Access to Electron-Deficient 2,2-Disubstituted Chromanes: A Highly Regioselective One-Pot Synthesis via an Inverse-Electron-Demand [4 + 2] Cycloaddition of ortho-Quinone Methides

Article abstract of DOI:10.1021/acs.joc.9b02036

We report the one-pot synthesis of 2,2-disubstituted chromanes with electron-withdrawing substituents. This reaction provides a simple yet efficient route to a wide range of electron-deficient chromanes in high yield and excellent regioselectivity. The reaction of salicylaldehyde with 1,1-disubstituted ethylenes smoothly furnishes these electron-deficient chromanes, which can be further transformed into functionalized chromanes or chromene. For example, BW683C was effectively synthesized from 5-chlorosalicylaldehyde with 4-chlorostyrene in two steps in excellent yield. The present reaction thus provides versatile access to functionalized electron-deficient chromanes and chromenes and therefore constitutes a promising tool for the synthesis of biologically and photochemically active molecules.

Full text of DOI:10.1021/acs.joc.9b02036

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Access to Electron-Deficient 2,2-Disubstituted Chromanes: A Highly
Regioselective One-Pot Synthesis via an Inverse-Electron-Demand [4
+ 2] Cycloaddition of ortho-Quinone Methides
Kenta Tanaka, Mami Kishimoto, Yosuke Asada, Yuta Tanaka, Yujiro Hoshino,* and Kiyoshi Honda*
Graduate School of Environment and Information Sciences, Yokohama National University, Tokiwadai, Hodogaya-ku, Yokohama
240-8501, Japan
S
* Supporting Information
ABSTRACT: We report the one-pot synthesis of 2,2-disubstituted chromanes with electron-withdrawing substituents. This
reaction provides a simple yet efficient route to a wide range of electron-deficient chromanes in high yield and excellent
regioselectivity. The reaction of salicylaldehyde with 1,1-disubstituted ethylenes smoothly furnishes these electron-deficient
chromanes, which can be further transformed into functionalized chromanes or chromene. For example, BW683C was
effectively synthesized from 5-chlorosalicylaldehyde with 4-chlorostyrene in two steps in excellent yield. The present reaction
thus provides versatile access to functionalized electron-deficient chromanes and chromenes and therefore constitutes a
promising tool for the synthesis of biologically and photochemically active molecules.
ethylenes to furnish the corresponding chromanes.5 This
sequence successfully provides chromanes that bear strongly
Owing to their unique biological properties, the development
electron-withdrawing groups such as NO2, CN, and CF3.
INTRODUCTION
■
of efficient synthetic methods for chromanes has attracted
We have previously developed an acid-catalyzed synthesis of
significant attention in organic chemistry and medicinal
ortho-quinone methides (o-QMs) from salicylaldehyde in the
science.1 Most biologically active chromanes contain multiple
presence of trimethyl orthoformate under mild conditions.6
substituents, especially electron-donating moieties such as the
During that study, we investigated the inverse-electron-
methoxy group.1 Based on the characteristic features of these
demand [4 + 2] cycloaddition reaction of in situ-generated
compounds, a number of research groups have explored the
strongly electron-withdrawing o-QMs with arylalkynes, which
synthesis of chromanes that bear electron-donating moieties
afforded 2H-chromenes.7 To expand the access to chromanes
with electron-withdrawing substituents, we report herein a
highly regioselective one-pot synthesis of electron-deficient
2,2-disubstituted chromanes using easily available substrates
(Scheme 1b). This reaction provides a simple yet efficient
route to a wide range of electron-deficient chromanes.
(Scheme 1a).2 In comparison, chromanes substituted with
electron-withdrawing groups have received substantially less
attention. Some chromanes that bear electron-withdrawing
substituents exhibit biological (for example, antirhinoviral,
antihypertensive, and antimicrobial) activity (Figure 1).3
Despite the number of reports on these functionalized
chromanes, the synthesis of such electron-deficient compounds
has been much less explored. In addition, the previously
reported synthetic methods suffer from requirements such as
laborious reaction procedures and functionalization with
strongly electron-withdrawing groups.3,4 Recently, Ohwada
and co-workers have demonstrated that 4H-1,2-benzoxazines
with various electron-withdrawing substitutes react with
RESULTS AND DISCUSSION
■
Initially, we screened the reaction of 5-nitrosalicylaldehyde
(1a) with 1,1-diphenylethylene (2a) using a variety of acid
Received: July 25, 2019
Published: October 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b02036
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Scheme 1. Synthesis of Chromanes with Various Substituents
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
TfOH
TfOH
solvent
yield (%)
c
1
2
MeOH
DMF
nr
c
nr
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
TfOH
TfOH
TfOH
TfOH
CH3CN
THF
69
25
79
85
32
15
8
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
PhSO3H
MeSO3H
p-TsOH·H2O
HBF4·OEt2
TFA
18
c
nr
d
c
CSA
nr
c
PhCO2H
Pd(OAc)2
Sc(OTf)3
Al(OTf)3
BF3·OEt2
TfOH
nr
c
nr
15
26
trace
71
63
0
Figure 1. Selected examples of bioactive chromanes with electron-
withdrawing substituents.
e
18
f
19
TfOH
TfOH
catalysts and solvents at room temperature (Table 1). When
polar solvents such as dimethylformamide (DMF) and MeOH
were used in the presence of catalytic amounts of
trifluoromethanesulfonic acid (TfOH; 20 mol %), the reaction
did not afford any of the targeted products (entries 1 and 2).
However, CH3CN efficiently promotes the reaction, providing
the desired chromane (3a) in 69% yield (entry 3). In addition,
moderately polar to nonpolar solvents such as tetrahydrofuran
(THF), CH2Cl2, and toluene are also suitable (entries 4−6),
whereby especially toluene effectively increased the product
yield to 85%. Other Brønsted acids did not efficiently provide
the product (entries 7−13).8 Subsequently, we confirmed that
the strong Brønsted acid TfOH smoothly promotes the
g
20
a
All reactions were carried out using 1a (0.5 mmol), 2a (1.5 mmol),
CH(OMe)3 (1.0 mmol), and the corresponding catalyst (20 mol %)
in the specified solvent (5.0 mL) at room temperature for 1 h. Isolate
yield. nr: no reaction. CSA: (+)-10-camphorsulfonic acid. Amount
of 2a: 1.0 mmol. Amount of TfOH: 10 mol %. From room
temperature (1 h) to 100 °C (1 h).
b
c
d
e
f
g
generation of an o-QM from salicylaldehyde 1a. The use of
Pd(OAc)2, which is a soft Lewis acid, was not successful (entry
14), while Sc(OTf)3, which is a hard Lewis acid catalyst that
has been used in the [4 + 2] cycloaddition of salicylaldehydes
B
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with ethylenes by Yadav and co-workers,9 affords the product
in 15% yield (entry 15). TfOH is an inexpensive organic
catalyst that is much easier to handle than Sc(OTf)3. Other
hard Lewis acid catalysts afforded low product yields (entries
16 and 17), while decreasing the amounts of 2a or TfOH did
not improve the product yield (entries 18 and 19). Next, we
examined the effect of reaction temperature on the yield. When
the reaction mixture was initially stirred at room temperature
(1 h) and then heated to 100 °C (1 h), 4-alkenylchromane 4a
was obtained in 74% yield instead of 4-methoxychromane 3a
(entry 20, Figure 2). This result suggests that the elimination
that the bisphenyl groups may effectively stabilize the benzyl
cation of the intermediate (vide infra).15
Subsequently, we examined the corresponding reactions
between acetophenones and salicylaldehydes. Under acidic
conditions, in the presence of trimethyl orthoformate,
acetophenone A is converted into 1-methoxy-1-phenyl ethyl-
ene C via acetal B (Scheme 2).16 Initially, when 4′-
nitroacetophenone was treated with 5-nitrosalicylaldehyde,
the desired cycloadduct (6a) was obtained in high yield (Table
3). Although acetophenones that bear strongly electron-
withdrawing groups are usually unsuitable dienophile sub-
strates for inverse-electron-demand Diels−Alder reactions, this
reaction proceeded smoothly to give the desired chromanes.17
This may tentatively be ascribed to the fact that the methoxy
group on ethylene C (Scheme 2) effectively promotes the
reaction as an electron-donating group. Fortunately, single
crystals suitable for an X-ray diffraction analysis were obtained,
from which the relative stereochemistry of cis- and trans-
chromanes 6a was determined.18 The separation of cis/trans
isomers can be achieved by column chromatography, and the
isolated ratio is shown in Table 3. When we examined the use
of 3 equiv (excess) of acetophenone, the mixture of the desired
product and acetophenone could not be completely separated
by column chromatography. Therefore, we examined the
amount of salicylaldehyde used, and optimal results were
obtained for 2 equiv, that is, the consumption of acetophenone
was virtually complete and only the desired chromane was
isolated. 4′-Nitrileacetophenone also readily undergoes this
transformation (6b). Halogen-functionalized derivatives are
also good substrates to afford 6c−e. Salicylaldehydes that bear
strongly to moderately electron-withdrawing groups also
furnished the corresponding cycloadducts in good yield (6f−
k). The parent salicylaldehyde was also suitable for the
reaction (6l). It is noteworthy that this reaction is applicable to
various substrates with electron-withdrawing groups, which
stereoselectively give electron-deficient 2,2-disubstituted chro-
manes.
Further transformations of chromane 3a are shown in
Scheme 3. When 3a was treated with TsNH2 in the presence of
FeCl3, 4-aminochromane 7a was obtained in high yield.
Moreover, the reaction of 3a with allyltrimethylsilane afforded
4-alkylchromane 8a. 4-Amino- and 4-alkylchromanes are found
in natural products and biologically active compounds, with,
for example, antimicrobial, potassium-channel-opening, and
other bio-organic properties.3,19 The hydrogenation of 3a
furnished 6-aminochromane 9a in good yield. 6-Amino-
chromanes also exhibit diverse bioactivity.20 Interestingly,
when 3a was treated with N-bromosuccinimide (NBS), 3-
bromochromene 10a was obtained in 75% yield. This reaction
thus provides a new synthetic route to 3-bromochromenes,21
which may lead to photochromic 2,2,3-triaryl-2H-chromenes.22
It should be noted here that this reaction represents a feasible
route to chromenes, leading to the effective synthesis of
photochemically active molecules. For example, BW683C is a
highly effective inhibitor of the replication of certain serotypes
of rhinovirus.3a Recently, the synthesis of BW683C has been
reported, including a modular synthesis of 2-alkyl- and 2-
arylchromans via a three-step sequence and a regioselective
domino synthesis of 2-alkylflavans via a hidden Brønsted acid
catalysis.23 To demonstrate the synthetic utility of the method
presented herein, we synthesized BW683C in two steps in 90%
yield from 5-chlorosalicylaldehyde with 4-chlorostyrene
(Scheme 4). It should be noted here that this method is
Figure 2. 4-Alkenylchromane 4a.
of the methoxy group from chromane 3a under acidic
conditions at 100 °C furnishes a dihydropyrylium salt, which
could react with 1,1-disubstituted ethylene to yield the
corresponding 4-alkenylchromane. This synthetic strategy
constitutes a new method to control the formation of
carbon−carbon or carbon−oxygen bonds via controlling the
reaction temperature. The thus-obtained chromanes, which
contain carbon−carbon or carbon−oxygen bonds at the 4-
position, represent important structural motifs in natural
products and medicinal chemistry.10 Against this background,
we examined the scope of this selective, direct, and
temperature-controlled synthetic route to 4-alkoxy and 4-
alkenylchromanes.
