Diversity oriented approach to crownophanes by enyne metathesis and Diels-Alder reaction as key steps

Article abstract of DOI:10.1021/jo300766f

Various crownophanes are assembled starting with simple phenol derivatives such as catechol, resorcinol, and hydroquinone. Here, cross-enyne metathesis (CEM) and Diels-Alder (DA) reaction have been used as key steps. This strategy has embedded six diversi

Full text of DOI:10.1021/jo300766f

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Note
Diversity Oriented Approach to Crownophanes by Enyne
Metathesis and Diels-Alder Reaction as Key Steps
Sambasivarao Kotha, and Gopalkrushna Tulshidas Waghule
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo300766f • Publication Date (Web): 25 Jun 2012
Downloaded from http://pubs.acs.org on July 7, 2012
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Diversity Oriented Approach to Crownophanes by Enyne Metathesis and
Diels−Alder Reaction as Key Steps
Sambasivarao Kotha, * Gopalkrushna T. Waghule
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai- 400 076, India
e-mail: srk@chem.iitb.ac.in
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Various crownophanes are assembled starting with simple phenol derivatives such as catechol,
resorcinol and hydroquinone. Here, cross enyne metathesis (CEM) and Diels−Alder (DA)
reaction have been used as key steps. This strategy has embedded six diversity points.
The pioneering studies of Pederson, Lehn and Cram was the beginning of molecular
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,2
recognition. Structural rigidity in macrocycles draws a special attention in supramolecular
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chemistry due to the binding properties, and their extended use in material science.
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Crownophanes exhibit hybrid properties of crown ethers and cyclophanes in structural aspect.
They are also useful building blocks in supramolecular chemistry. Ethylene oxy linkage present
in crown ether moiety provides flexibility and the phenyl rings impart rigidity to the macrocyclic
system. Moreover, hard oxygen atoms can act as redox active components. Crownophanes are
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also used as hosts for cation, anion, and neutral molecules. Haptoselectivity (binding of more
than one metal atoms in the molecule) in crownophanes is an interesting aspect in macrocycles.
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Enzymes and biomembranes contain a variety of ions and their functions are understood on the
basis of molecular recognition principles. Macrocycles like crownophanes can play crucial role
in similar processes. A variety of olefination reactions are utilized during the formation of
cyclophanes. For example, McMurry reaction, Ramberg-Backlund reaction, ring-closing
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metathesis (RCM), and Wittig reaction. Cross enyne metathesis (CEM) is a useful tool to create
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diene moieties in the macrocyclic system. CEM involving ethylene as a coupling partner is an
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atom economy reaction. Although, crownophanes are prepared by different routes, assembly
of crownophanes by a simple and general strategy is worthy of systematic investigation. Our
strategy to crownophanes hinges on double cross enyne metathesis and Diels−Alder (DA)
reaction as key steps. By adopting the same strategy we are able to prepare both symmetrical as
well as unsymmetrical crownophanes. Symmetrical crownophane synthesis involves two
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direction synthesis. There are six diversity points (D -D , Scheme 1) in our strategy. Utilization
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of double cross enyne metathesis to design polycyclics is rare, and here we report our results to
assemble crownophanes via enyne metathesis, and DA reaction as key steps. These two
strategies are powerful tools to install C−C bonds, and a strategic combination of these two
reactions can be used to create diverse polycyclic aromatic compounds to achieve ‘‘step
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economy”.
At each stage of diversity point, by judicious selection of proper functional
groups, one can generate a library of cyclophane derivatives containing crown ether moieties. In
our theme, one can visualize involvement of a variety of tactics to generate diversity. For
example, choice of various resorcinol derivatives (D ) (e. g. -m, -o, -p derivatives and the other
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corresponding heteroaromatics) ethylene oxy linkage can be extended (D ), or oxygen atom can
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be replaced by other heteroatoms (D ). CEM provides an opportunity to introduce various
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ethylene derivatives (D ). During the DA sequence a variety of dienophiles (D ) can be
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incorporated in cyclophane moiety. Electron withdrawing groups such as ester functionality can
easily be introduced during the DA sequence. The ester group can be further synthetically
manipulated to generate additional diversity (D ) in the target macrocyclic system.
