Tandem Addition/Electrocyclization/Benzylation of Alkyl Aryl-1,3-dienes and Aromatic Aldehydes: Access to Highly Substituted Indenes

Article abstract of DOI:10.1021/acs.joc.9b00679

BF₃·Et₂O-mediated synthesis of multisubstituted indenes from alkyl aryl-1,3-dienes and aromatic aldehydes through tandem addition/4π-electrocyclization/benzylation via tetrahydroindeno-oxepine/quinone methide followed by an intramole

Full text of DOI:10.1021/acs.joc.9b00679

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Article
Tandem Addition/Electrocyclization/Benzylation of Alkyl Aryl-1,3-
dienes and Aromatic Aldehydes: Access to Highly Substituted Indenes
S K Mahesh, Jagadeesh Babu Nanubolu, and Gangarajula Sudhakar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00679 • Publication Date (Web): 29 May 2019
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Tandem Addition/Electrocyclization/Benzylation of Alkyl Aryl-1,3-dienes and Aromatic
Aldehydes: Access to Highly Substituted Indenes
†
‡
,†
S. K. Mahesh, Jagadeesh Babu Nanubolu, Gangarajula Sudhakar*
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†
‡
Department of Organic Synthesis & Process Chemistry, and Centre for X-ray Crystallography,
CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India.
Email: gsudhakar@iict.res.in
Ar
OH
Ar
O
Ar
MeO
Ar
MeO
Highly substituted indenes
from new synthetic pathway
MeO
R1
Ar
R1
MeO
O
ArCHO
R1
R1
Up to 3 C-C bond formations
Up to 30 examples
Lewis
Acid
R2
OMe
R2
OMe
R2
OMe R2
MeO
Abstract: BF .Et O mediated synthesis of multisubstituted indenes from alkyl aryl-1,3-dienes
3
2
and aromatic aldehydes through tandem addition/4π-electrocyclization/ and benzylation via
tetrahydroindeno-oxepine/quinone methide followed by the intramolecular 1,6-hydride transfer
is described. This novel reaction pathway was established by the isolation of potential
intermediates and with the support of deuterium labelling studies. In addition, the generality of
this method has been demonstrated by reacting various aromatic aldehydes, which ascertained
the role of aldehyde's electronic effect on the formation of indene derivatives and
tetrahydroindeno-oxepines.
Introduction: Indenes have emerged as vital scaffolds and are often found in various
pharmaceutically important molecules, bioactive natural products,1e,1g,2 functional materials,3
1
4
and metallocene-based olefin polymerization catalyst ligands. The simple structure associated
with such diverse applications of indenes have naturally drawn the attention of several research
groups to develop synthetic methods, and a significant number of reports already exist,5
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including those from transition-metal catalyzed reactions.5b,5d,5e,5f,5g,6 Apart from dehydration of
7
indanols, many conventional approaches for the synthesis of indene derivatives involve direct
intramolecular cyclization of suitably prepared precursors. Certainly, efforts in developing a
variety of intramolecular cyclization precursors such as alcohol substrates,6e,8 2-substituted
ethynylmalonates,9 2-alkenylphenylacetylenes,10 cinnamyl N-tosyl hydrazones,11 2-alkyl-1-
ethynylbenzene derivatives12 arylacetoacetates,13 alkyl aryl dienes14 and converting them into
indene derivatives under optimized reaction conditions have increased the versatility of these
approaches. However, it is highly desirable to access multisubstituted indenes from tandem
reactions which lead to the accelerated synthesis of complex molecules from readily available
starting materials in a convergent manner. Nevertheless, few reports are available for the
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synthesis of indenes from tandem reactions, including some intermolecular tandem C-C bond
formation reactions.6g,16 With interest in Nazarov cyclization (NC), we have developed novel
17
electrocyclization precursors18 for selectivity (regioselective products)18a and reactivity that
provided a variety of structurally diverse indenes and substituted cyclopentadienes.18b-d We
envisaged combining Nazarov cyclization precursor with activated electrophile for additional
bond formation reaction (one-pot multi-reaction process) will result in a more efficient and
straightforward route to obtain substituted indenes having the desired functional groups. Also,
these one-pot reactions are highly advantageous and can minimize protection/deprotection
manipulations, work-up, and purification processes.19
Results and Discussion: We have attempted a cascade reaction of addition followed by a
Nazarov cyclization as shown in figure 1, with the expectation of obtaining indene framework 2
having hydroxyl functional group, two stereogenic centers and formation of two C-C bonds in
one pot from alkyl aryl-1,3-diene 1 and aromatic aldehydes in acidic conditions via intermediates
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A and B. Curiously, our investigation led to the formation of highly substituted indene 3 with
ketone functional group and formation of three C-C bonds from a novel synthetic pathway via
compound 2 and a new tetrahydroindeno-oxepine 4. Herein, we disclose the formation of several
highly substituted indenes and their key intermediates from an unexpected pathway, including
substrate scope, limitations, and mechanistic aspects.
1
1
1
1
1
1
1
1
1
1
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Previous work:
OR
CO R
2
CO R
RO C
2
2
RO C
2
OA
CO R
2
R3
R1
R2
R3
R4
R1
R3
R4
R1

 electro
R5
R5
R5
cyclization
R4
R2
R2
This work
MeO
LA
O
O
LA
Ar
R1
H
Ar
ArCHO
MeO
R1
MeO
R1
Lewis
Acid
R2
1
R2
R2
MeO
A
B
MeO
MeO
4
 electro
cyclization OH
Ar
Ar
O
Ar
Ar
MeO


O

Ar
MeO
R1
MeO
R1
R1


R2
3
R2
R2
MeO
MeO
2
4
MeO
unexpected
unexpected
expected
Figure 1. Previous and present plan of work and unexpected products 3 and 4.
Our investigation started by reacting 1a18b with benzaldehyde with various Lewis/Brønsted acids
(Table 1). Initially, we did not observe the desired product with TiCl and SnCl at 78 °C
4
4
(entries 1-2), whereas with TfOH at the same temperature complex mixture was found (entry 3).
Nonetheless, with 1.5 equiv BF .OEt , we observed two new spots on TLC with ~25% reaction
3
2
conversion (at 78 °C) which on leaving at rt gave entirely unexpected product 3a in 40% yield
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(
entry 4). Further, with 2 equiv of benzaldehyde at 78 °C to 0 °C or rt, the reaction conversion
increased dramatically, and to our surprise, only 3a was obtained in 62-68% yield (entry 5-6).
Increasing the duration of the reaction and concentration of BF .OEt improved the yield of 3a
3
2
0
1
2
3
4
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1
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9
0
(entries 7 and 8). The attempt to uncover 2a resulted in finding an optimum yield for 3a: treating
1
a with 2.5 equiv of benzaldehyde and 3.5 equiv of BF .OEt afforded 3a in 96% yield (entry 9).
3
2
Interestingly, with BF .OEt (2.2 equiv) and PhCHO (1.2 equiv) and quenching the reaction at
3
2

78 °C after 3 h gave initially expected product 2a (47%), along with 3a (15%), and other
unexpected products, tetrahydroindeno-oxepines 4a1-4a2 (dr 6:4, 25%) (entry 10 of Table 1 and
Scheme 1). Compound 2a was isolated as an inseparable diastereomeric mixture (dr 1.5:1), thus
converting it to compound 5 provided simplified NMR, which further facilitated in assigning the
structure of 2a (Scheme 1). The structure and relative configuration of 4a1 was further
confirmed by the single crystal X-ray analysis (Scheme 1).20
Table 1. Optimization of reaction conditions for 3a and formation of 2a and 4a
Ph
Ph

Ph
MeO
OH
O
MeO
Me
Me
PhCHO
conditions
Table 1
MeO
Me
Me

1a
Me
OMe
Me
2a
3a
MeO
MeO
PhCHO (equiv) time 2a/3a/4a (Yield %)a
Entry Reagent (equiv) Temp
1
) TiCl (1.5)
-78 C
-78 C
-78 C
-78 C
1.1
1.1
1.1
1.1
2h
3h
2h
2h
nr
4
2
) SnCl (1.5)
nr
cm
4
3) TfOH (1.5)
4
) BF .Et O (1.5)
only 3a (40) a
3
2
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) BF .Et O (2.0)
-78 C
0 C
0 C
0 C
rt
2.0
2.0
2.0
2.5
2.5
1.2
2h
2h
4h
4h
6h
3h
only 3a (62) a
only 3a (68)a
3
2
) BF .Et O (2.0)
3
2
1
1
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9
0
7) BF .Et O (2.5)
only 3a (83)a
3
2
only 3a (92)a
8
9
1
) BF .Et O (3.0)
3 2
) BF .Et O (3.5)
only 3a (96)
3
2
0) BF .Et O (2.2)
-78 C
2a(47)/3a(15)/4a(25)b
3
2
a
All reactions were performed with 0.1 mmol of 1a in 1 mL of CH Cl (0.1 M). Reaction was run
2
2
b
at -78 C/0 °C to rt; based on recovery of starting material (brsm); nr: no reaction; cm: complex
mixture.
2
1
Having obtained novel products 3a and 4a1-4a2, we carried out systematic control experiments
to find out the relation among 2a, 3a, and 4a1-4a2, and also to gain insight into the reaction
mechanism (Scheme 1). First, reacting 2a with benzaldehyde under optimized reaction
conditions delivered 3a in 88% yield, indicating compound 2a is an intermediate of 3a. Besides,
we observed 4a1-4a2 in high yields in short reaction times along with a small amount of 3a
when compound 2a was reacted at 78 °C (with benzaldehyde and BF .Et O). On the other hand,
3
2
increasing the reaction temperature from 78 °C to rt, 4a1-4a2 slowly diminished and 3a formed
in 76% yield, implying that 4a1-4a2 might also be intermediates of 3a. This was evidenced by
reacting 4a1, and 4a2 individually or their mixture with BF .Et O at rt, which gave 3a in good
3
2
yield. Overall, these experiments suggest that under standard reaction conditions, 1a would
provide 3a through 2a and tetrahydroindeno oxepines 4a1-4a2.
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Scheme 1. The reaction and control experiments
Ph
Ph
MeO
MeO
Me
Me
O
PhCHO
Me
0
1
2
3
4
5
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7
8
9
0
1
2
3
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9
0
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9
0
1
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0
1
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8
9
0
BF .Et O
3
2
CH Cl , rt
1a
2
2
BF
h
MeO
BF .Et O, CH2Cl2
Me
O
3a
3
3
.Et2
.Et
MeO
3
2
BF3
2
°
C,
Ph

