4178.
(20) Lei, S.; Tahara, K.; De Schryver, F. C.; Van der Auweraer, M.;
Tobe, Y.; De Feyter, S. Angew. Chem., Int. Ed. 2008, 47, 2964.
(21) Tahara, K.; Lei, S.; Mossinger, D.; Kozuma, H; Auweraer, M. D.
̈
V.; Inukai, K.; De Schryver, F. C.; Hoger, S.; Tobe, Y.; De Feyter, S.
̈
Chem. Commun. 2008, 3897.
(22) Tahara, K.; Okuhata, S.; Adisoejoso, J.; Lei, S.; Fujita, T.; De
Feyter, S.; Tobe, Y. J. Am. Chem. Soc. 2009, 131, 17583.
(23) Hisaki, I.; Senga, H.; Sakamoto, Y.; Tsuzuki, S.; Tohnai, N.;
Miyata, M. Chem.Eur. J. 2009, 15, 13336.
(24) Kaleta, J.; Mazal, C. Org. Lett. 2011, 13, 1326.
(25) Matzger, A. J.; Shim, M.; Vollhardt, K. P. C Chem. Commun.
1999, 1871.
(26) Tahara, K.; Fujita, T.; Sonoda, M.; Shiro, M.; Tobe, Y. J. Am.
Chem. Soc. 2008, 130, 14339.
(27) Sadowy, A. L.; Tykwinski, R. R. In Modern Supramolecular
Chemistry. Strategies for Macrocyclic Synthesis; Diederich, F., Stang, P. J.,
Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim, 2008; p 185.
(28) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467.
(29) Pal, M.; Kundu, G., N. J. Chem. Soc., Perkin Trans. 1 1996, 5,
449.
(30) Pu, Y.-J.; Takahashi, M.; Tsuchida, E.; Nishide, H. Chem. Lett.
1999, 39, 161.
(31) Eickmeier, C.; Junga, H.; Matzger, A. J.; Scherhag, F.; Shim, M.;
Vollhardt, K. P. C Angew. Chem., Int. Ed. 1997, 36, 2103.
(32) Nishide, H.; Takahashi, M.; Takashima, J.; Pu, Y.-J.; Tsuchida, E.
J. Org. Chem. 1999, 64, 7375.
(33) Ouahabi, A. A.; Baxter, P. N. W.; Gisselbrecht, J.-P.; De Cian, A.;
Brelot, L.; Kyritsakas-Gruber, N. J. Org. Chem. 2009, 74, 4675.
(34) Kiguchi, M.; Tahara, K.; Takahashi, Y.; Hasui, K.; Tobe, Y.
Chem. Lett. 2010, 39, 788.
(35) Iyoda, M.; Sirinintasak, S.; Nishiyama, Y.; Vorasingha, A.;
Sultana, F.; Nakao, K.; Kuwatani, Y.; Matsuyama, H.; Yoshida, M.;
Miyake, Y. Synthesis 2004, 1527.
(36) Miljanic, O. S.; Vollhardt, K. P. C; Whitener, G. D. Synlett. 2003,
29.
(37) Zhang, W.; Brombosz, S. M.; Mendoza, J. L.; Moore, J. S. J. Org.
Chem. 2005, 70, 10198.
(38) Cho, H. M.; Weissman, H.; Moore, J. S. J. Org. Chem. 2008, 73,
4256.
(39) Jiang, J.; Tew, G. N. Org. Lett. 2008, 10, 4393.
(40) Iyoda, M.; Vorasingha, A.; Kuwatani, Y.; Yoshida, M.
Tetrahedron Lett. 1998, 39, 4701.
(41) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467.
(42) Boese, R.; Matzger, A. J.; Vollhardt, K. P. C J. Am. Chem. Soc.
1997, 119, 2052.
(43) Severin, R.; Reimer., J.; Doye, S. J. Org. Chem. 2010, 75, 3518.
(44) Pal, M.; Kandu, N. G. J. Chem. Soc., Perkin Trans. 1 1996, 449.
(45) Barbieri, R. S.; Bellato, C. R.; Dias, A. K. C.; Massabni, A. C.
Catal. Lett 2006, 109, 171.
(46) Zhang, W.; Wu, H.; Liu, Z.; Zhong, P.; Zhang, L.; Huang, X.;
Cheng, J. Chem. Commun. 2006, 46, 4826.
(47) Kovalenko, S. V.; Peabody, S.; Manoharan, M.; Clark, R. J.;
Alabugin, I. V. Org. Lett. 2004, 6, 2457.
̌
́
(48) Zimmermann, B.; Baranovic, G.; Stefanic’, Z.; Ro_man, M. J.
Mol. Struct. 2006, 794, 115.
(49) Dunogues, J.; N’Gabe, D; Laguerre, M.; Duffaut, N; Calas, R.
Organometallics 1982, 1, 1525.
(50) Fisher, J. W.; Trinkle, K. L. Tetrahedron Lett. 1994, 35, 2505.
(51) Chee, G.-L. Synlett 2001, 1593.
(52) Iida, K.; Tokiwa, S.; Ishii, T.; Kajiwara, M. J. Labelled Compd.
Radiopharm. 2002, 45, 569.
(53) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112.
(54) Spek, A. L. Acta Crystallogr. 2009, D65, 148.
74
dx.doi.org/10.1021/jo202016v | J. Org. Chem. 2012, 77, 68−74