Intramolecular etherification and polyene cyclization of π-Activated Alcohols Promoted by Hot Water

Article abstract of DOI:10.1021/jo502636d

Hot water, acting as a mildly acidic catalyst, efficiently promoted intramolecular direct nucleophilic substitution reactions of unsaturated alcohols with heteroatom or carbon nucleophiles. In a mixed solvent of water and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), polyene cyclizations using allylic alcohols as initiators gave the desired cyclized products, and in neat HFIP, a tricyclization reaction gave a tetracyclic product in 51% chemical yield.

Full text of DOI:10.1021/jo502636d

Article
pubs.acs.org/joc
Intramolecular Etherification and Polyene Cyclization of π‑Activated
Alcohols Promoted by Hot Water
Feng-Zhi Zhang, Yan Tian, Guo-Xing Li, and Jin Qu*
State Key Laboratory and Institute of Elemento-organic Chemistry, Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: Hot water, acting as a mildly acidic catalyst,
efficiently promoted intramolecular direct nucleophilic sub-
stitution reactions of unsaturated alcohols with heteroatom or
carbon nucleophiles. In a mixed solvent of water and
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), polyene cyclizations
using allylic alcohols as initiators gave the desired cyclized
products, and in neat HFIP, a tricyclization reaction gave a
tetracyclic product in 51% chemical yield.
In addition to being an environmentally benign reaction
medium, water has unique chemical and physical properties
that allow it to catalyze organic reactions.4,6 In previous studies,
we showed that under refluxing conditions water can act as a
mildly acidic catalyst to promote organic reactions traditionally
catalyzed by Brønsted acid or Lewis acid catalysts.7 Recently,
we found that the SN1 hydrolysis of allylic and benzylic alcohols
occurs in hot water, and we systematically studied the effects of
various reaction parameters on the outcome of this reaction.7c
We were interested in determining whether an intramolecular
heteroatom or carbon nucleophile could react with different
kinds of π-stabilized carbocations preferentially over solvent
water. Herein, we report that efficient intramolecular ether-
ification and polyene cyclization reactions can be carried out in
water or a mixed solvent of water and 1,1,1,3,3,3-hexafluoro-2-
propanol (HFIP) under refluxing conditions.
INTRODUCTION
■
The use of direct nucleophilic substitution reactions of alcohols
to build carbon−heteroatom and carbon−carbon bonds has
obvious advantages. First, alcohols with a wide variety of
chemical structures are abundant in the natural world, the
structural motif of an alcohol can be readily incorporated into a
target molecule by means of these reactions. Second, water is
the only byproduct of the reaction. However, the poor leaving
ability of the hydroxyl group disfavors direct nucleophilic
substitution, and therefore alcohols generally have to be
transformed into the corresponding halides, carboxylates, or
sulfonates, which are better leaving groups, before reaction with
a nucleophile. Various catalytic methods employing Lewis acid
or Brønsted acid catalysts1 or transition-metal catalysts2 have
been developed to mediate the direct nucleophilic substitutions
of alcohols in organic solvents.
For SN1 substitutions of alcohols, the use of water as the
solvent generally used to be avoided because water was
expected to instantly trap the carbocation intermediate and give
back the starting material. However, by comparing the N
parameters of π-systems and the N1 parameters of water or
aqueous−alcoholic solvent mixtures, Mayr et al. predicted that
solvolytically generated carbocations could be trapped by π-
nucleophiles ([Nuc] = 1 mol/L) in aqueous solution if the N of
the corresponding π nucleophile is greater than the N1 of the
aqueous solvent.3 In 2007 and 2008, Cozzi et al. showed that
water can facilitate the departure of the hydroxyl group of an
electron-rich benzylic alcohol, and the generated carbocation
can react with carbon, sulfur, and nitrogen nucleophiles in
water.4 In addition, reactions of carbocations generated from
less-electron-rich benzylic alcohols can be carried out in 2,2,2-
trifluoroethanol, which is less nucleophilic than water.4b In
RESULTS AND DISCUSSION
■
Intramolecular Etherifications Promoted by Hot
Water. First, we tested various substrates to determine
whether intramolecular etherification would take place in
refluxing water without an additional catalyst (Table 1).8 We
found that the phenoxy group of substrate 1a readily displaced
the benzylic hydroxyl group to give 2H-chromene 2a in 86%
yield after 3 h (entry 1, Table 1).9 Methoxy-substituted
substrate 1b gave a 95% yield of 2b under the same conditions
(entry 2), and substrates bearing electron-withdrawing groups
on one or both of the phenyl rings (1c−e) gave slightly lower
yields of the desired ethers (entries 3−5). Sulfonamide was also
a suitable nucleophile: substrate 1f gave 1,2-dihydroquinoline
2f in 85% yield (entry 6). Photochromic compound 2g could
be prepared in 82% yield by reaction of substrate 1g in refluxing
water for 4 h (entry 7).10
́
2012, the research groups of Najera and Cozzi reported that
perfluoroalcohols can promote direct nucleophilic substitution
reactions of allylic alcohols and benzylic alcohols more
effectively than water can.5
Received: November 18, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/jo502636d
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a
Table 1. Synthesis of 2H-Chromenes and 1,2-
Dihydroquinoline
Table 2. Intramolecular Etherification in Water
a
a
b
Reaction conditions: 0.2 mmol of alcohol in H2O (20 mL). Isolated
yield.
A relatively stable carbocation intermediate is crucial for an
SN1 substitution in water.3 We found that intermolecular
nucleophilic substitutions of cinnamic alcohol with various
nucleophiles failed in water because the unstable carbocation
was quenched by water before it could react with other
nucleophiles. However, intramolecular substitution reactions of
diols 3a−d, which are structurally similar to cinnamic alcohol,
did take place in water to give cyclic ethers 4a−d in 70−79%
yields (entries 1−4, Table 2, note that although 3c has been
reported to cyclize to 4a in 91% yield with a boronic acid
catalyst in CH3NO2 at room temperature, the isomeric 3a only
react slowly at 80 °C and give 4a in 17% yield after 15 h1o).
