Diversity-oriented approach to macrocyclic cyclophane derivatives by Suzuki-Miyaura cross-coupling and olefin metathesis as key steps

Article abstract of DOI:10.1021/jo2020714

Palladium-catalyzed Suzuki-Miyaura (SM) cross-coupling reaction with allylboronic acid pinacol ester and titanium assisted cross-metathesis (CM)/ring-closing metathesis (RCM) cascade has been used to synthesize macrocyclic cyclophane derivatives.

Full text of DOI:10.1021/jo2020714

Article
pubs.acs.org/joc
Diversity-Oriented Approach to Macrocyclic Cyclophane Derivatives
by Suzuki−Miyaura Cross-Coupling and Olefin Metathesis as Key
Steps‡
Sambasivarao Kotha,* Arjun S. Chavan, and Mobin Shaikh
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai- 400076 India
S
* Supporting Information
ABSTRACT: Palladium-catalyzed Suzuki−Miyaura (SM)
cross-coupling reaction with allylboronic acid pinacol ester
and titanium assisted cross-metathesis (CM)/ring-closing
metathesis (RCM) cascade has been used to synthesize
macrocyclic cyclophane derivatives.
Hopf's group reported a simple synthetic route to [3.4]-
paracyclophane (1) via extrusion of sulfur dioxide under flash
vacuum pyrolysis (FVP) conditions.6a Earlier, Cram and
Allinger have also synthesized [3.4]paracyclophane with acyloin
condensation as a key step.6c In 1982, Lehner and Krois
reported the synthesis of [3.4]metacyclophane (2) with a
carbene insertion reaction as a key step (Figure 1).6e
INTRODUCTION
■
Suzuki−Miyaura (SM) cross-coupling reaction1 has attracted a
great deal of attention in organic synthesis in recent times.
Ring-closing metathesis (RCM)2 has also widely been used for
macrocyclic synthesis,3 which is commonly found in many
natural products, pharmaceuticals, materials science, catalysis,
and supramolecular chemistry.4a−d,e−k,l These two themes are
individually used in combination with other C−C bond
forming reactions to synthesize a variety of polycyclic
compounds.4m Among polycycles, cyclophanes5 play an
important role in host−guest chemistry. Therefore, there is a
continuous need to develop new methods for the synthesis of
cyclophanes by efficient and simple routes. Several methods are
available to synthesize various cyclophane derivatives, including
pyrolysis of sulfones6a and polymerization of p-xylene,6b acyloin
condensation,6c,f carbene insertion,6d,e Wurtz coupling,6f and
Ni-catalyzed Grignard coupling.6g However, syntheses of
cyclophanes using RCM,7 SM cross-coupling,8 or a combina-
tion of these two methods are limited.9 Kwochka and co-
workers have reported various cyclophane derivatives by SM
cross-coupling reaction of bis-9-BBN adduct of various dienes
with aryl bromides.8b Kotha and co-workers synthesized the
[1.1.6]metacyclophane derivatives by SM cross-coupling and
RCM as key steps.9a Guan’s group has synthesized the m-
terphenyl-based cyclophanes by utilizing the SM cross-coupling
and RCM strategy.9b In continuation with our interest in
cyclophane synthesis,10 here we conceived a short synthetic
route to [3.4]cyclophane derivatives with SM cross-coupling
and RCM as key steps. A strategy based on these two key
reactions is expected to be unique and concise because of the
inherent nature of the efficiency in C−C bond formation and
also because of the catalytic nature of these reactions. Recently,
Figure 1. [3.4]Meta/paracyclophane.
Our strategy begins with dialkylation of active methylene
compound (AMC) with a suitably functionalized benzyl
bromide derivative, followed by the introduction of allyl
group or alkenyl group with the aid of SM cross-coupling
reaction. Finally, RCM and hydrogenation sequence can lead to
the required cyclophane derivatives (Figure 2). The diversity-
oriented approach conceived here is capable of producing a
variety of cyclophane derivatives. Here, several diversity points
are available at our disposal. The first one is related to the
selection of active methylene moiety and the second point of
diversity involves the variation of the aromatic unit related to
benzyl bromide component. For example, introduction of
Received: October 11, 2011
Published: November 30, 2011
© 2011 American Chemical Society
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Scheme 1. Attempts to Synthesize Cyclophane Derivative by
RCM
Figure 2. Our strategy to cyclophane derivatives.
heteroaryl derivatives such as furan- or thiophene-based
molecules will open up additional opportunities for further
synthetic manipulation. The third variation involves utilization
of various commercially available unsaturated boronic acid
components during the cross-coupling reaction, which will
deliver cyclophanes of varying ring size. The double bond left at
the end of RCM sequence would provide an additional handle
for further synthetic maneuver.
dinitrofluorene (4) was chosen as an active methylene partner.
