Application of Nazarov type electrocyclization to access [6,5,6] and [6,5,5] core embedded new polycycles: An easy entry to tetrahydrofluorene scaffolds related to Taiwaniaquinoids and C-nor-D homosteroids

Article abstract of DOI:10.1039/c0ob00892c

An easy, efficient and concise approach to tetrahydrofluorene [6,5,6]ABC tricyclic core embedded new polycycles has been achieved under relatively mild and catalytic Nazarov type electrocyclization conditions, using 2 mol% of Sc(OTf)₃ in anhydr

Full text of DOI:10.1039/c0ob00892c

Organic &
Biomolecular
Chemistry
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Volume 9 | Number 13 | 7 July 2011 | Pages 4697–4988
ISSN 1477-0520
FULL PAPER
Ritesh Singh and Gautam Panda
Application of Nazarov type
electrocyclization to access [6,5,6]
and [6,5,5] core embedded new
polycycles
1477-0520(2011)9:13;1-V

Organic &
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PAPER
Application of Nazarov type electrocyclization to access [6,5,6] and [6,5,5]
core embedded new polycycles: an easy entry to tetrahydrofluorene scaffolds
related to Taiwaniaquinoids and C-nor-D homosteroids†‡
Ritesh Singh and Gautam Panda*
Received 18th October 2010, Accepted 12th January 2011
DOI: 10.1039/c0ob00892c
An easy, efficient and concise approach to tetrahydrofluorene [6,5,6]ABC tricyclic core embedded new
polycycles has been achieved under relatively mild and catalytic Nazarov type electrocyclization
conditions, using 2 mol% of Sc(OTf)3 in anhydrous DCM (dichloromethane) at room temperature, with
high yields. The generality of the reaction has been illustrated by synthesizing diverse polycycles
embedded with rare heterotricyclic [6,5,5]ABC skeletons.
Introduction
Tetra-(and hexa-) hydrofluorene cores form an unusual [6,5,6]ABC
tricyclic skeleton, found in Taiwaniaquinoids,1 a class of natural
products (Fig. 1) which are rather uncommon in nature. During
the past decade, several of its members have received special
attention among organic chemists owing to their bioactivities;
for example Standishinal, obtained from the stem bark of Thuja
standishii,3 has demonstrated aromatase inhibitory activities
whereas Taiwaniaquinones A,1a D1b and Taiwaniaquinols A,1a
C1d are known to exhibit significant antitumor promoting activity
against KB epidermoid carcinoma cancer cells. Besides, the [6,5,6]
carbotricyclic core also features in steroidal alkaloids of C-nor-
D-homo systems like jervine, veratramine and cyclopamines2a
showing significant biological properties viz. severe teratogenic
effects2b and inhibition of hedgehog signaling pathway activities.2c
In light of such promising bioactivities and the structural
intrigue of tetra-(and hexa-) hydrofluorene skeleton, these classes
of terpenoids and steroidal alkaloids have attracted diverse
synthetic strategies towards total synthesis as well as construc-
tion of the unique tetra-(and hexa-) hydrofluorene carbotri-
cyclic [6,5,6]ABC skeleton. In the literature several strategies are
described to access 4a-substituted/unsubstituted hexahydroflu-
orene skeletons. These include the acid-catalyzed cyclization
of substituted benzylcyclohexanols,4 inter- and intramolecular
[3 + 2] cycloadditions,5 and the cyclization of an arylradical,6
aryllithium,7 or arylpalladium8 tethered to a methylene cyclo-
hexane. By contrast studies dealing with the synthesis of 4a-
substituted/unsubstituted tetrahydrofluorenes are scarce9 and,
Fig. 1 Representative natural tetrahydrofluorene cores and our hetero
4a-unsubstituted tetrahydrofluorene skeletons.
moreover, no reports could be found in the literature with a
heteroatom impregnated in a carbotricyclic [6,5,6]ABC skeleton
either with or without 4a-substitution in the aforementioned
skeleton. Therefore, to us, it became highly desirable to design and
synthesize the hetero [6,5,6] tricyclic system embedded new scaf-
folds resembling the structural framework of Taiwaniaquinoids
and C-nor-D-homo steroids.
Medicinal and Process Chemistry Division, Central Drug Research Institute,
Lucknow, 226001, UP, India. E-mail: gautam.panda@gmail.com, gautam_
panda@cdri.res.in; Fax: +91-522-2623405; Tel: +91-522-2612411-18, Ext.
4385, 4603
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c0ob00892c
Results and discussion
Towards our continued research interest in the application of
Nazarov cyclization to access new classes of [6,5,6]ABC tricyclic
core embedded heterocycles10a and the use of Sc(OTf)3, an
‡ CDRI communication number 8028
4782 | Org. Biomol. Chem., 2011, 9, 4782–4790
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environmentally benign catalyst for C-C bond formation,10b,10c we
embarked upon the idea to utilize pentadienyl cationic cyclization
to access hetero 4a-unsubstituted tetrahydrofluorene skeleton
embedded diverse heterocycles.
In the Nazarov reaction,11 one of the key intermediates gener-
ated for cyclization is a hydroxy pentadienyl cation (c), which is
generated upon activation from the action of Lewis or Brønsted
acid to a divinyl ketone substrate. In an effort, to extend this
type of electrocyclization, we sought to generate pentadienyl
cation (f) from a different substrate, i.e. divinyl alcohol, to
accomplish the desired goal (Scheme 1). A literature survey
revealed only a few reports of such types of Nazarov cyclization
using trifluoroacetic acid/BF3·Et2O as the catalyst.12 However,
a similar type of intramolecular Friedel–Crafts alkylation has
been reported by Majetich et al.13 and Alvarez-Manzaneda et al.14
towards construction of a 4a-methyl tetrahydrofluorene skeleton
using SnCl4 and BF3·Et2O as catalyst.
Scheme 2 Synthesis of aryl vinyl alcohol 3. aReagents and Conditions: (a)
PBr3, dry benzene, 60 ◦C, 24 h, 60–64%. (b) (i) n-BuLi, dry THF, -78 ◦C,
N2, 5–10 mins. ii) 5, -78 ◦C to rt, 2 h, 55–60%.
Table 1 Catalyst optimization for Nazarov type cyclization
Entry Substrate
Catalyst
Conditions Time (min)
Yielda
1
2
3
4
5
6
3a
3a
3b
3b
3b
3a
3a
3b
3b
3c
CF3SO3H
H2SO4
CF3COOH
p-TsOH
AlCl3
DCM, rt
DCM, rt
DCM, rt
DCM, rt
DCM, rt
DCM, rt
DCM, rt
DCM, rt
DCM, rt
benzene,rt
5
60%
65%
68%
65%
62%
75%
77%
89%
—
13
15
12
10
16
14
30
45
28
FeCl3
7
BF3.Et2O
Sc(OTf)3
AuCl3
Scheme 1 Nazarov cyclization and proposed Nazarov type cyclization to
accomplish desired scaffolds.
b8
9
c10
Sc(OTf)3
82%
Herein, we report a concise and efficient synthetic route to
construct heteroatom incorporated tricyclic [6,5,6]ABC skeleton
embedded benzoannulated heterocycles under very mild reaction
conditions using Sc(OTf)3 as the cyclization promoter. This
synthetic strategy has been further exploited to access diverse
[6,5,5]ABC heterotricyclic core embedded new polycycles.
