Bi(OTf)3-Mediated Intramolecular Olefinic Cyclization: Synthesis of Substituted Aryl-Dihydronaphthalenes and Indenes

Article abstract of DOI:10.1021/acs.joc.7b01278

In this article, a facile two-step and one-pot synthetic route for the preparation of substituted aryl dihydronaphthalenes starting from 2-allylbenzaldehydes via Grignard 1,2-addition and Bi(OTf)₃-catalyzed intramolecular olefinic cyclization has been developed. A five-membered ring indene skeleton is also prepared via olefin isomerization, 1,2-addition followed by cyclization. Some key structures are determined using single-crystal X-ray crystallography. A possible mechanism is presented herein.

Full text of DOI:10.1021/acs.joc.7b01278

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Note
Bi(OTf)3-mediated Intramolecular Olefinic Cyclization:
Synthesis of Substituted Aryl-Dihydronaphthalenes and Indenes
Chieh-Kai Chan, Nai-Chen Hsueh, Yu-Lin Tsai, and Meng-Yang Chang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01278 • Publication Date (Web): 15 Jun 2017
Downloaded from http://pubs.acs.org on June 15, 2017
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The Journal of Organic Chemistry
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Bi(OTf)3-mediated Intramolecular Olefinic Cyclization: Synthesis of Substituted
Aryl-Dihydronaphthalenes and Indenes
Chieh-Kai Chan, Nai-Chen Hsueh, Yu-Lin Tsai and Meng-Yang Chang*
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Department of Medicinal and Applied Chemistry, Kaohsiung Medical University Hospital, Kaohsiung Medical University,
Kaohsiung 807, Taiwan
ABSTRACT: In this article, a facile two-step and one-pot synthetic route for the preparation of substituted aryl dihy-
dronaphthalenes starting from 2-allylbenzaldehydes via Grignard 1,2-addition and Bi(OTf)3-catalyzed intramolecular olefinic
cyclization has been developed. A five-membered ring indene skeleton is also prepared via olefin isomerization, 1,2-addition fol-
lowed by cyclization. Some key structures are determined using single-crystal X-ray crystallography. A possible mechanism is pre-
sented herein.
The preparation of carbocycles, regarded as a crucial struc-
tural motif in many compounds with meaningful utilization
in pharmaceutical and industry fields, plays an important
role and acts as an useful synthetic tool in organic synthe-
sis.1 In particular, five- and six-membered carbocycles have
been recognized as important framework in medicinal
chemistry and bioactive natural products with privileged
characteristics.2 Among them, the six-membered dihy-
dronaphthalene derivatives have attracted considerable
attention due to existing bioactive natural products such as
cyclogalgravin, magnoshinin, trilobatin A and B, a wide
range of biological activities3 and useful synthetic interme-
diates.4 Nevertheless, a five-membered indene core is also
found in some natural products, such as cyanosporaside A,
taiwaniaquinol D, and trikentramine5 and serves as signifi-
cant precursors for organometallic catalysts6 and bioactive
molecules.7 With these advantages and the importance of
dihydronaphthalene and indene compounds, many methods
have been developed to construct the skeletons. The exist-
ing methodologies include transition metal-catalyzed C-H
bond activation8, photocatalytic annulation9, ring-
expansion of cyclopropanes10 or cyclopropenes11, organo-
metallic nucleophilic addition12, and Lewis13 or Brønsted14
acid-catalyzed Friedel-Crafts cyclization.
Scheme 1. Synthesis of dihydronaphthalenes and indenes
In 2003, Yamamoto and colleagues described a Cu(OTf)2-
catalyzed [4+2] cycloaddition reaction of alkynylbenzalde-
hydes with alkenes to form dihydronaphthalene deriva-
tives.15 Recently, Luo’s group reported a Cu(OTf)2-
catalyzed intramolecular conjugated addition of alkenes to
α,β-unsaturated carbonyls to construct dihydronaphthalene
and indene skeletons.16 Our study attempts to develop the
versatilities of 2-allylbenzaldehyde17 and the utilizations of
18
Bi(OTf)3 in organic methodologies, and to show a com-
parison of these metal triflate-mediated synthetic works for
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the synthesis of dihydronaphthalenes or indenes. However,
aReaction was run on a 0.5 mmol scale with 3a, 2h. bIsolat-
ed yield. 74% of 3a was recovered. Unknown products
were isolated.
c
d
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substituted 2-allylbenzaldhydes including olefin and alde-
hyde groups were selected as the starting materials to de-
velop the synthetic route. The preparation of substituted
Next, benzyl alcohol 3a was selected as the model substrate
to screen the metal triflate-mediated intramolecular cycliza-
tion of reaction conditions. As shown in Table 1, the in-
volvement of various metal triflates as catalyst was tested
for the construction of dihydronaphthalene 4a. Catalytic
amounts of Ag(OTf), Mg(OTf)2, Zn(OTf)2, Cu(OTf)2,
Ni(OTf)2, Hg(OTf)2, Sn(OTf)2, Sc(OTf)3, Ga(OTf)3,
Fe(OTf)3, In(OTf)3 and Bi(OTf)3 provided different results
dihydronaphthalenes
and
indenes
from
2-
allylbenzaldehydes using Bi(OTf)3 as a catalyst have not
been developed. Herein, a Bi(OTf)3-mediated intramolecu-
lar cyclization of aryl-substituted benzylic alcohol for the
preparation of substituted aryl-dihydronaphthalenes and
indenes starting from versatile 2-allylbenzaldehydes is
reported (Scheme 1).
Initially, a series of substituted 2-allylbenzaldehyde 2 was
prepared from isovanillin (1) in a three-step process with
excellent yields overall (Scheme 2).17 On the basis of our
experience, we believe that the 1,2-addition of 2-
allylbenzaldehyde 2 with a Grignard reagent could be con-
ducted smoothly and provide corresponding alcohol in high
yields.17a Unfortunately, the benzyl alcohols 3 were unsta-
ble, only representative 3a-3d were provided (Scheme 3).
Scheme 2. Three-step synthesis of 2-allylbenzaldehyde 2
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in CH2Cl2 at 25 C for 2 h. In entry 1, Ag(OTf) only pro-
vided 4a in 15% with recovered 3a in a yield of 74% . Us-
ing Mg(OTf)2, Zn(OTf)2, Cu(OTf)2, Ni(OTf)2, Sc(OTf)3 or
Ga(OTf)3 as catalyst, the reaction was unworkable and no
isolation of desired product 4a was observed (entries 2-7).
Other metal triflates such as Fe(OTf)3, In(OTf)3 and
Hg(OTf)2 promoted the reaction to proceed, and the isolat-
ed yields of 4a was ranged from 58% to 65% (entries 8-10).
Notably, Sn(OTf)3 and Bi(OTf)3 increased the desired
product 4a in higher 81% and 85% yields, respectively
(entries 11-12). No obvious yields changes occurred when
increasing the amounts of Bi(OTf)3, the volume of CH2Cl2
or the reaction temperature (entries 13-15). Further exam-
ined other solvent, including MeNO2, MeCN, C2H4Cl2,
benzene and dioxane, but the yields of 4a was declined
(entries 16-20). By the use of TfOH, only 25% 4a was ob-
tained with complex mixture (entry 21).