With the optimized conditions in hand, we examined the
scope and limitations of the formation of 4-methoxychromanes
and 4-alkenylchromanes (Table 2). Salicylaldehydes with
strongly to moderately electron-withdrawing groups were
well tolerated, under both conditions A and B (3a−f, 4a−f).
2-Hydroxy-1-naphthoaldehyde furnished 3g together with
chromene 5g as an inseparable mixture in 33 and 32% yields,
respectively. When the quantitative ratio of the starting
materials was optimized (1/2 = 2:1), chromene 5g was
selectively obtained in 66% yield. Chromene 5g is a
photochromic material,11 which suggests that the present
method may also represent a facile and efficient one-pot
approach to the synthesis of chromene-based photochromic
materials from easily available starting materials.12 In addition,
high yield was obtained under condition B (4g). The parent
salicylaldehyde is also a good substrate for the formation of
chromanes 3h and 4h. The 1,1-diphenylethylene with p-chloro
groups afforded the corresponding products (3i and 4i) in
good yield. The reaction using a 1,1-dialkylethylene, that is, 1-
methyl-1-phenylethylene, proceeded under condition A (3j
and 3k).10,13,14 Interestingly, spiro compounds were obtained
when 9-methylene-9H-thioxanthene and 5-methylene-5H-
dibenzo[a,d][7]annulene were used as the dienophile (3l
and 3m). Styrene was also a good substrate under condition
A,14 suggesting that the reaction can be applied to not only 1,1-
disubstituted olefins but also monosubstituted ones. Diaryl-
ethylenes were suitable under condition B, while other
ethylenes furnished complex mixtures (4j−n), which suggests
C
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e
Table 2. Synthesis of 4-Methoxychromanes 3 and 4-Alkenylchromanes 4
a
b
A complex mixture was obtained. Salicylaldehyde (2.0 mmol) and the 1,1-disubstituted ethylene (1.0 mmol) were stirred for 24 h. The product
c
d
yield is given with respect to the ethylene. 1H NMR yield. Salicylaldehyde (2.0 equiv) and ethylene (1.0 equiv) were reacted for 6 h. The product
yield was calculated on the basis of the ethylene. Condition A: 1 (0.5 mmol), 2 (1.5 mmol), CH(OMe)3 (1.0 mmol), and TfOH (20 mol %) in
e
toluene (5.0 mL) at room temperature for 1 h; condition B: 1 (0.5 mmol), 2 (1.5 mmol), CH(OMe)3 (1.0 mmol), and TfOH (20 mol %) in
toluene (5.0 mL) at room temperature (1 h) and then at 100 °C (1 h).
A mechanism for the present reaction is proposed in Scheme
5. An o-QM is generated from salicylaldehyde 12 with
trimethyl orthoformate via acetal 13 under acidic conditions.
An inverse-electron-demand Diels−Alder reaction of the o-QM
with a 1,1-disubstituted ethylene (14) affords chromane 15,
probably via a concerted mechanism and an endo addi-
tion.13,14,24 The formation of 4-alkenylchromane 4a from 4-
methoxychromane 3a under the reaction conditions outlined
in Scheme 6 (1) strongly suggests that the retro-Diels−Alder
reaction occurs at 100 °C and regenerates the starting
compounds o-QM and 1,1-diphenylethylene in situ [Scheme
Scheme 2. Generation of 1-Phenyl-1-methoxy Ethylene C in
the Presence of an Acid Catalyst
based on easily available substrates and inexpensive catalysts
and provides the products in excellent yield.3a,23
D
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a
Table 3. Reaction of Acetophenones with Salicylaldehydes
a
b
1
The ratio of cis/trans isomers was determined by H NMR spectroscopy. Reaction conducted at 40 °C for 24 h.
Scheme 3. Further Transformations of Chromane 3a
Scheme 5. Proposed Mechanism for the Reaction of
Salicylaldehyde (12) with 1,1-Disubstituted Ethylenes
6 (2)]. The elimination of the methoxy group on chromane 15
under acidic conditions would then afford cationic inter-
mediate 16, before 17 could be generated via either path A or
B. Intermediate 16 could be attacked from the exo side of the
dihydrobenzopyrylium ring by the 1,1-disubstituted ethylene
to yield the stable dibenzyl cation 17 (path A).25
Dihydropyrylium 16 could also react with the 1,1-disubstituted
ethylene via an endo approach to give 17 (path B).26 Based on
density functional theory (DFT) calculations at the theoretical
level of B3LYP with the 6-31G(d,p) basis set, path A might be
energetically more favorable than path B.27 Finally, the loss of a
proton from 17 would afford the desired product (18). Further
Scheme 4. Two-Step Synthesis of BW683C
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1,1-Bis(3-fluorophenyl)ethylene. Yellow oil (455.3 mg, 13% yield).
1H NMR (500 MHz, CDCl3): δ 7.34−7.27 (m, 2H), 7.13−7.07 (m,
2H), 7.05−7.00 (m, 4H), 5.51 (s, 2H). The spectroscopic data were
consistent with literature values.34
Scheme 6. Reaction of Chromane 3a in the Absence of 1,1-
Diphenyl Ethylenes
1,1-Bis(4-methoxyphenyl)ethylene. White solid (1.0934 g, 91%
1
yield). H NMR (300 MHz, CDCl3): δ 7.30−7.24 (m, 4H), 6.90−
6.83 (m, 4H), 5.29 (s, 2H), 3.83 (s, 6H). The spectroscopic data were
consistent with literature values.35
2-Heptyl-1-nonene. Colorless liquid (742.3 mg, 66% yield). H
1
NMR (300 MHz, CDCl3): δ 4.68 (s, 2H), 1.99 (t, J = 6.8 Hz, 4H),
1.46−1.36 (m, 4H), 1.28 (m, 16H), 0.88 (t, J = 7.2 Hz, 6H). The
spectroscopic data were consistent with literature values.32
9-Methylene-9H-thioxanthene. Yellow solid (143.6 mg, 15%
1
yield). H NMR (500 MHz, CDCl3): δ 7.65−7.61 (m, 2H), 7.37−
7.34 (m, 2H), 7.28−7.24 (m, 4H), 5.55 (s, 2H). The spectroscopic
data were consistent with literature values.36
5-Methylene-5H-dibenzo[a,d][7]annulene. White solid (685.5
mg, 73% yield). 1H NMR (500 MHz, CDCl3): δ 7.42−7.23 (m,
8H), 6.83 (s, 2H), 5.26 (s, 2H). The spectroscopic data were
consistent with literature values.37
studies on the scope and mechanism of this reaction are
currently in progress and will be reported in due course.
General Procedure for the Synthesis of Chromanes.
Synthesis of Chromane 3. Salicylaldehyde 1 (0.50 mmol), 1,1-
disubstituted ethylene 2 (1.5 mmol), and trimethyl orthoformate (1.0
mmol) were dissolved in dry toluene (5.0 mL) under an atmosphere
of nitrogen before trifluoromethanesulfonic acid (20 mol %) was
added to the reaction mixture. After stirring at room temperature for 1
h, the reaction mixture was neutralized with 5% aqueous (aq)
NaHCO3. The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (5.0 mL × 3). The combined organic
phases were washed with brine, dried over MgSO4, and filtered. The
filtrate was concentrated in vacuo. The resulting residue was purified
by column chromatography on silica gel (hexane/ethyl acetate = 50/
1, v/v) to afford chromane 3.
Synthesis of Chromane 4. Salicylaldehyde 1 (0.50 mmol), 1,1-
disubstituted ethylene 2 (1.5 mmol), and trimethyl orthoformate (1.0
mmol) were dissolved in dry toluene (5.0 mL) under an atmosphere
of nitrogen before trifluoromethanesulfonic acid (20 mol %) was
added to the reaction mixture. After stirring at room temperature for 1
h, the reaction mixture was heated to 100 °C (oil bath) and stirred for
1 h. Then, every 15 min, a three-way stopcock was carefully opened
three times to quickly discharge gaseous methanol. After the reaction
was completed, the reaction mixture was neutralized with 5% aq
NaHCO3. The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (5.0 mL × 3). The combined organic
phases were washed with brine, dried over MgSO4, and filtered. The
filtrate was concentrated in vacuo. The resulting residue was purified
by column chromatography on silica gel (hexane) to afford chromane
4.
Synthesis of Chromane 6. Salicylaldehyde 1 (2.0 mmol),
acetophenone 2 (1.0 mmol), and trimethyl orthoformate (4.0
mmol) were dissolved in dry toluene (5.0 mL) under an atmosphere
of nitrogen before trifluoromethanesulfonic acid (20 mol %) was
added to the reaction mixture. After stirring at room temperature for
1.5 h, the reaction mixture was neutralized with 5% aq NaHCO3. The
organic layer was separated, and the aqueous layer was extracted with
ethyl acetate (5.0 mL × 3). The combined organic phases were
washed with brine, dried over MgSO4, and filtered. The filtrate was
concentrated in vacuo. The resulting residue was purified by column
chromatography on silica gel (hexane/ethyl acetate = 20/1, v/v) to
afford chromane 6.
CONCLUSIONS
■
We have developed a highly regioselective one-pot method for
the generation of electron-deficient 2,2-disubstituted chro-
manes via an inverse-electron-demand [4 + 2] cycloaddition.
When 1,1-disubstituted ethylenes or acetophenones are
reacted with salicylaldehydes that bear electron-withdrawing
groups, the desired chromanes are obtained in high yield and
excellent regioselectivity. The reaction of salicylaldehydes with
1,1-disubstituted ethylenes generates 4-methoxychromanes at
room temperature, whereas 4-alkenylchromanes are obtained
when the reaction is carried out at room temperature and then
at 100 °C. Further transformations of the electron-deficient
chromanes furnished functionalized chromanes or chromene.
For example, BW683C was synthesized from 5-chlorosalicy-
laldehyde and 4-chlorostyrene in 90% yield in two steps. The
present reaction thus provides versatile access to functionalized
electron-deficient chromanes and chromenes and therefore
constitutes a promising tool for the synthesis of biologically
and photochemically active molecules.