In analogy with the aryl vinyl ketone as a Nazarov substrate,10a,15
we chose to use aryl vinyl alcohol 3 for the current studies; our
work took impetus from the required divinyl alcohol substrate at
hand which was synthesized from ketone 1 following the standard
reaction conditions as depicted in Scheme 2.
In the quest for hetero 4a-unsubstituted tetrahydrofluorene
skeleton embedded polycycles, substrate 3a and 3b were subjected
to reaction with various catalytic Lewis and protic acids, to search
for the best catalyst required for such substrates (Table 1).
It was observed that the reaction proceeded with most of the
catalysts screened during optimization, at room temperature using
dichloromethane (DCM) as reaction solvent; however, noticeably
better results were obtained in terms of yield when Sc(OTf)3 was
used as the reaction promoter. The mildness of the reaction can
be judged by the fact that reaction occurred in only 30 min at
room temperature using just 2 mol% of Sc(OTf)3 as catalyst in
anhydrous DCM to provide the coveted heterotricyclic [6,5,6]ABC
skeleton embedded polycycles 4a and 4b with very high yields
a Isolated yield after column chromatography. b yield of 3a (88%) c yield of
3d (85%)
(88% and 89%). Stronger Lewis and Brønsted acids such as triflic
acid (CF3SO3H), AlCl3, H2SO4, BF3·Et2O required less reaction
time for cyclization when used in stoichiometric amounts but with
diminished yields. Treatment with AuCl3 gave only decomposed
product as observed on TLC.
Unfortunately, to our dismay substrate 3c and 3d failed to
provide the cyclized product when DCM was used as reaction
medium, although the starting material was consumed (as depicted
by TLC); however, when cyclization was attempted using dry
benzene as the solvent system, we were pleased to observe in each
case a single spot on TLC, which proved to be the desired cyclized
products 4c and 4d with yields of 82% and 85% respectively
after NMR characterization. It was therefore concluded that for
the sulfur embedded substrates, chlorinated solvents were not a
suitable reaction medium in which to perform this cyclization.
It is worth mentioning that the other substrates (3a, 3b) cyclized
as efficiently in anhydrous benzene as in DCM without affecting
the yield of the reaction. With the optimized reaction conditions at
hand, we desired to check the generality of such type of cyclization
on different set of heteroaryl or aryl vinyl alcohol substrates to
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access heterotricyclic [6,5,6] or [6,5,5]ABC skeleton embedded
heterocycles.
The substrates required for the purpose (6a–j, 9) were syn-
thesized, following similar reaction conditions as for Scheme 2
(Scheme 3).
We further attempted to extend the scope of this cyclization us-
ing heteroaryl substrates under the optimized reaction conditions;
the results obtained, as summarized in (Table 2), present some
interesting observations. The reactions proved to be mild enough
as the heteroaryl substrates were consumed using just 2 mol% of
Sc(OTf)3 in anhydrous DCM or benzene at room temperature
to provide the cyclized products. Amongst the indole based
substrates, 2-substituted indole substrates (6a, 6b, 6c) cyclized
promptly within a minute to furnish the desired heterotricyclic
[6,5,5] skeleton embedded heterocycles (10a, 10b, 10c) in high
yields (90–92%), whereas their 3-substituted counterpart (6d)
took longer to cyclize (10d) with lesser yield (64%), which is
probably due to the 3-position being the more reactive site in
indoles as compared to the 2-position; however, the noticeable
point was the drastic decrease in the yield. Disappointingly, 3-
substituted benzothiophene (6i), 3-substituted thiophene (6e) and
2-substituted furan based substrate (6f) did not cyclize to give the
desired product, although the starting material was consumed (as
observed on TLC).
To the best of our knowledge this is the first report using
heteroaromatic based substrates to optimize this type of Nazarov
type cyclization, in the event leading to various heteroatom incor-
porated [6,5,5] tricyclic skeleton embedded hetero(poly)cycles.
Conclusion
In conclusion we have reported an easy, general and expedient
route to access a variety of uncommon hetero [6,5,6]ABC tetrahy-
drofluorene cores resembling all carbotricyclic [6,5,6] tetrahy-
drofluorene cores present in Taiwaniaquinoids as well as in C-
nor-D-homo steroids. Efforts have also been made to synthesize
several hetero [6,5,5] tricyclic systems via Nazarov type cyclization.
This is the first such heteroaromatic Nazarov system, showing
excellent regioselectivity under very mild reaction conditions using
just 2 mol% Sc(OTf)3 and providing high yielding functionalized
scaffolds that could serve as valuable building blocks towards
Diversity Oriented Synthesis. Their bioevaluation and the asym-
metric version of the Nazarov reaction in this system is currently
underway in our lab and will be reported in due course.
Scheme 3 Synthesis of aryl/heteroaryl vinyl alcohols 6, 9.
In order to study the effect of substituents on cyclization
to access heterotricyclic [6,5,6] skeletons, substrate 6g and 6h
(entry 7, 9; Table 2) were subjected to the optimized reaction
conditions, Sc(OTf)3 in anhydrous DCM or benzene, but even
after stirring for 24 h at room temperature no other spot apart
from starting material could be detected on TLC. However, when
we used triflic acid (1 eq.) in anhydrous benzene, surprisingly we
obtained the isomerized cyclized product 11g and 11i rather than
desired isomers 10g and 10i, in moderate yields of 67% and 65%
respectively (Scheme 3).
Here we would like to mention that no unisomerized product
1
(10g, 10i) was observed in H NMR analysis of crude reaction
Experimental section
mixture. Further, nitrogen incorporated monosubstituted aryl
substrate 9 (entry 8), cyclized smoothly using triflic acid (1 eq.)
in anhydrous DCM to provide scaffold 10h with good yield (79%);
in fact it was also cyclized with Sc(OTf)3 as catalyst in 24 h at
room temperature. Subsequently, it was concluded that electron
donating groups on aryl substrates activate the system towards
efficient cyclization, while unsubstituted aryl substrates not only
render the system to be sluggish in cyclization, but also lead
to allylic isomerization, probably due to increase in acidity of
the proton at the 4a position in heteroatom impregnated 4aH-
tetrahydrofluorene derivatives (10g, 10i) leading to thermody-
namically more stable products (11g, 11i). The dramatic shift
of one of the gem dimethyl singlets and the presence of lone
benzylic singlets in the 1H NMR of the products 10 clearly
distinguishes it from the isomerized products 11 and 6 (see
supporting information†). Thereafter, an all carbocyclic system
6j was checked for its propensity towards this type of cyclization
and pleasingly furnished the product 10j in 85% yield.16
All dry reactions were carried out under argon or nitrogen in oven-
dried glassware using standard gas-tight syringes, cannulas and
septa. All reagents and solvents were dried prior to use according
to standard methods. Commercial reagents were used without
further purification unless otherwise stated. Reactions were mon-
itored on silica gel TLC plates (coated with TLC grade silica gel,
obtained from Merck). The detecting agent used (for TLC) was
iodine vapors. Column chromatography was performed over silica
gel (100–200 mesh) procured from Qualigens (India) using freshly
distilled solvents. Mass spectra were recorded using electron spray
ionization (ESI-MS) or Fast atom bombardment spectra (FAB-
MS) on a JEOL SX 102 spectrometer using argon/xenon as the
FAB gas. IR spectra were recorded on a Perkin–Elmer FT-IR RXI
1
spectrometer. H NMR and 13C NMR spectra were recorded on
Bruker DPX-200 (operating at 200 MHz for 1H and 50 MHz for
13C) or DPX-300 (operating at 300 MHz for 1H and 75 MHz for
13C) spectrometer using CDCl3 +CCl4 and DMSO-d6 as solvents.
