A diversity-oriented approach to diphenylalkanes by strategic utilization of [2+2+2] cyclotrimerization, cross-enyne metathesis and diels-alder reaction

Article abstract of DOI:10.1002/ejoc.200800924

A novel and efficient approach towards the synthesis of poly-substituted diphenylalkane derivatives have been demonstrated using a strategic combination of [2+2+2] cyclotrimerization, ethylene cross-enyne metathesis and Diels-Alder reaction as key steps.

Full text of DOI:10.1002/ejoc.200800924

FULL PAPER
DOI: 10.1002/ejoc.200800924
A Diversity-Oriented Approach to Diphenylalkanes by Strategic Utilization of
[2+2+2] Cyclotrimerization, Cross-Enyne Metathesis and Diels–Alder Reaction
Sambasivarao Kotha*[a] and Priti Khedkar[a]
Keywords: Cyclotrimerization / Diels–Alder reaction / Diphenylalkanes / Diversity-oriented approach / Metathesis
A novel and efficient approach towards the synthesis of poly-
wise functionalization of acetylenic termini of α,ω-diyne scaf-
substituted diphenylalkane derivatives have been demon- fold to build functionalized aromatic units.
strated using a strategic combination of [2+2+2] cyclo-
trimerization, ethylene cross-enyne metathesis and Diels–
Alder reaction as key steps. The strategy involves the step-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The diphenylalkane structural motif is present in a vari-
ety of natural products and biologically important mole-
cules. For example, viscolin 1 (Figure 1) is a naturally oc-
curring 1,3-diphenylpropane, isolated from the Viscum col-
oratum,[1] a hemiparasite herb used in Chinese medicine as
a curative for a number of ailments such as hemorrhage,
pleurisy, gout, heart disease, epilepsy, arthritis, and hyper-
tension.[2] Also, 1,2-diphenylethane derivatives are known
to possess cytotoxic activity towards genital fibroblasts.[3]
Some diphenylethane derivatives (for instance 2) are known
to possess antiestrogenic activity.[4] The neuroendocrine ef-
fects of (+)-1,4-diphenylbutane-2,3-diol (3, DPB) which is
testicular in origin has been subject of intense studies.[5] Lo-
pinavir (ABT-378) 4 containing the 1,6-diphenylalkane
backbone is an antiretroviral of the protease inhibitor class.
It is marketed by Abbott as Kaletra®, a coformulation with
a subtherapeutic dose of ritonavir, as a component of com-
bination therapy to treat HIV/AIDS.[6]
Synthetic routes to prepare diphenylalkane derivatives
are limited,[7,8] and most of these methods involve the use
of benzenoid precursors and thereby limit the scope for in-
corporation of desirable substituents in the aromatic ring.
Further, many of these procedures are not general in nature
and they are not applicable for the preparation of di-
phenylalkane derivatives containing alkyl chain of varying
length. However, in 1980, Japanese investigators demon-
strated a general approach to diphenylalkane derivatives
containing alkyl chains of varied length, although benze-
noid compounds have been used as starting materials.[8]
Motivated by these findings, the two acetylenic ends of un-
Figure 1. Various biologically active diphenylalkane derivatives.
tethered α,ω-diyne scaffolds (for instance 5) have been used
for the assembly of aromatic units and a new approach to
polysubstituted diphenylalkane derivatives via a strategic
utilization of [2+2+2] cyclotrimerization reaction,[9] cross-
enyne metathesis (CEM)[10] and Diels–Alder (DA) reac-
tion[11] as key steps has been conceived. The methodology
proposed here constitutes a diversity-oriented approach[12]
as there are several points of diversity where structural vari-
ations can be incorporated in the target molecule.
Results and Discussion
The theme proposed here involves the generation of
novel polysubstituted benzene derivatives 6, containing ter-
minal alkyne appendage by performing [2+2+2] cyclo-
trimerization of α,ω-diynes 5 and monoyne 5a. These com-
pounds seem to be suitable substrates for performing an-
[a] Department of Chemistry, Indian Institute of Technology –
Bombay,
Powai, Mumbai 400076, India
Fax: +91-22-2572-3480
E-mail: srk@chem.iitb.ac.in
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Diversity-Oriented Approach to Diphenylalkanes
Scheme 1. Strategies proposed for the synthesis of polysubstituted diphenylalkanes.
other [2+2+2] cyclotrimerization with monoyne 5b leading and found that the polysubstituted benzene derivatives 14–
to the formation of diphenylalkane derivative such as 8 17 were produced. The hexamethyl mellitate was also gener-
(path B, Scheme 1). Moreover, compounds of type 6 ap- ated in all the cases, the formation of which can be attrib-
peared to be suitable candidates for the synthesis of densely uted to self-trimerization of DMAD (Scheme 2).
functionalized diphenylalkane derivatives of type 7 via eth-
ylene CEM followed by DA reaction (path A, Scheme 1).
Yamamoto and co-workers have demonstrated tactical
utilization of Cp*Ru(cod)Cl in cyclotrimerization reactions
Recent advances in transition metal-catalyzed [2+2+2] to assemble various polycyclic molecules.[19] When we em-
cyclotrimerizations has paved the way for assembling di- ployed, Cp*Ru(cod)Cl to achieve cyclotrimerization reac-
verse molecular frames of synthetic interest.[9] In particular, tion between α,ω-diynes 9–12 and DMAD (13) various
rhodium-catalyzed [2+2+2] cyclotrimerization reac- polysubstituted benzene derivatives such as 14–17 were ob-
tions[13–15] are widely used to design complex molecular ar- tained (Scheme 2). However, with ruthenium catalyst
rays. Also, we have demonstrated a tactical utilization of DMAD self-trimerization product, hexamethyl mellitate 18,
Wilkinson’s catalyst, RhCl(PPh3)3 to deliver highly func- was not generated in detectable amounts. High dilution
tionalized compounds.[16] Although, few reports[17] deal conditions, changing the molar equivalence of diyne to
with the usage of transition metal complexes to effect monoyne and varying the sequence of addition of starting
[2+2+2] cyclotrimerizations of the untethered α,ω-diynes, materials, gave the same products. When the monoyne part-
only limited examples demonstrate the use of rhodium com- ner was changed to but-2-yne-1,4-diol, 1,4-diacetoxy-2-bu-
plexes.[14c,14s,18]
In connection with our major program directed towards zation products could be isolated.
