Synthesis of substituted 2-arylindanes from e -(2-stilbenyl)methanols via lewis acid-mediated cyclization and nucleophililc transfer from trialkylsilyl reagents

Article abstract of DOI:10.1021/jo4013755

A preparative method for the synthesis of functionalized 2-arylindanes has been developed via the Lewis acid-mediated ring closure of stilbenyl methanols followed by nucleophilic transfer from trialkylsilyl reagents. The reactions gave the corresponding p

Full text of DOI:10.1021/jo4013755

Article
pubs.acs.org/joc
Synthesis of Substituted 2‑Arylindanes from E‑(2-
Stilbenyl)methanols via Lewis Acid-Mediated Cyclization and
Nucleophililc Transfer from Trialkylsilyl Reagents
Pakornwit Sarnpitak,† Kanokrat Trongchit,† Yulia Kostenko,† Supaporn Sathalalai,† M. Paul Gleeson,‡
Somsak Ruchirawat,†,§ and Poonsakdi Ploypradith*,†,§
†Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, and Program in Chemical Biology, Chulabhorn Graduate
Institute, 54 Kamphaeng Phet 6, Talat Bangken, Laksi, Bangkok, Thailand 10210
‡Department of Chemistry, Kasetsart University, 50 Phahonyothin Road, Bangkok, Thailand 10900
§Center of Excellence on Environmental Health and Toxicology, Commission on Higher Education (CHE), Ministry of Education,
Thailand
S
* Supporting Information
ABSTRACT: A preparative method for the synthesis of function-
alized 2-arylindanes has been developed via the Lewis acid-
mediated ring closure of stilbenyl methanols followed by
nucleophilic transfer from trialkylsilyl reagents. The reactions gave
the corresponding products in moderate to high yields and
diastereoselectivity. The solvent as well as the nucleophile played
an important role in determining the type(s) of product arising
either from nucleophilic addition (indanes) or loss of a proton β to the indanyl-type carbocations (indenes). Electron-donating
groups on the fused aromatic ring (Y and Z = OMe) or the presence of electron-withdrawing groups (NO2) on the nonfused Ar
ring facilitate the cyclization. In contrast, the presence of electron-donating groups (OMe) on the nonfused Ar ring impedes the
process. In the case of Cl on the nonfused Ar ring, temperature modulates the resonance versus inductive field effects on the
overall reaction pathways involving cyclization to form the indanyl-type cation. Quantum chemical calculations supported the
intermediacy of the carbocation species and the transfer of hydride from triethylsilane (Nu = H) to the indanyl-type cations to
form the trans-1,2-disubstituted indane as the single diastereomer product.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
The requisite starting material, benzyl alcohol 11, was readily
available in two steps from 2-bromobenzaldehyde 9 via the
Heck reaction23,24 to generate the stilbene 10 that reacted with
phenyllithium to furnish the product, as shown in Scheme 2.
Both steps proceeded smoothly in 78−84% and 98% yields,
respectively.
Optimization of the Reaction Conditions. First, as
shown in Scheme 3, in the absence of a nucleophile, with BF3·
Et2O as a Lewis acid, the reaction gave only the corresponding
indene products 12 (1−10%) and 13 (5−9%) among
unidentifiable byproducts, suggesting that, for compound 11,
the ensuing loss of a benzylic proton β to the indanyl-type
carbocation to give 12 or 1,2-hydride shift followed by loss of
proton to produce 13 was not a major pathway. It should be
noted that similar results were obtained with both stoichio-
metric and catalytic amounts of BF3·Et2O.
Indane constitutes an important core of natural products such
as those shown in Figure 1, including quadrangularin A (1)1,2
as well as paucifloral F (2),3,4 α-amino acid derivatives (3),5 and
medicinal agents6 such as the anticancer indane carbocyclic
nucleosides (4).7 It should be noted that both quadrangularin A
and paucifloral F feature the 2,3-trans-2-arylindane as their core
structure. A number of useful preparative methods, including
the reactions mediated by metal salt complexes, have been
developed for various substituted indanes such as mutisianthol
(5),8,9 trikentrins,10−15 herbindoles,10−15 and taiwaniaqui-
noids16,17 (e.g., (+)-trans-trikentrin A (6), herbindole A (7),
and taiwaniaquinol A (8)).
In recent years, the work in our group has involved the use of
Lewis or Brønsted acids for a number of organic trans-
formations.18,19 Herein, we wish to report a facile synthetic
method for an efficient preparation of substituted 2-arylindanes
with a range of substitutions around the indane core. Our
strategy has focused on the formation of the cyclopentane ring
via a Lewis acid-mediated ring closure of the olefin to form the
indanyl cation which can be further reacted by a number of
nucleophiles (see Scheme 1).20−22
Next, in order to minimize the structural complexity of the
product(s), hydride was selected as a nucleophile. The effects of
different Lewis and Brønsted acids, hydride sources, and
Received: November 20, 2012
Published: July 26, 2013
© 2013 American Chemical Society
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Figure 1. Natural and synthetic substituted indanes.
a
Scheme 1. A Strategy Toward the Substituted 2-Arylindanes
Table 1. Screening the Conditions for 14
b
c
entry
1
acid
solvent
time (h)
yield (%)
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
TFA
CH2Cl2
CH2Cl2
PhMe
0.1
1.0
0.1
240
1.5
1.5
1.5
4
90
54
60
0
d
2
e
3
f
4
THF
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
35
60
0
e
6
g
CF3SO3H
PTS-Si
Scheme 2. Preparation of Benzyl Alcohol 10
7
8
9
InCl3
83
99
ZnCl2
25
a
Unless noted otherwise, the reactions were performed at 0 °C using
b
1.5 equiv of Lewis or Brønsted acid and 1.5 equiv of Et3SiH. Other
Lewis acids such as PdCl2, PtCl4, SnCl4, TiCl3, and AlCl3 gave no
desired indane product. Isolated yield. Catalytic amount (15 mol %)
of BF3·Et2O was employed. The product was obtained with trace
amount of unidentified impurities. An unidentifiable mixture of
c
d
e
f
g
compounds was obtained. The corresponding indanol 16 was
obtained.
product; only complex mixtures of unidentifiable byproducts
were observed in those cases. InCl3, BF3·Et2O, and ZnCl2 gave
the best yields (83−99%; entries 1, 8, and 9) of the 1,2-trans-
diphenylindane 14 as a single diastereomer, while other Lewis
acids including PdCl2, PtCl4, TiCl3, AlCl3, and SnCl4 gave no
desired product. Use of Brønsted acids (entries 5 and 6) such
as trifluoroacetic acid (TFA)25 or trifluoromethanesulfonic acid
(TfOH) gave the corresponding indane 14, albeit in lower
yields (35 and 60%, respectively). It should be noted that the
use of BF3·Et2O and Et3SiH is typically expected to yield the
deoxygenated product 15 which, under these conditions, was
not observed.26 A stoichiometric amount of BF3·Et2O was
required, giving the product in much higher yield than the
catalytic amount (90 vs 54% yields; entries 1 and 2). The effect
of different solvents can be observed when BF3·Et2O was used
(entries 1−4). Dichloromethane (CH2Cl2) gave the best result,
providing 14 in 90% yield compared with 60% when toluene
was used. It should be noted that the reaction performed in
tetrahydrofuran (THF) did not furnish the product; decom-
position of 11 into a mixture of unidentifiable compounds was
Scheme 3. Products from Different Reaction Conditions
solvents were investigated, and the results are summarized in
Table 1. After some experimentation, it was found that the use
of Et3SiH as a hydride source gave the best results, while other
sources of hydride such as NaBH4, NaCNBH3, and
diisobutylaluminium hydride (DIBAL-H) gave no desired
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observed instead when the reaction was allowed to reach room
temperature and stirred for 240 h. Interestingly, when p-
toluenesulfonic acid on the surface of silica (PTS-Si) was
employed (entry 7), the reaction furnished the corresponding
indanol 16 as a 1.7:1 inseparable mixture of epimers at the C1
position in 80% yield, slightly favoring the trans relationship
between the two adjacent stereocenters.27 Similar mixtures of
the epimers were obtained from the reactions both in the
presence and absence of Et3SiH, suggesting that water,
presumably from the protonation of the hydroxy group by
the immobilized PTS-Si or from solvent, rather than the
hydride, acts as a nucleophile (see the discussion on the
plausible mechanism in a subsequent section).
Scope of Substrates. Because it was easier to handle and
gave yields comparable to ZnCl2 with much shorter reaction
time, BF3·Et2O was selected for the subsequent studies. We
next investigated the effects of a different group at the benzylic
position (X = alkyl or aryl). Starting from the aldehydes 9 and
17 or acetophenone 18, the corresponding Heck products 10,
19, and 20 could be prepared in good yields (70−99%).
Subsequently, either (1) nucleophilic addition to the aldehyde
10 or 19 or (2) borohydride reduction of the aldehyde 10 or
acetophenone 20 furnished the corresponding benzyl alcohols
21−28 in moderate to good yields (15−91%), as shown in
Scheme 4. It should be noted that low yield (15%) was
Table 2. Scope of Substrates Containing Different R
Groups
a
b
entry
compound
R
product
yield (%)
1
2
3
4
21
22
23
24
25
11
26
27
H
29
30
31
32
33
14
34
35
0
Me
i-Pr
99
50
85
50
90
60
75
tert-Bu
c
5
CH2SO2Me
Ph
6
7
8
3,4-diOMePh
4-OCF3Ph
a
Unless noted otherwise, the reactions were performed in CH2Cl2 at 0
b
°C using 1.5 equiv of BF3·Et2O and 1.5 equiv of Et3SiH. Isolated
yield. A 2:1 mixture of unassignable cis and trans isomers was
c
obtained.
Table 3. Product Distribution as a Result of Acid and
a
Solvent Effects on the Reactions of 28
Scheme 4. Preparation of Benzyl Alcohols 21−28
b
entry
1
acid
solvent
36:37
yield (%)
c
BF3·Et2O
CH2Cl2
CH2Cl2
MeCN
PhMe
100:0
100:0
11:1
12
d
2
86
83
67
86
95
68
72
63
99
3
4
5
10:1
e
DME
1.3:1
0.3:1
0:100
0:100
100:0
100:0
e
6
1,4-dioxane
Et2O
e
7
e
8
THF
9
InCl3
TFA
CH2Cl2
CH2Cl2
10
a
Unless noted otherwise, the reactions were performed at 0 °C using
b
1.5 equiv of BF3·Et2O and 1.5 equiv of Et3SiH. Isolated yield.
c
Besides the desired product, only unidentified baseline materials were
d
e
obtained. Catalytic amount (15 mol %) of BF3·Et2O was used. The
obtained from the addition of i-Pr group to the aldehyde 10
because of the competing “hydride” transfer from i-PrMgBr to
the aldehyde, yielding the reduced product 21.
reactions took 15 h to complete.
two methoxy groups in 28 directed the reactions to provide the
corresponding indane 36 (from nucleophilic addition of
hydride to the indanyl cation) as well as the indene 37 (from
the loss of proton at the 2-position), depending on the solvent.
The indane was obtained in 86% yield exclusively from the
reaction in CH2Cl2 (entries 1−2) while those in THF and Et2O
(entries 7 and 8) furnished the indene exclusively in good
yields (68 and 72%, respectively). When CH2Cl2 was used as
solvent, the reaction employing catalytic amount of BF3·Et2O
(15 mol %) proceeded more cleanly and gave 36 in much
higher yield than that with 1.5 equiv of the Lewis acid.
Interestingly, other solvents gave both products in different
ratios (entries 3−6). It is evident that the more coordinating
oxygen-containing solvents (1,2-dimethoxyethane (DME), 1,4-
dioxane, Et2O, and THF) furnished the indene more
preferentially than other solvents. Thus, the different ratios of
products 36 and 37 neither depend on nor reflect the relative
polarity of solvents. As shown in Scheme 5, the mechanism for
The results of BF3·Et2O-mediated cyclization of 21−27
followed by hydride addition from Et3SiH are summarized in
Table 2. Except for the primary benzyl alcohol 21, all the
secondary benzyl alcohols containing alkyl or aryl substituents
(11 and 22−27) gave the corresponding substituted trans-2-
phenylindanes 14 and 30−35 in moderate to excellent yields
(50−99%). When compound 21 was subjected to the reaction
conditions, only a complex mixture was obtained without any
trace of the indane 29. Presumably, the corresponding initial
primary benzylic carbocation generated from 21 was unstable
under the reaction conditions and underwent decomposition
prior to cyclization to the subsequent indanyl-type carbocation
and hydride addition. It should be noted that the product 33
was obtained as a 2:1 mixture of unassignable cis and trans
diastereomers.