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Scheme 1. diversity strategy to crownophanes involving various points
The First step in our journey towards crownophane synthesis involves generation of enyne
metathesis precursor such as 3a (Scheme 2). In this regard, commercially available resorcinol
(1a) was treated with bis(2-chloroethyl) ether with aqueous NaOH as a base under reflux
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conditions to generate bisphenol 2a (37% yield). Similar procedure was employed to generate
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bisphenols 2b and 2c. Although the crown compound 3a can be prepared by using but-2-yne 1,
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4-dibromide we found improved yield of 3a (97%) by using but-2-yne 1, 4-ditosylate 7. It is
interesting to note that the ditosylate 7 is a better coupling partner in connection with the
preparation of 3 (or 5) rather than the corresponding dibromide [i.e., but-2-yne 1,4-dibromide].
Compound 3a undergoes CEM in presence of Grubbs second generation catalyst to give the
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corresponding diene 8a. H NMR spectral data of the diene 8a indicates the presence of olefin
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moieties at δ 5.27, and 5.33, which was further supported by C NMR spectral data. Various
dienes (8a-8c and 9a-9c) prepared here seems to be stable at room temperature and they
decompose around 190 °C.
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Scheme 2. Preparation of enyne building blocks 3a-3c and 5a-5c
Later, the diene 9a was subjected to DA reaction with DMAD (dimethyl acetylenedicarboxylate)
under toluene reflux conditions. The DA product was contaminated with partially aromatized
product. Therefore, isolation and identification of the DA adduct was not attempted and the
crude product was directly reacted with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) to
give the aromatized product 4a in 83% yield after column chromatography (Scheme 3).
Scheme 3. Synthesis of crownophanes via CEM and DA reaction as key steps
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To generalize this strategy, we prepared various crownophane derivatives starting with catechol
and hydroquinone.
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Table 1. Preparation of crownophanes 6a-6c via CEM and DA reaction as key steps
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Along similar lines, compounds 5a-5c were prepared and subjected to CEM, DA reaction and
aromatization sequences to deliver the crownophanes 6a-6c involving the corresponding diene
intermediates 8a-8c (Table 1).
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Table 2. Preparation of crownophanes 4a-4c via CEM and DA reaction as key steps
Various other enyne building blocks that has undergone CEM, DA reaction, and aromatization
sequences are shown in Table 2. All the new products obtained in this sequence are well
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characterized by H NMR and C NMR spectral data and further supported by HRMS data.
Further, dienes 8b and 9b were treated with tetracyanoethylene to get crownphanes 10 and 11
with good yield as shown in Table 3.
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Table 3. Preparation of crownophanes 10-11 using tetracyanoethylene as a dienophile
In conclusion, we have demonstrated a new and simple methodology for the synthesis of
crownophanes via CEM and DA reaction as key steps, and our strategy has embedded six
diversity points which can generate a library of crown compounds. It is interesting to note that
our strategy involve creation of eight new C-C bonds during CEM and DA sequence achieving
step economy and atom economy. By adopting two directional synthesis the brevity of the
synthetic strategy has increased substantially.
Experimental Section
General procedure for cyclization of bisphenol with 7
To a well stirred solution of bisphenol 2a-2c (500 mg, 1.72 mmol) in dry acetonitrile (20 mL)
was added K CO (1.18 g, 8.60 mmol) and the reaction mixture was further refluxed for 0.5 h. A
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solution of but-2-yne 1, 4-ditosylate (681 mg, 1.72 mmol) 7 in acetonitrile was added and
refluxed for 24 h. At the conclusion of the reaction (TLC monitoring), the reaction mixture was
cooled and filtered through celite. The filtrate was concentrated under reduced pressure to give
the crude product, which was further purified by silica gel column chromatography using
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appropriate mixture of ethyl acetate/ petroleum ether, which affords pure cyclized product 3a-3c
as a white solid.