tyne, or 1,2-bis(trimethylsilyl)acetylene no such trimeri-
the synthesis of annulated benzocycloalkane derivatives,
Alkyne building blocks have been used as starting mate-
various α,ω-diynes such as 1,5-hexadiyne (9), 1,6-hep- rials in many processes such as Sonogashira reaction,[20]
tadiyne (10), 1,7-octadiyne (11) and 1,8-nonadiyne (12), Glaser coupling,[21] Pauson–Khand reaction,[22] enyne me-
were subjected to [2+2+2] cyclotrimerization reaction with tathesis,[23] and [2+2+2] cyclotrimerization[9] reactions. This
dimethyl acetylenedicarboxylate (DMAD, 13). We em- has resulted in the emergence of various methods to gener-
ployed Wilkinson’s catalyst to affect this transformation ate terminal acetylenic compounds.[24] However, some of
Scheme 2. Preparation of polysubstituted benzene derivatives.
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S. Kotha, P. Khedkar
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these procedures involve lengthy synthetic sequences and traditional cobalt catalyst CpCo(CO)2 was found to be fu-
strong bases. Gratifyingly, we found that the [2+2+2] cyclo- tile to effect the cotrimerization between 14 and DMAD.
trimerization reaction of α,ω-diynes and DMAD can be uti- In a series of separate experiments, both Wilkinson’s cata-
lized to generate terminal alkynes in a single step. More- lyst and CpCo(CO)2 were found to be inefficient to catalyze
over, this methodology may permit the preparation of aro- the self-trimerization of 14.
matic unit with a flexible substitution pattern, depending
Metal-catalyzed olefin metathesis[25] undoubtedly has a
upon the monoyne employed. Thus, the strategy employed profound impact on organic synthesis and is widely used
here provides a unique opportunity to assemble the aro- for C–C bond formation. The commercial availability of
matic core containing terminal alkyne in a single step under Grubbs’ first- and second-generation catalysts (G-I or G-
mild reaction conditions.
II) (Figure 3)[26] has provided an easy access to a wide range
Literature precedence indicates that metallocyclopentadi- of complex compounds. The literature examples[10] and our
enes are key intermediates in transition metal-catalyzed previous experience[10a,10b] suggested that ethylene CEM
cyclotrimerization reactions.[9,14c] Among the various mech- can be a valuable process to create 1,3-diene at the alkyne
anistically possible rhodacyclopentadiene intermediates[14c] terminal of polysubstituted benzene derivatives. The DA re-
we have considered two such intermediates which can jus- action performed at diene may deliver the diphenylalkane
tify the formation of products obtained in the present inves- derivative.
tigation. Various other alternative rhodacyclopentadiene in-
termediates[14c] might have formed under the reaction con-
ditions employed but their involvement could not be in-
ferred based on the products isolated. RhI complex proba-
bly couples oxidatively with two acetylenic moieties thereby
delivering RhI rhodacyclopentadienes 19 and 20. Later on,
an insertion or a Diels–Alder-type process incorporates the
third acetylenic partner into the rhodacyclopentadiene in-
termediate. Finally, reductive elimination of RhI is consid-
ered to complete the catalytic cycle. Reaction of 19 with one
molecule of 13, or 20 reacting with one end of diyne moiety
Figure 3. Commonly used ruthenium-based metathesis catalysts.
can account the formation of polysubstituted benzene de-
rivatives 6Ј. The isolation of hexamethyl mellitate 18 can be
explained on the basis of DMAD molecule reacting with
In this regard, the alkynes 14–17 were subjected to CEM
rhodacyclopentadiene 20 (Figure 2).
with ethylene in presence of a G-II catalyst, using toluene
Various polysubstituted benzene derivatives 14, 15, 16 as a solvent. We were pleased to obtain diene derivatives
and 17 (Scheme 2) obtained via [2+2+2] cyclotrimerization 21–24 in excellent yields (Scheme 3). Before the addition of
reaction appear to be ideal candidates for the synthesis of catalyst, the reaction mixture was degassed by bubbling eth-
functionalized diphenylalkane derivatives. In principle, rep- ylene and then the reaction mixture was maintained under
etition of [2+2+2] cyclotrimerization process at the alkyne ethylene atmosphere. The yield of these reactions was re-
terminal of these molecular entities 14–17 can produce markably reduced when dichloromethane was used as a sol-
highly functionalized diphenylalkane derivatives (Scheme 1, vent. When the CEM was attempted with G-I, consumption
Path B). When the terminal alkyne 14 was subjected again of the starting material was found to be sluggish and even
to cyclotrimerization in the presence of Wilkinson’s catalyst high catalyst loading seems to be ineffective in accelerating
using DMAD as a monoyne partner, only the starting ma- the rate of the reaction. The dienes 21–24 were found to
terial was recovered and most of the DMAD was found to be stable and could be isolated and characterized by the
undergo self-trimerization to deliver 18. Even the use of the spectroscopic methods.
Figure 2. Probable mechanistic pathways defining the formation of terminal alkyne containing polysubstituted benzenes.
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Diversity-Oriented Approach to Diphenylalkanes
Scheme 3. Preparation of diphenylalkanes.