Scheme 3. Synthesis of benzyl alcohol 3
Table 1. Conditions for the construction of 4aa
As shown in Table 2, the 1,2-addition of 2 with a Grignard
reagent, including the electron-neutral PhMgBr, the elec-
tron-withdrawing group 4-FC6H4MgBr, and the electron-
donating 4-MeC6H4MgBr and 4-OMeC6H4MgBr reacted in
a high yield. Owing to unstable benzyl alcohol, the crude
product was used without further purification, and a
Bi(OTf)3 catalyst was added to the solvent of in-situ benzyl
entry catalyst (mol %), solvent (mL), temp (oC) 4a (%)b
1
2
AgOTf (2), CH2Cl2 (20), 25
Mg(OTf)2 (2), CH2Cl2 (20), 25
Zn(OTf)2 (2), CH2Cl2 (20), 25
Cu(OTf)2 (2), CH2Cl2 (20), 25
Ni(OTf)2 (2), CH2Cl2 (20), 25
Sc(OTf)3 (2), CH2Cl2 (20), 25
Ga(OTf)3 (2), CH2Cl2 (20), 25
Fe(OTf)3 (2), CH2Cl2 (20), 25
In(OTf)3 (2), CH2Cl2 (20), 25
Hg(OTf)2 (2), CH2Cl2 (20), 25
Sn(OTf)2 (2), CH2Cl2 (20), 25
Bi(OTf)3 (2), CH2Cl2 (20), 25
Bi(OTf)3 (5), CH2Cl2 (20), 25
Bi(OTf)3 (2), CH2Cl2 (30), 25
Bi(OTf)3 (2), CH2Cl2 (20), 100
Bi(OTf)3 (2), MeNO2 (20), 25
Bi(OTf)3 (2), MeCN (20), 25
Bi(OTf)3 (2), (CH2Cl)2 (20), 25
Bi(OTf)3 (2), benzene (20), 25
Bi(OTf)3 (2), dioxane (20), 25
TfOH (2), CH2Cl2 (20), 25
15c
─
o
alcohol in CH2Cl2 at 25 C. The desired dihydronaphtha-
lenes 4a-4p were obtained in modest to good yields be-
tween 76% and 88%. The structure of 4a was confirmed by
single-crystal X-ray diffraction.19
3
─
4
─
5
─
Table 2. Synthesis of 4a,b
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─
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The Journal of Organic Chemistry
Scheme 5. Possible mechanism
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aConditions: for 1,2-addition, 2 (1.0 mmol), ArMgBr (1.0
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M, 1.5 mL, 1.5 mmol), dry THF (10 mL), 0 oC, 3h; for cy-
clization, Bi(OTf)3 (13 mg, 2.0 mol%), CH2Cl2 (20 mL), 25
oC, 2h. bIsolated yields.
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Based on the results in Tables 1-3, a mechanism for the
preparation of dihydronaphthalene 4a and indene 6a were
proposed, as shown in Scheme 5.18 First, 1,2-addition of
terminal olefin 2a or internal olefin 5a with a Grignard
reagent (PhMgBr) gave corresponding benzylic alcohol.
For 4a, the formation of A was by alcohol moiety chelated
with Bi(OTf)3. A tandem intramolecular cyclization was
formed by an ene-reaction to form B. After the methoxy
group promoted debismuthation, the in-situ generated
HOBi(OTf)3 anion deprotonated the H (red) of B to afford
4a. For 6a, Bi(OTf)3 chelated with hydroxyl group to give
intermediate C. Then an intramolecular ene reaction was
achieved to obtain D. Following the above pathway of 4a,
the in situ generated HOBi(OTf)3 anion deprotonated the H
(blue) of E to construct 6a.
Other prepared 2-allylbenzaldehydes were also inves-
tigated in this two-step procedure.17 As shown in Scheme 6,
mono-methoxy substituted benzaldehyde 2e and aryl-
substituted benzaldehyde 2f were suitable for the synthesis
of aryl-substituted dihydronaphthalenes 4q-4t in good
yields. Similarly, through the NaOH-mediated olefin mi-
gration to construct 5e-5f, the corresponding indenes 6q-6t
were isolated in high yields. Furthermore, after changing
ArMgBr to MeMgBr for the addition with 2a in this two-
step procedure, no desired product was observed, instead of
dimer 7 that was expected. Therefore, we believe that di-
benzylic alcohol is more powerful than mono-benzylic al-
cohol in this annulation. The structure of 4t was confirmed
by single-crystal X-ray diffraction.19
To our delight, changing the double bond position met our
goal. Therefore, using a NaOH/MeOH system to transfer
the terminal double bond on 2 to the internal double bond
on 5 is completely migrated (Scheme 4).17c,d,20 Based on the
results in Table 1, we believe that the internal double bond
benzaldehyde 5 is also suitable for this one-pot two-step
preparation of substituted indenes. As shown in Table 3,
the reaction of vinylbenzaldehyde 5 with a Grignard rea-
gent is smooth. Bi(OTf)3-catalyzed synthesis of the desired
indenes 6a-6p in the yields ranged from 78% to 94%. The
structure of 6a, 6d, 6f and 6h were confirmed by single-
crystal X-ray diffraction.19
Scheme 4. Synthesis of 5
Table 3. Synthesis of 6a,b
Scheme 6. Reaction scope
aConditions: for 1,2-addition, 5 (1.0 mmol), ArMgBr (1.0
o
M, 1.5 mL, 1.5 mmol), dry THF (10 mL), 0 C, 3h; for cy-
clization, Bi(OTf)3 (13 mg, 2.0 mol%), CH2Cl2 (20 mL), 25
In summary, a Bi(OTf)3-mediated intramolecular cycliza-
tion for synthesis substituted aryl-dihydronaphthalenes has
oC, 2h. bIsolated yields.
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17.2 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.60 (ddt, J = 1.6, 6.0,
been developed. Further investigation was made into changing
the terminal olefin to an internal olefin in the optimal condi-
tion, and the corresponding substituted aryl-indenes were also
prepared in high yields. The structures of some products were
confirmed by X-ray single-crystal diffraction analysis.
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16.0 Hz, 1H), 3.38 (ddt, J = 1.6, 6.0, 16.0 Hz, 1H), 2.34 (s, 3H),
1.86 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 152.1 (2x), 147.2,
140.5, 137.5, 137.0, 135.2, 131.4, 129.1, 129.0 (2x), 126.7 (2x),
125.3, 123.0, 115.1, 110.3, 72.2, 60.8, 55.6, 30.0, 21.1.
5
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EXPERIMENT SECTION
General
2-Allyl-3,4-dimethoxyphenyl(4-methoxyphenyl)methanol
(3d).
Yield = 90% (283 mg); Colorless oil; HRMS (ESI, M++Na) calcd
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for C19H22O4Na 337.1416, found 337.1415; H NMR (400 MHz,
CDCl3): δ 7.23 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.8 Hz, 1H), 6.85
(d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.8 Hz, 1H), 6.01-5.91 (m, 1H),
5.95 (s, 1H), 5.02 (dq, J = 1.6, 10.0 Hz, 1H), 4.92 (dq, J = 1.6,
17.2 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.61-3.55
(m, 1H), 3.35 (ddt, J = 1.6, 6.4, 15.6 Hz, 1H), 2.18 (br s, 1H); 13C
NMR (100 MHz, CDCl3): δ 158.8, 152.0, 147.2, 137.5, 135.6,
135.2, 131.3, 128.1 (2x), 122.8, 115.1, 113.7 (2x), 110.3, 72.0,
60.8, 55.6, 55.2, 29.9.
All reagents and solvents were obtained from commercial
sources and used without further purification. Reactions were
routinely carried out under an atmosphere of dry nitrogen with
magnetic stirring. Products in organic solvents were dried with
anhydrous magnesium sulfate before concentration in vacuo.
Purity was determined by NMR and melting point. Melting
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1
points were determined with a SMP3 melting apparatus. H
and 13C NMR spectra were recorded on a Varian spectrometer
operating at 400 and at 100 MHz, respectively. Chemical
shifts (δ) are reported in parts per million (ppm) and the cou-
pling constants (J) are given in Hertz. High resolution mass
spectra (HRMS) were measured with a mass spectrometer
microTOF-Q by ESI using a hybrid ion-trap. X-ray crystal
structures were obtained with a diffractometer (CAD4, Kappa
CCD).
General synthetic route for the synthesis of 4a-4t, 6a-6t and 7.
A solution of a Grignard reagent (1.0 M in THF, 1.5 mL, 1.5
mmol) was added to a stirred solution of skeletons 2 and 5 (1.0
mmol) in THF (10 mL) at ice bath. The reaction mixture was
o
stirred at 25 C for 3 h. Water (5 mL) was added to the reaction
mixture and the mixture was filtered through a short plug of Celite.