EXPERIMENTAL SECTION
■
General Information. Infrared (IR) spectra were recorded on
1
JASCO FT/IR-4100. H NMR spectra were recorded on a Bruker
DRX-300 (300 MHz) spectrometer, a Bruker DRX-500 (500 MHz)
spectrometer, or a JEOL ECA-500 (500 MHz) spectrometer with
tetramethylsilane (TMS) as the internal standard. Chemical shifts are
reported in ppm relative to TMS (δ 0). NMR data are reported as
follows: chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet), coupling constants, integration. 13C{1H} NMR
spectra were recorded on a Bruker DRX-500 (126 MHz)
spectrometer or a JEOL ECA-500 (126 MHz) spectrometer under
complete proton decoupling. Chemical shifts are reported in ppm
relative to the solvent resonance of CDCl3 (δ 77.0). High-resolution
mass spectra (HRMS) were recorded on a Hitachi High-Technologies
Nanofrontier LD Spectrometer [electrospray ionization (ESI)/time-
of-flight]. Column chromatography was carried out on Cica-reagent
silica gel 60 N (spherical; particle size: 63−210 μm). Thin-layer
chromatography (TLC) was carried out on Merck TLC plates with
silica gel (60 F254). Single-crystal X-ray diffraction analyses were
performed at 223 K using a Rigaku XtaLAB P200 diffractometer with
a graphite-monochromated Cu Kα radiation (λ = 1.54187 Å). Unless
otherwise noted, commercially purchased reagents were used as
received. 1,1-Disubstituted ethylenes were prepared according to
published methods.28−38
Characterization Data for the Chromanes. 4-Methoxy-6-
nitro-2,2-diphenylchromane (3a). 5-Nitrosalicylaldehyde (84.3 mg,
0.50 mmol), 1,1-diphenylethylene (264 μL, 1.5 mmol), trimethyl
orthoformate (109 μL, 1.0 mmol), and dry toluene (5.0 mL). Yellow
1
solid (154.2 mg, 85% yield). H NMR (300 MHz, CDCl3): δ 8.30
(dd, J = 2.8, 0.9 Hz, 1H), 8.13 (dd, J = 9.0, 2.6 Hz, 1H), 7.45−7.27
(m, 10H), 7.14 (d, J = 9.0 Hz, 1H), 4.28 (dd, J = 10.9, 5.7 Hz, 1H),
3.54 (s, 3H), 3.34 (dd, J = 13.4, 5.5 Hz, 1H), 2.46 (dd, J = 13.4, 10.7
Hz 1H); 13C{1H} NMR (126 MHz, CDCl3): δ 158.8, 144.1, 141.9,
141.7, 128.9, 128.4, 128.0, 127.8, 125.8, 125.7, 125.0, 124.3, 124.1,
1,1-Bis(4-chlorophenyl)ethylene. Yellow solid (572.1 mg, 77%
1
yield). H NMR (300 MHz, CDCl3): δ 7.35−7.20 (m, 8H), 5.45 (s,
2H). The spectroscopic data were consistent with literature values.33
F
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117.5, 84.4, 71.1, 56.5, 36.3; IR [attenuated total reflection (ATR)]:
1585, 1516, 1478, 1432, 1338, 1253, 1098, 1081, 1017, 900, 752, 697
cm−1; HRMS (ESI+) m/z calcd for C22H19NO4Na ([M + Na]+):
384.1206, found: 384.1226.
2,3-Dihydro-1-methoxy-3,3-diphenyl-1H-naphto[2,1-b]pyran
(3g). 2-Hydroxy-1-naphthaldehyde (86.1 mg, 0.50 mmol), 1,1-
diphenylethylene (264 μL, 1.5 mmol), trimethyl orthoformate (109
μL, 1.0 mmol), and dry toluene (5.0 mL). White solid (61.0 mg, 33%
1
yield). H NMR (300 MHz, CDCl3): δ 7.87 (d, J = 8.7 Hz, 1H),
4-Methoxy-2,2-diphenyl-6-tosyloxychromane (3b). 2-Hydroxy-5-
tosyloxybenzaldehyde (145.4 mg, 0.50 mmol), 1,1-diphenylethylene
(264 μL, 1.5 mmol), trimethyl orthoformate (109 μL, 1.0 mmol), and
7.74−7.70 (m, 2H), 7.53−7.39 (m, 5H), 7.33−7.14 (m, 8H), 4.97 (t,
J = 6.6 Hz, 1H), 3.39 (s, 3H), 3.21−3.13 (m, 1H), 3.07−2.99 (m,
1H); 13C{1H} NMR (126 MHz, CDCl3): δ 152.4, 144.7, 143.5,
132.8, 130.5, 129.5, 128.4, 128.3, 128.1, 127.4, 127.2, 126.5, 126.3,
125.8, 123.9, 123.4, 119.3, 114.1, 82.1, 69.9, 54.2, 36.5; IR (ATR):
1737, 1624, 1446, 1233, 1215, 1095, 1079, 1060, 908, 814, 733, 696
cm−1; HRMS (ESI+) m/z calcd for C26H22O2Na ([M + Na]+):
389.1512, found: 389.1522.
1
dry toluene (5.0 mL). White solid (226.9 mg, 94% yield). H NMR
(300 MHz, CDCl3): δ 7.66 (d, J = 7.6 Hz, 2H), 7.43−7.37 (m, 4H),
7.35−7.22 (m, 8H), 6.97 (dd, J = 3.0, 0.8 Hz, 1H), 6.92 (d, J = 8.9
Hz, 1H), 6.80−6.75 (m, 1H), 4.21 (dd, J = 10.9, 5.7 Hz, 1H), 3.35 (s,
3H), 3.19 (dd, J = 13.2, 5.7 Hz, 1H), 2.48−2.36 (m, 4H); 13C{1H}
NMR (126 MHz, CDCl3): δ 152.2, 145.0, 144.9, 143.0, 142.5, 132.4,
129.6, 128.6, 128.5, 128.2, 127.6, 127.4, 126.0, 125.6, 124.3, 122.9,
121.2, 117.6, 83.0, 71.2, 55.6, 36.2, 21.6; IR (ATR): 1486, 1449, 1364,
1173, 1132, 1091, 1026, 943, 892, 838, 808, 735, 663 cm−1; HRMS
(ESI+) m/z calcd for C29H26O5NaS ([M + Na]+): 509.1393, found:
509.1383.
4-Methoxy-6-methoxycarbonyl-2,2-diphenylchromane (3c).
Methyl 3-formyl-4-hydroxybenzoate (90.4 mg, 0.50 mmol), 1,1-
diphenylethylene (264 μL, 1.5 mmol), trimethyl orthoformate (109
μL, 1.0 mmol), and dry toluene (5.0 mL). White solid (156.8 mg,
83% yield). 1H NMR (500 MHz, CDCl3): δ 8.07 (s, 1H), 7.91 (d, J =
8.5 Hz, 1H), 7.47−7.40 (m, 4H), 7.35−7.19 (m, 6H), 7.09 (d, J = 8.5
Hz, 1H), 4.29 (dd, J = 10.4, 5.7 Hz, 1H), 3.83 (s, 3H), 3.48 (s, 3H),
3.28 (dd, J = 13.2. 5.4 Hz, 1H), 2.50−2.546 (m, 1H); 13C{1H} NMR
(126 MHz, CDCl3): δ 166.7, 157.5, 144.7, 142.4, 130.7, 129.6, 128.6,
128.3, 127.7, 127.5, 125.9, 125.7, 123.3, 122.7, 117.0, 83.4, 71.4, 56.1,
51.7, 36.5; IR (ATR): 1707, 1585, 1493, 1448, 1296, 1262, 1212,
1117, 1093, 1025, 928, 766, 708 cm−1; HRMS (ESI+) m/z calcd for
C24H22O4Na ([M + Na]+): 397.1410, found: 397.1415.
6-Bromo-4-methoxy-2,2-diphenylchromane (3d). 5-Bromosalicy-
laldehyde (99.7 mg, 0.50 mmol), 1,1-diphenylethylene (264 μL, 1.5
mmol), trimethyl orthoformate (109 μL, 1.0 mmol), and dry toluene
(5.0 mL). White solid (219.7 mg, quant.). 1H NMR (300 MHz,
CDCl3): δ 7.47−7.38 (m, 5H), 7.38−7.16 (m, 8H), 6.94 (d, J = 8.7
Hz, 1H), 4.26 (dd, J = 10.6, 5.7 Hz, 1H), 3.48 (s, 3H), 3.24 (dd, J =
13.4, 5.8 Hz), 2.44 (dd, J = 13.4, 10.7 Hz, 1H); 13C{1H} NMR (126
MHz, CDCl3): δ 152.7, 145.0, 142.5, 132.0, 130.0, 128.7, 128.3,
127.7, 127.5, 126.1, 125.8, 125.4, 118.8, 113.0, 83.0, 71.5, 56.1, 36.5;
IR (ATR): 1474, 1264, 1217, 1100, 1060, 1020, 915, 888, 829, 699
cm−1; HRMS (ESI+) m/z calcd for C22H19O2Na79Br ([M + Na]+):
417.0461, found: 417.0451.
4-Methoxy-2,2-diphenylchromane (3h). Salicylaldehyde (48.3 μL,
0.50 mmol), 1,1-diphenylethylene (264 μL, 1.5 mmol), trimethyl
orthoformate (109 μL, 1.0 mmol), and dry toluene (5.0 mL). White
1
solid (131.5 mg, 83% yield). H NMR (300 MHz, CDCl3): δ 7.52−
7.39 (m, 4H), 7.35−7.18 (m, 8H), 7.05 (dd, J = 8.3, 1.1 Hz, 1H), 6.90
(t, J = 7.4 Hz, 1H), 4.33 (dd, J = 10.6, 5.7 Hz, 1H), 3.47 (s, 3H), 3.24
(dd, J = 13.6, 5.7 Hz, 1H), 2.49 (dd, J = 13.2, 10.6 Hz, 1H); 13C{1H}
NMR (126 MHz, CDCl3): δ 153.6, 145.4, 143.0, 129.0, 128.5, 128.2,
127.4, 127.3, 127.2, 126.2, 125.8, 123.2, 120.7, 116.9, 82.5, 71.8, 55.8,
36.8; IR (ATR): 1581, 1486, 0445, 1228, 1216, 1096, 1020, 757, 700
cm−1; HRMS (ESI+) m/z calcd for C22H20O2Na ([M + Na]+):
339.1356, found: 339.1360.
2,2-Bis(4-chlorophenyl)-4-methoxychromane (3i). Salicylalde-
hyde (48.3 μL, 0.50 mmol), 1,1-bis(4-chlorophenyl)ethylene (373.7
mg, 1.5 mmol), trimethyl orthoformate (109 μL, 1.0 mmol), and dry
toluene (5.0 mL). White solid (122.1 mg, 63% yield). 1H NMR (300
MHz, CDCl3): δ 7.40−7.32 (m, 5H), 7.32−7.23 (m, 5H), 7.20 (dt, J
= 7.3, 0.9 Hz, 1H), 7.03 (dd, J = 7.9, 1.1 Hz, 1H), 6.92 (td, J = 7.4, 1.1
Hz, 1H), 4.30 (dd, J = 10.2, 5.7 Hz, 1H), 3.46 (s, 3H), 3.12 (dd, J =
13.4, 5.8 Hz, 1H), 2.47 (dd, J = 13.6, 10.2 Hz, 1H); 13C{1H} NMR
(126 MHz, CDCl3): δ 153.1, 143.4, 141.4, 133.5, 133.5, 129.3, 128.9,
128.5, 127.6, 127.5, 127.2, 122.9, 121.2, 116.9, 81.6, 71.5, 55.9, 36.6;
IR (ATR): 1486, 1455,1230, 1091, 1011, 816, 753 cm−1; HRMS (ESI
+) m/z calcd for C22H18O2Na35Cl2 ([M + Na]+): 407.0576, found:
407.0573.
