Novel cyclization cascades to functionalized indanes and tetrahydronaphthalenes

Article abstract of DOI:10.1016/j.tet.2010.03.062

Cyclization cascades involving C-C bond formations followed by lactonization reactions provide fast access to structurally complex tricyclic indane and tetrahydronaphthalene derivatives. Crown Copyright

Full text of DOI:10.1016/j.tet.2010.03.062

Tetrahedron 66 (2010) 6639–6646
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel cyclization cascades to functionalized indanes and tetrahydronaphthalenes
,
Zulfiqar A. Khan a, Michio Iwaoka b, Thomas Wirth a
*
a School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK
b Department of Chemistry, School of Science, Tokai University, Kitakaname, Hiratsuka-shi, Kanagawa 259-1292, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclization cascades involving C–C bond formations followed by lactonization reactions provide fast
access to structurally complex tricyclic indane and tetrahydronaphthalene derivatives.
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Received 11 January 2010
Received in revised form 24 February 2010
Accepted 15 March 2010
Available online 30 March 2010
Keywords:
Carbocyclizations
Cascade reactions
Indanes
Iodine
Tetrahydronaphthalenes
1. Introduction
2. Results and discussion
The formation of new carbon–carbon bonds by carbocyclizations
has been an attractive area of research and proven to be a useful tool
for the synthesis of carbocyclic molecules.1 The medicinal importance
of molecules possessing indane2 and 1,2,3,4-tetrahydronaphthalene
moieties3 is well documented. Strigolactones are a group of sesqui-
terpene lactones and their synthetic analogues can act as hormone
stimulants for seed-germination/symbiotic fungi and even as shoot
branching inhibitors.4 Indane derivatives have also been used as
versatile ligands in asymmetric ruthenium catalyzed transfer hy-
drogenation reaction of ketones.5 There are various methods avail-
ablefor thesynthesis of indane and tetrahydronaphthalene skeletons.
Common routes for the synthesis of tetrahydronaphthalenes are by
hydrogenation of naphthalenes,6 by Friedel–Crafts alkylations,7 by
dehydration of alcohols,8 or by gold-catalyzed benzannulations of 3-
hydroxy-1,5-enynes.9 Indane and tetrahydonaphthalene can also be
synthesized by reduction of indanones and 3,4-dihydronaphthalen-
1(2H)ones.10 Straightforward approaches for the synthesis of indanes
are [3þ2] cycloadditions of benzyl cations with styrenes11 or palla-
dium catalyzed intramolecular carboannulation reactions.12 How-
ever, some drawbacks present in these classical methods include the
use of expensive transition metal catalysts, the use of strong acidic
conditions or sometimes highreaction temperatures. Therefore, facile
and effective methods for the synthesis of indanes and tetrahy-
dronaphthalenes are still sought after.
Recently we have reported the synthesis of indene derivatives
by iodine mediated endo-cyclizations of malonate moieties onto
alkynes.13 In our efforts towards the synthesis of carbocycles we
report herein the synthesis of indane and 1,2,3,4-tetrahydronaph-
thalene derivatives by iodine mediated carboannulations of
stilbene derivatives with a subsequent cascade reaction leading
to indene and tetrahydronaphthalene-based tricyclic lactone
derivatives.
The stilbene derivatives used in this investigation were syn-
thesized from 2-iodobenzyl alcohol 1 by mesylation and addition of
dimethylmalonate to give derivative 2, followed by a Heck reaction
to 3 similar to compounds prepared for selenium mediated cycli-
zations (Scheme 1).14 Alternatively, a Heck reaction can be per-
formed using ethyl 2-iodobenzoate. After reduction with lithium
aluminium hydride a similar sequence of mesylation and reaction
with dimethylmalonate can be carried out to provide compounds of
type 3.
1. MsCl
2. NaH,
Pd(OAc)2
Ar
dimethyl-
malonate
CO2Me
CO2Me
Ar
CO2Me
CO2Me
OH
I
I
1
2
3
Scheme 1. Synthesis of the cyclization precursors 3.
* Corresponding author. E-mail address: wirth@cf.ac.uk (T. Wirth).
0040-4020/$ – see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.062

6640
Z.A. Khan et al. / Tetrahedron 66 (2010) 6639–6646
Different reagent combinations were screened to find optimal
these two hydrogen atoms. Such sequences have already been
reported.20 A subsequent SN1 type substitution is very unlikely under
the reaction conditions and should lead to the thermodynamically
favoured trans-isomer (the cis-isomer 4ais about 0.22 kcal/mol higher
in energy).21 Under the reaction conditions we suggest an activation of
the iodine in A by reaction with an iodonium cation followed by
a reductive elimination of B towards the tricyclic lactone derivative 4a
as shown in Scheme 2. This is regarded as a ligand coupling of the
substituents on the iodine with retention of configuration, which can
alsobeobserved with otherhypervalentcompounds22 and with metal
catalysts.23 The close proximity tothe phenyl substituent as evidenced
by the X-ray structure (Fig. 1) leads to a high-field shift of proton H9,
reaction conditions for the iodine-mediated carbocyclization of 3a.
Compound 3a (Ar¼Ph) was treated with NaHfollowed byaddition of
ICl and heated at reflux for one hour, which resulted in the formation
of some addition of iodine monochloride to the double bond, but
carbocyclic products were notobtained (Table 1, entry 1). Reaction of
compound 3a with iodine and pyridine led to the complete recovery
of starting material (Table 1, entry 2). When compound 3a was
treated with bis(trifluoroacetoxyiodo)benzene, an unidentified
mixture of products was formed (Table 1, entry 3). Reaction of 3a
with sodium hydride followed by iodine15 resulted in the formation
of two products, 4a and 5a in 70% combined yield (Table 1, entry 4).
which is observed at
isomer 4a could be explained by an initial diiodination of alkene 3a
d
¼5.57 ppm. Alternatively, the observed cis-
Table 1
followed by two subsequent SN2 reactions.
Cyclization of 3a to indene 4a and tetrahydronaphthalene 5a
CO2Me
1.5 equiv NaH
1.5 equiv I2
CO2Me
CO2Me
Ph
CO2Me
O
1.5 equiv NaH
1.5 equiv I2
CO2Me
O
Ph
H
O
H
CO2Me
CO2Me
Ph
+
THF, reflux
O
O
H
O
THF, reflux
H
H
Ph
H
3a
Ph
4a
5a
3a
4a
Entry Reagent
Base
Time [h]a Yield of 4a [%] Yield of 5a [%]
CO2Me
IŠ
1
2
3
4
5
6
ICl
I2
NaH
Pyridine
d
1
3
0
0
0
52
48
28
0
0
0
18
15
34
CO2Me
CO2Me
O Me
I+
PhI(OCOCF3)2
16b,c
1.5
30b
4.5
H
O
H
H
I2
I2
I2
NaH
I+
Ph
KOtBu
K2CO3
I
H
I
Ph
a
b
c
Reaction performed at 65 ꢀC.
Reaction performed at 20 ꢀC.
The reaction was carried out in dichloromethane instead of THF.
A
B
Scheme 2. Suggested mechanism for the formation of 4a.
