Diversity-oriented approach to biologically relevant molecular frameworks starting with β-naphthol and using the claisen rearrangement and olefin metathesis as key steps

Article abstract of DOI:10.1002/chem.200600540

A diversity-oriented approach for the synthesis of various structurally different molecular frameworks from readily accessible and common precursors is described. A Claisen rearrangement followed by ring-closing metathesis or ethylene-promoted ring-closin

Full text of DOI:10.1002/chem.200600540

DOI: 10.1002/chem.200600540
Diversity-Oriented Approach to Biologically Relevant Molecular
Frameworks Startingwith b-Naphthol and Usingthe Claisen Rearran ge ment
and Olefin Metathesis as Key Steps
[
a]
Sambasivarao Kotha,* Kalyaneswar Mandal, Arti Tiwari, and Shaikh M. Mobin
Abstract: A diversity-oriented approach for the synthesis of various structurally
different molecular frameworks from readily accessible and common precursors is
Keywords: Claisen rearrangement ·
diversity-oriented synthesis · meta-
thesis · naphthoxepines · spiro com-
pounds
described. A Claisen rearrangement followed by ring-closing metathesis or ethyl-
ene-promoted ring-closing enyne metathesis has been utilized as the key synthetic
transformation to generate naphthoxepine derivatives. The ring-closing metathesis
approach has also been used to generate spirocyclic compounds and the pleiadene
framework.
Introduction
structural element present in numerous biologically active
molecules. In addition, naphthoxepine derivatives 1 and 2
[3]
Recently there has been increasing interest, both in academ-
ia and in industry, in the synthesis of diverse collection of
drug-like” molecules and their screening for lead identifi-
cation with optimized properties useful for medicinal chem-
istry—this is the goal of diversity-oriented synthesis
DOS). DOS involves three key elements: building blocks,
are used as antipsychotic drugs. Similarly, naphthoxepine
oxime ether 3 was found to be useful as a potential hypoten-
[4]
“
sive agent, whilst the dibenzoxepine derivative isoxepac
[5]
(4) is used as an antiinflammatory drug.
[1]
(
stereochemistry, and molecular skeleton.
Generation of high levels of stereochemical and/or skele-
tal diversity is considered highly challenging. Divergent re-
action pathways are efficient means of generating structural
diversity, particularly through the creation of diverse molec-
ular frameworks and functional groups. Skeletal diversity is
generated by the use of different sets of reagents or reaction
conditions to transform common substrates into collections
[2]
of products with varied molecular skeletons.
Here we report a diversity-oriented approach for the syn-
thesis of skeletally different molecular frameworks from one
or more readily available starting material(s) through the
application of simple reactions such as the Claisen rear-
rangement and olefin metathesis as key steps (Scheme 1).
The skeletons (A–D) shown in Scheme 1 are the core
structural motifs for various biologically active natural or
unnatural products. Oxepine A, for example, is an important
Interestingly, trans-2,3-pleiadanedicarboxylic acid (5) has
been identified as a promising inhibitor of prephenate dehy-
drogenase (PDH) in the E. coli T-protein responsible for the
[6]
biosynthesis of tyrosine.
In connection with molecular framework
D (Scheme 1), it has been found that a sim-
ilar spirocyclic cyclopentanoid core is pres-
ent in a variety of pharmacologically active
[
a] Prof. Dr. S. Kotha, K. Mandal, A. Tiwari, S. M. Mobin
Department of Chemistry
Indian Institute of Technology, Bombay
Powai, Mumbai-400 076 (India)
Fax : (+91)22-2572-3480
[7]
terpenoids such as stemaranes and scopa-
dulanes. A broad pharmacological profile
has been observed for scopadulan diter-
E-mail: srk@chem.iitb.ac.in
8024
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FULL PAPER
thesis as a key step have been
[14]
developed.
Although RCM
has gained popularity, enyne
metathesis is less well ex-
[15]
plored.
Intramolecular
enyne metathesis is particularly
attractive as the double bond
of the enyne is cleaved and the
alkylidene part of the alkene
migrates to the alkyne carbon,
giving
a cyclized compound
containing a 1,3-diene moiety,
a useful synthon for various cy-
[16]
cloaddition strategies.
Results and Discussion
For the synthesis of oxepine
molecular frameworks A and
B (Scheme 1), O-allylation of
b-naphthol derivatives 11a–c
was carried with allyl bromide
Scheme 1. Synthesis of a diverse range of molecular frameworks from b-naphthol derivatives.
[8]
penes. Scopadulcic acid B, and scopadulciol are powerful
+
+
inhibitors of H and K adenosine triphosphate. Conforma-
tionally constrained analogues of N-phenyl-N’-aralkylurea 6
[9]
act as potential ACAT inhibitors, whereas the spirocyclic
model compound 7 binds with remarkable efficiency to
bulged DNA oligonucleotides, offering potential for the
[10]
design of therapeutic agents.
and potassium carbonate by stirring in acetone at room tem-
perature. Claisen rearrangements of compounds 12a–c were
then achieved with the aid of microwave irradiation (MWI)
on a silica gel support in the absence of solvent, and the
products 13a–c were obtained within 7 min (Scheme 2).
MWI has become a useful tool in organic synthesis, thanks
to the rate enhancement, higher yields, and improved selec-
tivity often observed with respect to more conventional re-
[
17]
Although various synthetic approaches to these ring skel-
etons are available, there is a need to develop a unified ap-
proach in which such a diverse range of molecular frame-
works can be assembled from a readily accessible common
precursor in a short synthetic sequence. Motivated by these
considerations, we have conceived a diversity-oriented ap-
proach for the generation of skeletally different molecular
frameworks from the readily available b-naphthol by use of
microwave-assisted silica gel-supported Claisen rearrange-
action conditions.
We found that the Claisen rearrange-
ments of 12a–c under MWI conditions on a silica gel sup-
port had advantages over the conventional conditions in sev-
[18]
eral respects. Some of these include: i) quick and econom-
ically advantageous, and ii) better safety, due to the absence
of solvent during the reaction. In addition, the end products
are usually separable from the silica gel by simple chroma-
tography.
The desired building blocks 14a–c for the RCM reactions
were prepared by O-allylation of the b-naphthol derivatives
13a–c by the conventional allylation procedure reported
previously. Repetition of the same reaction sequence with
propargyl bromide in place of allyl bromide resulted in the
generation of enyne building blocks 15a–c in good yields
(Scheme 2).
[11]
ments and Grubbs catalyst-induced ring-closing metathe-
ses (RCMs) or ring-closing enyne metatheses (RCEMs) as
key steps. The preliminary results of this research were pub-
[12]
[12]
lished during 2004.
With the development of the commercially available and
[13a]
[13b]
[13c]
well defined metal carbene complexes 8,
9,
and 10,
olefin metathesis has attracted much attention from synthet-
ic organic chemists, and numerous strategies based on meta-
With the diene and enyne building blocks to hand, the
metathesis reaction to provide the desired oxepine skeletons
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S. Kotha et al.
Since some of these dienes
were found to be highly sensi-
tive substrates, they were im-
mediately used for Diels–
Alder (DA) reactions. Hence,
to obtain skeletally diverse
naphthoxepine
derivatives,
dienes 17a–c were treated with
various reactive dienophiles
(
18–21), and the results of the
highly stereoselective DA reac-
tions are summarized in
Table 1. Heating of diene 17a
with dimethyl acetylenedicar-
boxylate (DMAD, 18) afforded
the desired DA adduct 22 in a
moderate
isolated
yield
(
entry 1, Table 1), while the
DA reaction between the
diene 17a and p-toluenesulfo-
nylacetylene (19) furnished a
Scheme 2. Preparation of RCM and RCEM precursors.
9
:1 mixture of regioisomers
was attempted (Scheme 3). Treatment of the dienes 14a–c
with the catalyst 8 (5 mol%) at room temperature in di-
chloromethane (DCM) as solvent furnished the desired
Scheme 4. RCEM of 15.
[22]
2
3a and 23b in 61% combined yield (entry 2, Table 1).
Several attempts to isolate the minor isomer (23b) in its
pure form by silica gel column chromatography were unsuc-
cessful. The cycloaddition between compound 17a and N-
phenylmaleimide (20) afforded the single diastereomer 28 in
a moderate yield (38%; entry 3, Table 1). Along similar
lines, treatment of diene 17a with trans-1,2-bis(phenylsulfo-
nyl)ethylene (21) in toluene proceeded smoothly, delivering
the DA adduct 29 (entry 4, Table 1) as a single diastereomer
in 42% yield, whereas similarly, the DA reactions between
dienes 17b or 17c and 21 under reaction conditions identical
to those described for diene 17a provided the corresponding
cycloadducts 30 and 31 in moderate and good yields, respec-
tively (entries 5 and 6, Table 1). The low to moderate yields
of some of the cycloadducts could be attributed to the pro-
pensity of these sensitive dienes to polymerize. In a separate
experiment, the cycloaddition between compound 17c and
21 was therefore conducted without isolation of the diene,
in order to avoid diene decomposition during workup and
Scheme 3. RCM of 14 and attempted RCEM of 15a.
[
19]
naphthoxepine derivatives 16a–c in good yields. However,
attempted RCEM of compound 15a to deliver 17a in the
presence either of Grubbs first-generation catalyst (8) or of
the more reactive second-generation catalysts (9 and 10)
with stirring in DCM at room temperature was unsuccessful.
Even under forcing reaction conditions (toluene at reflux)
no detectable amount of metathesis product formation was
observed, the unreacted starting material being recovered.
In view of the beneficial role of ethylene in RCEM, we
decided to conduct the RCEM under ethylene. Attempts
to achieve metathesis of compound 15a under ethylene in
DCM in the presence of Grubbs first-generation catalyst (8)
were unsuccessful, but the more reactive second-generation
catalysts 9 and 10 gave the desired RCEM product in the
[
20]
[23]
purification. Although a slight improvement in the yield
(33% over two steps) was observed, this one-pot operation
[
21]
presence of ethylene in good yield (Scheme 4).
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Diversity-Oriented Approach to Biologically Relevant Molecular Frameworks
FULL PAPER
Table 1. Diels–Alder reactions between compounds 17a–c and dieno-
philes 18–21.
[
a]
Entry Diene
Dienophile
Diels–Alder adduct
Yield
[
b]
[
%]
1
17a
49
Figure 1. Stereochemistries assigned for 23a, 24, and 26.
was unequivocally established by single-crystal X-ray analy-
sis, as shown in Figure 2. Unambiguous assignments of the
1
other analogues 25 and 27 were achieved by H NMR analy-
2
17a
61
sis, through comparison of their coupling constants with
those observed for cycloadduct 26.
3
17a
38
4
5
6
17a
17b
17c
42
74
54
Figure 2. ORTEP diagram of compound 26.
In addition to the expected three-bond coupling in H,H-
COSY, Hd/d’ of compound 26 shows cross-peaks with Ha
(
Figure 3A) and Hf/f’ (Figure 3B), corresponding to long-
range homoallylic coupling over five bonds. Similar weak
homoallylic coupling was also observed in the H,H-COSY
spectra of other analogues of 26.
[
a] All the reactions were carried out in toluene at 908C or reflux tem-
perature. [b] Yield of isolated product.
5
Figure 3. Homoallylic coupling ( J) observed from H,H-COSY of 26.
was not taken further because of the increasingly complex
nature of the product mixture (by TLC).
It appeared that naphthalene-2,7-diol might also be a suit-
able starting material for assembling a 7,10-dihydropleia-
dene framework (C, Scheme 1). To begin with, O-allylation
of naphthalene-2,7-diol (28) was carried out under conven-
tional allylation conditions with allyl bromide and potassium
carbonate in the presence of catalytic amounts of tetrabutyl-
ammonium hydrogensulfate (TBAHS), with stirring in ace-
tone at room temperature (Scheme 5). Attempted Claisen
rearrangements of 29 either by conventional heating or
under MWI conditions produced complex mixtures of prod-
The stereochemistries of all the cycloadducts were deter-
1
13
mined with the aid of H, C, NOE, and COSY NMR spec-
tral analysis. The regiochemistry of the major isomer 23a
was established from the observed NOE between H and H
a
b
in the NOE difference spectrum (Figure 1). In compound
1
2
4, the observed coupling constants for H in the H NMR
b
spectrum were found to be 9.2 Hz and 6.5 Hz, reflecting the
cis relationship between H , H , and H (Figure 1), while in
a
b
c
compound 26 the stereochemical assignment of H and H
a
b
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S. Kotha et al.
Scheme 7. RCM of 32a in the presence of Grubbs first-generation cata-
lyst.
Palladium/carbon-catalyzed hydrogenations of the two
isomers 33a and 34 both gave the same reduced products 35
and 36 in 1:1 ratios, which further confirmed that compound
Scheme 5. Synthesis of a 7,10-dihydropleiadene derivative from 28.
3
4
seems to be the double bond isomer of 33a
[12]
(
Scheme 8).
ucts as indicated by TLC, but a one-pot Claisen rearrange-
ment and acetyl protection procedure exclusively delivered
the desired rearranged product 30 (79%). RCM of the
diene 30 in the presence of Grubbs first-generation catalyst
(
8) in DCM at room temperature gave the pleiadene deriva-
tive 31 in 96% yield.
In an attempt to produce the cyclopentanoid spiro skele-
ton D (Scheme 1), the desired diolefinic precursor was pre-
pared by Claisen rearrangement of compound 14 on a silica
gel support under MWI conditions (Scheme 6), but only in-
Scheme 8. Pd/C-catalyzed hydrogenations of 33a and 34.
Alcohol 36 appears to be the product of complete reduc-
tion of either compound 33a or 34, and its structure was
confirmed by its reoxidation to the corresponding ketone 35
(
Scheme 8). Later on, the ketone 35 was converted into the
corresponding known hydrazone derivative and its identity
[25]
was established by melting point comparison.
At this juncture we were suspecting that prolonged heat-
ing might be responsible for the isomerization of 33a to 34,
and to examine this possibility, compound 33a was heated at
reflux in toluene in the absence of Grubbs catalyst for seven
days. No isomerized product 34 was observed, however,
which clearly indicates that thermal isomerization of 33a to
34 in the absence of Grubbs catalyst was not viable, but in
the presence of Grubbs catalyst 8 (10 mol%) under the
above conditions, compound 33a gave the isomerized prod-
Scheme 6. Synthesis of cyclopentanoid spirocyclics from b-naphthol.
complete conversion of the starting material was observed,
with the ratio of the starting material and the product re-
maining constant after 7 min (optimized time) of exposure
to MWI conditions. Even after prolonged exposure
[12]
(
>20 min) of the reaction mixture to MWI conditions the
uct 34 in 66% yield (Scheme 9).
starting material and product ratio remained the same.
Treatment of olefin 32 with the more reactive second-gen-
eration catalyst 9 in DCM at room temperature gave the ex-
[12]
pected metathesis product 33 in good yield (Scheme 6),
though RCM of compound 32a in the presence of Grubbs
first-generation catalyst was found to be very slow. Products
33a and 34 were obtained when compound 32a was heated
Scheme 9. Grubbs catalyst-induced isomerization of 33a.
at reflux in toluene in the presence of the Grubbs catalyst 8
[24]
for seven days. Both of these products exhibited charac-
ꢀ
1
teristic dienone absorption bands at 1663 and 1664 cm , re-
spectively, in their IR spectra and showed molecular ion
Recent literature reports dealing with olefin isomerization
in the presence of Grubbs catalyst are limited to substrates
containing oxygen or nitrogen substituents in their allylic or
homoallylic positions. We have observed that isomeriza-
tion of the double bond is also feasible in the presence of
Grubbs catalyst under thermal conditions in the absence of
alcohol, ether, or amide functional groups in the allylic or
homoallylic positions. A possible mechanism for the isomer-
1
peaks at m/z 196 in their mass spectra. The H NMR spec-
[26]
tral data for compound 34 included two different multiplets,
corresponding to the two nonequivalent olefinic protons,
and the presence of 14 lines in the proton-decoupled
13
C NMR spectral data indicated that 34 was an isomer of
[12]
33a (Scheme 7).