The effects of substituents on the fused benzene ring were
also investigated. As summarized in Table 3, the presence of
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After some experimentation by varying temperature and the
amount of BF3·Et2O, the desired products 45−47 could be
obtained in moderate to excellent yields (51−99%). Because
1.5 equiv of BF3·Et2O led to the complete consumption of the
starting material 42 without any indane product, it was
necessary to lower the amount of the Lewis acid in the final
step to 15 mol % for 42 (this is similar to the reaction of 28 to
form indane 36), and thus BF3·Et2O was employed with 43 and
then with 44 for comparison.29 At 0 °C, both 43 and 44 gave
the products 46 and 47 in good yield (71%); 42 gave the
product 45 in much lower yield (51%). When lowering the
temperature to −40 °C,30 only 44 gave 47 in virtually
quantitative yield (99%) while both 42 and 43 gave the
corresponding indane products 45 and 46 in moderate yields
(58%). For comparison, compound 11, without any substituent
on the Ar group (Ar = Ph), gave the product 14 in 54% yield
(Table 1, entry 2) when 15 mol % of BF3·Et2O was used at 0
°C. It is apparent that changing the reaction temperature had
little effect on the yield of this reaction for 42. In the cases of 43
and 44, lowering the temperature affected the yields of the
reactions in the opposite directionlower in the case of 43 but
higher in that of 44.
Scheme 5. A Proposed Mechanism for the Formation of 36
and 37
To account for these results, the electronic nature of these
substituents was considered. In the cases of 42 and 44, the
methoxy (OMe) and the nitro (NO2) groups are clearly
electron-donating (EDG) and electron-withdrawing (EWG)
groups, respectively, via resonance effects, which modulate the
electron density in the stibenyl olefin moiety (increased with
OMe and decreased with NO2 with reference to H). However,
in the case of Cl in 43, it appears that both resonance and
inductive field effects govern the overall effects of the Cl
substituent; the extent and contribution of each effect may vary
under different reaction conditions.31 By resonance, the Cl
substituent on an aromatic system is normally considered to be
an EDG; however, inductively, Cl deactivates the aromatic ring
and can be considered to be an EWG.31 In our case, the effects
from Cl appeared to be temperature-dependent. At 0 °C, the
inductive field effect of Cl seemed to predominate as the yields
of 46 and 47 were similar (71%). In other words, Cl behaves as
an EWG at 0 °C. At −40 °C, the resonance effect of Cl through
the aromatic system appeared to contribute more significantly
as the yield of 46 decreased to be similar to that of 45 (58%);
Cl is an EDG under this reaction condition. These results
suggested that the presence of the EWG on this aromatic ring
facilitates the cyclization step of the initial carbocations to the
indanyl-type cations. In contrast, the presence of the EDG on
the same ring appears to encumber such cyclization (see
Plausible Mechanisms for the Formation of the Products in a
subsequent section).
the formation of indene 37 may proceed via the carbocation
and involve p-quinone methide and the participation of either
one or both of the methoxy groups (both intermediates A and
B). The structure of indene 37 was confirmed by hydro-
genation, which gave the corresponding indane 38 as a 9:1
mixture of diastereomers favoring the addition of hydrogen to
the olefin from the face opposite the phenyl group. Use of
InCl3 and TFA in CH2Cl2 as solvent gave only the indane 36 in
63 and 99% yields, respectively (entries 10 and 11).
The electronic effects from the nonfused aromatic (Ar)
group were also investigated. When 4-methoxystyrene, 4-
chlorostyrene, and 4-nitrostyrene were employed in the Heck
reactions, the corresponding benzaldehydes 39−41 were
obtained in moderate to good yields (65−93%), as shown in
Scheme 6.28 Subsequent PhLi or PhMgBr addition gave the
requisite benzyl alcohol 42−44 in good yields (70−71%); these
alcohols were then subjected to BF3·Et2O-mediated cyclization
followed by hydride transfer from Et3SiH.
Scheme 6. Preparation of 2-Arylindanes 45−47 with
Different Ar Groups via Heck Reactions
Scope of Nucleophiles. With the developed condition
(BF3·Et2O in CH2Cl2) in hand, we then investigated the scope
of nucleophilic transfer from the trialkylsilyl reagents as
summarized in Table 4. The azide, allyl, chloride, bromide,
and iodide groups were transferred smoothly from the
corresponding trimethylsilyl (TMS)-containing reagents to
the indanyl-type cation, yielding the corresponding products
48−54 in 33−75% yields without any additive (entries 1−3 and
7−9). The azidoindane 48 was obtained in a 9:1 diastereomeric
ratio while the allyl indane 49 and the haloindanes 50−52 were
obtained in 1:1−3:1 ratios, with slight preference for the 1,2-
trans relationship. Both alcohols 42 and 43, upon reacting with
TMS-N3, gave the corresponding azidoindanes 53 and 54 in 61
and 65% yields, respectively, with slight preference for the 1,2-
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a
Table 4. Scope of Nucleophilic Transfer from Trialkylsilyl Reagents
b
entry
Ar
Nu
equiv of BF3·Et2O
additive
equiv of additive
Prod
Hα:Hβ
yield (%)
1
2
3
4
5
6
Ph
N3
allyl
allyl
allyl
allyl
allyl
Cl
1.5
none
none
none
0.0
0.0
0.0
1.5
1.5
3.0
0.0
0.0
0.0
0.0
0.0
48
49
49
49
49
49
50
51
52
12
53
54
9:1
1:1
1:1
N/A
1:1
1:2
3:1
2:1
3:1
N/A
2:1
3:1
75
c
1.5
<79
68
0.15
0.15
2.0
d
e
TBAF
0
f
TBAF
TBAF
none
none
none
none
none
none
23
f
3.5
27
g
,
h
h
7
8
9
0.15
0.15
0.15
2.0
48
72
33
32
61
65
h
Br
g,
I
10
11
12
F
i
4-OMePh
4-ClPh
N3
N3
0.15
0.15
i
0.0
a
b
c
Unless noted otherwise, the reactions were performed at 0 °C and 1.5 equiv of Me3Si−Nu. Isolated yield. The product was obtained with some
d
unknown and inseparable impurities. TBAF was added as a solution in CH2Cl2 pretreated with excess Na2SO4 to remove any trace amount of
e
f
g
water. No reaction occurred; starting material recovered. Significant amount of indene 12 (55−63%) was also isolated. The reaction was
h
i
performed at −30 °C. The reactions were purified by passing the crude reaction mixture through a plug of silica. The ratios reported for Hα:Hβ of
the crude and the isolated diastereomers were comparable.
trans relationship. It should be noted that the 1,2,3-trans and
1,2-cis-2,3-trans indane products 53 and 54, unlike other indane
products 48−52, were separable by chromatography. The
presence of tetrabutylammonium fluoride (TBAF) in excess as
additive did not furnish the corresponding fluoroindane
(entries 4−6). When only a catalytic amount of BF3·Et2O
was employed, the formation of the tetrabutylammonium
neat or as solutions in CDCl3, the iodoindane 52 was found to
be unstable as a solution in CDCl3 at room temperature and
readily decomposed to the indene 13. After some exper-
imentation, 52 could be kept refrigerated (at ca. −20 °C) either
neat or as a solution in CDCl3 without detectable
decomposition.
It was anticipated that water, even in trace amounts, may
compete with halides during these reactions. Thus, excess
Na2SO4 was added to the reaction using TMSBr.32 No
detrimental effects or significant differences were observed
with added Na2SO4; the corresponding bromoindane 51 was
obtained in 69% yield as a 2:1 mixture of diastereomers.
The source of halides was also investigated. Because of its
more labile nature, iodoindane 52 was more difficult to handle
when compared with chloroindane 50 and bromoindane 51, so
we decided to focus on the use of tetrabutylammonium
chloride (TBACl) and tetrabutylammonium bromide (TBAB)
as nucleophiles for these reactions (see Scheme 7). Because of
tetrafluoroborate (Bu4N+BF4 ) presumably occurred more
−
readily while resulting in complete recovery of the starting
material 11 (entry 4). However, in the presence of a slight
excess of BF3·Et2O relative to TBAF (entries 5−6), the
corresponding product allylindane 49 was obtained, albeit in
low yields (23−27%), with significant amount of indene 12
(55−63%). In the presence of TBAF alone (entry 10), only the
indene 12 was obtained in 32% yield, suggesting that the
fluoride ion from TBAF did not act as a nucleophile or
effectively facilitate the transfer of the allyl group from
allyltrimethylsilane by mediating the cleavage of the allyl
group from the silicon atom.
Scheme 7. Tetrabutylammonium Halides as Nucleophiles
It should be noted that temperature plays an important role
for the transfer of the chloride and iodide to form chloroindane
50 and iodoindane 52, respectively. When these reactions were
performed either at 0 °C or from 0 °C to room temperature, a
significant amount of indene 12 was observed. At lower
temperature (−30 °C), the reaction gave the desired products
50 and 52 cleanly in moderate yields of 48 and 33%,
respectively. It was also observed that purification of these
haloindanes 50−52 by column chromatography on silica led to
significant or complete decomposition of the products to
mixtures of indenes 12 and 13, among other unidentified
products. Thus, following the complete consumption of 11,
these reactions were passed through a plug of silica to remove
any baseline materials. This procedure gave the homogeneous
their hygroscopic nature, we anticipated that adding these
ammonium salts directly to the reactions would introduce
significant amounts of water which would act as a nucleophile
and compete with the halides during these reactions. Thus, it is
crucial that the solutions of these tetrabutylammonium halides
in CH2Cl2 are treated with excess Na2SO4 to remove any water
prior to their addition.32 The results showed that the TBACl
gave the product 50 in identical yield (48%) with a slightly
lower diastereoselectivity (2:1) when compared with the
reaction employing TMSCl (48% yield and 3:1 diastereomeric
1
products shown by both H and 13C NMR spectra (see the
Supporting Information); the mass of each reaction following
the procedure was then used to calculate the percent yield
(entries 7−9). While both chloroindane 50 and bromoindane
51 were chemically robust even at room temperature either
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ratio). However, TBAB furnished the bromoindane 51 in lower
yield (53%) with a slightly lower diastereoselectivity (1:1)
when compared with the reaction using TMSBr (72% yield and
2:1 diastereomeric ratio).
Plausible Mechanisms for the Formation of the
Products. A plausible mechanism for the formation of indane
is depicted in Scheme 8, proposing that the carbocation 55 is
important mechanistic insights which supported and signified
the cyclization process to form the subsequent indanyl-type
cation such as 58. From Table 3 and Scheme 5, the reactions of
benzyl alcohol 28, with two methoxy groups on the fused
aromatic ring, gave indane 36 via a series of stabilized
carbocations. The results implied that, on the fused aromatic
ring, these EDGs which can stabilize the initially-formed
carbocation (a species similar to 55) as well as others along the
reaction pathway may facilitate the cyclization to form the
subsequent indanyl-type carbocation (A in Scheme 5 which is
similar to 58 in Scheme 8), ultimately leading to the formation
of the indane product.34
Scheme 8. A Proposed Mechanism for the Formation of
Indane 59 and Indenes 61 and 62
On the other hand, the electronic effects from the nonfused
Ar group of 42−44 indicated that the presence of EDGs on the
nonfused aromatic ring hampered the cyclization while that of
EWG facilitated it. As shown in Scheme 9, by resonance,
following the formation of the initial carbocation 63, the EDG
(X = OMe) in 42 increased the electron density (δ−) at the α-
carbon of the stilbenyl olefin system, as shown in transition
state 64, rendering the cyclization to form the indanyl-type
cation 65 less favorable because of the increasing carbocationic
character (δ+) on the β-carbon which, in turn, was required to
cyclize with the carbocation. Contrary to the EDGs, by
resonance and inductive field effect, the strongly electron-
withdrawing nitro group at the same position in 44 decreased
the electron density of the aromatic ring, thereby providing
stabilization for the developing anionic character (δ−) on the β-
carbon for the subsequent cyclization to form 65 via the
transition state 66. Consequently, the EWG on the nonfused
aromatic ring would also increase the carbocationic character
(δ+) on the α-carbon, favoring the formation of the indanyl-
type cation 65. For Cl as a substituent on the aromatic ring,
depending on reaction conditions, the transition state similar to
64 (X = Cl) may predominate at low temperature (−40 °C),
while at higher temperature (0 °C) the other transition state
like 66 (X = Cl) may predominate instead. These results clearly
delineated the significance of both carbocationic character
developing on the α-carbon and anionic character on the β-
carbon of the stilbenyl olefin moiety for the successful
cyclization to form the indanyl-type cation. Taken together,
the results from the reactions of 28 and 42−44 unequivocally
indicated the importance of carbocation stability as well as the
parameters which affect it both for the initially formed
carbocation like 55 (or 63) and the indanyl-type cation 65
during this Lewis or Brønsted acid-mediated cyclization prior to
the nucleophilic transfer from the trialkylsilyl reagents.34
expected to form from the initial complexation by Lewis acid or
protonation by Brønsted acid at the hydroxy group. Subsequent
direct nucleophilic addition to this carbocation to form the
corresponding product 56 was not observed. Instead, the
carbocation 55 underwent cyclization with a stilbenyl olefin
moiety to form either the cis- or trans-indanyl-type cations 57
or 58, indicating that the intramolecular cyclization occurred
more readily than the direct intermolecular nucleophilic
addition to the carbocation 55.33 Our observation of the
product 59 was consistent with the formation of the
corresponding trans-indanyl cation 58 without any detectable
cis-diastereomer 60. The trans-indanyl cation 58 may also
undergo (1) direct loss of β-proton to produce the indene 61
or (2) 1,2-hydride shift followed by loss of β-proton to furnish
the indene 62.20
The electronic effects from the substituents on the fused
(28) or nonfused (42−44) aromatic ring to form the
corresponding indane products (36 and 45−47) provided
Scheme 9. Further Mechanistic Insights for Cyclization of 42−44 and the Importance of the Indanyl-Type Cationic
Intermediates 65
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Scheme 10. A Plausible Mechanism for the Transfer of Nucleophiles
Scheme 11. Concerted versus Stepwise Reaction Mechanisms for Quantum Chemical Calculations
It should be noted that the hydride addition required
activation of the Si−H bond which could be mediated by the
fluoride ion from BF3·Et2O.35−37 In the case of the Brønsted
acids (TFA and TfOH), the weak conjugate base could activate
the Si−H bond albeit less effectively as evident by lower yields.