4784 | Org. Biomol. Chem., 2011, 9, 4782–4790
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Table 2 Nazarov type cyclization of aryl/heteroaryl substrates
Entry
a1
Substrate (6)
Product (10)
Time (min)
1
Yield (%)
91%
a2
1
90%
a3
1
92%
64%
a4
12
a5
Decomposed
Decomposed
10
16
—
—
a6
b7
25
20
67%
79%
b8
b9
30
65%
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Table 2 (Contd.)
Entry
c10
Substrate (6)
Product (10)
Time (min)
—
Yield (%)
—
Uncharacterized
product
a11
1
85%
a 2 mol% Sc(OTf)3 in dry DCM/benzene at rt. b 1 equiv. Triflic acid in dry benzene at rt. c with all optimized reacn conditions in Table 1.
1
Tetramethylsilane (0.00 ppm) served as an internal standard in 1H
NMR and CDCl3 (77.0 ppm), DMSO-d6 (40.0) in 13C NMR. All
spectra were recorded at 25 ◦C. Coupling constants (J values) are
given in hertz (Hz). Chemical shifts are expressed in parts per
million (ppm).
(Neat): 3414, 3021, 2358, 1591, 1216,758, 668 cm-1; H NMR
(300 MHz, CDCl3 + CCl4): d 7.00–6.94 (m, 1H), 6.91–6.85 (m,
3H), 6.75–6.60 (m, 3H), 5.70 (s, 1H), 5.52 (s, 1H), 3.78 (s, 3H),
3.77 (s, 3H), 1.86 (s, br, 1H), 1.40 (s, 6H); 13C NMR (75 MHz,
CDCl3 + CCl4): d 153.1, 149.2, 148.9, 134.2, 133.4, 129.0, 127.5,
123.9, 120.5, 120.2, 119.5, 116.8, 111.1, 110.2, 75.7, 72.5, 55.8, 55.7,
27.9; MS (ESI): m/z 309 [M–OH]+; Anal. Calcd. for C20H22O4: C,
73.60; H, 6.79. Found: C, 73.71; H, 6.90.
Experimental procedures and characterization data
Typical procedure to prepare allyl alcohols
(3,4-Dimethoxyphenyl)(2,2-dimethyl-2H -thiochromen-4-yl)-
methanol (3c). As described for 3a, 2c (500 mg, 1.96 mmol) in
THF (20 mL), n-BuLi (1.2 mL, 1.96 mmol) and veratraldehyde
(293 mg, 1.76 mmol) in THF (2 mL) furnished 3c (395 mg, 59%)
as a viscous colourless oil, Rf = 0.48 (AcOEt/hexane, 20 : 80); IR
(3,4-Dimethoxyphenyl)(7-methoxy-2,2-dimethyl-2H-chromen-
4-yl)methanol (3a). To a stirred solution of bromo substrate 2a
(500 mg, 1.40 mmol) in anhydrous THF (20 mL) at -78 C and
◦
under N2, n-BuLi (1.6 M in hexane, 1.2 mL, 1.40 mmol) was
added. The resulting yellow solution was stirred at -78 ◦C for 5–
10 min after which veratraldehyde 5 (192 mg, 1.16 mmol) in THF
(2 mL) was added at the same temperature and stirred at room
temperature for 1h. After quenching with water, THF was removed
in vacuo. The mixture was extracted with ethyl acetate (3 ¥ 20
mL), washed with brine and dried over Na2SO4. The concentrated
extract was subjected to column chromatography on silica gel and
elution with 20% ethyl acetate in hexane furnished alcohol 3a
(364 mg, 55%) as a viscous green oil, Rf = 0.61 (AcOEt/hexane,
20 : 80); IR (Neat): 3431, 2360, 1560, 1217,761, 670 cm-1; 1H NMR
(300 MHz, CDCl3 + CCl4): d 6.95–6.91 (m, 2H), 6.87 (d, 1H, J =
8.6 Hz), 6.80 (d, 1H, J = 7.9 Hz), 6.36 (d, 1H, J = 2.5 Hz), 6.26
(dd, 1H, J1 = 2.6 Hz, J2 = 8.6 Hz), 5.68 (s, 1H), 5.53 (s, 1H), 3.85
(s, 3H), 3.84 (s, 3H), 3.72 (s, 3H), 2.03 (s, br, 1H), 1.47 (s, 6H);
13C NMR (75 MHz, CDCl3 + CCl4): d 160.4, 154.5, 149.2, 148.8,
134.4, 133.3, 124.8, 124.8, 119.5, 113.4, 111.2, 110.3, 106.5, 102.2,
76.0, 72.6, 55.8, 5.7, 55.0, 27.9; MS (ESI): m/z 339 [M–OH]+;
Anal. Calcd. for C21H24O5: C, 70.77; H, 6.79. Found: C, 70.65; H,
6.85.
1
(Neat): 3430, 3020, 2331, 1571, 1212, 760, 660 cm-1; H NMR
(300 MHz, CDCl3 + CCl4): d 7.30–7.27 (m, 1H), 7.19 (dd, 1H,
J1 = 1.0, J2 = 7.8), 7.09–7.03 (m, 1H), 6.99–6.91 (m, 3H), 6.81–
6.79 (m, 1H), 6.12 (s, 1H), 5.66 (s, 1H), 3.86 (s, 3H), 3.83 (s, 3H),
2.10 (s, br,1H), 1.49 (s, 3H), 1.47 (s, 3H); 13C NMR (75 MHz,
CDCl3 + CCl4): d 149.1, 148.6, 137.0, 134.8, 133.1, 132.8, 130.8,
127.9, 127.4, 127.3, 125.4, 119.4, 111.1, 110.2, 55.7, 55.6, 40.2,
28.9; MS (ESI): m/z 325 [M–OH]+; Anal. Calcd. for C20H22O3S:
C, 70.15; H, 6.48. Found: C, 70.22; H, 6.57.
(3,4-Dimethoxyphenyl)(7-methoxy-2,2-dimethyl-2H-thiochro-
men-4-yl)methanol (3d). As described for 3a, 2d (500 mg, 1.75
mmol) in THF (20 mL), n-BuLi (1.1 mL, 1.75 mmol) and
veratraldehyde (264 mg, 1.60 mmol) in THF (2 mL) furnished
3d (378 mg, 58%) as a viscous colourless oil, Rf = 0.46
(AcOEt/hexane, 20 : 80); IR (Neat): 3429, 3021, 2329, 1569, 1213,
761, 669 cm-1; 1H NMR (300 MHz, CDCl3 + CCl4): d 7.06 (d, 1H,
J = 8.7 Hz), 6.85 (d, 2H, J = 7.9 Hz), 6.76–6.72 (m, 2H), 6.46 (dd,
1H, J1 = 2.6 Hz, J2 = 8.7 Hz), 5.92 (s, 1H), 5.53 (s, 1H), 3.82 (s,
3H), 3.79 (s, 3H), 3.72 (s, 3H), 2.28 (s, br,1H), 1.47 (s, 3H), 1.45 (s,
3H); 13C NMR (75 MHz, CDCl3 + CCl4): d 158.4, 149.1, 148.6,
136.7, 135.0, 134.7, 130.3, 126.7, 123.9, 119.3, 112.6, 111.3, 111.1,
110.2, 74.2, 55.7, 55.5, 54.9, 40.6, 29.3, 29.1; MS (ESI): m/z 355
[M–OH]+; Anal. Calcd. for C21H24O4S: C, 67.72; H, 6.49. Found:
C, 67.61; H, 6.57.