To this end, fluorene-based precursor 9,9-bis(p-bromobenzyl)-
2,7-dinitrofluorene (12) was prepared by the C-9 dibenzylation
of 2,7-dinitrofluorene (4) with 2 equiv of p-bromobenzyl
bromide in presence of K2CO3 in dry acetonitrile under phase-
transfer catalysis (PTC) conditions. Because of the poor
solubility of 2,7-dinitrofluorene (4), low yield of the product 12
was observed. Next, we subjected the dibromo derivative 12 to
Pd-catalyzed SM cross-coupling reaction with excess of
allylboronic acid pinacol ester to obtain the diallyl product 13
in 45% yield. Then, we attempted the RCM of diallyl
compound 13 with Grubbs first- as well as second-generation
catalysts, but unfortunately diallyl substrate 13 did not deliver
the required cyclophane derivative 14 by RCM sequence
(Scheme 2).
At this junction, we considered an alternate active methylene
precursor that may overcome the solubility problem associated
with the compound 4. Therefore, we choose the diethyl
malonate (DEM) (5) as active methylene partner, and it was
successfully dibenzylated in the presence of K2CO3 under
acetonitrile reflux conditions or 4 N NaOH under PTC
conditions using benzyl triethylammonium chloride (BTEACl)
to give compounds 15a−b.16 We have also attempted the
dibenzylation reaction under KF-Celite conditions in acetoni-
trile. Unfortunately, monobenzylated product was obtained as
major product. These dibenzylated derivatives 15a−b were
allylated by SM cross-coupling reaction with excess of
allylboronic acid pinacol ester with the aid of Pd(0) catalyst.14
Having prepared the diallyl compounds 16a−b, our attention
was focused on the RCM step. Initially, treatment of the diallyl
compound 16a with Grubbs first-generation catalyst gave low
yield of the RCM product. Later, the reaction was carried out
with Grubbs first- as well as second-generation catalysts under
different reaction conditions (such as G-II, DCM at 40 °C; G-I,
RESULTS AND DISCUSSION
■
In connection with a major program aimed at designing various
polycyclic compounds using SM cross-coupling and RCM as
key steps,11 we conceived a short and alternative route to
cyclophanes by utilizing SM cross-coupling and RCM
sequence.
Among various active methylene compounds 3−7 (Figure
3), we have chosen ethyl isocycanoacetate (3) to prepare p-
vinyl derivative 8 using 4-vinyl benzyl chloride10a,b and
subjected to RCM.12 Unfortunately, the reaction did not lead
to the expected ring-closing product 9 (Scheme 1).Therefore,
we thought that the substrate containing a vinyl appendage may
not be long enough to undergo the RCM reaction, and
therefore, the replacement of vinyl group with allyl moiety may
increase the chances for cyclization reaction. The required
diallyl derivatives 10a and 10b were obtained by SM cross-
coupling reaction of the corresponding dibromo derivatives13
with allylboronic acid pinacol ester as coupling partner.14 Later,
the diallylated compounds 10a and 10b were subjected to
RCM reaction under various reaction conditions; unfortunately,
the RCM reaction failed to deliver the required cyclophane
derivatives 11a−b. Later, we tried the RCM protocol under
Lewis acid catalysis conditions involving titanium isopropoxide
[Ti(iOPr)4]. However, these conditions are also not useful to
realize RCM. X-ray crystal structure of similar derivatives
indicated unfavorable disposition of the double bonds, which is
responsible for the unsuccessful RCM sequence.15
By increasing the steric bulk of active methylene compound,
one may be able to design a precursor with a favorable
conformation suitable for RCM. Therefore, we intend to alter
the active methylene component, and in this regard, the 2,7-
Figure 3. Active methylene components.
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Scheme 2. Another Attempt to Synthesize
[3.4]Paracyclophane Derivative by RCM
Figure 5. The molecular crystal structure of 17b with 50% probability.
Scheme 3. Synthesis of Macrocyclic Cyclophane Derivatives
18a−b and 20
toluene/rt; and G-II, toluene/80 °C) gave no RCM product;
i.e., [3.4]cyclophane derivative was not formed in good yield.
Finally, we found that Lewis acid such as titanium(IV)
isopropoxide aids the metathesis process with Grubbs first
generation catalyst in dry DCM at 40 °C to deliver the
macrocyclic product 17a in moderate yield.17 In the case of m-
allyl derivative 16a, metathesis reaction gave the [3.4]-
cyclophane derivative 19 by RCM along with the dimeric
product 17a by CM-RCM sequence, but in the case of p-allyl
derivative 16b, we isolated only macrocyclic dimer 17b. The
formation of dimeric cyclophane derivatives 17a−b and
monomer 19 was further confirmed by single crystal X-ray
crystallographic data (Figures 4 and 5),18 which clearly shows
that the double bonds are in trans arrangement. The dimeric
cyclophane derivatives 17a−b were crystallized in triclinic
crystal system with space group P-1, and monomeric
cyclophane derivative 19 was crystallized in orthorhombic
crystal system with space group Fdd2. In the case of 17a, some
disorder with one ester group and one benzene ring has been
observed. Hydrogenation of unsaturated cyclophane derivatives
17a−b and 19 using 5% Pd/C in the presence of hydrogen in
dry ethyl acetate furnished the saturated cyclophanes19 18a−b
and 20, respectively. The aromatic proton (C−CH*−C) of
[3.4]metacyclophane derivative 20 is more shielded (6.02 ppm)
as compared to macrocyclic cyclophane derivative 18a (6.84
ppm) (C−CH*−C) (Scheme 3).
bromide derivatives involving 1,3-diketone seems to be a
nontrivial task. Various attempts to dibenzylate 1,3-indanedione
(6) were unsuccessful under NaH/THF conditions. On the
basis of our earlier experience,21 1,3-indanedione (6) was
successfully dialkylated using freshly prepared KF-Celite in one
Later, we considered 1,3-indanedione20 (6) as the active
methylene component. The dialkylation process with benzyl
Figure 4. The molecular crystal structure of 17a with 50% probability and 19 with 30% probability.