The reaction of the (Z)-stilbene derivative 3a0 under identical
reaction conditions led to the tricyclic lactone 4a0 as shown in
Scheme 3. The reaction of 3 to 4 is a stereospecific reaction and in
additional experiments it was confirmed that no epimerization is
taking place under the reaction conditions. Related compounds to 4
have been synthesized recently using lithiated aryloxiranes and
alkylidene malonates.24 Compound 3a was epoxidized with mCPBA
in 95% yield and the resulting epoxide 6 treated with potassium tert-
butoxide in tert-butanol. After re-esterification using methanol and
sulfuric acid the compounds 4a and 4a0 were obtained in 46% overall
yield as shown in Scheme 3. Under the reaction conditions, however,
epimerization occurred towards the thermodynamically more sta-
ble isomer 4a0 and a mixture of 4a and 4a0 (ratio 1:2) was isolated.
The same two products 4a and 5a were observed when
exchanging the base to potassium tert-butoxide and performing the
reaction at room temperature (Table 1, entry 5). tert-Butyl hypo-
iodite16 is formed upon reaction of iodine with potassium tert-but-
oxide, a versatile reagent for electrophilic17 but also for radical
functionalizations.18 Using a weaker base such as potassium car-
bonate (Table 1, entry 6) resulted in an increased amount of cycliza-
tion product 5a.
The products 4a and 5a, resulting from either an initial 5-exo-trig
cyclization leading to 4a, or a 6-endo-trig cyclization leading to 5a
can be separated by column chromatography. Both compounds are
formed as single diastereomers as judged from their NMR spectra.
Product 4a is a colourless crystalline compound and the stereo-
chemistry was confirmed by X-ray analysis as shown in Figure 1.19
CO2Me
O
CO2Me
CO2Me
1.5 equiv NaH
1.5 equiv I2
O
H
H
Ph
THF, reflux
Ph
3a'
4a'
1. t-BuOK
t-BuOH
CO2Me
O
CO2Me
CO2Me
Ph
2. H+, MeOH
+ 4a'
O
H
O
CO2Me
CO2Me
H
Ph
6
4a
H
Ph
HO
H
Scheme 3. Mechanistic investigations towards cyclization products 4a and 4a0.
Figure 1. X-ray structure of 4a and optimized structure 5a by calculation.
The cis-relationship between hydrogens H11 and H13 is remark-
able. Therefore, the reaction sequence cannot consist of an iodo-
carbocyclizationfollowedbyanSN2substitutionoftheiodinewithone
of the ester moieties, as this would lead to a trans-arrangement of
NOE experiments of compound 5a suggest an axial position of
the phenyl substituent, as irradiation at H10 resulted only in an
NOE at H1. Furthermore, the calculated structure 5a (Fig. 1)
indicated a dihedral angle H1–C–C–H10 of 50ꢀ, whereas calculations

Z.A. Khan et al. / Tetrahedron 66 (2010) 6639–6646
6641
of the stereoisomer with an equatorial phenyl substituent showed
a dihedral angle of 88ꢀ. The coupling constant between H1 and H10
was determined to be J¼3.0 Hz, which, according to the Karplus
equation, matches with a torsion angle of 50ꢀ. In addition, ab-initio
calculations of the NMR shifts of the two different stereoisomers
showed best correlation with isomer 5a providing further proof of
the structure. The cis-arrangement of the hydrogens H1 and H10 is
noteworthy, as such an isomer cannot be formed by a simple SN2
displacement of the iodine in C after the initial iodocyclization
reaction. In order to account for the observed stereochemistry, we
suggest the activation of the iodine in C by another iodine elec-
trophile and a participation of the phenyl substituent. This will lead
to the intermediate phenonium ion D, which is then opened to 5a
as shown in Scheme 4. The involvement of phenonium ions in
iodine mediated cyclizations has already been reported.25
3c (R¼1-naphthyl, Table 2, entry 3) and 3e (R¼2-Cl–C6H4, Table 2,
entry 5) with a ratio of about 1:3 for the exo/endo cyclization.
In conclusion, we have developed cyclization cascades of stilbene
derivatives with iodine electrophiles, which afforded novel indane
and tetrahydonaphthalene compounds in a one-pot reaction from
simple starting materials. We report an intramolecular carbon–
carbon bond formation promoted by iodine electrophiles via either
5-exo- or 6-endo-trig cyclizations and a detailed investigation of the
subsequent lactonization with a unique stereochemical outcome.
The synthetic potential of the novel structures is presently being
explored.
3. Experimental section
3.1. 1-Vinylnaphthalene26
A
mixture of CH3PPh3Br (12.9 mmol, 4.61 g) and KOtBu
1.5 equiv NaH
1.5 equiv I2
CO2Me
(14 mmol, 1.57 g) in dry toluene (30 mL) was stirred at 0 ꢀC for
30 min and at rt for 4 h. The reaction mixture was cooled to 0 ꢀC
followed by addition of 1-naphthaldehyde (11.8 mmol, 1.84 g). The
reaction mixture was stirred overnight at rt. The solvent was
evaporated under reduced pressure. The crude product was puri-
fied by column chromatography using hexane as eluent to yield
(11.8 mmol, 1.81 g, quantitative) 1-vinylnaphthalene as colourless
oil. The spectroscopic data are in agreement with literature.26
CO2Me
CO2Me
Ph
Ph
H
O
H
THF, reflux
O
3a
5a
CO2Me
CO2Me
CO2Me
O
Me
O
3.2. General procedure for Heck reactions (GP1)27
I
C
D
A mixture of methyl 2-iodobenzoate (15 mmol, 4.0 g), styrene
(18.0 mmol, 1.87 g), triethylamine (32.0 mmol, 4.4 mL), palladium
acetate (0.48 mmol, 323 mg) and triphenylphosphine (0.96 mmol,
251 mg) were heated under reflux at 110 ꢀC for 5 h. Solid products
were isolated by diluting the reaction mixtures with 200 ml of 10%
aq hydrochloric acid with stirring to dissolve the salts and excess
amine. The crude product was extracted with ethyl acetate
(3ꢁ20 mL). The combined organic phases were dried with MgSO4
and evaporated under reduced pressure. Finally, the crude product
was purified by column chromatography (EtOAc/hexane 1:12).
Scheme 4. Suggested mechanism for the formation of 5a.
In order to further evaluate the scope of this reaction a range of
different substituted compounds 3 were prepared according to
Scheme 1 and subjected to similar reaction conditions. The prod-
ucts 4 and 5 are formed in this reaction with consistent good overall
yields (47–79%). Depending on the substituent, different ratios of
4:5 have been observed as shown in Table 2.