InCl3-promoted reaction may proceed via a different
mechanism.38 For PTS-Si, because the conjugate base p-
toluenesulfonyl anion was immobilized on silica, Et3SiH was
not activated to deliver the hydride, and similar results arising
from nucleophilic addition by water were obtained both in the
presence and absence of Et3SiH.
Unlike the hydride transfer, the allyl and azide groups are
likely to undergo direct nucleophilic addition to the indanyl-
type cation 67 generated from 11 via the terminal olefin of the
allyl group39,40 or the nitrogen atom of the azide group,41,42 as
shown in Scheme 10. The positive charge on the carbocation
6840 or nitrogen 69 can be stabilized by the β-Si atom.43
Subsequent nucleophilic attack (presumably by fluoride ion
from BF3·Et2O) on Si then led directly to the products. In the
case of chloride, bromide, or iodide transfer from the
corresponding trimethylsilyl halides, greater ionic character of
the Si-halogen bond when compared to that of either the Si-
allyl or the Si−N3 bond may have led, under the reaction
conditions, to generation of the corresponding halide ions
which then reacted with the indanyl-type cation to furnish the
haloindane products. Similar results using different sources of
halides (TMS-halides versus TBACl or TBAB) supported this
proposed mechanism for the transfer of halides.
to study the reaction in detail. Theoretically, the reaction of
compound 11, BF3·Et2O, and Et3SiH can give rise to four
distinct cyclic products. The trans-stereochemical selectivity
observed here therefore suggests that the mechanism leading to
the preferred product is (a) stereochemically distinct and (b)
significantly lower in energy than the mechanisms leading to
the other products.
In principle, the chemical reaction could occur in a stepwise
fashion, involving the formation of a discrete carbocation,
followed by ring closure, and finally hydride transfer.
Alternatively, the reaction could proceed in a concerted
fashion, with the formation of the carbocation ion occurring
alongside the ring closure and hydride transfer (see Scheme
11).
The relative energetics associated with the different
mechanisms, and the relative energies of the different products,
are reported in Figure 2 and Table 5. The reaction to form the
cyclic products may commence from the initial nonbonded
complex formed by 11, BF3·Et2O, and Et3SiH, resulting in the
formation of two possible distinct conformations, complexes 70
and 71, as shown in Figure 3. The two complexes differ in the
orientation of the two substituents that are ortho to each other
on the phenyl ring.
Structures of complexes 70 and 71 correspond to the
chemisorbed complex formed between 11 and BF3 via the
formation of a B−O bond (∼1.6 Å). Both complexes can form
the corresponding discrete carbocations, 72 or 73, by the loss
of BF3OH− via the transition states TS1 (17.4 kcal/mol) or
TS2 (19.9 kcal/mol), respectively. Both carbocations, 72 and
73, can undergo cyclization to form the corresponding five-
membered ring indanyl-type cations, resulting in a 5-trans
Quantum Chemical Calculations. To gain further insight
into the reaction and to account for our experimental
observations, quantum chemical calculations were employed
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Figure 2. The energetic profile associated with the formation of four possible products from the reaction of 11 in the presence of BF3·Et2O and
Et3SiH.
configuration for 72 via the transition state TS5 and a 5-cis
configuration for 73 via the transition state TS6. The barrier
associated with this step is considerably lower for the 5-trans
carbocation 67 (3.4 kcal/mol) than for the 5-cis carbocation 74
(10.0 kcal/mol). In the final step of the hydride transfer from
Et3SiH, the 5-trans carbocation 67 and the 5-cis carbocation 74
subsequently gave the corresponding 5-trans indane 14 and 5-
cis indane 75 via the transition states TS9 and TS10,
respectively (Figure 4). It should be noted that while the
barriers associated with the final step are equivalent at 5.7 kcal/
mol, the 5-trans indane 14 is 1.0 kcal/mol lower in energy.
Alternatively, both the 5-trans carbocation 67 and 5-cis
carbocation 74 may be formed directly from the chemisorbed
complex via the simultaneous C−O bond breakage and the
intramolecular C−C bond formation and cyclization via the
transition states TS3 and TS4, respectively, without the explicit
carbocations 72 or 73 (see Figure 3). However, the barriers for
both cases (20.6 kcal/mol for 5-trans carbocation 67 via TS3
and 26.9 kcal/mol for 5-cis carbocation 74 via TS4) are higher
than those leading to the formation of the discrete carbocations
72 (17.4 kcal/mol) and 73 (19.9 kcal/mol), suggesting that
these alternative pathways are less important. In addition, a
concerted process involving the simultaneous C−O bond
breakage, intramolecular C−C bond formation and cyclization,
and hydride transfer can be completely ruled out for the five-
membered ring products due to steric constraints.
Theoretically, the corresponding four-membered ring
benzocyclobutene (BCB) products are also possible outcomes
of the reaction. However, analysis of the results presented in
Figure 2 shows that these BCB products are considerably
higher in energy (24.7 kcal/mol) compared to the five-
membered ring indanes. The BCB products can be formed by
two distinct pathways. First, complexes 70 and 71 can directly
cyclize to form the four-membered ring products via the
simultaneous C−O bond breakage, C−C bond formation and
cyclization, and hydride transfer (transition states TS7 and TS8,
respectively). As shown in Figure 4, both transition states TS7
(39.4 kcal/mol) and TS8 (41.7 kcal/mol) are extremely high in
energy for the corresponding trans- and cis-BCB products 76
and 77, respectively. Alternatively, both trans- and cis-BCB
products can arise by stepwise processes of lower energy
pathways involving either 72 or 73 and transition states TS11
(barrier of 17.5 kcal/mol) or TS12 (barrier of 18.7 kcal/mol),
respectively. While these barriers are considerably lower than
those for the concerted processes, they are still remarkably
higher than the equivalent barriers (TS5, which is 3.4 kcal/mol,
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Table 5. Energies of the Different Structures
intermediate
energy (kcal/mol)
complex 70
complex 71
TS1
TS2
TS3
TS4
72
−6.11
−5.91
11.34
13.99
14.53
20.95
11.09
11.53
14.50
21.57
3.81
73
TS5
TS6
74
67
1.70
TS9
TS10
75
7.44
9.51
−4.69
−5.74
33.31
35.79
28.54
30.26
20.05
18.95
14
TS7
TS8
TS11
TS12
77
76
or TS6, which is 10.0 kcal/mol) leading to the five-membered
indane products. Thus, the quantum chemical calculations
clearly showed that the formation of the BCBs is much less
favorable than the corresponding indanes.
The quantum chemical calculations undertaken to study the
BF3-mediated cyclization of compound 11 followed by hydride
transfer from Et3SiH showed that the formation of the observed
indane product 14 is likely to proceed via discrete albeit short-
lived carbocations (e.g., 72) and not via a concerted process.
The energetic profile and calculated energies of transition states
also supported the observation that the trans-indane is the
exclusive product from these reactions.
CONCLUSIONS
■
In summary, a novel synthetic method for the synthesis of 2-
arylindane derivatives has been developed based on the Lewis
acid-mediated cyclization of E-(2-stilbenyl)methanols followed
by the nucleophililc transfer from trialkylsilyl reagents. The
reaction has been found to be suitable for a relatively wide
range of substrates and nucleophiles, providing various
substituted and functionalized 2-arylindanes in good to
excellent yields (up to 99%). Among the Lewis and Brønsted
acids screened, BF3·Et2O was found to be most effective for this
reaction as evident by good to excellent yields of the products
and short reaction time. Solvents play an important role in
determining the types of products generated from the reactions.
In general, CH2Cl2 was found to be the solvent of choice for
these reactions. In addition to the transfer of hydride from
Et3SiH, transfer of azide, allyl, chloride, bromide, and iodide
from the corresponding trimethylsilyl reagents to the indanyl-
type carbocation furnished the corresponding products in
moderate to good yields. Cyclization to form the indanyl-type
carbocation proceeded with high stereoselectivity to give the
trans-indanyl-type cation as the only observed intermediate;
however, the nucleophilic transfer from the trialkylsilyl reagents
to the indanyl-type cation proceeded only in moderate to good
diastereoselectivity. Electron-donating groups on the fused
Figure 3. Predicted minima from quantum chemical calculations.
aromatic ring are beneficial as they stabilize the carbocations
along the reaction pathways; the presence of electron-
withdrawing groups on the nonfused aromatic ring directs the
reaction toward cyclization to form the indanyl-type cation by
stabilizing the developing anionic characters on the 2-position
of the newly formed indane systems. Quantum chemical
calculations of the energetic profile of the plausible complexes
as well as intermediates and transition states along the distinct
pathways further supported and confirmed that the most likely
mechanism of this reaction commenced with the complexation
between the Lewis acid (BF3·Et2O) and the hydroxyl group of
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Figure 4. Predicted transition states from quantum chemical calculations.
(LRMS) mass spectra were obtained either using electron ionization
(EI) or time-of-flight (TOF), while high resolution (HRMS) mass
spectra were obtained using time-of-flight (TOF) via atmospheric
pressure chemical ionization (APCI) or electrospray ionization (ESI).
Melting points were uncorrected.
the starting material E-(2-stilbenyl)methanol followed by the
generation of the corresponding discrete carbocation which
readily underwent the intramolecular cyclization to yield the
C1−C2 substituted trans-indanyl-type carbocation. Subsequent
nucleophilic transfer from the trialkylsilyl agents to such trans-
indanyl-type carbocation then furnished the C1−C2 trans-
indane product exclusively. Applications of the developed
method toward the synthesis of biologically active compounds
as well as natural products are under way and will be reported
in due course.
General Procedure for the Heck Reaction. To a stirred solution
under argon atmosphere of 2-bromobenzaldehyde (9 or 17) or 2-
bromoacetophenone (18) (1 equiv) in N,N-dimethylformamide
(DMF) was added styrene (5 equiv), sodium carbonate (Na2CO3, 2
equiv), and tetrakis-triphenylphosphine palladium(0) or bis-
(triphenylphosphine)palladium(II) (0.01 equiv). The reaction mixture
was heated to 120 °C for 18 h. Then, the reaction was allowed to cool
to room temperature. Water and ethyl acetate (EtOAc) were added;
the two phases were separated. The aqueous layer was extracted twice
with EtOAc. The combined organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure to
give the crude product which was further purified by column
chromatography on silica (EtOAc/hexanes) to furnish the desired
products (10, 19, 20, 39−41).
EXPERIMENTAL SECTION
■
General Experimental Methods. Unless otherwise noted,
reactions were run in oven-dried round-bottomed flasks. THF was
distilled from sodium benzophenone ketyl or purified by the solvent
purification system, while CH2Cl2 was also purified by the solvent
purification system prior to use. All other compounds were used as
received from the suppliers; PTS-Si (p-TsOH immobilized on silica)
employed in these experiments possessed the surface area of 500 m2/g
as indicated by the supplier. The crude reaction mixtures were
concentrated by a rotary evaporator that removed organic solvents
under reduced pressure. Column chromatography was performed
using silica gel 60 (particle size 0.06−0.2 mm; 70−230 mesh ASTM).
Analytical thin-layer chromatography (TLC) was performed with silica
(E)-2-Styrylbenzaldehyde (10). The product was obtained as a
yellow oil (5% EtOAc/hexanes as an eluent, 1.48 g, 84%). IR (neat):
1
νmax 3061, 3025, 2839, 2739, 1690, 1595, 1196 cm−1. H NMR (300
̅
MHz, CDCl3): δ 7.06 (d, 1H, J = 16.2 Hz), 7.25−7.46 (m, 4H), 7.59
(d, 3H, J = 7.8 Hz), 7.72 (d, 1H, J = 7.8 Hz), 7.84 (d, 1H, J = 7.8 Hz),
8.05 (d, 1H, J = 15.9 Hz), 10.3 (s, 1H). 13C NMR (75 MHz, CDCl3):
δ 124.8, 127.0, 127.2, 128.3, 128.8, 132.3, 132.9, 133.7, 134.0, 136.7,
139.9, 192.7. LRMS−EI m/z (relative intensity) 208 (100, M+), 207
(41), 179 (51), 178 (65), 165 (31), 152 (17), 130 (18), 89 (29), 77
(21), 76 (28). TOF−HRMS calcd for C15H13O (M + H)+ 209.0961,
found 209.0954.