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Scheme 4. Synthesis of Macrocyclic Cyclophane Derivatives 24a−b
Figure 6. The molecular crystal structure of 23a and 23b with 30% probability.
step.22,23 Thus, the 1,3-indanedione (6) was treated with 2.2
equiv of bromobenzyl bromide in dry acetonitrile under KF-
CONCLUSION
■
Herein, we have demonstrated a short and efficient synthetic
route to macrocyclic cyclophane derivatives by utilizing SM
cross-coupling reaction and CM/RCM cascade. The present
methodology opens up a new and short synthetic sequence to
several macrocyclic cyclophane derivatives without the
involvement of protecting groups. Various diversity points
involved in this strategy provide ample opportunities to
generate a library of cyclophane derivatives.
Celite conditions to generate the required dibenzylated
products 21a−b in good yields. Along similar lines, allylation
was achieved by SM cross-coupling reaction with excess of
allylboronic acid pinacol ester under CsF and Pd(PPh3)4 in dry
THF reflux conditions to deliver the required diallyl derivatives
22a−b in good yield. Then, these diallylated compounds 22a−
b were subjected to metathesis reaction with G-I in the
presence of Ti(iOPr)4 to deliver macrocyclic cyclophane
derivatives 23a−b. The formation of macrocyclic products
23a−b was further confirmed by single crystal X-ray crystallo-
graphic studies (Figure 6),24 which clearly show that the double
bonds are in trans arrangement. The macrocyclic cyclophane
derivatives 23a−b were crystallized in monoclinic crystal
system with space group P21/c. Later, the macrocyclic products
23a−b were hydrogenated using catalytic amount of 5% Pd/C
or PtO2 in the presence of hydrogen in dry ethyl acetate to
deliver the saturated macrocyclic cyclophane derivatives 24a−b
(Scheme 4). The aromatic protons attached to the benzene ring
EXPERIMENTAL SECTION
■
General Remarks. All the reactions were monitored by employing
TLC technique using appropriate solvent system for development.
Reactions involving oxygen-sensitive reagents or catalysts were
performed in degassed solvents. Dry tetrahydrofuran (THF) was
obtained by distillation over sodium benzophenone ketyl freshly prior
to use. Dichloromethane was distilled over P2O5 and acetonitrile over
CaH2. Magnesium sulfate/sodium sulfate was dried in an oven at 130
°C for one day. All the solvent extracts were washed successively with
water and brine (saturated sodium chloride solution), dried over
anhydrous magnesium sulfate/sodium sulfate, and concentrated at the
reduced pressure on a rotary evaporator. Yields refer to the
chromatographically isolated yield. All the commercial grade reagents
were used without further purification. NMR samples were generally
1
of indanedione experience a greater shielding effect in the H
NMR (δ 5.50 ppm) spectrum of 24b.
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made in chloroform-d solvent, and chemical shifts were reported in δ
scale using tetramethylsilane (TMS) as an internal standard. The
standard abbreviation s, d, t, q and m, refer to singlet, doublet, triplet,
quartet, and multiplet, respectively. Coupling constants (J) are
reported in Hertz.
Diethyl 2,2-bis(p-Allylbenzyl) Malonate (16b). Spectral data:
yield 90%; Rf = 0.55 (silica gel, 10% EtOAc/petroleum ether); H
1
NMR (400 MHz, CDCl3) δ 7.09 (s, 8H), 5.94 (m, 2H), 5.07 (m, 4H),
4.10 (q, J = 7.2 Hz, 4H), 3.35 (dt, J1 = 6.7 Hz, J2 = 1.4 Hz, 4H), 3.18
(s, 4H), 1.16 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
171.2, 138.8, 137.6, 134.2, 130.4, 128.6, 115.9, 61.3, 60.4, 40.0, 38.7,
14.1; IR (neat, cm−1) 2979, 1733, 1513, 1444, 1267, 1179; HRMS (Q-
Tof) m/z [M + H]+ calcd for C27H33O4 421.2379, found 421.2365.
Synthesis of Compounds 17a−b and 19. A solution of diallyl
compound 16a−b (65 mg, 0.15 mmol) in dry DCM (25 mL) was
degassed with N2 gas for 5 min, then 20 mol % of Ti(iOPr)4 (8.8 mg,
0.03 mmol) and 10 mol % of Grubbs first generation catalyst (12.7
mg) were added, and the reaction mixture was stirred at 40 °C for 7 h.
After the completion of the reaction, the solvent was removed under
reduced pressure, and the product was purified by silica gel column
chromatography. Elution of the column with 10% ethyl acetate/
petroleum ether gave the RCM products. In the case of starting
material 16a, we have isolated the two products 17a and 19.