Under the same reaction conditions, the etherifications of
benzylic alcohols 3e−i afforded spiro tetrahydrofurans and
tetrahydropyrans 4e−i in 79−85% yields (entries 5−9, the
control experiments showed that 3g did not react in refluxing
methanol or 2-propanol, which indicated that the reactions did
not initiate at raised temperature in a polar protic solvent and
confirmed that water played a catalytic role in the reactions; see
Supporting Information).
a
b
Reaction conditions: 0.2 mmol of alcohol in H2O (20 mL). Isolated
yield.
Table 3. Synthesis of Spiroketal Enol Ethers and Fused
Cyclopentenones in Water
a
Spiroketal enol ether derivatives have been synthesized by
intramolecular cyclization of 2-furylcarbinols.11 Here we found
that in refluxing water, 2-furylcarbinol 5a gave spiroacetal enol
ether 6a in 62% yield, together with a side product with higher
polarity than 6a. This side product was determined to be fused
cyclopentenone 7a, which was generated from 6a through a
thermal 4π electrocyclic rearrangement reaction described by
Piancatelli et al.12 A control experiment confirmed that 6a
could be quantitatively transformed into 7a in refluxing water
for 12 h. When the temperature of the cyclization reaction of 5a
was lowered to 60 °C, a higher yield 6a (77%) was obtained,
and the yield of 7a was reduced to 10% (entry 1, Table 3). A
higher yield of 7a (91%) could be achieved by refluxing 5a in
water for 24 h. 2-Furylcarbinols 5b and 5c, which bear electron-
donating or electron-withdrawing groups, respectively, on the
phenyl ring showed reactivities similar to that of 5a at 60 °C
and under refluxing conditions (entries 3−6). Reaction of
styrenyl-substituted enol ether 5d at 60 °C gave a 1:2 mixture
of spiroacetal enol ethers (E)- and (Z)-6d (entry 7), and
a
b
Reaction conditions: 0.2 mmol substrate in H2O (20 mL). Isolated
yields.
reaction of thiophene-substituted substrate 5e gave 6e in 76%
yield at 60 °C and gave the natural product chrycorin (7e) in
70% yield under refluxing conditions (entry 10).13
B
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We next turned our attention to intramolecular nucleophilic
substitution reactions with carbon nucleophiles.1o,14 We found
that intramolecular Friedel−Crafts reactions of alcohols 8a−c
proceeded in refluxing water, but the yields of the cyclized
products were only 11−23% after 24 h (data not shown).
However, substrate 8d, which bears a hydroxyl group on the
phenyl ring, gave a 65% yield of the cyclization product under
the same conditions (entry 4, Table 4). We conjectured that
reported studies on the epoxide-opening cyclizations templated
by a preformed tetrahydropyran ring (promoted by neutral
water at 70 °C). The controlled experiment performed in
polypropylene tube furnished similar endo/exo selectivity
suggesting that the glass surface was not responsible for the
observed high endo selectivity.18
Intramolecular Polyene Cyclizations of Allylic Alco-
hols Promoted by Hot Water. There has been long-standing
interest in nonenzymatic polyene cyclization reactions for the
rapid construction of polycyclic frameworks. Polyene cycliza-
tions are usually carried out in nonprotic solvents that do not
trap the carbocation intermediate. We were interested to see
whether polyene cyclization with an allylic alcohol as initiator
groups could be carried out in water.19 An initial experiment
showed that allylic alcohol 10a was unreactive in refluxing
water. We speculated that the failure of the reaction might have
been due to insufficient solvation of the hydrophobic substrate
in the aqueous solution. Therefore, we added a small amount of
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), which is a better
hydrogen-bond donor and has higher ionizing power than
water, as well as better ability to solubilize organic compounds.
At a H2O:HFIP ratio of 3:1 (v/v), a cyclization cascade
afforded an 80% yield of a dicyclized product with very high
diastereoselectivity (entry 1, Table 5). Allylic alcohols 10b and
Table 4. Intramolecular Direct Nucleophilic Substitution by
a
a Phenyl Ring
a
Table 5. Intramolecular Dicyclization Reactions
a
Reaction conditions: 0.05 mmol of substrate in refluxing H2O (50
b
c
d
mL). Isolated yield. E/Z isomer ratio >20:1. Reaction conditions:
0.2 mmol of substrate in H2O (20 mL) under a N2 atmosphere.
the poor aqueous solubility of substrates 8a−c might have
slowed their reactions,7f,15 and by reducing the concentrations
of 8a−c, we were able to obtain 80−90% yields of the desired
cyclization products within 24 h (entries 1−3).
Two reviewers raised a question about whether the reactions
were actually catalyzed by the glass surface and water was just a
polar solvent. Theoretically, the possibility that the reactions
were catalyzed by the glass surface does exist because the glass
surface is slightly acidic (the pKa of silanol is estimated to be
13.6) and some types of laboratory glassware may leach Lewis-
acidic metals into aqueous solution. The controlled experi-
ments were then performed in PFA round-bottom flasks16 and
base-washed round-bottom flasks using compounds 5a and 8b
as the substrates (see Supporting Information). The exper-
imental results showed that the reactions could proceed well in
PFA or base-washed round-bottom flasks. The chemical yields
obtained from base-washed and acetone-washed reaction flasks
were comparable, but the reactions employing PFA reaction
flasks were slightly slower than reactions employing glass
reaction flasks (the chemical yields were 85−95% of the average
yields obtained from glass reaction flasks). The possible reason
might be the less efficient heat transfer while using a PFA
reaction flask. Or it might be that the PFA surface disturbs the
self-ionization of water, which is similar to the addition of an
organic solvent to water.17 Recently, Professor Jamison
a
Reaction conditions: 0.1 mmol of substrate in refluxing 3:1
b
c
H2O:HFIP (v/v, 5 mL). Isolated yield. The diastereomeric (dr)
d
ratio was determined by 1H NMR spectroscopy. Under a N2
atmosphere.
10c, which bear one or two methoxy groups on the phenyl ring,
gave similar yields and diastereoselectivities (entries 2 and 3),
and the formation of 11c was confirmed by X-ray
crystallography (Figure 1). It is noteworthy that the current
method, unlike the method using a Lewis acid catalyst, did not
require the protection of the phenoxy group in 10d (entry 4).