4-Methoxy-2-methyl-6-nitro-2-phenylchromane (3j). 5-Nitrosali-
cylaldehyde (83.6 mg, 0.50 mmol), α-methylstyrene (195 μL, 1.5
mmol), trimethyl orthoformate (109 μL, 1.0 mmol), and dry toluene
(5.0 mL). Yellow oil (127.2 mg, 85% yield, diastereomeric ratio 3:2).
1H NMR (500 MHz, CDCl3): (major) δ 8.38 (d, J = 2.8 Hz, 1H),
8.10 (m, 1H), 7.47−7.38 (m, 1H), 7.34−7.23 (m, 4H), 7.04 (dd, J =
10.7, 9.1 Hz, 1H), 4.57 (dd, J = 9.1, 5.7 Hz, 1H), 3.45 (s, 3H), 2.54
(ddd, J = 13.6, 5.7, 1.6 Hz, 1H), 2.20 (dd, J = 13.6, 9.1 Hz, 1H), 1.69
(s, 3H); (minor) δ 8.26 (dd, J = 2.8 Hz, 1H), 8.11 (m, 1H), 7.47−
7.38 (m, 1H), 7.34−7.23 (m, 4H), 7.04 (dd, J = 10.7, 9.1 Hz, 1H),
4.02 (dd, J = 10.6, 5.5 Hz, 1H), 3.48 (s, 3H), 2.90 (dd, J = 13.4, 5.5
Hz, 1H), 2.09 (dd, J = 13.4, 10.6 Hz, 1H), 1.74 (s, 3H); 13C{1H}
NMR (126 MHz, CDCl3): (mixture) δ 158.9, 158.6, 145.0, 143.6,
141.2, 141.1, 128.7, 128.3, 127.3, 124.9, 124.8, 124.8, 124.1, 124.0,
123.0, 117.7, 117.1, 81.2, 80.3, 70.9, 70.7, 56.2, 56.1, 37.8, 36.8, 31.2,
26.4; IR (ATR) (mixture): 1586, 1514, 1477, 1336, 1324, 1259, 1102,
1085, 749, 698 cm−1; HRMS (ESI+) m/z calcd for C17H17NO4Na
([M + Na]+): 322.1050, found: 322.1062.
4-Methoxy-2,2-diphenyl-7-tosyloxychromane (3e). 2-Hydroxy-4-
tosyloxybenzaldehyde (84.3 mg, 0.49 mmol), 1,1-diphenylethylene
(264 μL, 1.5 mmol), trimethyl orthoformate (109 μL, 1.0 mmol), and
1
dry toluene (5.0 mL). White solid (210.6 mg, 88% yield). H NMR
(500 MHz, CDCl3): δ 7.70 (d, J = 8.2 Hz, 2H), 7.40−7.35 (m, 4H),
7.32−7.26 (m,6H), 7.25−7.19 (m, 3H), 6.73−6.69 (m, 1H), 6.54 (d,
J = 8.5 H, 1H), 4.23 (dd, J = 10.4, 5.4 Hz, 1H), 3.43 (s, 3H), 3.22
(dd, J = 11.8, 5.8 Hz, 1H), 2.45−2.38 (m, 4H); 13C{1H} NMR (126
MHz, CDCl3): δ 154.1, 149.7, 145.2, 144.7, 142.4, 132.3, 129.6,
128.5, 128.5, 128.2, 128.2, 127.6, 127.4, 126.0, 125.6, 122.4, 114.6,
110.8, 83.2, 71.3, 56.0, 36.5, 21.6; IR (ATR): 1594, 1492, 1370, 1191,
1177, 1110, 1090, 963, 811, 698 cm−1; HRMS (ESI+) m/z calcd for
C29H26O5NaS ([M + Na]+): 509.1393, found: 509.1393.
2,2-Diheptyl-4-methoxy-6-nitrochromane (3k). 5-Nitrosalicylal-
dehyde (83.6 mg, 0.50 mmol), 2-heptyl-1-nonene (432 μL, 1.5
mmol), trimethyl orthoformate (109 μL, 1.0 mmol), and dry toluene
7-Bromo-4-methoxy-2,2-diphenylchromane (3f). 4-Bromosalicy-
laldehyde (84.3 mg, 0.51 mmol), 1,1-diphenylethylene (264 μL, 1.5
mmol), trimethyl orthoformate (109 μL, 1.0 mmol), and dry toluene
1
1
(5.0 mL). Yellow oil (30.4 mg, 15% yield). H NMR (300 MHz,
(5.0 mL). Yellow solid (157.1 mg, 78% yield). H NMR (500 MHz,
CDCl3): δ 8.34 (dd, J = 3.0, 0.8 Hz, 1H), 8.05 (dd, J = 9.0, 3.0 Hz,
1H), 6.84 (d, J = 9.0 Hz, 1H), 4.41 (dd, J = 8.5, 5.8 Hz, 1H), 3.52 (s,
3H), 2.20 (dd, J = 13.6, 5.7 Hz, 1H), 1.88 (dd, J = 13.6, 8.7 Hz, 1H),
1.75−1.51 (m, 4H), 1.37−1.22 (m, 20H), 0.92−0.84 (m, 6H);
13C{1H} NMR (126 MHz, CDCl3): δ 159.2, 140.9, 125.0, 123.0,
117.7, 81.9, 71.0, 56.5, 37.7, 36.3, 33.0, 31.8, 31.7, 29.9, 29.9, 29.2,
29.1, 23.3, 23.2, 22.6, 22.6, 14.1, 14.0; IR (ATR): 2926, 2855, 1586,
1518, 1479, 1334, 1260, 1085, 750 cm−1; HRMS (ESI+) m/z calcd
for C24H40NO4 ([M + H]+): 406.2952, found: 406.2948.
CDCl3): δ 7.42 (m, 4H), 7.34−7.29 (m, 4H), 7.27−7.21 (m, 3H),
7.18 (dd, J = 8.2, 1.0 Hz, 1H), 7.02 (dd, J = 8.2, 1.9 Hz, 1H), 4.25
(dd, J = 10.7, 5.7 Hz, 1H), 3.45 (s, 3H), 3.23 (dd, J = 13.6, 5.7 Hz,
1H), 2.44 (dd, J = 13.6, 10.7 Hz, 1H); 13C{1H} NMR (126 MHz,
CDCl3): δ 154.4, 144.9, 142.5, 128.7, 128.3, 127.7, 127.5, 126.1,
125.7, 123.9, 122.4, 122.0, 119.9, 83.2, 71.4, 55.9, 36.6; IR (ATR):
1598, 1477, 1406, 1225, 1090, 1016, 814, 700 cm−1; HRMS (ESI+)
m/z calcd for C22H19O2Na79Br ([M + Na]+): 417.0461, found:
417.0449.
G
DOI: 10.1021/acs.joc.9b02036
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
4-Methoxy-6-nitrospiro[chromane-2,9′-thioxanthene] (3l). 5-Ni-
trosalicylaldehyde (36.5 mg, 0.22 mmol), 9-methylene-9H-thioxan-
thene (143.6 mg, 0.68 mmol), trimethyl orthoformate (50 μL, 0.46
Hz, 1H), 2.81 (dd, J = 13.9, 5.4 Hz, 1H), 2.37−2.28 (m, 1H);
13C{1H} NMR (126 MHz, CDCl3): δ 166.8, 157.7, 145.2, 144.8,
142.2, 141.1, 139.5, 130.8, 129.7, 129.7, 129.3, 128.6, 128.3, 128.2,
127.4, 127.2, 127.1, 127.0, 126.0, 125.6, 124.8, 122.6, 117.2, 82.4,
51.7, 38.6, 33.8; IR (ATR): 1713, 1491, 1285, 1259, 763, 695 cm−1;
HRMS (ESI+) m/z calcd for C37H31O3 ([M + H]+): 523.2268,
found: 523.2267.
1
mmol), and dry toluene (2.2 mL). White solid (95.4 mg, quant.). H
NMR (500 MHz, CDCl3): δ 8.39 (dd, J = 2.9, 1.2 Hz, 1H), 8.28 (dd,
J = 9.2, 2.9 Hz, 1H), 7.78 (dd, J = 8.0, 1.2 Hz, 1H), 7.55−7.53 (m,
1H), 7.50 (d, J = 7.4 Hz, 1H), 7.37−7.34 (m, 2H), 7.32−7.27 (m,
2H), 7.25−7.18 (m, 2H), 3.92 (dd, J = 10.6, 4.9 Hz, 1H), 3.29 (s,
3H), 3.19−3.15 (m, 1H), 1.76 (dd, J = 13.2, 10.3 Hz, 1H); 13C{1H}
NMR (126 MHz, CDCl3): δ 159.4, 141.9, 138.2, 135.9, 129.8, 127.8,
127.8, 127.6, 127.2, 126.9, 126.7, 125.5, 124.9, 124.7, 124.3, 123.8,
116.7, 81.2, 70.2, 56.3, 31.0; IR (ATR): 1586, 1434, 1335, 1255,
1240, 1087, 1020, 747 cm−1; HRMS (ESI+) m/z calcd for
C22H18NO4S ([M + H]+): 392.0951, found: 392.0969.
4-Methoxy-6-nitrospiro[chromane-2,5′-dibenzo[a,d][7]-
annulene] (3m). 5-Nitrosalicylaldehyde (83.2 mg, 0.50 mmol), 5-
methylene-5H-dibenzo[a,d][7]annulene (306.4 mg, 1.5 mmol),
trimethyl orthoformate (109 μL, 1.0 mmol), and dry toluene (5.0
mL). White solid (188.9 mg, 98% yield). 1H NMR (500 MHz,
CDCl3): δ 8.29−8.20 (m, 2H), 8.01 (d, J = 7.9 Hz, 1H), 7.49−7.46
(m, 1H), 7.43−7.39 (m, 4H), 7.35−7.26 (m, 3H), 7.13 (s, 2H), 3.65
(dd, J = 10.6, 4.9 Hz, 1H), 3.48−3.44 (m, 1H), 3.27 (s, 3H), 1.76
(dd, J = 13.5, 10.6 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ
158.4, 141.7, 139.7, 137.4, 131.9, 131.7, 130.9, 130.0, 129.9, 129.2,
128.9, 127.2, 127.1, 125.2, 124.7, 124.3, 123.8, 123.3, 117.0, 82.8,
70.5, 56.0, 29.2; IR (ATR): 1473, 1376, 1262, 1034, 908, 739, 575
cm−1; HRMS (ESI+) m/z calcd for C24H20NO4 ([M + H]+):
386.1387, found: 386.1377.