1
gel 60 F254 aluminum sheets. Chemical shifts for H nuclear magnetic
resonance (NMR) spectra were reported in parts per million (ppm, δ)
downfield from tetramethylsilane. Splitting patterns are described as
singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad
(br), and doublet of doublet (dd). Resonances for infrared (IR)
spectra were reported in wavenumbers (cm−1). Low resolution
(E)-4,5-Dimethoxy-2-styrylbenzaldehyde (19). The product
was obtained as a yellow solid (30% EtOAc/hexanes, 2.48 g, 75%). mp
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1
(EtOAc/hexanes) 148−150 °C. IR (neat): νmax 3002, 2936, 2835,
1597, 1494, 1450, 1177, 1017 cm−1. H NMR (300 MHz, CDCl3): δ
2.28 (d, 1H, J = 3.3 Hz), 6.18 (d, 1H, J = 2.4 Hz), 6.92 (d, 1H, J = 16.2
Hz), 7.25−7.40 (m, 13H), 7.46−7.51 (m, 1H), 7.57−7.62 (m, 1H).
13C NMR (75 MHz, CDCl3): δ 73.4, 125.9, 126.3, 126.6, 126.8, 127.1,
127.6, 127.7, 127.8, 128.5, 128.7, 131.2, 135.8, 137.3, 140.7, 143.0.
LRMS−EI m/z (relative intensity) 286 (4, M+), 196 (15), 195 (100),
194 (59), 178 (27), 165 (21), 105 (22), 91 (24), 77 (24). TOF−
HRMS calcd for C21H17O (M − H)+ 285.1274, found 285.1270.
(E)-2-Methyl-1-(2-stilbenyl)propan-1-ol (23). The product was
obtained as a light yellow oil (20% EtOAc/hexanes, 43.6 mg, 15%). IR
̅
1
1669, 1591, 1508, 1273, 1102 cm−1. H NMR (300 MHz, CDCl3): δ
3.96 (s, 3H), 4.03 (s, 3H), 6.97 (d, 1H, J = 16.2 Hz), 7.10 (s, 1H),
7.27−7.35 (m, 1H), 7.36−7.43 (m, 3H), 7.52−7.58 (m, 2H), 7.89 (d,
1H, J = 16.2 Hz), 10.33 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 56.1,
56.2, 108.8, 111.0, 123.6, 126.5, 126.8, 128.3, 128.8, 133.3, 135.6,
136.8, 148.9, 153.7, 190.0. LRMS−EI m/z (relative intensity) 268
(100, M+), 237 (23), 209 (20), 191 (20), 165 (51), 153 (30), 152
(41), 91 (18), 69 (37), 57 (49). TOF−HRMS calcd for C17H17O3 (M
+ H)+ 269.1172, found 269.1170.
(E)-1-(2-Stilbenyl)ethanone (20). The product was obtained as a
(neat): νmax 3428 (br), 3026, 2959, 1599, 1494, 1468, 1448, 1003
̅
cm−1. H NMR (300 MHz, CDCl3): δ 0.83 (d, 3H, J = 6.9 Hz), 1.01
1
yellow-brown oil (10% EtOAc/hexanes, 0.30 g, 70%). IR (neat): νmax
̅
3060, 3024, 1678, 1354, 1267, 1241 cm−1. 1H NMR (300 MHz,
CDCl3): δ 2.61 (s, 3H), 6.99 (d, 1H, J = 16.2 Hz), 7.22−7.39 (m, 4H),
7.45−7.55 (m, 3H), 7.63−7.72 (m, 3H). 13C NMR (75 MHz, CDCl3):
δ 29.9, 126.8, 127.2, 127.3, 127.4, 127.9, 128.6, 129.0, 131.6, 137.2,
137.3, 137.4, 202.2. LRMS−EI m/z (relative intensity) 222 (100, M+),
221 (41), 207 (47), 179 (52), 178 (86), 152 (20), 145 (62), 89 (31),
76 (22). TOF−HRMS calcd for C16H15O (M + H)+ 223.1117, found
223.1111.
(d, 3H, J = 6.6 Hz), 1.89 (br s, 1H), 1.97−2.10 (m, 1H), 4.78 (d, 1H, J
= 6.6 Hz), 6.94 (d, 1H, J = 15.9 Hz), 7.22−7.30 (m, 3H), 7.30−7.42
(m, 2H), 7.42−7.55 (m, 4H), 7.55−7.61 (m, 1H). 13C NMR (75
MHz, CDCl3): δ 17.8, 19.6, 34.8, 76.4, 126.1, 126.14, 126.5, 126.7,
127.4, 127.6, 127.7, 128.7, 130.8, 135.6, 137.5, 141.3. LRMS−EI m/z
(relative intensity) 252 (10, M+), 210 (16), 209 (100), 178 (18), 165
(19), 131 (83), 103 (70), 91 (28), 77 (18). TOF−HRMS calcd for
C18H20O (M+) 252.1509, found 252.1516.
(E)-2-(4-Methoxystyryl)benzaldehyde (39). The product was
(E)-2,2-Dimethyl-1-(2-stilbenyl)propan-1-ol (24). The product
was obtained as a colorless oil (20% EtOAc/hexanes, 61.9 mg, 48%).
obtained as an orange oil (10% EtOAc/hexanes, 0.43 g, 70%). IR
(neat): νmax 3004, 1693, 1606, 1595, 1250, 1175 cm−1. 1H NMR (300
IR (neat): νmax 3451 (br), 3026, 2954, 1599, 1495, 1479, 1448, 1363,
̅
̅
1176, 1043, 1004 cm−1. 1H NMR (300 MHz, CDCl3): δ 0.96 (s, 9H),
1.85 (br s, 1H), 4.96 (s, 1H), 6.91 (d, 1H, J = 15.9 Hz), 7.23−7.32 (m,
3H), 7.33−7.41 (m, 2H), 7.44−7.59 (m, 5H). 13C NMR (75 MHz,
CDCl3): δ 26.3, 37.0, 76.9, 126.0, 126.5, 127.0, 127.2, 127.4, 127.6,
127.9, 128.7, 130.6, 136.5, 137.6, 140.1. LRMS−EI m/z (relative
intensity) 266 (5, M+), 210 (17), 209 (100), 178 (18), 165 (16), 31
(85), 103 (66), 91 (25), 77 (15), 57 (13). TOF−HRMS calcd for
C19H22O (M+) 266.1665, found 266.1668.
MHz, CDCl3): δ 3.81 (s, 3H), 6.90 (d, 2H, J = 8.1 Hz), 6.99 (d, 1H, J
= 16.2 Hz), 7.38 (t, 1H, J = 7.5 Hz), 7.49 (d, 2H, J = 8.7 Hz), 7.55 (d,
1H, J = 7.2 Hz), 7.68 (d, 1H, J = 7.8 Hz), 7.80 (d, 1H, J = 7.8 Hz),
7.90 (d, 1H, J = 16.2 Hz), 10.30 (s, 1H). 13C NMR (75 MHz, CDCl3):
δ 55.3, 114.1, 122.3, 126.9, 127.1, 128.2, 129.7, 132.1, 133.5, 133.6,
140.3, 159.8, 192.6. LRMS−EI m/z (relative intensity) 238 (1, M+),
195 (95), 194 (58), 178 (33), 167 (28), 165 (22), 149 (100), 105
(27), 91 (17), 77 (28). TOF−HRMS calcd for C16H14O2Na (M +
Na)+ 261.0886, found 261.0879.
(E)-(4,5-Dimethoxy-2-Stilbenyl)(phenyl)methanol (28). The
(E)-2-(4-Chlorostyryl)benzaldehyde (40). The product was
product was obtained as a yellow sticky gum (30% EtOAc/hexanes,
obtained as a yellow oil (10% EtOAc/hexanes, 47.1 mg, 65%). IR
0.65 g, 99%). IR (neat): νmax 3499 (br), 3026, 2934, 1602, 1509, 1449,
̅
(neat): νmax 3036, 3023, 2841, 2739, 1693 cm−1. 1H NMR (300 MHz,
1274, 1202, 1097 cm−1. 1H NMR (300 MHz, CDCl3): δ 2.36 (s, 1H),
3.88 (s, 3H), 3.97 (s, 3H), 6.22 (s, 1H), 6.88 (d, 2H, J = 16.2 Hz), 7.05
(s, 1H), 7.12 (s, 1H), 7.24−7.50 (m, 10H). 13C NMR (75 MHz,
CDCl3): δ 55.8, 55.9, 72.3, 108.7, 110.0, 125.4, 126.4, 126.6, 127.5,
128.1, 128.5, 128.6, 129.4, 133.8, 137.4, 143.3, 148.4, 148.9. LRMS−EI
m/z (relative intensity) 346 (23, M+), 328 (13), 256 (18), 255 (100),
254 (31), 224 (46), 223 (24), 165 (26), 149 (23), 105 (28), 91 (29),
77 (33), 57 (23). TOF−HRMS calcd for C23H22O3 (M+) 346.1563,
found 346.1557.
̅
CDCl3): δ 7.00 (d, 1H, J = 18.0 Hz), 7.26−7.36 (m, 2H), 7.43−7.56
(m, 3H), 7.58−7.61 (m, 1H), 7.71 (d, 1H, J = 6.0 Hz), 7.83 (dd, 1H, J
= 1.5, 9.0 Hz), 8.05 (d, 1H, J = 18.0 Hz), 10.28 (s, 1H). 13C NMR (75
MHz, CDCl3): δ 125.6, 127.1, 127.9, 128.2, 129.0, 132.4, 132.95,
132.97, 133.8, 133.9, 135.5, 139.4, 192.8. LRMS−EI m/z (relative
intensity) 244 (23, M+2), 242 (73, M+), 207 (52), 179 (52), 178
(100), 176 (33), 149 (54), 111 (10), 77 (16). TOF−HRMS calcd for
C15H11ClONa (M + Na)+ 265.0391, found 265.0378.
(E)-(2-(4-Methoxystyryl)phenyl)methanol (42). The product
(E)-2-(4-Nitrostyryl)benzaldehyde (41). The product was
obtained as a brown solid (10% EtOAc/hexanes, 115.0 mg, 93%).
was obtained as a yellow oil (10% EtOAc/hexanes, 0.20 g, 70%). IR
1
(neat): νmax 3421 (br), 3058, 3030, 1606, 1249, 1175 cm−1. H NMR
mp (EtOAc/hexanes) 122−123 °C. IR (neat): νmax 3063, 2923, 2852,
̅
̅
1693, 1595, 1531, 1340 cm−1. 1H NMR (300 MHz, CDCl3): δ 7.11 (d,
1H, J = 15.0 Hz), 7.52−7.57 (m, 1H), 7.62−7.78 (m, 4H), 7.86 (d,
1H, J = 6.0 Hz), 8.23−8.34 (m, 3H), 10.26 (s, 1H). 13C NMR (75
MHz, CDCl3): δ 124.15, 127.25, 127.43, 128.7, 130.1, 130.9, 133.8,
134.0, 193.0. LRMS−EI m/z (relative intensity) 253 (46, M+), 178
(63), 167 (27), 149 (100), 111 (21), 97 (40), 83 (30), 77 (19), 69
(60). TOF−HRMS calcd for C15H11NO3Na (M + Na)+ 276.0631,
found 276.0621.
(300 MHz, CDCl3): δ 2.23 (s, 1H) 3.82 (s, 3H), 6.19 (s, 1H), 6.86−
6.90 (m, 3H), 7.22−7.39 (m, 10H), 7.54 (d, 1H, J = 6.0 Hz), 7.58 (d,
1H, J = 6.3 Hz). 13C NMR (75 MHz, CDCl3): δ 55.3, 73.3, 114.1,
123.7, 126.1, 126.8, 127.1, 127.4, 127.8, 127.9, 128.5, 130.2, 130.7,
136.1, 140.5, 143.1, 159.3. LRMS−EI m/z (relative intensity) 316 (2,
M+), 167 (26), 149 (100), 121 (25), 91 (5), 77 (7), 71 (37), 69 (38),
57 (37). TOF−HRMS calcd for C22H20O2Na (M + Na)+ 339.1356,
found 339.1357.
(E)-(2-(4-Chlorostyryl)phenyl)methanol (43). The product was
obtained as a white solid (10% EtOAc/hexanes, 61.6 mg, 70%). mp
General Procedure for the Synthesis of 11, 23, 24, 28, and
42−44. To a stirred solution (1 equiv) of 10 or 19 in dry THF at −78
°C under argon atmosphere was added phenyllithium or phenyl-
magnesium bromide (for 11, 28, 42−44), i-propylmagnesium chloride
(for 23), t-butyllithium (for 24) (1.5 equiv). The reaction mixture was
stirred at −78 °C for 30 min, then warmed to room temperature and
stirred until all of the starting material was consumed as monitored by
TLC. Water and EtOAc were added, and the two phases were
separated. The aqueous layer was extracted twice with EtOAc. The
combined organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure to give the crude
product which was further purified by column chromatography on
silica (EtOAc/hexanes) to furnish the desired products.