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Diversity-Oriented Approach to Biologically Relevant Molecular Frameworks
FULL PAPER
ization reaction, involving a 16-electron Ru complex, may
involve intramolecular hydrogen transfer followed by b-
[12]
elimination.
However, it is believed that the ruthenium
hydride species generated in situ by catalyst decomposition
[27]
is responsible for the isomerization.
A structurally similar but strategically different approach
to spiro systems starting from tetralone and indanone deriv-
atives such as 37 and 38 has been conceived. In order to
demonstrate the spiroannulation strategy, the desired diallyl
precursor materials (39 and 40) were prepared by allylation
of the tetralone or indanone derivatives (37 and 38, respec-
tively) by treatment with allyl bromide in the presence of
sodium hydride with stirring in THF at room temperature
(
Scheme 10).
Scheme 11. RCM of 39 and 40 in the presence of Grubbs first-generation
catalyst.
4
6 but instead produced a rearranged product 44 (Path a,
Scheme 12). A different sequence based on palladium/
carbon-catalyzed hydrogenation, followed by pyridinium
[28]
chlorochromate(PCC)-mediated benzylic oxidation, how-
A
H
E
N
ever, furnished the desired intermediate 46 (Path b,
Scheme 12), which has previously been converted to com-
[4]
pound 3 in a couple of steps.
Conclusion
This approach to DOS clearly demonstrates our capability
to deliver a diverse set of biologically relevant cyclic struc-
tures from bench-top chemicals through the use of micro-
wave-assisted silica gel-supported Claisen rearrangements
and Grubbs catalyst-induced metatheses as key steps. Non-
metathetic behavior of Grubbs catalyst was observed in ad-
dition to the metathesis reaction. Because of the presence of
reactive functionality in the end product we anticipate that
our method should also be extendable to the construction of
appendage-diverse small-molecule libraries. In view of the
importance of the molecular frameworks described here and
Scheme 10. Preparation of RCM precursors.
With various diallylated products now to hand, the next
task was to demonstrate the key RCM reactions for the
preparation of spirocyclic tetralone and indanone deriva-
tives. Exposure of olefins 39a–b and 40a–d to catalyst 8 in
toluene at reflux thus furnished the desired spiro cyclopen-
tanoid derivatives 41a–b and 42a–d, respectively, in good
yields (Scheme 11).
To demonstrate the utility of
this approach we would like to
disclose a formal total synthe-
sis of naphthoxepine oxime
ether 3, a potential hypoten-
sive agent. Two synthetic
routes from oxepine 16a to the
desired
key
intermediate
ketone 46 can be envisaged.
Initially, a sequence consisting
of 2-iodoxybenzoic acid(IBX)-
A
H
R
U
mediated benzylic oxidation
followed by Wilkinsonꢁs cata-
lyst-induced hydrogenation did
not furnish the desired ketone
Scheme 12. Formal synthesis of compound 3.
Chem. Eur. J. 2006, 12, 8024 – 8038
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8029

S. Kotha et al.
the simplicity of the procedure, our methodology is likely to
find useful application in the design of small “drug-like”
molecules.
to afford compound 32a as a colorless liquid (22 mg, 73%) along with
unreacted starting material 14a (7 mg, 23%); H NMR (400 MHz,
1
CDCl
CH ), 2.90 (dd, J = 13.6, 7.2 Hz, 2H; 2”CHHCH=CH
H; 2”CH CH=CH ), 5.21–5.32 (m, 2H; 2”CH CH=CH
3
, 258C, TMS): d = 2.59 (dd, J = 13.4, 7.2 Hz, 2H; 2”CHHCH=
), 4.77–4.87 (m,
), 6.16 (d, J =
2
2
4
2
2
2
2
1
1
0 Hz, 1H; C(O)CH=CH), 7.20–7.32 (m, 2H; ArH), 7.39 (d, J = 10 Hz,
1
H; C(O)CH=CH), 7.43–7.46 ppm (m, 2H; ArH); H NMR chemical
[
32b]
Experimental Section
shift values were matched with literature values.
1
,1-Diallyl-6-bromonaphthalen-2(1H)-one (32b): Compound 14b (76 mg,
A
H
R
U
G
General remarks: All reactions were monitored by thin layer chromatog-
raphy (TLC) carried out on glass plates coated with Acmeꢁs silica gel
GF 254 (containing 13% calcium sulfate as a binder). Visualization of
the spots on TLC plates was achieved by exposure either to iodine vapor
or to UV light. Flash chromatography was performed on Acmeꢁs silica
gel (100–200 mesh). Petroleum ether refers to the fraction of boiling
point 60–808C. Metathesis catalysts were purchased from Sigma–Aldrich
Chemical Co., Milwaukee, USA. All the commercial grade reagents were
0.25 mmol) was mixed with silica gel (710 mg), and the system was then
irradiated in a microwave oven for 7 min as described in the general pro-
cedure. The crude reaction mixture was then subjected to flash chromato-
graphic purification (silica gel, EtOAc in petroleum ether, 0.5 ! 2.5%)
to afford compound 32b as a colorless liquid (53 mg, 70%) along with
unreacted starting material 14b (20 mg, 26%). R
f
= 0.25 (silica gel,
EtOAc/petroleum ether 1:49); H NMR (400 MHz, CDCl , 258C, TMS):
d = 2.54 (dd, J = 13.6, 7.2 Hz, 2H; 2”CHHCH=CH ), 2.89 (dd, J =
13.6, 7.2 Hz, 2H; 2”CHHCH=CH ), 4.79–4.86 (m, 4H; 2”CH CH=
CH ), 5.2–5.3 (m, 2H; 2”CH CH=CH ), 6.19 (d, J 10.4 Hz, 1H;
1
3
2
used without further purification. Infrared spectra were recorded on a
2
2
1
Nicolet Impact 400 FT-IR spectrometer in KBr/CHCl
(
3
/CCl
4
.
H NMR
2
2
2
=
1
3
300, 400 MHz) and C NMR (75.4, 100.6 MHz) spectra were determined
at room temperature on a Varian VXR 300 or AX 400 Mercury Plus in
CDCl solutions. In some cases (to save CDCl ) we have used CDCl and
CCl systems to record NMR spectral data. Coupling constants (J values)
are given in hertz (Hz). Chemical shifts are expressed in parts per million
ppm) downfield from tetramethylsilane as internal reference. High-reso-
C(O)CH=CH), 7.30 (d, J = 7.6 Hz, 1H; ArH), 7.31 (d, J = 10.0 Hz, 1H;
C(O)CH=CH), 7.45 (d, J = 2.4 Hz, 1H; ArH), 7.55 ppm (dd, J = 8,
1
3
3
3
3
2.2 Hz, 1H; ArH); C NMR (75.4 MHz, CDCl
3
, 258C, TMS): d = 46.1,
4
55.8, 118.5, 120.5, 127.2, 128.7, 131.9, 132.1, 132.5, 132.8, 142.5, 143.6,
ꢀ
1
202.4 ppm; IR (neat): n˜ = 1658 cm (C=Ost); UV (CHCl ): l (e) =
3
max
ꢀ
1
3
ꢀ1
(
302 nm (5122 mol dm cm ); HRMS (Q-Tof ES+): m/z calcd for
C H OBr [M+H]: 303.0385; found: 303.0400.
lution mass spectra were determined on a Micromass Q-Tof spectrome-
ter. Elemental analysis was performed on a Carlo–Erba MOD 1106 CHN
analyzer.
1
6
16
1
,1-Diallyl-6-methoxynaphthalen-2
A
H
R
U
G
(
81 mg, 0.32 mmol) was mixed with silica gel (750 mg), and the system
General procedure for Claisen rearrangements: Preactivated silica gel
was then irradiated in a microwave oven for 7 min as described in the
general procedure. The crude reaction mixture was then subjected to
flash chromatographic purification (silica gel, EtOAc in petroleum ether,
0.5 ! 3%) to afford compound 32c as a colorless liquid (63 mg, 78%)
(
100–200 mesh, 5–10 times the weight of the starting substrate; preactiva-
tion of the silica gel was achieved by MWI (Ken Star, OM-992E) for
min) was added to a dichloromethane solution of starting material in a
5
beaker and the solvent was then evaporated. The resulting homogeneous
mixture of the substrate and silica gel was then irradiated in a microwave
oven (power 800 W) for 7 min (optimized time). The crude reaction mix-
ture was purified by flash chromatography. Elution of the column with
an appropriate mixture of ethyl acetate and petroleum ether gave the re-
quired product.
along with unreacted starting material 14c (15 mg, 19%). R = 0.1 (silica
f
1
gel, EtOAc/petroleum ether 1:49); H NMR (400 MHz, CDCl , 258C,
3
TMS): d = 2.55 (dd, J = 13.4, 7.0 Hz, 2H; 2”CHHCH=CH ), 2.87 (dd,
2
J = 13.4, 7.4 Hz, 2H; 2”CHHCH=CH ), 3.85 (s, 3H; OCH ), 4.77–4.87
2
3
(m, 4H; 2”CH CH=CH ), 5.22–5.32 (m, 2H; 2”CH CH=CH ), 6.16 (d,
2
2
2
2
J = 9.6 Hz, 1H; C(O)CH=CH), 6.82 (d, J = 2.8 Hz, 1H; ArH), 7.0 (dd,
8, 2.8 Hz, 1H; ArH), 7.34 ppm (d, J 9.2 Hz, 2H; ArH and
, 258C, TMS): d 46.3,
55.29, 55.33, 113.8, 115.9, 118.0, 126.5, 128.1, 131.8, 132.7, 135.5, 145.1,
[
29]
1
-Allyl-2-naphthol (13a): Compound 12a (1.16 g, 6.3 mmol) was mixed
J
=
=
1
3
with silica gel (5 g) and the system was then irradiated in a microwave
oven as described in the general procedure for 7 min. The crude reaction
mixture was then directly loaded onto a silica gel column, elution of
which with EtOAc/petroleum ether (2%) gave compound 13a as a
C(O)CH=CH); C NMR (75.4 MHz, CDCl
3
=
ꢀ
1
3
158.0, 203.4 ppm; IR (neat): n˜ = 1651 cm (C=Ost); UV (CHCl ): lmax
ꢀ
1
3
ꢀ1
(e) = 308 nm (5091 mol dm cm ); HRMS (Q-Tof ES+): m/z calcd for
[
29b]
brown, crystalline solid (958 mg, 82%). M.p. 578C (lit.: 568C).
C
17
H
19
O
2
[M+H]: 255.1385; found: 255.1381.
[
30]
[33]
1
-Allyl-6-bromo-2-naphthol (13b): Compound 12b (218 mg, 0.8 mmol)
1-Allyl-2-(allyloxy)naphthalene (14a):
Potassium carbonate (200 mg,
was mixed with silica gel (2 g), and the system was then irradiated in a
microwave oven for 7 min as described in the general procedure. The
crude reaction mixture was then directly loaded onto a silica gel column,
elution of which with EtOAc/petroleum ether (2%) gave compound 13b
1.4 mmol) and allyl bromide (140 mg, 1.2 mmol) were added to a solution
of compound 13a (133 mg, 0.7 mmol) in dry acetone and the reaction
mixture was then allowed to stir at room temperature. After completion
of the reaction (4 h, TLC monitoring) the crude reaction mixture was fil-
tered through a celite pad. The residue was washed with dichloromethane
[
30]
as a white, crystalline solid (184 mg, 84%). M.p. 908C (lit.: 86–878C).
[
31]
(
3”10 mL), and evaporation of the solvent gave the crude product,
1
-Allyl-6-methoxy-2-naphthol (13c):
Compound 12c (201 mg,
0
.9 mmol) was mixed with silica gel (2 g), and the system was then irradi-
which was loaded onto a silica gel column, elution of which with petrole-
ated in a microwave oven for 7 min as described in the general proce-
dure. The crude reaction mixture was then directly loaded onto a silica
gel column, elution of which with EtOAc/petroleum ether (2.5%) gave
um ether gave compound 14a as a colorless liquid (145 mg, 90%);
1
H NMR (400 MHz, CDCl
), 4.67 (dt, J = 4.8, 1.6 Hz, 2H; OCH
CH=CH ), 5.28 (d, J = 10.4 Hz, 1H; OCH CH=CHH), 5.44 (d, J
= 17.2 Hz, 1H; OCH CH=CHH), 6.0–6.14 (m, 2H; 2”CH CH=CH ),
3
, 258C, TMS): d = 3.89 (dt, J = 6.0, 2.0 Hz,
2H; ArCH
ArCH
2
2
), 4.98–5.03 (m, 2H;
compound 13c as a white, crystalline solid (176 mg, 88%). M.p. 908C;
2
2
2
1
H NMR (400 MHz, CDCl
CH=CH ), 3.89 (s, 3H; OCH
OH), 6.0–6.10 (m, 1H; CH CH=CH
.10 (d, J = 2.4 Hz, 1H; ArH), 7.16 (dd, J = 9, 2.6 Hz, 1H; ArH), 7.55
d, J 8.8 Hz, 1H; ArH), 7.80 ppm (d, J 9.2 Hz, 1H; ArH);
C NMR (75.4 MHz, CDCl , 258C, TMS): d = 29.5, 55.4, 106.9, 116.0,
17.4, 118.5, 119.0, 124.7, 127.0, 128.6, 130.4, 135.9, 149.7, 155.7 ppm.
3
, 258C, TMS): d = 3.79 (d, J = 5.6 Hz, 2H;
), 5.01–5.10 (m, 3H; CH CH=CH and
), 7.06 (d, J = 8.8 Hz, 1H; ArH),
2
2
2
CH
2
2
3
2
2
7.25 (d, J = 8.2 Hz, 1H; ArH), 7.34 (ddd, J = 8.0, 7.0, 0.8 Hz, 1H;
ArH), 7.47 (ddd, J = 8.3, 6.6, 1.2 Hz, 1H; ArH), 7.72 (d, J = 8.8 Hz,
1H; ArH), 7.78 (d, J = 8.0 Hz, 1H; ArH), 7.95 ppm (d, J = 8.8 Hz, 1H;
2
2
7
1
(
=
=
ArH); H NMR chemical shift values were matched with literature
1
3
[33]
values.
3
1
1
-Allyl-2-(allyloxy)-6-bromonaphthalene (14b): Potassium carbonate
[
32]
1
,1-Diallylnaphthalen-2
A
C
H
T
R
E
U
N
G
(1H)-one (32a):
Compound 14a (30 mg,
(194 mg, 1.4 mmol) and allyl bromide (127 mg, 1.0 mmol) were added to
a solution of compound 13b (185 mg, 0.703 mmol) in dry acetone. The re-
action mixture was then allowed to stir at room temperature for 4 h and
was then filtered through a celite pad. The residue was washed with
DCM (3”10 mL). Evaporation of the solvent gave the crude product,
0
.134 mmol) was mixed with silica gel (346 mg), and the system was then
irradiated in a microwave oven for 7 min as described in the general pro-
cedure. The crude reaction mixture was then subjected to flash chromato-
graphic purification (silica gel, EtOAc in petroleum ether, 0.5 ! 2.0%)
8030
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8024 – 8038

Diversity-Oriented Approach to Biologically Relevant Molecular Frameworks
FULL PAPER
which was loaded onto a silica gel column, and elution of the column
HRMS (Q-Tof ES+): m/z calcd for C14
275.0085.