Compound 17a. Spectral data: yield 30%; Rf = 0.27 (silica gel,
10% EtOAc/petroleum ether); mp 168−170 °C; 1H NMR (400 MHz,
CDCl3) δ 7.15−7.01 (m, 12H), 6.87 (m, 4H), 5.67 (m, 4H), 4.16 (q, J
= 7.2 Hz, 8H), 3.35 (d, J = 4.9 Hz, 8H), 3.12 (s, 8H), 1.23 (t, J = 7.2
Hz, 12H); 13C NMR (100 MHz, CDCl3) δ 171.2, 140.5, 136.5, 131.1,
130.7, 128.6, 127.3, 127.3, 61.4, 60.0, 39.2, 37.6, 14.1; IR (KBr, cm−1)
2850, 1730, 1598, 1384, 1351, 1198, 1042; HRMS (Q-Tof) m/z [M +
H]+ calcd for C50H57O8 785.4053, found 785.4060.
Compound 19. Spectral data: yield 15%; Rf = 0.62 (silica gel, 10%
EtOAc/petroleum ether); mp 134−136 °C; 1H NMR (400 MHz,
CDCl3) δ 7.16 (t, J = 7.6 Hz, 2H), 7.03 (d, J = 7.5 Hz, 2H), 6.71 (d, J
= 7.8 Hz, 2H), 6.63 (s, 2H), 5.65 (m, 2H), 4.37 (q, J = 7.2 Hz, 4H),
3.24 (d, J = 6.2 Hz, 4H), 3.04 (bs, 4H), 1.36 (t, J = 7.2 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 171.6, 139.8, 135.8, 135.1, 130.7, 128.6,
127.1, 125.6, 61.8, 58.9, 38.6, 37.5, 14.3; IR (KBr, cm−1) 2812, 1729,
1598, 1384, 1351, 1202; HRMS (Q-Tof) m/z [M + H]+ calcd for
C25H29O4 393.2066, found 393.2072.
Compound 17b. Spectral data: yield 54%; Rf = 0.27 (silica gel,
10% EtOAc/petroleum ether); mp 186−188 °C; 1H NMR (400 MHz,
CDCl3) δ 7.14−7.07 (m, 16H), 5.66 (m, 4H), 4.21 (q, J = 7.2 Hz,
8H), 3.35 (d, J = 5.2 Hz, 8H), 3.16 (s, 8H), 1.25 (t, J = 7.2 Hz, 12H);
13C NMR (100 MHz, CDCl3) δ 171.3, 139.5, 133.9, 130.8, 130.3,
128.6, 61.5, 59.9, 38.6, 37.0, 14.2; IR (KBr, cm−1) 2811, 1733, 1598,
1384, 1351, 1191; HRMS (Q-Tof) m/z [M + H]+ calcd for C50H57O8
785.4053, found 785.4060.
Synthesis of Compounds 18a−b and 20. To a solution of
olefinic compound 17a−b or 19 (10 mg) in dry ethyl acetate (10 mL),
20 mol % of 5% Pd/C was added, and the mixture was stirred at room
temperature under hydrogen atmosphere (1 atm) for 6 h. After the
completion of the reaction, the solvent was evaporated under reduced
pressure, and the product was purified by silica gel column
chromatography. Elution of the column with 7.5% ethyl acetate/
petroleum ether gave the hydrogenated products in good yield.
Compound 18a. Spectral data: yield 80%; Rf = 0.36 (silica gel,
10% EtOAc/petroleum ether); mp 154−158 °C; 1H NMR (300 MHz,
CDCl3) δ 7.14 (t, J = 7.5 Hz, 4H), 7.05 (d, J = 7.8 Hz, 4H), 7.01 (s,
4H), 6.84 (d, J = 7.5 Hz, 4H), 4.21 (q, J = 7.2 Hz, 8H), 3.15 (s, 8H),
2.65 (m, 8H), 1.72 (m, 8H), 1.25 (t, J = 7.2 Hz, 12H); 13C NMR (100
MHz, CDCl3) δ 171.4, 142.4, 136.4, 131.2, 128.5, 127.2, 126.7, 61.5,
59.8, 37.5, 36.1, 31.7, 14.2; IR (KBr, cm−1) 2931, 2811, 1733, 1598,
1384, 1351, 1197; HRMS (Q-Tof) m/z [M + H]+ calcd for C50H61O8
789.4366, found 789.4389.
Compound 18b. Spectral data: yield 90%; Rf = 0.36 (silica gel,
10% EtOAc/petroleum ether); mp 166−168 °C; 1H NMR (300 MHz,
CDCl3) δ 6.95 (ABq, J1 = 8.4 Hz, J2 = 2.6 Hz, 16H), 4.17 (q, J = 7.2
Hz, 8H), 3.13 (s, 8H), 2.57 (m, 8H), 1.52 (m, 8H), 1.20 (t, J = 7.2 Hz,
12H); 13C NMR (100 MHz, CDCl3) δ 171.5, 140.8, 133.5, 130.3,
128.5, 61.4, 59.6, 38.1, 34.9, 29.8, 14.1; IR (KBr, cm−1) 2933, 2813,
1727, 1598, 1384, 1351, 1208; HRMS (Q-Tof) m/z [M + H]+ calcd
for C50H61O8 789.4366, found 789.4377.