(EtOAc/hexanes) 66−68 °C. IR (neat): νmax 3421 (br), 3058, 3029,
̅
2924, 2854, 1492 cm−1. 1H NMR (300 MHz, CDCl3): δ 2.39 (s, 1H),
6.12 (s, 1H), 6.83 (d, 1H, J = 18.0 Hz), 7.28−7.36 (m, 12H), 7.44−
7.50 (m, 1H), 7.53−7.59 (m, 1H). 13C NMR (75 MHz, CDCl3): δ
73.5, 126.3, 126.6, 126.5, 126.2, 127.6, 127.7, 127.9, 128.0, 128.5,
128.8, 129.7, 133.3, 135.5, 135.8, 140.7, 143.0. LRMS−EI m/z
(relative intensity) 322 (2, M+2), 320 (6, M+), 195, (100), 177 (33),
149 (53), 125 (21), 97 (24), 91 (32), 77 (28), 69 (54). TOF−HRMS
calcd for C21H17ClO (M+) 320.0962, found 320.0963.
(E)-(2-(4-Nitrostyryl)phenyl)methanol (44). The product was
obtained as a yellow oil (10% EtOAc/hexanes, 47.4 mg, 71%). IR
(E)-Phenyl(2-stilbenyl)methanol (11). The product was ob-
tained as a yellowish white solid (30% EtOAc/hexanes, 1.24 g, 98%).
(neat): νmax 3544, 3393 (br), 3062, 3030, 2926, 1593, 1513, 1494,
̅
1
1339 cm−1. H NMR (300 MHz, CDCl3):δ 2.30 (br s, 1H), 6.17 (s,
mp (EtOAc/hexanes) 113−115 °C. IR (neat): νmax 3353 (br), 3027,
1H), 6.94 (d, 1H, J = 16.1 Hz), 7.26−7.36 (m, 6H), 7.38−7.52 (m,
̅
8291
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3H), 7.54−7.62 (m, 3H), 8.18 (d, 2H, J = 8.8 Hz). 13C NMR (75
MHz, CDCl3): δ 73.6, 124.0, 126.4, 126.6, 126.9, 127.6, 128.1, 128.2,
128.4, 128.5, 126.7, 130.7, 134.7, 141.7, 142.9, 143.8, 146.7. LRMS−EI
m/z (relative intensity) 331 (0.3, M+), 227 (12), 167 (28), 149 (100),
97 (22), 83 (19), 77 (6), 71 (43), 69 (53), 57 (42). TOF−HRMS
calcd for C21H17NO3 (M+) 331.1203, found 331.1207.
mmol) in THF (5 mL) was added via syringe. The resulting mixture
was warmed up to room temperature and stirred until the starting
material was consumed as indicated by TLC. Water (10 mL) and
EtOAc (10 mL) were added, and the two phases were separated. The
aqueous layer was extracted with EtOAc (2 × 15 mL), and the
combined organic phases were washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure to give the crude
product which was further purified by column chromatography on
silica (15% EtOAc/hexanes) to furnish the desired product 26 as a
(E)-(2-Stilbenyl)methanol (21). To a stirred solution of 10 (0.43
g, 2.07 mmol) in absolute MeOH (10 mL) was added NaBH4 (0.09 g,
2.27 mmol). This was stirred at room temperature for 30 min and then
concentrated. Water (10 mL) and EtOAc (10 mL) were added, and
the two phases were separated. The aqueous layer was extracted with
EtOAc (2 × 10 mL). The combined organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure to give the product 21 as a white solid (0.39 g, 91%) which
was recrystallized from EtOAc/hexanes. mp (EtOAc/hexanes) 89−91
light yellow oil (0.16 g, 44%). IR (neat): νmax 3503 (br), 3001, 2925,
̅
2852, 1596, 1512, 1463, 1450, 1417, 1258, 1234, 1137, 1026 cm−1. 1H
NMR (300 MHz, CDCl3): δ 2.66 (br s, 1H), 3.74 (s, 3H), 3.78 (s,
3H), 6.04 (s, 1H), 6.71−6.92 (m, 4H), 7.18−7.41 (m, 8H), 7.46−7.51
(m, 1H), 7.53−7.56 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 55.8,
55.9, 73.3, 110.2, 111.1, 120.2, 126.1, 126.4, 126.6, 126.8, 127.8, 127.9,
128.7, 131.2, 135.8, 137.4, 140.1. LRMS−EI m/z (relative intensity)
346 (2, M+), 269 (19), 268 (100), 253 (8), 240 (12), 225 (21), 209
(29), 193 (18), 181 (19), 165 (50), 152 (34), 126 (15), 91 (14), 82
(15), 76 (27), 57 (20). TOF−HRMS calcd for C23H22O3 (M+)
346.1563, found 346.1560.
°C. IR (neat): νmax 3332 (br), 3247, 3030, 2920, 2866, 1738, 1596,
̅
1578, 1490, 1479, 1452, 1371, 1042 cm−1. 1H NMR (300 MHz,
CDCl3): δ 1.61 (br s, 1H), 4.84 (d, 2H, J = 5.4 Hz), 7.05 (d, 1H, J =
15.9 Hz), 7.25−7.37 (m, 6H), 7.46 (d, 1H, J = 16.2 Hz), 7.53 (d, 2H, J
= 7.5 Hz), 7.66 (d, 1H, J = 8.1 Hz). 13C NMR (75 MHz, CDCl3): δ
63.6, 125.3, 126.0, 126.7, 127.7, 127.8, 128.3, 128.6, 131.2, 136.3,
137.3, 137.8. TOF−HRMS calcd for C15H13O (M − H)+ 209.0972,
found 209.0969.
(E)-(2-Stilbenyl)(4-(trifluoromethoxy)phenyl)methanol (27).
A solution (1.50 M) of the Grignard solution was prepared by mixing
1-bromo-4-(trifluoromethoxy)benzene (0.67 mL, 4.51 mmol) and
magnesium (0.37 g, 1.54 mmol) in Et2O (3 mL). To this mixture was
added iodine as catalyst, and the mixture was stirred for 15 min at
room temperature. After bubbles disappeared, the Grignard solution
(0.51 mL, 0.77 mmol) was transferred to the solution of (E)-2-
styrylbenzaldehyde 10 (0.80 g, 0.38 mmol) in Et2O (3 mL). The
reaction mixture was stirred for 1 h at 0 °C. Then the resulting mixture
was warmed up to room temperature. Water (5 mL) and EtOAc (5
mL) were added, and the two phases were separated. The aqueous
layer was extracted with EtOAc (2 × 10 mL), and the combined
organic phases were washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure to give the crude product
which was further purified by preparative TLC (10% EtOAc/hexanes)
to furnish the desired product 27 as a colorless oil (0.12 g, 87%). IR
(E)-1-(2-Stilbenyl)ethanol (22). To a stirred solution of 20 (0.16
g, 0.697 mmol) in absolute EtOH (10 mL) was added NaBH4 (0.04 g,
1.05 mmol). This was stirred at room temperature for 30 min and then
concentrated. Water (10 mL) and EtOAc (10 mL) were added, and
the two phases were separated. The aqueous layer was extracted with
EtOAc (2 × 10 mL). The combined organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure to give the crude product which was further purified by
column chromatography on silica (10% EtOAc/hexanes) to furnish 22
as a light yellow oil (0.12 g, 75%). IR (neat): νmax 3357 (br), 3026,
̅
2973, 1599, 1493, 1448, 1369, 1259, 1071 cm−1. 1H NMR (300 MHz,
CDCl3): δ 1.52 (d, 3H, J = 6.3 Hz), 5.31 (q, 1H, J = 6.5 Hz), 6.97 (d,
1H, J = 15.9 Hz), 7.24−7.45 (m, 6H), 7.47−7.61 (m, 5H). 13C NMR
(75 MHz, CDCl3): δ 24.4, 67.2, 125.0, 125.6, 126.2, 126.6, 127.6,
127.8, 128.0, 128.7, 131.3, 135.0, 137.4, 143.0. LRMS−EI m/z
(relative intensity) 224 (20, M+), 209 (80), 178 (25), 165 (18), 133
(58), 131 (20), 115 (15), 105 (29), 103 (31), 91 (100), 77 (24).
TOF−HRMS calcd for C16H16O (M+) 224.1196, found 224.1203.
(E)-2-(Methylsulfonyl)-1-(2-stilbenyl)ethanol (25). To a stirred
solution of dimethyl sulfone (0.21 g, 2.18 mmol) in THF (15 mL) at
−78 °C was added n-butyllithium (1.2 M in hexanes, 1.82 mL, 2.18
mmol) via syringe. After 1 h, a solution of (E)-2-styrylbenzaldehyde 10
(0.30 g, 1.45 mmol) in THF (5 mL) was added via syringe. The
resulting mixture was warmed up to room temperature and stirred
until the starting material was consumed as indicated by TLC. Then,
the reaction was cooled to 0 °C. Water (15 mL) and EtOAc (15 mL)
were added, and the two phases were separated. The aqueous layer
was extracted with EtOAc (2 × 15 mL), and the combined organic
phases were washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure to give a crude product which
was further purified by column chromatography on silica (50%
EtOAc/hexanes) to furnish 25 as a light yellow oil (0.18 g, 40%). IR
(neat): νmax 3356, 3028, 1506, 1450, 1254, 1220, 1162, 1017 cm−1. 1H
̅
NMR (300 MHz, CDCl3): δ 6.21 (s, 1H), 6.94 (d, 1H, J = 16.2 Hz),
7.18 (d, 2H, J = 8.1 Hz), 7.23−7.47 (m, 12H), 7.60−7.64 (m, 1H).
13C NMR (75 MHz, CDCl3): δ 72.7, 120.5 (q, JC−F = 255.8 Hz),
120.9, 125.6, 126.6, 126.62, 127.2, 127.9, 127.94, 128.1, 128.3, 131.7,
136.0, 137.2, 140.4, 141.8, 148.5. LRMS−EI m/z (relative intensity)
370 (6, M+), 352 (5), 280 (15), 279 (92), 278 (60), 195 (24), 194
(30), 178 (38), 165 (44), 152 (17), 105 (43), 91 (100), 77 (36).
TOF−HRMS calcd for C22H17F3O2 (M+) 370.1175, found 370.1170.
General Procedure for the Synthesis of Indane via Lewis
Acid-Mediated Cyclization Followed by Nucleophilic Transfer
from the Silyl Reagents. To a stirred solution of the E-(2-
stilbenyl)methanols (0.02−0.03 g, 1 equiv) 11, 21−28, and 42−44 in
solvents (CH2Cl2, PhMe, THF, MeCN, cyclohexane, 1,2-dimethoxy-
ethane (DME), 1,4-dioxane, Et2O) at 0 °C was added trialkylsilyl
reagent (type and equivalent as indicated in each Table or Scheme).
Then, a Lewis or Brønsted acid (type and equivalent as indicated in
each Table or Scheme) was added, and the resulting mixture was
stirred at 0 °C until the starting material was consumed as monitored
on TLC. The reaction mixture was concentrated and purified by
preparative TLC (EtOAc/hexanes) to furnish the desired product.
1,2-Diphenyl-1H-indene (12). The product was obtained as a
(neat): νmax 3473 (br), 3027, 2928, 1599, 1495, 1292, 1127, 1056
̅
1
cm−1. H NMR (300 MHz, CDCl3): δ 3.00 (s, 3H), 3.10−3.25 (m,
2H), 3.38 (dd, 1H, J = 9.9, 14.7 Hz), 5.75 (d, 1H, J = 9.9 Hz), 6.97 (d,
1H, J = 15.9 Hz), 7.24−7.42 (m, 6H), 7.50−7.61 (m, 4H). 13C NMR
(75 MHz, CDCl3): δ 42.6, 61.5, 66.2, 124.0, 125.5, 125.5, 126.7, 128.1,
128.2, 128.6, 128.8, 132.6, 134.8, 136.8, 138.1. LRMS−EI m/z
(relative intensity) 302 (11, M+), 222 (20), 205 (20), 178 (27), 165
(14), 145 (20), 131 (100), 115 (21), 103 (26), 91 (53), 77 (18).
TOF−HRMS calcd for C17H18NaO3S (M + Na)+ 325.0869, found
325.0865.
light yellow oil (2% EtOAc/hexanes, 2.30 mg, 8%). IR (neat): νmax
̅
2923, 2847, 1710, 1599, 1491, 1456 cm−1. 1H NMR (300 MHz,
CDCl3): δ 4.97 (s, 1H), 7.07−7.27 (m, 10H), 7.36−7.42 (m, 3H),
7.50 (d, 2H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): δ 56.2, 121.1,
123.8, 125.4, 126.6, 126.7, 127.0, 127.3, 127.8, 128.0, 135.0, 140.0,
143.2, 149.1, 149.9. TOF−HRMS calcd for C21H16 (M+) 268.1247,
found 268.1255.