(3,4-Dimethoxyphenyl)(2,2-dimethyl-2H-chromen-4-yl)meth-
anol (3b). As described for 3a, 2b (500 mg, 2.09 mmol) in THF
(20 mL), n-BuLi (1.3 mL, 2.09 mmol) and veratraldehyde (312 mg,
1.88 mmol) in THF (2 mL) furnished 3b (409 mg, 60%) as a
viscous colourless oil, Rf = 0.59 (AcOEt/hexane, 20 : 80); IR
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(1-Benzyl-1H-indol-2-yl)(7-methoxy-2,
2-dimethyl-2H-chro-
(210 mg, 1.88 mmol) in THF (2 mL) furnished 6e (313 mg, 55%)
as a viscous colourless oil, Rf = 0.53 (AcOEt/hexane, 20 : 80); IR
men-4-yl) methanol (6a). As described for 3a, 2a (500 mg,
1.96 mmol) in THF (20 mL), n-BuLi (1.2 mL, 1.96 mmol) and
N-benzyl indole 2-carboxaldehyde (393 mg, 1.66 mmol) in THF
(2 mL) furnished 6a (418 mg, 54%) as a viscous colourless oil,
Rf = 0.51 (AcOEt/hexane, 20 : 80); IR (Neat): 3417, 3010, 2330,
1211, 759, 670 cm-1; 1H NMR (200 MHz, CDCl3): d 7.57 (d, 1H,
J = 7.5 Hz), 7.33–7.02 (m, 8H), 6.47 (d, 2H, J = 7.7 Hz), 6.37 (d,
1H, J = 2.5 Hz), 6.14–6.10 (m, 1H), 5.71 (s, 1H), 5.67 (s, 1H), 5.54
(s, 2H), 3.71 (s, 3H), 2.00 (s, 1H), 1.46 (s, 3H), 1.43 (s, 3H); MS
(FAB): m/z 410 [M–OH]+; Anal. Calcd. for C28H27NO3: C, 79.03;
H, 6.40; N, 3.29. Found: C, 78.95; H, 6.34; N, 3.35.
1
(Neat): 3404, 3021, 2359, 1216, 760 cm-1; H NMR (300 MHz,
CDCl3): d 7.30–7.26 (m, 2H), 7.14–7.06 (m, 3H), 6.85–6.73 (m,
2H), 5.81 (s, 1H), 5.72 (s, 1H), 2.38 (s, br, 1H), 1.47 (s, 6H); 13C
NMR (75 MHz, CDCl3): d 153.0, 143.2, 133.4, 129.0, 127.4, 126.5,
126.1, 123.7, 122.6, 120.4, 120.1, 116.7, 75.7, 68.9, 27.7, 27.6; MS
(ESI): m/z 255 [M–OH]+; Anal. Calcd. for C16H16O2S: C, 70.56;
H, 5.92. Found: C, 70.67; H, 6.05.
(2, 2-Dimethyl-2H-chromen-4-yl)(Phenyl) methanol (6g). As
described for 3a, 2b (500 mg, 1.85 mmol) in THF (20 mL), n-
BuLi (1.2 mL, 1.85 mmol) and benzaldehyde (176 mg, 1.66 mmol)
in THF (2 mL) furnished 6g (322 mg, 58%) as a viscous colourless
oil, Rf = 0.56 (AcOEt/hexane, 20 : 80); IR (Neat): 3430, 3019, 2360,
1210, 759, 669 cm-1; 1H NMR (300 MHz, CDCl3): d 7.48 (d, 1H,
J = 1.6), 7.45 (d, 1H, J = 1.0), 7.41–7.29 (m, 3H), 7.12–7.03 (m,
2H), 6.83 (dd, 1H, J1 = 1.0, J2 = 8.0), 6.75 (m, 1H), 5.84 (d, 1H, J =
1.2), 5.69 (d, 1H, J = 2.5), 2.17 (d, 1H, J = 3.8), 1.50 (s, 3H), 1.50
(s, 3H); MS (ESI): m/z 249 [M–OH]+; Anal. Calcd. for C18H18 O2:
C, 81.17; H, 6.81; Found: C, 81.19; H, 6.91.
(1-Benzyl-1H-indol-2-yl)(2, 2-dimethyl-2H-chromen-4-methanol
(6b). As described for 3a, 2b (500 mg, 2.09 mmol) in THF
(20 mL), n-BuLi (1.3 mL, 2.09 mmol) and N-benzyl indole
2-carboxaldehyde (594 mg, 1.88 mmol) in THF (2 mL) fur-
nished 6b (471 mg, 57%) as a viscous colourless oil, Rf = 0.54
(AcOEt/hexane, 20 : 80); IR (Neat): 3429, 3021, 2359, 1620, 1218,
1
765 cm-1; H NMR (300 MHz, CDCl3): d 7.59 (d, 2H, J = 7.7),
7.35–7.20 (m, 5H), 7.16–7.03 (m, 4H), 6.58 (d, 2H, J = 4.1), 6.49
(s, 1H), 5.89 (d, 1H, J = 1.1), 5.74 (s, 1H), 5.61 (d, 1H, J = 16.9),
5.53 (d, 1H, J = 16.8), 2.02 (s, br, 1H), 1.51 (s, 3H), 1.47 (s, 3H);
13C NMR (75 MHz, CDCl3): d 152.7, 139.5, 138.2, 137.8, 129.0,
128.8, 127.6, 127.5, 127.2, 126.2, 123.5, 122.4, 121.1, 120.4, 120.2,
119.8, 116.6, 109.6,102.6, 75.9, 65.3, 46.9, 27.7, 27.6; MS (ESI):
m/z 396 [M+1]+, 378 [M–OH]+; Anal. Calcd. for C27H25 NO2: C,
82.00; H, 6.37; N, 3.54. Found: C, 81.92; H, 6.45; N, 3.61.
(2, 2-Dimethyl-2H-thiochromen-4-yl)(Phenyl) methanol (6h).
As described for 3a, 2c (500 mg, 1.96 mmol) in THF (20 mL), n-
BuLi (1.2 mL, 1.96 mmol) and benzaldehyde (188 mg, 1.78 mmol)
in THF (2 mL) furnished 6h (317 mg, 51%) as a viscous colourless
oil, Rf = 0.54 (AcOEt/hexane, 20 : 80); IR (Neat): 3429, 3016,
2361, 1213, 764, 671 cm-1; 1H NMR (300 MHz, CDCl3): d 7.45–
7.42 (m, 2H), 7.38–7.36 (m, 1H), 7.33–7.24 (m, 4H), 7.11–7.06 (m,
1H), 7.01–6.96 (m, 1H), 6.12 (s, 1H), 5.77 (s, 1H), 2.11 (s, br, 1H),
1.50 (s, 3H), 1.48 (s, 3H); MS (ESI): m/z 265 [M–OH]+; Anal.
Calcd for C18H18OS: C, 76.56; H, 6.42; Found: C, 76.69; H, 6.38.