The DA reaction of 21–24 has been accomplished by use various ethylene derivatives to effect CEM sequence
heating a solution of diene and dienophile, 13 in toluene at and introduce an additional functionality in the 1,3-diene
80 °C (Scheme 3). Partial aromatization of the DA product component. Designing of unsymmetrical molecules starting
was observed when the reaction mixture was heated at re- with symmetrical synthons is of major concern in organic
flux temperature in toluene. However, prolonged refluxing synthesis.[27] As we have created desymmetrization in highly
in toluene did not lead to complete aromatization. When symmetrical starting materials, α,ω-diynes, this method of-
the reaction was performed at room temp. or at 50 °C no fers the additional value. In view of the tactical utilization
formation of DA product was observed. Also, an attempt of highly atom-economical processes such as [2+2+2] cyclo-
to perform the DA reaction at lower temperature using trimerization, CEM and DA reaction, our approach can be
Lewis acid, such as BF3·OEt2, as a catalyst was proved to regarded as a “Green Route” for the synthesis of densely
be futile.
functionalized diphenylalkanes.
All the DA adducts 25–28 were subsequently aromatized
by using 2,3-dichoro-5,6-dicyano-p-benzoquinone (DDQ).
Although conventional conditions involving heating the
DA adduct and DDQ in toluene were found to be ineffec-
tive, microwave irradiation of the reaction mixture delivered
the corresponding aromatized diphenylalkane derivatives
29–32 in good yields (Scheme 3).
Experimental Section
General: Analytical TLC was performed on glass plates (10ϫ5 cm)
coated with silica gel G or GF 254 (containing 13% CaSO4 as a
binder). Visualization of the spots on TLC plate was achieved
either by exposure to I2 vapour or UV light. Column chromatog-
raphy was performed using silica gel (100–200 mesh) and column
was usually eluted with ethyl acetate and petroleum ether (boiling
range 60–80 °C) mixture. Melting points are uncorrected. 1H NMR
and 13C NMR spectroscopic data were recorded on a Varian VXR
300 and Varian VXR 400 spectrometers using TMS as an internal
standard and CDCl3 or C6D6 as the solvent. The coupling con-
stants (J) are given in Hertz (Hz). Chemical shifts are expressed in
parts per million (ppm) downfield from internal reference, tet-
ramethylsilane. The standard abbreviation s, d, t, q, m, dd and td,
refer to singlet, doublet, triplet, quartet, multiplet, doublet of doub-
let, and triplet of doublet respectively. Mass spectroscopic data was
recorded on a Q-TOF micromass machine. Infrared (IR) spectra
were recorded on a Nicolet Impact-400 FT IR spectrometer. Solid
samples were recorded as KBr wafers and liquid samples were re-
corded as neat. Melting points were recorded on Labhosp or Veego
melting point apparatus and are uncorrected.
Conclusions
A simple and novel route to terminal alkyne containing
aromatic compounds has been established via exclusive
monofunctionalization of commercially available α,ω-di-
ynes. A diversity oriented approach towards the synthesis of
densely functionalized diphenylalkane derivatives has been
established via a sequential implementation of [2+2+2]
cyclotrimerization, ethylene CEM and DA reaction. The
two different polysubstituted aromatic rings are built at the
two ends of α,ω-diyne scaffold in a stepwise manner. This
strategy offers four points of diversity. The first aspect is
the commercial availability of α,ω-diynes of varying chain
length. The second diversity point is the utilization of
[2+2+2] cyclotrimerization where the monoyne can be al-
tered. The third dimension is the utilization of DA reaction
1,5-Hexadiyne (9), 1,6-heptadiyne (10), 1,7-octadiyne (11), 1,8-
nonadiyne (12), DMAD (13), and Wilkinson’s catalyst were pur-
where different dienophiles can be used. Finally, one can chased from Alfa-Aesar-Lancaster (Whitelund, U. K.). Second-
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S. Kotha, P. Khedkar
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generation Grubbs’ catalyst (G-II) was purchased from Fluka
chemicals (Switzerland).
solid. Data for compound 15: Rf = 0.47 (silica gel, 40% EtOAc/
petroleum ether), m.p. 62–64 °C. 1H NMR (400 MHz, CDCl3): δ
= 1.79–1.87 (m, 2 H), 2.02 (t, J = 2.4 Hz, 1 H), 2.23 (dt, J1 = 6.8,
J2 = 2.8 Hz, 2 H), 2.84 (t, J = 8 Hz, 2 H), 3.91–3.92 (m, 12 H),
7.99 (s, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 18.2, 29.7,
32.3, 53.0, 53.1, 53.1, 53.3, 69.4, 83.4, 130.0, 130.2, 133.5, 134.2,
Preparation of Alkyne 14
a) Using Wilkinson’s Catalyst: To a solution of 1,5-hexadiyne 9
(110 mg, 1.41 mmol) in dry degassed ethanol (12 mL) maintained
under nitrogen, was added 13 (1 g, 7.04 mmol) and Wilkinson’s cat-
alyst (13 mg, 0.014 mmol, 1 mol-%). The resulting pale yellow solu-
tion was refluxed for 24 h. The reaction mixture was then cooled
to room temp. and the solvent was removed under reduced pressure
to obtain brown, sticky crude product which was charged on a
silica gel column. Elution of the column with 20% EtOAc/petro-
leum ether gave the unreacted 13 (226 mg) followed by the polysub-
stituted benzene derivative 14 (210 mg, 41%) as a colorless solid.
Further elution of the column with 40% EtOAc/petroleum ether
furnished, hexamethyl mellitate 18 (162 mg, 49%[28]) as a colorless
crystalline solid. Data for compound 18: Rf = 0.19 (silica gel, 40%
EtOAc/petroleum ether), m.p. 186 °C.[29]
137.1, 141.8, 165.2, 165.8, 167.5, 167.7 ppm. IR (KBr): ν = 2955,
˜
1966, 1728, 1651, 1440, 1155 cm–1. HRMS (Q-Tof): m/z calcd. mass
399.1056 for C19H20O8Na [M + Na]+; found 399.1043.