Table 2
Cyclization of stilbenes 3 to indanes 4 and tetrahydronaphthalenes 5
3.3. (E)-Methyl 2-styrylbenzoate28
1.5 equiv NaH
CO2Me
CO2Me
CO2Me
R
CO2Me
O
1.5 equiv I2
THF, reflux
R
O
The title compound was obtained according to GP1 and isolated
+
as yellow oil in 87% yield (13.2 mmol, 3.15 g) after purification. 1H
H
O
R
O
H
H
NMR (500 MHz, CDCl3):
d
¼8.03 (1H, d, J¼16.0 Hz, CH]CH–Ph), 7.97
H
(1H, d, J¼8.0 Hz, Ar–H), 7.76 (1H, d, J¼8.0 Hz), 7.60 (2H, d, J¼7.5 Hz),
7.54 (1H, t, J¼8.0 Hz), 7.31–7.42 (4H, m), 7.04 (1H, d, J¼16.0 Hz,
CH]CH–Ph), 3.96 (3H, s, COOCH3) ppm; 13C NMR (125 MHz,
3
4
5
Entry
R
Time [h] Yield of 4 [%] Yield of 5 [%] Ratio 4:5
CDCl3):
d
¼167.9, 139.3, 137.5, 132.2, 131.5, 130.7, 128.7 (2ꢁC), 128.6,
1
2
3
4
5
6
7
3a: Ph
1.5
3
3.5
3
3
3
52
53
18
55
20
37
47
18
24
55
19
59
37
0
3:1
127.9, 127.5, 127.2, 127.0, 126.9 (2ꢁC), 52.2 ppm. The spectroscopic
3b: 4-Me–C6H4
3c: 1-Naphthyl
3d: 2-Naphthyl
3e: 2-Cl–C6H4
3f: 4-Cl–C6H4
2:1
1:3a
3:1
data are in agreement with literature.28
1:3a
1:1a
1:0
3.4. (E)-Methyl 2-(4-methylstyryl)benzoate14
3g: 2,6-Cl2–C6H3 2.5
a
The product mixture of 4 and 5 could not be separated, ratio determined by 1
H
The title compound was obtained according to GP1 as colourless
NMR spectroscopy.
crystals in 80% yield (12 mmol, 3.02 g) after purification.
Mp: 74 ꢀC; (lit. mp: 74 ꢀC);14 1H NMR (500 MHz, CDCl3):
d¼7.87
The ratio of exo cyclization (leading to 4) and endo-cyclization
(leading to 5) is influenced by the nature of the substituent R. The
preference of an exo-cyclization overan endo-cyclization is found for
most substrates. The ortho-disubstituted derivative 3g leading
exclusively to the exo-cyclized product 4g (Table 2, entry 7) could be
seen as another proof for the mechanism depicted in Scheme 3. The
formation of a phenonium intermediate is not possible with 3g.
Compounds 3 with one substituent in the ortho-positionwere found
to react preferentially via an endo-cyclization route as evidenced by
(1H, d, J¼16.2 Hz), 7.84 (1H, d, J¼8.0 Hz), 7.64 (1H, d, J¼8.0 Hz),
7.44 (1H, t, J¼7.5 Hz), 7.37 (2H, d, J¼8.0 Hz), 7.23 (1H, t, J¼7.5 Hz),
7.10 (2H, d, J¼7.5 Hz), 6.92 (1H, d, J¼16.2 Hz, CH]CH), 3.85 (3H, s,
COOCH3), 2.29 (3H, s, ArCH3) ppm; 13C NMR (125 MHz, CDCl3):
d
¼168.0, 139.4, 137.8, 134.7, 132.1, 131.4, 130.7, 129.4 (2ꢁC), 128.5,
127.0, 126.9, 126.8 (2ꢁC), 126.4, 52.1, 21.3 ppm; IR ( ):¼3041, 2936,
n
1761, 1715, 1591, 1510, 1289, 1255, 1242, 1126, 1073, 962, 804,
740 cmꢂ1. HRMS (ESI): m/z [MþH]þ calcd for C17H17O2: 253.1223;
found: 253.1222.

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Z.A. Khan et al. / Tetrahedron 66 (2010) 6639–6646
3.5. General procedure for the reduction of 2-substituted
stilbenes (GP2)1b,29,30
d
¼168.9 (2ꢁC), 140.2, 139.8, 130.5, 128.8, 128.4, 100.4, 52.6, 51.6,
39.4 (2ꢁC) ppm; IR (
n
): 2951, 1735, 1467, 1434, 752 cmꢂ1; Spec-
troscopic data are in agreement with literature.32
A solution of the corresponding ester (9 mmol) in dry diethyl
ether (20 mL) was added to suspension of LiAlH4 (10.8 mmol,
410 mg) in dry diethyl ether (100 mL) at 0 ꢀC. After stirring for 2 h,
the reaction was quenched with aq Na2SO4 solution (20 mL). After
drying the organic phase with MgSO4 the residue was purified by
flash chromatography with petroleum ether/ethyl acetate (4:1) as
eluent to give corresponding alcohols in good yields.
3.10. (E)-Dimethyl 2-(2-styrylbenzyl)malonate (3a)
The title compound was prepared by GP3 starting from corre-
sponding alcohol (9.52 mmol, 2 g) as yellow oil in 40% yield
(3.79 mmol, 1.23 g).
1H NMR (500 MHz, CDCl3):
d
¼7.64 (1H, d, J¼8.0 Hz), 7.57 (2H, d,
J¼8.0 Hz), 743–7.39 (3H, m), 7.32–7.29 (2H, m), 7.22 (2H, d,
J¼7.5 Hz) 7.04 (1H, d, J¼16.0 Hz), 3.73–3.70 (m, 7H, CH2CH- and
2ꢁCOOCH3), 3.43 (2H, d, CH2CH) ppm; 13C NMR (125 MHz, CDCl3):
3.6. (E)-(2-Styrylphenyl)methanol14
The title compound was obtained according to GP2 by the
reaction of corresponding ester (9 mmol, 2.2 g) with LiAlH4
(10.8 mmol, 0.41 g) to give 92% yield (8 mmol, 1.74 g) of the alcohol
as colourless crystals after purification.
d
¼169.3 (2ꢁC), 137.4, 136.4, 135.5, 131.2, 130.2, 128.8 (2ꢁC), 127.9,
127.8, 127.5, 126.7 (2ꢁC), 126.1, 125.4, 52.9, 52.7, 32.4 (2ꢁC) ppm; IR
(n): 3022, 2944, 2840, 1739, 1595, 1491, 1436, 1341, 1280, 1228, 1155,
1025, 965, 762, 693 cmꢂ1
;
HRMS (ES): [MþNH4]þ calcd for
Mp: 103 ꢀC; (lit. mp: 103 ꢀC);14 1H NMR (500 MHz, CDCl3):
C20H24NO4: 342.1700; found: 342.1702.
d
¼7.69 (1H, d, J¼7.5 Hz), 7.56 (2H, d, J¼7.5 Hz), 7.48 (1H, d,
J¼16.2 Hz, CH]CH–Ph), 7.42–7.30 (6H, m), 7.04 (1H, d, J¼16.2 Hz,
3.11. (E)-Dimethyl 2-(2-(4-methylstyryl)benzyl)malonate (3b)
CH]CH–Ph), 4.86 (2H, s, CH2OH) ppm; 13C NMR (125 MHz, CDCl3):
d
¼137.9, 137.4, 136.4, 131.3, 128.7 (2ꢁC), 128.6, 128.3, 127.9, 127.8,
The title compound was prepared by GP3 starting from corre-
sponding alcohol (7.5 mmol, 1.68 g) as yellow oil in 53% yield
(3.96 mmol, 1.34 g).