,
O,
-78 °C, 3 h
8
8%
Ph
rt,
-78
,
PhCHO
Cl2
OH
CH
2
CH
O
MeO
Me
2
Cl
DMP
CH Cl2
MeO
Me
2
,

2
3
4
a (15%) +
a1-4a2 (25%)
Me
2a (47%)
r t ,
90%
, 2
Me
1
MeO
5
h ,
MeO
.
O 3 E t
CH Cl
8 7 %
BF3.Et2O,
2
2
B F
-78 °C, 3 h, 76%
Ph
Ph
Me
O
O
Ph
MeO
Me
Ph
MeO
Me
+
Me
MeO
MeO
4a2
4a1
a
All reactions were performed in 1 mmol scale in 0.1 M CH Cl .
2
2
Based on the control experiments in Scheme 1, we propose a plausible reaction mechanism for
the formation of indene 3a from 1a (Scheme 2). We surmise that benzaldehyde would coordinate
with the Lewis acid (BF .Et O) to form an active complex I, which is attacked by alkyl aryl-1,3-
3
2
diene, i. e. 1a, to give an intermediate II (via addition of alkene to activated aldehyde to form the
first C-C bond) comprising of the incipient arylvinyl cation, a requisite for Nazarov cyclization.
Subsequently, II would undergo electrocyclization16d to give addition/Nazarov cyclization
product 2a (formation of second C-C bond). This would further react with another equivalent of
active complex I to attain hemiacetal complex III, which is attacked by an electron-rich aryl
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group to provide tetrahydroindeno-oxepines 4a1-4a2 via IV (formation of third C-C bond).
Consequently, the excess amount of BF .Et O present in the reaction mixture would coordinate
3
2
with oxepine oxygen to form the ionic complex V, and then the duly positioned methoxy group
would facilitate the opening of oxepine ring to form the quinone methide VI. Finally, an
intramolecular 1,6-hydride transfer would provide 3a as exemplified in Scheme 2.
Scheme 2. The proposed reaction mechanism for the formation of 3a from 1a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
OEt .F B
O
H
2
3
H
OEt .F B
O
2
3
O
O
I
OEt .F B
2
3
I
Ph
H
Ph
Ph
Ph
Me
MeO
Me
MeO
MeO
Me
4

con
Addition
C-C (1)
electrocyclization
C-C (2)
Me
Me
2a
Me
MeO
H
MeO
II
1a
MeO
Ph
OEt .F B
Ph
2
3
O
O
Ph
Ph
MeO

O

Ph
H
MeO
Ph
O
Me
Me
MeO
Me
Me

C-C (3)
Me
MeO
IV
Me
III
OMe
4a1-4a2
OMe
Ph
1
Ph
F3B
F3BO
Ph
Ph
H
O
Ph
H
2
3
Ph
6
5
O
MeO
,6-hydride shift
BF3
MeO
4
Me
Me
MeO
Me
1
-
Me
Me
Me
VI
MeO
3a
OMe
V
OMe
To ascertain the proposed mechanism, we have conducted experiments with deuterium-labelled
compounds as shown in Scheme 3. Treating compound 1a with benzaldehyde-α-D122 under
standard reaction conditions afforded D2-3a in 86% yield, whereas the same reaction performed
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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at 78 °C followed by quenching at 78 °C furnished D1-2a in 50% yield (brsm). Treating D1-
2
a with benzaldehyde-α-D1 afforded D2-3a, apparently due to the intramolecular 1,6-hydride
transfer. This was further confirmed by reacting D1-2a with benzaldehyde, and obtaining D1-3a
in 90% yield. The 1,5 and 1,6-hydride shift adjacent to nitrogen (tert-amine effect) or oxygen
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
(
ether) are well known in the literature, but to the best of our knowledge, the intramolecular
1,6-hydride shift from adjacent to the hydroxyl group to in situ generated quinone methide has
not been previously reported. The transformation of 2a to 3a is also reminiscent of the
intermolecular benzylation of arenes to synthesize diarylmethanes, in which benzyl phenyl ether,
benzyl hydroxamate, benzyl fluoride, and benzyl alcohol were commonly employed as an
24
electrophilic source. Notably, in this study aromatic aldehydes served as electrophile to obtain
diarylmethanes through a redox/multi-reaction process in one-pot.
Scheme 3. Deuterium labelling experiments
MeO
Me
Me
PhCDO
D
D
O
BF .Et O, CH Cl , rt
3
2
2
2
MeO
Me
MeO
1a
PhCDO CH Cl
Me
2
2
BF .Et O -78 °C
MeO D2-3a (86%)
3
2
Cl2
CH2
O,
Et2
.
D
BF3
rt,
80%
9
h,
D
O
OH
Me
MeO
MeO
Me
PhCHO
BF .Et O, CH Cl , rt
3
2
2
2
Me
Me
MeO D1-2a
MeO
D1-3a (90%)
(50% (brsm))
With optimal reaction conditions for the synthesis of 3a including its reaction mechanism in
hand, we became interested in the scope and generality of this novel method and results are
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illustrated in Scheme 4. First, variations of the indene ring (substitutions R and R ) were
1
2
explored: Me at R and Et, Ph, and di-Me at R -position afforded 3b-d in excellent yields (92-
1
2
i
95%). A substrate bearing Ph at R and Pr at R positions worked well to give 3e in 94% yield.
1
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Compounds containing tricyclic systems 3f-g were also obtained in good yields. Next, we
explored the substrate scope with various differently substituted aromatic aldehydes. 3,5-
Dimethoxybenzaldehyde, and 2-naphthaldehyde furnished as expected, indenes 3h (95%) and 3i
i
t
(
89%) in excellent yields. Alkyl groups (Me, Et, Pr, and Bu) at para-position on benzaldehyde
provided compounds 3j-m in 90-94% yields. Benzaldehydes bearing halogens (Cl and Br) at
para, and (F) at the meta-position were also efficiently involved in the reaction to yield
corresponding indenes 3n-p in 89-94% yields. Notably, aromatic aldehydes bearing electron-
withdrawing groups (EWGs) prolonged the reaction time to provide indenes with p-
nitrobenzaldehyde, p-cyanobenzaldehyde, and 4-chloro-3-nitrobenzaldehyde affording 3q-s in
70-79% yields after 5 days. The same compounds provided tetrahydroindeno oxepines 4q (84%,
dr 8:2), 4r (90%, dr 9:1), and 4s (86%, dr 8:2) under standard reaction conditions. Of note, the
reaction of 2,6-dichlorobenzaldehyde even after prolonged reaction time furnished only
tetrahydroindeno oxepines 4t1 and 4t2 (single crystal X-ray analysis confirmed the structure) in
9
1% yield and 9:1 diastereomeric ratio, and no indene derivative was observed. This may be due
to the steric hindrance of two O,O-dichloro atoms on two aryl groups, deterring the coordination
of Lewis acid with the oxygen atom of oxepine, which could be detrimental to the formation of
quinone methide. Conversely, 1a with aliphatic aldehydes under standard reaction conditions
resulted in a complex mixture. However, with paraformaldehyde at 78 °C gave a trace amount
of addition/Nazarov cyclization product (not shown), and with ketones 1a did not react.
Scheme 4. Substrate scope with various groupsa,b
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Ar
Ar
MeO
MeO
R1
O
ArCHO, BF .Et O
3
2
R1
CH Cl , rt
R2
2
2
MeO
R2
MeO
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
O
MeO
Me
MeO
Me
MeO
OMe
Ph
3
3
a: R = Me (96%)
b: R = Et (92%)
3c: R = Ph (95%)
Me
d (93%)
Me
R
Me
MeO
MeO
MeO
e (94%)
Me
3
3
MeO
OMe
O
O
Me Me
MeO
O
Me
MeO
MeO
MeO
Me
3g (84%)
Me
MeO
MeO
3f (89%)
MeO
3h (95%)
R
F
3
3
3
j: R = Me (93%)
k: R = Et (90%)
l: R = iPr (93%)
F
R
3m: R = tBu (94%)
3n: R = Cl (94%)
O
O
O
MeO
Me
MeO
Me
Me
3o: R = Br (93%)
MeO
3
q: R = NO (75%)
r: R = CN (79%)
2
Me
3
Me
3i (89%)
Me
MeO
O
3p (89%)
MeO
NO2
MeO
Cl
R
Cl
O N
2
O N
2
Cl
NO2
R
Cl
O