Preparation of Alkyne 16
a) Using Wilkinson’s Catalyst: To a solution of 1,7-octadiyne 11
(160 mg, 1.5 mmol) in dry degassed ethanol (12 mL) maintained
under nitrogen, was added 13 (1.0 g, 7.04 mmol) and Wilkinson’s
catalyst (14.2 mg, 0.015 mmol, 1 mol-%). The resulting pale yellow
solution was refluxed for 24 h. The reaction mixture was then co-
oled to room temp. and the solvent was removed under reduced
pressure to obtain brown, sticky crude product which was charged
on a silica gel column. Elution of the column with 20% EtOAc/
petroleum ether gave the unreacted 13 (250 mg) followed by the
polysubstituted benzene derivative 15 (263 mg, 45%) as a colorless
solid. Further elution of the column with 40% EtOAc/petroleum
ether furnished, hexamethyl mellitate 18 (148 mg, 44%[28]) as a col-
orless crystalline solid.
b) Using Cp*Ru(cod)Cl Catalyst: To a solution of 1,5-hexadiyne 9
(48 mg, 0.615 mmol) in dry degassed dichloroethane (20 mL) main-
tained under nitrogen was added 13 (440 mg, 3.09 mmol) and
Cp*Ru(cod)Cl (6 mg, 0.015 mmol, 2.5 mol-%). The resulting yel-
low solution was refluxed for 24 h. The reaction mixture was then
cooled to room temp. and the solvent was removed under reduced
pressure to obtain brown, sticky crude product which was charged
on a silica gel column. Elution of the column with 20% EtOAc/
petroleum ether gave the unreacted 13 (148 mg) followed by the
polysubstituted benzene derivative 14 (59 mg, 26%) as a colorless
solid. Data for compound 14: Rf = 0.43 (silica gel, 40% EtOAc/
petroleum ether), m.p. 78–80 °C. 1H NMR (400 MHz, CDCl3): δ
= 2.00 (t, J = 2.4 Hz, 1 H), 2.52 (dt, J1 = 8.8, J2 = 2.4 Hz, 2 H),
2.94 (t, J = 7.2 Hz, 2 H), 3.86–3.92 (m, 12 H), 8.06 (s, 1 H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 20.0, 32.3, 53.0, 53.0, 53.1,
53.3, 70.3, 82.3, 130.0, 130.1, 133.8, 134.4, 136.9, 140.3, 165.0,
b) Using Cp*Ru(cod)Cl Catalyst: To a solution of 1,7-octadiyne
11 (20 mg, 0.188 mmol) in dry degassed dichloroethane (10 mL)
maintained under nitrogen was added 13 (164 mg, 1.15 mmol) and
Cp*Ru(cod)Cl (3.5 mg, 0.009 mmol, 5 mol-%). The resulting yel-
low solution was refluxed for 24 h. The reaction mixture was then
cooled to room temp. and the solvent was removed under reduced
pressure to obtain brown, sticky crude product which was charged
on a silica gel column. Elution of the column with 20% EtOAc/
petroleum ether gave the unreacted 13 (128 mg) followed by the
polysubstituted benzene derivative 16 (30 mg, 41%) as a colorless
solid. Data for compound 16: Rf = 0.39 (silica gel, 40% EtOAc/
petroleum ether), m.p. 80 °C. 1H NMR (400 MHz, CDCl3): δ =
1.53–1.63 (m, 2 H), 1.70–1.77 (m, 2 H), 1.96 (t, J = 2.4, Hz, 1 H),
2.21 (dt, J1 = 6.4, J2 = 2.4 Hz, 2 H), 2.73 (t, J = 8 Hz, 2 H), 3.86–
3.92 (m, 12 H), 7.96 (s, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3):
δ = 18.0, 27.9, 29.9, 32.7, 52.8, 52.9, 52.9, 53.1, 68.7, 83.8, 129.8,
130.0, 133.1, 133.8, 136.7, 142.3, 165.0, 165.7, 167.4, 167.5 ppm.
165.8, 167.3, 167.6 ppm. IR (KBr): ν = 3304, 2954, 2305, 1736,
˜
1440, 1158 cm–1. HRMS (Q-Tof): m/z calcd. mass 385.0899 for
C18H18O8Na [M + Na]+; found 385.0898.
Preparation of Alkyne 15
a) Using Wilkinson’s Catalyst: To a solution of 1,6-heptadiyne 10
(161 mg, 1.75 mmol) in dry degassed ethanol (12 mL) maintained
under nitrogen, was added 13 (1.2 g, 8.45 mmol) and Wilkinson’s
catalyst (16 mg, 0.017 mmol, 1 mol-%). The resulting pale yellow
solution was refluxed for 24 h. The reaction mixture was then
cooled to room temp. and the solvent was removed under reduced
pressure to obtain brown, sticky crude product which was charged
on a silica gel column. Elution of the column with 20% EtOAc/
petroleum ether gave the unreacted 13 (200 mg) followed by the
polysubstituted benzene derivative 15 (291 mg, 44%) as a colorless
solid. Further elution of the column with 40% EtOAc/petroleum
ether furnished, hexamethyl mellitate 18 (135 mg, 34%[28]) as a col-
orless crystalline solid.
IR (KBr): ν = 2950, 1727, 1437, 1149 cm–1. HRMS (Q-Tof): m/z
˜
calcd. mass 413.1212 for C20H22O8Na [M + Na]+; found 413.1213.