6-Bromo-4-(2,2-diphenylethenyl)-2,2-diphenylchromane (4d).38
5-Bromosalicylaldehyde (99.7 mg, 0.50 mmol), 1,1-diphenylethylene
(264 μL, 1.5 mmol), trimethyl orthoformate (109 μL, 1.0 mmol), and
1
dry toluene (5.0 mL). White solid (218.4 mg, 81% yield). H NMR
(500 MHz, CDCl3): δ 7.41−7.33 (m, 5H), 7.30−7.17 (m, 12H),
7.12−7.04 (m, 5H), 6.94 (d, J = 8.8 Hz, 1H), 6.09 (d, J = 9.8 Hz,
1H), 3.58−3.50 (m, 1H), 2.77 (dd, J = 14.2, 5.4 Hz, 1H), 2.29 (dd, J
= 14.0, 12.5 Hz, 1H).
2,2-Diphenyl-4-(2,2-diphenylethenyl)-7-tosyloxychromane (4e).
2-Hydroxy-4-tosyloxybenzaldehyde (145.3 mg, 0.50 mmol), 1,1-
diphenylethylene (264 μL, 1.5 mmol), trimethyl orthoformate (109
μL, 1.0 mmol), and dry toluene (5.0 mL). White solid (250.3 mg,
1
79% yield). H NMR (500 MHz, CDCl3): δ 7.78−7.70 (m, 2H),
7.42−7.18 (m, 17H), 7.14−7.05 (m, 3H), 7.05−6.99 (m, 3H), 6.62
(d, J = 2.5 Hz, 1H), 6.55 (dd, J = 8.4, 2.4 Hz, 1H), 6.04 (d, J = 9.3 Hz,
1H), 3.55−3.46 (m, 1H), 2.77 (dd, J = 13.9, 5.4 Hz, 1H), 2.46 (s,
3H), 2.27 (dd, J = 14.0, 12.5 Hz, 1H); 13C{1H} NMR (126 MHz,
CDCl3): δ 154.1, 148.9, 145.3, 145.2, 144.5, 142.2, 141.2, 139.5,
132.6, 130.0, 129.7, 129.5, 129.3, 128.6, 128.6, 128.3, 128.3, 128.2,
127.5, 127.5, 127.3, 127.1, 127.0, 126.2, 125.6, 123.9, 114.6, 111.2,
82.1, 38.6, 33.7, 21.7; IR (ATR): 1489, 1349, 1174, 1091, 963, 828,
820, 809, 695 cm−1; HRMS (ESI+) m/z calcd for C42H35O4S ([M +
H]+): 635.2251, found: 635.2271.
(2S*,4S*)-4-Methoxy-6-nitro-2-phenylchromane (3n). 5-Nitro-
salicylaldehyde (166.6 mg, 1.0 mmol), styrene (58 μL, 0.50 mmol),
trimethyl orthoformate (109 μL, 1.0 mmol), and dry toluene (5.0
mL) for 24 h. Yellow solid (125.0 mg, 88% yield, cis/trans = 93/7).
1H NMR (500 MHz, CDCl3): δ 8.42 (d, J = 2.8 Hz, 1H), 8.06 (dd, J
7-Bromo-4-(2,2-diphenylethenyl)-2,2-diphenylchromane (4f).6c
4-Bromosalicylaldehyde (99.3 mg, 0.49 mmol), 1,1-diphenylethylene
(264 μL, 1.5 mmol), trimethyl orthoformate (109 μL, 1.0 mmol), and
= 9.0, 2.7 Hz, 1H), 7.52−7.37 (m, 5H), 6.93 (d, J = 8.5 Hz, 1H), 5.25
(dd, J = 12.0, 1.9 Hz, 1H), 4.75 (dd, J = 10.7, 5.7 Hz, 1H), 3.55 (s,
3H), 2.65 (ddd, J = 13.1, 5.8, 2.2 Hz, 1H), 2.14−2.02 (m, 1H);
13C{1H} NMR (126 MHz, CDCl3): δ 159.8, 141.5, 139.3, 128.7,
128.6, 126.0, 124.8, 124.4, 123.9, 117.1, 78.0, 72.9, 56.3, 34.4; IR
(ATR): 2929, 1584, 1512, 1342, 1253, 1080, 749 cm−1; HRMS (ESI
+) m/z calcd for C16H15NO4 ([M + H]+): 286.1074, found:
286.1075.
1
dry toluene (5.0 mL). White solid (230.7 mg, 86% yield). H NMR
(500 MHz, CDCl3): δ 7.40−7.32 (m, 5H), 7.32−7.18 (m, 11H),
7.13−7.07 (m, 5H), 7.01−6.94 (m, 2H), 6.06 (d, J = 9.5 Hz, 1H),
3.49 (ddd, J = 12.4, 9.5, 5.5 Hz, 1H), 2.79 (dd, J = 14.0, 5.5 Hz, 1H),
2.29 (dd, J = 13.9, 12.3 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3):
δ 154.4, 145.4, 144.5, 142.3, 141.2, 139.5, 130.1, 130.0, 129.3, 128.6,
128.4, 128.3, 128.2, 127.5, 127.4, 127.3, 127.1, 127.0, 126.2, 125.6,
124.0, 123.7, 120.6, 120.2, 82.1, 38.6, 33.7; IR (ATR): 1508, 1445,
1228, 1031, 759, 695 cm−1; LRMS (EI+) m/z calcd for C35H2879Br O
([M + H]+): 543.1318, found: 543.1.
2,3-Dihydro-1-(2,2-dipenylethenyl)-3,3-diphenyl-1H-naphto[2,1-
b]pyran (4g). 2-Hydroxy-1-naphthaldehyde (85.8 mg, 0.50 mmol),
1,1-diphenylethylene (264 μL, 1.5 mmol), trimethyl orthoformate
(109 μL, 1.0 mmol), and dry toluene (5.0 mL). White solid (220.6
mg, 86% yield). 1H NMR (500 MHz, CDCl3): δ 7.94 (d, J = 8.5 Hz,
1H), 7.70 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.57−7.51
(m, 2H), 7.49−7.45 (m, 3H), 7.42 (d, J = 8.2 Hz, 2H), 7.33−7.10 (m,
13H), 7.08−7.04 (m, 3H), 6.07 (d, J = 9.1 Hz, 1H), 3.99−3.91 (m,
1H), 2.97 (dd, J = 14.2, 6.6 Hz, 1H), 2.56 (dd, J = 14.2, 10.1 Hz, 1H);
13C{1H} NMR (126 MHz, CDCl3): δ 151.6, 145.5, 142.6, 141.4,
6-Nitro-2,2-diphenyl-4-(2,2-diphenylvinyl)chromane (4a).38 5-
Nitrosalicylaldehyde (82.3 mg, 0.49 mmol), 1,1-diphenylethylene
(264 μL, 1.5 mmol), trimethyl orthoformate (109 μL, 1.0 mmol), and
1
dry toluene (5.0 mL). Yellow solid (185.6 mg, 74% yield). H NMR
(300 MHz, CDCl3): δ 8.09−8.03 (m, 2H), 7.43−7.23 (m, 15H),
7.16−7.03 (m, 6H), 6.08 (d, J = 9.4 Hz, 1H), 3.68−3.55 (m, 1H),
2.87 (dd, J = 14.3, 5.3 Hz, 1H), 2.35 (dd, J = 14.1, 12.6 Hz, 1H).
2,2-Diphenyl-4-(2,2-diphenylethenyl)-6-tosyloxychromane (4b).
2-Hydroxy-5-tosyloxybenzaldehyde (143.4 mg, 0.49 mmol), 1,1-
diphenylethylene (264 μL, 1.5 mmol), trimethyl orthoformate (109
μL, 1.0 mmol), and dry toluene (5.0 mL). White solid (165.6 mg,
1
69% yield). H NMR (500 MHz, CDCl3): δ 7.68−7.61 (m, 2H),
7.41−7.31 (m, 5H), 7.31−7.18 (m, 8H), 7.16−7.04 (m, 9H), 6.95 (d,
J = 9.1 Hz, 1H), 6.89−6.79 (m, 1H), 6.64 (d, J = 2.8 Hz, 1H), 5.89
(d, J = 9.5 Hz, 1H), 3.49−3.37 (m, 1H), 2.75 (dd, J = 14.0, 5.5 Hz,
1H) 2.26−2.21 (m, 4H); 13C{1H} NMR (126 MHz, CDCl3): δ
152.2, 145.4, 145.0, 144.8, 143.1, 142.2, 141.1, 139.4, 132.6, 129.5,
129.4, 129.2, 128.6, 128.4, 128.3, 128.2, 128.2, 127.5, 127.4, 127.3,
127.0, 126.2, 125.8, 125.6, 122.1, 121.8, 118.0, 81.9, 38.4, 34.0, 21.5;
IR (ATR): 1483, 1370, 1175, 1092, 948, 832, 695 cm−1; HRMS (ESI
+) m/z calcd for C42H34O4NaS ([M + Na]+): 657.2070, found:
657.2076.
140.7, 139.9, 134.0, 133.1, 129.7, 129.4, 128.8, 128.8, 128.4, 128.3,
128.2, 128.1, 127.4, 127.2, 127.1, 127.1, 126.9, 126.3, 125.9, 125.7,
124.3, 123.1, 119.7, 116.9, 81.1, 40.0, 32.5; IR (ATR): 1058, 1248,
1228, 1033, 821, 697 cm−1; HRMS (ESI+) m/z calcd for C39H31O
([M + H]+): 515.2369, found: 515.2345.
4-(2,2-Diphenylethenyl)-2,2-diphenylchromane (4h). Salicylalde-
hyde (48.3 μL, 0.50 mmol), 1,1-diphenylethylene (264 μL, 1.5
mmol), trimethyl orthoformate (109 μL, 1.0 mmol), and dry toluene
1
(5.0 mL). White solid (192.0 mg, 83% yield). H NMR (500 MHz,
CDCl3): δ 7.43−7.33 (m, 5H), 7.31−7.20 (m, 10H), 7.19−7.03 (m,
8H), 6.86 (t, J = 7.4 Hz, 1H), 6.13 (d, J = 9.4 Hz, 1H), 3.61−3.52 (m,
1H), 2.80 (dd, J = 14.0, 5.5 Hz, 1H), 2.33 (dd, J = 13.9, 12.3 Hz, 1H);
13C{1H} NMR (126 MHz, CDCl3): δ 153.6, 146.0, 144.1, 142.8,
141.5, 139.7, 130.8, 129.4, 128.8, 128.5, 128.3, 128.2, 128.2, 127.8,
127.3, 127.3, 127.2, 127.0, 126.9, 126.3, 125.7, 124.8, 120.6, 117.3,
81.5, 38.8, 34.0; IR (ATR): 1483, 1444, 4091, 1015, 759, 750, 698
4-(2,2-Diphenylethenyl)-6-methoxycarbonyl-2,2-diphenyl-chro-
mane (4c). Methyl-3-formyl-4-hydroxybenzoate (89.0 mg, 0.49
mmol), 1,1-diphenylethylene (264 μL, 1.5 mmol), trimethyl
orthoformate (109 μL, 1.0 mmol), and dry toluene (5.0 mL).