O
MeO
MeO
MeO
Me
Me
Me
Me
s (70%)
Me
4q: R = NO2 (84%, dr 8:2)
Me
s (86%, dr 8:2)
MeO
MeO
MeO
4
3
4
r: R = CN (90%, dr 9:1)
Cl
Cl
Cl
Cl
O
Cl
O
Cl
Cl
MeO
Cl
MeO
Me
Me
Me
)-4t1 (91%)
MeO
(
Me
()-4t2
MeO
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a
Reaction conditions: ArCHO (0.25 mmol) was dissolved in CH Cl (0.5 mL) at rt under argon
2
2
atmosphere, and then BF .Et O (0.35 mmol) was added. After 15-20 minutes, alkyl aryl 1,3-
3
2
dienes 1 (0.1 mmol) in CH Cl (0.5 mL) was cannulated drop wise and the reaction mixture was
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
b
run for 6 h; diastereomeric ratio (dr) is based on the H NMR; The products 3q-s were obtained
after running the reaction mixture for 5 days.
Our further attempts to perform this reaction in one-pot with two different aromatic aldehydes by
taking both together or sequential addition led either to a complex mixture or indenes with homo
aryl groups in low yields. Nevertheless, this compelling reaction pathway prompted us to explore
the possibility of 2a reacting with various aromatic aldehydes, which can lead to the formation of
indene derivatives with two different aryl groups, thus expanding the scope of this method
further. We were delighted to observe the reaction of various aromatic and heteroaromatic
aldehydes, for instance, p-bromobenzaldehyde, 3,5-dimethoxybenzaldehyde, 2-naphthaldehyde,
and 2-thiophenecarboxaldehyde, with 2a provided 3t-w in excellent yields (Scheme 5).
Interestingly, aromatic aldehydes bearing EWGs such as p-nitrobenzaldehyde, p-
cyanobenzaldehyde,
4-chloro-3-nitrobenzaldehyde,
2,6-dichlorobenzaldehyde,
and
pentafluorobenzaldehyde also furnished indenes 3x-z and 3aa-ab in 78-86% yields within
stipulated reaction time, except in case of 3y and 3ab (1 h). Further, p-cyanobenzaldehyde and
pentafluorobenzaldehyde provided tetrahydroindeno oxepines 4y and 4ab, respectively under
standard reaction conditions.
Scheme 5. Substrate scope with two different aryl groups.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
4
4
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5
5
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5
5
5
5
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R
Ph
Ph
OH
CHO
R
O
MeO
Me
MeO
Me
BF .Et O, CH Cl , rt
3
2
2
2
Me
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
MeO
MeO
2a
3
MeO
MeO
OMe
Br
O
MeO
O
O
Me
MeO
Me
Me
Me
Me
u (94%)
Me
MeO 3t (89%)
MeO
MeO
3v (94%)
3
R1
R
Cl
O
S
O
O
MeO
Me
Cl
MeO
Me
MeO
Me
Me
Me
Me
MeO 3aa (83%)
MeO
3x: R = NO , R = H (85%)
MeO 3w
(
85%)
2
1
3y: R = CN, R = H (86%)
1
3z: R = Cl, R = NO (78%)
1
2
F
F
F
F
F
F
NC
F
O
O