The filtrate was concentrated under reduced pressure. The residue
was extracted with EtOAc (3 x 30 mL). The combined organic
layers were washed with brine, dried, filtered and evaporated to
afford crude product under reduced pressure. Without further
purification, a solution of the resulting secondary alcohol in DCM
(10 mL) was added to a mixture of Bi(OTf)3 (13 mg, 2.0 mol%) in
General synthetic route for the synthesis of 3a-3d. A solution
of a Grignard reagent (1.0 M in THF, 1.5 mL, 1.5 mmol) was
added to a stirred solution of 2 (1.0 mmol) in THF (10 mL) at ice
o
o
bath. The reaction mixture was stirred at 25 C for 3 h. Water (5
DCM (20 mL). After being stirred at 25 C for 2 h, the mixture
mL) was added to the reaction mixture and the mixture was fil-
tered through a short plug of Celite. The filtrate was concentrated
under reduced pressure. The residue was extracted with EtOAc (3
x 30 mL). The combined organic layers were washed with brine,
dried, filtered and evaporated to afford crude product under re-
duced pressure. Purification on silica gel (hexanes/EtOAc =
6/1~3/1) afforded 3a-3d.
was filtered through a short silica gel column. The filtrate was
dried, filtered, and evaporated to yield crude compound. Purifica-
tion on silica gel (hexanes/EtOAc = 10/1~6/1) afforded 4a-4t, 6a-
6t and 7.
5,6-Dimethoxy-1-phenyl-1,2-dihydronaphthalene (4a). Yield =
85% (226 mg); Colorless solid; mp = 97-98 oC (recrystallized
from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for
C18H18O2Na 289.1205, found 289.1197; 1H NMR (400 MHz,
CDCl3): δ 7.34-7.30 (m, 2H), 7.27-7.22 (m, 3H), 6.93 (dt, J = 1.6,
9.6 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H),
6.07 (dt, J = 4.4, 9.6 Hz, 1H), 4.09-4.05 (m, 1H), 3.87 (s, 3H),
3.84 (s, 3H), 2.65-2.59 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
151.3, 144.6, 131.2, 128.4 (3x), 128.3 (2x), 127.9, 127.7, 126.4,
123.2, 122.0, 110.4, 61.1, 55.7, 43.4, 31.9. Single-crystal X-ray
diagram: crystal of 4a was grown by slow diffusion of EtOAc into
a solution of 4a in CH2Cl2 to yield colorless prisms. The
compound crystallizes in the Orthorhombic crystal system, space
group P b c n, a = 20.772(2) Å , b = 7.4286(8) Å , c = 18.5851(17)
Å , V = 2867.8(5) Å 3, Z = 8, dcalcd = 1.234 g/cm3, F(000) = 1136,
2 range 1.96-26.47o, R indices (all data) R1 = 0.1256, wR2 =
0.3111.
2-Allyl-3,4-dimethoxyphenyl(phenyl)methanol (3a). Yield = 88%
(250 mg); Colorless oil; HRMS (ESI, M++Na) calcd for
C18H20O3Na 307.1310, found 307.1312; 1H NMR (400 MHz,
CDCl3): δ 7.35-7.24 (m, 5H), 7.04 (d, J = 8.4 Hz, 1H), 6.79 (d, J
= 8.4 Hz, 1H), 6.03-5.94 (m, 1H), 6.00 (s, 1H), 5.03 (dq, J = 1.6,
10.0 Hz, 1H), 4.94 (dq, J = 1.6, 17.2 Hz, 1H), 3.85 (s, 3H), 3.80 (s,
3H), 3.66-3.57 (m, 2H), 3.45-3.39 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 152.1, 147.2, 143.4, 137.5, 135.0, 131.5, 128.2 (2x),
127.2, 126.7 (2x), 123.2, 115.1, 110.3, 72.3, 60.8, 55.5, 29.9.
2-Allyl-3,4-dimethoxyphenyl(4-fluorophenyl)methanol (3b). Yield
= 92% (278 mg); Colorless oil; HRMS (ESI, M++Na) calcd for
C18H19FO3Na 325.1216, found 325.1213; 1H NMR (400 MHz,
CDCl3): δ 7.31-7.27 (m, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.97 (d, J
= 8.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.01-5.92 (m, 1H), 5.96 (s,
1H), 5.02 (dq, J = 1.6, 10.0 Hz, 1H), 4.91 (dq, J = 1.6, 17.2 Hz,
1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.58 (ddt, J = 1.6, 6.0, 16.0 Hz,
1H), 3.39 (ddt, J = 1.6, 6.0, 16.0 Hz, 1H), 2.21 (br s, 1H); 13C
NMR (100 MHz, CDCl3): δ 162.0 (d, J = 243.3 Hz), 152.2, 147.3,
139.2, 137.5, 134.9, 131.4, 128.4 (d, J = 7.5 Hz, 2x), 123.1, 115.2,
115.0 (d, J = 21.3 Hz, 2x), 110.4, 71.7, 60.8, 55.6, 29.9.
1-(4-Fluorophenyl)-5,6-dimethoxy-1,2-dihydronaphthalene (4b).
Yield = 88% (250 mg); Orange gum; HRMS (ESI, M++Na) calcd
for C18H17FO2Na 307.1110, found 307.1105; 1H NMR (400 MHz,
CDCl3): δ 7.19-7.14 (m, 2H), 7.01-6.95 (m, 2H), 6.93-6.90 (m,
1H), 6.66 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 6.04 (dt, J
= 4.4, 10.0 Hz, 1H), 4.06-4.02 (m, 1H), 3.85 (s, 3H), 3.84 (s, 3H),
2.66-2.49 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 161.5 (d, J =
243.3 Hz), 151.5, 144.7, 140.2 (d, J = 2.3 Hz), 131.0, 129.7 (d, J
= 8.3 Hz, 2x), 127.9, 127.5, 123.1, 122.1, 115.1 (d, J = 21.2 Hz,
2x), 110.5, 61.1, 55.7, 42.6, 32.0.
2-Allyl-3,4-dimethoxyphenyl(p-tolyl)methanol (3c). Yield = 85%
(253 mg); Colorless oil; HRMS (ESI, M++Na) calcd for
C19H22O3Na 321.1467, found 321.1465; 1H NMR (400 MHz,
CDCl3): δ 7.27 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.14
(d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.4 Hz, 1H), 6.03-5.94 (m, 1H),
5.97 (br s, 1H), 5.03 (dq, J = 1.6, 10.0 Hz, 1H), 4.79 (dq, J = 1.6,
5,6-Dimethoxy-1-(p-tolyl)-1,2-dihydronaphthalene (4c). Yield =
82% (230 mg); Yellow gum; HRMS (ESI, M++Na) calcd for
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Page 5 of 9
The Journal of Organic Chemistry
C19H20O2Na 303.1361, found 303.1358; 1H NMR (400 MHz,
C21H24O2Na 331.1674, found 331.1667; 1H NMR (400 MHz,
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5
6
7
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CDCl3): δ 7.11 (br s, 4H), 6.90 (dt, J = 1.6, 9.6 Hz, 1H), 6.64 (d, J
= 8.4 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H), 6.05 (dt, J = 4.4, 9.6 Hz,
1H), 4.05-4.00 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 2.61-2.56 (m,
2H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 151.3, 144.5,
141.5, 135.9, 131.5, 129.1 (2x), 128.3 (2x), 128.0, 127.8, 123.2,
122.0, 110.4, 61.1, 55.7, 43.0, 32.0, 21.0.
CDCl3): δ 7.33-7.21 (m, 5H), 6.94 (dt, J = 1.6, 10.0 Hz, 1H), 6.64
(d, J = 8.0 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 6.04 (dt, J = 4.4,
10.0 Hz, 1H), 4.08-4.04 (m, 1H), 4.01-3.95 (m, 2H), 3.82 (s, 3H),
2.64-2.58 (m, 2H), 1.84-1.77 (m, 2H), 1.60-1.50 (m, 2H), 1.01 (t,
J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 151.5, 144.7,
144.0, 131.2, 129.1, 128.4 (2x), 128.3 (2x), 127.3, 126.3, 122.9,
122.4, 110.6, 73.5, 55.8, 43.4, 32.3, 31.9, 19.2, 13.9.
5,6-Dimethoxy-1-(4-methoxyphenyl)-1,2-dihydronaphthalene (4d).