126.7 (2ꢁC), 126.0, 125.4, 63.7 ppm. Spectroscopic data are in
agreement with literature.31
1H NMR (500 MHz, CDCl3):
d
¼7.52 (1H, d, J¼7.5 Hz), 7.36 (2H, d,
3.7. (E)-(2-(4-Methylstyryl)phenyl)methanol14
J¼8.0 Hz), 7.26 (1H, d, J¼16.0 Hz), 7.17–7.15 (2H, m), 7.11 (3H, d,
J¼7.5 Hz), 6.92 (1H, d, J¼16 Hz), 3.62–3.60 (m, 7H, CH2CH– and
2ꢁCOOCH3), 3.32 (2H, d, J¼7.5 Hz), 2.29 (3H, s) ppm; 13C NMR
The title compound was obtained according to GP2 by the
reaction of corresponding ester (9 mmol, 2.2 g) with LiAlH4
(10.8 mmol, 0.41 g) gave 88% yield (7.9 mmol, 1.78 g) as colourless
crystals after purification.
(125 MHz, CDCl3):
d
¼169.3 (2ꢁC), 137.8, 136.5, 135.4, 134.7, 131.1,
130.2, 129.5 (2ꢁC), 127.6 (2ꢁC), 127.4, 126.6, 126.0, 124.4, 52.9, 52.6,
32.4 (2ꢁC), 21.3 ppm; IR (
n): 3024, 2953, 1750, 1736, 1511, 1435,
Mp: 127 ꢀC; (lit. mp: 127 ꢀC);14 1H NMR (400 MHz, CDCl3):
1023 cmꢂ1; HRMS: [MþNH4]þ calcd for C21H26NO4: 356.1856;
d
¼7.57 (1H, d, J¼7.2 Hz), 7.35 (2H, d, J¼8.0 Hz), 7.30–7.19 (4H, m),
7.11–7.09 (2H, m), 6.95 (1H, d, J¼16.0 Hz), 4.75 (2H, s, CH2OH), 2.29
(3H, s, ArCH3) ppm; 13C NMR (125 MHz, CDCl3):
¼137.80, 137.75,
136.6, 134.6, 131.2 (2ꢁC), 129.4, 128.6, 128.3, 127.6, 126.6 (2ꢁC),
found: 356.1855.
d
3.12. (E)-Dimethyl 2-(2-(2-(naphthalen-1-yl)-
vinyl)benzyl)malonate (3c)
125.9, 124.3, 63.7, 21.3 ppm; IR (
n
):¼3356, 3276, 3025, 2917, 2863,
1512, 1478, 1044 cmꢂ1; HRMS calcd for C16H20ON: 242.1539; found:
242.1540.
The title compound was prepared by Heck reaction of com-
pound 2 (1.43 mmol, 0.5 g) with 1-vinylnaphthalene (1.71 mmol,
0.26 g) according to GP1 as yellow oil in 89% yield (1.25 mmol,
0.47 g).
3.8. General procedure for the synthesis of malonate
derivatives (GP3)
1H NMR (500 MHz, CDCl3):
d
¼8.14 (1H, d, J¼8.0 Hz), 7.80 (1H, d,
J¼7.5 Hz), 7.75–7.70 (3H, m), 7.65 (1H, d, J¼7.5 Hz), 7.48–7.42 (3H,
m), 7.33 (1H, d, J¼16.0 Hz), 7.25–7.15 (3H, m), 3.65 (1H, t, J¼7.5 Hz,
CH2CH), 3.58 (6H, s, 2ꢁCOOCH3), 3.35 (2H, d, J¼7.5 Hz) ppm; 13C
To a solution of the corresponding alcohol (7.0 mmol) in CH2Cl2
(25 mL) were added Et3N (9.0 mmol, 0.9 g) and methanesulfonyl
chloride (8.0 mmol, 0.91 g) at 0 ꢀC. After being stirred for 1 h at rt
the mixture was poured into 10% aq HCl (15 mL) and extracted with
ether (3ꢁ15 mL). The combined organic phases were dried on
MgSO4 and evaporated under reduced pressure. The mesylate was
dissolved in dry THF (5 mL) and added to a solution of NaH (60% in
mineral oil, 9.0 mmol, 0.36 g) and dimethylmalonate (9 mmol,
1.18 g) in THF (30 mL), then the reaction mixture was heated at
reflux for 6–36 h. The mixture was poured into 10% aq HCl (15 mL)
and extracted with ether (3ꢁ20 mL). The combined ether extracts
were dried over MgSO4 and evaporated under reduced pressure.
The residue was subjected to flash chromatography (12:1 hexane/
EtOAc) to give the malonate derivatives.
NMR (125 MHz, CDCl3):
131.4, 130.2, 128.7, 128.6, 128.4, 128.3, 127.9, 127.5, 126.5, 126.2,
d
¼169.2 (2ꢁC), 136.8, 135.6, 135.0, 133.8,
125.9, 125.8, 123.9, 123.8, 52.9, 52.6, 32.3 (2ꢁC) ppm; IR (
n): 3032,
2925, 2851, 1750, 1736, 1437, 1221 cmꢂ1; HRMS: [MþNH4]þ calcd
for C24H26NO4: 392.1856; found: 392.1858.
3.13. (E)-Dimethyl 2-(2-(2-(naphthalen-2-yl)-
vinyl)benzyl)malonate (3d)
The title compound was prepared by Heck reaction of com-
pound 2 (1.43 mmol, 0.5 g) with 2-vinylnaphthalene (1.71 mmol,
0.26 g) according to GP1 as colourless crystalline solid in 76% yield
(1.09 mmol, 0.41 g).
3.9. Dimethyl 2-(2-iodobenzyl)malonate (2)32
Mp: 133–134 ꢀC; 1H NMR (500 MHz, CDCl3):
d
¼7.91–7.81 (5H,
The title was prepared according to GP3 by the reaction of 2-
iodobenzyl alcohol 1 (11 mmol, 2.85 g) in 68% yield (8.28 mmol,
2.88 g) as colourless oil.
m), 7.71 (1H, d, J¼8.0 Hz), 7.57 (1H, d, J¼16 Hz), 7.50 (2H, t, J¼7.5
Hz), 7.34–7.26 (3H, m), 7.24 (1H, d, J¼16 Hz), 3.77 (1H, t, J¼8.0 Hz,
CH2CH), 3.73 (6H, s, 2ꢁCOOCH3), 3.49 (2H, d, J¼7.5 Hz) ppm; 13C
1H NMR (500 MHz, CDCl3):
d¼7.84 (1H, d, J¼8.0 Hz), 7.28–7.24
NMR (125 MHz, CDCl3):
d
¼169.3 (2ꢁC), 136.4, 135.6, 134.9, 133.7,
(2H, m), 6.93 (1H, t, J¼8.0 Hz), 3.88 (1H, t, J¼7.8 Hz), 3.72 (6H, s,
133.2, 131.3, 130.3, 128.4, 128.1, 127.82, 127.75, 127.5, 126.9, 126.4,
126.09,126.05,125.8, 123.6, 53.0, 52.6, 32.4 (2ꢁC) ppm; IR ( ): 3031,
COOCH3), 3.35 (2H, d, J¼7.8 Hz) ppm; 13C NMR (125 MHz, CDCl3):
n

Z.A. Khan et al. / Tetrahedron 66 (2010) 6639–6646
6643
2924, 2851, 1751, 1733, 1436, 1220 cmꢂ1; HRMS: [MþNH4]þ calcd
(3 equiv)) were used as bases instead of NaH (Table 1, entries 5
and 6).
for C24H26NO4: 392.1856; found: 392.1858.