Refluxing of alcohol 12 in the above-described mixed solvent
resulted in the formation of the trans,trans-tricyclized product
13 and the trans,cis-tricyclized product 14 in 26% total yield,
along with a mixture of mono- and dicyclized products in 21%
C
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Article
a
Table 6. Intramolecular Tricyclization Reactions
bc
,
yield (%)
entry
solvent
time (h)
13 + 14/13:14
mono- and dicyclized products
1
2
3
4
3:1 H2O:HFIP (v/v)
1:1 H2O:HFIP (v/v)
1:2 H2O:HFIP (v/v)
HFIP
12
10
6
26 (2.7:1)
31 (2.5:1)
32 (2.5:1)
51 (3:1)
21
22
25
3
23
a
b
c
Reaction conditions: 0.1 mmol of substrate in mixed solvent or pure HFIP (5 mL) under refluxing conditions. Isolated yield. The diastereomeric
1
ratio was determined by H NMR spectroscopy.
(HRMS) were performed on a high resolution ESI−FTICR mass
spectrometer.
Preparation of Substrates 1a−g. Substrates 1a−e,20 1f,g21 were
prepared according to previously reported procedures.
(E)-2-(1-Hydroxy-3-(4-methoxyphenyl)allyl)phenol (1b). Colorless
1
oil: H NMR (CDCl3, 400 MHz) δ 2.65 (d, J = 2.8 Hz, 1H), 3.80 (s,
3H), 5.52 (d, J = 7.2 Hz, 1H), 6.35 (dd, J = 15.8, 7.3 Hz, 1H), 6.58 (d,
J = 15.8 Hz, 1H), 6.83−6.87 (m, 3H), 6.91 (d, J = 8.1 Hz, 1H), 7.05
(d, J = 7.6 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.31−7.33 (m, 2H), 7.92
(s, 1H); 13C NMR (CDCl3, 100 MHz) δ 159.6, 155.5, 131.8, 129.3,
128.7, 128.0, 127.6, 126.7, 125.7, 120.0, 117.3, 114.0, 76.7, 55.3;
HRMS (ESI) for C16H16O3Na calcd for [M + Na]+ m/z 279.0997,
found 279.0995.
Figure 1. ORTEP diagram of 11c.
total yield (entry 1, Table 6). Increasing the volume ratio of
HFIP increased the speed of the reaction as well as the total
yield of the tricyclization products (entries 2 and 3); the yield
reached 51% in pure HFIP (entry 4). The mixture of mono-
and dicyclized products could be transformed into tricyclized
products in 72% yield by treatment with trifluoroacetic acid;
thus the combined yield of tricyclized products obtained from
the reaction in entry 4 was 68%.19b,j
(E)-2-(1-Hydroxy-3-(4-(trifluoromethyl)phenyl)allyl)phenol (1d).
1
Colorless oil: H NMR (CDCl3, 400 MHz) δ 5.25 (br s, 1H), 5.54
(d, J = 6.2 Hz, 1H), 6.54 (dd, J = 15.8, 6.2 Hz, 1H), 6.64 (d, J = 15.9
Hz, 1H), 6.86−6.91 (m, 2H), 7.05 (dd, J = 7.5, 1.2 Hz, 1H), 7.21 (t, J
= 7.2 Hz, 1H), 7.41−7.45 (m, 2H), 7.53−7.55 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ 155.2, 139.5, 131.6, 130.0, 129.6, 127.6, 126.8,
125.5 (q, J = 3.9 Hz), 125.4, 125.4, 120.3, 117.3, 75.7; HRMS (ESI)
for C16H12F3O2 calcd for [M − H]+ m/z 293.0789, found 293.0792.
(E)-4-Chloro-2-(3-(4-chlorophenyl)-1-hydroxyallyl)phenol (1e).
1
Colorless oil: H NMR (CDCl3, 400 MHz) δ 2.86 (d, J = 3.2 Hz,
CONCLUSION
■
1H), 5.48 (dd, J = 6.8, 2.7 Hz, 1H), 6.38 (dd, J = 15.8, 7.0 Hz, 1H),
6.59 (d, J = 15.8 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 2.5 Hz,
1H), 7.15 (dd, J = 8.6, 2.6 Hz, 1H), 7.27−7.32 (m, 4H), 7.83 (s, 1H);
13C NMR (CDCl3, 100 MHz) δ 154.1, 134.2, 134.0, 131.3, 129.2,
128.8, 128.8, 128.0, 127.2, 126.8, 124.8, 118.7, 75.7; HRMS (ESI) for
C15H11Cl2O2 calcd for [M − H]+ m/z 293.0136, found 293.0145.
(E)-1-(1-Hydroxy-3-phenylallyl)naphthalen-2-ol (1g). Yellow oil:
1H NMR (CDCl3, 400 MHz) δ 2.98 (d, J = 2.4 Hz, 1H), 6.34 (d, J =
In summary, intramolecular direct nucleophilic substitutions of
unsaturated alcohols could be realized in water without an
additional catalyst. In a mixed solvent of water and HFIP,
polyene cyclizations using allylic alcohols as the initiator gave
the desired cyclized products, and the use of neat HFIP
afforded tricyclization products in a high yield that was
comparable to the yields obtained by catalysis with Lewis
acids or Brønsted acids. The unique catalytic effects of water
and HFIP demonstrated here can be expected to facilitate the
extensive use of these solvents as reaction media and promoters
in organic synthesis.
5.5 Hz, 1H), 6.51 (dd, J = 15.8, 6.5 Hz, 1H), 6.67 (d, J = 15.8 Hz, 1H),
7.14 (d, J = 8.9 Hz, 1H), 7.20−7.25 (m, 2H), 7.29−7.38 (m, 3H),
7.42−7.51 (m, 2H), 7.70−7.77 (m, 3H), 9.04 (s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 154.3, 135.9, 131.8, 130.1, 128.9, 128.5, 128.0,
127.1, 126.8, 126.7, 123.0, 121.0, 119.8, 115.3, 72.8; HRMS (ESI) for
C19H16O2Na calcd for [M + Na]+ m/z 299.1048, found 299.1043.