Yield = 86% (255 mg); Brown gum; HRMS (ESI, M++Na) calcd
5-Butoxy-1-(4-fluorophenyl)-6-methoxy-1,2-dihydronaphthalene
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for C19H20O3Na 319.1310, found 319.1305; H NMR (400 MHz,
(4j). Yield = 83% (271 mg); Yellow gum; HRMS (ESI, M++Na)
1
CDCl3): δ 7.13 (d, J = 8.8 Hz, 2H), 6.91 (dt, J = 1.6, 10.0 Hz, 1H),
6.85 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 8.4
Hz, 1H), 6.05 (dt, J = 4.4, 10.0 Hz, 1H), 4.03-3.98 (m, 1H), 3.85
(s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 2.60-2.54 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 158.1, 151.3, 144.6, 136.6, 131.6, 129.3
(2x), 127.9, 127.8, 123.1, 122.0, 113.7, 110.4, 70.5, 61.1, 55.7,
55.2, 42.6, 32.0.
calcd for C21H23FO2Na 349.1580, found 349.1574; H NMR (400
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MHz, CDCl3): δ 7.21-7.17 (m, 2H), 7.03-6.98 (m, 3H), 6.68 (d, J
= 8.0 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.05 (dt, J = 4.4, 9.6 Hz,
1H), 4.09-3.98 (m, 3H), 3.84 (s, 3H), 2.69-2.61 (m, 1H), 2.59-
2.51 (m, 1H), 1.88-1.81 (m, 2H), 1.64-1.55 (m, 2H), 1.05 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 161.4 (d, J = 242.6
Hz), 151.5, 143.9, 140.3 (d, J = 3.0 Hz), 130.8, 129.6 (d, J = 7.6
Hz, 2x), 128.0, 127.0, 122.8, 122.4, 114.9 (d, J = 21.3 Hz, 2x),
110.5, 73.4, 55.6, 42.6, 32.3, 32.0, 19.2, 13.8.
5-Isopropoxy-6-methoxy-1-phenyl-1,2-dihydronaphthalene (4e).
Yield = 81% (238 mg); Yellow gum; HRMS (ESI, M++Na) calcd
1
for C20H22O2Na 317.1518, found 317.1512; H NMR (400 MHz,
5-Butoxy-6-methoxy-1-(p-tolyl)-1,2-dihydronaphthalene
(4k).
CDCl3): δ 7.33-7.21 (m, 5H), 6.95 (dt, J = 1.6, 10.0 Hz, 1H), 6.65
(d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 6.01 (dt, J = 4.4, 9.6
Hz, 1H), 4.48-4.41 (m, 1H), 4.09-4.04 (m, 1H), 3.81 (s, 3H), 2.68-
2.53 (m, 2H), 1.34 (t, J = 6.0 Hz, 6H); 13C NMR (100 MHz,
CDCl3): δ 151.7, 144.8, 142.6, 131.1, 128.9, 128.4 (2x), 128.3
(2x), 126.8, 126.3, 123.1, 122.7, 110.5, 75.3, 55.7, 43.5, 31.9,
22.54, 22.51.
Yield = 80% (258 mg); Orange gum; HRMS (ESI, M++Na) calcd
1
for C22H26O2Na 345.1831, found 345.1827; H NMR (400 MHz,
CDCl3): δ 7.14 (br s, 4H), 6.96 (dt, J = 1.6, 10.0 Hz, 1H), 6.66 (d,
J = 8.0 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.06 (dt, J = 4.4, 10.0
Hz, 1H), 4.05-3.98 (m, 3H), 3.83 (s, 3H), 2.64-2.58 (m, 2H), 2.37
(s, 3H), 1.86-1.79 (m, 2H), 1.62-1.54 (m, 2H), 1.03 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 151.4, 141.6, 135.8, 131.4,
129.2, 129.0 (2x), 128.2 (2x), 128.0, 127.4, 122.9, 122.3, 110.5,
73.4, 55.8, 43.0, 32.3, 32.0, 21.0, 19.2, 13.9.
1-(4-Fluorophenyl)-5-isopropoxy-6-methoxy-1,2-
dihydronaphthalene (4f). Yield = 87% (272 mg); Yellow gum;
HRMS (ESI, M++Na) calcd for C20H21FO2Na 335.1423, found
335.1420; 1H NMR (400 MHz, CDCl3): δ 7.19-7.11 (m, 2H), 7.02
(s, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.0 Hz, 1H), 6.51 (d,
J = 8.0 Hz, 1H), 6.03-5.98 (m, 1H), 4.51-4.44 (m, 1H), 4.06 (t, J =
8.0 Hz, 1H), 3.82 (s, 3H), 2.68-2.60 (m, 1H), 2.57-2.49 (m, 1H),
1.35 (t, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 161.4 (d,
J = 242.5 Hz), 151.7, 142.6, 140.4 (d, J = 3.0 Hz), 130.8, 129.6 (d,
J = 7.6 Hz, 2x), 128.8, 126.5, 123.1, 122.6, 115.0 (d, J = 20.5 Hz,
2x), 110.5, 75.3, 55.6, 42.6, 32.0, 22.48, 22.45.
5-Butoxy-6-methoxy-1-(4-methoxyphenyl)-1,2-
dihydronaphthalene (4l). Yield = 80% (271 mg); Orange gum;
HRMS (ESI, M++Na) calcd for C22H26O3Na 361.1780, found
361.1777; 1H NMR (400 MHz, CDCl3): δ 7.13 (d, J = 8.8 Hz, 2H),
6.85 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 8.4
Hz, 1H), 6.05-6.01 (m, 1H), 4.03-3.94 (m, 4H), 3.81 (s, 3H), 3.80
(s, 3H), 2.60-2.53 (m, 2H), 1.83-1.76 (m, 2H), 1.58-1.49 (m, 2H),
1.00 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 158.1,
151.4, 136.7, 131.6, 129.3 (2x), 129.1, 128.1, 127.5, 122.8, 122.3,
113.7 (2x), 110.5, 73.5, 55.8, 55.2, 42.6, 32.3, 32.0, 19.2, 13.9.
5-Isopropoxy-6-methoxy-1-(p-tolyl)-1,2-dihydronaphthalene (4g).
Yield = 89% (274 mg); Yellow gum; HRMS (ESI, M++Na) calcd
5-(Cyclopentyloxy)-6-methoxy-1-phenyl-1,2-dihydronaphthalene
1
for C21H24O2Na 331.1674, found 331.1669; H NMR (400 MHz,
(4m). Yield = 81% (259 mg); Yellow gum; HRMS (ESI, M++Na)
1
CDCl3): δ 7.14 (br s, 4H), 6.98 (d, J = 10.0 Hz, 1H), 6.66 (d, J =
8.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.03 (dt, J = 4.4, 10.0 Hz,
1H), 4.50-4.44 (m, 1H), 4.08-4.04 (m, 1H), 3.83 (s, 3H), 2.64-
2.58 (m, 2H), 2.37 (s, 3H), 1.36 (t, J = 6.0 Hz, 6H); 13C NMR
(100 MHz, CDCl3): δ 151.6, 142.6, 141.7, 135.7, 131.3, 129.2,
129.0 (2x), 128.2 (2x), 126.9, 123.0, 122.7, 110.4, 75.3, 55.7, 43.0,
32.0, 22.52, 22.49, 21.0.
calcd for C22H24O2Na 343.1674, found 343.1670; H NMR (400
MHz, CDCl3): δ 7.32-7.20 (m, 5H), 6.90 (dt, J = 1.6, 9.6 Hz, 1H),
6.64 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 6.00 (dt, J = 4.8,
9.6 Hz, 1H), 4.85-4.81 (m, 1H), 4.07-4.03 (m, 1H), 3.81 (s, 3H),
2.06-1.85 (m, 4H), 1.81-1.65 (m, 4H), 1.63-1.59 (m, 2H); 13C
NMR (100 MHz, CDCl3): δ 151.5, 144.8, 142.8, 131.2, 130.0,
128.4 (2x), 128.3 (2x), 126.9, 126.3, 122.9, 122.7, 110.7, 84.9,
55.8, 43.5, 32.74, 32.69, 31.9, 23.7 (2x).