3.14. (E)-Dimethyl 2-(2-(2-chlorostyryl)benzyl)malonate (3e)
3.18. rac-(3S,3aR,8aS)-Methyl 1-oxo-3-phenyl-3,3a,8,8a-
tetrahydro-1H-indeno[2,1-c]furan-8a-carboxylate (4a)
The title compound was prepared by a Heck reaction of com-
pound 2 (1.43 mmol, 0.5 g) with 2-chlorostyrene (1.71 mmol,
237 mg) according to GP1 as yellow oil in 73% yield (1.06 mmol,
0.38 g).
The title compound was prepared by using compound 3a
(0.19 mmol, 62 mg) as starting material according to GP4 as col-
ourless crystalline solid in 52% yield (0.097 mmol, 30 mg).
1H NMR (500 MHz, CDCl3):
d
¼7.77 (1H, d, J¼8.0 Hz), 7.69 (1H, d,
Mp: 131 ꢀC; 1H NMR (CDCl3, 500 MHz):
(3H, d, J¼7.5 Hz), 7.07 (1H, t, J¼7.5 Hz), 6.72 (1H, t, J¼7.5 Hz), 6.08 (1H,
d, J¼6.3 Hz), 5.57 (1H, d, J¼8.0 Hz), 4.41 (1H, d, J¼6.3 Hz), 3.85 (3H, s,
COOCH3), 3.64–3.62 (2H, m, CH2) ppm; 13C NMR (CDCl3, 125 MHz):
d
¼7.30–7.28 (3H, m), 7.12
J¼7.5 Hz), 7.44–7.40 (3H, m), 7.32–7.28 (3H, m), 7.26–7.22 (2H, m),
3.73–3.71 (7H, m, CH2CH- and 2ꢁCOOCH3), 3.44 (2H, d, J¼7.5 Hz)
ppm; 13C NMR (125 MHz, CDCl3):
d¼169.2 (2ꢁC),136.2, 135.7, 135.5,
133.5, 130.2, 129.9, 128.7, 128.2, 128.1, 127.5, 127.2, 127.0, 126.8,
d
¼175.4, 169.3, 141.0, 135.7, 134.9, 128.7, 128.43, 128.40 (2ꢁC), 126.8,
126.5, 53.0, 52.6, 32.2 (2ꢁC) ppm; IR (
n): 3063, 3015, 2954, 2928,
126.4, 126.2 (2ꢁC),124.6, 83.0, 62.5, 56.9, 53.5, 39.2 ppm; IR (
n): 3066,
2870, 1740,1723, 1483,1251,1161 cmꢂ1; HRMS: [MþNH4]þ calcd for
2917, 2947,1775,1734,1481,1436,1247,1150 cmꢂ1;HRMS: [MþNH4]þ
C20H23ClNO4: 376.1310; found: 376.1315.
calcd for C19H20NO4: 326.1387; found: 326.1390.
3.15. (E)-Dimethyl 2-(2-(4-chlorostyryl)benzyl)malonate (3f)
3.19. (1S,4S,10S)-Methyl 3-oxo-10-phenyl-1,3,4,5-tetrahydro-
1,4-methanobenzo[c]oxepine-4-carboxylate (5a)
The title compound was prepared by a Heck reaction of com-
pound 2 (1.43 mmol, 0.5 g) with 4-chlorostyrene (1.71 mmol,
237 mg) according to GP1 as yellow oil in 72% yield (1.04 mmol,
358 mg).
The title compound was prepared by using compound 3a
(0.19 mmol, 62 mg) as starting material according to GP4 as yellow
oil in 18% yield (0.033 mmol, 11 mg).
1H NMR (CDCl3, 500 MHz):
d
¼7.52 (1H, d, J¼7.5 Hz), 7.39 (2H, d,
J¼8.5 Hz), 7.31–7.26 (3H, m), 7.14–7.11 (3H, m), 6.89 (1H, d,
J¼16 Hz), 3.62–3.60 (7H, m, CH2CH– and 2ꢁCOOCH3), 3.32 (2H, d,
1H NMR (CDCl3, 500 MHz):
d
¼7.39–7.37 (3H, m), 7.32–7.20 (6H,
m), 5.49 (1H, d, J¼3 Hz), 4.31 (1H, d, J¼3.0 Hz), 3.80–3.45 (2H, m),
3.55 (3H, s, COOCH3) ppm; 13C NMR (CDCl3, 125 MHz):
¼175.3,
170.0, 140.7, 139.9, 139.0, 128.9, 128.8 (2ꢁC), 128.5, 128.1, 125.2
J¼7.5 Hz) ppm; 13C NMR (125 MHz, CDCl3):
d¼169.2 (2ꢁC), 136.0,
d
135.9, 135.6, 133.4, 130.2, 129.8, 128.9 (2ꢁC), 128.0, 127.9 (2ꢁC),
126.1 (2ꢁC), 52.9, 52.7, 32.3 (2ꢁC) ppm; IR (
n
): 3028, 2952, 2844,
(2ꢁC), 125.1, 123.9, 86.0, 60.5, 60.0, 53.2, 40.5 ppm; IR (
n): 2954,
1749, 1736, 1599, 1435, 1229 cmꢂ1; HRMS: [MþNH4]þ calcd for
2923, 1784, 1736, 1625, 1541, 1247, 1035 cmꢂ1; HRMS: [MþNH4]þ
calcd for C19H20NO4: 326.1387; found: 326.1390.
C20H23ClNO4: 376. 1310; found: 376.1314.
NOE Experiment on compound 5a: The proton at 4.31 ppm (H1)
was irradiated and only a 4.93% enhancement in the signal for
proton at 5.49 ppm (H10) was observed.
3.16. (E)-Dimethyl 2-(2-(2,6-dichlorostyryl)benzyl)-
malonate (3g)
The title compound was prepared by Heck reaction of com-
pound 2 (1.43 mmol, 0.5 g) with 2,6-dichlorostyrene (1.71 mmol,
296 mg) according to GP1 as yellow oil in 66% (0.37 g) as a yellow
crystalline solid.
3.20. (3S,3aR,8aS)-Methyl 1-oxo-3-(p-tolyl)-3,3a,8,8a-
tetrahydro-1H-indeno[1,2-c]furan-8a-carboxylate (4b)
The title compound was prepared by using compound 3b
(0.19 mmol, 64 mg) as starting material according to GP4 as col-
ourless crystalline solid in 53% yield (0.1 mmol, 32 mg).