General procedure for Intramolecular Etherifications in
Table 1. 2-Phenyl-2H-chromene (2a).22 Substrate 1a (45 mg, 0.2
mmol) was suspended in water (20 mL), and then the mixture was
heated under refluxing condition. After the reaction was completed as
determined by TLC, the reaction mixture was cooled to room
temperature and was extracted with EtOAc (3 × 30 mL). The organic
phase was dried over MgSO4, filtered, and evaporated under reduced
pressure. The crude product was purified by flash column
chromatography on silica gel (EtOAc/petroleum ether = 1:25) to
EXPERIMENTAL SECTION
■
General Methods. Unless specially indicated, all reactions were
carried out in aerial atmosphere. Water used in the reactions was from
Milli-Q Ultrapure Water Purification System or Watson’s distilled
water (pH = 5.5−6.5). Reaction temperatures reported in the tables
were the temperatures of the oil bath. Organic solvents used were
purified by standard methods. Flash column chromatographies were
performed using the indicated solvent system on Qingdao−Haiyang
silica gel (200−300 mesh). Melting points were measured using open
capillary tubes and are uncorrected. All of the compounds were
characterized by 1H and 13C NMR peaks recorded are relative to
1
give the desired product 2a (36 mg, 86% yield). Colorless oil: H
NMR (CDCl3, 400 MHz) δ 5.80 (dd, J = 9.8, 3.4 Hz, 1H), 5.91−5.92
(m, 1H), 6.53 (dd, J = 9.8, 1.7 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.86
(td, J = 7.4, 0.8 Hz, 1H), 7.01 (dd, J = 7.4, 1.6 Hz, 1H), 7.11 (td, J =
1
internal standards: TMS (δ = 0.00) for H NMR and CDCl3 (δ =
77.00) for 13C NMR spectra. High resolution mass spectral analyses
D
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7.8, 1.6 Hz, 1H), 7.32−7.47 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ
153.1, 140.8, 129.4, 128.6, 128.3, 127.0, 126.6, 124.8, 124.0, 121.3,
121.1, 116.0, 77.3.
NMR (CDCl3, 400 MHz) δ 1.67−1.86 (m, 3H), 1.96−2.04 (m, 1H),
2.08−2.16 (m, 1H), 2.26−2.33 (m, 1H), 2.43 (br s, 2H), 2.78−2.86
(m, 1H), 2.96−3.04 (m, 1H), 3.69 (t, J = 5.6 Hz, 2H), 7.22−7.24 (m,
3H), 7.34−7.37 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 147.5,
142.8, 128.2, 126.7, 125.0, 122.9, 83.3, 63.2, 40.2, 37.2, 29.4, 27.6;
HRMS (ESI) for C12H16O2Na calcd for [M + Na]+ m/z 215.1048,
found 215.1043.
2-(4-Methoxyphenyl)-2H-chromene (2b).22 Following the general
1
procedure (45 mg, 95% yield). Colorless oil: H NMR (CDCl3, 400
MHz) δ 3.80 (s, 3H), 5.78 (dd, J = 9.8, 3.4 Hz, 1H), 5.86−5.87 (m,
1H), 6.54 (dd, J = 9.8, 1.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.83−
6.90 (m, 3H), 7.01 (dd, J = 7.4, 1.3 Hz, 1H), 7.09 (td, J = 7.8, 1.5 Hz,
1H), 7.37−7.40 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 159.7,
153.1, 132.9, 129.4, 128.6, 126.5, 124.9, 124.0, 121.3, 121.0, 116.0,
114.0, 76.8, 55.3.
1-(4-Hydroxybutyl)-1,2,3,4-tetrahydronaphthalen-1-ol (3g). Pre-
1
pared using the similar procedure of 3e. Colorless viscous oil: H
NMR (CDCl3, 400 MHz) δ 1.29−1.59 (m, 5H), 1.79−1.89 (m, 5H),
1.99−2.07 (m, 2H), 2.69−2.83 (m, 2H), 3.62 (t, J = 6.4 Hz, 2H), 7.07
(d, J = 7.2 Hz, 1H), 7.15−7.20 (m, 2H), 7.51 (d, J = 6.8 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 142.4, 136.6, 128.8, 127.0, 126.2, 126.1,
72.4, 62.5, 41.9, 35.9, 32.9, 29.8, 20.2, 19.8; HRMS (ESI) for
C14H20O2Na calcd for [M + Na]+ m/z 243.1361, found 243.1356.
1-(4-Hydroxybutyl)-2,3-dihydro-1H-inden-1-ol (3h). Prepared
6-Chloro-2-phenyl-2H-chromene (2c).22 Following the general
1
procedure (39 mg, 80% yield). Colorless oil: H NMR (CDCl3, 400
MHz) δ 5.86 (dd, J = 9.8, 3.5 Hz, 1H), 5.90−5.91 (m, 1H), 6.48 (dd, J
= 9.8, 1.4 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 6.99−7.06 (m, 2H),
7.32−7.44 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 151.6, 140.2,
129.0, 128.7, 128.6, 127.0, 126.1, 126.0, 125.8, 123.1, 122.6, 117.3,
77.3.
1
using the similar procedure of 3e. Colorless viscous oil: H NMR
(CDCl3, 400 MHz) δ 1.38−1.61 (m, 4H), 1.70−1.78 (m, 1H), 1.87−
1.95 (m, 2H), 2.04−2.11 (m, 1H), 2.16 (br s, 1H), 2.25−2.32 (m,
1H), 2.77−2.85 (m, 1H), 2.95−3.02 (m, 1H), 3.62 (t, J = 6.0 Hz, 2H),
7.21−7.32 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 147.5, 142.8,
127.9, 126.4, 124.7, 122.8, 83.4, 62.0, 39.7, 32.7, 29.4, 20.2; HRMS
(ESI) for C13H17O2 calcd for [M − H]− m/z 205.1229, found
205.1236.
2-(4-(Trifluoromethyl)phenyl)-2H-chromene (2d).22 Following the
general procedure (41 mg, 74% yield). Colorless oil: 1H NMR
(CDCl3, 400 MHz) δ 5.79 (dd, J = 9.8, 3.5 Hz, 1H), 5.94−5.99 (m,
1H), 6.56 (dd, J = 9.8, 1.3 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.89 (dt,
J = 7.4, 1.0 Hz, 1H), 7.02 (dd, J = 7.4, 1.4 Hz, 1H), 7.14 (td, J = 8.0,
1.6 Hz, 1H), 7.56−7.64 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ
152.8, 144.7, 129.7, 127.1, 126.8, 125.6 (q, J = 3.5 Hz), 124.5, 123.9,
121.5, 121.1, 116.0, 76.2.