5-Isopropoxy-6-methoxy-1-(4-methoxyphenyl)-1,2-
dihydronaphthalene (4h). Yield = 83% (269 mg); Orange gum;
HRMS (ESI, M++Na) calcd for C21H24O3Na 347.1623, found
347.1617; 1H NMR (400 MHz, CDCl3): δ 7.12 (d, J = 8.4 Hz, 2H),
6.93 (dt, J = 1.6, 10.0 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 6.64 (d, J
= 8.4 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 6.00 (dt, J = 4.4, 10.0 Hz,
1H), 4.46-4.40 (m, 1H), 4.01 (dd, J = 7.2, 9.6 Hz, 1H), 3.81 (s,
5-(Cyclopentyloxy)-1-(4-fluorophenyl)-6-methoxy-1,2-
dihydronaphthalene (4n). Yield = 82% (277 mg); Yellow gum;
HRMS (ESI, M++Na) calcd for C22H23FO2Na 361.1580, found
361.1576; 1H NMR (400 MHz, CDCl3): δ 7.21-7.16 (m, 2H),
7.03-6.95 (m, 3H), 6.68 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 8.4 Hz,
1H), 6.02 (dt, J = 4.4, 9.6 Hz, 1H), 4.91-4.88 (m, 1H), 4.09-4.05
(m, 1H), 3.84 (s, 3H), 2.69-2.61 (m, 1H), 2.59-2.51 (m, 1H), 2.01-
1.93 (m, 4H), 1.83-1.73 (m, 2H), 1.67-1.63 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 161.4 (d, J = 242.5 Hz), 151.5, 140.3 (d, J =
3.1 Hz), 130.8, 129.6 (d, J = 7.5 Hz, 2x), 129.5, 128.6, 126.6,
122.9, 122.5, 114.9 (d, J = 20.4 Hz, 2x), 110.6, 84.7, 55.6, 42.6,
32.7, 32.6, 31.9, 23.6 (2x).
3H), 3.80 (s, 3H), 2.64-2.48 (m, 2H), 1.32 (t, J = 6.4 Hz, 6H); 13
C
NMR (100 MHz, CDCl3): δ 158.1, 151.6, 142.6, 136.8, 131.5,
129.3 (2x), 128.9, 126.9, 123.1, 122.7, 113.7 (2x), 110.5, 75.3,
55.7, 55.2, 42.6, 32.0, 22.54, 22.51.
5-Butoxy-6-methoxy-1-phenyl-1,2-dihydronaphthalene (4i). Yield
= 82% (253 mg); Yellow gum; HRMS (ESI, M++Na) calcd for
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The Journal of Organic Chemistry
Page 6 of 9
5-(Cyclopentyloxy)-6-methoxy-1-(p-tolyl)-1,2-dihydronaphthalene
crystal X-ray diagram: crystal of 4t was grown by slow diffusion
(4o). Yield = 76% (254 mg); Orange gum; HRMS (ESI, M++Na)
of EtOAc into a solution of 4t in CH2Cl2 to yield colorless prisms.
The compound crystallizes in the Triclinic crystal system, space
group P -1, a = 11.399(2) Å , b = 11.510(2) Å , c = 19.440(4) Å , V
= 2240.2(8) Å 3, Z = 2, dcalcd = 1.294 g/cm3, F(000) = 920, 2
range 1.09-28.30o, R indices (all data) R1 = 0.0781, wR2 = 0.1123.
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calcd for C23H26O2Na 357.1831, found 357.1822; H NMR (400
MHz, CDCl3): δ 7.17 (s, 4H), 6.98 (d, J = 8.0 Hz, 1H), 6.69 (d, J
= 8.4 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.09-6.05 (m, 1H), 4.93-
4.89 (m, 1H), 4.09 (dd, J = 7.6, 9.6 Hz, 1H), 3.86 (s, 3H), 2.67-
2.61 (m, 2H), 2.40 (s, 3H), 2.37-1.94 (m, 4H), 1.84-1.73 (m, 2H),
1.71-1.67 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 151.4, 142.6,
141.6, 135.7, 131.3, 128.9 (2x), 128.7, 128.2 (2x), 126.9, 122.8,
122.6, 110.6, 84.7, 55.7, 43.0, 32.7, 32.6, 31.9, 23.6 (2x), 21.0.
4,5-Dimethoxy-2-methyl-1-phenyl-1H-indene (6a). Yield = 93%
o
(248 mg); Colorless solid; mp = 117-118 C (recrystallized from
hexanes and EtOAc); HRMS (ESI, M++Na) calcd for C18H18O2Na
1
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289.1205, found 289.1198; H NMR (400 MHz, CDCl3): δ 7.32-
5-(Cyclopentyloxy)-6-methoxy-1-(4-methoxyphenyl)-1,2-
7.22 (m, 3H), 7.07-7.04 (m, 2H), 6.81 (d, J = 8.0 Hz, 1H), 6.74 (s,
1H), 6.64 (d, J = 8.0 Hz, 1H), 4.31 (s, 1H), 3.98 (s, 3H), 3.87 (s,
3H), 1.94 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 151.4, 150.2,
142.3, 141.4, 139.9, 137.6, 128.6 (2x), 128.0 (2x), 126.6, 123.4,
118.9, 108.6, 61.1, 59.0, 56.0, 15.3. Single-crystal X-ray diagram:
crystal of 6a was grown by slow diffusion of EtOAc into a
solution of 6a in CH2Cl2 to yield colorless prisms. The compound
crystallizes in the Triclinic crystal system, space group P -1, a =
7.0295(6) Å , b = 9.8296(8) Å , c = 11.7070(9) Å , V = 725.41(11)
Å 3, Z = 2, dcalcd = 1.219 g/cm3, F(000) = 284, 2 range 1.88-
26.49o, R indices (all data) R1 = 0.0935, wR2 = 0.1873.
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dihydronaphthalene (4p). Yield = 78% (273 mg); Brown gum;
HRMS (ESI, M++Na) calcd for C23H26O3Na 373.1780, found
373.1772; 1H NMR (400 MHz, CDCl3): δ 7.14 (d, J = 8.4 Hz, 2H),
6.92 (dt, J = 2.0, 10.0 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 6.66 (d, J
= 8.4 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.02 (dt, J = 4.4, 10.0 Hz,
1H), 4.88-4.84 (m, 1H), 4.03 (dd, J = 7.6, 9.6 Hz, 1H), 3.82 (s,
3H), 3.81 (s, 3H), 2.64-2.55 (m, 2H), 2.00-1.88 (m, 4H), 1.79-
1.62 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 158.0, 151.4, 142.7,
136.7, 131.5, 129.2 (2x), 128.7, 127.0, 122.8, 122.6, 113.6 (2x),
110.6, 84.8, 55.7, 55.1, 42.6, 32.7, 32.7, 32.0, 23.6 (2x).
5-Methoxy-1-phenyl-1,2-dihydronaphthalene (4q). Yield = 73%
(172 mg); yellow gum; HRMS (ESI, M++Na) calcd for
C17H16ONa 259.1099, found 259.1098; 1H NMR (400 MHz,
CDCl3): δ 7.33-7.23 (m, 5H), 7.07 (t, J = 8.0 Hz, 1H), 6.97 (dt, J
= 1.6, 10.0 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.47 (d, J = 7.6 Hz,
1H), 6.01 (dt, J = 4.4, 9.6 Hz, 1H), 4.13-4.09 (m, 1H), 3.88 (s,
3H), 2.71-2.56 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 154.7,
144.4, 139.2, 128.4 (2x), 128.3 (2x), 127.6, 126.4, 126.0, 123.3,
121.7, 120.5, 109.0, 55.6, 43.9, 31.5.
1-(4-Fluorophenyl)-4,5-dimethoxy-2-methyl-1H-indene
(6b).