-Methoxy-1,4-dihydronaphtho
6 mg, 0.007 mmol, 5 mol%) was added to a solution of diene 14c
(35 mg, 0.137 mmol) in dry, degassed DCM (3 mL), and the reaction mix-
ture was allowed to stir at room temperature. After completion of the re-
action (1 h, TLC monitoring), the solvent was removed under reduced
pressure and the crude product was purified by flash chromatography
(silica gel, EtOAc in petroleum ether, 2%) to give compound 16c as a
H12OBr [M+H]: 275.0072; found:
with petroleum ether gave compound 14b as a colorless liquid (199 mg,
1
9
3%). R
f
=
0.6 (silica gel, EtOAc/petroleum ether 1:49); H NMR
9
(
A
H
R
U
[2,1-b]oxepine (16c): Grubbs catalyst 9
(
400 MHz, CDCl
3
, 258C, TMS): d
), 4.66 (dt, J 5.2, 1.6 Hz, 2H; OCH
CH=CH ), 5.28 (dd, J = 10.6, 1.6 Hz, 1H; OCH
17, 1.6 Hz, 1H; OCH CH=CHH), 5.96–6.12 (m, 2H; 2”
CH=CH ), 7.25 (d, J = 8.8 Hz, 1H; ArH), 7.51 (dd, J = 9.2, 2.4 Hz,
=
3.85 (dt, J
), 4.93–5.02 (m, 2H;
CH=CHH), 5.43
= 6, 1.6 Hz, 2H;
ArCH
ArCH
(
2
2
=
2
2
2
dd, J
=
2
CH
2
2
1
H; ArH), 7.62 (d, J = 9.2 Hz, 1H; ArH), 7.79 (d, J = 9.2 Hz, 1H;
1
3
ArH), 7.92 ppm (d, J = 2.0 Hz, 1H; ArH); C NMR (75.4 MHz, CDCl
3
,
white, crystalline solid (30 mg, 96%). R = 0.3 (silica gel, EtOAc/petrole-
f
1
2
1
=
58C, TMS): d = 29.3, 70.2, 115.3, 116.0, 117.2, 117.4, 121.9, 125.6, 127.0,
29.6, 130.3, 130.5, 131.8, 133.6, 136.4, 153.8 ppm; UV (CHCl ): lmax (e)
252 nm (7952 mol dm cm ).
um ether 1:49); m.p. 828C; H NMR (300 MHz, CDCl , 258C, TMS): d =
3
3
3.87–3.96 (m, 5H; ArCH and OCH ), 4.60–4.69 (m, 2H; OCH ), 5.52 (d,
2
3
2
ꢀ
1
3
ꢀ1
J = 8.1 Hz, 1H; ArCH
2
CH), 5.94–6.0 (m, 1H; OCH
2
CH), 7.13 (d, J =
2
8
9
2
.4 Hz, 1H; ArH), 7.17 (dd, J = 8.8, 2.4 Hz, 1H; ArH), 7.25 (d, J =
.4 Hz, 1H; ArH), 7.60 (d, J = 8.4 Hz, 1H; ArH), 7.94 ppm (d, J =
1
-Allyl-2-(allyloxy)-6-methoxynaphthalene (14c): Potassium carbonate
(
198 mg, 1.4 mmol) and allyl bromide (129 mg, 1.0 mmol) were added to
.6 Hz, 1H; ArH); HRMS (Q-Tof ES+): m/z calcd for C15
15 2
H O [M+H]:
a solution of compound 13c (153 mg, 0.715 mmol) in dry acetone. The re-
action mixture was then allowed to stir at room temperature for 4 h and
filtered through a celite pad, and the residue was washed with DCM (3”
27.1072; found: 227.1082.
1-Allyl-2-(prop-2-yn-1-yloxy)naphthalene (15a): Anhydrous powdered
potassium carbonate (414 mg, 3 mmol) and propargyl bromide (250 mg,
2.1 mmol) were added to a solution of compound 13a (259 mg, 1.4 mmol)
in dry acetone (10 mL). The reaction mixture was then allowed to stir at
room temperature for 6 h and was then filtered through a celite pad. The
residue was washed with dichloromethane (3”10 mL), the solvent was
removed under reduced pressure, and the crude product was purified by
flash column chromatography (silica gel, EtOAc in petroleum ether, 1%)
1
0 mL). Evaporation of the solvent gave the crude product, which was
loaded onto a silica gel column, and elution of the column with petrole-
um ether gave compound 14c as a colorless liquid (174 mg, 96%). R
0
f
=
1
.36 (silica gel, EtOAc/petroleum ether 1:49); H NMR (300 MHz,
CDCl
H; OCH
ArCH CH=CH
18, 1.6 Hz, 1H; OCH
CH=CH ), 7.09 (d, J = 2.4 Hz, 1H; ArH), 7.15 (dd, J = 9.2, 2.8 Hz,
3
, 258C, TMS): d = 3.86 (dt, J = 6, 1.6 Hz, 2H; ArCH
), 4.63 (dt, J = 5.2, 1.6 Hz, 2H; OCH ), 4.95–5.0 (m, 2H;
), 5.26 (dd, J = 10.4, 1.6 Hz, 1H; OCH CH=CHH), 5.43
CH=CHH), 5.98–6.13 (m, 2H; 2”
2
), 3.89 (s,
3
3
2
2
2
2
to provide compound 15a as a white, crystalline solid (280 mg, 90%). R
=
f
(
dd, J
=
2
1
0.4 (silica gel, EtOAc/petroleum ether 1:49); m.p. 388C; H NMR
CH
1
2
2
(
300 MHz, CDCl , 258C, TMS): d = 2.49 (t, J = 2.5 Hz, 1H; CH
3
2
Cꢁ
H; ArH), 7.22 (d, J = 9.2 Hz, 1H; ArH), 7.61 (d, J = 9.2 Hz, 1H;
1
3
CH), 3.89 (d, J = 5.8 Hz, 2H; CH CH=CH ), 4.81 (d, J = 2.5 Hz, 2H;
CH
CH
1H; ArH), 7.76 (d, J = 9.2 Hz, 1H; ArH), 7.80 (d, J = 8.1 Hz, 1H;
3
ArH), 7.95 ppm (d, J = 8.4 Hz, 1H; ArH); C NMR (75.4 MHz, CDCl ,
ArH), 7.85 ppm (d, J = 9.2 Hz, 1H; ArH); C NMR (75.4 MHz, CDCl
3
,
2
2
CꢁCH), 4.96–5.03 (m, 2H; CH
2
CH=CH ), 5.98–6.11 (m, 1H;
2
2
2
1
l
58C, TMS): d = 29.4, 55.3, 70.6, 106.3, 115.0, 116.0, 117.0, 119.0, 122.2,
25.3, 126.5, 128.5, 130.4, 134.0, 136.8, 152.1, 155.9 ppm; UV (CHCl ):
276 nm (5740 mol dm cm ); HRMS (Q-Tof ES+): m/z
[M+H]: 255.1385; found: 255.1396.
,4-Dihydronaphtho[2,1-b]oxepine (16a): Grubbs catalyst 9 (5 mg,
2
2
CH=CH ), 7.34–7.39 (m, 2H; ArH), 7.48 (ddd, J = 8.5, 6.9, 1.1 Hz,
3
ꢀ1
3
ꢀ1
max (e)
=
1
3
calcd for C17
19 2
H O
2
1
3
2
58C, TMS): d = 29.4, 57.6, 75.4, 79.2, 115.2, 115.4, 122.7, 123.8, 123.9,
1
0
0
A
C
H
T
R
E
U
N
G
26.4, 128.1, 128.5, 130.0, 133.2, 136.7, 152.7 ppm; IR (neat): n˜
=
.006 mmol, 5 mol%) was added to a solution of diene 14a (30 mg,
.13 mmol) in dry, degassed DCM (3 mL), and the reaction mixture was
ꢀ1
ꢀ1
293 cm (ꢁCꢀH st), 2121 cm (CꢁC st); UV (CHCl
3
): lmax (e)
=
ꢀ1
3
ꢀ1
83 nm (4387 mol dm cm ); HRMS (Q-Tof ES+): m/z calcd for
15O [M+H]: 223.1123; found: 223.1130.
-Allyl-6-bromo-2-(prop-2-yn-1-yloxy)naphthalene (15b): Anhydrous
allowed to stir at room temperature. After completion of the reaction
4 h, TLC monitoring), the solvent was removed under reduced pressure
16
C H
(
1
and the crude product was purified by flash chromatography (silica gel,
EtOAc in petroleum ether, 1.5%) to give compound 16a as a white, crys-
talline solid (24 mg, 92%). R
1
powdered potassium carbonate (220 mg, 1.6 mmol) and propargyl bro-
mide (142 mg, 1.2 mmol) were added to a solution of compound 13b
f
= 0.35 (silica gel, EtOAc/petroleum ether
, 258C, TMS): d = 3.91 (d,
), 4.60–4.63 (m, 2H; OCH ), 5.5 (d, J = 11.4 Hz,
CH), 7.23 (d, J =
(
212 mg, 0.8 mmol) in dry acetone (7 mL). The reaction mixture was then
1
:49); m.p. 848C; H NMR (300 MHz, CDCl
3
allowed to stir at room temperature for 4 h and was then filtered through
a celite pad. The residue was washed with dichloromethane (3”10 mL),
the solvent was removed under reduced pressure, and the crude product
was purified by flash column chromatography (silica gel, EtOAc in petro-
leum ether, 1%) to provide compound 15b as a white, crystalline solid
J = 3 Hz, 2H; ArCH
2
2
1
8
7
1
H; ArCH
2
CH), 5.96 (dt, J = 11.4, 5.2 Hz, 1H; OCH
2
.4 Hz, 1H; ArH), 7.35 (dd, J = 7.8, 6.9 Hz, 1H; ArH), 7.45 (dd, J =
.2, 8.4 Hz, 1H; ArH), 7.67 (d, J = 8.7 Hz, 1H; ArH), 7.77 (d, J = 8 Hz,
H; ArH), 7.98 ppm (d, J = 8.4 Hz, 1H; ArH); C NMR (75.4 MHz,
+ CCl4, 258C, TMS): d = 24.7, 70.6, 121.8, 123.1, 124.3, 126,
26.1, 128.1 (2C), 128.7, 130.5, 131.2, 131.8, 156.2 ppm; UV (CHCl
1
3
(
6
1
230 mg, 95%). R
f
= 0.6 (silica gel, EtOAc/petroleum ether 1:49); m.p.
48C; H NMR (300 MHz, CDCl , 258C, TMS): d = 2.50 (t, J = 2.4 Hz,
H; CH CH=CH ), 4.82 (d, J
2.1 Hz, 2H; CH CH=CH ), 5.95–6.08
), 7.38 (d, J = 9 Hz, 1H; ArH), 7.52 (dd, J = 9.1,
CDCl
1
3
1
3
3
): lmax
CꢁCH), 3.85 (dt, J = 5.7, 1.5 Hz, 2H; CH
2
2
2
ꢀ1
3
ꢀ1
+
(
e) = 283 nm (3888 mol dm cm ); MS: m/z: 196 [M] ; elemental anal-
ysis calcd (%) for C14 12O: C 85.68, H 6.16; found: C 85.28, H 6.51.
-Bromo-1,4-dihydronaphtho[2,1-b]oxepine (16b): Grubbs catalyst
=
2
CꢁCH), 4.91–5.03 (m, 2H; CH
2
2
H
(
m, 1H; CH
2
CH=CH
2
9
A
H
R
U
G
9
2.4 Hz, 1H; ArH), 7.66 (d, J = 9 Hz, 1H; ArH), 7.81 (d, J = 9.3 Hz,
1H; ArH), 7.94 ppm (d, J = 2.4 Hz, 1H; ArH); C NMR (75.4 MHz,
CDCl , 258C, TMS): d = 29.3, 57.5, 75.7, 78.9, 115.5, 116.3, 117.7, 122.9,
1
3
(
(
3 mg, 0.004 mmol, 5 mol%) was added to a solution of diene 14b
23 mg, 0.076 mmol) in dry, degassed DCM (3 mL), and the reaction mix-
3
ture was allowed to stir at room temperature. After completion of the re-
action (1 h, TLC monitoring), the solvent was removed under reduced
pressure and the crude product was purified by flash chromatography
125.8, 127.2, 129.7, 130.4, 131.0, 131.8, 136.4, 152.9 ppm; IR (neat): n˜ =
ꢀ
1
ꢀ1
3296 cm (ꢁCꢀH st), 2121 cm (CꢁC st); UV (CHCl
): lmax (e)
284 nm (5522 mol dm cm ); HRMS (Q-Tof ES+): m/z calcd for
14O([ M+HꢀBr]: 222.1045; found: 222.1039.
=
3
ꢀ
1
3
ꢀ1
(
silica gel, EtOAc in petroleum ether, 1.5%) to give compound 16b as a
16
C H
white, crystalline solid (20 mg, 96%). R
leum ether 1:49); m.p. 1108C; H NMR (300 MHz, CDCl
f
= 0.54 (silica gel, EtOAc/petro-
, 258C, TMS):
), 5.51–5.57 (m,
CH), 7.29 (d, J = 8.7 Hz, 1H;
1-Allyl-6-methoxy-2-(prop-2-yn-1-yloxy)naphthalene (15c): Anhydrous
powdered potassium carbonate (246 mg, 1.78 mmol) and propargyl bro-
mide (159 mg, 1.3 mmol) were added to a solution of compound 13c
(191 mg, 0.89 mmol) in dry acetone (7 mL). The reaction mixture was
then allowed to stir at room temperature for 6 h and filtered through a
celite pad. The residue was washed with dichloromethane (3”10 mL),
the solvent was removed under reduced pressure, and the crude product
was purified by flash column chromatography (silica gel, EtOAc in petro-
leum ether, 1.5%) to provide compound 15c as a colorless liquid
1
3
d = 3.88–3.90 (m, 2H; ArCH
2 2
), 4.64–4.67 (m, 2H; OCH
1
H; ArCH CH), 5.93–6.01 (m, 1H; OCH
2
2
ArH), 7.55 (dd, J = 9.1, 2.1 Hz, 1H; ArH), 7.61 (d, J = 8.4 Hz, 1H;
ArH), 7.89 (d, J = 9 Hz, 1H; ArH), 7.97 ppm (d, J = 2.4 Hz, 1H;
1
3
ArH); C NMR (75.4 MHz, CDCl
3
, 258C, TMS): d = 24.7, 70.7, 118.4,
1
1
23.1, 125.0, 125.6, 127.3, 128.1, 129.4, 130.2, 130.6, 131.0, 132.3,
56.4 ppm; UV (CHCl ): lmax (e) = 252 nm (6328 mol dm cm );
3
ꢀ
1
3
ꢀ1
Chem. Eur. J. 2006, 12, 8024 – 8038
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8031

S. Kotha et al.
1
3
(
280 mg, 90%). R
f
=
0.36 (silica gel, EtOAc/petroleum ether 1:49);
H NMR (300 MHz, CDCl , 258C, TMS): d = 2.48 (t, J = 2.4 Hz, 1H;
CH CH=CH ), 3.90 (s, 3H;
CꢁCH), 3.86 (dt, J = 4.5, 1.5 Hz, 2H; CH
OCH ), 4.78 (d, 2.1 Hz, 2H; CH
CꢁCH), 4.94–5.03 (m, 2H;
CH CH=CH ), 5.97–6.10 (m, 1H; CH CH=CH ), 7.10 (d, J = 2.7 Hz,
H; ArH), 7.16 (dd, J = 9.3, 2.4 Hz, 1H; ArH), 7.33 (d, J = 9 Hz, 1H;
ArH), 7.64 (d, J = 8.7 Hz, 1H; ArH), 7.86 ppm (d, J = 9 Hz, 1H;
J = 2.1 Hz, 1H; ArH); C NMR (75.4 MHz, CDCl
3
, 258C, TMS): d =
1
3
24.5, 70.4, 111.1, 118.4, 122.8, 124.8, 127.4, 127.9, 129.5, 130.11, 130.13,
130.6, 132.3, 136.7, 137.5, 156.2 ppm; HRMS (Q-Tof ES+): m/z calcd for
2
2
2
3
J
=
2
C
16
H
14OBr [M+H]: 301.0228; found: 301.0231.