(1-Benzyl-1H-indol-2-yl)(2, 2-dimethyl-2H-thiochromen-4-yl)
methanol (6c). As described for 3a, 2c (500 mg, 1.96 mmol)
in THF (20 mL), n-BuLi (1.2 mL, 1.96 mmol) and N-benzyl
indole 2-carboxaldehyde (418 mg, 1.78 mmol) in THF (2 mL)
furnished 6c (481 mg, 55%) as a viscous colourless oil, Rf = 0.56
(AcOEt/hexane, 20 : 80); IR (Neat): 3410, 3021, 2358, 1216, 762,
(7-Methoxy-2, 2-dimethyl-2H-chromen-4-yl)(5-methylfuran-2-
yl) methanol (6f). As described for 3a, 2a (500 mg, 1.85 mmol) in
THF (20 mL), n-BuLi (1.2 mL, 1.85 mmol) and 5-methyl furfural
(183 mg, 1.66 mmol) in THF (2 mL) furnished 6f (312 mg, 56%)
as a viscous colourless oil, Rf = 0.52(AcOEt/hexane, 20 : 80); IR
1
669 cm-1; H NMR (300 MHz, CDCl3): d 7.55 (d, 1H, J = 7.4
Hz), 7.32–7.16 (m, 6H), 7.12–6.95 (m, 4H), 6.78–6.69 (m, 2H),
6.37 (s, 1H), 6.15 (s, 1H), 5.73 (s, 1H), 5.59 (d, 1H, J = 16.8 Hz),
5.47 (d, 1H, J = 17.1 Hz), 2.03 (s, 1H), 1.49 (s, 3H), 1.42 (s, 3H);
13C NMR (75 MHz, CDCl3): d 149.7, 149.1, 140.8, 137.3, 133.5,
129.7, 128.8, 127.6, 127.4, 127.1, 126.6, 124.9, 124.8, 124.6, 120.4,
120.2, 119.2, 118.6, 115.0, 110.4, 55.1, 48.9, 48.3, 29.7, 22.7; MS
(ESI): m/z 394 [M–OH]+; Anal. Calcd. for C27H25 NOS: C, 78.18;
H, 6.12; N, 3.40. Found: C, 78.09; H, 6.23; N, 3.29.
1
(Neat): 3432, 3023, 2360, 1213, 760 cm-1; H NMR (300 MHz,
CDCl3): d 6.98 (d, 1H, J = 8.4), 6.43 (d, 1H, J = 2.5), 6.36 (dd, 1H,
J1 = 2.5, J2 = 8.5), 6.07 (d, 1H, J = 2.8), 5.89 (d, 1H, J = 2.1), 5.77
(d, 1H, J = 0.8), 5.65 (s, 1H), 3.77 (s, 3H), 2.31 (s, 3H), 2.17 (s, br,
1H), 1.47 (s, 6H); MS (ESI): m/z 283 [M–OH]+; Anal. Calcd. for
C18H20 O4: C, 71.98; H, 6.71; Found: C, 72.90; H, 6.59.
(1-Benzyl-2,2-dimethyl-1,2-dihydroquinolin-4-yl)(3-methoxy-
phenyl)methanol (9). As described for 3a, 8 (500 mg, 2.70 mmol)
in THF (20 mL), n-BuLi (1.7 mL, 2.70 mmol) and 7 (678 mg, 2.45
mmol) in THF (2 mL) furnished 9 (566 mg, 54%) as a viscous
colourless oil, Rf = 0.51(AcOEt/hexane, 20 : 80); IR (Neat): 3438,
3022, 2356, 1213, 769 cm-1; 1H NMR (300 MHz, CDCl3): d 7.34–
7.25 (m, 5H), 7.21 (d, 1H, J = 6.4 Hz), 7.10–7.07 (m, 2H), 6.937 (d,
1H, J = 7.6 Hz), 6.87–6.82 (m, 2H), 6.44 (t, 1H, J = 7.5 Hz), 6.28
(d, 1H, J = 8.3 Hz), 5.73 (s, 1H), 5.69 (s, 1H), 4.52 (s, 2H), 3.80
(s, 3H), 2.04 (s, br, 1H), 1.44 (s, 3H), 1.43 (s, 3H); MS (ESI): m/z
368 [M–OH]+; Anal. Calcd. for C26H27 NO2: C, 81.01; H, 7.06; N,
3.63. Found: C, 81.13; H, 6.96; N, 3.75.
(1-Benzyl-1H-indol-3-yl)(2,2-dimethyl-2H-thiochromen-4-yl)-
methanol (6d). As described for 3a, 2c (500 mg, 1.96 mmol)
in THF (20 mL), n-BuLi (1.2 mL, 1.96 mmol) and N-benzyl
indole 3-carboxaldehyde (418 mg, 1.78 mmol) in THF (2 mL)
furnished 6d (462 mg, 53%) as a viscous colourless oil, Rf = 0.58
(AcOEt/hexane, 20 : 80); IR (Neat): 3430, 3021, 1569, 1216, 759,
1
670 cm-1; H NMR (300 MHz, CDCl3): d 7.73–7.67 (m, 2H),
7.35 (d, 1H, J = 1.5 Hz), 7.29–7.17 (m, 5H), 7.16–7.09 (m, 4H),
7.07–6.95 (m, 4H), 5.53 (s, 2H), 3.93 (d, 1H, J = 1.4 Hz), 1.60 (s,
3H), 1.06 (s, 3H); MS (ESI): m/z 394[M–OH]+; Anal. Calcd for
C27H25NOS: C, 78.80; H, 6.12; N, 3.40. Found: C, 78.91; H, 6.01;
N, 3.54.
(2,2-Dimethyl-2H-chromen-4-yl)(thiophen-3-yl)methanol (6e).
As described for 3a, 2b (500 mg, 2.09 mmol) in THF (20 mL),
n-BuLi (1.3 mL, 2.09 mmol) and thiophene 3-carboxaldehyde
Benzo[b]thiophen-3-yl (7-methoxy-2, 2-dimethyl-2H-chromen-4-
yl) methanol (6i). As described for 3a, 2a (500 mg, 1.85 mmol)
in THF (20 mL), n-BuLi (1.2 mL, 1.85 mmol) and thianaphthene
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©

3-carbaldehyde (269 mg, 1.66 mmol) in THF (2 mL) furnished 6i
(412 mg, 63%) as a viscous colourless oil, Rf = 0.51(AcOEt/hexane,
( )-8, 9-Dimethoxy-6, 6-dimethyl-6, 6a-dihydroindeno [1, 2-c]
thiochromene (4c). As described for 4a, 3c (100 mg, 0.30 mmol) in
anhydrous benzene (10 mL), and Sc(OTf)3 (2 mol%), furnished 4c
(77 mg, 82%) as a colourless semi solid, Rf = 0.69 (AcOEt/hexane,
10 : 90); IR (KBr): 1438, 1216, 1028, 763 cm-1; 1H NMR (300 MHz,
DMSO-d6): d 7.79–7.75 (m, 1H), 7.27 (d, 1H, J = 1.37 Hz), 7.16
(s, 1H), 7.14–7.06 (m, 3H), 7.04 (s, 1H), 3.88 (s, 3H), 3.81 (s, 3H),
3.80 (s, 1H), 1.80 (s, 3H), 0.82 (s, 3H); MS (ESI): m/z 325 [M+1]+;
Anal. Calcd. for C20H20O2S: C, 74.04; H, 6.21. Found: C, 74.14;
H, 6.17.