Dibenzylation of Diethyl Malonate. Method A. To an
aqueous solution of 4 N NaOH (2 mL), benzyltriethyl ammonium
chloride (142 mg, 0.62 mmol) was added, and the mixture was stirred
for 5 min. Then, diethyl malonate (100 mg, 0.625 mmol) and bromo
benzylbromide (344 mg, 1.37 mmol) were added, and the mixture was
stirred at room temperature for 3 h. After the completion of the
reaction, the reaction mixture was diluted with water and extracted
with ethyl acetate (3 × 20 mL). The combined organic layer was
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The product was purified by silica gel column
chromatography. Elution of the column with 2% of ethyl acetate/
petroleum ether gave the pure 2,2-dibenzylated diethyl malonates in
good yield.
Method B. To a solution of diethyl malonate (100 mg, 0.62 mmol)
in dry acetonitrile (15 mL), 10 equiv of K2CO3 (862.5 mg, 6.25
mmol), tetrabutylammonium hydrogen sulfate (212 mg, 0.62 mmol),
and 2.2 equiv of bromo benzylbromide (344 mg, 1.37 mmol) were
added, and the mixture was refluxed for 36 h. After the completion of
the reaction, the reaction mixture was filtered over short pad of Celite
through a sintered funnel and washed with ethyl acetate (20 mL). The
combined organic layer was concentrated under reduced pressure, and
the product was purified by silica gel column chromatography. Elution
of the column with 2% ethyl acetate/petroleum ether gave the
required 2,2-dibenzylated diethyl malonates in good yield.
Diethyl 2,2-bis(m-Bromobenzyl) Malonate (15a). Spectral
data: yield ∼60%; Rf = 0.5 (silica gel, 10% EtOAc/petroleum ether);
mp 62−64 °C; 1H NMR (400 MHz, CDCl3) δ 7.38 (dq, J1 = 7.8 Hz,
J2 = 1.4 Hz, 2H), 7.30 (t, J = 1.7 Hz, 2H), 7.15 (t, J = 7.6 Hz, 2H), 7.10
(dt, J1 = 7.8 Hz, J2 = 1.4 Hz, 2H), 4.13 (q, J = 7.2 Hz, 4H), 3.16 (s,
4H), 1.18 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 170.5,
138.6, 133.3, 130.3, 129.9, 128.9, 122.4, 61.7, 60.2, 39.3, 14.0; IR (KBr,
cm−1) 2960, 2811, 1715, 1594, 1384, 1351, 1257; HRMS (Q-Tof) m/z
[M + H]+ calcd for C21H23O4Br2 496.9963, found 496.9981.
Diethyl 2,2-bis(p-Bromobenzyl) Malonate (15b). Spectral data:
yield ∼70%; Rf = 0.5 (silica gel, 10% EtOAc/petroleum ether); mp
106−110 °C; 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.4 Hz, 4H),
7.02 (d, J = 8.8 Hz, 4H), 4.11 (q, J = 7.2 Hz, 4H), 3.14 (s, 4H), 1.16 (t,
J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 170.7, 135.3, 131.9,
131.5, 121.2, 61.6, 61.0, 39.1, 14.0; IR (KBr, cm−1) 2964, 2811, 2111,
1731, 1594, 1351, 1199; HRMS (Q-Tof) m/z [M + H]+ calcd for
C21H23O4Br2 496.9963, found 496.9962.
Synthesis of Compounds 16a and 16b. A solution of diethyl
2,2-bis(bromobenzyl) malonate 15a−b (100 mg, 0.20 mmol), cesium
fluoride (122 mg, 0.80 mmol), and Pd(PPh3)4 (11.6 mg, 5 mol %) in
dry THF (20 mL) was stirred at rt for 10 min, and then, allylboronic
acid pinacol ester (135 mg, 0.80 mmol) was added dropwise and
stirred at 80 °C for 24 h. Again, cesium fluoride (61 mg, 0.40 mmol),
Pd(PPh3)4 (11.6 mg, 5 mol %), and allylboronic acid pinacol ester (68
mg, 0.40 mmol) were added, and the mixture was stirred for another
24 h. After the completion of the reaction, the reaction mixture was
diluted with ether and washed with water (3 × 20 mL). The organic
layer was dried over Na2SO4 and concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography. Elution of the column with 2% ethyl acetate/
petroleum ether gave the diallyl products 16a−b.
Diethyl 2,2-bis(m-Allylbenzyl) Malonate (16a). Spectral data:
1
yield 73%; Rf = 0.55 (silica gel, 10% EtOAc/petroleum ether); H
NMR (400 MHz, CDCl3) δ 7.19 (t, J = 7.6 Hz, 2H), 7.06 (d, J = 7.9
Hz, 2H), 7.02 (d, J = 7.6 Hz, 2H), 6.99 (s, 2H), 5.95 (m, 2H), 5.07
(m, 4H), 4.11 (q, J = 7.2 Hz, 4H), 3.35 (d, J = 6.7 Hz, 4H), 3.19 (s,
4H), 1.17 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 171.1,
140.0, 137.6, 136.7, 130.7, 128.4, 128.1, 127.3, 116.0, 61.4, 60.3, 40.3,
39.0, 14.1; IR (neat, cm−1) 2979, 1733, 1445, 1196, 1095, 915; HRMS
(Q-Tof) m/z [M + H]+ calcd for C27H33O4 421.2379, found 421.2363.