White solid (231.2 mg, 90% yield). H NMR (500 MHz, CDCl3): δ
7.89−7.82 (m, 2H), 7.43−7.32 (m, 5H), 7.30−7.16 (m, 10H), 7.10−
7.04 (m, 6H), 6.13 (d, J = 9.5 Hz, 1H), 3.84 (s, 3H), 3.59 (t, J = 12.9
1
H
DOI: 10.1021/acs.joc.9b02036
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The Journal of Organic Chemistry
Article
cm−1; HRMS (ESI+) m/z calcd for C35H29O ([M + H]+): 465.2213,
found: 465.2198.
11.0 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ 156.5, 142.4,
137.8, 134.8, 128.8, 127.5, 125.3, 124.7, 123.7, 117.5, 103.2, 70.7,
56.7, 50.6, 38.5; IR (ATR): 1509, 1332, 1104, 1027, 892 cm−1;
HRMS (ESI+) m/z calcd for C17H16NO5Na35Cl ([M + Na]+):
372.0609, found: 372.0602.
2,2-Bis(4-chlorophenyl)-4-(2,2-bis(4-chlorophenyl)ethenyl)-
chromane (4i).38 Salicylaldehyde (48.3 μL, 0.50 mmol), 1,1-bis(4-
chlorophenyl)ethylene (371.8 mg, 1.5 mmol), trimethyl orthoformate
(109 μL, 1.0 mmol), and dry toluene (5.0 mL). Yellow solid (285.7
mg, 95% yield). 1H NMR (500 MHz, CDCl3): δ 7.38 (d, J = 7.5 Hz,
2H), 7.30−7.23 (m, 6H), 7.20−6.98 (m, 11H), 6.89 (t, J = 7.4 Hz,
1H), 6.12 (d, J = 9.8 Hz, 1H), 3.45−3.38 (m, 1H), 2.61 (dd, J = 13.9,
5.4 Hz, 1H), 2.31−2.23 (m, 1H).
(2S*,4S*)-2-(2,4-Difluorophenyl)-2,4-dimethoxy-6-nitrochro-
mane (6e). 5-Nitrosalicylaldehyde (333.0 mg, 2.0 mmol), 2′,4′-
difluoroacetophenone (126 μL, 1.0 mmol), trimethyl orthoformate
(438 μL, 4.0 mmol), and dry toluene (5.0 mL). Yellow solid (264.7
1
mg, 75% yield, cis/trans = 1/7). H NMR (500 MHz, CDCl3): δ
8.47−8.42 (m, 1H), 8.15 (dd, J = 8.8, 2.8 Hz, 1H), 7.72 (dt, J = 8.8,
6.3 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.97 (t, J = 8.2 Hz, 1H), 6.93−
6.88 (m, 1H), 4.85 (dd, J = 11.0, 6.3 Hz, 1H), 3.56 (s, 3H), 3.13 (s,
3H), 3.05 (dd, J = 13.1, 6.2 Hz, 1H), 1.89 (dd, J = 13.1, 11.2 Hz, 1H);
13C{1H} NMR (126 MHz, CDCl3): δ 163.4 (dd, J = 252.0, 11.9 Hz),
160.0 (dd, J = 254.8, 11.9 Hz), 156.0, 142.4, 130.0 (dd, J = 9.2, 4.6
Hz), 125.4, 124.8, 123.8, 122.0 (dd, J = 11.0, 4.6 Hz), 117.5, 111.3
(dd, J = 21.1, 3.7 Hz), 105.0 (t, J = 26.1 Hz), 101.8 (d, J = 3.7 Hz),
70.4, 56.8, 50.8, 36.2 (d, J = 2.8 Hz); IR (ATR): 1515, 1343, 1102,
851 cm−1; HRMS (ESI+) m/z calcd for C17H15NO5F2Na ([M +
Na]+): 374.0811, found: 374.0795.
3,3-Diphenyl-3H-naphto[2,1-b]pyran (5g). 2-Hydroxy-1-naph-
thaldehyde (172.6 mg, 1.0 mmol), 1,1-diphenylethylene (87.8 μL,
0.50 mmol), trimethyl orthoformate (109 μL, 1.0 mmol), and dry
1
toluene (5.0 mL) for 6 h. White solid (110.5 mg, 66% yield). H
NMR (500 MHz, CDCl3): δ 7.95 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.1
Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.52−7.43 (m, 5H), 7.34−7.27 (m,
6H), 7.27−7.22 (m, 2H), 7.20 (d, J = 8.8 Hz, 1H), 6.25 (d, J = 9.7
Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ 150.5, 144.8, 129.8,
129.8, 129.3, 128.5, 128.1, 127.7, 127.5, 127.0, 126.6, 123.6, 121.3,
119.5, 118.3, 114.0, 82.5; IR (ATR): 1737, 1260, 1216, 1093, 1008,
802, 697 cm−1; HRMS (ESI+) m/z calcd for C25H19O ([M + H]+):
335.1430, found: 335.1439.
(2S*,4S*)-2,4-Dimethoxy-6-nitro-2-(4-nitrophenyl)chromane
(6a). 5-Nitrosalicylaldehyde (334.6 mg, 2.0 mmol), 4′-nitroacetophe-
none (163.5 mg, 1.0 mmol), trimethyl orthoformate (438 μL, 4.0
mmol), and dry toluene (5.0 mL) at 40 °C for 24 h. Yellow solid
(282.0 mg, 79% yield, cis/trans = 1/11). 1H NMR (500 MHz,
CDCl3): δ 8.49−8.46 (m, 1H), 8.33 (d, J = 7.9 Hz, 2H), 8.18 (dd, J =
8.8, 2.8 Hz, 1H), 7.82−7.78 (m, 2H), 7.13 (d, J = 9.1 Hz, 1H), 4.87
(dd, J = 10.9, 6.2 Hz, 1H), 3.55 (s, 3H), 3.10 (s, 3H), 2.77 (dd, J =
13.1, 6.2 Hz, 1H), 1.85 (dd, J = 13.2, 11.0 Hz, 1H); 13C{1H} NMR
(126 MHz, CDCl3): δ 156.1, 148.3, 146.1, 142.7, 127.3, 125.2, 125.0,
124.0, 123.9, 117.6, 102.9, 70.6, 56.9, 50.9, 38.4; IR (ATR): 1509,
1344, 1086, 749 cm−1; HRMS (ESI+) m/z calcd for C17H16N2O7Na
([M + Na]+): 383.0850, found: 383.0867.
(2S*,4S*)-2-(4-Cyanophenyl)-2,4-dimethoxy-6-nitrochromane
(6b). 5-Nitrosalicylaldehyde (334.8 mg, 2.0 mmol), 4′-cyanoaceto-
phenone (144.2 mg, 1.0 mmol), trimethyl orthoformate (438 μL, 4.0
mmol), and dry toluene (5.0 mL) at 40 °C for 24 h. Yellow solid
(325.0 mg, 96% yield, cis/trans = 1/8). 1H NMR (500 MHz, CDCl3):
δ 8.46 (d, J = 2.8 Hz, 1H), 8.17 (dd, J = 8.8, 2.8 Hz, 1H), 7.79−7.75
(m, 2H), 7.75−7.71 (m, 2H), 7.11 (d, J = 9.1 Hz, 1H), 4.86 (dd, J =
11.0, 6.3 Hz, 1H), 3.54 (s, 3H), 3.08 (s, 3H), 2.74 (dd, J = 13.2, 6.3
Hz, 1H), 1.82 (dd, J = 13.2, 11.0 Hz, 1H); 13C{1H} NMR (126 MHz,
CDCl3): δ 156.1, 144.3, 142.6, 132.6, 126.9, 125.2, 124.9, 123.8,
118.3, 117.5, 112.9, 102.9, 70.6, 56.8, 50.9, 38.4; IR (ATR): 3492,
2932, 2232, 1516, 1341, 1258, 1030, 839, 758 cm−1; HRMS (ESI+)
m/z calcd for C18H16N2O5Na ([M + Na]+): 363.0951, found:
363.0961.
(2S*,4S*)-2,4-Dimethoxy-6-nitro-2-phenylchromane (6f). 5-Ni-
trosalicylaldehyde (334.0 mg, 2.0 mmol), acetophenone (117 μL, 1.0
mmol), trimethyl orthoformate (438 μL, 4.0 mmol), and dry toluene
1
(5.0 mL). Yellow solid (294.9 mg, 94% yield, cis/trans = 1/8). H
NMR (500 MHz, CDCl3): δ 8.46 (dd, J = 2.7, 1.1 Hz, 1H), 8.15 (dd,
J = 9.0, 2.7 Hz, 1H), 7.60−7.56 (m, 2H), 7.52−7.45 (m, 2H), 7.45−
7.41 (m, 1H), 7.10 (d, J = 8.8 Hz, 1H), 4.86 (dd, J = 11.2, 6.2 Hz,
1H), 3.53 (s, 3H), 3.09 (s, 3H), 2.78 (dd, J = 13.2, 6.3 Hz, 1H), 1.85
(dd, J = 13.2, 11.4 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ
156.9, 142.4, 139.2, 128.8, 128.7, 126.0, 125.4, 124.8, 123.8, 117.6,
103.7, 70.8, 56.7, 50.6, 38.7; IR (ATR): 1519, 1331, 1103, 1027, 893,
746 cm−1; HRMS (ESI+) m/z calcd for C17H17NO5Na ([M + Na]+):
338.0999, found: 338.1013.
(2S*,4S*)-6-Cyano-2,4-dimethoxy-2-phenylchromane (6g). 5-
Cyanosalicylaldehyde (292.2 mg, 2.0 mmol), acetophenone (117
μL, 1.0 mmol), trimethyl orthoformate (438 μL, 4.0 mmol), and dry
toluene (5.0 mL). Yellow solid (273.6 mg, 93% yield, cis/trans = 1/
5.5). 1H NMR (500 MHz, CDCl3): δ 7.85 (d, J = 1.0 Hz, 1H), 7.62−
7.56 (m, 2H), 7.52 (dd, J = 8.5, 1.9 Hz, 1H), 7.49−7.38 (m, 3H), 7.08
(d, J = 8.5 Hz, 1H),4.83 (dd, J = 11.2, 6.2 Hz, 1H), 3.50 (s, 3H), 3.08
(s, 3H), 2.75 (dd, J = 13.2, 6.3 Hz, 1H), 1.83 (dd, J = 13.1, 11.1 Hz,
1H); 13C{1H} NMR (126 MHz, CDCl3): δ 155.2, 139.4, 132.8,
131.9, 128.7, 128.6, 125.9, 125.8, 119.1, 117.9, 105.0, 103.3, 70.7,
56.5, 50.5, 38.7; IR (ATR): 2246, 1255, 1026, 701 cm−1; HRMS (ESI
+) m/z calcd for C18H18NO3 ([M + H]+): 296.1281, found:
296.1286.