Preparation of Alkyne 17
a) Using Wilkinson’s Catalyst: To a solution of 1,8-nonadiyne 12
(160 mg, 1.33 mmol) in dry degassed ethanol (12 mL) maintained
under nitrogen, was added 13 (960 mg, 6.7 mmol) and Wilkinson’s
catalyst (8.6 mg, 0.009 mmol, 1 mol-%). The resulting pale yellow
solution was refluxed for 24 h. The reaction mixture was then
cooled to room temp. and the solvent was removed under reduced
pressure to obtain brown, sticky crude product which was charged
on a silica gel column. Elution of the column with 20% EtOAc/
petroleum ether gave the unreacted 13 (210 mg) followed by the
polysubstituted benzene derivative 17 (261 mg, 48%) as a thick col-
orless liquid. Further elution of the column with 40% EtOAc/pe-
b) Using Cp*Ru(cod)Cl Catalyst: To a solution of 1,6-heptadiyne
10 (52 mg, 0.565 mmol) in dry degassed dichloroethane (12 mL)
maintained under nitrogen was added 13 (401 mg, 2.82 mmol) and
Cp*Ru(cod)Cl (5 mg, 0.013 mmol, 2.4 mol-%). The resulting yel-
low solution was refluxed for 24 h. The reaction mixture was then
cooled to room temp. and the solvent was removed under reduced
pressure to obtain brown, sticky crude product which was charged
on a silica gel column. Elution of the column with 20% EtOAc/
petroleum ether gave the unreacted 13 (160 mg) followed by the
polysubstituted benzene derivative 15 (71 mg, 33%) as a colorless
troleum ether furnished, hexamethyl mellitate 18 (107 mg, 33%[28]
)
as a colorless crystalline solid.
b) Using Cp*Ru(cod)Cl Catalyst: To a solution of 1,8-nonadiyne
12 (160 mg, 1.33 mmol) in dry degassed dichloroethane (30 mL)
maintained under nitrogen was added 13 (924 mg, 6.5 mmol) and
Cp*Ru(cod)Cl (12.5 mg, 0.033 mmol, 2.5 mol-%). The resulting
yellow solution was refluxed for 24 h. The reaction mixture was
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Diversity-Oriented Approach to Diphenylalkanes
then cooled to room temp. and the solvent was removed under
reduced pressure to obtain brown, sticky crude product which was
charged on a silica gel column. Elution of the column with 20%
EtOAc/petroleum ether gave the unreacted 13 (187 mg) followed by
the polysubstituted benzene derivative 17 (201 mg, 37%) as a thick
purified by flash chromatography. Elution of the column with 20%
EtOAc/petroleum ether furnished the desired diene 23 (39 mg,
87%) as a colorless oil. Rf = 0.54 (silica gel, 40% EtOAc/petroleum
ether). H NMR (400 MHz, CDCl3): δ = 1.52–1.66 (m, 4 H), 2.23
(t, J = 7.2 Hz, 2 H), 2.72 (t, J = 8 Hz, 2 H), 3.86–3.92 (m, 12 H),
4.97–5.07 (m, 3 H), 5.20 (d, J = 18 Hz, 1 H), 6.36 (dd, J1 = 18, J2
1
colorless liquid. Data for compound 17: Rf = 0.36 (silica gel, 40%
1
EtOAc/petroleum ether). H NMR (400 MHz, CDCl3): δ = 1.41– = 10.8 Hz, 1 H), 7.95 (s, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3):
1.62 (m, 6 H), 1.93 (t, J = 2.4 Hz, 1 H), 2.17 (dt, J1 = 7.2, J2
2.4 Hz, 2 H), 2.69 (t, J = 8 Hz, 2 H), 3.86–3.92 (m, 12 H), 7.93 (s, 133.2, 133.9, 136.9, 138.9, 142.8, 145.9, 165.2, 165.9, 167.6, 167.8
1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 18.3, 28.1, 28.4, ppm. IR (KBr): ν = 2952, 1963, 2295, 1732, 1199, 1157 cm–1.
=
δ = 27.8, 31.0, 31.0, 33.3, 52.8, 53.0, 53.2, 113.3, 116.0, 129.9, 130.1,
˜
30.6, 33.3, 52.9, 53.1, 53.3, 68.5, 84.4, 129.8, 130.1, 133.3, 134.0,
HRMS (Q-Tof): m/z calcd. mass 419.1706 for C22H28O8 [M +
136.9, 142.7, 165.2, 165.9, 167.6, 167.8 ppm. IR (KBr): ν = 2952,
H]+; found 419.1697.
˜
2861, 2115, 1735, 1439, 1157 cm–1. HRMS (Q-Tof): m/z calcd. mass
427.1369 for C21H24O8Na [M + Na]+; found 427.1371.
Preparation of Diene 24: The alkyne 17 (70 mg, 0.162 mmol) in dry
toluene (12 mL) was degassed with ethylene gas for 10 min and
Grubbs’ catalyst, G-II (8 mg, 0.0094 mmol, 6 mol-%) was then
added to it. The reaction vessel was kept under 1 atm. ethylene
pressure (using balloon pressure) and reaction mixture was stirred
at room temp. At the conclusion of the reaction (2.5 h, TLC moni-
toring), pressure was released and the resulting dark brown solu-
tion was concentrated under reduced pressure. The crude product
was purified by flash chromatography. Elution of the column with
20% EtOAc/petroleum ether furnished the desired diene 24 (68 mg,
91%) as a colorless oil. Rf = 0.51 (silica gel, 40% EtOAc/petroleum
Preparation of Diene 21: The solution of alkyne 14 (49 mg,
0.135 mmol) in dry toluene (12 mL) was degassed with ethylene gas
for 10 min and Grubbs’ catalyst, G-II (6 mg, 0.007 mmol, 5 mol-
%) was then added to it. The reaction vessel was kept under 1 atm.