Yield = 94% (267 mg); Orange gum; HRMS (ESI, M++Na) calcd
for C18H17FO2Na 307.1110, found 307.1105; 1H NMR (400 MHz,
CDCl3): δ 7.01-6.94 (m, 4H), 6.76 (d, J = 8.4 Hz, 1H), 6.71 (t, J =
1.6 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 4.26 (s, 1H), 3.96 (s, 3H),
3.86 (s, 3H), 1.90 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 161.7
(d, J = 242.6 Hz), 151.5, 150.0, 142.1, 141.5, 137.6, 135.6 (d, J =
3.0 Hz), 129.5 (d, J = 7.6 Hz, 2x), 123.5, 118.8, 115.4 (d, J = 21.2
Hz, 2x), 108.6, 61.1, 58.2, 56.1, 15.2.
1-(4-Fluorophenyl)-5-methoxy-1,2-dihydronaphthalene
(4r).
4,5-Dimethoxy-2-methyl-1-(p-tolyl)-1H-indene (6c). Yield = 92%
(258 mg); Orange gum; HRMS (ESI, M++Na) calcd for
C19H20O2Na 303.1361, found 303.1360; 1H NMR (400 MHz,
CDCl3): δ 7.11 (d, J = 7.6 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 6.80
(d, J = 8.0 Hz, 1H), 6.73-6.71 (m, 1H), 6.63 (d, J = 8.0 Hz, 1H),
4.27 (s, 1H), 3.97 (s, 3H), 3.86 (s, 3H), 2.34 (s, 3H), 1.93 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 151.3, 150.4, 142.5, 141.4, 137.6,
136.8, 136.1, 129.3 (2x), 127.9 (2x), 123.3, 118.8, 108.6, 61.1,
58.7, 56.1, 21.0, 15.3.
Yield = 83% (211 mg); Colorless gum; HRMS (ESI, M++Na)
1
calcd for C17H15FONa 277.1005, found 277.1008; H NMR (400
MHz, CDCl3): δ 7.19-7.16 (m, 2H), 7.10-7.06 (m, 2H), 7.01-6.94
(m, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 7.6 Hz, 1H), 5.99
(dt, J = 4.0, 10.0 Hz, 1H), 4.08 (t, J = 8.0 Hz, 1H), 3.87 (s, 3H),
2.70-2.62 (m, 1H), 2.59-2.51 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 161.5 (d, J = 242.6 Hz), 154.8, 140.1 (d, J = 3.1 Hz),
139.0, 129.7 (d, J = 7.5 Hz, 2x), 127.7, 125.7, 123.5, 121.8, 120.3,
115.1 (d, J = 21.2 Hz, 2x), 109.1, 55.6, 43.1, 31.6.
4,5-Dimethoxy-1-(4-methoxyphenyl)-2-methyl-1H-indene
(6d).
Yield = 94% (278 mg); Colorless solid; mp = 92-93 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for
C19H20O3Na 319.1310, found 319.1306; 1H NMR (400 MHz,
CDCl3): δ 6.95 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.79
(d, J = 8.0 Hz, 1H), 6.70 (s, 1H), 6.63 (d, J = 8.0 Hz, 1H), 4.24 (s,
1H), 3.96 (s, 3H), 3.85 (s, 3H), 3.79 (s, 3H), 1.91 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 158.4, 151.3, 150.5, 142.5, 141.4,
137.6, 131.8, 129.0 (2x), 123.1, 118.8, 114.0 (2x), 108.5, 61.1,
58.3, 56.1, 55.1, 15.2. Single-crystal X-ray diagram: crystal of 6d
was grown by slow diffusion of EtOAc into a solution of 6d in
CH2Cl2 to yield colorless prisms. The compound crystallizes in
the Monoclinic crystal system, space group P 21/n, a = 7.6240(7)
Å , b = 23.566(2) Å , c = 8.4581(7) Å , V = 1516.8(2) Å 3, Z = 4,
dcalcd = 1.298 g/cm3, F(000) = 632, 2 range 1.73-26.52o, R indi-
ces (all data) R1 = 0.0531, wR2 = 0.1345.
5-Methoxy-1-(p-tolyl)-1,2-dihydronaphthalene (4s). Yield = 77%
(193 mg); Colorless gum; HRMS (ESI, M++Na) calcd for
C18H18ONa 273.1255, found 273.1256; 1H NMR (400 MHz,
CDCl3): δ 7.17 (br s, 4H), 7.11 (t, J = 8.0 Hz, 1H), 7.02 (dt, J =
1.6, 10.0 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 8.0 Hz,
1H), 6.05 (dt, J = 4.4, 10.0 Hz, 1H), 4.12 (dd, J = 8.0, 9.6 Hz, 1H),
3.91 (s, 3H), 2.74-2.59 (m, 2H), 2.45 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 154.7, 141.3, 139.5, 135.8, 129.0 (2x), 128.2 (2x),
127.6, 126.1, 123.0, 121.7, 120.4, 108.9, 55.5, 43.5, 31.6, 21.0.
8-([1,1'-Biphenyl]-4-yl)-1-(4-fluorophenyl)-5,6-dimethoxy-1,2-
dihydronaphthalene (4t). Yield = 90% (393 mg); Colorless solid;
mp = 188-189 oC (recrystallized from hexanes and EtOAc);
HRMS (ESI, M++Na) calcd for C30H25FO2Na 459.1736, found
459.1738; 1H NMR (400 MHz, CDCl3): δ 7.64-7.60 (m, 2H), 7.50
(d, J = 8.4 Hz, 2H), 7.48-7.44 (m, 2H), 7.39-7.34 (m, 1H), 7.06-
7.01 (m, 3H), 6.89 (s, 3H), 6.87 (s, 1H), 6.76 (s, 1H), 5.88-5.83
(m, 1H), 4.07 (d, J = 6.8 Hz, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 2.82-
2.75 (m, 1H), 2.46-2.40 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
161.2 (d, J = 241.8 Hz), 151.1, 144.2, 140.9 (d, J = 3.1 Hz), 140.6,
140.0, 139.7, 136.9, 129.5 (2x), 129.2 (d, J = 7.6 Hz, 2x), 128.8
(2x), 128.1, 127.3, 127.0 (2x), 126.9, 126.4 (2x), 126.3, 122.7,
114.7 (d, J = 21.3 Hz, 2x), 113.1, 61.3, 55.8, 38.0, 32.3. Single-
4-Isopropoxy-5-methoxy-2-methyl-1-phenyl-1H-indene (6e). Yield
= 85% (250 mg); Orange gum; HRMS (ESI, M++Na) calcd for
C20H22O2Na 317.1518, found 317.1512; 1H NMR (400 MHz,
CDCl3): δ 7.32-7.23 (m, 5H), 7.05-7.02 (m, 2H), 6.79 (d, J = 8.4
Hz, 1H), 6.68-6.67 (m, 1H), 6.62 (d, J = 8.4 Hz, 1H), 4.49-4.43
(m, 1H), 4.30 (s, 1H), 3.83 (s, 3H), 1.92 (s, 1H), 1.38 (d, J = 6.4
Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 152.0, 149.8, 142.0,
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140.2, 139.4, 128.6 (2x), 128.3, 128.1 (2x), 126.6, 124.1, 118.7,
1.06 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 161.6 (d,
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6
7
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108.6, 75.2, 59.1, 56.0, 22.7, 22.6, 15.3.
J = 242.6 Hz), 151.8, 149.6, 141.9, 140.7, 138.2, 135.7 (d, J = 3.1
Hz), 129.4 (d, J = 7.6 Hz, 2x), 123.7, 118.6, 115.3 (d, J = 21.3 Hz,
2x), 108.8, 73.3, 58.2, 56.0, 32.3, 19.1, 15.1, 13.8.
1-(4-Fluorophenyl)-4-isopropoxy-5-methoxy-2-methyl-1H-indene
o
(6f). Yield = 88% (275 mg); Colorless solid; mp = 82-83 C (re-
crystallized from hexanes and EtOAc); HRMS (ESI, M++Na)
4-Butoxy-5-methoxy-2-methyl-1-(p-tolyl)-1H-indene (6k). Yield =
78% (251 mg); Orange gum; HRMS (ESI, M++Na) calcd for
C22H26O2Na 345.1831, found 345.1826; 1H NMR (400 MHz,
CDCl3): δ 7.11 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 6.79
(d, J = 8.0 Hz, 1H), 6.69 (s, 1H), 6.63 (d, J = 8.0 Hz, 1H), 4.27 (s,
1H), 4.13-4.07 (m, 2H), 3.85 (s, 2H), 2.38-2.32 (m, 1H), 2.34 (s,
3H), 1.93 (s, 3H), 1.88-1.78 (m, 2H), 1.61-1.55 (m, 2H), 1.03 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 151.7, 150.1,
142.4, 140.6, 138.4, 137.0, 136.1, 129.3 (2x), 128.0 (2x), 123.5,
118.7, 108.8, 73.5, 58.8, 56.2, 32.4, 21.0, 19.2, 15.3, 13.9.