9-(3-Hydroxypropyl)-9,10-dihydroanthracen-9-ol (3i). Prepared
using the similar procedure of 3e. Light yellow solid: mp = 131−
6-Chloro-2-(4-chlorophenyl)-2H-chromene (2e).22 Following the
general procedure (42 mg, 76% yield). Colorless oil: 1H NMR
(CDCl3, 400 MHz) δ 5.82 (dd, J = 9.8, 3.5 Hz, 1H), 5.87 (dd, J = 3.5,
1.6 Hz, 1H), 6.50 (dd, J = 9.8, 1.1 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H),
6.99 (d, J = 2.5 Hz, 1H), 7.05 (dd, J = 8.6, 2.5 Hz, 1H), 7.32−7.37 (m,
4H); 13C NMR (CDCl3, 100 MHz) δ 151.3, 138.6, 134.4, 129.2,
128.9, 128.4, 126.2, 126.0, 125.4, 123.5, 122.4, 117.3, 76.4.
2-Phenyl-1-tosyl-1,2-dihydroquinoline (2f).23 Following the gen-
eral procedure (61 mg, 85% yield). White solid: mp = 124−125 °C
(lit.3 mp = 125 °C); 1H NMR (CDCl3, 400 MHz) δ 2.35 (s, 3H), 5.88
(dd, J = 9.6, 6.0 Hz, 1H), 6.02 (d, J = 6.0 Hz, 1H), 6.28 (d, J = 9.6 Hz,
1H), 6.96 (d, J = 7.2 Hz, 1H), 7.08−7.14 (m, 3H), 7.18−7.24 (m,
4H), 7.33−7.34 (m, 4H), 7.64 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 143.4, 138.3, 136.1, 132.9, 129.1, 128.6, 128.4, 128.2,
127.9, 127.6, 127.4, 127.2, 126.5, 126.4, 126.2, 125.5, 56.9, 21.5.
3-Phenyl-3H-benzo[f]chromene (2g).24 Following the general
1
132 °C; H NMR (CDCl3, 400 MHz) δ 1.38−1.45 (m, 2H), 1.76−
1.79 (m, 2H), 2.03 (br s, 1H), 2.96 (br s, 1H), 3.47 (t, J = 6.2 Hz, 2H),
3.88−4.03 (m, 2H), 7.23−7.32 (m, 6H), 7.75 (d, J = 7.6 Hz, 2H); 13C
NMR (CDCl3, 100 MHz) δ 142.8, 133.9, 127.3, 126.9, 126.5, 124.9,
74.1, 62.9, 39.9, 35.0, 27.1; HRMS (ESI) for C17H18O2Na calcd for [M
+ Na]+ m/ z 277.1204, found 277.1202.
General Procedure for Intramolecular Etherifications in
Table 2. (E)-2-Styryltetrahydrofuran (4a).1o Substrate 3a (39 mg,
0.2 mmol) was suspended in water (20 mL), and then the mixture was
heated under refluxing condition. After the reaction was completed as
determined by TLC, the reaction mixture was cooled to room
temperature and was extracted with EtOAc (3 × 30 mL). The organic
phase was dried over MgSO4, filtered, and evaporated under reduced
pressure. The crude product was purified by flash column
chromatography on silica gel (EtOAc/petroleum ether = 1:50) to
1
give the desired product 4a (27 mg, 75% yield). Colorless oil: H
1
NMR (CDCl3, 400 MHz) δ 1.69−1.76 (m, 1H), 1.90−2.01 (m, 2H),
2.08−2.17 (m, 1H), 3.81−3.87 (m, 1H), 3.94−4.00 (m, 1H), 4.45−
4.50 (m, 1H), 6.21 (dd, J = 15.8, 6.6 Hz, 1H), 6.58 (d, J = 15.8 Hz,
1H), 7.20−7.24 (m, 1H), 7.28−7.32 (m, 2H), 7.37−7.39 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ 136.8, 130.5, 130.4, 128.5, 127.4, 126.4,
79.6, 68.1, 32.4, 25.9.
procedure (42 mg, 82% yield). Colorless oil: H NMR (CDCl3, 400
MHz) δ 5.93 (dd, J = 9.8, 3.7 Hz, 1H), 5.97−5.98 (m, 1H), 7.07 (d, J
= 8.8 Hz, 1H), 7.23 (s, 1H), 7.32−7.38 (m, 4H), 7.46−7.51 (m, 3H),
7.64 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 8.5 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ 151.2, 140.5, 129.8, 129.7,
129.3, 128.6, 128.5, 128.4, 127.1, 126.6, 123.6, 123.4, 121.2, 120.2,
118.0, 114.1, 76.9.
(E)-2-Styryltetrahydro-2H-pyran (4b).1o Following the general
Preparation of Substrates 3a−i. Substrates 3a−d1o were prepared
according to previously reported procedures.
1
procedure (26 mg, 70% yield). Colorless oil: H NMR (CDCl3, 400
MHz) δ 1.21−1.81 (m, 6H), 3.47 (t, J = 14.0 Hz, 1H), 3.87−4.01 (m,
2H), 6.14 (dd, J = 21.2, 7.6 Hz, 1H), 6.51 (d, J = 21.2 Hz, 1H), 7.14−
7.31 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 137.0, 130.8, 129.7,
128.4, 127.4, 126.4, 78.0, 68.4, 32.2, 25.8, 23.4.
1-(3-Hydroxypropyl)-1,2,3,4-tetrahydronaphthalen-1-ol (3e). A
solution of i-PrMgCl (2.75 mL, 2.0 M in THF, 5.5 mmol) was
added to a THF (10 mL) solution of 3-iodopropan-1-ol (930 mg, 5.5
mmol) at −78 °C. After 5 min, a hexane solution of n-BuLi (4.38 mL,
2.4 M in hexanes, 10.5 mmol) was added, and then to it was added 1-
tetralone (730 mg, 5.0 mmol). After 30 min, a saturated aqueous
NH4Cl (10 mL) solution was added, and the mixture was extracted
with EtOAc (3 × 50 mL). The combined organic extracts were dried
over Na2SO4, filtered, and evaporated under reduced pressure. The
residue was purified by silica gel column chromatography (EtOAc/
petroleum ether = 1:1) to afford the desired product 3e (823 mg, 80%
Spiro[furan-2(3H),1′(2′H)-naphthalene] (4e).25 Following the
general procedure (31 mg, 83% yield). Colorless oil: 1H NMR
(CDCl3, 400 MHz) δ 1.72−1.83 (m, 1H), 1.85−1.88 (m, 2H), 1.93−
2.15 (m, 5H), 2.73−2.82 (m, 2H), 4.00−4.05 (m, 1H), 4.11−4.16 (m,
1H), 7.04 (d, J = 7.5 Hz, 1H), 7.11−7.20 (m, 2H), 7.40 (d, J = 7.6 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ 142.6, 136.8, 128.4, 126.7,
126.4, 126.1, 82.8, 68.4, 40.4, 35.9, 29.3, 26.6, 21.1.