-Methoxy-3-vinyl-1,4-dihydronaphtho[2,1-b]oxepine (17c): Catalyst
13 mg, 0.015 mmol, 13 mol%, in two portions at 2 h interval) was added
to a solution of enyne 15c (30 mg, 0.119 mmol) in dry, degassed DCM
10 mL) as described in the general procedure and the reaction mixture
was then stirred at room temperature in the presence of ethylene
1 atm). After completion of the reaction (4 h, TLC monitoring) the re-
sulting brown solution was concentrated under reduced pressure and the
crude product was then purified by flash column chromatography (silica
gel, EtOAc in petroleum ether, 1.5%) to afford diene 17c as a colorless
= 0.38 (silica gel, EtOAc/petroleum ether 1:49);
H NMR (300 MHz, CDCl , 258C, TMS): d = 3.90–3.96 (m, 5H; ArCH
and OCH ), 4.83 (d, J = 1.8 Hz, 2H; OCH ), 4.89 (d, J = 17.4 Hz, 1H;
CH=CHH), 4.90 (d, J = 12.3 Hz, 1H; CH=CHH), 6.05 (t, J = 6.0 Hz,
1H; CH CH), 6.22 (dd, J = 18.0, 11.4 Hz, 1H; CH=CH ), 7.12–7.19 (m,
2H; ArH), 7.27 (d, J = 9.9 Hz, 1H; ArH), 7.61 (d, J = 8.4 Hz, 1H;
2
2
2
2
9
A
H
R
U
G
9
1
(
1
3
ArH); C NMR (75.4 MHz, CDCl
7
1
(
(
3
, 258C, TMS): d = 29.5, 55.4, 58.0,
(
5.3, 79.4, 106.5, 115.3, 116.4, 119.2, 123.3, 125.6, 126.7, 128.6, 131.1,
ꢀ
1
ꢀ1
36.8, 151.4, 156.3 ppm; IR (neat): n˜ = 3292 cm (ꢁCꢀH st), 2121 cm
;
(
ꢀ1
3
ꢀ1
CꢁC st); UV (CHCl
): lmax (e) = 275 nm (5128 mol dm cm ); HRMS
[M+H]: 253.1229; found: 253.1238.
3
Q-Tof ES+): m/z calcd for C17
17 2
H O
General experimental procedure for the ring-closing enyne metathesis of
5a–c: The enyne compound (1 equiv) in dry DCM was degassed with ni-
trogen for 15 min and then with ethylene gas for 10 min. Grubbs catalyst
or 10 (9–13 mol%, portionwise addition at different time intervals) was
then added, and finally the vessel was kept under 1 atm ethylene pressure
balloon pressure). The reaction mixture was then stirred at room tem-
1
liquid (15 mg, 50%). R
f
1
3
2
9
3
2
(
2
2
perature. After completion of the reaction (TLC monitoring), the pres-
sure was released, the resulting brown solution was concentrated under
reduced pressure, and the crude product was purified by silica gel flash
chromatography. Elution of the column with an appropriate mixture of
ethyl acetate and petroleum ether gave the required compound.
1
3
ArH), 7.92 ppm (d, J = 9 Hz, 1H; ArH); C NMR (75.4 MHz, CDCl
258C, TMS): d = 24.6, 55.4, 70.6, 106.8, 110.8, 118.9, 122.0, 124.5, 126.8-
(2C), 128.2, 130.2, 132.4, 136.7, 137.8, 154.4, 156.6 ppm; HRMS (Q-Tof
ES+): m/z calcd for C17 [M+H]: 253.1229; found: 253.1232.
3
,
AHCTREUNG
17 2
H O
RCEM of 15a with Hoveyda catalyst 10: Catalyst 10 (6 mg, 0.009 mmol,
General procedure for the Diels–Alder reactions of 17a–c: Dienophile
(1.5 equiv) was added to a solution of the diene 17 (1 equiv) in dry tol-
uene and the mixture was heated in toluene. After completion of the re-
action (TLC monitoring), the solution was concentrated under reduced
pressure and the crude product was purified by silica gel flash chroma-
tography. Elution of the column with an ethyl acetate and petroleum
ether mixture gave the desired DA adduct.
1
0 mol%, in two portions at 1.5 h interval) was added to a solution of
enyne 15a (20 mg, 0.09 mmol) in dry, degassed DCM (4 mL) as described
in the general procedure and the reaction mixture was then stirred at
room temperature in the presence of ethylene (1 atm). After completion
of the reaction (3 h, TLC monitoring) the resulting brown solution was
concentrated under reduced pressure and the crude product was then pu-
rified by flash column chromatography (silica gel, EtOAc in petroleum
Diels–Alder reaction between 17a and DMAD: Dienophile 18 (19 mg,
ether, 1%) to afford 3-vinyl-1,4-dihydronaphtho
colorless liquid (10 mg, 50%). R = 0.42 (silica gel, EtOAc/petroleum
ether 1:49); H NMR (300 MHz, CDCl , 258C, TMS): d = 3.99 (d, J =
), 4.85 (d, J = 1.8 Hz, 2H; OCH ), 4.90 (d, J =
8.3 Hz, 1H; CH=CHH), 4.91 (d, J = 11.4 Hz, 1H; CH=CHH), 6.07 (t,
CH), 6.23 (dd, J = 18.0, 10.8 Hz, 1H; CH=CH ),
.31 (d, J = 8.7 Hz, 1H; ArH), 7.40 (ddd, J = 7.5, 7.5, 1.2 Hz, 1H;
ArH), 7.51 (ddd, J = 7.7, 7.7, 1.2 Hz, 1H; ArH), 7.73 (d, J = 8.7 Hz,
H; ArH), 7.83 (d, J = 8.5 Hz, 1H; ArH), 8.03 ppm (d, J = 8.4 Hz, 1H;
A
H
R
U
G
0
0
.134 mmol) was added to
.112 mmol) in toluene (12 mL) and the mixture was heated (908C, 24 h).
a solution of the diene 17a (25 mg,
f
1
3
The reaction mixture was concentrated under reduced pressure and the
crude product was purified by flash column chromatography (silica gel,
EtOAc in petroleum ether, 15%) to afford DA adduct 22 as a colorless,
6
1
.3 Hz, 2H; ArCH
2
2
J = 6.3 Hz, 1H; CH
2
2
thick liquid (20 mg, 49%). R
f
= 0.33 (silica gel, EtOAc/petroleum ether
:4); H NMR (400 MHz, CDCl , 258C, TMS): d = 2.97 (dd, J = 14.4,
0.4 Hz, 1H; ArCHH), 3.06–3.09 (m, 1H; C=CHCHH), 3.19 (dd, J =
.6, 2.6 Hz, 1H; C=CHCHH), 3.39–3.45 (m, 1H; ArCH CH), 3.77 (dd, J
14.6, 1.8 Hz, 1H; ArCHH), 3.83 (s, 3H; OCH ), 3.92 (s, 3H; OCH ),
.25 (d, J = 12.4 Hz, 1H; OCHH), 4.71 (d, J = 12.8 Hz, 1H; OCHH),
5.78 (t, J = 3.2 Hz, 1H; C=CHCH ), 7.24 (d, J = 8.8 Hz, 1H; ArH),
7
1
1
1
6
3
1
2
ArH); HRMS (Q-Tof ES+): m/z calcd for C16H15O [M+H]: 223.1123;
found: 223.1114.
=
3
3
4
RCEM of 15a with Grubbs catalyst 9: Grubbs catalyst
9
(9 mg,
2
0
.01 mmol, 10 mol%, in two portions at 1.5 h interval) was added to a
7.40–7.44 (m, 1H; ArH), 7.50–7.55 (m, 1H; ArH), 7.70 (d, J = 8.8 Hz,
1H; ArH), 7.83 (d, J = 8.4 Hz, 1H; ArH), 7.99 ppm (d, J = 8.8 Hz, 1H;
solution of enyne 15a (20 mg, 0.09 mmol) in dry, degassed DCM (3 mL)
as described in the general procedure and the reaction mixture was then
stirred at room temperature in the presence of ethylene (1 atm). After
completion of the reaction (3 h, TLC monitoring) the resulting brown
solution was concentrated under reduced pressure and the crude product
was then purified by flash column chromatography (silica gel, EtOAc in
ꢀ
1
ArH); IR (neat): n˜ = 1727 cm (C=Ost); UV (CHCl
3
): lmax (e) =
240 nm (30800 mol dm cm ); HRMS (Q-Tof ES+): m/z calcd for
Na [M+Na]: 387.1208; found: 387.1198.
Diels–Alder reaction between 17a and 19: Dienophile 19 (21 mg,
.117 mmol) was added to a solution of the diene 17a (20 mg, 0.09 mmol)
ꢀ
1
3
ꢀ1
22 20 5
C H O
0
petroleum ether, 1%) to afford the diene 3-vinyl-1,4-dihydronaphtho[2,1-
b]oxepine (17a) as a colorless liquid (9 mg, 45%).
A
H
R
U
G
in toluene (7 mL) and the mixture was heated (908C, 24 h). The reaction
mixture was concentrated under reduced pressure and the crude product
was purified by flash column chromatography (silica gel, EtOAc in petro-
leum ether, 15%) to afford DA adduct 23 as a mixture of two regioisom-
ers (22 mg, 23a/23b = 9:1) in 61% combined yield. The data given
9
-Bromo-3-vinyl-1,4-dihydronaphtho
11 mg, 0.013 mmol, 9 mol%, in two portions at 2 h interval) was added
to a solution of enyne 15b (45 mg, 0.149 mmol) in dry, degassed DCM
10 mL) as described in the general procedure and the reaction mixture
was then stirred at room temperature in the presence of ethylene
1 atm). After completion of the reaction (4 h, TLC monitoring) the re-
A
H
R
U
G
9
(
(
below are only for the major isomer 23a. R
f
= 0.20 (silica gel, EtOAc/
petroleum ether 1:4); m.p. 1708C; H NMR (300 MHz, CDCl , 258C,
TMS): d = 2.43 (s, 3H; CH ), 2.84–2.87 (m, 2H; C=CHCH ), 3.10 (dd, J
= 15.0, 10.5 Hz, 1H; ArCHH), 3.37–3.44 (m, 1H; ArCH CH), 3.65 (dd,
J = 15.0, 2.7 Hz, 1H; ArCHH), 4.41 (d, J = 12.9 Hz, 1H; OCHH), 4.66
(d, J = 12.6 Hz, 1H; OCHH), 5.69 (brs, 1H; OCH C=CH), 7.15–7.17
(m, 1H; ArCH CHCH=C), 7.19 (d, J = 8.7 Hz, 1H; ArH), 7.29 (d, J =
1
3
(
3
2
sulting brown solution was concentrated under reduced pressure and the
crude product was then purified by flash column chromatography (silica
gel, EtOAc in petroleum ether, 1.5%) to afford diene 17b as a white,
2
2
crystalline solid (30 mg, 67%). R
f
= 0.62 (silica gel, EtOAc/petroleum
ether 1:49); m.p. 1228C; H NMR (300 MHz, CDCl , 258C, TMS): d =
.95 (d, J = 5.7 Hz, 2H; ArCH ), 4.85 (d, J = 1.5 Hz, 2H; OCH ), 4.91
d, J = 17.4 Hz, 1H; CH=CHH), 4.92 (d, J = 12.0 Hz, 1H; CH=CHH),
.05 (t, J = 5.7 Hz, 1H; CH CH), 6.22 (dd, J = 18.2, 11.4 Hz, 1H; CH=
CH ), 7.32 (d, J = 9 Hz, 1H; ArH), 7.55 (dd, J = 9.2, 2.4 Hz, 1H; ArH),
.62 (d, J = 9 Hz, 1H; ArH), 7.88 (d, J = 9 Hz, 1H; ArH), 7.97 ppm (d,
2
1
3
8.1 Hz, 2H; ArH), 7.41–7.47 (m, 1H; ArH), 7.54–7.60 (m, 1H; ArH),
3
(
6
2
2
7.66–7.72 (m, 3H; ArH), 7.83 (d, J = 8.4 Hz, 1H; ArH), 8.05 ppm (d, J
1
3
3
= 8.4 Hz, 1H; ArH); C NMR (75.4 MHz, CDCl , 258C, TMS): d =
2
21.7, 24.7, 32.8, 37.8, 77.3, 120.6, 121.7, 123.0, 124.4, 124.6, 126.7, 128.2,
128.4, 128.8, 129.9, 130.9, 132.8, 135.4, 135.7, 137.9, 138.4, 144.5,
2
ꢀ
1
ꢀ1
7
2 2
157.4 ppm; IR (neat): n˜ = 1309 cm (SO , asym. st), 1148 cm (SO ,
8032
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8024 – 8038

Diversity-Oriented Approach to Biologically Relevant Molecular Frameworks
FULL PAPER
ꢀ
1
3
ꢀ1
sym. st); UV (CHCl
Q-Tof ES+): m/z calcd for
03.1377.
Diels–Alder reaction between 17a and N-phenylmaleimide: Dienophile
1
0
3
): lmax (e) = 244 nm (12462 mol dm cm ); HRMS
(ꢂ)-11,12-Bis-(benzenesulfonyl)-3-methoxy-8,10,11,12,12a,13-hexahydro-
(
4
C
25
H
23
O
3
S
[M+H]: 403.1368; found:
7-oxa-benzo
A
T
U
A
H
R
U
G
(30 mg, 0.097 mmol) was added to a solution of the diene 17c (15 mg,
.059 mmol) in toluene (15 mL) and the mixture was heated at reflux in
0
toluene. After the completion of the reaction (39 h, TLC monitoring) the
solution was concentrated under reduced pressure and the crude product
was purified by flash column chromatography (silica gel, EtOAc in petro-
9 (28 mg, 0.16 mmol) was added to a solution of the diene 17a (18 mg,
.08 mmol) in toluene (10 mL) and the mixture was heated in toluene
908C, 12 h). The solution was concentrated under reduced pressure and
the crude product was purified by flash column chromatography (silica
(
leum ether, 30%) to afford DA adduct 27 as a white solid (18 mg, 54%).