Mp: 82–83 ꢀC; 1H NMR (500 MHz, CDCl3):
d¼7.69 (1H, d,
J¼8.0 Hz), 7.35 (1H, d, J¼16.5 Hz), 7.29 (2H, d, J¼8.0 Hz, Ar–H), 7.24–
7.12 (3H, m), 7.05 (1H, dd, J¼8.0 Hz), 6.95 (1H, d, J¼16.5 Hz), 3.69
(1H, t, J¼6.5 Hz), 3.61 (6H, s, COOCH3), 3.29 (2H, d, J¼6.5 Hz) ppm;
Mp: 136 ꢀC; 1H NMR (CDCl3, 500 MHz):
(2H, d, J¼7.5 Hz), 6.74 (1H, t, J¼7.5 Hz), 6.05 (1H, d, J¼6.5 Hz), 5.64
(1H, J¼7.5 Hz), 4.38 (1H, d, J¼6.5 Hz), 3.84 (3H, s, COOCH3), 3.58–3.63
(2H, m), 2.32 (3H, s, ArCH3) ppm; 13C NMR (CDCl3, 125 MHz):
d
¼7.13–7.08 (4H, m), 6.99
13C NMR (125 MHz, CDCl3):
d
¼169.2 (2ꢁC), 136.2, 135.7, 134.61,
134.57, 134.1, 130.3, 128.6 (2ꢁC), 128.33, 128.25, 127.5, 126.6, 125.3,
52.8, 52.6, 32.3 (2ꢁC) ppm; IR (
n): 3063, 3015, 2954, 2928, 2841,
d
¼175.4, 169.4, 141.0, 138.5, 135.8, 131.8, 129.1 (2ꢁC), 128.3, 126.9,
1740, 1723, 1578, 1483, 1251, 1222 cmꢂ1
C20H22O4Cl2N: 410.0920; found: 410.0926.
; HRMS: calcd for
126.4,126.2 (2ꢁC),124.5, 83.1, 62.5, 56.9, 53.5, 39.2, 21.3 ppm; IR (
n):
3025, 2956, 2925, 2853, 1770, 1735, 1431, 1252 cmꢂ1; HRMS:
[MþNH4]þ calcd for C20H22NO4: 340.1543; found: 340.1539.
3.17. General procedure for the double cyclization to indanes
and tetrahydronaphthalenes (GP4)
3.21. (1S,4S,10S)-Methyl 3-oxo-10-(p-tolyl)-1,3,4,5-tetrahydro-
1,4-methanobenzo[c]oxepine-4-carboxylate (5b)
Sodium hydride (0.285–0.475 mmol [1.5–2.5 equiv]) was
added to a solution of stilbene malonate (0.19 mmol) in THF
(15 mL) and the reaction mixture was stirred for five minutes at
rt. Iodine (0.285–0.475 mmol [1.5–2.5 equiv]) was added to the
reaction mixture, which was then heated at reflux for 1.5–3.5 h.
The reaction mixture was cooled to rt and a saturated solution
of Na2S2O3 (10 mL) was added. The aqueous layer was extracted
with ether (2ꢁ15 mL). The combined organic phases were
washed with water (2ꢁ5 mL) and brine (4 mL). After evaporation
of the solvent in vacuum the crude mixture was purified by
flash chromatography (EtOAc/hexane 1:20). For some experi-
ments KOtBu (0.285 mmol (1.5 equiv)) and K2CO3 (0.57 mmol
The title compound was prepared by using compound 3b
(0.19 mmol, 64 mg) as starting material according to GP4 as yellow
oil in 24% yield (0.043 mmol, 14.0 mg).
1H NMR (CDCl3, 500 MHz):
d
¼7.27–7.24 (5H, m), 7.17–7.08(3H, m),
5.44 (1H, d, J¼3.0 Hz), 4.29 (1H, d, J¼3.0 Hz), 3.85 (3H, s, COOCH3),
3.83–3.60 (2H, m), 2.31 (s, 3H, ArCH3) ppm; 13C NMR (CDCl3,
125 MHz):
d
¼175.3, 170.1, 140.8, 139.9, 138.3, 136.0, 129.5 (2ꢁC),128.8,
128.1,125.2 (2ꢁC),125.1,123.9, 86.2, 60.7, 60.0, 53.2, 40.5, 21.2 ppm;IR
(n
): 2952, 2924, 1780, 1739, 1608, 1516, 1435, 1246 cmꢂ1; HRMS:
[MþNH4]þ calcd for C20H22NO4: 340.1543; found: 340.1539.

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Z.A. Khan et al. / Tetrahedron 66 (2010) 6639–6646
3.22. (3R,3aS,8aR)-Methyl 3-(naphthalen-1-yl)-1-oxo-
3,3a,8,8a-tetrahydro-1H-indeno[1,2-c]furan-8a-carboxylate
(4c) and (1S,4S,10S)-Methyl 10-(naphthalen-1-yl)-3-oxo-
1,3,4,5-tetrahydro-1,4-methanobenzo[c]oxepine-4-
carboxylate (5c)
4f:5f is 1:1 (NMR). IR (n): 3063, 3028, 2951, 2853, 1778, 1736, 1598,
1493, 1458, 1434, 1411, 1247, 1148 cmꢂ1; HRMS: [MþNH4]þ calcd for
C19H19ClNO4: 360.0997; found: 360.1003.
3.27. (3S,3aR,8aS)-Methyl 3-(2,6-dichlorophenyl)-1-oxo-
3,3a,8,8a-tetrahydro-1H-indeno[1,2-c]furan-8a-carboxylate
(4g)
The title compounds were prepared by using compound 3c
(0.19 mmol, 71 mg) as starting material according to GP4 as an oil in
72% yield (0.134 mmol, 49 mg) as an inseparable mixture. Ratio of
4c:5c is 18:55 (NMR).
The title compound was prepared by using compound 3g
(0.19 mmol, 75 mg) as starting material according to GP4 as col-
ourless crystalline solid in 47% yield (0.087 mmol, 33 mg).
IR (n): 3055, 2953, 2927, 2853, 1790, 1729, 1601, 1512, 1435,
1246 cmꢂ1; HRMS: [MþNH4]þ calcd for C23H22NO4: 376.1543;
Mp: 151 ꢀC; 1H NMR (CDCl3, 500 MHz):
7.15–7.11 (3H, m), 7.00 (1H, d, J¼8.0 Hz), 6.78 (1H, t, J¼8.0 Hz), 6.65
(1H, d, J¼8.0 Hz), 5.95 (1H, d, J¼7.5 Hz), 4.66 (1H, d, J¼8.0 Hz), 3.85
(3H, s, COOCH3), 3.83–3.67 (2H, m) ppm; 13C NMR (CDCl3,125 MHz):
d
¼7.35 (1H, d, J¼8.0 Hz),
found: 376.1545.
3.23. (3R,3aS,8aR)-Methyl 3-(naphthalen-2-yl)-1-oxo-
3,3a,8,8a-tetrahydro-1H-indeno[1,2-c]furan-8a-carboxylate
(4d)
d
¼175.1, 169.6, 141.4, 136.9, 136.3, 134.5, 133.8, 130.5, 130.1, 128.4,
128.1,126.7,124.9,124.5, 80.9, 61.2, 54.6, 53.7, 39.4 ppm; IR (n): 3029,
2952, 2928, 1775, 1747, 1560, 1436, 1284 cmꢂ1; HRMS calcd for
C19H14Cl2O4: 376.0264; found: 376.0265.
The title compound was prepared by using compound 3d
(0.19 mmol, 71 mg) as starting material according to GP4 as col-
ourless crystalline solid in 55% yield (0.10 mmol, 37 mg).