Spiro[tetrahydrofuran-2,1′-indan] (4f).26 Following the general
1
1
yield). White solid: mp = 84−85 °C; H NMR (CDCl3, 400 MHz) δ
procedure (27 mg, 79% yield). Colorless oil: H NMR (CDCl3, 400
1.59−2.14 (m, 10H), 2.70−2.88 (m, 2H), 3.62−3.75 (m, 2H), 7.06−
7.24 (m, 3H), 7.56 (d, J = 9.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
δ 142.6, 136.5, 128.9, 127.1, 126.3, 126.1, 72.3, 63.3, 39.1, 35.9, 29.7,
27.3, 19.8; HRMS (ESI) for C13H17O2 calcd for [M − H]− m/z
205.1229, found 205.1227.
MHz) δ 2.08−2.25 (m, 6H), 2.77−2.84 (m, 1H), 2.97−3.04 (m, 1H),
3.95−4.02 (m, 2H), 7.22−7.29 (m, 4H); 13C NMR (CDCl3, 100
MHz) δ 146.6, 143.2, 127.9, 126.6, 124.7, 122.7, 91.8, 67.9, 39.6, 37.1,
29.7, 26.6.
Spiro[1H-2-benzopyran-1,1′-cyclohexane] (4g).27 Following the
general procedure (33 mg, 81% yield). Colorless oil: 1H NMR
(CDCl3, 400 MHz) δ 1.56−1.94 (m, 9H), 2.34−2.40 (m, 1H), 2.70−
1-(3-Hydroxypropyl)-2,3-dihydro-1H-inden-1-ol (3f). Prepared
1
using the similar procedure of 3e. White solid: mp = 69−70 °C; H
E
DOI: 10.1021/jo502636d
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The Journal of Organic Chemistry
Article
2.86 (m, 2H), 3.80−3.84 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H), 7.13 (td, J
= 7.6, 1.6 Hz, 1H), 7.22 (t, J = 7.2 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H);
13C NMR (CDCl3, 100 MHz) δ 142.7, 136.6, 128.3, 127.0, 126.7,
104.4, 98.8, 75.7, 67.4, 55.4, 42.0, 27.3, 26.8; HRMS (ESI) for
C16H18O4Na calcd for [M + Na]+ m/z 297.1103, found 297.1108.
2-(4-(Trifluoromethyl)benzylidene)-1,6-dioxaspiro[4.4]non-3-ene
(6c).31 Following general procedure (46 mg, 82% yield). Yellow oil:
1H NMR (CDCl3, 400 MHz) δ 2.01−2.16 (m, 2H), 2.20−2.40 (m,
2H), 3.97−4.32 (m, 2H), 5.42 (s, 1H), 6.12 (d, J = 5.5 Hz, 1H), 6.35
(d, J = 5.6 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H);
13C NMR (CDCl3, 100 MHz) δ 157.7, 139.8, 132.5, 129.6, 128.0,
127.2, 125.8, 125.1 (q, J = 3.4 Hz), 121.4, 99.9, 69.4, 35.9, 24.6.
5-(4-(Trifluoromethyl)phenyl)-3,4,7,7a-tetrahydrocyclopenta[b]-
pyran-6(2H)-one (7c).31 Following general procedure (49 mg, 87%
yield). Pale yellow oil: 1H NMR (CDCl3, 400 MHz) δ 1.81−1.89 (m,
2H), 2.50−2.64 (m, 2H), 2.90 (dd, J = 18.4, 6.4 Hz, 1H), 3.03−3.07
(m, 1H), 3.79 (td, J = 11.6, 3.2 Hz, 1H), 4.09−4.12 (m, 1H), 4.62 (dd,
J = 6.4, 3.2 Hz, 1H), 7.43 (d, J = 7.6 Hz, 2H), 7.68 (d, J = 7.6 Hz, 2H);
13C NMR (CDCl3, 100 MHz) δ 202.2, 170.2, 137.1, 133.9, 130.3,
126.1, 73.8, 61.7, 36.0, 29.8, 28.9, 25.8, 20.0.
Spiro[cyclohexane-1,1′(3′H)-isobenzofuran] (4h).28 Following the
general procedure (31 mg, 81% yield). Colorless oil: 1H NMR
(CDCl3, 400 MHz) δ 1.60−1.86 (m, 6H), 2.24−2.28 (m, 2H), 2.78−
2.85 (m, 1H), 2.99−3.03 (m, 1H), 3.69−3.89 (m, 2H), 7.22−7.39 (m,
4H); 13C NMR (CDCl3, 100 MHz) δ 147.6, 142.7, 128.1, 126.6,
124.7, 123.2, 85.0, 63.6, 34.6, 34.1, 29.6, 25.8, 21.0.
4′,5′-Dihydro-3′H,10H-spiro[anthracene-9,2′-furan] (4i). Follow-
ing the general procedure (40 mg, 85% yield). White solid: mp = 58−
59 °C; 1H NMR (CDCl3, 400 MHz) δ 1.97−2.10 (m, 4H), 3.95 (dd, J
= 17.8, 15.8 Hz, 2H), 4.45 (t, J = 6.4 Hz, 2H), 7.19−7.23 (m, 2H),
7.27−7.31 (m, 4H), 7.57−7.61 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ 144.2, 134.2, 127.1, 126.4, 126.3, 123.3, 83.8, 70.8, 39.9, 35.9,
25.6; HRMS (ESI) for C17H17O calcd for [M + H]+ m/z 237.1279,
found 237.1270.
130.0, 129.4, 125.3 (q, J = 3.4 Hz), 75.6, 67.4, 42.0, 26.8, 26.6.