(2S*,4S*)-2,4-Dimethoxy-2-phenyl-6-tosyloxychromane (6h). 2-
Hydroxy-5-tosyloxybenzaldehyde (290.7 mg, 1.0 mmol), acetophe-
none (58 μL, 0.50 mmol), trimethyl orthoformate (219 μL, 2.0
mmol), and dry toluene (2.5 mL). Yellow solid (187.6 mg, 85% yield,
(2S*,4S*)-2-(4-Fluorophenyl)-2,4-dimethoxy-6-nitrochromane
(6c). 5-Nitrosalicylaldehyde (332.9 mg, 2.0 mmol), 4′-fluoroaceto-
phenone (121 μL, 1.0 mmol), trimethyl orthoformate (438 μL, 4.0
mmol), and dry toluene (5.0 mL). Yellow solid (295.5 mg, 89% yield,
1
cis/trans = 1/11). H NMR (500 MHz, CDCl3): δ 7.81−7.74 (m,
2H), 7.61−7.55 (m, 2H), 7.45−7.40 (m, 2H), 7.39−7.36 (m, 1H),
7.33 (d, J = 8.51 Hz, 2H), 7.17−7.12 (m, 1H), 6.92−6.86 (m, 1H),
6.86−6.82 (m, 1H), 4.77 (dd, J = 11.0, 6.3 Hz, 1H), 3.35 (s, 3H),
3.04 (s, 3H), 2.63 (dd, J = 12.9, 6.3 Hz, 1H), 2.46 (s, 3H), 1.80 (dd, J
= 13.1, 11.2 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ 150.2,
145.1, 143.6, 140.0, 132.6, 129.7, 128.5, 128.5, 126.0, 125.3, 122.7,
121.0, 117.6, 102.6, 71.0, 55.8, 50.3, 38.5, 21.6; IR (ATR): 2970,
1371, 1176, 947, 838, 730 cm−1; HRMS (ESI+) m/z calcd for
C24H24O6NaS ([M + Na]+): 463.1186, found: 463.1202.
1
cis/trans = 1/13). H NMR (500 MHz, CDCl3): δ 8.45 (d, J = 2.8
Hz, 1H), 8.14 (dd, J = 8.8, 2.8 Hz, 1H), 7.63−7.54 (m, 2H), 7.18−
7.08 (m, 3H), 4.86 (dd, J = 11.2, 6.2 Hz, 1H), 3.54 (s, 3H), 3.08 (s,
3H), 2.77 (dd, J = 13.1, 6.2 Hz, 1H), 1.83 (dd, J = 13.2, 11.0 Hz, 1H);
13C{1H} NMR (126 MHz, CDCl3): δ 162.8 (d, J = 248.9 Hz), 156.6,
142.3, 135.1 (d, J = 2.8 Hz), 127.9 (d, J = 8.3 Hz), 125.3, 124.7,
123.7, 117.5, 115.5 (d, J = 22.0 Hz), 103.3, 70.7, 56.6, 50.5, 38.7; IR
(ATR): 1509, 1218, 1024, 842, 751 cm−1; HRMS (ESI+) m/z calcd
for C17H16NO5FNa ([M + Na]+): 356.0905, found: 356.0897.
(2S*,4S*)-2-(4-Chlorophenyl)-2,4-dimethoxy-6-nitrochromane
(6d). 5-Nitrosalicylaldehyde (335.0 mg, 2.0 mmol), 4′-chloroaceto-
phenone (123 μL, 1.0 mmol), trimethyl orthoformate (438 μL, 4.0
mmol), and dry toluene (5.0 mL). Yellow solid (352.0 mg, quant.,
cis/trans = 1/12). 1H NMR (500 MHz, CDCl3): δ 8.45 (dd, J = 2.8,
1.0 Hz, 1H), 8.20−8.12 (m, 1H), 7.56−7.50 (m, 2H), 7.47−7.40 (m,
2H), 7.10 (d, J = 8.8 Hz, 1H), 4.84 (dd, J = 11.0, 6.3 Hz, 1H), 3.54 (s,
3H), 3.07 (s, 3H), 2.75 (dd, J = 13.1, 6.2 Hz, 1H), 1.82 (dd, J = 13.2,
(2S*,4S*)-6-Bromo-2,4-dimethoxy-2-phenylchromane (6i). 5-
Bromosalicylaldehyde (403.2 mg, 2.0 mmol), acetophenone (117
μL, 1.0 mmol), trimethyl orthoformate (438 μL, 4.0 mmol), and dry
toluene (5.0 mL). Yellow solid (342.9 mg, 98% yield, cis/trans = 1/
18). 1H NMR (500 MHz, CDCl3): δ 7.68−7.52 (m, 3H), 7.46−7.28
(m, 4H), 6.89 (d, J = 8.6 Hz, 1H), 4.82 (dd, J = 10.9, 6.3 Hz, 1H),
3.46 (s, 3H), 3.05 (s, 3H), 2.68 (dd, J = 13.5, 6.5 Hz, 1H), 1.82 (dd, J
= 12.9, 11.2 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ 150.7,
140.1, 131.7, 129.9, 128.5, 126.3, 126.0, 118.7, 113.9, 102.5, 71.2,
I
DOI: 10.1021/acs.joc.9b02036
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Article
56.3, 50.3, 38.8; IR (ATR): 2937, 1483, 1237, 1027, 908, 700 cm−1;
HRMS (ESI+) m/z calcd for C17H17O3Na79Br ([M + N]+): 371.0253
found: 371.0269.
84.2, 46.8, 38.9, 21.5; IR (ATR): 3251, 1513, 1316, 1158, 667, 556
cm−1; HRMS (ESI+) m/z calcd for C28H24N2O5NaS ([M + Na]+):
523.1298, found: 523.1318.
(2S*,4S*)-2,4-Dimethoxy-2-phenyl-7-tosyloxychromane (6j). 2-
Hydroxy-4-tosyloxybenzaldehyde (574.1 mg, 2.0 mmol), acetophe-
none (117 μL, 1.0 mmol), trimethyl orthoformate (438 μL, 4.0
mmol), and dry toluene (5.0 mL). Yellow solid (312.3 mg, 71% yield,
Transformation of 4-Methoxy-6-nitro-2,2-diphenylchromane
(3a) into 4-Allyl-6-nitro-2,2-diphenylchromane (8a). 4-Methoxy-6-
nitro-2,2-diphenylethylene (3a, 38.1 mg, 0.11 mmol), allyltrimethylsi-
lane (159 μL, 1.0 mmol), and FeCl3 (10 mol %) were dissolved in
CH2Cl2 (1.0 mL). After stirring at reflux for 7 h, the reaction mixture
was quenched with H2O. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate (5.0 mL × 3). The
combined organic layer was washed with brine, dried over MgSO4,
and filtered. The filtrate was concentrated in vacuo. The resulting
residue was purified by preparative TLC on silica gel (hexane) to
afford 4-allyl-6-nitro-2,2-diphenylchromane (8a, 27.8 mg, 71% yield)
as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.14 (dd, J = 2.7, 1.1
Hz, 1H), 8.07 (ddd, J = 8.8, 2.8, 0.6 Hz, 1H), 7.45−7.40 (m, 2H),
7.40−7.27 (m, 7H), 7.25−7.21 (m, 1H), 7.15 (d, J = 9.1 Hz, 1H),
5.84−5.74 (m, 1H), 5.21−5.13 (m, 2H), 2.99 (dd, J = 14.2, 5.4 Hz,
1H), 2.89−2.76 (m, 2H), 2.41−2.30 (m, 1H), 2.18 (dd, J = 14.2, 12.0
Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ 159.7, 144.9, 142.4,
141.4, 134.6, 128.7, 128.4, 127.7, 127.6, 126.1, 125.9, 125.7, 123.8,
123.6, 118.4, 118.0, 83.6, 37.9, 37.5, 31.2; IR (ATR): 2925, 1577,
1506, 1250, 1095, 1009, 748, 699 cm−1; HRMS (ESI+) m/z calcd for
C24H21NO3Na ([M + Na]+): 394.1414, found: 394.1426.
Transformation of 4-Methoxy-6-nitro-2,2-diphenylchromane
(3a) to 6-Amino-4-methoxy-2,2-diphenylchromane (9a). To 4-
Methoxy-6-nitro-2,2-diphenylethylene (3a, 91.1 mg, 0.25 mmol) in
EtOAc (2.5 mL), palladium on charcoal (10%, 14.9 mg) was added.
After being stirred under hydrogen for 4 h, the reaction mixture was
filtered. The filtrate was concentrated in vacuo to afford 6-amino-4-
methoxy-2,2-diphenylchromane (9a, 86.1 mg, quant.) as a white solid.
1H NMR (500 MHz, CDCl3): δ 7.45−7.40 (m, 4H), 7.32−7.18 (m,
6H), 6.87 (d, J = 8.8 Hz, 1H), 6.66 (d, J = 2.8 Hz, 1H), 6.57 (dd, J =
8.5, 3.2 Hz, 1H), 4.26 (dd, J = 10.4, 5.7 Hz, 1H), 3.45 (s, 3H), 3.20
(dd, J = 13.2, 6.0 Hz, 1H), 3.06 (s, 2H), 2.46 (dd, J = 13.2, 10.7 Hz,
1H); 13C{1H} NMR (126 MHz, CDCl3): δ 146.7, 145.7, 143.1,
139.8, 128.4, 128.2, 127.3, 127.1, 126.3, 125.8, 123.5, 117.6, 116.9,
113.5, 82.1, 71.9, 55.6, 36.8; IR (ATR): 3356, 2818, 1493, 1216,
1089, 1018, 797, 735, 698 cm−1; HRMS (ESI+) m/z calcd for
C22H22NO2 ([M + H]+): 332.1645, found: 332.1656.
Transformation of 4-Methoxy-6-nitro-2,2-diphenylchromane
(3a) to 3-Bromo-4-methoxy-6-nitro-2,2-diphenyl-2H-chromene
(10a). A mixture of 4-methoxy-6-nitro-2,2-diphenylethylene (3a,
91.4 mg, 0.25 mmol) and NBS (136.0 mg, 0.76 mmol) was stirred at
reflux for 24 h in CCl4 (5.0 mL) under an atmosphere of nitrogen.
After that, the reaction mixture was quenched with H2O. The organic
layer was separated, and the aqueous layer was extracted with CH2Cl2.
The organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The resulting residue was purified by column chromatography
on silica gel (hexane) to afford 3-bromo-4-methoxy-6-nitro-2,2-
diphenyl-2H-chromene (10a, 83.4 mg, 75% yield) as a white solid. 1H
NMR (500 MHz, CDCl3): δ 8.20 (d, J = 2.8 Hz, 1H), 8.06 (dd, J =
8.8, 2.8 Hz, 1H), 7.43−7.38 (m, 4H), 7.37−7.32 (m, 6H), 6.99 (d, J =
8.8 Hz, 1H), 3.91 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ
157.9, 149.7, 142.6, 141.4, 128.7, 128.6, 127.9, 126.0, 120.1, 118.3,
117.7, 111.2, 89.6, 60.1; IR (ATR): 2962, 1519, 1341, 1260, 1069,
967, 907, 800, 751, 695 cm−1; HRMS (ESI+) m/z calcd for
C22H17NO479Br ([M + H]+): 438.0336, found: 438.0344.