Compound 20. Spectral data: yield 90%; Rf = 0.67 (silica gel, 10%
EtOAc/petroleum ether); mp 78−82 °C; 1H NMR (400 MHz,
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CDCl3) δ 7.15 (t, J = 7.6 Hz, 2H), 6.96 (d, J = 7.5 Hz, 2H), 6.77 (d, J
= 7.8 Hz, 2H), 6.02 (s, 2H), 4.38 (q, J = 7.2 Hz, 4H), 3.16 (s, 4H),
2.48 (m, 4H), 1.50 (m, 4H), 1.36 (t, J = 7.2 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 172.3, 140.7, 135.5, 132.1, 128.9, 128.0, 125.1, 62.0,
57.0, 37.8, 34.1, 25.3, 14.3; IR (KBr, cm−1) 2931, 2854, 1732, 1447,
1265, 1207; HRMS (Q-Tof) m/z [M + H]+ calcd for C25H31O4
395.2222, found 395.2218.
Synthesis of 2,2-bis(Bromobenzyl) 1,3-Indanedione (21a
and 21b). To a solution of 1,3-indanedione (6) (1 g, 6.85 mmol)
and bromobenzyl bromide (3.77 g, 15.07 mmol) in dry acetonitrile
(40 mL), freshly prepared KF-Celite (7 g) was added, and the reaction
mixture was stirred at rt for 24 h. Again, 3 g of KF-Celite was added,
and the stirring was continued for another 24 h. After the completion
of the reaction, the reaction mixture was filtered through sintered
funnel, and solvent was removed under reduced pressure. The crude
product was purified by silica gel column chromatography. Elution of
the column with 5% ethyl acetate/petroleum ether gave the 2,2-
bis(bromobenzyl) 1,3-indanedione 21a−b as a white crystalline
compound.
2,2-Bis(m-Bromobenzyl) 1,3-Indanedione (21a). Spectral data:
yield 74%; Rf = 0.63 (silica gel, 10% EtOAc/petroleum ether); mp
184−186 °C; 1H NMR (400 MHz, CDCl3) δ 7.68 (dd, J1 = 5.6 Hz, J2
= 2.8 Hz, 2H), 7.58 (dd, J1 = 5.6 Hz, J2 = 2.8 Hz, 2H), 7.12 (m, 4H),
6.91 (m, 4H), 3.18 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 202.7,
142.6, 137.5, 135.7, 132.9, 130.1, 129.7, 128.7, 122.7, 122.2, 61.6, 40.8;
IR (KBr, cm−1) 2923, 1736, 1702, 1593, 1352, 1249, 782; HRMS (Q-
Tof) m/z [M + H]+ calcd for C23H17O2Br2 482.9595, found 482.9599.
2,2-Bis(p-Bromobenzyl) 1,3-Indanedione (21b). Spectral data:
yield 70%; Rf = 0.63 (silica gel, 10% EtOAc/petroleum ether); mp
162−164 °C; 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J1 = 5.6 Hz, J2
= 2.8 Hz, 2H), 7.59 (dd, J1 = 5.6 Hz, J2 = 2.8 Hz, 2H), 7.14 (d, J = 8.4
Hz, 4H), 6.85 (d, J = 8.4 Hz, 4H), 3.18 (s, 4H); 13C NMR (75 MHz,
CDCl3) δ 203.1, 142.6, 135.8, 134.2, 131.6, 131.3, 122.7, 121.0, 61.7,
40.7; IR (KBr, cm−1) 2923, 1741, 1705, 1593, 1490, 1353, 1251, 1075,
1016, 808, 792; HRMS (Q-Tof) m/z [M + H]+ calcd for C23H17O2Br2
482.9595, found 482.9590.
Synthesis of 2,2-bis(Allylbenzyl) 1,3-Indanedione (22a and
22b). A solution of 2,2-bis(bromobenzyl) 1,3-indanedione 21a−b (1
g, 2.07 mmol), cesium fluoride (1.26 g, 8.26 mmol), and Pd(PPh3)4
(119 mg, 5 mol %) in dry THF (50 mL) was stirred at rt for 10 min,
then allylboronic acid pinacol ester (1.34 g, 8.26 mmol) was added
dropwise, and the mixture was stirred at 80 °C for 24 h. Again, cesium
fluoride (630 mg, 4.13 mmol), Pd(PPh3)4 (60 mg, 2.5 mol %), and
allylboronic acid pinacol ester (700 mg, 4.32 mmol) were added, and
the mixture was stirred at 80 °C for another 24 h. After the completion
of the reaction, the reaction mixture was diluted with ether and washed
with water (3 × 20 mL). The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The crude product was purified
by silica gel column chromatography. Elution of the column with 2%
ethyl acetate/petroleum ether gave the diallylated products 22a−b as a
white crystalline solid.
62.4, 41.3, 39.7; IR (KBr, cm−1) 3075, 2918, 1739, 1702, 1595, 1358,
1250, 914; HRMS (Q-Tof) m/z [M + H]+ calcd for C29H27O2
407.2011, found 407.2001.