1
R
f
= 0.17 (silica gel, EtOAc/petroleum ether 3:7); m.p. 2058C; H NMR
gel, EtOAc in petroleum ether, 20%) to afford DA adduct 24 as a white
(
300 MHz, CDCl
(dd, 15.2, 2.4 Hz, 1H; ArCHH), 3.20 (d,
ArCH CH), 3.67 (dd, J 15.2, 12 Hz, 1H; ArCHH), 3.91 (s, 3H;
OCH ), 4.21–4.23 (m, 1H; CH CHSO Ph), 4.25 (brs, 1H; CHCHSO Ph),
.41 (d, J = 13.2 Hz, 1H; OCHH), 4.70 (d, J = 13.2 Hz, 1H; OCHH),
.79 (brs, 1H; C=CHCH ), 7.00 (dd, J = 7.1, 2.1 Hz, 1H; ArH), 7.08 (d,
3
, 258C, TMS): d = 2.59 (brs, 2H; C=CHCH
2
), 2.96
solid (12 mg, 38%). R
m.p. 1408C; H NMR (300 MHz, CDCl
f
= 0.38 (silica gel, EtOAc/petroleum ether 3:7);
, 258C, TMS): d = 2.34–2.41 (m,
H; C=CHCHH), 2.87 (ddd, J = 15.6, 6.6, 2.1 Hz, 1H; C=CHCHH),
.10–3.39 (m, 1H; ArCH CH), 3.35–3.44 (m, 1H; NC(O)CHCH ), 3.50
dd, J = 9.2, 6.5 Hz, 1H; NC(O)CHCH), 3.78 (dd, J = 16.0, 3.0 Hz, 1H;
ArCHH), 4.04 (dd, J 16.0, 13.2 Hz, 1H; ArCHH), 4.51 (d, J
2.9 Hz, 1H; OCHH), 5.16 (d, J = 12.9 Hz, 1H; OCHH), 6.06 (t, J =
.3 Hz, 1H; C=CHCH ), 7.05 (d, J = 9.3 Hz, 1H; ArH), 7.24–7.54 (m,
H; ArH), 7.62 (d, J = 9 Hz, 1H; ArH), 7.77 (d, J = 7.5 Hz, 1H; ArH),
1
J
=
J =
12 Hz, 1H;
3
2
=
1
3
3
2
2
2
2
2
4
5
(
2
=
=
J = 2.1 Hz, 1H; ArH), 7.13 (d, J = 6.6 Hz, 1H; ArH), 7.30 (d, J =
1
3
7
8
6
7
.9 Hz, 1H; ArH), 7.46–7.53 (m, 3H; ArH), 7.58–7.63 (m, 3H; ArH),
2
1
3
.72 (t, J = 5.6 Hz, 1H; ArH), 7.86–7.88 ppm (m, 4H; ArH); C NMR
, 258C, TMS): d = 21.4, 32.9, 34.4, 55.3, 55.4, 63.1,
(
75.4 MHz, CDCl
3
1
3
3
.08 ppm (d, J = 8.7 Hz, 1H; ArH); C NMR (100.6 MHz, CDCl , 258C,
TMS): d = 24.6, 27.2, 38.0, 40.3, 44.9, 71.7, 118.1, 121.4, 122.7, 123.7,
25.1, 126.6, 126.7, 128.5, 128.7, 128.9, 129.4, 130.0, 131.9, 133.8, 140.4,
7
1
7.3, 106.6, 118.8, 119.3, 122.1, 123.9, 124.4, 126.9, 128.1, 128.8, 128.9,
29.6, 129.7, 131.7, 134.3, 134.5, 136.3, 137.1, 137.6, 156.0, 156.3 ppm; IR
1
1
(
ꢀ1
ꢀ1
(
neat): n˜ = 1308 cm (SO
CHCl ): lmax (e) 250 nm (10706 mol dm cm ); HRMS (Q-Tof
[M+H]: 561.1406; found: 561.1423.
2 2
, asym. st), 1146 cm (SO , sym. st); UV
ꢀ
1
54.8, 177.1, 178.7 ppm; IR (neat): n˜
=
3
1708 cm (C=Ost); UV
ꢀ1
3
ꢀ1
(
3
=
ꢀ1
ꢀ1
CH
m/z calcd for C26
ꢂ)-11,12-Bis-(benzenesulfonyl)-8,10,11,12,12a,13-hexahydro-7-
oxabenzo[5,6]cyclohepta[1,2-a]naphthalene (25): Dienophile 21 (17 mg,
.055 mmol) was added to a solution of the diene 17a (8 mg, 0.036 mmol)
2
Cl
2
): lmax (e) = 244 nm (4334 mol dm cm ); HRMS (Q-Tof ES+):
ES+): m/z calcd for C31
29 6 2
H O S
H
3
22NO [M+H]: 396.1600; found: 396.1602.
[
34]
2
,7-Bis(allyloxy)naphthalene (29): Anhydrous powdered potassium car-
ACHTREUNG
(
bonate (6.9 g, 0.05 mol), allyl bromide (2.5 mL, 31.0 mmol), and a catalyt-
ic amount of tetrabutylammonium hydrogensulfate were added to a solu-
tion of naphthalene-2,7-diol (2 g, 12.5 mmol) in dry acetone (50 mL). The
reaction mixture was then allowed to stir at room temperature for 30 min
and was then filtered through a celite pad. The residue was washed with
dichloromethane (3”30 mL), the solvent was removed under reduced
pressure, and the crude product was purified by flash column chromatog-
raphy (silica gel, EtOAc in petroleum ether, 1.5%) to afford compound
A
C
H
T
R
E
U
N
G
ACHTREUNG
0
in toluene (12 mL) and the mixture was heated (908C, 24 h). The solution
was concentrated under reduced pressure and the crude product was pu-
rified by flash column chromatography (silica gel, EtOAc in petroleum
ether, 35%) to afford DA adduct 25 as a white solid (8 mg, 42%). R
.18 (silica gel, EtOAc/petroleum ether 3:7); m.p. 204–2058C; H NMR
f
=
1
0
(
300 MHz, CDCl
dd, J 15.3, 2.1 Hz, 1H; ArCHH), 3.27 (d, J
CH), 3.69 (dd, J = 15, 12 Hz, 1H; ArCHH), 4.18–4.21 (m, 1H;
CHSO Ph), 4.24 (brs, 1H; CHCHSO Ph), 4.47 (d, J = 13.2 Hz, 1H;
OCHH), 4.74 (d, J = 13.5 Hz, 1H; OCHH), 5.80 (brs, 1H; C=CHCH ),
.16 (d, J = 9 Hz, 1H; ArH), 7.29–7.79 (m, 13H; ArH), 7.84–7.87 ppm
3
, 258C, TMS): d = 2.60 (brs, 2H; C=CHCH
2
), 3.01
2
6
9 as a white, crystalline solid (2.24 g, 75%). M.p. 648C (lit.: 62.5–
38C).
(
=
=
12.3 Hz, 1H;
[34]
ArCH
CH
2
[34]
1
,8-Diallylnaphthalene-2,7-diyl diacetate (30):
Pyridine (173 mg,
2
2
2
2
.19 mmol) and catalytic amount of 4-(dimethylamino)pyridine were
2
added to a solution of 29 (210 mg, 0.88 mmol) in acetic anhydride
1 mL). The reaction mixture was then heated at reflux. After the com-
7
(
1
3
(
m, 2H; ArH); C NMR (100.6 MHz, CDCl
3
, 258C, TMS): d = 21.6,
2.9, 34.4, 55.5, 63.3, 77.3, 119.3, 121.7, 122.9, 123.2, 124.2, 126.4, 128.4,
28.6, 129.0 (2C), 129.8 (2C), 130.6, 133.1, 134.4, 134.5, 136.4, 137.1,
pletion of the reaction (18 h, TLC monitoring), the solvent was removed
under reduced pressure and the crude product was purified by flash
column chromatography (silica gel, EtOAc in petroleum ether, 3%) to
3
1
1
ꢀ
1
ꢀ1
37.7, 157.6 ppm; IR (neat): n˜ = 1309 cm (SO
, sym. st); UV (CHCl ): lmax (e) = 248 nm (6760 mol dm cm );
HRMS (Q-Tof ES+): m/z calcd for C30 [M+H]: 531.1300; found:
31.1307.
ꢂ)-11,12-Bis-(benzenesulfonyl)-3-bromo-8,10,11,12,12a,13-hexahydro-7-
oxa-benzo[5,6]cyclohepta[1,2-a]naphthalene (26): Dienophile 21 (25 mg,
.08 mmol) was added to solution of the diene 17b (17 mg,
.056 mmol) in toluene (10 mL) and the mixture was heated at reflux.
2
, asym. st), 1147 cm
f
afford compound 30 as a white, crystalline solid (225 mg, 79%). R =
ꢀ
1
3
ꢀ1
(
SO
2
3
0
1
.53 (silica gel, EtOAc/petroleum ether 1:19); m.p. 1058C (lit.: 103–
03.58C).
H
27
O
5
S
2
[34]
5
Ring-closing metathesis of 30: Grubbs catalyst 8 (4 mg, 0.005 mmol,
mol%) was added to a solution of diene 30 (31 mg, 0.096 mmol) in dry,
(
5
A
C
H
T
R
E
U
N
G
A
H
R
U
G
degassed DCM (4 mL), and the reaction mixture was allowed to stir at
room temperature. After the completion of the reaction (7 h, TLC moni-
toring), the solvent was removed under reduced pressure, and the crude
product was purified by flash chromatography (silica gel, EtOAc in pe-
troleum ether, 3%) to give 7,10-dihydrocyclohepta[de]naphthalene-1,6-
diyl diacetate (31) as a white, crystalline solid (27 mg, 96%). Rf = 0.43
0
0
a
After the completion of the reaction (48 h, TLC monitoring), the solution
was concentrated under reduced pressure and the crude product was pu-
rified by flash chromatography (silica gel, EtOAc in petroleum ether,
1
3
0%) to afford DA adduct 26 as a white solid (25 mg, 74%). R
f
= 0.2
(silica gel, EtOAc/petroleum ether 1:19); m.p. 202–2038C; H NMR
1
(
silica gel, EtOAc/petroleum ether 3:7); m.p. 2228C; H NMR (300 MHz,
(300 MHz, CDCl , 258C, TMS): d = 2.39 (s, 6H; 2”COCH ), 3.77 (d, J
3
3
CDCl
3
, 258C, TMS): d = 2.59 (brs, 2H; C=CHCH
.6 Hz, 1H; ArCHH), 3.25 (d, J = 12 Hz, 1H; ArCH
5.3, 12 Hz, 1H; ArCHH), 4.16–4.19 (m, 1H; CH CHSO
H; CHCHSO Ph), 4.48 (d, J = 13.2 Hz, 1H; OCHH), 4.74 (d, J =
2.9 Hz, 1H; OCHH), 5.81 (brs, 1H; C=CHCH ), 7.17 (d, J = 8.7 Hz,
H; ArH), 7.32 (d, J = 9.0 Hz, 1H; ArH), 7.39–7.62 (m, 7H; ArH), 7.72
2
), 2.95 (dd, J = 15.3,
CH), 3.68 (dd, J =
Ph), 4.22 (brs,
= 6.0 Hz, 4H; 2”ArCH
2
2
), 6.15 (t, J = 4.2 Hz, 2H; 2”ArCH CH), 7.08
1
3
2
1
1
1
1
2
(d, J = 9.3 Hz, 2H; ArH), 7.63 ppm (d, J = 9 Hz, 2H; ArH); C NMR
(75.4 MHz, CDCl , 258C, TMS): d = 21.0, 25.9, 120.9, 125.9, 128.5, 130.7,
132.2, 134.2, 145.8, 169.7 ppm; IR (neat): n˜ = 1748 cm (C=Ost); UV
2
2
3
ꢀ1
2
ꢀ1
3
ꢀ1
(CHCl
m/z calcd for C18
3
): lmax (e) = 288 nm (6059 mol dm cm ); HRMS (Q-Tof ES+):
Na [M+Na]: 319.0946; found: 319.0956.
2
16 4
H O
1
3
(
(
1
1
t, J
=
7.1 Hz, 1H; ArH), 7.82–7.91 ppm (m, 5H; ArH); C NMR
, 258C, TMS): d = 21.6, 32.9, 34.3, 55.5, 63.2, 77.3,
18.0, 119.6, 123.0, 123.4, 124.7, 127.5, 128.9, 129.0, 129.6, 129.8 (2C),
30.5, 131.7, 131.8, 134.5, 134.6, 136.1, 137.1, 137.6, 157.8 ppm; IR (neat):
RCM of 32a with Grubbs second-generation catalyst 9: Grubbs catalyst
9 (7 mg, 0.008 mmol, 6 mol%) was added to a solution of compound 32a
(32 mg, 0.14 mmol) in dry, degassed DCM (5 mL) and the reaction mix-
ture was then allowed to stir at room temperature. After completion of
the reaction (6 h, TLC monitoring), the solvent was removed under re-
duced pressure and the crude product was purified by flash column chro-
matography (silica gel, EtOAc in petroleum ether, 2%) to afford 2’H-spi-
100.6 MHz, CDCl
3
ꢀ1
ꢀ1
n˜ = 1308 cm (SO
250 nm (9676 mol dm cm ); HRMS (Q-Tof ES+): m/z
Br [M+H]: 609.0405; found: 609.0380.
2 2 3
, asym. st), 1146 cm (SO , sym. st); UV (CHCl ):
ꢀ1
3
ꢀ1
l
max (e)
=
calcd for C30
26 5 2
H O S
Chem. Eur. J. 2006, 12, 8024 – 8038
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8033

S. Kotha et al.
ꢀ
1
ro[cyclopent-3-ene-1,1’-naphthalen]-2’-one (33a) as
23 mg, 83%). R 0.15 (silica gel, EtOAc/petroleum ether 1:49);
H NMR (300 MHz, CDCl , 258C, TMS): d = 2.62 (d, J = 13.8 Hz, 2H;
”CHHCH), 3.17 (d, J = 13.8 Hz, 2H; 2”CHHCH), 5.78 (s, 2H; 2”
a
colorless liquid
(neat): n˜
=
1
1664 cm (C=Ost); UV (CHCl
3
): lmax (e)
=
307 nm
[M] :
ꢀ
3
ꢀ1
+
(
f
=
(5246 mol dm cm ); HRMS (EI): m/z calcd for
196.0888; found: 196.0889.
C
14
H
12
O
1
3
2
Isomerization of 33a to 34 in the presence of Grubbs first-generation cat-
alyst: Grubbs catalyst 8 (9 mg, 0.01 mmol, 10 mol%, added portionwise
at different time intervals) was added to a solution of compound 33a
CHHCH), 6.19 (d, J = 9.9 Hz, 1H; C(O)CH=CH), 7.26–7.30 (m, 2H;
ArH), 7.36–7.39 (m, 2H; ArH), 7.43 ppm (d, J = 9.6 Hz, 1H; ArH);
1
3
C NMR (75.4 MHz, CDCl
3 4
+ CCl , 258C, TMS): d = 49.3, 55.9, 125.1,
(
20 mg, 0.1 mmol) in dry, degassed toluene (5 mL) and the reaction mix-
1
=
25.8, 126.8, 128.1, 128.7, 129, 130.5, 144.9, 149.6, 203.7 ppm; IR (neat): n˜
ture was then heated at reflux. After completion of the reaction (48 h,
TLC monitoring) the solvent was removed under reduced pressure and
the crude product was purified by silica gel column chromatography. Elu-
tion of the column with EtOAc/petroleum ether (2%) gave 2’H-spiro[cy-
clopent-2-ene-1,1’-naphthalen]-2’-one (34) as a colorless liquid (13 mg,
66%) showing the same spectral data as compound 34 obtained by RCM
of 32a.
ꢀ
1
1663 cm
(C=Ost); UV (CHCl
3
):
l
max (e)
=
308 nm
ꢀ1
3
ꢀ1
(
4624 mol dm cm ); HRMS (EI): m/z calcd for
C
14
H
12
O
[M+H]:
1
96.0888; found: 196.0874.