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a: 480 mg, yield: 82%; mp: 116-118 °C; H NMR (400 MHz, CDCl ): δ = 3.91 (t, J = 4.36 Hz,
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4H), 4.11 (t, J = 4.35 Hz, 4H), 4.72 (s, 4H), 6.50 (d, J = 7.5 Hz, 4H), 6.63 (t, J = 1.9 Hz, 2H),
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7.11 (t, J = 8.3 Hz, 2H); C NMR (100 MHz, CDCl ): δ = 55.8, 67.5, 70.0, 82.6, 102.0, 106.9,
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+
09.3, 129.8, 158.6, 160.1; HRMS (Q-Tof) m/z: [M+H] calcd. for C H O 341.1389, found
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-
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41.1393. IR (neat): υmax 1599, 1159, 1351, 2718, 2809 cm .
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3b: 556 mg, yield: 95%; mp 141-143 °C; H NMR (400 MHz, CDCl ): δ = 4.05 (t, J = 5.1 Hz,
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4
H), 4.19 (t, J = 5.1 Hz, 4H), 4.71 (s, 4H), 6.88-7.00 (m, 8H); C NMR (100 MHz, CDCl ): δ =
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+
59.4, 69.3, 70.2, 82.3, 114.9, 117.7, 121.7, 123.4, 148.1, 150.3; HRMS (Q-Tof): m/z = [M+H]
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calcd. for C H O 341.1389, found 341.1381. IR (neat): υ 1017, 1124, 1266, 1500, 3034 cm
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0
21
5
max
1
.
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c: 463 mg, yield: 79%; mp 150-152 °C; H NMR (400 MHz, CDCl ): δ = 3.84-3.86 (m, 4H),
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.12-4.14 (m, 4H), 4.65 (s, 4H), 6.69 (d, J = 2.8 Hz, 4H); 6.70 (d, J = 2.8 Hz, 4H); C NMR
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(
100 MHz, CDCl ): δ = 56.4, 69.1, 70.0, 83.5, 116.3, 116.4, 151.3, 153.5; HRMS (Q-Tof) m/z:
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+
[M+H] calcd. for C H O 341.1389, found 341.1393. IR (neat): υ
739, 896, 1129, 1200,
max
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-
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509, 1653, 3054 cm .
General procedure for the preparation of dienes
Cyclized product 3a-c or 5a-c [(100 mg, 0.294 mmol), or (100 mg, 0.313 mmol)] was dissolved
in dry DCM (10-20 mL) and it was degassed by N for 5 min., then Grubbs second generation
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catalyst (5 mol %) was added. Further the reaction mixture was degassed with ethylene, and
stirred at rt under ethylene for 24 h. After the completion of the reaction (TLC monitoring), the
solvent was removed on a rotavapour. The crude product was purified by silica gel column
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chromatography. Elution of the column with appropriate mixture of ethyl acetate/petroleum ether
gave the pure diene 9a-c and 8a-c as a white solid.
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a: 89.00 mg, yield: 82%; mp 76-78 °C; H NMR (400 MHz, CDCl ): δ = 3.88-3.90 (m, 4H),
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.12-4.13 (m, 4H), 4.76 (s, 4H), 5.27 (s, 2H), 5.33(s, 2H), 6.55 (t, J = 2 Hz, 2H), 6.46-6.49 (ddd,
J =1 Hz, J =2 Hz, J = 8 Hz, 2H), 6.57-6.60 (ddd, J = 1 Hz, J = 2 Hz, J = 8 Hz, 2H), 7.15 (t, J
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3
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=
8Hz, 2H); C NMR (100 MHz, CDCl ): δ = 68.0, 69.2, 69.9, 103.2, 106.8, 108.9, 114.5,
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+
29.8, 140.9, 159.6, 160.3; HRMS (Q-Tof) m/z: [M+H] calcd. for C H O 369.1702, found
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25
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369.1695. IR (neat): υmax 1155, 1181, 1489, 1603, 2933 cm .