ethylene pressure (using balloon pressure) and reaction mixture was
stirred at room temp. At the conclusion of the reaction (4 h, TLC
monitoring), pressure was released and the resulting dark brown
solution was concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography. Elution of the column
with 20% EtOAc/petroleum ether furnished the desired diene 21
(48 mg, 91%) as a colorless oil. Rf = 0.62 (silica gel, 40% EtOAc/
petroleum ether). 1H NMR (400 MHz, CDCl3): δ = 2.51 (t, J =
7.6 Hz, 2 H), 2.87–2.91 (m, 2 H), 3.87–3.92 (m, 12 H), 4.96–5.13
1
ether). H NMR (400 MHz, CDCl3): δ = 1.25–1.66 (m, 6 H), 2.20
(t, J = 7.2 Hz, 2 H), 2.70 (t, J = 8 Hz, 2 H), 3.86–3.92 (m, 12 H),
4.97–5.06 (m, 3 H), 5.21 (d, J = 17.6 Hz, 1 H), 6.36 (dd, J1 = 17.6,
J2 = 10.8 Hz, 1 H), 7.95 (s, 1 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 27.9, 29.3, 31.0, 31.3, 33.5, 52.9, 53.1, 53.3, 113.3,
115.8, 129.8, 130.1, 133.2, 134.0, 137.0, 139.0, 142.9, 146.4, 165.3,
(m, 3 H), 5.27 (d, J = 17.6 Hz, 1 H), 6.37 (dd, J1 = 17.6, J2
=
11.2 Hz, 1 H), 7.95 (s, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3):
δ = 32.5, 33.0, 53.0, 53.1, 53.1, 53.3, 113.8, 117.1, 129.9, 130.1,
133.5, 134.2, 137.0, 138.3, 142.2, 144.7, 165.2, 165.9, 167.6, 167.8
166.0, 167.7, 167.8 ppm. IR (neat): ν = 2952, 2344, 1963, 1644,
˜
1260 cm–1. HRMS (Q-Tof): m/z calcd. mass 455.1682 for
ppm. IR (KBr): ν = 2926, 2197, 1964, 1741, 1245 cm–1. HRMS
˜
C23H28O8Na [M + Na]+; found 455.1668.
(Q-Tof): m/z calcd. mass 391.1393 for C20H23O8 [M + H]; found
391.1384.
Preparation of Compound 25: To a solution of diene 21 (48 mg,
0.123 mmol) in toluene (12 mL) was added 13 (58 mg, 0.40 mmol)
and the reaction mixture was heated at 80 °C. At the conclusion
of the reaction (16 h, TLC monitoring), the reaction mixture was
concentrated under the reduced pressure and the crude product was
purified by column chromatography. Elution of the column with
30% EtOAc/petroleum ether furnished the desired compound 25
(42 mg, 64%) as a colorless thick liquid. Rf = 0.25 (silica gel, 40%
Preparation of Diene 22: The alkyne 15 (36 mg, 0.089 mmol) in dry
toluene (12 mL) was degassed with ethylene gas for 10 min and
Grubbs’ catalyst, G-II (6 mg, 0.007 mmol, 7.5 mol-%) was then
added to it. The reaction vessel was kept under 1 atm. ethylene
pressure (using balloon pressure) and reaction mixture was stirred
at room temp. At the conclusion of the reaction (4 h, TLC monitor-
ing), pressure was released and the resulting dark brown solution
was concentrated under reduced pressure. The crude product was
purified by flash chromatography. Elution of the column with 20%
EtOAc/petroleum ether furnished the desired diene 22 (33 mg,
85%) as a colorless oil. Rf = 0.62 (silica gel, 40% EtOAc/petroleum
1
EtOAc/petroleum ether). H NMR (400 MHz, C6D6): δ = 1.88 (t,
J = 7.2 Hz, 2 H), 2.49–2.53 (m, 2 H), 2.73–2.81 (m, 3 H), 3.41–
3.53 (m, 15 H), 3.68 (s, 3 H), 4.93 (br. s, 1 H), 7.61 (s, 1 H) ppm.
13C NMR (100.6 MHz, C6D6): δ = 29.2, 31.0, 31.8, 38.3, 52.0, 52.7,
52.7, 52.9, 118.3, 131.4, 132.0, 132.6, 133.6, 134.0, 137.0, 142.6,
165.6, 166.8, 167.6, 167.7, 168.2, 168.5; 13C ppm. NMR
(100.6 MHz, CDCl3): δ = 28.7, 30.5, 31.5, 38.0, 52.4, 52.4, 53.0,
53.1, 53.1, 53.3, 118.0, 130.1, 130.2, 131.8, 132.0, 133.3, 133.5,
134.0, 136.9, 141.9, 165.1, 165.9, 167.5, 167.7, 168.3, 168.6 ppm.
1
ether). H NMR (400 MHz, CDCl3): δ = 1.78–1.82 (m, 2 H), 2.27
(t, J = 7.6 Hz, 2 H), 2.73 (t, J = 8 Hz, 2 H), 3.84–3.92 (m, 12 H),
4.99–5.09 (m, 3 H), 5.19 (d, J = 17.6 Hz, 1 H), 6.37 (dd, J1 = 17.6,
J2 = 10.8 Hz, 1 H), 7.96 (s, 1 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 29.5, 31.2, 33.3, 52.9, 53.1, 53.3, 113.6, 116.4, 129.9,
130.1, 133.3, 134.0, 137.0, 138.7, 142.6, 145.4, 165.2, 165.9, 167.6,
IR (neat): ν = 2958, 1731, 1659, 1436, 1157 cm–1. HRMS (Q-Tof):
˜
m/z calcd. mass 555.1478 for C26H28O12Na [M + Na]+; found
167.8 ppm. IR (KBr): ν = 2952, 1963, 2295, 1732, 1199, 1157 cm–1.
˜
555.1495.
HRMS (Q-Tof): m/z calcd. mass 427.1369 for C21H24O8Na [M +
Na]+; found 427.1388.