2-(3-Phenylallylidene)-1,6-dioxaspiro[4.4]non-3-ene (6d, E/Z =
1:2).32 Following general procedure (34 mg, 71% yield). Yellow oil: 1H
NMR (CDCl3, 400 MHz) δ 2.07−2.34 (m, 4H), 3.98−4.01 (m, 1H),
4.17−4.25 (m, 1H), 5.38 (d, J = 11.2 Hz, 0.66H, Z-isomer), 5.79 (d, J
= 11.6 Hz, 0.33H, E-isomer), 6.03 (s, 0.63H, Z-isomer), 6.12 (s,
0.30H, E-isomer), 6.27−6.30 (m, 0.60H, Z-isomer), 6.38−6.46 (m,
1H), 6.79−6.94 (m, 0.66H), 7.12−7.42 (m, 6H).
Preparation of Substrates 5a−e. Substrates 5a−e were prepared
according to previously reported procedures.11d
3-(5-((2,4-Dimethoxyphenyl)(hydroxy)methyl)furan-2-yl)propan-
1-ol (5b). Yellow solid: mp = 83−86 °C; 1H NMR (CDCl3, 400 MHz)
δ 1.42 (br s, 1H), 1.86−1.93 (m, 2H), 2.72 (t, J = 7.2 Hz, 2H), 2.97
(br s, 1H), 3.68 (dd, J = 10.8, 6.0 Hz, 2H), 3.81 (s, 3H), 3.82 (s, 3H),
5.92−5.94 (m, 3H), 6.47−6.50 (m, 2H), 7.21 (d, J = 8.8 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 160.6, 157.9, 155.2, 154.3, 128.7, 121.9,
107.5, 105.6, 104.2, 98.8, 66.2, 62.1, 55.5, 55.4, 31.0, 24.4; HRMS
(ESI) for C16H20O5Na calcd for [M + Na]+ m/ z 315.1208, found
315.1211.
(E)-5-Styryl-3,4,7,7a-tetrahydrocyclopenta[b]pyran-6(2H)-one
(7d).30 Following general procedure (41 mg, 86% yield). Colorless oil:
1H NMR (CDCl3, 400 MHz) δ 1.86−1.97 (m, 2H), 2.42 (dd, J = 18.4,
2.8 Hz, 1H), 2.50 (td, J = 13.2, 6.4 Hz, 1H), 2.80 (dd, J = 18.4, 6.4 Hz,
1H), 3.16 (dt, J = 14.4, 2.0 Hz, 1H), 3.74 (td, J = 11.6, 2.8 Hz, 1H),
4.08 (dt, J = 11.6, 2.0 Hz, 1H), 4.44 (d, J = 5.6 Hz, 1H), 6.74 (d, J =
16.4 Hz, 1H), 7.26−7.28 (m, 1H), 7.32−7.36 (m, 2H), 7.48−7.50 (m,
2H), 7.76 (d, J = 16.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 203.2,
168.1, 137.3, 134.5, 133.1, 128.6, 128.1, 126.6, 116.1, 75.3, 67.2, 42.4,
26.8, 25.9.
General Procedure for the Synthesis of Spiroketal Enol
Ethers and Cyclopentenones in Table 3. 2-Benzylidene-1,6-
dioxaspiro[4.4]non-3-ene (6a).29 Substrate 5a (47 mg, 0.2 mmol)
was suspended in water (20 mL), and then the mixture was stirred at
60 °C, After the reaction was completed as determined by TLC, the
reaction mixture was cooled to room temperature and was extracted
with EtOAc (3 × 30 mL). The organic phase was dried over MgSO4,
filtered, and evaporated under reduced pressure. The crude product
was purified by flash column chromatography on silica gel (EtOAc/
petroleum ether = 1:7) to give products 6a (33 mg, 77% yield) and 7a
2-(Thiophen-2-ylmethylene)-1,6-dioxaspiro[4.4]non-3-ene (6e).29
1
Following general procedure (33 mg, 76% yield). Colorless oil: H
NMR (CDCl3, 400 MHz) δ 2.04−2.17 (m, 2H), 2.20−2.27 (m, 1H),
2.33−2.46 (m, 1H), 4.01−4.06 (m, 1H), 4.28 (td, J = 8.0, 3.2 Hz, 1H),
5.76 (s, 1H), 6.07 (d, J = 5.6 Hz, 1H), 6.35 (d, J = 5.6 Hz, 1H), 6.95−
6.98 (m, 1H), 7.05 (d, J = 3.6 Hz, 1H), 7.17 (d, J = 5.2 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 154.3, 139.2, 131.3, 128.5, 126.7, 124.9,
124.2, 120.7, 95.3, 69.0, 35.9, 24.4.
1
(5 mg, 10% yield). Compound 6a; Colorless oil: H NMR (CDCl3,
400 MHz) δ 1.95−2.06 (m, 2H), 2.12−2.32 (m, 2H), 3.93 (q, J = 7.6
Hz, 1H), 4.15−4.20 (m, 1H), 5.32 (s, 1H), 5.95 (d, J = 5.6 Hz, 1H),
6.26 (d, J = 5.6 Hz, 1H), 7.03−7.21 (m, 3H), 7.54 (d, J = 8.0 Hz, 2H);
13C NMR (CDCl3, 100 MHz) δ 155.9, 136.1, 130.9, 129.8, 128.2,
5-(Thiophen-2-yl)-3,4,7,7a-tetrahydrocyclopenta[b]pyran-6(2H)-
one (chrycorin) (7e).30 Following general procedure (31 mg, 70%
1
yield). Colorless oil: H NMR (CDCl3, 400 MHz) δ 1.87−1.94 (m,
128.1, 125.6, 121.0, 101.2, 69.0, 35.9, 24.5.
2H), 2.48 (dd, J = 18.4, 2.8 Hz, 1H), 2.58−2.66 (m, 1H), 2.88 (dd, J =
18.4, 6.4 Hz, 1H), 3.43−3.47 (m, 1H), 3.75−3.82 (m, 1H), 4.08−4.11
(m, 1H), 4.52−4.53 (m, 1H), 7.10−7.13 (m, 1H), 7.41 (d, J = 3.2 Hz,
1H), 7.50 (d, J = 3.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 201.6,
166.4, 131.2, 131.1, 127.9, 127.0, 126.6, 75.5, 67.3, 41.8, 26.8, 26.4.