RCM of 32b with Grubbs second-generation catalyst 9: Grubbs catalyst
9
3
(1.5 mg, 0.002 mmol, 2.5 mol%) was added to a solution of compound
2b (22 mg, 0.072 mmol) in dry, degassed DCM (3 mL) and the reaction
mixture was then allowed to stir at room temperature. After completion
of the reaction (2 h, TLC monitoring), the solvent was removed under re-
duced pressure and the crude product was purified by flash column chro-
matography (silica gel, EtOAc in petroleum ether, 2%) to afford 6’-
bromo-2’H-spiro[cyclopent-3-ene-1,1’-naphthalen]-2’-one (33b) as a col-
Palladium/carbon-catalyzed hydrogenation of 33a: Pd (10% on carbon,
13 mg) and freshly distilled ethyl acetate (15 mL) were placed in a three-
necked flask (25 mL). The solvent was saturated with hydrogen (atmos-
pheric pressure) for 30 min, followed by addition of 33a (24 mg,
0.12 mmol) in ethyl acetate (1 mL). After completion of the reaction
(1 h, TLC monitoring), the catalyst was removed by filtration, the filtrate
was concentrated, and the crude product was then purified by silica gel
flash column chromatography. Elution of the column with EtOAc/petro-
leum ether (2%) gave 3’,4’-dihydro-2’H-spiro[cyclopentane-1,1’-naphtha-
len]-2’-one (35) as a colorless liquid (12 mg, 48%). Rf = 0.4 (silica gel,
EtOAc/petroleum ether 1:19); m.p. (2,4-dinitrophenylhydrazone deriva-
orless liquid (18 mg, 91%). R
1
1
f
= 0.2 (silica gel, EtOAc/petroleum ether
:49); H NMR (300 MHz, CDCl , 258C, TMS): d 2.60 (d, J
3.8 Hz, 2H; 2”CHHCH), 3.16 (d, J = 13.5 Hz, 2H; 2”CHHCH), 5.79
CH), 6.25 (d, J = 9.9 Hz, 1H; C(O)CH=CH), 7.26 (d, J
7.8 Hz, 1H; ArH), 7.38 (d, J = 9.9 Hz, 1H; C(O)CH=CH), 7.45–
1
3
=
=
(
s, 2H; 2”CH
2
=
1
3
7
4
2
3
.49 ppm (m, 2H; ArH); C NMR (75.4 MHz, CDCl
9.1, 55.7, 120.3, 126.0, 127.4, 128.5, 129.8, 131.4, 133.1, 143.6, 148.1,
3
, 258C, TMS): d =
[
25]
tive of 35) 118–1198C (lit.: 122–1238C);
Continued elution of the
ꢀ
1
03.6 ppm; IR (neat): n˜ = 1662 cm (C=Ost); UV (CHCl
3
): lmax (e) =
03 nm (6683 mol dm cm ); HRMS (Q-Tof ES+): m/z calcd for
12OBr [M+H]: 275.0072; found: 275.0071.
RCM of 32c with Grubbs second-generation catalyst 9: Grubbs catalyst 9
1.5 mg, 0.002 mmol, 1.8 mol%) was added to a solution of compound
2c (24 mg, 0.094 mmol) in dry, degassed DCM (2 mL) and the reaction
column with the same solvent system gave (ꢂ)-3’,4’-dihydro-2’H-spiro[cy-
ꢀ
1
3
ꢀ1
clopentane-1,1’-naphthalen]-2’-ol (36) as a white, crystalline solid (11 mg,
C
14
H
45%). Rf = 0.1 (silica gel, EtOAc/petroleum ether 1:19); m.p. 708C;
1
H NMR (300 MHz, CDCl
.17 (m, 10H; (CH and CH(OH)CH
ArCHH), 3.15 (td, J = 16.6, 8.1 Hz, 1H; ArCHH), 3.80 (d, J = 4 Hz,
3
, 258C, TMS): d = 1.55 (brs, 1H; OH), 1.75–
2
2
)
4
2
), 2.8 (td, J = 17.2, 6 Hz, 1H;
(
3
1
3
1
H; CHOH), 7.04–7.27 ppm (m, 4H; ArH); C NMR (75.4 MHz,
CDCl , 258C, TMS): d = 25.7, 26.7, 27.3, 27.6, 37.1, 41.9, 51.3, 74.5,
25.5, 126.3, 127.5, 128.6, 134.7, 145.0 ppm; IR (neat): n˜ = 3377 cm (br,
mixture was then allowed to stir at room temperature. After completion
of the reaction (2 h, TLC monitoring), the solvent was removed under re-
duced pressure and the crude product was purified by flash column chro-
matography (silica gel, EtOAc in petroleum ether 2.5%) to afford 6’-me-
thoxy-2’H-spiro[cyclopent-3-ene-1,1’-naphthalen]-2’-one (33c) as a color-
3
ꢀ
1
1
ꢀ
1
3
ꢀ1
OꢀH st); UV (CHCl
tal analysis calcd (%) for C14
.97.
): lmax (e) = 266 nm (574 mol dm cm ); elemen-
18O: C 83.11, H 8.97; found: C 82.78, H
3
H
8
less liquid (20 mg, 94%). R
1
1
f
= 0.05 (silica gel, EtOAc/petroleum ether
:49); H NMR (300 MHz, CDCl , 258C, TMS): d 2.60 (d, J
3.5 Hz, 2H; 2”CHHCH), 3.15 (d, J = 13.8 Hz, 2H; 2”CHHCH), 3.83
), 5.79 (s, 2H; 2”CH CH), 6.22 (d, J 9.9 Hz, 1H;
C(O)CH=CH), 6.81 (d, J = 2.7 Hz, 1H; ArH), 6.92 (dd, J = 8.5, 2.9 Hz,
H; ArH), 7.29 (d, J = 8.4 Hz, 1H; ArH), 7.41 ppm (d, J = 9.9 Hz, 1H;
1
=
=
Palladium/carbon-catalyzed hydrogenation of compound 34: Pd (10% on
carbon, 14 mg) and freshly distilled ethyl acetate (15 mL) were placed in
a three-necked flask (25 mL). The solvent was saturated with hydrogen
(atmospheric pressure) for 30 min, followed by addition of 34 (26 mg,
0.13 mmol) in ethyl acetate (1 mL). After completion of the reaction
(1 h, TLC monitoring), the catalyst was removed by filtration, the filtrate
was concentrated, and the crude product was then purified by silica gel
flash column chromatography. Elution of the column with EtOAc/petro-
leum ether (2%) gave compound 35 (13 mg, 49%) and 36 (11 mg, 42%).
3
(
s, 3H; OCH
3
2
=
1
1
3
C(O)CH=CH); C NMR (75.4 MHz, CDCl
3
, 258C, TMS): d = 49.3, 55.4
(
2C), 113.4, 116.4, 125.3, 126.8, 128.6, 128.8, 141.6, 145.1, 158.1,
ꢀ
1
2
04.0 ppm; IR (neat): n˜ = 1661 cm (C=Ost); UV (CHCl
3
): lmax (e) =
58 nm (9189 mol dm cm ); HRMS (Q-Tof ES+): m/z calcd for
[M+H]: 227.1072; found: 227.1083.
RCM of 32a with Grubbs first-generation catalyst: Grubbs catalyst 8
55 mg, 0.07 mmol, 10 mol%, added portionwise at different time inter-
ꢀ
1
3
ꢀ1
2
C
1
15
H
15
O
2
The H spectral data for these compounds were found to be identical
with those for the earlier reported compounds.
(
Oxidation of compound 36: Compound 36 (10 mg, 0.05 mmol) in anhy-
drous DCM (3 mL) was added in one portion to a vigorously stirred sus-
pension of PCC (15 mg, 0.07 mmol) in anhydrous DCM (10 mL), and stir-
ring was continued at room temperature for 2 h. Anhydrous ether
(50 mL) was added and decanted off, and the black residue was washed
with ether (3”20 mL). The combined ether extracts were concentrated
and the crude product was purified by flash column chromatography.
Elution of the column (silica gel) with EtOAc/petroleum ether (10%)
gave compound 35 (9 mg, 92%) as a colorless liquid showing the same
spectral data as compound 35 obtained by Pd/carbon-catalyzed reduction
of compounds 33a or 34.
vals) was added to a solution of compound 32a (150 mg, 0.7 mmol) in
dry, degassed toluene (15 mL). The reaction mixture was then heated at
reflux for 7 days, the solvent was then removed under reduced pressure,
and the crude product was purified by silica gel column chromatography.
Elution of the column with EtOAc/petroleum ether (2%) gave starting
material (11 mg) and 33a (23 mg, 19%, based on starting material recov-
ered) showing the same spectral data as compound 33a obtained by
RCM of 32a with second-generation Grubbs catalyst 9. Further elution
of the column with EtOAc/petroleum ether (2%) gave 2’H-spiro[cyclo-
pent-2-ene-1,1’-naphthalen]-2’-one (34) as a colorless liquid (41 mg, 34%,
based on starting material recovered). R
f
= 0.1 (silica gel, EtOAc/petro-
leum ether 1:49); H NMR (300 MHz, CDCl + CCl , 258C, TMS): d =
.01–2.09 (m, 1H; CHHCH CH=CH), 2.53–2.78 (m, 3H; CHHCH CH=
CH), 5.54 (dt, J = 5.4, 2.1 Hz, 1H; CH CH=CH), 6.20 (d, J = 9.5 Hz,
H; C(O)CH=CH), 6.23 (dt, J = 5.4, 2.2 Hz, 1H; CH CH=CH), 7.20–
.36 (m, 4H; ArH), 7.46 ppm (d, J 9.8 Hz, 1H; C(O)CH=CH);
, 258C, TMS): d = 32.8, 40.2, 65.9, 125.3,
27.2, 127.4, 129.1, 129.5, 130.4, 133.4, 135.6, 145.4, 146.4, 203.6 ppm; IR
General procedure for the diallylation: A solution of tetralone (1 equiv)
in dry THF (5 mL) was added dropwise with stirring under nitrogen to a
solution of sodium hydride (2.5 equiv) in dry THF (7 mL) in a flame-
dried flask. The allyl bromide (2.5 equiv) was then added and the reac-
tion mixture was stirred at room temperature. After completion (TLC
monitoring), the reaction mixture was quenched with ethyl acetate, dilut-
ed with water, and extracted with diethyl ether (50”3 mL). The organic
layer was washed with water and brine and dried over sodium sulfate,
1
3
4
2
2
2
2
1
7
2
=
1
3
C NMR (75.4 MHz, CDCl
3
1
8034
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8024 – 8038

Diversity-Oriented Approach to Biologically Relevant Molecular Frameworks
FULL PAPER
the crude product was purified by silica gel column chromatography, and
elution of the column with EtOAc/petroleum ether gave the desired dia-
llylated product.
(d, J = 2 Hz, 1H; ArH), 6.89 (dd, J = 8.6, 2 Hz, 1H; ArH), 7.66 ppm
1
3
(d, 1H; J = 8.4 Hz, ArH); C NMR (75.4 MHz, CDCl , 258C, TMS): d
3
= 36.0, 41.8 (2C), 52.3, 55.6, 109.4, 109.5, 115.5, 118.3, 125.4 (2C), 129.9,
ꢀ1
[
35]
133.5, 155.9, 165.6, 207.9 ppm; IR (neat): n˜
=
1654 cm (C=Ost);
2
,2-Diallyl-3,4-dihydronaphthalen-1
A
H
R
U
G
Compound 37a
HRMS (Q-Tof ES+): m/z calcd for C16
18 2
H O [M+H]: 265.1204; found:
(
500 mg, 3.56 mmol) and allyl bromide (0.81 mL, 8.9 mmol) were added
to a solution of sodium hydride (356 mg, 8.9 mmol) in dry THF (7 mL).
The reaction mixture was allowed to stir at room temperature for 4 h,
and the reaction was then worked up with ether (3”50 mL) as described
in the general procedure. Evaporation of the solvent gave the crude
product, which was loaded onto a silica gel column, elution of which with
265.1211.
2,2-Diallyl-5-bromo-2,3-dihydroinden-1-one (40c): 5-Bromoindanone
(38c, 100 mg, 0.48 mmol) and allyl bromide (0.1 mL, 1.18 mmol) were
added to a solution of sodium hydride (47.5 mg, 1.18 mmol) in dry THF
(5 mL). The reaction mixture was allowed to stir at room temperature
for 3 h and the reaction was then worked up with ether (3”50 mL) as de-
scribed in the general procedure. Evaporation of the solvent gave the
crude product, which was loaded onto a silica gel column, elution of
which with EtOAc/petroleum ether (1%) gave compound 40c (90 mg,
EtOAc/petroleum ether (2%) gave compound 39a (515 mg, 66%) as a
1
faint yellow oil. H NMR (400 MHz, CDCl
3
, 258C, TMS): d = 2.02 (t, J
ABq, J = 8.4, 8.0 Hz, 2H; 2”
ABq, J = 10.8, 7 Hz, 2H; 2”CHHCH=CH ),
.98 (t, J = 6.4 Hz, 2H; ArCH ), 5.03–5.16 (m, 4H; CH CH=CH ), 5.72–
.83 (m, 2H; CH CH=CH ), 7.21 (d, J = 7.6 Hz, 1H; ArH), 7.28 (td, J
7.6, 0.8 Hz, 1H; ArH), 7.45 (td, 1H; J = 7.4, 1.4 Hz, ArH), 8.04 (dd, J
7.8, 1.2 Hz, 1H; ArH).
1
=
2 2 2
6.4 Hz, 2H; ArCH CH ), 2.30 (d =
1
CHHCH=CH
2
), 2.5 (d =
2
2
2
5
2
2
2
6
5%) as a pale yellow liquid. R
f
= 0.9 (silica gel, EtOAc/petroleum
1
1
2
2
ether 1:10); H NMR (400 MHz, CDCl
, 258C, TMS): d = 2.30 (d =
ABq,
3
2
=
1
J = 13.4, 8 Hz, 2H; 2”CHHCH=CH
H; 2”CHHCH=CH ), 3.0 (s, 2H; ArCH
CH CH=CH ), 5.51–5.61 (m, 2H; 2”CH CH=CH ), 7.49 (dt, J = 8.0,
2
), 2.44 (d =
2
ABq, J = 13.8, 6.4 Hz,
=
2
2
2
), 4.97–5.09 (m, 4H; 2”
2
,2-Diallyl-6-methoxy-3,4-dihydronaphthalen-1
A
H
R
U
G
2
2
2
2
1
3
thoxytetralone (37b, 200 mg, 1.37 mmol) and allyl bromide (0.37 mL,
0.8 Hz, 1H; ArH), 7.59 ppm (d, J
= 9.2 Hz, 2H; ArH); C NMR
3
3
.43 mmol) were added to
.43 mmol) in dry THF (7 mL), the reaction mixture was allowed to stir
a
solution of sodium hydride (137 mg,
(75.4 MHz, CDCl , 258C, TMS): d = 35.8, 41.8 (2C), 52.5, 118.8 (2C),
3
125.1 (2C), 129.8, 130.3, 131.1, 133.1, 135.7, 154.7, 208.7 ppm; IR (neat):
ꢀ1
at room temperature for 8 h, and the reaction was then worked up with
ether (3”50 mL) as described in the general procedure. Evaporation of
the solvent gave the crude product, which was loaded onto a silica gel
column, and elution of the column with EtOAc/petroleum ether (4%)
15 16
n˜ = 1639 cm (C=Ost); HRMS (Q-Tof ES +): m/z calcd for C H OBr
[M+H]: 291.0385; found: 291.0379.