3.28. (E)- and (Z)-1-Bromo-2-(2-phenylethenyl)benzene
Mp: 183 ꢀC; 1H NMR (CDCl3, 500 MHz):
d
¼7.82–7.70 (4H, m),
7.66 (1H, s), 7.48–7.42 (2H, m), 7.18 (1H, d, J¼8.0 Hz) 7.13 (1H, d,
J¼7.5 Hz), 7.04 (1H, t, J¼7.5 Hz), 6.25 (1H, d, J¼6.5 Hz), 5.54 (1H, d,
J¼8.0 Hz), 4.50 (1H, d, J¼6.5 Hz), 3.87 (3H, s, COOCH3), 3.70–3.65
To a stirred solution of benzyltriphenylphosphonium chloride
(10 mmol, 3.9 g) in dry THF (40 mL) at 0 ꢀC n-BuLi (2.5 M solution in
hexane, 10 mmol, 4 mL) was added dropwise. The red solution was
stirred for 0.5 h. A solution of 2-bromobenzaldehyde (10 mmol,
1.9 g) in dry THF (5 mL) was added dropwise. The reaction solution
was warmed to room temperature and stirred for 1 h. After addi-
tion of water (100 mL), the reaction mixture was extracted with
ethyl acetate (3ꢁ30 mL). The organic phases were dried with
MgSO4, evaporated under reduced pressure and purified by flash
chromatography using petroleum ether as eluent to give the
product in 93% yield (9.57 mmol, 2.48 g) as colourless oil containing
a mixture of (E)- and (Z)-isomer (1:2.1).
(2H, m, CH2) ppm; 13C NMR (CDCl3, 125 MHz):
d
¼175.4, 169.3, 141.0,
135.6, 133.3, 133.0, 132.3, 128.4, 128.18, 128.16, 127.9, 126.8, 126.6,
126.56, 126.50, 125.5, 124.6, 123.9, 83.2, 62.6, 56.8, 53.6, 39.2 ppm;
IR (
n
): 3068, 2917, 2947, 1777, 1732, 1479 cmꢂ1; HRMS: [MþNH4]þ
calcd for C23H22NO4: 376.1543; found: 376.1546.
3.24. (1S,4S,10S)-Methyl 10-(naphthalen-2-yl)-3-oxo-1,3,4,5-
tetrahydro-1,4-methanobenzo[c]oxepine-4-carboxylate (5d)
The title compound was prepared by using compound 3d
(0.19 mmol, 71 mg) as starting material according to GP4 as yellow
oil in 19% yield (0.036 mmol, 13 mg).
(Z)-1-Bromo-2-(2-phenylethenyl)benzene: 1H NMR (CDCl3,
500 MHz):
d
¼6.73 (1H, d, J¼12.1 Hz), 6.66 (1H, d, J¼12.1 Hz), Rest of
signals merged in aromatic region with E substrate; IR (n): 3152,
1H NMR (CDCl3, 500 MHz):
(3H, m), 7.50–7.45 (3H, m), 7.34–7.23 (1H, m), 7.34–7.23 (3H, m), 5.66
d
¼7.88 (1H, d, J¼8.0 Hz), 7.83–7.80
3057, 2969, 2920, 1597, 1558, 1322 cmꢂ1. The spectroscopic data are
in agreement with literature.33
(1H, d, J¼3.0 Hz), 4.39 (1H, d, J¼3.0 Hz), 3.78–3.47 (2H, m), 3.49 (3H,
s, COOCH3) ppm; 13C NMR (CDCl3, 125 MHz):
d¼175.4, 170.0, 140.7,
3.29. (E) and (Z)-1-Formyl-2-(2-phenylethenyl)benzene
140.0, 136.2, 133.14, 133.10, 129.0, 128.9, 128.14, 128.10, 127.8, 126.8,
126.6, 125.1, 124.3, 123.9, 122.8, 86.1, 60.6, 60.0, 53.2, 40.5 ppm; IR
The Grignard reagent was prepared by refluxing 1-bromo-2-(2-
phenylethenyl) benzene (3.86 mmol, 1 g) and magnesium turnings
(4.16 mmol, 0.1 g) in dry THF (20 mL) for 2 h. A solution of DMF
(0.5 mL) in THF (5 mL) was added slowly. The reaction mixture was
allowed to cooled to room temperature. The reaction mixture was
further stirred for 3 h. The reaction mixture was quenched with aq
NH4Cl (15 mL) and extracted with diethyl ether (2ꢁ20 mL). The
combined organic phases were dried over anhydrous Na2SO4 and
then evaporated under reduced pressure. The crude product was
purified by flash chromatography (ethyl acetate/hexane 1:10) and
obtained in 68% yield (2.59 mmol, 0.54 g) as a yellow oil containing
(E) and (Z)-isomers in a ratio of 1: 2.1.
(n ;
): 3056, 2952, 2932, 2856, 1780, 1736, 1603, 1434, 1245 cmꢂ1
HRMS: [MþNH4]þ calcd for C23H22NO4: 376.1543; found: 376.1546.
3.25. (3S,3aR,8aS)-Methyl 3-(2-chlorophenyl)-1-oxo-3,3a,8,8a-
tetrahydro-1H-indeno[1,2-c]furan-8a-carboxylate (4e) and
(1S,4S,10R)-Methyl 10-(2-chlorophenyl)-3-oxo-1,3,4,5-
tetrahydro-1,4-methanobenzo[c]oxepine-4-carboxylate (5e)
The title compounds were prepared by using compound 3e
(0.19 mmol, 68 mg) as starting material according to GP4 as oil in
79% yield (0.147 mmol, 51 mg) as an inseparable mixture. Ratio of
4e:5e is 20:59 (NMR).
(Z)-Isomer: 1H NMR (500 MHz, CDCl3): 10.14 (1H, s, CHO) ppm;
13C NMR (125 MHz, CDCl3): 192.1 (C]O) ppm; E-isomer: 1H NMR
IR (n
): 3062, 2952, 2847,1785,1733,1435,1244,1099 cmꢂ1; HRMS:
[MþNH4]þ calcd for C19H19ClNO4: 360.0997; found: 360.1002.