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9b: 100.00 mg, yield: 93%; mp 78-80 °C; H NMR (400 MHz, CDCl ): δ = 3.97 (t, J = 4.36 Hz,
3
1
H), 4.13 (t, J = 4.36 Hz, 4H), 4.77 (s, 4H), 5.35 (s, 2H), 5.40 (s, 2H), 6.91-7.01 (m, 8H); C
3
4
NMR (100 MHz, CDCl ): δ 69.9, 70.4, 72.1, 115.6, 115.8, 117.0, 121.9, 122.4, 142.2, 149.5,
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+
50.0; HRMS (Q-Tof) m/z: [M+H] calcd. for C H O 369.1702, found 369.1698. IR (neat):
1
22
25
5
-1
υmax 1017, 1124, 1266, 1500, 3034 cm .
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9c: 75.00 mg, yield: 69%; mp 130-132 °C; H NMR (400 MHz, CDCl ): δ = 3.77-3.79 (m, 4H),
3
4
.12-4.14 (m, 4H), 4.73 (s, 4H), 5.53 (s, 4H), 6.47 (s, 4H), 6.48 (d, J = 9.1 Hz, 4H), 6.66 (d, J =
1
3
9.1 Hz, 4H); C NMR (100 MHz, CDCl ): δ = 69.4, 70.2, 70.5, 116.4, 116.4, 116.8, 141.3,
3
+
52.4, 153.0; HRMS (Q-Tof) m/z: [M+H] calcd. for C H O 369.1702, found 369.1699. IR
1
22
25
5
-1
(neat): υmax 896, 1042, 1127, 1266, 1507, 2855 cm .
1
8a: 91.60 mg, yield: 78%; mp 140-142 °C; H NMR (400 MHz, CDCl ): δ = 4.71 (s, 8H), 5.20
3
(s, 4H), 5.29 (s, 4H), 6.54 (dd, J = 8.5 Hz, J = 2 Hz, 4H), 6.62 (t, J = 2 Hz, 2H), 7.16 (t, J = 8.5
1
3
Hz, 2H); C NMR (100 MHz, CDCl ): δ = 69.3, 102.6, 107.4, 114.5, 129.7, 141.5, 159.6;
3
+
HRMS (Q-Tof) m/z: [M+H] calcd. for C H O 377.1753, found 377.1743. IR (neat): υ
2
4
25
4
max
-1
048, 1248, 1737, 3019 cm .
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b: 72.85 mg, yield: 62%; mp 128-130 °C; H NMR (400 MHz, CDCl ): δ 4.68 (s, 8H), 5.29 (s,
3
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H), 5.38 (s, 4H), 6.94-7.02 (m, 8H); C NMR (100 MHz, CDCl ): δ = 72.4, 115.3, 117.4,
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+
22.6, 142.4, 150.2; HRMS (Q-Tof) m/z: [M+H] calcd. for C H O 377.1753, found
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77.1758. IR (neat): υmax 896, 1046, 1134, 1266, 1498 cm .
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8c: 71.60 mg, yield: 61%; mp 128-130 °C; H NMR (400 MHz, CDCl ): δ = 4.68 (s, 8H), 5.29
3
1
3
(
s, 4H), 5.38 (s, 4H), 6.94-7.02 (m, 8H); C NMR (100 MHz, CDCl ): δ = 71.4, 115.3, 117.4,
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+
20.6, 143.4, 150.3; HRMS (Q-Tof) m/z: [M+H] calcd. for C H O 377.1753, found
1
2
4
25
4
-1
377.1758. IR (neat): υmax 1013, 1499, 1597, 2918, 3097 cm .
General procedure for Diels−Alder reaction with DMAD
To a stirred solution of the diene [9a-9c (50 mg, 0.136 mmol) or 8a-8c (50 mg, 0.133 mmol)] in
toluene (15 mL) was added DMAD [(23.19 mg, 0.272 mmol) for 9a-9c and (46.38 mg, 0.327
mmol) for 8a-8c] under N and the reaction mixture was refluxed for 30 h. Crude reaction
2
contains DA adduct and partially aromatized product. Later, DDQ was added, and the reaction
mixture was further refluxed for 24 h. At the conclusion of the reaction (TLC monitoring), the
solvent was removed on a rotavapour. The crude reaction mixture was diluted with ethyl acetate
and then washed with aq. KOH solution and then with brine. The combined organic layer was
concentrated under reduced pressure and the crude product was purified by column
chromatography by eluting with appropriate mixture of ethyl acetate/petroleum ether mixture.