1
20 : 80); IR (Neat): 3438, 3022, 2356, 1213, 769 cm-1; H NMR
(300 MHz, CDCl3): d 7.98–7.93 (m, 1H), 7.90–7.85 (m, 1H), 7.45–
7.37 (m, 3H), 6.98 (d, 1H, J = 8.5 Hz), 6.45 (d, 1H, J = 2.6 Hz),
6.33 (dd, 1H, J1 = 2.6, J2 = 8.6 Hz), 6.03 (s, 1H), 5.70 (d, 1H, J =
1.0 Hz), 3.76 (s, 3H), 2.22 (s, br, 1H), 1.48 (s, 3H), 1.47 (s, 3H);
13C NMR (75 MHz, CDCl3): d 160.6, 154.5, 140.9, 137.6, 136.6,
132.4, 125.5, 125.0, 124.6, 124.5, 124.2, 122.9, 122.3, 113.5, 106.7,
102.4, 76.3, 67.5, 55.2, 27.8, 27.7; MS (ESI): m/z 335 [M–OH]+;
Anal. Calcd. for C21H20O3S: C, 71.56; H, 5.72; Found: C, 71.43;
H, 6.90.
( )-3,8,9-Trimethoxy-6,6-dimethyl-6,6a-dihydroindeno[1,2-c]-
thiochromene (4d). As described for 4a, 3d (100 mg, 0.27 mmol) in
anhydrous benzene (10 mL), and Sc(OTf)3 (2 mol%), furnished 4d
(80 mg, 85%) as a colourless semi solid, Rf = 0.75 (AcOEt/hexane,
10 : 90); IR (KBr): 1460, 1217, 1044, 764 cm-1; 1H NMR (300 MHz,
DMSO-d6): d 7.73 (d, 1H, J = 9.3 Hz), 7.16 (s, 2H), 7.01 (s, 1H),
6.74 (d, 1H, J = 2.6 Hz), 6.72 (s, 1H), 3.83 (s, 1H), 3.79 (s, 3H), 3.78
(s, 3H), 3.75 (s, 3H), 1.80 (s, 3H), 0.82 (s, 3H); 13C NMR (75 MHz,
DMSO-d6): d 159.5, 149.7, 147.3, 143.8, 138.7, 135.0, 134.8, 127.6,
125.1, 122.9, 113.1, 110.8, 105.7, 58.4, 56.9, 56.5, 56.1, 49.0, 28.9,
23.7; MS (ESI): m/z 355 [M+1]+;Anal. Calcd. for C21H22O3S: C,
71.16; H, 6.26. Found: C, 71.24; H, 6.17.
(3,4-Dihydronaphthalen-1-yl)(3,4-dimethoxyphenyl)methanol
(6j). As described for 3a, 2e (200 mg, 0.95 mmol) in THF
(15 mL), n-BuLi (0.60 mL, 0.95 mmol) and veratraldehyde
(164 mg, 0.86 mmol) in THF (2 mL) furnished 6j (74 mg, 52%)
as viscous colourless oil, Rf = 0.32(AcOEt/hexane, 20 : 80); IR
(Neat): 3433, 3018, 2354, 1214, cm-1; 1H NMR (300 MHz, CDCl3):
d 7.14–7.11 (m, 1H), 7.07–6.99 (m, 3H), 6.92–6.86 (m, 2H), 6.73
(d, 1H, J = 8.3 Hz), 6.11–6.09 (m, 1H), 5.63 (s, br, 1H), 3.77 (s,
3H), 3.76 (s, 3H), 2.69 (t, 2H, J = 7.8 Hz), 2.30–2.24 (m, 2H); 13
C
NMR (75 MHz, CDCl3): d 148.9, 148.5, 138.3, 136.7, 135.0, 133.0,
127.6, 126.9, 126.8, 126.2, 123.5, 119.3, 111.0, 110.3, 73.7, 55.8,
55.8, 28.2, 22.9; MS (ESI): m/z 289 [M–OH]+; Anal. Calcd. for
C19H20O3: C, 77.00; H, 6.80; Found: C, 77.13; H, 6.94.
( )-11-Benzyl-3-methoxy-6,6-dimethyl-6a,11-dihydro-6H-
5-oxa-11-aza- benzo[5,6]pentaleno[2,1-b]naphthalene (10a). As
described for 4a, 6a (100 mg, 0.23 mmol) in anhydrous DCM
(10 mL), and Sc(OTf)3 (2 mol%), furnished 10a (87 mg, 91%) as a
greenish semi solid, Rf = 0.74 (AcOEt/hexane, 10 : 90); IR (KBr):
Typical procedure for Nazarov type cyclization
1
1602, 1450, 1217, 1041, 762 cm-1; H NMR (300 MHz, DMSO-
( )-3,8,9-Trimethoxy-6,6-dimethyl-6,6a-dihydroindeno[1,2-c]-
chromene (4a). To a stirred solution of substrate 3a (100 mg, 0.28
mmol) in anhydrous DCM or benzene (10 mL) at room tempera-
ture, was added Sc(OTf)3 (2 mol%) at the same temperature and
the reaction was stirred vigorously until completion (as observed
on TLC). It was then neutralized by saturated Na2CO3 solution at
0 ◦C, extracted with DCM or ethyl acetate (3 ¥ 10 mL) and dried
over anhydrous Na2SO4. After evaporation of the solvent, the
residue was subjected to column chromatography on silica gel and
elution with 10% ethyl acetate in hexane furnished the cyclized
product 4a (83 mg, 88%) as a colourless semi solid, Rf = 0.66
(AcOEt/hexane, 10: 90); IR (KBr): 1451, 1216,1039, 760 cm-1; 1H
NMR (300 MHz, DMSO-d6): d 7.52 (d, 1H, J = 8.3 Hz), 7.06
(s, 1H), 6.99 (s, 1H), 6.90 (d, 1H, J = 1.6 Hz), 6.52 (dd, 1H, J1 =
2.6 Hz, J2 = 8.6 Hz), 6.40 (dd, 1H, J1 = 2.4 Hz, J2 = 7.9 Hz), 3.78
(s, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.72 (s, 3H), 1.80 (s, 3H), 0.68
(s, 3H); MS (ESI): m/z 339 [M+1]+; Anal. Calcd. for C21H22O4: C,
74.54; H, 6.55. Found: C, 74.45; H, 6.44.
d6): d 7.52 (d, 1H, J = 8.6 Hz), 7.51–7.44 (m, 2H), 7.33–7.18 (m,
5H), 7.15 (d, 1H, J = 1.5 Hz), 7.07–6.97 (m, 2H), 6.55 (dd, 1H,
J1 = 2.5, J2 = 8.6 Hz), 6.47 (d, 1H, J = 2.5 Hz), 5.5 (s, 2H), 3.74 (s,
4H), 1.92 (s, 3H), 0.76 (s, 3H); 13C NMR (75 MHz, DMSO-d6): d
160.7, 154.3, 151.4, 145.8, 140.5, 138.5, 129.1, 127.8, 127.4, 125.6,
124.4, 120.4, 120.0, 118.1, 115.7, 113.9, 111.9, 111.4, 108.5, 102.3,
82.7, 55.7, 51.6, 47.9, 29.7, 19.4; MS (ESI): m/z 408 [M+1]+; Anal.
Calcd. for C28H25 NO2: C, 82.53; H, 6.18; N, 3.44. Found: C, 82.42;
H, 6.08; N, 3.52.