,2-Diallyl-5,6-dimethoxy-2,3-dihydroinden-1-one (40d): 5,6-Dimethox-
yindanone (38d, 500 mg, 6.5 mmol) and allyl bromide (0.55 mL,
2
gave compound 39b (182 mg, 63%) as a yellow, oily liquid. R
f
= 0.6
6
6
.5 mmol) were added to
.5 mmol) in dry THF (7 mL). The reaction mixture was allowed to stir
a solution of sodium hydride (260 mg,
1
(
silica gel, EtOAc/petroleum ether 1:10); H NMR (400 MHz, CDCl ,
3
1
2
58C, TMS): d = 2.00 (t, J = 6.8 Hz, 2H; ArCH
2
CH
ABq, J = 13.6, 6.8 Hz,
), 2.90 (t, 2H; J = 6.4 Hz, ArCH ), 3.84 (s, 3H;
), 5.04–5.08 (m, 4H; 2”CH CH=CH ), 5.72–5.84 (m, 2H; 2”
2 2
CH=CH ), 6.60 (d, J = 2 Hz, 1H; ArH), 6.80 (dd, J = 8.8, 2 Hz,
2 2
), 2.30 (d = ABq, J
at room temperature for 8 h and the reaction was then worked up with
ether (3”100 mL) as described in the general procedure. Evaporation of
the solvent gave the crude product, which was loaded onto a silica gel
column, elution of which with EtOAc/petroleum ether (5%) gave com-
1
=
14, 7.6 Hz, 2H; 2”CHHCH=CH
2 2
), 2.50 (d =
2
H; 2”CHHCH=CH
2
2
OCH
3
2
2
CH
H; ArH), 8.00 ppm (d, J = 8.8 Hz, 1H; ArH); C NMR (75.4 MHz,
CDCl , 258C, TMS): d = 25.6, 30.7, 39.5 (2C), 47.6, 55.5, 112.4, 113.4
2C), 118.2 (2C), 125.6, 130.5, 134.2, 145.8, 163.5, 199.8 ppm; IR (neat):
pound 40d (505 mg, 71%) as a white, crystalline solid. R
gel, EtOAc/petroleum ether 1:10); m.p. 778C; H NMR (400 MHz,
f
= 0.25 (silica
1
3
1
1
3
1
CDCl
CHHCH=CH
.81 (s, 2H; ArCH
3
, 258C, TMS): d = 2.16 (d =
2
ABq, J = 13.6, 8.4 Hz, 2H; 2”
ABq, J = 13.6, 6.4 Hz, 2H; 2”CH CH=CH ),
), 3.77 (s, 3H; OCH ), 3.83 (s, 3H; OCH ), 4.82–4.95
CH=CH ), 6.73 (s,
, 258C,
(
1
ꢀ1
2
), 2.31 (d =
2
2
2
n˜ = 1671 cm (C=Ost); HRMS (Q-Tof ES +): m/z calcd for C17
M+H]: 229.1228; found: 229.1238.
21 2
H O
2
2
3
3
[
(
m, 4H; 2”CH
2
CH=CH
2
), 5.41–5.51 (m, 2H; 2”CH
2
2
[
36]
2
,2-Diallyl-2,3-dihydroinden-1-one (40a):
Indan-1-one (38a, 500 mg,
13
1
H; ArH), 7.02 ppm (s, 1H; ArH); C NMR (75.4 MHz, CDCl
3
3
.78 mmol) and allyl bromide (0.805 mL, 9.46 mmol) were added to a sol-
TMS): d = 35.6, 41.7 (2C), 52.3, 55.9, 56.0, 104.1, 107.2, 107.3, 118.2,
ution of sodium hydride (378 mg, 9.46 mmol) in dry THF (7 mL), the re-
action mixture was then allowed to stir at room temperature for 4 h, and
the reaction was then worked up with ether (3”100 mL) as described in
the general procedure. Evaporation of the solvent gave the crude prod-
uct, which was loaded onto a silica gel column, elution of which with
EtOAc/petroleum ether (2%) gave compound 40a as a yellow, oily
1
1
29.3, 133.5 (2C), 148.1, 149.4, 155.7, 208.2 ppm; IR (neat): n˜
=
ꢀ1
694 cm (C=Ost); HRMS (Q-Tof ES +): m/z calcd for C17
21 3
H O
[
M+H]: 273.1491; found: 273.1499.
General procedure for the RCM: Grubbs first-generation catalyst (10–
5 mol%) was added to a solution of a diallylated derivative of a sub-
1
strate in dry toluene. The reaction mixture was degassed with nitrogen
for 20 min and then heated at reflux under nitrogen for 48 h. The solvent
was then removed on a rotary evaporator and the resulting crude product
was loaded onto a silica gel column, elution of which with EtOAc/petro-
leum ether gave the RCM product.
f
liquid (593 mg, 74%). R = 0.7 (silica gel, EtOAc/petroleum ether 1:10);
1
1
H NMR (400 MHz, CDCl
.4 Hz, 2H; 2”CHHCH=CH
CHHCH=CH ), 3.03 (s, 2H; ArCH
CH ), 5.54–5.64 (m, 2H; 2”CH CH=CH
ArH), 7.43 (d, J = 8 Hz, 1H; ArH), 7.58 (td, J = 7.4 Hz, 1.2 Hz, 1H;
3
, 258C, TMS): d = 2.31 (d =
2
ABq, J = 13.6,
1
8
2
), 2.45 (d =
2
ABq, J = 13.8, 6.8 Hz, 2H; 2”
), 4.96–5.09 (m, 4H; 2”CH
2
2
2
CH=
2
2
2
), 7.35 (t, J = 7.4 Hz, 1H;
RCM of 2,2-diallyl-3,4-dihydronaphthalen-1(2H)-one (39a): Grubbs
A
H
R
U
G
1
3
ArH), 7.73 ppm (d, J = 7.6 Hz, 1H; ArH); C NMR (75.4 MHz, CDCl
3
,
first-generation catalyst (21.8 mg, 12 mol%) was added to a solution of
diallylated 1-tetralone 39a (50 mg, 0.23 mmol) in dry toluene (5 mL) and
the system was heated at reflux for 48 h. Evaporation of the solvent gave
the crude product, which was loaded onto a silica gel column, elution of
which with EtOAc/petroleum ether (3%) gave compound 41a as a
2
1
58C, TMS): 36.0, 41.6 (2C), 52.1, 118.4 (2C), 123.7 (2C), 126.1, 127.3,
33.3, 134.8, 136.6, 152.8, 209.6 ppm; IR (neat): n˜ = 1711 cm (C=Ost).
ꢀ
1
2
,2-Diallyl-5-methoxy-2,3-dihydroinden-1-one (40b): 5-Methoxyindanone
(
38b, 200 mg, 1.23 mmol) and allyl bromide (0.3 mL, 3.08 mmol) were
added to a solution of sodium hydride (123.5 mg, 3.08 mmol) in dry THF
7 mL). The reaction mixture was allowed to stir at room temperature
yellow, oily liquid (41 mg, 94%). R
f
= 0.7 (silica gel, EtOAc/petroleum
, 258C, TMS): d = 2.07 (t, J =
17.6, 2.4 Hz, 2H; 2”CH=
CHCHH), 2.79 (dd, J = 19.2, 2.4 Hz, 2H; 2”CH=CHCHH), 2.94 (t, J =
6.4 Hz, 2H; ArCH ), 5.56 (s, 2H; CH=CH), 7.13 (d, J = 8 Hz, 1H;
ArH), 7.21 (t, J = 7.6 Hz, 1H; ArH), 7.36 (td, J = 7.2, 1.2 Hz, 1H;
1
(
ether 1:10); H NMR (400 MHz, CDCl
3
for 6 h and the reaction was then worked up with ether (3”50 mL) as de-
scribed in the general procedure. Evaporation of the solvent gave the
crude product, which was loaded onto a silica gel column, elution of
which with EtOAc/petroleum ether (2%) gave compound 40b (208 mg,
2 2
6.4 Hz, 2H; ArCH CH ), 2.29 (dd, J =
2
1
3
7
0%) as a yellow, viscous liquid. R
f
= 0.5 (silica gel, EtOAc/petroleum
3
ArH), 7.98 ppm (d, J = 8 Hz, 1H; ArH); C NMR (75.4 MHz, CDCl ,
258C, TMS): d = 26.2, 35.0, 41.9 (2C), 52.1, 126.8, 128.2, 128.4 (2C),
128.8, 131.8, 133.3, 143.6, 201.4 ppm; IR (neat): n˜ = 1682 cm (C=Ost),
HRMS (Q-Tof ES+): m/z calcd for C14H14O [M+H]: 199.1123; found:
1
1
ether 1:10); H NMR (400 MHz, CDCl
J = 13.4, 8 Hz, 2H; 2”CHHCH=CH
2
5
3
, 258C, TMS): d = 2.29 (d =
2
ABq,
1
ꢀ1
2
), 2.44 (d =
), 2.97 (s, 2H; ArCH
CH=CH ), 5.54–5.64 (m, 2H; 2”CH
2
ABq, J = 13, 6.4 Hz,
H; 2”CHHCH=CH
.09 (m, 4H; 2”CH
2
2
), 3.87 (s, 3H; OCH
3
), 4.96–
), 6.84
2
2
2
CH=CH
2
199.1131.
Chem. Eur. J. 2006, 12, 8024 – 8038
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8035

S. Kotha et al.
RCM of 2,2-diallyl-6-methoxy-3,4-dihydronaphthalen-1
A
H
R
U
G
solvent gave the crude product, which was loaded onto a silica gel
column, elution of which with EtOAc/petroleum ether (6%) gave com-
Grubbs first-generation catalyst (17.6 mg, 11 mol%) was added to a solu-
tion of diallylated 6-methoxytetralone 39b (50 mg, 0.24 mmol) in dry tol-
uene (5 mL) and the system was heated at reflux for 48 h under nitrogen
atmosphere. The solvent was then removed in a rotary evaporator and
the resulting crude product was loaded onto a silica gel column, elution
of which with EtOAc/petroleum ether (2%) gave the RCM product 41b
f
pound 42d (36 mg, 80%) as a white, crystalline solid. R = 0.2 (silica gel,
1
EtOAc/petroleum ether 1:10); m.p. 1538C; H NMR (400 MHz, CDCl3,
258C, TMS): d = 2.33 (d, J = 14.8 Hz, 2H; 2”CH=CHCHH), 2.89 (d, J
= 14.4 Hz, 2H; 2”CH=CHCHH), 3.09 (s, 2H; ArCH ), 3.92 (s, 3H;
2
OCH ), 3.97 (s, 3H; OCH ), 5.73 (s, 2H; CH=CH), 6.86 (s, 1H; ArH),
3
3
1
3
(
40 mg, 90%) as a yellowish liquid. R
f
= 0.4 (silica gel, EtOAc/petrole-
um ether 1:10); H NMR (400 MHz, CDCl , 258C, TMS): d = 2.12 (t, J
6.8 Hz, 2H; ArCH CH ), 2.36 (d, J = 14.8 Hz, 2H; 2”CH=CHCHH),
.87 (d, J = 14.8 Hz, 2H; 2”CH=CHCHH), 2.98 (t, 2H; J = 6.4 Hz,
ArCH ), 3.85 (s, 3H; OCH ), 5.63 (s, 2H; CH=CH), 6.67 (d, J = 1.6 Hz,
H; ArH), 6.83 (dd, J = 8.8, 2.4 Hz, 1H; ArH), 8.03 ppm (d, J = 8 Hz,
7.26 ppm (s, 1H; ArH); C NMR (75.4 MHz, CDCl , 258C, TMS): d =
3
1
3
45.6 (2C), 55.8, 56.22, 56.24, 56.3, 104.8 (2C), 107.5, 128.9 (2C), 148.1,
ꢀ
1
=
2
2
149.7, 155.7, 209.2 ppm; IR (neat): n˜ = 1694 cm (C=Ost); HRMS (Q-
Tof ES +): m/z calcd for C H O [M+H]: 245.1178; found: 245.1185.
2
1
5
17
3
2
3
Naphtho
added to a solution of compound 16a (25 mg, 0.127 mmol) in DMSO
3 mL) and the mixture was heated to 808C for 8 h. The reaction mixture
was then cooled to room temperature, diluted with Et Oand washed
with NaHCO (5%, 2”10 mL), water (2”10 mL), and brine (10 mL) and
A
H
R
U
G
A
H
R
U
1
1
4
2
1
3
H; ArH); C NMR (75.4 MHz, CDCl
3
, 258C, TMS): d = 26.5, 35.1,
(
2.1 (2C), 51.6, 55.5, 112.4, 113.3, 125.2, 128.2 (2C), 130.7, 146.1, 163.5,
2
ꢀ
1
00.4 ppm; IR (neat): n˜ = 1671 cm (C=Ost); HRMS (Q-Tof ES +): m/
[M+H]: 229.1272; found: 229.1268.
3
z calcd for C15
17 2
H O
dried over anhydrous sodium sulfate. Evaporation of the solvent gave the
crude product, which was loaded onto a silica gel column, elution of
which with EtOAc/petroleum ether (5%) gave compound 43 (17 mg,
64%) as a thick, yellow liquid. Rf = 0.2 (silica gel, EtOAc/petroleum
RCM of 2,2-diallyl-2,3-dihydroinden-1-one (40a): Grubbs first-generation
catalyst (19.36 mg, 10 mol%) was added to a solution of diallylated
indan-1-one 40a (50 mg, 0.24 mmol) in dry toluene (5 mL) and the
system was heated at reflux for 48 h. Evaporation of the solvent gave the
crude product, which was loaded onto a silica gel column, elution of
which with EtOAc/petroleum ether (2%) gave compound 42a (32 mg,
1
ether 1:19); H NMR (400 MHz, CDCl , 258C, TMS): d = 4.65 (s, 2H;
3
OCH ), 6.61 (d, J = 12.0 Hz, 1H; COCH=CH), 7.33 (d, J = 8.8 Hz, 1H;
2
ArH), 7.49–7.53 (m, 1H; ArH), 7.61–7.65 (m, 1H; ArH), 7.86–7.89 (m,
8
1%) as a reddish brown, viscous liquid. R
f
= 0.6 (silica gel, EtOAc/pe-
troleum ether 1:10); H NMR (400 MHz, CDCl , 258C, TMS): d = 2.33
d, J = 16 Hz, 2H; 2”CH=CHCHH), 2.91 (d, J = 16 Hz, 2H; 2”CH=
2H; ArH), 8.00 (d, J = 12.8 Hz, 1H; COCH=CH), 7.11 ppm (d, J =
1
13
3
8.4 Hz, 1H; ArH); C NMR (100.6 MHz, CDCl , 258C, TMS): d = 79.3,
3
(
120.7, 121.0, 123.1, 125.5, 128.1, 129.1, 129.8, 130.9, 133.0, 133.4, 137.3,
ꢀ
1
CHCHH), 3.18 (s, 2H; ArCH
2
), 5.73 (s, 2H; CH=CH), 7.40 (td, J = 8.4,
3 max
159.1, 197.5 ppm; IR (neat): n˜ = 1668 cm (C=Ost); UV (CHCl ): l
ꢀ
1
3
ꢀ1
0
0
.4 Hz, 1H; ArH), 7.6 (td, J = 8, 0.8 Hz, 1H; ArH), 7.79 (dd, J = 8,
(e) = 238 nm (6006 mol dm cm ); HRMS (Q-Tof ES+): m/z calcd for
C H O [M+H]: 211.0759; found: 211.0751.
1
3
.8 Hz, 1H; ArH), 7.73 ppm (d,
J = 8 Hz, 1H; ArH); C NMR
1
4
11
2
(
1
1
75.4 MHz, CDCl
3
, 258C, TMS): d = 45.5, 45.6, 55.6, 62.3, 110.1, 124.4,
1
0
,2-Dihydronaphtho
.047 mmol) in dry benzene and ethanol (14 mL, 1:1) in a sealed tube
A
H
E
N
A
H
R
U
G
26.6, 127.6, 128.9, 134.9, 136.4, 152.9, 210.6 ppm; IR (neat): n˜
=
ꢀ
1
710 cm (C=Ost); HRMS (Q-Tof ES +): m/z calcd for C13
H
12ONa
was degassed with nitrogen for 10 mins. Wilkinsonꢁs catalyst (2 mg,
.002 mmol, 5 mol%) was added and hydrogen gas was bubbled for
[
M+Na]: 207.0786; found: 207.0788.