1
4a: 57.20 mg, yield: 83%; mp 186-188 °C; H NMR (400 MHz, CDCl ): δ = 3.88-3.95 (m, 4H),
3
3
2
1
.92 (s, 6H), 4.12-4.15 (m, 4H), 5.17 (s, 4H), 6.51-6.66 (m, 4H), 7.19 (t, J = 8 Hz, 2H), 7.89 (s,
1
3
H); C NMR (100 MHz, CDCl ): δ = 52.9, 67.8, 68.1, 69.9, 103.1, 107.4, 108.2, 129.0, 130.2,
3
+
31.8, 138.7, 159.6, 160.2, 167.8; HRMS (Q-Tof) m/z: [M+H] calcd. for C H O 509.1812,
2
8
29
9
-1
found 509.1823. IR (neat): υmax 1030, 1177, 765, 1350, 1727, 1489, 1602, 2931 cm .
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b: 43.50 mg, yield: 63%; mp 112-114 °C; H NMR (400 MHz, CDCl ): δ = 3.84 (t, J = 1.82
3
1
Hz, 4H), 4.13 (m, 4H), 3.92 (s, 6H), 5.25 (s, 4H), 6.85-7.06 (m, 8H), 8.04 (s, 2H); C NMR (100
3
MHz, CDCl ): δ = 52.8, 67.9, 69.7, 70.3, 113.1, 119.8, 121.2, 123.8, 123.4, 131.1, 139.5, 147.9,
3
10
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57
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60
+
50.9, 168.2; HRMS (Q-Tof) m/z: [M+H] calcd. for C H O 509.1812, found 509.1823. IR
1
28
29
9
-1
(neat): υmax 1046, 1117, 1351, 1598, 1727, 2922 cm .
1
4
c: 52.50 mg, yield: 76%; mp 186-188 °C; H NMR (400 MHz, CDCl ): δ = 3.77-3.78 (m, 4H),
3
3.92 (s, 6H), 4.12-4.14 (m, 4H), 5.07 (s, 4H), 6.52-6.53 (d, J = 7 Hz, 4H), 6.63-6.64 (d, J = 2 Hz,
1
3
4H), 7.80 (s, 2H); C NMR (100 MHz, CDCl ): δ 52.9, 69.0, 69.4, 69.6, 116.1, 116.3, 130.5,
3
+
32.0, 139.5, 153.0, 153.0, 167.3; HRMS (Q-Tof) m/z: [M+H] calcd. for C H O 509.1812,
1
2
8
29
9
-1
found 509.1813 IR (neat): υmax 1045, 1134, 1265, 1421, 1735 cm .
1
6a: 68.00 mg, yield: 78%; mp 210-212 °C; H NMR (400 MHz, CDCl ): δ = 3.90 (s, 12H), 5.15
3
(
s, 8H), 6.68 (dd, J = 8.2 Hz, J = 2 Hz, 4H), 6.85 (t, J = 2 Hz, 2H), 7.26 (t, J = 8.2 Hz, 2H), 7.88
1
3
(
s, 2H); C NMR (100 MHz, CDCl ): δ = 52.9, 67.9, 102.1, 108.2, 129.1, 130.5,
3
+
32.0, 138.5, 159.7, 167.7; HRMS (Q-Tof) m/z: [M+H] calcd. for C H O 657.1972, found
1
3
6
33 12
-1
6
57.1973. IR (neat): υmax 896, 1422, 1603, 1730, 2986 cm .
1
6b: 59.30 mg, yield: 68%; mp 208-210 °C; H NMR (400 MHz, CDCl ): δ = 3.89 (s, 12H), 5.10
3
1
3
(
s, 8H), 6.99-7.05 (m, 8H), 7.90 (s, 2H); C NMR (100 MHz, CDCl ): δ = 52.8, 69.4, 116.5,
3
+
23.0, 129.9, 131.9, 138.6, 149.2, 167.8; HRMS (Q-Tof) m/z: [M+H] calcd. for C H O
1
3
6
33 12
-1
657.1972, found 657.1973. IR (neat): υmax 1045, 1132, 1384, 1595, 1768, 2924 cm .