Synthesis of Compound 23a and 23b. A solution of diallyl
compound 22a−b (50 mg, 0.12 mmol) in dry DCM (25 mL) was
degassed with N2 for 5 min, then Ti(iOPr)4 (7 mg, 20 mol %) and 10
mol % of Grubbs first generation catalyst (10 mg) were added, and the
reaction mixture was stirred at 40 °C for 7 h. After the completion of
the reaction, the solvent was removed under reduced pressure, and the
product was purified by silica gel column chromatography. Elution of
the column with 10% ethyl acetate/petroleum ether mixture gave the
metathesis products 23a−b as white solids.
Compound 23a. Spectral data: yield 54%; Rf = 0.34 (silica gel,
1
10% EtOAc/petroleum ether); mp decomposed at 250 °C; H NMR
(400 MHz, CDCl3) δ 7.05 (dd, J1 = 5.6 Hz, J2 = 3.0 Hz, 4H), 6.94 (s,
4H), 6.89 (t, J = 7.6 Hz, 4H), 6.79 (d, J = 7.8 Hz, 4H), 6.72 (d, J = 7.6
Hz, 4H), 6.61 (dd, J1 = 5.6 Hz, J2 = 3.0 Hz, 4H), 5.31 (m, 4H), 3.27 (s,
8H), 3.21 (d, J = 4.0 Hz, 8H); 13C NMR (100 MHz, CDCl3) δ 203.3,
142.5, 140.4, 135.8, 134.8, 131.1, 129.8, 128.2, 127.7, 127.1, 122.3,
62.4, 41.5, 38.3; IR (KBr, cm−1) 2921, 2814, 1738, 1702, 1590, 1486,
1443, 1383, 1351, 1253; HRMS (Q-Tof) m/z [M + H]+ calcd for
C54H45O4 757.3318, found 757.3333.
Compound 23b. Spectral data: yield 45%; Rf = 0.34 (silica gel,
1
10% EtOAc/petroleum ether); mp decomposed at 230 °C; H NMR
(400 MHz, CDCl3) δ 6.87 (m, 12H), 6.71 (d, J = 8.0 Hz, 8H), 6.04
(dd, J1 = 5.6 Hz, J2 = 3.0 Hz, 4H), 4.97 (m, 4H), 3.19 (s, 8H), 3.06 (d,
J = 4.0 Hz, 8H); 13C NMR (100 MHz, CDCl3) δ 203.4, 142.3, 139.1,
134.4, 133.5, 130.4, 130.1, 128.5, 122.2, 62.9, 40.8, 37.9. IR (KBr,
cm−1) 2922, 2812, 1740, 1705, 1598, 1439, 1384, 1352, 1249; HRMS
(Q-Tof) m/z [M + H]+ calcd for C54H45O4 757.3318, found 757.3308.
Synthesis of Compounds 24a and 24b. To a solution of
olefinic compound 23a−b (10 mg, 0.02 mmol) in dry ethyl acetate
(10 mL), 5% Pd/C or 20 mol % of PtO2 was added, and the mixture
was stirred at rt under hydrogen atmosphere (1 atm) for 2 h. After the
completion of the reaction, the solvent was evaporated under reduced
pressure, and the product was purified by silica gel column
chromatography. Elution of the column with 10% ethyl acetate/
petroleum ether gave the hydrogenated products 24a−b in good yield.
Compound 24a. Spectral data: yield 80%; Rf = 0.54 (silica gel,
1
20% EtOAc/petroleum ether); mp decomposed at 250 °C; H NMR
(300 MHz, CDCl3) δ 6.88 (m, 12H), 6.77 (d, J = 7.6 Hz, 4H), 6.70 (d,
J = 7.6 Hz, 4H), 6.14 (dd, J1 = 5.6 Hz, J2 = 3.2 Hz, 4H), 3.22 (s, 8H),
2.45 (m, 8H), 1.29 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 203.4,
142.3, 142.1, 135.7, 134.6, 130.7, 128.0, 127.3, 126.8, 122.2, 62.4, 41.6,
35.5, 29.1; IR (KBr, cm−1) 2925, 2856, 1738, 1703, 1591, 1384, 1352,
1111; HRMS (Q-Tof) m/z [M + H]+ calcd for C54H49O4 761.3631,
found 761.3594.
Compound 24b. Spectral data: yield 80%; Rf = 0.54 (silica gel,
1
20% EtOAc/petroleum ether); mp decomposed at 230 °C; H NMR
2,2-Bis(m-Allylbenzyl) 1,3-Indanedione (22a). Spectral data:
yield 76%; Rf = 0.67 (silica gel, 10% EtOAc/petroleum ether); mp 84−
86 °C; 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J1 = 5.6 Hz, J2 = 3.2
Hz, 2H), 7.49 (dd, J1 = 5.6 Hz, J2 = 3.2 Hz, 2H), 6.94 (t, J = 7.2 Hz,
2H), 6.80 (m, 6H), 5.75−5.69 (m, 2H), 4.93 (dq, J1 = 8.4 Hz, J2 = 1.6
Hz, 2H), 4.79 (dq, J1 = 17.2 Hz, J2 = 1.6 Hz, 2H), 3.24 (s, 4H), 3.15
(d, J = 7.2 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 203.6, 143.0,
139.7, 137.3, 135.6, 135.1, 130.3, 128.2, 127.8, 127.2, 122.4, 115.6,
62.3, 41.6, 39.9; IR (KBr, cm−1) 3077, 2924, 1730, 1705, 1597, 1439,
1362, 1253, 994, 913; HRMS (Q-Tof) m/z [M + H]+ calcd for
C29H27O2 407.2011, found 407.2011.