O
F
F
MeO
MeO
F
Me
MeO
Me
Me
Me
Me
Me
4ab (89%, dr 7:3)
MeO
MeO
MeO
4y (83%, dr 8:2)
3
ab (81%)
a
Reaction conditions: ArCHO (0.12 mmol) was dissolved in CH Cl (0.5 mL) at rt under argon
2
2
atmosphere, and then BF .Et O (0.22 mmol) was added. After 15-20 min, indenyl alcohol 2a (0.1
3
2
mmol) in CH Cl (0.5 mL) was cannulated drop wise, and the reaction mixture was run for 30
2
2
min to 1 h.
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Based on the results in Scheme 4 and Scheme 5, we surmise that aromatic aldehydes with
or without electron-donating groups would give substituted indenes, while with electron-
withdrawing groups would yield tetrahydroindeno oxepines under standard reaction conditions.
This may be due to aromatic aldehydes bearing EWGs are more reactive than the aromatic
aldehydes with or without EDGs toward the formation of tetrahydroindeno oxepines. But, the
conversion of tetrahydroindeno oxepines into indenes is sluggish when aromatic aldehydes
having EWGs, apparently due to the instability of incipient cation in intermediates V and VI
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Scheme 2), decelerating the formation of quinone methide and subsequent 1,6-hydride shift,
thus, ending up the reaction at tetrahydroindeno oxepines.
Conclusion
In conclusion, we have developed an unprecedented method to access highly substituted indenes
from metal-free reaction conditions, using operationally simple and readily available starting
materials. Isolation of potential intermediates and deuterium labeling experiments unraveled the
novel reaction pathway. Various substrates were employed to demonstrate the generality of this
reaction and defined the role of the electronic effects of aromatic aldehydes: aromatic aldehydes
bearing EDGs would yield indenes derivatives, whereas, EWGs would provide tetrahydroindeno
oxepines. The optimum reaction conditions for the probable intermediates such as
addition/Nazarov cyclization product 2 and tetrahydroindeno oxepines 4 were also established.
The scope to add variations in the starting materials has enormous potential to build a compound
library for broad applications. The elaboration of this method and applications thereof is under
progress and will be reported in due course.
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6
Experimental Section
General Materials and Methods: Anhydrous solvents were dried and distilled by standard
methods before use. Commercially available reagents were used without further purification
unless otherwise specified. All the reactions were performed under an atmosphere of nitrogen or
argon in oven-dried glassware with magnetic stirring. Column chromatography was carried out
using silica gel (60-120 or 100-200 or 230-400 mesh) and basic Al O , and the column was
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
eluted with ethyl acetate-petroleum ether or hexane. Visualization of the spots on TLC plates
was achieved either by UV light or by staining in the plates in methanolic anisaldehyde-sulphuric
acid-acetic acid solution and charring on a hot plate. H NMR, 13C NMR were recorded in a
1
CDCl solvent on 600 MHz, 500 MHz, 400 MHz, 300 MHz, and 75 MHz, 100 MHz, 125
3
MHz,150 MHz spectrometers, respectively at ambient temperature. Chemical shifts are as δ
1
13
values relative to internal CHCl δ 7.26 or TMS δ 0.0 for H NMR and CHCl δ 77.0 for C
3
3
1
NMR. H NMR data is recorded as follows: chemical shift [multiplicity, coupling constant(s) J
(Hz), relative integral] where multiplicity is defined as: s = singlet; d = doublet; t = triplet; q =
quartet; dd = doublet of doublet; dt = doublet of triplet; dq = doublet of quartet; tt = triplet of
triplet; ddd = doublet of doublet of doublet; m = multiplet; brs = broad singlet; brd = broad
doublet; qq = quartet of quartet. FTIR spectra were recorded as KBr thin films or neat. Mass
spectra were recorded for ESI and are given in mass units (m/z). High resolution mass spectra
(HRMS) [ESI+] were obtained using either a TOF or a double focusing spectrometer. Melting
points were determined using Cintex melting point apparatus.Single crystal X-ray data for the
compounds were collected on Bruker Smart Apex CCD diffractometer and Bruker D8 QUEST.
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General procedure for the synthesis of alkyl aryl 1,3-dienes 1 from dienyl ketones:18b
(E)-1,3-Dimethoxy-5-(3-methylpenta-1,3-dien-2-yl)benzene (1a):
To a stirred solution of (E)-1-(3,5-dimethoxyphenyl)-2-methylbut-2-en-1-one18b (3.60 g,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
6.36 mmol, 1.0 equiv) in THF (82 mL) under argon at -78 ˚C was added
(trimethylsilyl)methyllithium solution (Me SiCH Li) (1 M in pentane, 25.0 mL, 24.54 mmol, 1.5
3
2
equiv) drop wise. The reaction mixture turned to yellow color, and the reaction was monitored
by using TLC. When the starting material completed, the reaction mixture was quenched with
aqueous NH Cl (10 mL) at -78 ˚C, followed by the addition of water (10 mL) and hexanes (20
4
mL). The separated aqueous phase was extracted with hexanes (300 mL), and the combined
organic phase was dried over anhydrous Na SO , filtered and concentrated in vacuo. The yellow
2
4
color oil residue was enough to keep the next reaction without further purification.
To a stirred solution of alcohol (4.50 g, 14.61 mmol, 1 equiv) in THF (73 mL) under
argon at 0 ˚C was added KHMDS (0.5 M in toluene, 58.5 mL, 29.22 mmol, 2.0 equiv) drop wise.
The reaction mixture turned to dark color, and when the starting material was consumed
completely (monitored by using TLC), it was quenched with aqueous NH Cl (30 mL), and
4
hexanes (50 mL). The separated aqueous phase was extracted with hexanes (300 mL), and the
combined organic phase was dried over anhydrous Na SO filtered and concentrated in vacuo.
2
4,
The dark color residue was purified by flash column chromatography by using basic Al O ,
2
3
hexanes as eluent (500 mL) to give alkylaryl 1,3-diene 1a as pale yellow oil (3.3 g, 80%). R =
f
1
0
.5 (5% EtOAc/hexanes); H NMR (400 MHz, CDCl ): δ 6.56 (d, J = 2.3 Hz, 2H), 6.40 (t, J =
3
2
.3 Hz, 1H), 5.56 (qq, J = 6.8, 1.3 Hz, 1H), 5.54 ( d, J = 1.7 Hz, 1H), 5.02 ( d, J = 1.7 Hz, 1H),
1
3
3.80 (s, 6H), 1.79 (pentet, J = 4.4, 2.8, 1.3 Hz, 3H), 1.59 (dq, J = 6.8, 1.3 Hz, 3H); C{H} NMR
(
100 MHz, CDCl ): δ 160.7, 148.4, 141.6, 136.9, 122.9, 113.2, 104.5, 99.3, 55.2, 24.0, 14.7; IR
3
(Neat): νmax 2938, 2835, 1600, 1459, 1426, 1339, 1291, 1202, 1153, 1115, 1052, 926, 843, 753,
+
7
00; HRMS (ESI-TOF) m/z calcd for C H O (M+H) 219.1385, found 219.1379.
1
4
19
2
2
-(4-Benzyl-5,7-dimethoxy-1,2-dimethyl-1H-inden-3-yl)-1-phenylethan-1-one (3a):
Benzaldehyde (0.35 mL, 3.44 mmol, 2.5 equiv) was dissolved in CH Cl (7 mL) under argon and
2
2
stirred at room temperature. To this, boron trifluoride diethyl etherate (BF .Et O) (0.60 mL,
3
2
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
.816 mmol, 3.5 equiv) was added dropwise. The reaction mixture was stirred for 15-20 minutes,
and (E)-1,3-dimethoxy-5-(3-methylpenta-1,3-dien-2-yl)benzene (1a)18b (300 mg, 1.376 mmol,
1.0 equiv) in CH Cl (7 mL) was cannulated dropwise to the reaction mixture. The dark color