(E)-(3,4-Dimethoxyphenyl)(2-stilbenyl)methanol (26). To a
solution of 4-bromoveratrole (0.15 mL, 1.05 mmol) in THF (10 mL)
was added t-butyllithium (1.7 M in pentane, 1.23 mL, 2.09 mmol) via
syringe, and the reaction mixture was stirred for 30 min at −78 °C. At
that time, a solution of (E)-2-styrylbenzaldehyde 10 (0.22 g, 1.05
2,3-Diphenyl-1H-indene (13). The product was obtained as a
light yellow oil (2% EtOAc/hexanes, 2.80 mg, 10%). IR (neat): νmax
̅
3053, 3025, 2924, 2853, 1710, 1603, 1488, 1459, 1443, 1391 cm−1. 1H
NMR (300 MHz, CDCl3): δ 3.93 (s, 2H), 7.19−7.29 (m, 8H), 7.35−
7.42 (m, 5H), 7.54 (d, 1H, J = 6.3 Hz). 13C NMR (75 MHz, CDCl3):
8292
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δ 41.2, 120.4, 123.6, 125.0, 126.0, 126.5, 126.9, 127.4, 127.8, 128.2,
128.3, 128.4, 128.8, 129.1, 129.4, 136.1, 136.6, 139.9, 141.1, 142.4,
146.9. TOF−HRMS calcd for C21H16 (M+) 268.1247, found 268.1254.
trans-1,2-Diphenyl-2,3-dihydro-1H-indene (14). The product
NMR (75 MHz, CDCl3): δ 39.8, 40.9, 41.9, 42.3, 47.4, 52.0, 56.0, 58.9,
121.3, 124.39, 124.41, 125.3, 125.7, 126.8, 127.1, 127.3, 127.4, 127.8,
128.0, 128.3, 128.8, 129.1, 133.8, 142.1, 142.8, 143.5, 145.4, 147.9.
LRMS−EI m/z (relative intensity) 284 (7), 207 (13), 206 (60), 205
(64), 204 (100), 203 (77), 202 (44), 189 (13), 178 (15), 165 (10),
149 (10), 128 (16), 101 (23), 91 (46), 83 (14), 71 (19), 69 (24), 57
(32). TOF−HRMS calcd for C17H19O2S (M + H)+ 287.1100, found
287.1097.
was obtained as a light yellow oil (10% EtOAc/hexanes, 86.6 mg,
1
73%). IR (neat): νmax 3060, 3027, 1602, 1495, 1453 cm−1. H NMR
̅
(300 MHz, CDCl3): δ 3.23 (dd, 1H, J = 10.0, 15.6 Hz), 3.41 (dd, 1H, J
= 8.0, 15.7 Hz), 3.56−3.65 (m, 1H), 4.41 (d, 1H, J = 9.6 Hz), 6.91 (d,
1H, J = 7.5 Hz), 7.05−7.09 (m, 2H), 7.13−7.31 (m, 11H). 13C NMR
(75 MHz, CDCl3): δ 40.2, 56.7, 59.7, 124.1, 125.0, 126.4, 126.5, 126.7,
127.0, 127.5, 128.3, 128.34, 128.5, 142.6, 143.2, 143.4, 145.9. LRMS−
EI m/z (relative intensity) 270 (55, M+), 192 (56), 191 (27), 179
(93), 178 (100), 165 (16), 115 (9), 91 (13). TOF−HRMS calcd for
C21H18 (M+) 270.1403, found 270.1409.
trans-1-(3,4-Dimethoxyphenyl)-2-phenyl-2,3-dihydro-1H-in-
dene (34). The product was obtained as a light yellow oil (10%
EtOAc/hexanes, 23.2 mg, 60%). IR (neat): νmax 3025, 2934, 2835,
̅
1591, 1516, 1454, 1418, 1257, 1234, 1138, 1028 cm−1. 1H NMR (400
MHz, CDCl3): δ 3.25 (dd, 1H, J = 10.4, 15.6 Hz), 3.40 (dd, 1H, J =
8.0, 15.4 Hz), 3.51−3.60 (m, 1H), 3.72 (s, 3H), 3.85 (s, 3H), 4.34 (d,
1H, J = 9.8 Hz), 6.56 (d, 1H, J = 1.9 Hz), 6.63 (dd, 1H, J = 1.9, 8.2
Hz), 6.76 (d, 1H, J = 8.2 Hz), 6.96 (d, 1H, J = 7.4 Hz), 7.16−7.33 (m,
8H). 13C NMR (100 MHz, CDCl3): δ 39.9, 55.8, 56.8, 59.5, 111.3,
111.6, 120.5, 124.1, 124.9, 126.4, 126.7, 126.9, 127.6, 128.3, 135.8,
142.6, 143.2, 145.9, 147.7, 148.9. LRMS−EI m/z (relative intensity)
330 (100, M+), 299 (27), 239 (95), 238 (53), 208 (67), 192 (79), 191
(54), 178 (27), 165 (50), 152 (25), 149 (27), 126 (31), 115 (26), 91
(60), 57 (36). TOF−HRMS calcd for C23H22O2 (M+) 330.1614,
found 330.1620.
trans-2,3-Diphenyl-2,3-dihydro-1H-inden-1-ol (16). The prod-
uct was obtained as a 1.7:1 mixture of diastereomer at C1 as colorless
oil (10% EtOAc/hexanes, 17.6 mg, 80%). IR (neat): νmax 2258, 3028,
̅
2899, 1601, 1495, 1476, 1453, 1266, 1208, 1108, 1050 cm−1. 1H NMR
(300 MHz, CDCl3): δ 2.31 (br s, 1H), 3.34 (dd, 1H, J = 8.6, 10.1 Hz),
3.70 (dd, 1H, J = 5.6, 9.2 Hz, minor), 4.33 (d, 1H, J = 9.9 Hz), 4.86 (d,
1H, J = 9.3 Hz, minor), 5.26 (d, 1H, J = 5.4 Hz, minor), 5.37 (d, 1H, J
= 8.4 Hz), 6.93 (d, 1H, J = 7.5 Hz), 6.98−7.02 (m, 1H, minor), 7.06−
7.19 (m, 3H), 7.19−7.39 (m, 20H), 7.46−7.53 (m, 3H). 13C NMR
(75 MHz, CDCl3): δ 53.4 (minor), 55.8, 61.5 (minor), 67.4, 76.8
(minor), 81.1, 123.5, 124.9, 125.2, 125.3, 126.6, 126.7, 127.2, 127.5,
127.53, 128.1, 128.3, 128.4, 128.5, 128.53, 128.56, 128.6, 129.1, 129.3,
137.7, 140.1, 132.2, 142.3, 143.0, 143.5, 143.9, 147.1. LRMS−EI m/z
(relative intensity) 286 (14, M+), 268 (11), 195 (100), 194 (25), 179
(15), 178 (19), 177 (16), 165 (26), 152 (12), 126 (6), 105 (10), 91
(12), 77 (9). TOF−HRMS calcd for C21H18O (M+) 286.1352, found
286.1351.
trans-2-Phenyl-1-(4-(trifluoromethoxy)phenyl)-2,3-dihydro-
1H-indene (35). The product was obtained as a yellow oil (10%
EtOAc/hexanes, 20.4 mg, 75%). IR (neat): νmax 3029, 2930, 1603,
̅
1508, 1479, 1257, 1222, 1164, 1106, 1019 cm−1. 1H NMR (400 MHz,
CDCl3): δ 3.25 (dd, 1H, J = 10.1, 15.7 Hz), 3.43 (dd, 1H, J = 9.6, 16.5
Hz), 3.50−3.59 (m, 1H), 4.43 (d, 1H, J = 9.5 Hz), 6.90 (d, 1H, J = 7.4
Hz), 7.09 (s, 4H), 7.17−7.34 (m, 8H). 13C NMR (100 MHz, CDCl3):
δ 40.2, 56.9, 59.1, 116.7, 120.5 (q, JC−F = 191.3 Hz), 120.8, 124.2,
124.8, 126.6, 126.7, 127.2, 127.4, 128.4, 129.6, 142.1, 142.6, 142.8,
145.2, 147.9. LRMS−EI m/z (relative intensity) 354 (52, M+), 276
(63), 263 (100), 262 (88), 192 (23), 191 (37), 179 (44), 178 (98),
177 (35), 165 (43), 152 (20), 115 (21), 91 (43), 77 (12), 69 (19).
TOF−HRMS calcd for C22H17F3O (M+) 354.1226, found 354.1233.
trans-5,6-Dimethoxy-1,2-diphenyl-2,3-dihydro-1H-indene
(36). The product was obtained as a light yellow oil (10% EtOAc/
trans-1-Methyl-2-phenyl-2,3-dihydro-1H-indene (30). The
product was obtained as a light yellow oil (10% EtOAc/hexanes,
19.7 mg, 99%). IR (neat): νmax 3028, 2926, 1603, 1494, 1454, 1374,
̅
1255, 1078 cm−1. 1H NMR (300 MHz, CDCl3): δ 1.29 (d, 3H, J = 6.9
Hz), 3.05−3.15 (m, 2H), 3.19−3.34 (m, 2H), 7.15−7.26 (m, 5H),
7.31−7.37 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 17.6, 40.5, 47.1,
55.7, 123.1, 124.1, 126.4, 126.6, 127.7, 128.4, 142.2, 143.4, 147.3.
LRMS−EI m/z (relative intensity) 208 (51, M+), 207 (69), 193 (39),
191 (24), 179 (36), 178 (62), 165 (28), 133 (54), 115 (66), 105 (78),
91 (100), 77 (81), 57 (40). TOF−HRMS calcd for C16H15 (M − H)+
207.1168, found 207.1177.
hexanes, 27.1 mg, 86%). IR (neat): νmax 3027, 2933, 1605, 1502, 1453,
̅
1
1301, 1216, 1097, 1031 cm−1. H NMR (300 MHz, CDCl3): δ 3.17
(dd, 1H, J = 9.3, 15.3 Hz), 3.37 (dd, 1H, J = 8.1, 13.4 Hz), 3.50−3.60
(m, 1H), 3.73 (s, 3H), 3.91 (s, 3H), 4.37 (d, 1H, J = 8.7 Hz), 6.46 (s,
1H), 6.85 (s, 1H), 7.05−7.09 (m, 2H), 7.16−7.30 (m, 8H). 13C NMR
(75 MHz, CDCl3): δ 40.1, 56.0, 57.2, 60.0, 107.2, 108.0, 126.3, 126.4,
127.5, 128.2, 128.3, 128.4, 134.3, 137.1, 143.6, 143.9, 148.4, 148.5.
LRMS−EI m/z (relative intensity) 330 (100, M+), 315 (12), 299 (26),
253 (16), 252 (19), 239 (53), 238 (31), 208 (36), 165 (38), 149 (35),
126 (22), 115 (21), 91 (42), 57 (38). TOF−HRMS calcd for
C23H23O2 (M + H)+ 331.1693, found 331.1700.
trans-1-Isopropyl-2-phenyl-2,3-dihydro-1H-indene (31). The
product was obtained as a light yellow oil (10% EtOAc/hexanes, 15.3
mg, 50%). IR (neat): νmax 3020, 2958, 2927, 1603, 1456, 1261, 1073,
̅
1031 cm−1. 1H NMR (400 MHz, CDCl3): δ 0.85 (d, 6H, J = 6.8 Hz),
2.00−2.11 (m, 1H), 2.85−2.94 (m, 1H), 3.15−3.19 (m, 1H), 3.28−
3.37 (m, 2H), 7.08−7.20 (m, 9H). 13C NMR (100 MHz, CDCl3): δ
19.0, 20.3, 22.5, 31.9, 41.4, 46.8, 59.9, 124.1, 124.6, 125.9, 126.2, 126.9,
128.4, 143.1, 145.1, 147.9. LRMS−EI m/z (relative intensity) 236 (18,
M+), 193 (100), 178 (26), 115 (53), 91 (24), 57 (16). TOF−HRMS
calcd for C18H19 (M − H)+ 235.1481, found 235.1486.
5,6-Dimethoxy-1,2-diphenyl-1H-indene (37). The product was
obtained as a light yellow oil (10% EtOAc/hexanes, 26.3 mg, 72%). IR
(neat): νmax 2934, 2832, 1577, 1597, 1556, 1459, 1464, 1312, 1215,
̅
1101 cm−1. 1H NMR (300 MHz, CDCl3): δ 3.78 (s, 3H), 3.91 (s, 3H),
4.89 (s, 1H), 6.75 (s, 1H), 6.97 (s, 1H), 7.11−7.26 (m, 9H), 7.45 (d,
2H, J = 7.8 Hz). 13C NMR (75 MHz, CDCl3): δ 56.0, 56.1, 104.5,
107.8, 126.2, 126.6, 126.8, 127.6, 127.8, 128.4, 128.8, 135.1, 138.7,
140.3, 142.0, 147.7, 148.8, 148.9. LRMS−EI m/z (relative intensity)
328 (100, M+), 313 (29), 297 (25), 252 (16), 241 (18), 239 (26), 207
(26), 191 (17), 165 (20), 164 (24), 149 (30), 126 (27), 120 (39), 113
(17), 107 (15), 91 (12), 71 (11), 57 (19). TOF−HRMS calcd for
C23H21O2 (M + H)+ 329.1536, found 329.1533.
trans-1-tert-Butyl-2-phenyl-2,3-dihydro-1H-indene (32). The
product was obtained as a light yellow oil (10% EtOAc/hexanes, 34.7
mg, 85%). IR (neat): νmax 3025, 1954, 1603, 1477, 1453, 1364, 1227,
̅
1
1031 cm−1. H NMR (300 MHz, CDCl3): δ 0.99 (s, 9H), 2.84−2.93
(m, 2H), 3.43−3.53 (m, 2H), 6.97−7.03 (m, 2H), 7.07−7.29 (m, 7H).