1
6
c: 62.70 mg, yield: 72%; mp 208-210 °C; H NMR (400 MHz, CDCl ): δ = 3.94 (s, 12H), 5.10
3
1
3
(
s, 8H), 6.54 (s, 8H), 7.81 (s, 4H); C NMR (100 MHz, CDCl ): δ = 53.0, 70.1, 116.1, 131.1,
3
+
32.2, 139.7, 154.0, 167.6; HRMS (Q-Tof) m/z: [M+H] calcd. for C H O 657.1972, found
1
3
6
33 12
-1
6
57.1973. IR (neat): υmax 1046, 1133, 1255, 1498, 1728 cm .
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General procedure for Diels−Alder reaction with Tetracyanoethylene
To a stirred solution of the diene [9b (50 mg, 0.136 mmol) or 8b (50 mg, 0.133 mmol)] in
toluene (15 mL) was added tetracyanoethelyne [(20.88 mg, 0.163 mmol) for 9b and (41.78 mg,
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
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0.326 mmol) for 8b] under N and the reaction mixture was refluxed for 20 h. At the conclusion
2
of the reaction (TLC monitoring), the solvent was removed on a rotavapour. The crude reaction
mixture was diluted with ethyl acetate washed with brine. The combined organic layer was
concentrated under reduced pressure and the crude product was purified by column
chromatography by eluting with appropriate mixture of ethyl acetate/petroleum ether mixture.
1
1
0: 66.38 mg, yield: 79%; mp 180-182 °C; H NMR (400 MHz, CDCl ): δ = 3.41 (s, 8H), 4.57
3
1
3
(
s, 8H), 6.89-6.99 (m, 8H); C NMR (100 MHz, CDCl ): δ = 34.9, 37.8, 67.3, 110.4, 117.4,
3
+
123.9, 128.1, 148.2; HRMS (Q-Tof) m/z: [M+Na] calcd. for C H N O Na 655.1818, found
3
8
24
8
4
-1
6
1
3
55.1818 IR (neat): υmax 1046, 1133, 1255, 1498, 2250 cm .
1
1: 65.95 mg, yield: 82%; mp 172-174 °C; H NMR (400 MHz, CDCl ): δ = 3.39 (s, 4H), 3.90-
3
1
.92 (m, 4H), 4.17-4.19 (m, 4H), 4.76 (s, 4H), 6.87-7.07 (m, 8H); C NMR (100 MHz, CDCl ):
3
3
δ = 34.1, 37.9, 66.74, 67.7, 69.6, 110.8, 113.7, 121.7, 122.0, 125.0, 127.2, 146.9, 151.1; HRMS
+
(Q-Tof) m/z: [M+H] calcd. for C H N O 497.1821, found 497.1825 IR (neat): υ
1046,
max
2
8
25
4
5
-
1
1
133, 1255, 1498, 2250 cm .
Acknowledgements
We thank DST, New Delhi for the financial support and SAIF, Mumbai for recording the
spectral data. GW thanks the CSIR, New Delhi for the award of a research fellowship. SK thanks
DST for the award of a J. C. Bose fellowship. This manuscript is dedicated to Prof. Henning
Hopf in appreciation of his monumental contribution to cyclophane chemistry.
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Supporting Information
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The H and C NMR spectra of all new compounds. This material is available free of charge via
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the Internet at http://pubs.acs.org.
References
th
Portion of work was presented at the 19 International Symposium on Olefin Metathesis
†
(
ISOM), Rennes, France, July 10–15, 2011.
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