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
solution was stirred at room temperature for 6 h and monitored by TLC. Thereaction mixture was
quenched with the saturated aqueous NaHCO (7 mL) at 0 C. The aqueous phase was extracted
3
with EtOAc (80 mL), and the combined organic layers were washed with brine solution (10 mL),
dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by using silica
2
4
gel column chromatography to afford the desired product ketone 3a as white foam (545 mg),
1
Yield: 96%; white foam; R = 0.5 (10%EtOAc/hexanes). H NMR (500 MHz, CDCl ): δ 7.85 (d,
f
3
J = 7.1 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.3 Hz, 2H), 7.18 (t, J = 7.4 Hz, 2H), 7.13
(m, 1H), 6.84 (d, J = 7.4 Hz, 2H), 6.40 (s,1H), 4.04 (s, 2H), 3.97 (s, 2H), 3.92 (s, 3H), 3.76 (s,
1
3
3
H), 3.39 (q, J = 7.3 Hz, 1H), 1.87 (s, 3H), 1.38 (d, J = 7.3 Hz, 3H); C{H} NMR (100 MHz,
CDCl ): δ197.0, 158.5, 153.9, 150.3, 145.2, 142.1, 136.7, 133.0, 128.9, 128.4, 128.2, 128.1,
3
1
27.7, 127.6 125.4, 112.5, 92.3, 56.3, 55.3, 45.0, 37.2, 30.0, 14.9, 12.3; IR (Neat): νmax 2925,
2
852, 1685, 1594, 1493, 1450, 1314, 1212, 1129, 1046, 767, 698; HRMS (ESI-TOF) m/z calcd
+
for C H O (M+H) 413.2117, found 413.2121.
2
8
29
3
Standard Procedure for Synthesis of Indenyl Alcohol (2a) & oxepines (4a1-4a2):
Gram scale synthesis (entry 10 of Table 1) Benzaldehyde (1.7 mL, 16.513 mmol, 1.2 equiv)
was dissolved in CH Cl (35 mL) under argon and cooled to -78 C. To this, BF .Et O (3.8 mL,
2
2
3
2
30.27 mmol, 2.2 equiv) was added dropwise. The reaction mixture was stirred at -78 C for 30
minutes and dienyl olefin 1a18b (3.0 g, 13.761 mmol, 1.0 equiv) in CH Cl (35 mL) was
2
2
cannulated dropwise to the reaction mixture, and the yellow color solution was stirred at -78 °C
for further 3 h. Thereaction mixture was quenched with the saturated aqueous NaHCO (10 mL)
3
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at -78C. The aqueous phase was extracted with EtOAc (120 mL), and the combined organic
layers were washed with brine solution (15 mL), dried over Na SO , filtered, and concentrated in
2
4
vacuo. The residue was purified by using silica gel column chromatography to provide indenyl
alcohol 2a (1.4 g, 47%, brsm), indene 3a (590 mg, 15%), and oxepines 4a1 & 4a2 (combined
weight 955 mg, 25%).
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-(5,7-Dimethoxy-1,2-dimethyl-1H-inden-3-yl)-1-phenylethanol (2a): Yield: (1.4 g, 47%,
1
brsm); dr: 1.5:1; Yellow foam; R = 0.5 (20% EtOAc/hexanes); H NMR (500 MHz, CDCl ): δ
f
3
7
.40-7.30 (m, 4H), 7.29-7.26 (m, 1H), 6.51 (d, J = 1.8 Hz, 0.4H), 6.50 (d, J = 1.8 Hz, 0.6H),
.32 (m, 1H), 4.95 (m, 1H), 3.86 (s, 3H), 3.85 (s, 1.3H), 3.84 (s, 1.7H), 3.26 (q, J = 7.3 Hz,
6
0.4H), 3.23 (q, J = 7.3 Hz, 0.6H), 2.96 (m, 1H), 2.86 (m, 1H), 2.10 (brs, 0.4H), 2.08 (brs, 0.6H),
13
1
.76 (s, 1.7H), 1.70 (s, 1.3H) 1.30 (d, J = 7.3 Hz, 1.7H), 1.23 (d, J = 7.3 Hz, 1.3H); C{H}
NMR (100 MHz, CDCl ): δ 160.5, 155.6, 149.2, 149.1, 147.3, 147.2, 144.1, 144.0, 130.8, 130.7,
3
128.2, 128.1, 127.5, 127.4, 126.8, 126.7, 125.8, 125.7, 96.5, 96.4, 94.7, 94.6, 73.2, 55.5, 55.1,
4
5.6, 45.5, 36.0, 35.9, 14.6, 14.4, 12.0, 11.9; IR (Neat): νmax 3443, 2959, 2929, 2839, 1595, 1590,
1
485, 1452, 1352, 1293, 1206, 1157, 1138, 1041, 933, 823, 758, 700; HRMS (ESI-TOF) m/z
+
calcd for C H O (M+H) 325.1814, found 325.1798.
21 25
3
(±)-(1S,3R,6R)-7,9-Dimethoxy-5,6-dimethyl-1,3-diphenyl-1,3,4,6-tetrahydroindeno[7,1-
1
cd]oxepine (4a1, top): Yellow foam; R = 0.6 (10%EtOAc/hexanes); H NMR (700 MHz,
f
CDCl ): δ 7.25-7.22 (m, 2H), 7.22-7.16 (m, 4H), 7.14-7.10 (m, 2H), 7.09 (d, J = 7.0 Hz, 2H),
3
6.57 (s, 1H), 6.33 (s, 1H), 4.70 (dd, J = 7.5, 5.7 Hz, 1H), 3.92 (s, 3H), 3.63 (s, 3H), 3.32 (q, J =
13
7
.3 Hz, 1H), 2.92 (d, J = 5.9 Hz, 2H), 1.86 (s, 3H), 1.32 (d, J = 7.3 Hz, 3H); C{H} NMR (175
MHz, CDCl ): δ 156.8, 154.2, 146.4, 144.9, 143.7, 141.4, 133.0, 128.8, 128.0, 127.6, 127.5,
3
1
27.2, 126.9, 125.9, 116.1, 91.7, 78.8, 73.5, 56.0, 55.3, 45.0, 37.7, 14.7, 12.5; IR (Neat): νmax
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922, 2852, 1600, 1590, 1511, 1452, 1359, 1297, 1207, 1154, 1122, 1066, 744; HRMS (ESI):
+
calcd for C H O (M-H) 411.1960, found 411.1954.
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(±)-
(1R,3R,6R)-7,9-Dimethoxy-5,6-dimethyl-1,3-diphenyl-1,3,4,6-tetrahydroindeno[7,1-
0
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1
cd]oxepine (4a2, bottom): combined Yield : 955 mg, (25%); H NMR (700 MHz, CDCl ): δ
3
7
.24 (t, J = 7.5 Hz, 2H), 7.22-7.18 (m, 4H), 7.16-7.08 (m, 4H), 6.58 (s, 1H), 6.32 (s, 1H), 4.71
(dd, J = 9.7, 3.5 Hz, 1H), 3.91 (s, 3H), 3.62 (s, 3H), 3.28 (q, J = 7.3 Hz, 1H), 2.96-2.87 (m, 2H),
1
3
1.86 (s, 3H), 1.36 (d, J = 7.3 Hz, 3H); C{H} NMR (175 MHz, CDCl ): δ 156.7, 154.1, 146.2,
3
1
7
44.8, 143.8, 141.4, 133.1, 128.9, 128.0, 127.7, 127.6, 127.2, 126.9, 125.9, 116.2, 91.7, 78.8,
3.3, 56.0, 55.3, 44.9, 37.9, 14.7, 12.4; IR (Neat): νmax 2924, 2856, 1603, 1592, 1513, 1450,
+
1361, 1295, 1156, 1123, 1062, 740; HRMS (ESI-TOF) m/z calcd for C H O (M-H) 411.1960,
2
8
27
3
found 411.1954.
Procedure for the Synthesis of 2-(5,7-dimethoxy-1,2-dimethyl-1H-inden-3-yl)-1-
phenylethan-1-one (5): To an 2-(5,7-dimethoxy-1,2-dimethyl-1H-inden-3-yl)-1-phenylethanol
(2a) (200 mg, 0.617 mmol, 1.0 equiv) solution in CH Cl (6 mL) was cooled to 0 C. Then Dess-
2
2
Martin periodinane (DMP) (340 mg, 0.802 mmol, 1.3 equiv) was added portion wise to the
reaction mixture, and slowly warmed to rt. The reaction mixture was monitored by TLC, and
after completion of the starting material, the reaction mixture was filtered through Celite. The
organic solution was washed with aq NaHCO solution, brine solution, dried over Na SO ,
3
2
4
filtered and evaporated under reduced pressure. The residue was purified by using silica gel
column chromatography to afford pure ketone 5. Yield: 180 mg, (90%); colorless oil; R = 0.5
f
1
(10%EtOAc/hexanes); H NMR (400 MHz, CDCl ): δ 8.02 (d, J = 7.0 Hz, 2H), 7.55 (t, J = 7.3
3
Hz, 1H), 7.45 (t, J = 7.3 Hz, 2H), 6.38 (d, J = 1.9 Hz, 1H), 6.28 (d, J = 1.9 Hz, 1H), 4.11 (s, 2H),
1
3
3
.83 (s, 3H), 3.77 (s, 3H), 3.32 (q, J = 7.3 Hz, 1H), 2.00 (s, 3H), 1.29 (d, J = 7.3 Hz, 3H); C{H}
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NMR (100 MHz, CDCl ): δ 197.3, 160.5, 155.6, 148.7, 146.9, 136.8, 133.0, 128.5, 128.4, 128.2,
3
1
26.6, 96.5, 95.0, 55.4, 55.1, 45.6, 36.4, 14.4, 12.5; IR (Neat): νmax 2961, 2928, 2852, 1688,
1592, 1450, 1354, 1286, 1209, 1138, 1084, 1023, 819, 772, 690; HRMS (ESI-TOF) m/z calcd for
1
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+
C H O (M+H) 323.1650, found 323.1641.
2
1
23
3
General Procedure for Synthesis of Oxepines (4a1-4a2): Benzaldehyde (0.17 mL, 1.666
mmol, 1.2 equiv) was dissolved in CH Cl (8 mL) under argon and stirred at -78 °C. To this,
2
2
BF .Et O (0.4 mL, 3.194 mmol, 2.3 equiv) was added dropwise. The reaction mixture was stirred
3
2
for 15-20 minutes, and indenyl alcohol 2a (450 mg, 1.388 mmol, 1.0 equiv) in CH Cl (6 mL)
2
2
was cannulated dropwise to the reaction mixture. The dark color solution was stirred at -78 °C
for 3 h. Thereaction mixture was quenched with the saturated aqueous NaHCO (5 mL) at -78
3