( ) 11-Benzyl-6, 6-dimethyl-6a, 11-dihydro-6H-5-oxa-11-aza-
benzo [5, 6] pentaleno [2, 1-b] naphthalene (10b). As described
for 4a, 6b (100 mg, 0.25 mmol) in anhydrous DCM (10 mL), and
Sc(OTf)3 (2 mol%), furnished 10b (86 mg, 90%) as a greenish semi
solid, Rf = 0.78 (AcOEt/hexane, 10 : 90); IR (KBr): 1605, 1451,
1216,1039, 760 cm-1; 1H NMR (300 MHz, DMSO-d6): d 7.61 (d,
1H, J = 7.8 Hz), 7.50 (s, 2H), 7.31–7.14 (m, 7H), 7.10–7.03 (m, 2H),
6.96–6.85 (m, 2H), 5.54 (s, 2H), 3.81 (s, 1H), 1.93 (s, 3H), 0.75 (s,
3H); 13C NMR (75 MHz, DMSO-d6): d 152.9, 150.9, 145.5, 140.7,
138.3, 129.3, 128.9, 127.7, 127.2, 124.4, 124.3, 121.1, 120.8, 118.2,
117.5, 116.9, 114.1, 111.4, 82.4, 51.6, 47.9, 29.7, 19.2; MS (ESI):
m/z 378 [M+1]+; Anal. Calcd. for C27H23NO: C, 85.91; H, 6.14;
N, 3.71. Found: C, 85.84; 6.06; N, 3.63.
( )-8,9-Dimethoxy-6,6-dimethyl-6,6a-dihydroindeno[1,2-c]chro-
mene (4b). As described for 4a, 3b (100 mg, 0.31 mmol) in
anhydrous DCM (10 mL), and Sc(OTf)3 (2 mol%), furnished 4b
(84 mg, 89%) as a colourless semi solid, Rf = 0.68 (AcOEt/hexane,
10 : 90); IR (KBr): 1449, 1217, 1029, 759 cm-1; 1H NMR (300 MHz,
DMSO-d6): d 7.64–7.61 (m, 1H), 7.17–7.05 (m, 4H), 6.93 (d, 1H,
J = 7.5 Hz), 6.84 (d, 1H, J = 8.1 Hz), 3.79 (s, 3H), 3.78 (s, 3H), 3.65
(s, 1H), 1.83 (s, 3H), 0.68 (s, 3H); 13C NMR (75 MHz, DMSO-
d6): d 152.9, 149.3, 147.4, 140.5, 138.9, 134.6, 129.5, 124.8, 123.7,
121.1, 120.3,117.5, 109.4, 105.7, 81.9, 56.5, 56.1, 55.4, 28.1, 19.3;
MS (ESI): m/z 309 [M+1]+; Anal. Calcd. for C20H20O3: C, 77.90;
H, 6.54. Found: C, 78.03; H, 6.65.
( )-11-Benzyl-6,6-dimethyl-6a,11-dihydro-6H-5-thia-11-aza-
benzo[5,6]pentaleno[2,1-b]naphthalene (10c). As described for 4a,
6c (100 mg, 0.24 mmol) in anhydrous benzene (10 mL), and
Sc(OTf)3 (2 mol%), furnished 10c (88 mg, 92%) as a greenish
viscous oil, Rf = 0.79 (AcOEt/hexane, 10 : 90); IR (KBr): 1451,
1
1216,1039, 760 cm-1; H NMR (300 MHz, DMSO-d6): d 7.84–
7.81 (m, 1H), 7.61 (d, 1H, J = 1.2 Hz), 7.57–7.54 (m, 1H),
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7.50–7.47 (m, 1H), 7.33–7.28 (m, 2H), 7.26–7.10 (m, 6H), 7.08–
7.02 (m, 2H), 5.56 (s, 2H), 4.02 (s, 1H), 1.89 (s, 3H), 0.85 (s, 3H);
13C NMR (75 MHz, CDCl3): d 150.1, 148.4, 140.8, 138.5, 132.9,
129.9, 129.1, 127.9, 127.8, 127.4, 127.2, 125.8, 125.3, 124.7, 120.6,
120.5, 119.3, 118.0, 117.1, 111.555.0, 48.8, 47.9, 29.7, 22.9; MS
(ESI): m/z 394 [M+1]+; Anal. Calcd. for C27H23 NS: C, 82.40; H,
5.89; N, 3.56. Found: C, 82.51; H, 5.78; N, 3.44.
1H, J = 7.7 Hz), 7.21–7.17 (m, 3H), 7.08 (s, 1H), 6.99 (s, 1H),
6.92 (s, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.47 (dd, 1H, J1 = 3.5, J2 =
13.2), 3.13–3.08 (m, 2H), 2.63–2.59 (m, 1H), 1.49–1.43 (m, 1H);
13C NMR (75 MHz, CDCl3): d 148.7, 147.7, 147.1, 139.6, 137.9,
136.4, 132.5, 129.0, 127.1, 126.3, 124.2, 122.0 107.2, 104.7, 56.3,
56.1, 49.1, 30.6, 28.7; MS (ESI): m/z 279 [M+1]+; Anal. Calcd. for
C19H18O2: C, 81.99; H, 6.52; Found: C, 82.11; H, 6.65.
( ) 7-Benzyl-6,6-dimethyl-6a,7-dihydro-6H-5-thia-7-aza-ben-
zo[4,5]pentaleno[2,1-a]naphthalene (10d). As described for 4a, 6d
(100 mg, 0.24 mmol) in anhydrous benzene (10 mL), and Sc(OTf)3
(2 mol%), furnished 10c (61 mg, 64%) as a colourless semi solid,
Rf = 0.79 (AcOEt/hexane, 10 : 90); IR (KBr): 1427, 1216, 1104,
761 cm-1. 1H NMR (300 MHz, DMSO-d6): d 7.83–7.80 (m,
1H), 7.60 (d, 1H, J = 1.5 Hz), 7.56–7.54 (m, 1H), 7.49–7.46 (m,
1H), 7.32–7.27 (m, 2H), 7.24–7.16 (m, 4H), 7.15–7.10 (m, 2H),
7.08–7.01 (m, 2H), 5.54 (s, 2H), 4.01 (d, 1H, J = 1. Hz), 1.88 (s,
3H), 0.85 (s, 3H); MS (ESI): m/z 394 [M+1]+; Anal. Calcd. for
C27H23 NS: C, 82.40; H, 5.89; N, 3.56. Found: C, 82.28; H, 6.01;
N, 3.44.
Acknowledgements
The authors thank the Department of Science and Technology
(DST) (SR/S1/OC-74/2009), New Delhi, India for financial
support and SAIF, CDRI for providing analytical data. Ritesh
thanks CSIR for the fellowship.
Notes and References
1 (a) W. Lin, J. Fang and Y. Cheng, Phytochemistry, 1995, 40, 871; (b) W.
Lin, J. Fang and Y. Cheng, Phytochemistry, 1996, 42, 1657; (c) K.
Kawazoe, M. Yamamoto, Y. Takaishi, G. Honda, T. Fujita, E. Sezik
and E. Yesilada, Phytochemistry, 1999, 50, 493; (d) C. Chang, S. Chien,
S. Lee and Y. Kuo, Chem. Pharm. Bull., 2003, 51, 1420; (e) C. Chang,
J. Chang, C. Kuo, W. Pan and Y. Kuo, Planta Med., 2005, 71, 72;
(f) M. Iwamoto, H. Ohtsu, H. Tokuda, H. Nishino, S. Matsunaga and
R. Tanaka, Bioorg. Med. Chem., 2001, 9, 1911; (g) T. Minami, M.
Iwamoto, H. Ohtsu, H. Ohishi, R. Tanaka and A. Yoshitake, Planta
Med., 2002, 68, 742; (h) J. R. Hanson, Nat. Prod. Rep., 2004, 21, 312.