Preparation of Compound 26: To a solution of diene 22 (28 mg,
0.069 mmol) in toluene (12 mL) was added 13 (30 mg, 0.21 mmol)
and the reaction mixture was heated at 80 °C. At the conclusion
of the reaction (18 h, TLC monitoring), the reaction mixture was
concentrated under the reduced pressure and the crude product was
purified by column chromatography. Elution of the column with
30% EtOAc/petroleum ether furnished the desired compound 26
(27 mg, 71%) as a colorless thick liquid. Rf = 0.25 (silica gel, 40%
EtOAc/petroleum ether). 1H NMR (300 MHz, C6D6): δ = 1.32–
Preparation of Diene 23: The alkyne 16 (41 mg, 0.098 mmol) in dry
toluene (12 mL) was degassed with ethylene gas for 10 min and
Grubbs’ catalyst, G-II (5.1 mg, 0.006 mmol, 6 mol-%) was then
added to it. The reaction vessel was kept under 1 atm. ethylene
pressure (using balloon pressure) and reaction mixture was stirred
at room temp. At the conclusion of the reaction (6 h, TLC monitor-
ing), pressure was released and the resulting dark brown solution
was concentrated under reduced pressure. The crude product was
Eur. J. Org. Chem. 2009, 730–738
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
735

S. Kotha, P. Khedkar
FULL PAPER
1.43 (m, 2 H) 1.64 (t, J = 7.2 Hz, 2 H), 2.40 (t, J = 7.2 Hz, 2 H),
2.69–2.75 (m, 2 H), 2.87–2.89 (m, 2 H), 3.42–3.53 (m, 15 H), 3.69
(16 mg, 0.070 mmol) was added and the resulting yellow solution
was irradiated in microwave oven for 8 min. The dark orange reac-
(s, 3 H), 5.02 (br. s, 1 H), 7.66 (s, 1 H) ppm. 13C NMR (100.6 MHz, tion mixture was then concentrated under reduced pressure and the
C6D6): δ = 28.6, 29.1, 31.0, 33.3, 36.5, 52.0, 52.6, 52.9, 52.9, 117.6,
131.4, 131.9, 133.1, 133.2, 133.2, 133.9, 134.1, 137.1, 143.0, 165.7,
crude product obtained was purified by column chromatography.
Elution of the column with 30% EtOAc/petroleum ether furnished
the desired diphenylalkane derivative 30 (14 mg, 67%) as a color-
166.7, 167.7, 167.7, 168.4, 168.5 ppm. IR (neat): ν = 3054, 1732,
˜
1422, 1266 cm–1. HRMS (Q-Tof): m/z calcd. mass 569.1635 for
less liquid. Rf = 0.25 (silica gel, 40% EtOAc/petroleum ether). H
1
C23H28O8Na [M + Na]+; found 569.1646.
NMR (400 MHz, CDCl3): δ = 1.96 (quint, J = 8 Hz, 2 H), 2.72 (t,
J = 8 Hz, 4 H), 3.83–3.92 (m, 18 H), 7.34 (dd, J = 7.6, J = 1.6 Hz,
1 H), 7.49 (d, J = 1.2 Hz, 1 H), 7.70 (d, J = 8 Hz, 1 H), 7.92 (s, 1
H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 32.1, 33.0, 35.3, 52.7,
52.8, 52.9, 53.1, 53.3, 128.8, 129.4, 129.5, 130.1, 130.3, 131.0, 132.9,
133.5, 133.9, 137.0, 141.9, 145.5, 165.1, 165.9, 167.5, 167.7, 167.8,
Preparation of Compound 27: To a solution of diene 23 (29 mg,
0.069 mmol) in toluene (12 mL) was added 13 (35 mg, 0.246 mmol)
and the reaction mixture was heated at 80 °C. At the conclusion
of the reaction (18 h, TLC monitoring), the reaction mixture was
concentrated under the reduced pressure and the crude product was
purified by column chromatography. Elution of the column with
30% EtOAc/petroleum ether furnished the desired compound 27
(23 mg, 59%) as a colorless thick liquid. Rf = 0.27 (silica gel, 40%
168.5 ppm. IR (neat): ν = 2117, 1644, 1264, 1108 cm–1. HRMS (Q-
˜
Tof): m/z calcd. mass 567.1478 for C27H28O12Na [M + Na]+; found
567.1502.
1
Preparation of Diphenylalkane Derivative 31: Compound 27 (18 mg,
0.032 mmol) was taken in anhydrous toluene (3 mL) and DDQ
(12 mg, 0.052 mmol) was added and the resulting yellow solution
was irradiated in microwave oven for 8 min. The dark orange reac-
tion mixture was then concentrated under reduced pressure and the
crude product obtained was purified by column chromatography.
Elution of the column with 30% EtOAc/petroleum ether furnished
the desired diphenylalkane derivative 31 (10 mg, 56%) as a color-
EtOAc/petroleum ether). H NMR (400 MHz, CDCl3): δ = 1.42–
1.62 (m, 4 H), 2.00–2.09 (m, 2 H), 2.71 (t, J = 8 Hz, 2 H), 2.86–
2.90 (m, 2 H), 2.99–3.01 (m, 2 H), 3.77–3.92 (m, 18 H), 5.40 (br. s,
1 H), 7.94 (s, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 26.8,
28.6, 30.5, 30.7, 33.3, 36.3, 52.3, 52.8, 53.0, 53.2, 116.7, 129.9,
130.1, 132.3, 133.1, 133.1, 133.3, 133.9, 136.9, 142.6, 165.2, 165.9,
167.6, 167.7, 168.5, 168.7 ppm. IR (neat): ν = 2953, 1966, 1735,
˜
1650, 1440, 1265 cm–1. HRMS (Q-Tof): m/z calcd. mass 583.1791
1
for C28H32O12Na [M + Na]+; found 583.1764.
less liquid. Rf = 0.27 (silica gel, 40% EtOAc/petroleum ether). H
NMR (300 MHz, CDCl3): δ = 1.64–1.66 (m, 4 H), 2.68–2.72 (m, 4
H), 3.85–3.92 (m, 18 H), 7.32 (dd, J = 7.8, J = 1.5 Hz, 1 H), 7.47
(d, J = 1.5 Hz, 1 H), 7.68 (d, J = 7.8 Hz, 1 H), 7.92 (s, 1 H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 29.8, 30.6, 30.6, 33.3, 35.4,
52.6, 52.7, 52.9, 53.1, 53.2, 128.7, 129.2, 129.4, 130.2, 131.0, 132.8,
133.9, 136.9, 142.4, 146.2, 165.2, 165.9, 167.6, 167.7, 167.9, 168.6
Preparation of Compound 28: To a solution of diene 24 (48 mg,
0.11 mmol) in toluene (12 mL) was added 13 (70 mg, 0.49 mmol)
and the reaction mixture was heated at 80 °C. At the conclusion
of the reaction (15 h, TLC monitoring), the reaction mixture was
concentrated under the reduced pressure and the crude product was
purified by column chromatography. Elution of the column with
30% EtOAc/petroleum ether furnished the desired compound 28
(46 mg, 72%) as a colorless thick liquid. Rf = 0.29 (silica gel, 40%
ppm. IR (neat): ν = 2923, 1642, 1266 cm–1. HRMS (Q-Tof): m/z
˜
calcd. mass 581.1656 for C28H30O12Na [M + Na]+; found 581.1656.