C. The aqueous phase was extracted with EtOAc (50 mL), and the combined organic layers
were washed with brine solution (5 mL), dried over Na SO , filtered, and concentrated in vacuo.
2
4
The residue was purified by using silica gel column chromatography to afford the desired
products, oxepines 4a1-4a2 (combined yield 430 mg, 76%) and ketone 3a (10%).
General Procedure for conversion of Oxepines (4a1-4a2) into Ketone (3a): Oxepines 4a1-
4
a2 (550 mg, 1.334 mmol, 1.0 equiv) was dissolved in CH Cl (14 mL) under argon and stirred
2 2
at room temperature. To this, BF .Et O (0.85 mL, 6.674 mmol, 5.0 equiv) was added dropwise.
3
2
The dark color solution was stirred at room temperature for 1 h. Thereaction mixture was
quenched with the saturated aqueous NaHCO (5 mL) at 0 C. The aqueous phase was extracted
3
with EtOAc (70 mL), and the combined organic layers were washed with brine solution (5 mL),
dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by using silica
2
4
gel column chromatography to afford the desired product ketone 3a as white foam (480 mg,
87%).
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Preparation of benzaldehyde-α-D1:22
S
S
O
n-BuLi, D O
2
D
HgCl , HgO
CHO
2
SH SH
S
S
D
MeOH:H O
CHCl , Dry HCl
THF, -78 °C- 0°C
87%
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reflux, 75%
0 °C-rt, 90%
Step 1: Dry hydrogen chloride was bubbled into a solution of 1,3-propanedithiol (4.72 mL,
7.169 mmol) and benzaldehyde (4.78 mL, 47.169 mmol) in chloroform (355 mL) at 0 °C until
4
the mixture saturated (10-15 minutes). After standing at 25 °C for 30 minutes, the mixture was
washed with two 50 mL portions of water, three 50 mL portions of 10% KOH solution, and two
5
0 mL portions of water, and dried over Na SO , and evaporated under reduced pressure. The
2 4
obtained solid was treated with 1 g of activated charcoal and crystallized from methanol (25 mL)
to give 2-phenyl-1,3-dithiane as colorless crystals (6.3 g, 90%). Step 2: 2-phenyl-1,3-dithiane
(4.8 g, 32.43 mmol) was dissolved in dry THF (160 mL) and cooled to -60 °C (dry
ice/chloroform bath). The reaction flask was deoxygenated with argon over 15-20 minutes, and a
solution of n-BuLi in hexane (1.6 M, 20.3 mL, 32.43 mmol) was then introduced over a period of
1
0 min into the dithiane solution. The reaction mixture was stirred at -60 °C for 6-7 h, and then
D O (>99.9% d, 3.6 mL, 194.58 mmol) was added slowly with stirring and the solution was
2
warmed to room temperature. The solution was neutralized at 0 °C with 1 N HCl (50 mL) and
THF was removed on a rotary evaporator. The solution was extracted with 150 mL portions of
CH Cl /pentane (1:1). The organic phase was washed with 1 N NaHCO (25 mL), water (25
2
2
3
mL), and saturated NaCl solution (25 mL). The residue after evaporation of the solvent was
recrystallized from methanol to give 2-phenyl-1,3-dithiane-2-D1, (4.2 g, 87%). The deuterium
1
incorporation was >90%, based on H NMR. Step 3: A solution of HgCl (5.74 g, 21.20 mmol)
2
in methanol/H O (9:1, 32 mL) was added to a stirred warm mixture (40 °C) of 2-phenyl-1,3-
2
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dithiane-2-D1 (1.58 g, 10.60 mmol) prepared above and HgO (2.0 g, 9.54 mmol) in the same
solvent mixture (19 mL) in a 100 mL flask. The mixture was refluxed with stirring for 4-5 h
under argon and the cooled to room temperature. The white precipitate was removed by
filtration, and the filtrate was distilled through a Vigreux column until about 10 mL remained. To
the residue CH Cl /pentane (1:1, 200 mL) was added, and the solution was washed twice with 20
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2
2
mL of 4 M NH OAc solution and twice with 10 mL portions of saturated NaCl solution and
4
dried over anhydrous Na SO . Solvent was removed by distillation as before to furnish 100 mL
2
4
of liquid, which was transferred to a 150 mL flask and distilled again through a 20-cm Vigreux
column under reduced pressure (27 mmHg). The fractions of benzaldehyde-α-D1 (900 mg, 80%)
with boiling point 78-80 °C were collected.
Standard Procedure for Synthesis of Ketone (D2-3a): Benzaldehyde-α-D1 (307 mg, 2.866
mmol, 2.5 equiv) was dissolved in CH Cl (5 mL) under argon and stirred at room temperature.
2
2
To this reaction mixture was added BF .Et O (0.5 mL, 4.01 mmol, 3.5 equiv) dropwise, and
3
2
stirred for 30 minutes. Then, dienylolefin i. e. 1a18b (250 mg, 1.146 mmol, 1.0 equiv) in CH Cl
2
2
(5 mL) was cannulated dropwise to the reaction mixture. The dark color solution was stirred at
room temperature for 8-9 hours and monitored by TLC. The reaction mixture was quenched with
the saturated aqueous NaHCO (5 mL) at 0 C. The aqueous phase was extracted with EtOAc (60
3
mL), and the combined organic layers were washed with brine solution (10 mL), dried over
Na SO , filtered, and concentrated in vacuo. The residue was purified by using silica gel column
2
4
chromatography to afford the desired product ketone (D2-3a) as colorless oil. Yield: 410 mg,
1
(
86%); colorless oil; R = 0.5 (10% EtOAc/hexanes); H NMR (400 MHz, CDCl ): δ 7.85 (d, J =
f
3
7
.4 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.22-7.06 (m, 3H), 6.84 (d, J = 7.4
Hz, 2H), 6.39 (s,1H), 4.04 (s, 2H), 3.92 (s, 3H), 3.76 (s, 3H), 3.38 (q, J = 7.3 Hz, 1H), 1.87 (s,
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1
H), 1.37 (d, J = 7.3 Hz, 3H); C{H} NMR (100 MHz, CDCl ): δ 197.1, 158.5, 154.0, 150.4,
3
45.2, 142.0, 136.7, 133.0, 128.9, 128.4, 128.2, 128.1, 127.7, 127.6, 125.4, 112.5, 92.3, 56.3,
55.3, 45.0, 37.2, 29.5 (t, J = 18.3 Hz), 14.9, 12.3; IR (Neat): νmax 2959, 2931, 2852, 2837, 1688,
601, 1461, 1447, 1354, 1296, 1207, 1157, 1125, 1086, 1022, 1000, 906, 804, 752, 719, 691;
0
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1
2
+
HRMS (ESI-TOF) m/z calcd for C H H O (M+H) 415.2234, found 415.2236.
2
8
27
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3
Standard Procedure for Synthesis of Indenyl Alcohol (D1-2a): Benzaldehyde-α-D1 (216 mg,
2.018 mmol, 1.2 equiv) was dissolved in CH Cl (8 mL) under argon and cooled to -78 C. To
2
2
this was added BF .Et O (0.5 mL, 3.869 mmol, 2.3 equiv) dropwise. The reaction mixture was
3
2
stirred at -78 C for 30 minutes and dienyl olefin i. e. 1a18b (366 mg, 1.6822 mmol, 1.0 equiv) in
CH Cl (8 mL) was cannulated dropwise to the reaction mixture, and the yellow color solution
2
2
was stirred at -78 °C for further 4 h. The reaction mixture was quenched with the saturated
aqueous NaHCO (5 mL) at -78 C. The aqueous phase was extracted with EtOAc (100 mL), and
3
the combined organic layers were washed with brine solution (10 mL), dried over Na SO ,
2
4
filtered, and concentrated in vacuo. The residue was purified by using silica gel column
chromatography to afford the desired product as yellow oil as an inseparable diastereomers D1-
2
a (270 mg, 50%) (brsm, 184 mg). Yield: 50% (brsm); dr: 1.5:1; Yellow oil; R = 0.5 (20%
f
1
EtOAc/hexanes); H NMR (500 MHz, CDCl ): δ 7.38-7.24 (m, 5H), 6.50 (d, J = 1.9 Hz, 0.6H),
3
6
.49 (d, J = 1.9 Hz, 0.4H), 6.31 (m, 1H), 3.86 (s, 3H), 3.85 (s, 1.7H), 3.84 (s, 1.3H), 3.25 (q, J =
7.4 Hz, 0.6H), 3.22 (q, J = 7.4 Hz, 0.4H), 2.96 (d, J = 7.4 Hz, 0.3H), 2.93 (d, J = 7.4 Hz, 0.7H),
2
1
.85 (d, J = 7.1 Hz, 0.7H), 2.83 (d, J = 7.1 Hz, 0.3H), 2.03 (brs, 1H), 1.75 (s, 1.3H), 1.70 (s,
1
3
.7H) 1.29 (d, J = 7.4 Hz, 1.3H), 1.22 (d, J = 7.4 Hz, 1.7H); C{H} NMR (100 MHz, CDCl ): δ
3
160.5, 155.6, 149.2, 149.1, 147.3, 147.2, 143.9, 143.8, 130.8, 130.7, 128.2, 128.1, 127.4, 127.3,
1
26.8, 126.7, 125.8, 125.7, 96.5, 96.4, 94.7, 94.6, 72.7 (t, J = 22.7 Hz), 55.5, 55.1, 45.6, 45.5,
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5.9, 35.8, 14.6, 14.4, 12.0, 11.9; IR (Neat): νmax 3443, 2958, 2927, 2852, 1590, 1483, 1449,
354, 1303, 1293, 1201, 1138, 1064, 941, 822, 752, 700; HRMS (ESI-TOF) m/z calcd for
2
+
C H HO (M+H) 326.1857, found 326.1861.
2
1
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1
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General Procedure for Synthesis of Ketone (D1-3a): Benzaldehyde (0.08 mL, 0.738 mmol,