(500 MHz, CDCl3):
CDCl3):
signals are merged. IR (n): 3081, 3060, 3024, 2957, 2930, 2857, 2745,
d
¼10.20 (1H, s, CHO) ppm; 13C NMR (125 MHz,
d
¼192.7 (C]O) ppm; Other signals of (E)- and (Z)-isomers
3.26. (3S,3aR,8aS)-Methyl 3-(4-chlorophenyl)-1-oxo-3,3a,8,8a-
tetrahydro-1H-indeno[1,2-c]furan-8a-carboxylate (4f) and
(1S,4S,10S)-Methyl 10-(4-chlorophenyl)-3-oxo-1,3,4,5-
tetrahydro-1,4-methanobenzo[c]oxepine-4-carboxylate (5f)
1695, 1596, 1566, 1494, 1446, 1193, 697 cmꢂ1. The spectroscopic
data are in agreement with literature.34
3.30. (E) and (Z)-2-(Styrylphenyl)methanol
The title compounds were prepared by using compound 3f
(0.19 mmol, 68 mg) as starting material according to GP4 as oil in
74% yield (0.134 mmol, 48 mg) as an inseparable mixture. Ratio of
Sodium borohydride (4.71 mmol, 0.17 g) was added to a solution
of (E)- and (Z)-1-formyl-2-(2-phenylethenyl)-benzene (3.12 mmol,

Z.A. Khan et al. / Tetrahedron 66 (2010) 6639–6646
6645
0.65 g) in dry ethanol (30 mL) at 0 ꢀC. The reaction mixture was
stirred for 16 h at rt. The reaction was cooled to 0 ꢀC and aq HCl
(1 M, 15 mL) was added carefully. The reaction mixture was
extracted with diethyl ether (3ꢁ20 mL). The combined organic
phases were washed with brine, dried with Na2SO4 and evaporated
under reduced pressure. The crude product was purified by flash
chromatography (ethyl acetate/hexane 1:10) and the product (E/Z
1:2.1) was obtained in 97% yield (2.95 mmol, 0.62 g) as colourless
oil.
were washed with brine (3ꢁ5 mL), dried with Na2SO4 and con-
centrated under reduced pressure. The crude was purified by flash
chromatography (ethyl acetate/hexane 1:10). The title compound
4a0 was obtained as a mixture with compound 4a (2:1) in 46%
overall yield (0.082 mmol, 25 mg).
1H NMR (500 MHz, CDCl3):
d
¼6.80 (2H, m, Ar–H), 5.64 (1H, d,
J¼5.0 Hz), 4.64 (1H, d, J¼5.0 Hz), 3.88 (3H, s, –COOCH3) ppm; 13C
NMR (125 MHz, CDCl3):
d
¼80.6, 56.0, 53.3, 49.8, 29.0 ppm. Other
signals are merged with compound 4a. IR (n): 3034, 2953, 2851,
(Z)-Isomer: 1H NMR (500 MHz, CDCl3):
Ar–CH]CH–Ph); 6.58 (1H, d, J¼12.2 Hz, Ar–CH]CH–Ph), 4.55 (2H,
s, –CH2OH) ppm; 13C NMR (125 MHz, CDCl3):
¼63.5 (CH2OH) ppm;
): 3381, 3064,
d¼6.65 (1H, d, J¼12.2 Hz,
1781, 1735, 1559, 1436, 1282, 1229, 1154, 1110 cmꢂ1; HRMS: [MþH]þ
calcd for C19H17O4: 309.1121; found: 309.1126.
d
Other signals of (E)- and (Z)-isomers are merged. IR (
n
3.34. Calculations
3021, 2920, 2851, 1597, 1559, 1443, 1040 cmꢂ1. HRMS: [MꢂH]þ calcd
for C15H13O: 209.0972; found: 209.0970.
Ab initio calculations were performed by using Gaussian 03
program (revision B.04).35 Geometries were fully optimized at
B3LYP/6-31G(d) level, and the obtained energy minimum struc-
tures were characterized by frequency calculation at the same
calculation level. The energies were corrected with zero-point
energies. The NMR chemical shifts were calculated at B3LYP/6-
31G(d) level by the Gauge-Independent Atomic Orbital (GIAO)
method36 using an NMR keyword.
3.31. (E)-and (Z)-Dimethyl 2-(2-styrylbenzyl)malonate
The title compound was prepared according to GP3 starting
from (E)- and (Z)-isomer of the corresponding alcohol (2.76 mmol,
0.58 g) in 28% yield (0.77 mmol, 0.25 g) as a colourless oil.
(Z)-Isomer: 1H NMR (500 MHz, CDCl3):
d
¼6.73 (1H, d, J¼12.2 Hz,
Ar–CH]CH–Ph); 6.69 (1H, d, J¼12.2 Hz, Ar–CH]CH–Ph), 3.70 (6H,
s, COOCH3), 3.28 (2H, d, J¼8.0 Hz, CH2) ppm; 13C NMR (125 MHz,
Acknowledgements
CDCl3):
d
¼32.82 (–CH2OH), 52.5 (OCH3), 52.6 (CH[COOMe]2), 169.3
(C]O) ppm. Other signals of (E)- and (Z)-isomers signals are
We thank the Higher Education Commission, Pakistan, for
support, the EPSRC National Mass Spectrometry Service Centre,
Swansea, for mass spectrometric data and Dr. B. Kariuki, Cardiff
University, for the X-ray analysis of 4a.
merged. IR (n): 3060, 3024, 2952, 2847, 1754, 1735, 1495, 1436, 1276,
1229, 1151 cmꢂ1; HRMS: [MþH]þ calcd for C20H21O4: 325.1434;
found: 325.1441.
3.32. Procedure for the synthesis of dimethyl 2-2(2-(3-
phenyloxiran-2-yl)benzyl)malonate (6)
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.03.062.
To a solution of compound 3a (1.26 mmol, 428 mg) in chloro-
form (20 mL) mCPBA (1.89 mmol, 423 mg) was added. The reaction
mixture was stirred at rt for 16 h. To the reaction mixture aq satd
NaHCO3 (2ꢁ15 mL) was added and extracted with diethyl ether
(3ꢁ20 mL). The combined organic phases were washed with brine,
dried with Na2SO4, evaporated under reduced pressure and sub-
jected to column chromatography (ethyl acetate/hexane 1:20). The
title compound was obtained in 95% yield (1.20 mmol, 410 mg) as
colourless oil.
References and notes
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1H NMR (500 MHz, CDCl3):
d¼7.42–7.36 (5H, m, Ar–H), 7.32–
7.26 (3H, m, Ar–H), 7.21 (1H, d, J¼7.4 Hz), 4.10 (1H, d, J¼1.9 Hz), 3.80
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CDCl3):
d
¼169.1, 169.0, 136.8, 135.8, 135.5, 129.5, 128.6, 128.4, 128.0,
127.5, 125.6, 124.7, 62.2, 60.4, 52.59, 52.55, 31.4 ppm; IR (n): 3070,
3033, 2953, 2847, 1754, 1734, 1575, 1491, 1456, 1435, 1282, 1232,
1153 cmꢂ1; HRMS: [MþNH4]þ calcd for C20H24O5N: 358.1649;
found: 358.1652.
3.33. (3S,3aS,8aR)-Methyl 1-oxo-phenyl-3,3a,8,8a-tetrahydro-
1H-indeno[2,1-c]furan-8a-carboxylate (4a0)
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(0.18 mmol, 61 mg) in t-BuOH (3 mL). The reaction mixture was
stirred for 6 h. The reaction mixture was quenched with aq 1 M HCl
(2ꢁ5 mL) and extracted with ethyl acetate (3ꢁ5 mL). The combined
organic phases were washed with brine (3ꢁ5 mL), dried with
Na2SO4 and evaporated under reduced pressure. The crude product
was dissolved in MeOH (6 mL) and treated with a catalytic amount
of concd H2SO4 in the presence of molecular sieves (4 Å). The
reaction mixture was stirred at rt for 24 h. The reaction mixture was
filtered. The filtrate was quenched with water (10 mL) and extrac-
ted with ethyl acetate (3ꢁ10 mL). The combined organic phases
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