13C NMR (75 MHz, CDCl3): δ 27.8, 35.36, 40.1, 45.9, 65.8, 124.2,
125.6, 125.8, 126.1, 126.8, 127.1, 128.5, 143.9, 144.4, 149.6. LRMS−EI
m/z (relative intensity) 250 (9, M+), 194 (44), 193 (100), 178 (22),
116 (13), 115 (54), 91 (19), 57 (16). TOF−HRMS calcd for C19H21
(M − H)+ 249.1638, found 249.1641.
trans-1-(Methylsulfonylmethyl)-2-phenyl-2,3-dihydro-1H-in-
dene (33). The product was obtained as a 2:1 mixture of unassignable
5,6-Dimethoxy-1,2-diphenyl-2,3-dihydro-1H-indene (38). To
a stirred solution of indene 37 (20.5 mg, 0.062 mmol) in EtOAc under
H2 atmosphere (a H2 balloon) was added Pd/C (0.05 equiv). The
reaction mixture was stirred for 18 h. At that time, the resulting
mixture was filtered through Celite, and the filtrate was concentrated
and purified by preparative TLC using 20% EtOAc/hexanes to furnish
the indane 38 as a yellowish oil (20.5 mg, 0.062 mmol, >99%). IR
cis and trans isomers as light yellow oil (30% EtOAc/hexanes, 28.0
1
mg, 50%). IR (neat): νmax 3026, 2927, 1459, 1294, 1126 cm−1. H
̅
NMR (300 MHz, CDCl3): δ 2.65 (s, 3H, minor), 2.88 (s, 3H, major),
2.99−3.17 (m, 2H), 3.25−3.45 (m, 2H), 3.46−3.57 (m, 2H), 3.79−
3.86 (m, 1H, minor), 4.57 (d, 1H, J = 9.0 Hz), 7.15 (s, 1H), 7.21−7.50
(m, 13H), 7.59 (d, 2H, J = 7.5 Hz), 7.95 (d, 1H, J = 7.2 Hz). 13C
(neat): νmax 3027, 2932, 1606, 1502, 1453, 1301, 1219, 1098 cm−1. 1H
̅
NMR (300 MHz, CDCl3): δ 3.18 (dd, 1H, J = 7.6, 15.3 Hz), 3.32 (dd,
8293
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1H, J = 8.7, 15.1 Hz), 3.74 (s, minor), 3.76 (s, 3H), 3.92 (s, minor),
3.94 (s, 3H), 4.04 (dd, 1H, J = 8.1, 16.2 Hz), 4.37 (d, J = 9.0 Hz,
minor), 4.60 (d, 1H, J = 8.1 Hz), 6.46 (s, minor), 6.58−6.60 (m, 2H),
6.66 (s, 1H), 6.80−6.82 (m, 2H), 6.94 (s, 1H), 6.96−7.05 (m, 6H),
7.16−7.25 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 36.9, 52.5, 56.0,
56.03, 56.9, 107.3, 108.4, 125.95, 125.97, 127.5, 127.6, 128.4, 129.0,
135.5, 136.9, 141.1, 141.2, 148.0, 148.5. LRMS−EI m/z (relative
intensity) 330 (100, M+), 315 (11), 299 (24), 252 (17), 239 (47), 238
(28), 208 (31), 165 (33), 126 (20), 115 (18), 91 (37). TOF−HRMS
calcd for C23H22O2 (M+) 330.1614, found 330.1623.
21H), 7.33−7.54 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 35.2, 36.2,
48.5, 50.1, 53.5, 59.1, 59.3, 62.6, 116.2, 116.9, 123.5, 124.8, 124.9,
125.1, 126.4, 126.95, 126.99, 128.17, 128.26, 128.3, 128.4, 128.5,
128.6, 128.7, 136.1, 137.0, 140.3, 142.0, 143.3, 145.2, 145.5, 145.9,
146.0. TOF−HRMS calcd for C24H22 (M+) 310.1716, found 310.1714.
trans-1-Chloro-2,3-diphenyl-2,3-dihydro-1H-indene (50).
The product was obtained as a light orange oil (5% EtOAc/hexanes,
18.9 mg, 59%). IR (neat): νmax 3060, 3028, 2920, 1709, 1601, 1494,
̅
1475, 1453 cm−1. 1H NMR (300 MHz, CDCl3): δ 3.69 (t, 1H, J = 9.3
Hz), 4.00 (dd, 1H, J = 6.0, 9.0 Hz, minor), 4.42 (d, 1H, J = 9.9 Hz),
4.91 (d, 1H, J = 10.2 Hz, minor), 5.49 (d, 1H, J = 8.7 Hz), 5.60 (d, 1H,
J = 5.4 Hz, minor), 6.94 (d, 4H, J = 7.2 Hz), 7.02−7.40 (m, 14H), 7.52
(t, 3H, J = 9.3 Hz). 13C NMR (75 MHz, CDCl3): δ 51.8 (minor), 57.4,
60.6 (minor), 66.90, 66.92 (minor), 67.5, 124.8, 124.9, 125.4, 126.6,
127.0, 127.2, 127.4, 127.7, 127.8, 127.9, 128.1, 128.3, 128.4, 128.5,
128.6, 128.7, 128.8, 129.0, 129.3, 129.4, 137.4, 139.0, 140.8,141.8,
142.3, 143.9, 146.9. TOF−HRMS calcd for C21H17 (M − Cl)+
269.1325, found 269.1327.
trans-2-(4-Methoxyphenyl)-1-phenyl-2,3-dihydro-1H-indene
(45). The product was obtained as a yellow oil (2% EtOAc/hexanes,
16.6 mg, 58%). IR (neat): νmax 3058, 3027, 1248, 1179 cm−1. 1H NMR
̅
(300 MHz, CDCl3): δ 3.20 (dd, 1H, J = 10.0, 15.6 Hz), 3.38 (dd, 1H, J
= 7.9, 15.6 Hz), 3.52−3.61 (m, 1H) 3.77 (s, 3H), 4.35 (d, 1H, J = 6.0
Hz), 6.79 (d, 2H, J = 8.7 Hz), 6.90 (d, 1H, J = 7.3 Hz), 7.07−7.31 (m,
10H). 13C NMR (75 MHz, CDCl3): δ 40.3, 55.2, 56.0, 59.9, 113.7,
124.1, 125.0, 126.5, 126.7, 126.9, 128.3, 128.4, 128.5, 130.7, 135.2,
142.7, 143.4, 146.0. LRMS−EI m/z (relative intensity) 300 (100, M+),
192 (63), 179 (74), 165 (37), 139 (41), 121 (43), 97 (49), 77 (21), 71
(60), 69 (89), 57 (61). TOF−HRMS calcd for C22H20O (M)+
300.1509, found 300.1516.
trans-1-Bromo-2,3-diphenyl-2,3-dihydro-1H-indene (51).
The product was obtained as a light yellow oil (5% EtOAc/hexanes,
26.4 mg, 72%). IR (neat): νmax 3060, 3028, 2925, 1724, 1602, 1493,
̅
1453 cm−1. 1H NMR (300 MHz, CDCl3): δ 3.82−3.91 (m, 2H), 4.48
(d, 1H, J = 9.3 Hz), 4.83 (d, 1H, J = 10.2 Hz, minor), 4.91 (d, 1H, J =
10.2 Hz), 5.60 (d, 1H, J = 8.7 Hz), 5.78 (d, 1H, J = 5.1 Hz, minor),
6.90−6.95 (m, 2H), 7.07 (d, 2H, J = 6.6 Hz), 7.24−7.40 (m, 19H),
7.49−7.56 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 51.6 (minor),
57.7, 58.3, 60.2 (minor), 60.7 (minor), 67.7, 124.7 (minor), 124.9,
125.4 (minor), 125.8, 127.0, 127.1, 127.4, 127.7, 127.8, 128.0, 128.1,
128.50, 128.51, 128.6, 128.7, 129.0, 129.1, 129.3, 138.3, 139.2, 140.4,
141.9, 142.2, 142.7, 144.0, 147.0. TOF−HRMS calcd for C21H17 (M −
Br)+ 269.1325, found 269.1320.
trans-2-(4-Chlorophenyl)-1-phenyl-2,3-dihydro-1H-indene
(46). The product was obtained as a yellow oil (2% EtOAc/hexanes,
10.1 mg, 58%). IR (neat): νmax 3063, 3027, 2932, 2851, 1600 cm−1. 1H
̅
NMR (300 MHz, CDCl3): δ 3.20 (dd, 1H, J = 10.1, 15.6 Hz), 3.40
(dd, 1H, J = 8.0, 15.7 Hz), 3.53−3.62 (m, 1H), 4.35 (d, 1H, J = 9.0
Hz), 6.91 (d, 1H, J = 9.0 Hz), 7.05−7.32 (m, 12H). 13C NMR (75
MHz, CDCl3): δ 40.1, 56.2, 59.9, 124.2, 125.0, 126.7, 126.9, 127.1,
128.5, 128.9, 132.1, 141.7, 142.4, 143.0. LRMS−EI m/z (relative
intensity) 306 (12, M+2), 304 (37, M+), 192 (32), 179 (100), 178
(80), 165 (23), 149 (12), 125 (14), 77 (12), 69 (14). TOF−HRMS
calcd for C21H16Cl (M − H)+ 303.0935, found 303.0943.
trans-1-Iodo-2,3-diphenyl-2,3-dihydro-1H-indene (52). The
product was obtained as a light pink oil (5% EtOAc/hexanes, 13.7 mg,
33%). 1H NMR (300 MHz, CDCl3): δ 3.23 (dd, 1H, J = 6.0, 12.0 Hz,
minor), 3.96 (t, 1H, J = 9.2 Hz), 4.56−4.61 (m, 2H), 5.74 (d, 1H, J =
9.0 Hz), 5.99 (d, 1H, J = 5.4 Hz, minor), 6.84 (d, 1H, J = 7.5 Hz,
minor), 6.89 (d, J = 7.2 Hz, 1H), 7.00−7.42 (m, 14H), 7.46−7.55 (m,
2H). 13C NMR (75 MHz, CDCl3): δ 34.9, 43.5 (minor), 52.0 (minor),
59.2, 59.8 (minor), 69.1, 124.3, 124.8, 125.4, 127.0, 127.2, 127.4,
127.6, 127.8, 128.1, 128.2, 128.45, 128.50, 128.6, 128.71, 128.78,
128.81, 129.1, 139.4, 139.9, 142.0, 143.5, 143.8, 144.5. TOF−HRMS
calcd for C21H17 (M − I)+ 269.1325, found 269.1333.
trans-2-(4-Nitrophenyl)-1-phenyl-2,3-dihydro-1H-indene
(47). The product was obtained as a yellow oil (2% EtOAc/hexanes,
15.5 mg, 99%). IR (neat): νmax 3063, 3027, 2942, 2853, 1560, 1519,
̅
1
1345 cm−1. H NMR (300 MHz, CDCl3): δ 3.19 (dd, 1H, J = 10.0,
15.1 Hz), 3.39 (dd, 1H, J = 8.0, 15.7 Hz), 3.59−3.68 (m, 1H), 4.33 (d,
1H, J = 9.0 Hz), 6.85 (d, 1H, J = 7.2 Hz), 6.98 (d, 2H, J = 1.6 Hz),
7.00−8.02 (m, 6H), 7.27 (d, 2H, J = 7.2 Hz), 8.05 (d, 2H, J = 1.6 Hz).