.2 equiv) was dissolved in CH Cl (3 mL) under argon and stirred at room temperature. To this,
1
2
2
was added BF .Et O (0.17 mL, 1.353 mmol, 2.2 equiv) dropwise. The reaction mixture was
3
2
stirred for 15-20 minutes, and indenyl alcohol D1-2a (200 mg, 0.615 mmol, 1.0 equiv) in CH Cl
2
2
(3 mL) was cannulated dropwise to the reaction mixture. The dark color solution was stirred at
room temperature for 30 minutes. The reaction mixture was quenched with the saturated aqueous
NaHCO (3 mL) at 0 C. The aqueous phase was extracted with EtOAc, and the combined
3
organic layers were washed with brine solution (5 mL), dried over Na SO , filtered, and
2
4
concentrated in vacuo. The residue was purified by using silica gel column chromatography to
afford the desired product ketone D1-3a. Yield: (230 mg, 90%); colorless oil; R = 0.5 (10%
f
1
EtOAc/hexanes); H NMR (500 MHz, CDCl ): δ 7.84 (d, J = 7.9 Hz, 2H), 7.59 (t, J = 7.3 Hz,
3
1
H), 7.45 (t, J = 7.9 Hz, 2H), 7.17 (t, J = 7.0 Hz, 2H), 7.12 (t, J = 7.0 Hz, 1H), 6.83 (d, J = 7.4
Hz, 2H), 6.39 (s,1H), 4.03 (s, 2H), 3.94 (t, J = 0.5 Hz,, 1H), 3.92 (s, 3H), 3.75 (s, 3H), 3.37 (q, J
1
3
=
7.3 Hz, 1H), 1.86 (s, 3H), 1.37 (d, J = 7.3 Hz, 3H); C{H} NMR (100 MHz, CDCl ): δ 197.1,
3
1
1
58.5, 153.9, 150.3, 145.2, 142.1, 136.7, 133.0, 128.9, 128.5, 128.4, 128.2, 128.1, 127.7, 125.4,
12.5, 92.3, 56.3, 55.3, 45.0, 37.2, 29.8 (t, J = 19.0 Hz), 14.9, 12.3; IR (Neat): νmax 2957, 2923,
2852, 1690, 1602, 1587, 1449, 1430, 1355, 1297, 1209, 1119, 1083, 1022, 990, 751, 720, 692;
2
+
HRMS (ESI-TOF) m/z calcd for C H HO (M+H) 414.2172, found 414.2174.
2
8
28
3
Standard Procedure for Synthesis of Ketones (3): Aromatic aldehyde (450 mg, 3.44 mmol,
.5 equiv) was dissolved in CH Cl (7 mL) under argon and stirred at room temperature. To this
2
2
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was added BF .Et O (0.6 mL, 4.816 mmol, 3.5 equiv) dropwise. The reaction mixture was stirred
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cannulated dropwise to the reaction mixture. The dark color solution was stirred at rt for 6 h and
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monitored by TLC. Thereaction mixture was quenched with the saturated aq NaHCO (7 mL) at
3
0
C. The aqueous phase was extracted with EtOAc, and the combined organic layers were
washed with brine solution (10 mL), dried over Na SO , filtered, and concentrated in vacuo. The
2
4
residue was purified by using silica gel column chromatography to afford the desired product
ketones 3.
2
-(4-Benzyl-1-ethyl-5,7-dimethoxy-2-methyl-1H-inden-3-yl)-1-phenylethanone (3b): Yield:
1
(225 mg, 92%); colorless oil; R = 0.5 (10% EtOAc/hexanes); H NMR (500 MHz, CDCl ): δ
f
3
7
.85 (d, J = 7.0 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 7.17 (t, J = 7.4 Hz,
H), 7.12 (t, J = 7.0 Hz, 1H), 6.83 (d, J = 7.0 Hz, 2H), 6.39 (s,1H), 4.09 (d, J = 18.4 Hz, 1H),
2
4.01 (d, J = 18.4 Hz, 1H), 4.00 (s, 1H), 3.94 (s, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.53 (t, J = 4.1
13
Hz, 1H), 2.41 (m, 1H), 1.88 (m, 1H), 1.84 (s, 3H), 0.46 (t, J = 7.4 Hz, 3H); C{H} NMR (100
MHz, CDCl ): δ 197.0, 158.5, 153.9, 147.9, 146.4, 142.2, 136.6, 133.0, 130.6, 128.4, 128.2,
3
1
28.1, 127.6, 125.3, 125.0, 112.3, 92.2, 56.3, 55.3, 50.4, 37.3, 30.0, 20.4, 12.4, 7.2; IR (Neat):
νmax 2960, 2923, 2852, 1688, 1586, 1450, 1358, 1309, 1207, 1118, 1107, 1024, 989, 948, 752,
+
7
31, 690; HRMS (ESI-TOF) m/z calcd for C H O (M+H) 427.2284, found 427.2267.
2
9
31
3
2
-(4-Benzyl-5,7-dimethoxy-2-methyl-1-phenyl-1H-inden-3-yl)-1-phenylethanone (3c): Yield:
1
(196 mg, 95%); colorless oil; R = 0.5 (10% EtOAc/hexanes); H NMR (500 MHz, CDCl ): δ
f
3
7
6
1
.90 (d, J = 7.1 Hz, 2H), 7.62 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.32-7.14 (m, 8H),
.91 (d, J = 7.1 Hz, 2H), 6.34 (s,1H), 4.45 (s, 1H), 4.12 (d, J = 4.7 Hz, 2H), 4.09 (d, J = 17.0 Hz,
1
3
H), 3.99 (d, J = 17.0 Hz, 1H), 3.75 (s, 3H), 3.64 (s, 3H), 1.71 (s, 3H); C{H} NMR (100 MHz,
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CDCl ): δ 197.0, 159.0, 153.9, 149.1, 145.8, 142.1, 140.1, 136.6, 133.1, 130.8, 128.4, 128.3,
3
1
28.2, 128.1, 128.0, 127.6, 127.5, 126.0, 125.4, 112.7, 93.2, 56.5, 56.2, 55.6, 37.3, 30.0, 12.8; IR
(Neat): νmax 2955, 2927, 2851, 1687, 1599, 1492, 1450, 1356, 1282, 1210, 1115, 1076, 1026,
1
1
1
1
1
1
1
1
1
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8
9
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2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
9
88, 756, 699; HRMS (ESI): calcd for C H O (M+H) 475.2295, found 475.2267.
3
3
31
3
2
-(4-Benzyl-5,7-dimethoxy-1,1,2-trimethyl-1H-inden-3-yl)-1-phenylethanone (3d): Yield:
1
(
163 mg, 93%); colorless oil; R = 0.5 (10% EtOAc/hexanes); H NMR (400 MHz, CDCl ): δ
f
3
7.84 (d, J = 7.0 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.45 (d, J = 7.9 Hz, 2H), 7.20-7.10 (m, 3H),
6
.85 (d, J = 7.0 Hz, 2H), 6.38 (s, 1H), 4.02 (s, 2H), 3.96 (s, 2H), 3.92 (s, 3H), 3.75 (s, 3H), 1.74
(
s, 3H), 1.36 (s, 3H); 13C{H} NMR (100 MHz, CDCl ): δ 197.1, 158.4, 154.9, 154.0, 144.0,
3
142.2, 136.7, 132.9, 131.8, 128.4, 128.2, 128.1, 127.7, 126.9, 125.4, 112.3, 92.4, 56.3, 55.2, 49.2,
3
1
4
7.3, 30.1, 21.7, 9.7; IR (Neat): νmax 2958, 2923, 2851, 1689, 1597, 1450, 1353, 1286, 1210,
+
136, 1074, 1024, 990, 948, 752, 691; HRMS (ESI-TOF) m/z calcd for C H O (M+H)
2
9
31
3
27.2292, found 427.2267.
2-(4-Benzyl-1-isopropyl-5,7-dimethoxy-2-phenyl-1H-inden-3-yl)-1-phenylethanone
(3e):
1
Yield: (176 mg, 94%); colorless oil; R = 0.5 (10% EtOAc/hexanes); H NMR (500 MHz,
f
CDCl ): δ 7.69 (d, J = 7.1 Hz, 2H), 7.49 (t, J = 7.3 Hz, 1H), 7.33 (t, J = 7.4 Hz, 2H), 7.21-7.10
3
(m, 5H), 7.06-6.96 (m, 3H), 6.63 (d, J = 7.4 Hz, 2H), 6.38 (s, 1H), 4.16 (d, J = 17.0 Hz, 1H),
4
1
7
.07 (dd, J = 18.4, 1.6 Hz, 1H), 3.98 (dd, J = 4.1, 1.6 Hz, 1H), 3.85 (s, 3H), 3.72 (d, J = 18.4 Hz,
H), 3.68 (s, 3H), 3.55 (d, J = 17.0 Hz, 1H), 2.54 (m, 1H), 0.70 (d, J = 7.0 Hz, 3H), 0.55 (d, J =
1
3
.0 Hz, 3H); C{H} NMR (100 MHz, CDCl ): δ 198.4, 158.6, 153.9, 151.3, 145.8, 141.9, 138.1,
3
136.4, 133.1, 132.7, 128.8, 128.4, 128.3, 128.1, 128.0, 127.6, 126.9, 126.2, 125.3, 113.1, 93.0,
5
6.3, 55.8, 55.2, 38.7, 30.1, 29.0, 20.6, 17.8; IR (Neat): νmax 2956, 2930, 2869, 1737, 1686, 1598,
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450, 1361, 1332, 1292, 1211, 1117, 1045, 988, 951, 751, 731, 702; HRMS (ESI-TOF) m/z calcd
+
for C H O (M+H) 503.2614, found 503.2580.
3
5
35
3
2
-(8-Benzyl-5,7-dimethoxy-2,3,4,4a-tetrahydro-1H-fluoren-9-yl)-1-phenylethanone
(3f):
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1
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Yield: (226 mg, 89%); white foam; R = 0.4 (10% EtOAc/hexanes); H NMR (400 MHz,
f
CDCl ): δ 7.84 (d, J = 7.0 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.44 (t, J = 7.3 Hz, 2H), 7.20-7.07
3
(m, 3H), 6.84 (d, J = 7.0 Hz, 2H), 6.39 (s, 1H), 4.05 (d, J = 7.3 Hz, 2H), 3.98 (d, J = 11.4 Hz,
2H), 3.91 (s, 3H), 3.76 (s, 3H), 3.21 (dd, J = 12.1, 5.5 Hz, 1H), 2.84 (m, 1H), 2.55 (d, J = 13.5
Hz, 1H), 2.17 (td, J = 13.4, 5.0 Hz, 1H), 1.92 (d, J = 12.1 Hz, 1H), 1.82 (d, J = 13.4 Hz, 1H),
1
.57 (qt, J = 13.2, 3.3 Hz, 1H), 1.20 (qt, J = 13.5, 3.7 Hz, 1H), 0.92 (qd, J = 13.0, 3.0 Hz, 1H);
1
3
C{H} NMR (400 MHz, CDCl ): δ 197.3, 158.5, 154.2, 152.5, 145.6, 142.1, 136.6, 132.9,
3
1
28.4, 128.2, 128.1, 127.7, 126.8, 125.6, 125.3, 112.9, 92.2, 56.4, 55.3, 48.0, 36.7, 32.0, 30.1,
2
8.0, 26.8, 25.5; IR (Neat): νmax 2931, 2851, 1688, 1586, 1449, 1358, 1327, 1211, 1116, 1052,
+
1
000, 950, 771, 731, 691; HRMS (ESI-TOF) m/z calcd for C H O (M+H) 439.2276, found
30 31
3
439.2267.
2
-(8-Benzyl-5,7-dimethoxy-1,1,4a-trimethyl-2,3,4,4a-tetrahydro-1H-fluoren-9-yl)-1-
1
phenylethanone (3g): Yield: (167 mg, 84%); white foam; R = 0.5 (10% EtOAc/hexanes); H
f
NMR (500 MHz, CDCl ): δ 7.83 (d, J = 7.7 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.7 Hz,
3
2
H), 7.20-7.10 (m, 3H), 6.79 (d, J = 7.0 Hz, 2H), 6.40 (s, 1H), 4.40 (d, J = 19.2 Hz, 1H), 4.22 (d,