1
calcd for C20H21FO2Na 335.1423, found 335.1416; H NMR (400
MHz, CDCl3): δ 6.99-6.94 (m, 4H), 6.74 (d, J = 8.4 Hz, 1H),
6.66-6.63 (m, 1H), 6.61 (d, J = 8.0 Hz, 1H), 4.46-4.40 (m, 1H),
4.26 (d, J = 0.8 Hz, 1H), 3.82 (s, 3H), 1.88 (d, J = 0.8 Hz, 3H),
1.35 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 161.7 (d,
J = 242.6 Hz), 152.2, 149.6, 141.9, 139.3 (d, J = 3.8 Hz), 135.9,
135.8, 129.5 (d, J = 7.6 Hz, 2x), 124.3, 118.7, 115.4 (d, J = 21.2
Hz, 2x), 108.7, 75.3, 58.3, 56.1, 22.7 (2x), 15.2. Single-crystal X-
ray diagram: crystal of 6f was grown by slow diffusion of EtOAc
into a solution of 6f in CH2Cl2 to yield colorless prisms. The
compound crystallizes in the Orthorhombic crystal system, space
group P 21 21 21, a = 8.1071(6) Å , b = 9.3064(7) Å , c =
22.2481(17) Å , V = 1678.6(2) Å 3, Z = 4, dcalcd = 1.236 g/cm3,
F(000) = 664, 2 range 1.83-26.40o, R indices (all data) R1 =
0.0483, wR2 = 0.1287.
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4-Butoxy-5-methoxy-1-(4-methoxyphenyl)-2-methyl-1H-indene
(6l). Yield = 88% (298 mg); Orange gum; HRMS (ESI, M++Na)
1
calcd for C22H26O3Na 361.1780, found 361.1775; H NMR (400
MHz, CDCl3): δ 6.98 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H),
6.80 (d, J = 8.0 Hz, 1H), 6.71 (s, 1H), 6.64 (d, J = 8.0 Hz, 1H),
4.27 (s, 1H), 4.16-4.10 (m, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 1.94 (s,
3H), 1.88-1.81 (m, 2H), 1.63-1.58 (m, 2H), 1.05 (t, J = 7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 158.3, 151.6, 150.1, 142.4,
140.6, 138.2, 131.9, 128.9 (2x), 123.3, 118.6, 114.0 (2x), 108.7,
73.3, 58.3, 56.0, 55.0, 32.3, 19.1, 15.2, 13.8.
4-Isopropoxy-5-methoxy-2-methyl-1-(p-tolyl)-1H-indene
(6g).
Yield = 83% (256 mg); Orange gum; HRMS (ESI, M++Na) calcd
1
for C21H24O2Na 331.1674, found 331.1670; H NMR (400 MHz,
CDCl3): δ 7.09 (d, J = 7.6 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 6.77
(d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 6.60 (d, J = 8.0 Hz, 1H), 4.47-
4.41 (m, 1H), 4.26 (s, 1H), 3.82 (s, 3H), 2.32 (s, 3H), 1.90 (s, 3H),
1.35 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 152.0,
150.0, 142.2, 137.1, 136.1, 129.3 (2x), 129.0, 128.7, 128.0 (2x),
124.0, 118.7, 108.7, 75.2, 58.8, 56.1, 22.69, 22.66, 21.0, 15.3.
4-(Cyclopentyloxy)-5-methoxy-2-methyl-1-phenyl-1H-indene (6m).
Yield = 80% (256 mg); Orange gum; HRMS (ESI, M++Na) calcd
1
for C22H24O2Na 343.1674, found 343.1668; H NMR (400 MHz,
CDCl3): δ 7.34-7.22 (m, 3H), 7.07-7.04 (m, 2H), 6.49 (d, J = 8.0
Hz, 1H), 6.68 (s, 1H), 6.63 (d, J = 8.0 Hz, 1H), 4.93-4.89 (m, 1H),
4.31 (s, 1H), 3.85 (s, 3H), 2.03-1.95 (m, 4H), 1.93 (s, 3H), 1.81-
1.63 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 151.9, 149.8, 142.1,
140.2, 139.35, 139.27, 128.6 (2x), 128.3, 128.1 (2x), 126.6, 124.0,
118.6, 108.9, 84.5, 59.1, 56.1, 32.82, 32.78, 23.6, 15.3.
4-Isopropoxy-5-methoxy-1-(4-methoxyphenyl)-2-methyl-1H-
indene (6h). Yield = 91% (295 mg); Colorless solid; mp = 73-74
oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na)
1
calcd for C21H24O3Na 347.1623, found 347.1618; H NMR (400
MHz, CDCl3): δ 6.93 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H),
6.76 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 1.6 Hz, 1H), 6.60 (d, J = 8.0
Hz, 1H), 4.46-4.40 (m, 1H), 4.23 (s, 1H), 3.82 (s, 3H), 3.78 (s,
3H), 1.89 (s, 3H), 1.35 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz,
CDCl3): δ 158.4, 152.0, 150.1, 142.3, 139.34, 139.29, 132.1,
129.0 (2x), 123.8, 118.6, 114.1 (2x), 108.7, 75.2, 58.4, 56.1, 55.2,
22.69, 22.66, 15.3. Single-crystal X-ray diagram: crystal of 6h
was grown by slow diffusion of EtOAc into a solution of 6h in
CH2Cl2 to yield colorless prisms. The compound crystallizes in
the Monoclinic crystal system, space group P 21, a = 5.4384(9) Å ,
4-(Cyclopentyloxy)-1-(4-fluorophenyl)-5-methoxy-2-methyl-1H-
indene (6n). Yield = 92% (311 mg); Orange gum; HRMS (ESI,
M++Na) calcd for C22H23FO2Na 361.1580, found 361.1576; 1H
NMR (400 MHz, CDCl3): δ 7.02-6.95 (m, 4H), 6.77 (d, J = 8.0
Hz, 1H), 6.67 (t, J = 1.6 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 4.93-
4.89 (m, 1H), 4.28 (s, 1H), 3.84 (s, 3H), 2.03-1.93 (m, 4H), 1.91
(s, 3H), 1.81-1.64 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 161.6
(d, J = 243.3 Hz), 152.0, 149.5, 141.9, 139.4, 139.1, 135.8 (d, J =
3.1 Hz), 129.4 (d, J = 7.6 Hz, 2x), 124.1, 118.5, 115.4 (d, J = 21.2
Hz, 2x), 108.9, 84.4, 58.3, 56.0, 32.8, 32.7, 23.6 (2x), 15.1.
b = 7.1721(12) Å , c = 22.371(3) Å , V = 869.7(2) Å 3, Z = 2, dcalcd
1.239 g/cm3, F(000) = 348, 2 range 0.91-26.58o, R indices (all
data) R1 = 0.0554, wR2 = 0.1431.
=
4-(Cyclopentyloxy)-5-methoxy-2-methyl-1-(p-tolyl)-1H-indene
(6o). Yield = 78% (261 mg); Orange gum; HRMS (ESI, M++1)
calcd for C23H26O2 334.1933, found 334.1932; 1H NMR (400
MHz, CDCl3): δ 7.23 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H),
7.93 (d, J = 8.0 Hz, 1H), 6.84-6.82 (m, 1H), 6.75 (d, J = 8.0 Hz,
1H), 5.09-5.05 (m, 1H), 4.41 (s, 1H), 3.95 (s, 3H), 2.46 (s, 3H),
2.20-2.06 (m, 4H), 2.06 (s, 3H), 1.94-1.77 (m, 4H); 13C NMR
(100 MHz, CDCl3): δ 151.7, 149.7, 142.1, 139.2, 139.1, 136.9,
135.8, 129.1 (2x), 127.8 (2x), 123.7, 118.4, 108.7, 84.2, 58.7, 55.9,
32.7, 32.6, 23.5 (2x), 20.8, 15.1.