2 (a) H.-J. Li, Y. Jiang and P. Li, Nat. Prod. Rep., 2006, 23, 735;
(b) W. Gaffield, in Studies in Natural Products Chemistry, ed. Atta-
ur-Rahman, Elsevier Science B.V., Amsterdam, 2000, 23, 563; (c) P.
Heretsch, L. Tzagkaroulaki and A. Giannis, Angew. Chem., Int. Ed.,
2010, 49, 3418 and citations therein.
( )-5-Benzyl-9-methoxy-6,6-dimethyl-6,6a-dihydro-5H-indeno-
[1,2-c]quinoline (10h). As described for 4a, 9 (100 mg, 0.26 mmol)
in anhydrous DCM (10 mL), and triflic acid (0.0225 mL, 0.26
mmol), furnished 10h (75 mg, 79%) as a a colourless semi solid,
Rf = 0.67 (AcOEt/hexane, 10 : 90); IR(KBr) : 3022, 2361, 1218,
1
763 cm-1; H NMR (300 MHz, DMSO-d6): d 7.55 (dd, 1H, J1 =
1.6, J2 = 7.9 Hz), 7.48–7.34 (m, 5H), 7.27–7.22 (m, 1H), 7.02–6.95
(m, 2H), 6.70–6.62 (m, 2H), 6.34 (d, 1H, J = 8.4 Hz), 4.87 (d,
1H, J = 18.7 Hz), 4.19 (d, 1H, J = 17.3 Hz), 3.78 (s, 3H), 3.71 (s,
1H), 1.74 (s, 3H), 0.62 (s, 3H); MS (ESI): m/z 368 [M+1]+; Anal.
Calcd. for C26H25 NO: C, 84.98; H, 6.86; N, 3.81. Found: C, 85.08;
H, 6.72; N, 3.93.
3 H. Ohtsu, M. Iwamoto, H. Ohishi, S. Matsunaga and R. Tanaka,
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4 (a) U. R. Ghatak and J. Chakravarty, Tetrahedron Lett., 1966, 7, 2449;
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1968, 24, 1577; (c) U. R. Ghatak, J. Chakravarty, R. Dasgupta and
P. J. Chakraborti, J. Chem. Soc., Perkin Trans. 1, 1975, 2438; (d) J.
Chakravarty, R. Dasgupta, J. K. Ray and U. R. Ghatak, Proc. Indian
Acad. Sci., 1977, 86A, 317; (e) P. J. Chakraborti, S. Ghosh, P. B. Kanjilal,
G. O. S. V. Satyanarayana and U. R. Ghatak, Indian J. Chem., 1979,
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5 S. R. Angle and D. O. Arnaiz, J. Org. Chem., 1992, 57, 5937.
6 (a) H. Ishibashi, T. Kobayashi, S. Nakashima and O. Tamura,
J. Org. Chem., 2000, 65, 9022; (b) H. Ishibashi, T. Kobayashi and D.
Takamatsu, Synlett, 1999, 1286.
6, 6-Dimethyl-6, 11-dihydroindeno [1, 2-c] chromene (11g). As
described for 4a, 6g (100 mg, 0.37 mmol) in anhydrous benzene
(10 mL), and triflic acid (0.0321 mL, 0.37 mmol), furnished 11g
(62 mg, 67%) as a colourless semi solid, Rf = 0.84 (AcOEt/hexane,
10 : 90); IR (KBr): 2364, 1667, 1595, 670 cm-1; 1H NMR (300 MHz,
DMSO-d6): d 7.49 (d, 2H, J = 6.9 Hz), 7.31–7.08 (m, 5H), 6.92–
6.78 (m, 2H), 3.70 (s, 2H), 1.68 (s, 6H) 13C NMR (75 MHz, DMSO-
d6): d 152.6, 144.4, 142.3, 134.7, 129.9, 127.5, 125.7, 125.1, 124.2,
121.7, 121.3, 120.9, 116.5, 79.3, 35.9, 28.2; MS (ESI): m/z 249
[M+1]+; Anal. Calcd. for C18H16 O: C, 87.06; H, 6.49; Found: C,
87.16; H, 6.38.
7 W. F. Bailey, T. Daskapan and S. Rampalli, J. Org. Chem., 2003, 68,
1334.
8 J. K. Mukhopadhyaya, S. Pal and U. R. Ghatak, Synth. Commun.,
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1097; (c) S. K. Das, R. Singh and G. Panda, Eur. J. Org. Chem., 2009,
4757.
11 For recent work and reviews on Nazarov chemistry, see: (a) M.
Harmata, Chemtracts, 2004, 17, 416; (b) M. A. Tius, Eur. J. Org. Chem.,
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6, 6-Dimethyl-6, 11-dihydroindeno [1, 2-c] thiochromene (11i).
As described for 4a, 6h (100 mg, 0.35 mmol) in anhydrous benzene
(10 mL), and triflic acid (0.032 mL, 0.35 mmol), furnished 11i
(60 mg, 65%) as a colourless semi solid, Rf = 0.82 (AcOEt/hexane,
1
10 : 90); IR (KBr): 2361, 1684, 669 cm-1; H NMR (300 MHz,
DMSO-d6): d 7.70 (d, 1H, J = 7.3 Hz), 7.52–7.49 (m, 2H), 7.27–
7.20 (m, 5H), 3.80 (s, 2H), 1.73 (s, 6H); MS (ESI): m/z 265 [M+1]+;
Anal. Calcd. for C18H16 S : C, 81.77; H, 6.10;. Found: C, 81.87; H,
5.98.
( )-8, 9-Dimethoxy-6,6a-dihydro-5H-benzo[a]fluorene (10j).
As described for 4a, 6j (70 mg, 0.24 mmol) in anhydrous DCM
(5 mL), and Sc(OTf)3 (2 mol%), furnished 10j (54 mg, 85%) as a
colourless semi solid, Rf = 0.67 (AcOEt/hexane, 10 : 90); IR (KBr):
1
1453, 1213, 1037 cm-1; H NMR (300 MHz, CDCl3): d 7.68 (d,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 4782–4790 | 4789
©

13 J. M. Shimkus, G. Majetich, 58th Southeastern Regional Meeting of
the American Chemical Society, Augusta, GA, November 1-4, 2006.
Abstract # SRM06-633.
14 E. Alvarez-Manzaneda, R. Chahboun, E. Cabrera, E.
Alvarez, A. Haidour, R. Alvarez-Manzaneda, R. Meneses,
H. Es-Samti and A. Ferna’ndez, J. Org. Chem., 2009, 74,
3384.
15 (a) K. F. Cheng, K. P. Chan and T. F. Lai, J. Chem. Soc., Perkin Trans.
1, 1991, 2461; (b) C. Song, D. Knight and M. Whatton, Org. Lett.,
2006, 8, 163; (c) J. A. Malona, J. M. Colbourne and A. J. Frontier, Org.
Lett., 2006, 8, 5661.
16 Bromo compound 2e was synthesized from commercially available a-
tetralone, following similar reaction conditions as in Scheme 2, and was
used immediately due to its unstable nature.
4790 | Org. Biomol. Chem., 2011, 9, 4782–4790
This journal is
The Royal Society of Chemistry 2011
©