J = 19.2 Hz, 1H), 3.89 (s, 1H), 3.89 (s, 3H), 3.75 (s, 1H), 3.75 (s, 3H), 2.60 (m, 1H), 1.89 (m,
1
3
1
H), 1.68-1.56 (m, 2H), 1.49 (s, 3H), 1.44-1.30 (m, 2H), 1.27 (s, 3H), 1.19 (s, 3H); C{H} NMR
(400 MHz, CDCl ): 198.3, 161.1, 158.2, 153.2, 143.9, 142.1, 136.8, 133.6, 132.9, 128.4, 128.2,
3
1
2
28.1, 127.7, 126.3, 125.3, 112.5, 92.9, 56.3, 55.2, 51.0, 43.2, 39.3, 36.4, 33.3, 32.1, 30.0, 27.0,
3.4, 18.9; IR(Neat): νmax 2946, 2911, 2835, 1685, 1596, 1464, 1448, 1350, 1299, 1217, 1118,
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059, 1033, 944, 691; HRMS (ESI-TOF) m/z calcd for C H O (M+H) 481.2740, found
33 37 3
81.2737.
2
-(4-(3,5-Dimethoxybenzyl)-5,7-dimethoxy-1,2-dimethyl-1H-inden-3-yl)-1-(3,5-
1
1
1
1
1
1
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0
1
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7
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1
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8
9
0
1
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7
8
9
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8
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7
8
9
0
dimethoxyphenyl)ethanone (3h): Yield: (145 mg, 95%); colorless oil; R = 0.5 (20%
f
1
EtOAc/hexanes); H NMR (400 MHz, CDCl ): δ 7.01 (d, J = 2.3 Hz, 2H), 6.67 (t, J = 2.3 Hz,
3
1
H), 6.36 (s, 1H), 6.21 (t, J = 2.3 Hz, 1H), 6.01 (d, J = 2.3 Hz, 2H), 4.00 (s, 2H), 3.90 (s, 3H),
3.90 (s, 2H), 3.80 (s, 6H), 3.75 (s, 3H), 3.63 (s, 6H), 3.35 (q, J = 7.3 Hz, 1H), 1.85 (s, 3H), 1.35
d, J = 7.3 Hz, 3H); 13C{H} NMR (100 MHz, CDCl ): δ 196.7, 160.7, 160.6, 158.5, 154.0,
(
3
1
50.3, 145.3, 145.0, 138.6, 128.8, 127.7, 112.0, 105.8, 105.7, 105.6, 97.4, 92.4, 56.4, 55.4, 55.3,
54.9, 45.0, 37.4, 30.2, 14.9, 12.3; IR (Neat): νmax 2959, 2932, 2837, 1687, 1593, 1460, 1426,
+
1
5
352, 1300, 1204, 1155, 1064, 927, 829, 772; HRMS (ESI-TOF) m/z calcd for C H O (M+H)
32 37 7
33.2539, found 533.2535.
2
-(5,7-Dimethoxy-1,2-dimethyl-4-(naphthalen-2-ylmethyl)-1H-inden-3-yl)-1-(naphthalen-2-
1
yl)ethanone (3i): Yield: (110 mg, 89%); colorless oil; R = 0.5 (20% EtOAc/hexanes); H NMR
f
(
400 MHz, CDCl ): δ 8.16 (s, 1H), 7.95-7.88 (m, 2H), 7.85 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.1
3
Hz, 2H), 7.67-7.50 (m, 4H), 7.44-7.34 (m, 2H), 7.17 (s, 1H), 6.97 (dd, J = 8.4, 1.5 Hz, 1H), 6.43
s, 1H), 4.12 (brs, 4H), 3.95 (s, 3H), 3.76 (s, 3H), 3.42 (q, J = 7.3 Hz, 1H), 1.88 (s, 3H), 1.40 (d,
(
1
3
J = 7.3 Hz, 3H); C{H} NMR (100 MHz, CDCl ): δ 196.8, 158.6, 154.1, 150.7, 145.5, 139.9,
3
1
1
35.6, 133.9, 133.6, 132.3, 131.9, 129.9, 129.6, 128.9, 128.4, 128.2, 127.8, 127.7, 127.6, 127.5,
27.4, 126.9, 126.6, 125.7, 125.6, 124.9, 123.9, 112.2, 92.4, 56.4, 55.3, 45.1, 37.2, 30.4, 14.9,
12.4; IR (Neat): νmax 2961, 2923, 2851, 1674, 1589, 1464, 1315, 1217, 1126, 1045, 815, 769;
+
HRMS (ESI-TOF) m/z calcd for C H O (M-H) 511.2268, found 511.2267.
3
6
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-(5,7-Dimethoxy-1,2-dimethyl-4-(4-methylbenzyl)-1H-inden-3-yl)-1-(p-tolyl)ethanone (3j):
1
Yield: (155 mg, 93%); colorless oil; R = 0.5 (10% EtOAc/hexanes); H NMR (400 MHz,
f
CDCl ): δ 7.76 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 6.98 (d, J = 7.9 Hz, 2H), 6.73 (d, J
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
8.3 Hz, 2H), 6.38 (s,1H), 4.01 (s, 2H), 3.91 (s, 3H), 3.90 (s, 2H), 3.74 (s, 3H), 3.36 (q, J = 7.3
13
Hz, 1H), 2.45 (s, 3H), 2.29 (s, 3H), 1.85 (s, 3H), 1.35 (d, J = 7.3 Hz, 3H); C{H} NMR (100
MHz, CDCl ): δ 196.7, 158.5, 153.9, 150.2, 145.3, 143.7, 139.1, 134.7, 134.2, 129.1, 128.8,
3
128.3, 127.7, 127.6, 127.5, 112.9, 92.3, 56.4, 55.3, 45.0, 37.1, 29.6, 21.6, 20.9, 14.9, 12.3; IR
(Neat): νmax 2957, 2930, 2871, 1685, 1610, 1512, 1461, 1353, 1295, 1205, 1116, 1080, 1046,
+
8
12, 712; HRMS (ESI-TOF) m/z calcd for C H O (M+H) 441.2420, found 441.2424.
3
0
33
3
2
-(4-(4-Ethylbenzyl)-5,7-dimethoxy-1,2-dimethyl-1H-inden-3-yl)-1-(4-ethylphenyl)ethanone
1
(3k): Yield: (142 mg, 90%); colorless oil; R = 0.5 (10%EtOAc/hexanes); H NMR (400 MHz,
f
CDCl ): δ 7.77 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.75 (d, J
3
=
8.0 Hz, 2H), 6.37 (s, 1H), 4.02 (s, 2H), 3.92 (s, 2H), 3.91 (s, 3H), 3.75 (s, 3H), 3.35 (q, J = 7.3
Hz, 1H), 2.74 (q, J = 7.5 Hz, 2H), 2.58 (q, J = 7.5 Hz, 2H), 1.84 (s, 3H), 1.35 (d, J = 7.3 Hz, 3H),
13
1
1
1
2
.29 (t, J = 7.5 Hz, 3H), 1.20 (t, J = 7.5 Hz, 3H); C{H} NMR (100 MHz, CDCl ): δ 196.7,
3
58.5, 153.8, 150.1, 149.8, 145.3, 141.1, 139.3, 134.4, 129.1, 128.4, 127.8, 127.7, 127.6, 127.5,
12.9, 92.3, 56.3, 55.3, 45.0, 37.2, 29.6, 28.9, 28.3, 15.5, 15.2, 14.9, 12.3; IR (Neat): νmax 2960,
924, 2853, 1683, 1635, 1604, 1458, 1311, 1182, 1054, 1017, 845, 827, 772, 712; HRMS (ESI-
+
TOF) m/z calcd for C H O Na (M+Na) 479.2584, found 479.2556.
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-(4-(4-Isopropylbenzyl)-5,7-dimethoxy-1,2-dimethyl-1H-inden-3-yl)-1-(4-
isopropylphenyl)ethanone (3l): Yield: (165 mg, 93%); colorless oil; R = 0.5 (10%
f
1
EtOAc/hexanes); H NMR (400 MHz, CDCl ): δ 7.77 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz,
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H), 7.02 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 8.0 Hz, 2H), 6.38 (s, 1H), 4.03 (s, 2H), 3.93 (s, 2H),
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The Journal of Organic Chemistry
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.91 (s, 3H), 3.75 (s, 3H), 3.35 (q, J = 7.3 Hz, 1H), 3.00 (septet, J = 13.8, 6.8 Hz, 2H), 2.84
(septet, J = 13.8, 6.8 Hz, 2H), 1.84 (s, 3H), 1.35 (d, J = 7.3 Hz, 3H), 1.31 (d, J = 6.8 Hz, 6H),
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1.22 (d, J = 6.8 Hz, 6H); C{H} NMR (100 MHz, CDCl ): δ 196.7, 158.5, 154.4, 153.9, 150.1,
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45.7, 145.3, 139.4, 134.6, 129.1, 128.4, 127.7, 127.6, 126.4, 126.1, 113.0, 92.4, 56.4, 55.3, 45.0,
7.3, 34.2, 33.5, 24.1, 24.0, 23.7, 14.9, 12.3; IR (Neat): νmax 2959, 2927, 2870, 1685, 1604, 1589,
461, 1354, 1294, 1216, 1117, 1080, 1054, 1018, 991, 928, 825, 771; HRMS (ESI-TOF) m/z
+
calcd for C H O (M-H) 495.2894, found 495.2893.
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-(4-(4-(tert-Butyl)benzyl)-5,7-dimethoxy-1,2-dimethyl-1H-inden-3-yl)-1-(4-(tert-
butyl)phenyl)ethanone (3m): Yield: (180 mg, 94%); colorless oil; R = 0.5 (10%
f
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EtOAc/hexanes); H NMR (400 MHz, CDCl ): δ 7.77 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz,
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H), 7.17 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 6.38 (s, 1H), 4.05 (s, 2H), 3.94 (s, 2H),
.91 (s, 3H), 3.76 (s, 3H), 3.35 (q, J = 7.3 Hz, 1H), 1.84 (s, 3H), 1.38 (s, 9H), 1.35 (d, J = 7.3 Hz,
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H), 1.28 (s, 9H); C{H} NMR (125 MHz, CDCl ): δ 196.8, 158.5, 156.6, 153.9, 150.1, 147.9,
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145.3, 139.0, 134.2, 129.2, 128.1, 127.7, 127.3, 125.3, 125.0, 113.1, 92.4, 56.4, 55.3, 45.0, 37.3,
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5.1, 34.2, 31.4, 31.1, 29.6, 14.9, 12.4; IR (Neat): νmax 2960, 2920, 2869, 1686, 1603, 1590,
462, 1407, 1362, 1295, 1268, 1217, 1117, 1081, 1021, 991, 825, 772; HRMS (ESI-TOF) m/z
+
calcd for C H O (M+H) 525.3353, found 525.3363.
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-(4-(4-Chlorobenzyl)-5,7-dimethoxy-1,2-dimethyl-1H-inden-3-yl)-1-(4-
chlorophenyl)ethanone (3n): Yield: (160 mg, 94%); yellow oil; R = 0.5 (10% EtOAc/hexanes);
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H NMR (500 MHz, CDCl ): δ 7.75 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.5
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Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 6.37 (s, 1H), 3.98 (d, J = 6.7 Hz, 2H), 3.91 (s, 3H), 3.89 (s,
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H), 3.74 (s, 3H), 3.37 (q, J = 7.3 Hz, 1H), 1.86 (s, 3H), 1.35 (d, J = 7.3 Hz, 3H); C{H} NMR
(100 MHz, CDCl ): δ 195.5, 158.5, 154.1, 151.0, 145.0, 140.4, 139.6, 134.8, 131.2, 129.5, 129.0,
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