2,2-Bis(p-Allylbenzyl) 1,3-Indanedione (22b). Spectral data:
yield 78%; Rf = 0.67 (silica gel, 10% EtOAc/petroleum ether); mp
124−126 °C; 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J1 = 5.6 Hz, J2
= 3.0 Hz, 2H), 7.50 (dd, J1 = 5.6 Hz, J2 = 3.2 Hz, 2H), 6.91 (d, J = 8.4
Hz, 4H), 6.81 (d, J = 8.4 Hz, 4H), 5.80−5.74 (m, 2H), 4.91 (dq, J1 =
10.0 Hz, J2 = 1.6 Hz, 2H), 4.78 (dq, J1 = 16.8 Hz, J2 = 1.6 Hz, 2H),
3.22 (s, 4H), 3.14 (d, J = 6.4 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ
203.8, 143.0, 138.4, 137.5, 135.2, 133.3, 130.1, 128.5, 122.6, 115.7,
(300 MHz, CDCl3) δ 6.82 (d, J = 8.0 Hz, 8H), 6.70 (d, J = 8.4 Hz,
8H), 6.59 (dd, J1 = 5.6 Hz, J2 = 3.2 Hz, 4H), 5.50 (dd, J1 = 5.6 Hz, J2 =
3.2 Hz, 4H), 3.17 (s, 8H), 2.31 (m, 8H), 0.96 (m, 8H); 13C NMR
(100 MHz, CDCl3) δ 203.5, 142.2, 140.8, 134.5, 133.3, 130.2, 128.1,
121.5, 63.4, 40.9, 35.1, 29.4; IR (KBr, cm−1) 2925, 2850, 1740, 1703,
1595, 1383, 1351, 1249; HRMS (Q-Tof) m/z [M + H]+ calcd for
C54H49O4 761.3631, found 761.3626.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
The H and 13C NMR spectra of all new compounds, X-ray
crystallographic data and refinement parameters for 17a, 17b,
19, 23a, and 23b, and a ZIP file containing CIF files giving
crystallographic data for 17a, 17b, 19, 23a, and 23b. This
material is available free of charge via the Internet at http://
pubs.acs.org.
487
dx.doi.org/10.1021/jo2020714 | J. Org. Chem. 2012, 77, 482−489

The Journal of Organic Chemistry
Article
124, 773. (d) Yoshinari, T.; Ohmori, K.; Schrems, M. G.; Pfaltz, A.;
Suzuki, K. Angew. Chem., Int. Ed. 2010, 49, 881; Angew. Chem. 2010,
122, 893. (e) Huang, M.; Song, L.; Liu, B. Org. Lett. 2010, 12, 2504.
(f) Jimenez, L.; Diederich, F. Tetrahedron Lett. 1989, 30, 2759.
(g) Diederich, F.; Lutter, H. D. J. Am. Chem. Soc. 1989, 111, 8438.
(h) Driggers, E. M.; Hale, S. P.; Lee, J.; Terrett, N. K. Nat. Rev. Drug
Discovery 2008, 7, 608. (i) Rajakumar, P.; Rasheed, A. M. A.; Rabia, A.
I.; Chamundeeswari, D. Bioorg. Med. Chem. Lett. 2006, 16, 6019.
(j) Rajakumar, P.; Rasheed, A. M. A.; Balu, P. M.; Murugesan, K.
AUTHOR INFORMATION
Corresponding Author
*Fax: (+) 91-22-25767152. E-mail: srk@chem.iitb.ac.in.
■
ACKNOWLEDGMENTS
■
We thank DST, New Delhi for the financial support and SAIF,
IIT Mumbai for recording the spectral data. A.S.C. thanks
CSIR, New Delhi for award of the research fellowship. S.K.
thanks the DST for the award of a J. C. Bose fellowship.
Bioorg. Med. Chem. 2006, 14, 7458. (k) Seel, C.; Vogtle, F. Angew.
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Chem., Int. Ed. 1992, 31, 528; Angew. Chem. 1992, 104, 542.
(l) Zakarian, J. E.; El-Azizi, Y.; Collins, S. K. Org. Lett. 2008, 10, 2927.
(m) Kotha, S.; Krishna, N. G.; Halder, S.; Misra, S. Org. Biomol. Chem.
2011, 9, 5597. (n) Kotha, S.; Meshram, M.; Tiwari, A. Chem. Soc. Rev.
2009, 38, 2065.
DEDICATION
■
‡Dedicated to Dr. Christian Bruneau on occassion of his 60th
birthday.
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obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. (Hydrogen atoms
are removed for better visualization.)
NOTE ADDED AFTER ASAP PUBLICATION
■
This paper published ASAP December 13, 2011. References
2,3,6,7,13,14 were corrected and this paper reposted December
20, 2011.
489
dx.doi.org/10.1021/jo2020714 | J. Org. Chem. 2012, 77, 482−489