0
RCM of 2,2-diallyl-5-methoxy-2,3-dihydroinden-1-one (40b): Grubbs
first-generation catalyst (23.6 mg, 14 mol%) was added to a solution of
bis-allylated 5-methoxyindanone 40b (50 mg, 0.21 mmol) in dry toluene
10 mins. Finally, the reaction vessel was kept under 1 atm hydrogen pres-
sure and stoppered tightly, and the reaction mixture was then heated at
808C. After completion of the reaction (12 h, TLC monitoring) the pres-
sure was released, the resulting brown solution was concentrated under
reduced pressure, and the crude product was purified by silica gel flash
chromatography. Elution of the column with 5% EtOAc/petroleum ether
gave compound 44 (9 mg, 89%) as a thick, colorless liquid. Rf = 0.2
(
5 mL) and the system was heated at reflux for 48 h. Evaporation of the
solvent gave the crude product, which was loaded onto a silica gel
column, elution of which with EtOAc/petroleum ether (4%) gave com-
pound 42b (40 mg, 93%) as an off-white solid. R
f
= 0.4 (silica gel,
EtOAc/petroleum ether 1:10); m.p. 1128C; H NMR (400 MHz, CDCl
58C, TMS): d = 2.32 (d, J = 15.2 Hz, 2H; 2”CH=CHCHH), 2.89 (d, J
15.2 Hz, 2H; 2”CH=CHCHH), 3.12 (s, 2H; ArCH ), 3.88 (s, 3H;
OCH ), 5.72 (s, 2H; CH=CH), 6.87 (d, J = 2 Hz, 1H; ArH), 6.92 (dd, J
8.6, 2.0 Hz, 1H; ArH), 7.71 ppm (d, J = 8.4 Hz, 1H; ArH); C NMR
75.4 MHz, CDCl , 258C, TMS): d = 45.7 (2C), 45.8, 55.8 (2C), 109.8,
15.5, 126.1, 128.91, 128.93, 129.6, 155.8, 165.6, 209.6 ppm; IR (neat): n˜ =
1
1
3
,
(silica gel, EtOAc/petroleum ether 1:19); H NMR (400 MHz, CDCl3,
2
=
258C, TMS): d = 3.26 (t, J = 6.8 Hz, 2H; ArCH ), 3.48 (t, J = 6.6 Hz,
2
2
2H; ArCH CH ), 4.58 (s, 2H; OCH ), 7.22 (d, J = 8.8 Hz, 1H; ArH),
2
2
2
3
7.27–7.48 (m, 1H; ArH), 7.52–7.57 (m, 1H; ArH), 7.70 (d, J = 8.8 Hz,
1H; ArH), 7.82–7.84 (m, 1H; ArH), 7.90 ppm (dd, J = 8.4, 0.8 Hz, 1H;
1
3
=
1
3
(
3
ArH); C NMR (100.6 MHz, CDCl , 258C, TMS): d = 24.8, 39.5, 79.3,
3
1
1
122.19, 122.22, 123.0, 125.0, 127.0, 128.8 (2C), 131.0, 133.3, 156.2,
ꢀ
1
ꢀ1
703 cm (C=Ost); HRMS (Q-Tof ES +): m/z calcd for C14
15 2
H O
2
2
12.1 ppm; IR (neat) : n˜ = 1727 cm (C=Ost); UV (CHCl
3
): lmax (e) =
ꢀ
1
3
ꢀ1
[
M+H]: 215.1072; found: 215.1070.
38 nm (7377 mol dm cm ); HRMS (Q-Tof ES+): m/z calcd for
[M+H]: 213.0916; found: 213.0907.
,2,3,4-Tetrahydronaphtho[2,1-b]oxepine (45):
4 mg) and freshly distilled ethyl acetate (10 mL) were placed in a three-
RCM of 2,2-diallyl-5-bromo-2,3-dihydroinden-1-one (40c): Grubbs first-
generation catalyst (16.9 mg, 15 mol%) was added to a solution of dially-
lated 5-bromoindanone 40c (40 mg, 0.13 mmol) in dry toluene (5 mL)
and the system was heated at reflux for 48 h. Evaporation of the solvent
gave the crude product, which was loaded onto a silica gel column, elu-
tion of which with EtOAc/petroleum ether (2%) gave compound 42c
14 13 2
C H O
[
37]
1
1
A
H
R
U
G
Pd (10% on carbon,
necked flask (25 mL). The solvent was saturated with hydrogen (atmos-
pheric pressure) for 30 min, followed by addition of 16a (80 mg,
0
.408 mmol) in ethyl acetate (1 mL). After completion of the reaction
(
33 mg, 90%) as a light yellow solid. R
f
= 0.8 (silica gel, EtOAc/petrole-
um ether 1:10); m.p. 838C; H NMR (400 MHz, CDCl , 258C, TMS): d =
.34 (d, J = 14.8 Hz, 2H; 2”CH=CHCHH), 2.88 (d, J = 15.2 Hz, 2H;
”CH=CHCHH), 3.15 (s, 2H; ArCH ), 5.72 (s, 2H; CH=CH), 7.52 (dd,
8, 0.8 Hz, 1H; ArH), 7.62–7.65 ppm (m, 2H; ArH); C NMR
, 258C, TMS): d = 45.1, 45.5 (2C), 55.8, 125.5 (2C),
1
(
6 h, monitored by H NMR), the catalyst was removed by filtration, the
1
3
filtrate was concentrated, and the crude product was then purified by
silica gel flash column chromatography. Elution of the column with
EtOAc/petroleum ether (1.5%) gave compound 45 as a white solid
2
2
J
2
1
3
=
(
f
65 mg, 81%). R = 0.35 (silica gel, EtOAc/petroleum ether 1:49); m.p.
(
75.4 MHz, CDCl
3
[37] 1
6
1
5
8
08C (lit.: 598C);
.88 (m, 2H; ArCH
.8 Hz, 2H; ArCH ), 4.12 (t, J = 5.8 Hz, 2H; OCH
.8 Hz, 1H; ArH), 7.36–7.40 (m, 1H; ArH), 7.46–7.51 (m, 1H; ArH),
H NMR (400 MHz, CDCl
3
, 258C, TMS): d = 1.82–
CH ), 3.26 (t, J =
), 7.20 (d, J =
1
1
28.7, 129.8, 130.2, 131.2, 135.2, 154.5, 209.1 ppm; IR (neat): n˜
=
2
CH ), 1.99–2.08 (m, 2H; OCH
2
2
2
ꢀ
1
706 cm (C=Ost); HRMS (Q-Tof ES +): m/z calcd for C13
H
12OBr
2
2
[
M+H]: 263.0072; found: 263.0067.
RCM of 2,2-diallyl-5,6-dimethoxy-2,3-dihydroinden-1-one (40d): Grubbs
first-generation catalyst (15.1 mg, 10 mol%) was added to a solution of
diallylated 5,6-dimethoxyindanone 40d (50 mg, 0.18 mmol) in dry toluene
7.64 (d, J = 8.8 Hz, 1H; ArH), 7.79–7.81 (m, 1H; ArH), 8.05 ppm (d, J
= 8.4 Hz, 1H; ArH); C NMR (100.6 MHz, CDCl , 258C, TMS): d =
3
25.0, 26.6, 32.1, 73.4, 122.2, 123.4, 124.1, 126.2, 127.6, 128.4, 128.7, 131.0,
1
3
(
5 mL) and the system was heated at reflux for 48 h. Evaporation of the
133.1, 158.4; MS (Q-Tof ES+): m/z = [M+H]: 199.
8036
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8024 – 8038

Diversity-Oriented Approach to Biologically Relevant Molecular Frameworks
FULL PAPER
[
38]
3
,4-Dihydronaphtho
and homogenized mixture of pyridinium chlorochromate (161 mg,
.75 mmol) and celite (2 g) was added to a solution of compound 45
15 mg, 0.075 mmol) in dry benzene (7 mL) and the reaction mixture was
A
C
H
T
R
E
U
N
G
[2,1-b]oxepin-1
A
H
R
U
G
A finely powdered
L. Abraham, Eur. J. Org. Chem. 2002, 1461–1471; c) Y. Chai, S.
Hong, H. A. Lindsay, C. McFarland, M. C. McIntosh, Tetrahedron
2002, 58, 2905–2928; d) U. Nubbemeyer, Synthesis 2003, 961–1008;
e) A. M. Castro, Chem. Rev. 2004, 104, 2939–3002; For selected ex-
amples of Claisen rearrangements see: f) V. A. Smit, S. I. Pogrebnoi,
Y. B. Kal’yan, M. Z. Krimer, Izv. Akad. Nauk SSSR, Ser. Khim.
1990, 1934–1935 [Chem. Abstr. 1990, 114, 23481]; g) S. I. Pogrebnoi,
Y. B. Kal’yan, M. Z. Krimer, V. A. Smit, Izv. Akad. Nauk SSSR, Ser.
Khim. 1991, 835–842 [Chem. Abstr. 1991, 115, 49277]; h) L. M. Har-
wood, A. J. Oxford, C. Thomson, J. Chem. Soc. Chem. Commun.
1991, 1303–1305; i) V. T. Nguyen, S. Debenedetti, N. De Kimpe, Tet-
rahedron Lett. 2003, 44, 4199–4201; j) B. Sreedhar, V. Swapna, C.
Sridhar, Synth. Commun. 2004, 34, 1433–1440; k) L. Abraham, M.
Koerner, M. Hiersemann, Tetrahedron Lett. 2004, 45, 3647–3650.
[12] For a preliminary communication, see: S. Kotha, K. Mandal, Tetra-
hedron Lett. 2004, 45, 1391–1394.
[13] a) P. Schwab, R. H. Grubbs, J. W. Ziller, J. Am. Chem. Soc. 1996,
118, 100–110; b) M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org.
Lett. 1999, 1, 953–956; c) S. B. Garber, J. S. Kingsbury, B. L. Gray,
A. H. Hoveyda, J. Am. Chem. Soc. 2000, 122, 8168–8179.
[14] a) Handbook of Metathesis, Vols. 1–3 (Ed.: R. H. Grubbs), Wiley-
VCH, Weinheim, 2003; For some selected reviews on olefin meta-
thesis, see: b) A. J. Phillips, A. D. Abell, Aldrichimica Acta 1999, 32,
75–89; c) A. Fꢂrstner, Angew. Chem. 2000, 112, 3140–3172; Angew.
Chem. Int. Ed. 2000, 39, 3012–3043; d) T. M. Trnka, R. H. Grubbs,
Acc. Chem. Res. 2001, 34, 18–29; e) S. Kotha, N. Sreenivasachary,
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2001, 40B,
0
(
then stirred and heated at reflux. After completion of the reaction (7 h,
TLC monitoring) the reaction mixture was diluted with diethyl ether
10 mL) and filtered through a short pad of celite and anhydrous magne-
(
sium sulfate. The residue was then washed with diethyl ether (2”10 mL),
the combined ether extracts were concentrated, and the crude product
was purified by silica gel flash column chromatography. Elution of the
column with EtOAc/petroleum ether (5%) gave compound 46 (12 mg,
[
38a] 1
7
5%) as a white solid. M.p. 1358C (lit.: 1388C).
H NMR (400 MHz,
, 258C, TMS): d = 2.30 (tt, J = 6.4, 6.8 Hz, 2H; OCH CH ), 2.98
), 4.34 (t, J = 6.4 Hz, 2H; OCH ), 7.21 (d, J
8.8 Hz, 1H; ArH), 7.40–7.45 (m, 1H; ArH), 7.53–7.56 (m, 1H; ArH),
CDCl
3
2
2
(
t, J = 6.8 Hz, 2H; COCH
2
2
=
7
(
=
.79 (d, J = 7.2 Hz, 1H; ArH), 7.86 (d, J = 8.8 Hz, 1H; ArH), 8.60 ppm
d, J = 8.8 Hz, 1H; ArH); C NMR (100.6 MHz, CDCl
27.9, 42.5, 73.0, 121.1, 124.9, 125.0, 128.3, 128.5, 130.3, 131.1, 133.8,
61.2, 204.3 ppm; IR (neat): n˜ = 1678 cm (C=Ost); HRMS (Q-Tof
ES+): m/z calcd for C14 [M+H]: 213.0916; found: 213.0913.
X-ray crystallographic data for compound 26:
09.53, monoclinic, space group, P2 , a = 12.0280(12), b = 7.7420(8), c
15.197(3) Š, b = 109.823(11)8, V = 1331.3(4) Š , T = 293(2) K, Z =
1
3
3
, 258C, TMS): d
ꢀ
1
1
13 2
H O
C
30
H
25BrO
5
S
2
,
M
=
6
=
1
3
ꢀ1
2
=
, m
A
C
H
T
R
E
U
N
G
(Mo-K
0.0423), observed with I > 2s(I), which were used in all refinements.
= 0.0444, wR = 0.0851 for the observed data.
a
) = 1.741 mm , 2830 reflections measured, 2711 unique (Rint
R
1
2
CCDC-603947 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
7
1
63–780; f) R. R. Schrock, A. H. Hoveyda, Angew. Chem. 2003,
15, 4740–4782; Angew. Chem. Int. Ed. 2003, 42, 4592–4633; g) S. J.
Connon, S. Blechert, Angew. Chem. 2003, 115, 1944–1968; Angew.
Chem. Int. Ed. 2003, 42, 1900–1923; h) R. H. Grubbs, Tetrahedron
2
004, 60, 7117–7140; i) M. D. McReynolds, J. M. Dougherty, P. R.
Hanson, Chem. Rev. 2004, 104, 2239–2258; j) K. C. Nicolaou, P. G.
Bulger, D. Sarlah, Angew. Chem. 2005, 117, 4564–4601; Angew.
Chem. Int. Ed. 2005, 44, 4490–4527. For some related examples in
this area, see: k) A. Srikrishna, M. S. Rao, S. J. Gharpure, N. C.
Babu, Synlett 2001, 1986–1988; l) S. K. Chattopadhyay, S. Maity, S.
Panja, Tetrahedron Lett. 2002, 43, 7781–7783; m) P. Beaulieu, W. W.
Ogilvie, Tetrahedron Lett. 2003, 44, 8883–8885; n) V. T. Nguyen, N.
De Kimpe, Tetrahedron Lett. 2004, 45, 3443–3446; o) S. Kotha, K.
Mandal, Tetrahedron Lett. 2004, 45, 2585–2588; p) T. W. Tsai, E. C.
Wang, S. R. Li, Y. H. Chen, Y. L. Lin, Y. F. Wang, K. S. Huang, J.
Chin. Chem. Soc. 2004, 51, 1307–1318; q) S. K. Chattopadhyay, R.
Dey, S. Biswas, Synthesis 2005, 403–406; r) K. S. Huang, S. R. Li,
Y. F. Wang, Y. L. Lin, Y. H. Chen, T. W. Tsai, C. H. Yang, E. C.
Wang, J. Chin. Chem. Soc. 2005, 52, 159–167; s) V. Gracias, A. F.
Gasiecki, S. W. Djuric, Tetrahedron Lett. 2005, 46, 9049–9052;
t) V. T. H. Nguyen, E. Bellur, P. Langer, Tetrahedron Lett. 2006, 47,
Acknowledgements
We thank the DST for financial support, the SAIF, Mumbai for providing
spectral facilities, and the National Single Crystal X-ray Diffraction Fa-
cility, Mumbai. K. M. and A. T. thank the CSIR, New Delhi for the
award of research fellowships.
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2
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[
[
[
[
[
[
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8038
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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