13C NMR (75 MHz, CDCl3): δ 39.8, 56.5, 59.9, 123.7, 124.2, 125.0,
127.0, 127.1, 128.3, 128.6, 141.8, 142.5, 145.2, 146.7, 151.1. LRMS−EI
m/z (relative intensity) 315 (24, M+), 179 (64), 178 (56), 149 (65),
111 (27), 97 (56), 77 (43), 57 (71). TOF−HRMS calcd for
C21H17NO2 (M+) 315.1254, found 315.1251.
trans-1-Azido-2-(4-methoxyphenyl)-3-phenyl-2,3-dihydro-
1H-indene (53a). The product was obtained as a yellow oil (2%
EtOAc/hexanes, 16.5 mg, 42%). IR (neat): νmax 3028, 2092, 1248,
̅
1
1178 cm−1. H NMR (300 MHz, CDCl3): δ 3.43 (t, 1H, J = 9.0 Hz),
trans-1-Azido-2,3-diphenyl-2,3-dihydro-1H-indene (48). The
product was obtained as a 9:1 mixture of diastereomers as light yellow
3.77 (s, 3H), 4.34 (d, 1H, J = 9.0 Hz), 4.98 (d, 1H, J = 12.0 Hz), 6.84
(dd, 2H, J = 3.0, 6.9 Hz), 6.95 (d, 1H, J = 9.0 Hz), 7.05−7.08 (m, 2H),
7.15−7.38 (m, 7H), 7.46 (d, 1H, J = 6.0 Hz). 13C NMR (75 MHz,
CDCl3): δ 55.2, 56.7, 63.3, 70.9, 114.1, 123.8, 125.3, 126.9, 127.7,
128.5, 128.9, 128.9, 131.3, 141.1, 141.8, 144.3, 158.8. LRMS−EI m/z
(relative intensity) 314 (23), 313 (100, (M−N2)+), 312 (79), 206
(86), 179 (95), 178 (95), 165 (45), 121 (90), 91 (20), 77 (30). TOF−
HRMS calcd for C22H19N3O (M+) 341.1523, found 341.1522.
cis-1-Azido-2-(4-methoxyphenyl)-3-phenyl-2,3-dihydro-1H-
indene (53b). The product was obtained as a yellow oil (2% EtOAc/
oil (10% EtOAc/hexanes, 19.0 mg, 75%). IR (neat): νmax 3029, 2915,
̅
2092, 1601, 1494, 1454, 1314, 1248, 1075, 1029 cm−1. 1H NMR (300
MHz, CDCl3): δ 3.49 (dd, 1H, J = 9.4, 9.5 Hz), 3.79−3.95 (m, minor),
4.39 (d, 1H, J = 9.9 Hz), 4.76−4.86 (m, minor), 5.03 (d, 1H, J = 8.7
Hz), 5.25 (d, J = 7.8 Hz, minor), 6.96 (d, 1H, J = 7.2 Hz), 7.07 (d, 2H,
J = 6.6 Hz), 7.16−7.40 (m, 12H), 7.47 (d, 1H, J = 7.2 Hz). 13C NMR
(75 MHz, CDCl3): δ 53.2 (minor), 56.7, 60.3 (minor), 63.9, 68.8
(minor), 70.9, 123.8, 125.3, 127.0, 127.4, 127.8, 127.9, 128.3, 128.4,
128.5, 128.6, 128.7, 129.0, 129.2, 139.5, 140.1, 141.8, 144.3. LRMS−EI
m/z (relative intensity) 283 (44), 282 (69), 269 (12), 206 (89), 192
(50), 191 (29), 179 (73), 178 (100), 165 (51), 152 (19), 91 (32), 77
(21), 69 (14), 57 (17). TOF−HRMS calcd for C21H17 (M − N3)+
269.1325, found 269.1320, calcd for C21H16N (M − N2 − H)+
282.1277, found 282.1275.
hexanes, 7.46 mg, 19%). IR (neat): νmax 3028, 2094, 1247, 1179 cm−1.
̅
1H NMR (300 MHz, CDCl3): δ 3.73−3.78 (m, 4H), 4.77 (d, 1H, J =
12.0 Hz), 5.03 (d, 1H, J = 6.0 Hz), 6.93 (d, 2H, J = 18.0 Hz), 6.99−
7.02 (m, 1H), 7.13−7.35 (m, 9H), 7.33−7.35 (m, 1H). 13C NMR (75
MHz, CDCl3): δ 55.2, 59.7, 68.9, 113.7, 124.8, 125.6, 126.9, 127.5,
128.4, 128.6, 129.0, 129.5, 130.2, 139.6, 141.6, 147.1, 158.7. LRMS−EI
m/z (relative intensity) 341 (M+), 314 (23), 313 (100), 312 (73), 206
(62), 179 (65), 178 (90), 165 (47), 149 (54), 121 (830, 97 (36), 77
(35). TOF−HRMS calcd for C22H19N3O (M+) 341.1523, found
341.1538.
trans-1-Allyl-2,3-diphenyl-2,3-dihydro-1H-indene (49). The
product was obtained as a light yellow solid (2% EtOAc/hexanes, 22.0
mg, 68%). IR (neat): νmax 3062, 3026, 2920, 1639, 1601, 1492, 1475,
̅
1452 cm−1. 1H NMR (300 MHz, CDCl3): δ 2.00−2.02 (m, 1H),
2.43−2.53 (m, 1H), 2.59−2.66 (m, 1H), 3.22 (t, 1H, J = 10.2 Hz),
3.46−3.59 (m, 2H), 3.90 (t, 1H, J = 8.4 Hz), 4.37 (d, 1H, J = 10.2 Hz),
4.73 (d, 1H, J = 9.3 Hz), 4.79 (d, 1H, J = 18.3 Hz), 4.91 (d, 1H, J = 9.9
Hz), 5.01 (d, 1H, J = 9.9 Hz), 5.07 (d, 1H, J = 17.1 Hz), 5.62−5.84
(m, 2H), 6.89−6.96 (m, 2H), 7.02 (d, 2H, J = 6.9 Hz), 7.16−7.29 (m,
trans-1-Azido-2-(4-chlorophenyl)-3-phenyl-2,3-dihydro-1H-
indene (54a). The product was obtained as a yellow oil (2% EtOAc/
hexanes, 6.41 mg, 47%). IR (neat): νmax 3328, 2921, 2094, 1600, 1492
̅
1
cm−1. H NMR (300 MHz, CDCl3): δ 3.45 (t, 1H, J = 9.0 Hz), 4.34
8294
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(d, 1H, J = 9.0 Hz), 4.99 (d, 1H, J = 9.0 Hz), 6.96 (d, 1H, J = 9.0 Hz),
7.06 (d, 2H, J = 6.0 Hz), 7.17−7.40 (m, 9H), 7.47 (d, 1H, J = 6.0 Hz).
13C NMR (75 MHz, CDCl3): δ 56.8, 63.4, 70.7, 123.9, 125.3, 127.2,
(9) Bianco, G. G.; Ferraz, H. M. C.; Costa, A. M.; Costa-Lotufo, L.
V.; Pessoa, C.; de Moraes, M. O.; Schrems, M. G.; Pfaltz, A.; Silva, L.
F., Jr. J. Org. Chem. 2009, 74, 2561−2566.
127.9, 128.5, 128.7, 128.9, 129.1, 129.3, 133.2, 137.9, 139.9, 141.4,
144.0. LRMS−EI m/z (relative intensity) 345 (1, M+), 319 (20), 318
(33), 317 (60), 316 (70), 206 (58), 192 (58), 179 (75), 178 (100),
165 (46), 140 (14), 125 (21), 77 (15). TOF−HRMS calcd for
C21H15ClN (M − N2 − H)+ 316.0888, found 316.0903.
́ ́
(10) Silva, L. F., Jr.; Craveiro, M. V.; Tebeka, I. R. M. Tetrahedron
2010, 66, 3875−3895.
(11) Silva, L. F., Jr.; Craveiro, M. V. Org. Lett. 2008, 10, 5417−5420.
(12) Buszek, K. R.; Brown, N.; Luo, D. Org. Lett. 2009, 11, 201−204.
(13) Liu, W.; Lim, H. J.; RajanBabu, T. V. J. Am. Chem. Soc. 2012,
134, 5496−5499.
cis-1-Azido-2-(4-chlorophenyl)-3-phenyl-2,3-dihydro-1H-in-
dene (54b). The product was obtained as a yellow oil (2% EtOAc/
(14) Jackson, S. K.; Kerr, M. A. J. Org. Chem. 2007, 72, 1405−1411.
(15) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550−3577.
(16) Hanson, J. R. Nat. Prod. Rep. 2004, 21, 312−320.
(17) Liang, G.; Xu, Y.; Seiple, I. B.; Trauner, D. J. Am. Chem. Soc.
2006, 128, 11022−11023.
(18) Batsomboon, P.; Phakhodee, W.; Ruchirawat, S.; Ploypradith, P.
J. Org. Chem. 2009, 74, 4009−4012.
hexanes, 2.45 mg, 18%). IR (neat): νmax 3750, 3610, 3029, 2924, 2100,
̅
1711, 1492 cm−1. 1H NMR (300 MHz, CDCl3): δ 3.75 (t, 1H, J = 9.0
Hz), 4.77 (d, 1H, J = 9.0 Hz), 5.06 (d, 1H, J = 6.0 Hz), 7.00 (s, 1H),
7.13 (d, 1H, J = 9.0 Hz), 7.26−7.36 (m, 10H), 7.475 (d, 1H, J = 3.0
Hz). 13C NMR (75 MHz, CDCl3): δ 53.6, 59.8, 68.5, 124.8, 125.7,
127.1, 127.7, 128.4, 128.3, 128.7, 129.7, 130.6. LRMS−EI m/z
(relative intensity) 345 (1, M+), 319 (20), 318 (32), 317 (58), 316
(67), 206 (460, 179 (74), 178 (100), 165 (46), 140 (12), 127 (12),
125 (20), 77 (16). TOF−HRMS calcd for C21H15ClN (M − N2 − H)+
316.0888, found 316.0896.
(19) Radomkit, S.; Sarnpitak, P.; Tummatorn, J.; Batsomboon, P.;
Ruchirawat, S.; Ploypradith, P. Tetrahedron 2011, 67, 3904−3914.
(20) This strategy was pioneered and investigated as a means for the
total synthesis of resveratrol-based natural products. Please see:
Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos, A. L. J.
Am. Chem. Soc. 2009, 131, 1753−1765.
Quantum Chemical Calculations. Quantum chemical calcula-
tions were performed using the M062X density functional theory
(DFT) method, with the 6-31+G(g,p) basis set, and a polarizable
continuum solvent model (PCM) of CH2Cl2. All minima and
transition states were confirmed from frequency calculations, the
former showing all positive frequencies and the latter a single negative
frequency. The thermochemically corrected free energies are reported
in Figure 2.
(21) Snyder, S. A.; Brill, Z. G. Org. Lett. 2011, 13, 5524−5527.
(22) Lantano, B.; Aguirre, J. M.; Finkielsztein, L.; Alesso, E. N.;
̃
Brunet, E.; Moltrasio, G. Y. Synth. Commun. 2004, 34, 625−641.
(23) We found that the use of Pd(PPh3)4 usually gave the product 10
in higher yield but Pd(PPh3)2Cl2 was more stable and easier to handle.
For reviews of Heck reactions, see: (a) Beletskaya, I. P.; Cheprakov, A.
V. Chem. Rev. 2000, 100, 3009−3066. (b) Dounay, A. B.; Overman, L.
E. Chem. Rev. 2003, 103, 2945−2963. (c) McCartney, D.; Guiry, P. J.
Chem. Soc. Rev. 2011, 40, 5122−5150.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
General information, copies of H and 13C NMR spectra of all
(24) For the seminal work on the Heck reactions, see: Heck, R. F.;
Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320−2322.
(25) The corresponding trifluoroacetate indane products from the
trifluoroacetate acting as a nucleophile to quench the indanyl-type
cation was not observed either at 0 °C to room temperature or at −30
°C. The results were different from those obtained by Snyder and co-
workers (see ref 20).
new compounds, the absolute energies and the vibrational
frequencies and intensities of all stationary points obtained on
the reaction pathway, and the Cartesian coordinates. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(26) For example, see: Li, K.; Vanka, K.; Thompson, W. H.; Tunge, J.
A. Org. Lett. 2006, 8, 4711−4714.
AUTHOR INFORMATION
Corresponding Author
*E-mail: poonsakdi@cri.or.th.
Notes
■
(27) Stereochemical assignment of the indanol 16 obtained as a 1.7:1
inseparable mixture of epimers at C1 position is based on (1) the
NMR assignment of peaks corresponding to protons at C1 (CHOH; δ
5.37 for major and 5.26 for minor), C2 (CHPh; δ 3.34 for major and
3.70 for minor), and C3 (CHArPh; δ 4.33 for major and 4.86 for
minor) as well as (2) the J values between H2 and H3 which are
consistently large for both isomers (9.3 and 9.9 Hz for H2; 9.2 and
10.1 Hz for H3), while the J value between H1 and H2 is large for the
major isomer (8.4 Hz, suggesting trans relationship) compared with
that of the minor isomer (5.4 Hz, suggesting cis relationship). These
data are in accordance with the assigned structures of the major isomer
possessing H1−H2 as well as H2−H3 in the trans relationship. On the
other hand, the minor isomer appears to possess H1−H2 cis and H2−
H3 trans relationship. In addition, the NOE experiments confirmed
the assignments (see S5 in the Supporting Information; NOE values of
1.44% and 1.69% were observed for H1−H2 in the trans relationship
of the major isomer, while those of 6.21% and 7.71% were observed
for the H1−H2 in the cis relationship of the minor isomer. Similar
NOE values of 0.96% and 1.35% were observed for the H2−H3 for
both isomers, suggesting H2−H3 in the trans relationship.)
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Thailand Research Fund (TRF;
BRG5580010 for P.P. and RSA 5480016 for M.P.G.), National
Science Foundation (NSF; NSF CHE-0850693 for Y.K.), and
Kasetsart University are gratefully acknowledged.
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Article
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