4-Butoxy-5-methoxy-2-methyl-1-phenyl-1H-indene (6i). Yield =
82% (253 mg); Orange gum; HRMS (ESI, M++Na) calcd for
C21H24O2Na 331.1674, found 331.1668; 1H NMR (400 MHz,
CDCl3): δ 7.29-7.19 (m, 4H), 7.03-7.01 (m, 1H), 6.76 (d, J = 8.0
Hz, 1H), 6.68-6.65 (m, 1H), 6.60 (d, J = 8.0 Hz, 1H), 4.27 (s, 1H),
4.10-4.04 (m, 2H), 3.83 (s, 3H), 1.90 (s, 3H), 1.82-1.75 (m, 2H),
1.58-1.52 (m, 2H), 1.00 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 151.7, 150.0, 142.2, 140.6, 140.1, 138.4, 128.6 (2x),
128.1 (2x), 126.6, 123.7, 118.8, 108.7, 73.5, 59.1, 56.2, 32.4, 19.2,
15.3, 13.9.
4-(Cyclopentyloxy)-5-methoxy-1-(4-methoxyphenyl)-2-methyl-1H-
indene (6p). Yield = 90% (315 mg); Colorless solid; mp = 82-83
oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++Na)
4-Butoxy-1-(4-fluorophenyl)-5-methoxy-2-methyl-1H-indene (6j).
Yield = 80% (261 mg); Orange gum; HRMS (ESI, M++Na) calcd
for C21H23FO2Na 349.1580, found 349.1574; 1H NMR (400 MHz,
CDCl3): δ 7.04-6.96 (m, 4H), 6.79 (d, J = 8.0 Hz, 1H), 6.73 (s,
1H), 6.66 (d, J = 8.0 Hz, 1H), 4.29 (s, 1H), 4.17-4.11 (m, 2H),
3.86 (s, 3H), 1.93 (s, 3H), 1.89-1.81 (m, 2H), 1.66-1.58 (m, 2H),
1
calcd for C23H26O3Na 373.1780, found 373.1772; H NMR (400
MHz, CDCl3): δ 6.94 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H),
6.77 (d, J = 7.6 Hz, 1H), 6.63-6.61 (m, 2H), 4.90-4.86 (m, 1H),
4.24 (s, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 2.01-1.93 (m, 4H), 1.90 (s,
3H), 1.79-1.61 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 158.3,
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151.9, 150.1, 142.3, 139.18, 139.17, 132.0, 129.0 (2x), 123.7,
AUTHOR INFORMATION
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7
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118.5, 114.0 (2x), 108.8, 84.5, 58.4, 56.1, 55.1, 32.82, 32.76, 23.6
(2x), 15.3.
Corresponding Author *Email: mychang@kmu.edu.tw
Notes The authors declare no competing financial interest.
4-Methoxy-2-methyl-1-phenyl-1H-indene (6q). Yield = 75% (177
mg); Colorless gum; HRMS (ESI, M++Na) calcd for C17H16ONa
ACKNOWLEDGMENT
1
259.1099, found 259.1098; H NMR (400 MHz, CDCl3): δ 7.29-
The authors would like to thank the Ministry of Science and
Technology of the Republic of China for financial support
(MOST 105-2113-M-037-001).
7.22 (m, 4H), 7.05-7.01 (m, 3H), 6.78-6.75 (m, 1H), 6.71-6.70 (m,
1H), 4.31 (s, 1H), 3.90 (s, 3H), 1.92 (d, J = 0.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 152.0, 150.5, 148.2, 139.7, 133.0, 128.7
(2x), 128.2 (2x), 126.7, 125.5, 123.3, 116.8, 109.0, 59.9, 55.5,
15.2.
9
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1-(4-Fluorophenyl)-4-methoxy-2-methyl-1H-indene (6r). Yield =
85% (216 mg); Colorless solid; mp = 68-69 oC (recrystallized
from hexanes and EtOAc); HRMS (ESI, M++Na) calcd for
C17H15FONa 277.1005, found 277.1007; 1H NMR (400 MHz,
CDCl3): δ 7.07-7.03 (m, 1H), 7.00-6.94 (m, 4H), 6.79-6.75 (m,
2H), 6.72-6.71 (m, 1H), 4.29 (s, 1H), 3.90 (s, 3H), 1.91 (d, J = 0.8
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 161.8 (d, J = 242.6 Hz),
152.1, 150.3, 147.9, 135.3 (d, J = 3.0 Hz), 132.9, 129.6 (d, J = 7.6
Hz, 2x), 125.6, 123.4, 116.6, 115.5 (d, J = 20.5 Hz, 2x), 109.1,
59.0, 55.4, 15.1.
4-Methoxy-2-methyl-1-(p-tolyl)-1H-indene (6s). Yield = 83% (208
mg); Colorless gum; HRMS (ESI, M++Na) calcd for C18H18ONa
1
273.1255, found 273.1253; H NMR (400 MHz, CDCl3): δ 7.09
(d, J = 7.6 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz,
2H), 6.79 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.71-6.69 (m, 1H),
4.29 (s, 1H), 3.90 (s, 3H), 2.33 (s, 3H), 1.93 (d, J = 0.4 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 152.0, 150.6, 148.3, 136.5, 136.2,
133.0, 129.4 (2x), 128.1 (2x), 125.4, 123.1, 116.7, 108.9, 59.5,
55.4, 21.1, 15.2.
7-([1,1'-Biphenyl]-4-yl)-1-(4-fluorophenyl)-4,5-dimethoxy-2-
methyl-1H-indene (6t). Yield = 86% (375 mg); Colorless gum;
HRMS (ESI, M++Na) calcd for C30H25FO2Na 459.1736, found
459.1735; 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 8.0 Hz, 2H),
7.49-7.46 (m, 4H), 7.41-7.38 (m, 1H), 7.19 (d, J = 8.0 Hz, 2H),
6.78-6.77 (m, 1H), 6.71-6.66 (m, 2H), 6.64-6.60 (m, 3H), 4.51 (s,
1H), 4.05 (s, 3H), 3.92 (s, 3H), 1.87 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 161.1 (d, J = 242.6 Hz), 151.8, 151.0, 140.8, 140.7,
139.7, 139.7, 139.5, 138.3, 134.4 (d, J = 3.0 Hz), 133.7, 129.4 (d,
J = 8.3 Hz, 2x), 128.8 (2x), 128.7 (2x), 127.2, 126.9 (2x), 126.4
(2x), 123.0, 114.6 (d, J = 21.2 Hz, 2x), 109.6, 61.3, 58.0, 56.0,
15.1.
4,4'-(Oxybis(ethane-1,1-diyl))bis(3-allyl-1,2-dimethoxybenzene)
(7). Yield = 78% (332 mg); Colorless gum; HRMS (ESI, M++Na)
1
calcd for C26H34O5Na 449.2304, found 449.2305; H NMR (400
MHz, CDCl3): δ 7.27 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H),
5.73-5.63 (m, 2H), 4.81 (dq, J = 1.6, 10.0 Hz, 2H), 4.69 (dq, J =
1.6, 17.2 Hz, 2H), 4.39 (q, J = 6.4 Hz, 2H), 3.88 (s, 6H), 3.79 (s,
6H), 3.30 (dq, J = 1.6, 13.6 Hz, 2H), 3.50 (dq, J = 1.6, 6.4 Hz,
2H), 1.32 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ
151.4 (2x), 146.8 (2x), 136.9 (2x), 135.5 (2x), 131.2 (2x), 121.3
(2x), 114.9 (2x), 110.8 (2x), 70.0 (2x), 60.6 (2x), 55.5 (2x), 29.6
(2x), 24.5 (2x).
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ASSOCIATED CONTENT
Supporting Information
Scanned spectroscopic data for all compounds and X-ray anal-
ysis data of 4a, 4t, 6a, 6d, 6f and 6h. This information is
available free of charge via the Internet at http://pubs.acs.org.
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