Preparation of Diphenylalkane Derivative 32: Compound 28 (21 mg,
0.036 mmol) was taken in anhydrous toluene (2 mL) and DDQ
(15 mg, 0.066 mmmol) was added and the resulting yellow solution
was irradiated in microwave oven for 8 min. The dark orange reac-
tion mixture was then concentrated under reduced pressure and the
crude product was purified by column chromatography. Elution of
the column with 30% EtOAc/petroleum ether furnished the desired
diphenylalkane derivative 32 (17 mg, 81%) as a colorless liquid.
Rf = 0.29 (silica gel, 40% EtOAc/petroleum ether). 1H NMR
(400 MHz, CDCl3): δ = 1.33–1.40 (m, 2 H), 1.59–1.68 (m, 4 H),
2.64–2.71 (m, 4 H), 3.86–3.92 (m, 18 H), 7.32 (dd, J = 8, J = 1.6 Hz,
1 H), 7.48 (d, J = 1.2 Hz, 1 H), 7.68 (d, J = 8 Hz, 1 H), 7.94 (s, 1
H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 28.9, 30.7, 30.9, 33.3,
35.5, 52.6, 52.7, 52.8, 53.0, 53.2, 128.7, 129.0, 129.4, 130.0, 130.2,
130.9, 132.8, 133.2, 133.9, 136.8, 142.7, 146.6, 165.2, 165.9, 167.6,
1
EtOAc/petroleum ether). H NMR (400 MHz, CDCl3): δ = 1.25–
1.62 (m, 6 H), 1.97–1.99 (m, 2 H), 2.69 (t, J = 8 Hz, 2 H), 2.89–
3.01 (m, 4 H), 3.78–3.92 (m, 18 H), 5.40 (br. s, 1 H), 7.95 (s, 1 H)
ppm. NMR (100.6 MHz, CDCl3): δ = 26.9, 28.6, 29.0, 30.5, 31.0,
33.4, 36.4, 52.3, 52.9, 53.0, 53.2, 116.4, 130.1, 132.5, 133.0, 133.2,
133.4, 134.0, 136.9, 142.8, 165.2, 165.9, 167.7, 168.7 ppm. IR
(neat): ν = 2954, 1965, 1727, 1650, 1438, 1264 cm–1. HRMS (Q-
˜
Tof): m/z calcd. mass 597.1954 for C29H34O12Na [M + Na]+; found
597.1954.
Preparation of Diphenylalkane Derivative 29: Compound 25 (28 mg,
0.05 mmol) was taken in anhydrous toluene (3 mL) and DDQ
(23 mg, 0.01 mmol) was added and the resulting yellow solution
was irradiated in microwave oven for 8 min. The dark orange reac-
tion mixture was then concentrated under reduced pressure and the
crude product obtained was purified by column chromatography.
Elution of the column with 30% EtOAc/petroleum ether furnished
the desired diphenylalkane derivative 29 (19 mg, 68%) as a color-
167.7, 167.9, 168.6 ppm. IR (neat): ν = 2923, 1734, 1638, 1265,
˜
1438 cm–1. HRMS (Q-Tof): m/z calcd. mass 573.1960 for
C29H33O12 [M + H]+; found 573.1960.
1
less liquid. Rf = 0.25 (silica gel, 40% EtOAc/petroleum ether). H
NMR (300 MHz, CDCl3): δ = 2.99 (br. s, 4 H), 3.87–3.93 (m, 18
H), 7.30 (dd, J = 7.8, J = 1.5 Hz, 1 H), 7.48 (d, J = 1.5 Hz, 1 H),
7.68 (d, J = 7.8 Hz, 1 H), 7.86 (s, 1 H) ppm. 13C NMR (100.6 MHz, Acknowledgments
CDCl3): δ = 35.2, 37.2, 52.7, 52.8, 53.1, 53.3, 128.9, 129.6, 129.8,
130.3, 130.4, 131.1, 132.9, 133.8, 134.2, 136.9, 141.0, 144.4, 165.0,
We thank the Department of Science & Technology (DST), New
Delhi for financial support and Sophisticated Analytical Instru-
ment Facility (SAIF), Bombay for recording spectroscopic data.
We are grateful to Prof. Y. Yamamoto (Nagoya University, Japan)
for the generous gift ruthenium catalyst, Cp*Ru(cod)Cl. One of the
authors (P. K.) thanks the Council of Scientific & Industrial Re-
search (CSIR), New Delhi for the award of research fellowship.
165.8, 167.4, 167.6, 167.8, 168.3 ppm. IR (neat): ν = 2923, 1733,
˜
1643, 1440, 1266 cm–1. HRMS (Q-Tof): m/z calcd. mass 553.1322
for C26H26O12Na [M + Na]+; found 553.1335.
Preparation of Diphenylalkane Derivative 30: Compound 26 (21 mg,
0.038 mmol) was taken in anhydrous toluene (3 mL) and DDQ
736
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 730–738

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Received: September 22, 2008
Published Online: December 29, 2008
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Eur. J. Org. Chem. 2009, 730–738