Synthesis of 11. 5-Chlorosalicylaldehyde (155.6 mg, 0.99 mmol),
p-chlorostyrene (64 μL, 0.5 mmol), and trimethyl orthoformate (109
μL, 1.0 mmol) were dissolved in dry toluene (5.0 mL) under an
atmosphere of nitrogen before trifluoromethanesulfonic acid (20 mol
%) was added. After stirring at room temperature for 24 h, the
reaction mixture was neutralized with 5% aq NaHCO3. The organic
layer was separated, and the aqueous layer was extracted with ethyl
acetate (5.0 mL × 3). The combined organic phases were washed
with brine, dried over MgSO4, and filtered before the filtrate was
concentrated in vacuo. The resulting residue was purified by column
chromatography on silica gel (hexane/chloroform = 3/1, v/v) to
afford (2S*,4S*)-6-chloro-2-(4-chlorophenyl)-4-methoxychromane
1
cis/trans = 1/11). H NMR (500 MHz, CDCl3): δ 7.74 (d, J = 8.6
Hz, 2H), 7.56 (d, J = 7.2 Hz, 2H), 7.48−7.33 (m, 4H), 7.30 (d, J =
8.0 Hz, 2H), 6.74−6.67 (m, 1H), 6.65−6.60 (m, 1H), 4.78 (dd, J =
10.9, 6.3 Hz, 1H), 3.44 (s, 3H), 3.01 (s, 3H), 2.68 (dd, J = 12.9, 6.0
Hz, 1H), 2.42 (s, 3H), 1.80 (dd, J = 13.2, 10.9 Hz, 1H); 13C{1H}
NMR (126 MHz, CDCl3): δ 152.1, 149.6, 145.2, 139.8, 132.3, 129.7,
128.5, 128.4, 127.9, 125.9, 123.3, 115.2, 111.1, 102.8, 71.1, 56.2, 50.2,
38.9, 21.6; IR (ATR): 2939, 2360, 1373, 1091, 963, 825, 702 cm−1;
HRMS (ESI+) m/z calcd for C24H24O6NaS ([M + Na]+): 463.1186,
found: 463.1195.
(2S*,4S*)-7-Bromo-2,4-dimethoxy-2-phenylchromane (6k). 4-
Bromosalicylaldehyde (410.1 mg, 2.0 mmol), acetophenone (117
μL, 1.0 mmol), trimethyl orthoformate (438 μL, 4.0 mmol), and dry
toluene (5.0 mL). Yellow solid (214.6 mg, 61% yield, cis/trans = 1/
1
7). H NMR (500 MHz, CDCl3): δ 7.60−7.56 (m, 2H), 7.46−7.41
(m, 2H), 7.40−7.35 (m, 2H), 7.20 (d, J = 1.72 Hz, 1H), 7.15 (dd, J =
8.3, 2.0 Hz, 1H), 4.79 (dd, J = 11.5, 6.3 Hz, 1H), 3.46 (s, 3H), 3.07
(s, 3H), 2.69 (dd, J = 12.9, 6.0 Hz, 1H), 1.83 (dd, J = 12.9, 11.2 Hz,
1H); 13C{1H} NMR (126 MHz, CDCl3): δ 152.4, 140.0, 128.5,
128.5, 126.0, 124.6, 123.4, 121.7, 120.0, 102.8, 71.1, 56.1, 50.4, 38.9;
IR (ATR): 3350, 2935, 1409, 1224, 991, 699 cm−1; HRMS (ESI+)
m/z calcd for C17H17O3Na79Br ([M + Na]+): 371.0253, found:
371.0258.
(2R*,4S*)- and (2S*,4S*)-2,4-Dimethoxy-2-phenylchromane
(6l). Salicylaldehyde (244 μL, 2.0 mmol), acetophenone (117 μL,
1.0 mmol), trimethyl orthoformate (438 μL, 4.0 mmol), and dry
toluene (5.0 mL). Yellow solid (169.2 mg, 63% yield, cis/trans = 1/
1
6.5). H NMR (500 MHz, CDCl3) (trans): δ 7.68−7.60 (m, 2H),
7.51 (d, J = 7.6 Hz, 1H), 7.47−7.41 (m, 2H), 7.41−7.35 (m, 1H),
7.27−7.22 (m, 1H), 7.09−7.00 (m, 2H), 4.87 (dd, J = 11.0, 6.3 Hz,
1H), 3.47 (s, 3H), 3.07 (s, 3H), 2.69 (dd, J = 13.1, 6.2 Hz, 1H), 1.88
(dd, J = 13.0, 11.0 Hz, 1H); (cis): δ 7.60−7.56 (m, 2H), 7.43−7.39
(m, 3H), 7.38−7.33 (m, 1H), 7.30−7.27 (m, 1H), 7.08−7.01 (m,
2H), 4.23 (dd, J = 5.7, 3.5 Hz, 1H), 3.54 (s, 3H), 3.11 (s, 3H), 2.63
(dd, J = 13.7, 3.6 Hz, 2H), 2.23 (dd, J = 14.7, 5.8 Hz, 2H); 13C{1H}
NMR (126 MHz, CDCl3) (trans): δ 151.6, 140.6, 128.8, 128.4, 128.3,
127.0, 126.1, 124.2, 121.4, 116.8, 102.3, 71.5, 56.0, 50.2, 39.2; (cis): δ
151.8, 140.9. 129.5, 129.5, 128.4, 128.2, 126.2, 123.0, 121.4, 117.4,
100.7, 71.8, 57.0, 50.4, 39.3; IR (ATR) (trans): 2938, 1449, 1213,
1092, 1025, 907, 751 cm−1; (cis): 1450, 1228, 1147, 1095, 1016, 808,
755, 565 cm−1; HRMS (ESI+) m/z calcd for C17H18O3Na ([M +
Na]+) (trans): 293.1148, found: 293.1159; (cis): 293.1148, found:
293.1158.
Transformation of Chromane 3a. Transformation of 4-
Methoxy-6-nitro-2,2-diphenylchromane (3a) into 6-Nitro-2,2-di-
phenyl-4-tosylamidechromane (7a). 4-Methoxy-6-nitro-2,2-diphe-
nylethylene (3a, 89.3 mg, 0.25 mmol), p-toluenesulfonamide (429.1
mg, 2.5 mmol), and FeCl3 (20 mol %) were dissolved in dry
dichloroethane (3.0 mL) under an atmosphere of nitrogen. After
stirring for 3 h at 60 °C, the reaction mixture was neutralized with
H2O. The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (5.0 mL × 3). The combined organic
phases were washed with brine, dried over Na2SO4, and filtered. The
filtrate was concentrated in vacuo. The resulting residue was purified
by column chromatography on silica gel (hexane/ethyl acetate = 5/1,
v/v) to afford 6-nitro-2,2-diphenyl-4-tosylamidechromane (7a, 111.6
mg, 90% yield) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.03
(dd, J = 9.1, 2.5 Hz, 1H), 7.94−7.90 (m, 1H), 7.77 (d, J = 8.2 Hz,
2H), 7.35 (d, J = 8.2 Hz, 2H), 7.34−7.23 (m, 10H), 7.09 (d, J = 9.1
Hz, 1H), 5.19 (s, 1H), 4.34 (td, J = 10.3, 5.5 Hz, 1H), 3.06 (dd, J =
13.7, 5.5 Hz, 1H), 2.50−2.41 (m, 4H); 13C{1H} NMR (126 MHz,
CDCl3): δ 159.0, 144.3, 143.2, 141.5, 141.2, 136.9, 130.0, 128.9,
128.4, 128.0, 128.0, 127.1, 125.7, 125.6, 125.1, 124.1, 123.0, 117.9,
J
DOI: 10.1021/acs.joc.9b02036
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
(11, 146.9 mg, 95% yield, cis/trans = 80/20) as a white solid. H
NMR (500 MHz, CDCl3): δ 7.45 (dd, J = 2.5, 1.0 Hz, 1H), 7.38 (s,
4H), 7.13 (dd, J = 8.7, 2.7 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 5.10
(dd, J = 12.0, 1.9 Hz, 1H), 4.71 (dd, J = 10.7, 6.0 Hz, 1H), 3.49 (s,
3H), 2.51 (ddd, J = 13.2, 6.1, 1.9 Hz, 1H), 2.07−1.97 (m, 1H);
13C{1H} NMR (126 MHz, CDCl3): δ 153.1, 138.9, 134.1, 129.0,
128.8, 127.4, 127.2, 126.0, 124.9, 118.0, 76.4, 73.3 56.1, 34.9; IR
(ATR): 2962, 1477, 1248, 1092, 814 cm−1; HRMS (ESI+) m/z calcd
for C15H11O35Cl2 ([M − OMe]+): 277.0182, found: 277.0179.
Synthesis of BW683C. (2S*,4S*)-6-Chloro-2-(4-chlorophenyl)-
4-methoxychromane (11, 74.3 mg, 0.24 mmol), triethylsilane (60 μL,
0.375 mmol), and FeCl3 (10 mol %) were dissolved in dichloroethane
(3.0 mL). After stirring at room temperature for 2 h, the reaction
mixture was quenched with H2O. The organic layer was separated,
and the aqueous layer was extracted with ethyl acetate. The combined
organic layer was washed with brine, dried over MgSO4, filtered, and
the filtrate was concentrated in vacuo. The resulting residue was
purified by column chromatography on silica gel (hexane/ethyl
acetate = 30/1, v/v) to afford 6-chloro-2-(4-chlorophenyl)chromane
(BW683C, 60.1 mg, 90% yield) as a white solid. 1H NMR (500 MHz,
CDCl3) δ 7.37−7.32 (m, 4H), 7.09−7.05 (m, 2H), 6.82 (d, J = 8.4
Hz, 1H), 5.02 (dd, J = 10.0, 2.6 Hz, 1H), 2.95 (ddd, J = 16.8, 11.0, 6.0
Hz, 1H), 2.78−2.73 (m, 1H), 2.21−2.15 (m, 1H), 2.02 (dtd, J = 13.8,
10.6, 5.2 Hz, 1H).21
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b02036.
■
S
Crystallographic data for compound cis-6a (CIF)
Crystallographic data for compound trans-6a (CIF)
Crystallographic data for compound cis-3n (CIF)
NMR spectra of new compounds, X-ray crystallographic
data of chromanes (cis-3n and 6a); characterization of
3n; computational data (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: hoshino-yujiro-hy@ynu.ac.jp (Y.H.).
*E-mail: honda-kiyoshi-rb@ynu.ac.jp (K.H.).
■
ORCID
Kenta Tanaka: 0000-0001-8253-3561
Yujiro Hoshino: 0000-0002-8373-8013
Notes
The authors declare no competing financial interest.
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