Preparation of Substrates 8a−d. Substrates 8a−d were prepared
according to previously reported procedures.1o
5-Phenyl-3,4,7,7a-tetrahydrocyclopenta[b]pyran-6(2H)-one
(7a).30 Following general procedure (39 mg, 91% yield). Colorless oil:
1H NMR (CDCl3, 400 MHz) δ 1.81−1.88 (m, 2H), 2.49 (dd, J = 18.4,
2.4 Hz, 1H), 2.53−2.59 (m, 1H), 2.87 (dd, J = 18.4, 6.4 Hz, 1H),
3.06−3.10 (m, 1H), 3.74−3.81 (m, 1H), 4.06−4.11 (m, 1H), 4.53−
4.55 (m, 1H), 7.26−7.44 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ
202.7, 168.7, 138.2, 130.2, 129.0, 128.3, 128.1, 75.6, 57.4, 42.0, 26.8,
26.5.
(E)-5-(4-Methoxyphenoxy)-1-phenylpent-2-en-1-ol (8b). Color-
1
less oil: H NMR (CDCl3, 400 MHz) δ 2.10 (s, 1H), 2.51 (q, J =
2-(2,4-Dimethoxybenzylidene)-1,6-dioxaspiro[4.4]non-3-ene
5.9 Hz, 2H), 3.75 (s, 3H), 3.95 (t, J = 6.5 Hz, 2H), 5.17 (br s, 1H),
5.76−5.88 (m, 2H), 6.81 (s, 4H), 7.24−7.36 (m, 5H); 13C NMR
(CDCl3, 100 MHz) δ 153.8, 152.9, 143.0, 134.7, 128.5, 127.8, 127.6,
126.2, 115.5, 114.6, 74.9, 67.8, 55.7, 32.2; HRMS (ESI) for
C18H20NaO3 calcd for [M + Na]+ m/z 307.1310, found 307.1301.
(E)-5-(3,5-Dimethoxyphenoxy)-1-phenylpent-2-en-1-ol (8c). Col-
orless oil: 1H NMR (CDCl3, 400 MHz) δ 1.97 (br s, 1H), 2.54 (q, J =
6.2 Hz, 2H), 3.76 (s, 6H), 3.97 (t, J = 6.6 Hz, 2H), 5.20 (d, J = 4.9 Hz,
1H), 5.78−5.90 (m, 2H), 6.07−6.08 (m, 3H), 7.26−7.30 (m, 1H),
7.33−7.39 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 161.5, 160.7,
142.9, 134.8, 128.5, 127.7, 127.6, 126.2, 93.4, 93.0, 75.0, 67.1, 55.3,
32.1; HRMS (ESI) for C19H23O4 calcd for [M + H]− m/z 315.1596,
found 315.1591.
1
(6b). Following general procedure (43 mg, 79% yield). Yellow oil: H
NMR (CDCl3, 400 MHz) δ 2.04−2.08 (m, 2H), 2.20−2.29 (m, 2H),
3.82 (s, 6H), 3.99−4.04 (m, 1H), 4.22−4.26 (m, 1H), 5.76 (s, 1H),
5.96 (s, 1H), 6.36−6.42 (m, 2H), 6.51 (d, J = 8.4 Hz, 1H), 8.03 (d, J =
8.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 158.8, 157.0, 154.7,
130.2, 129.8, 129.2, 120.8, 118.0, 104.5, 98.1, 94.1, 68.9, 55.5, 55.3,
36.0, 24.6; HRMS (ESI) for C16H19O4 calcd for [M + H]+ m/z
275.1283, found 275.1280.
5-(2,4-Dimethoxyphenyl)-3,4,7,7a-tetrahydrocyclopenta[b]-
pyran-6(2H)-one (7b). Following general procedure (45 mg, 82%
1
yield). Colorless oil: H NMR (CDCl3, 400 MHz) δ 1.75−1.89 (m,
2H), 2.36−2.49 (m, 2H), 2.70−2.88 (m, 2H), 3.72−3.76 (m, 4H),
3.82 (s, 3H), 4.08 (d, J = 11.4 Hz, 1H), 4.54 (d, J = 3.0 Hz, 1H), 6.50
(s, 1H), 6.55 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 203.1, 170.0, 161.1, 157.9, 135.1, 131.6, 111.8,
(E)-4-((5-Hydroxy-5-phenylpent-3-en-1-yl)oxy)phenol (8d). White
1
solid: mp = 100−102 °C; H NMR (CDCl3, 400 MHz) δ 1.99 (br s,
1H), 2.52 (q, J = 6.3 Hz, 2H), 3.94 (t, J = 6.6 Hz, 2H), 4.84 (br s, 1H),
F
DOI: 10.1021/jo502636d
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The Journal of Organic Chemistry
Article
5.21 (d, J = 5.6 Hz, 1H), 5.78−5.90 (m, 2H), 6.73−6.78 (m, 4H),
7.28−7.39 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 152.9, 149.6,
142.9, 134.6, 128.5, 128.0, 127.7, 126.2, 116.0, 115.7, 75.0, 67.8, 32.2;
HRMS (ESI) for C17H17O3 calcd for [M − H] − m/z 269.1178, found
269.1188.
2.30 (m, 3H), 2.56 (t, J = 7.3 Hz, 2H), 3.76 (s, 3H), 5.13 (t, J = 6.8
Hz, 1H), 5.57−5.64 (m, 1H), 6.07 (d, J = 15.4 Hz, 1H), 6.80 (d, J =
8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 7.23−7.38 (m, 10H); 13C NMR
(CDCl3, 100 MHz) δ 157.6, 146.4, 135.8, 135.4, 134.4, 131.0, 129.3,
128.5, 128.0, 127.0, 126.9, 126.5, 124.0, 113.6, 79.0, 55.2, 39.1, 35.1,
31.7, 30.1, 27.3, 15.8; HRMS (ESI) for C30H34NaO2 calcd for [M +
Na]+ m/z 449.2457, found 449.2451.
4-((3E,8E)-10-Hydroxy-4-methyl-10,10-diphenyldeca-3,8-dien-1-
yl)phenol (10d). Colorless oil: 1H NMR (CDCl3, 400 MHz) δ 1.41−
1.49 (m, 5H), 1.93−2.02 (m, 4H), 2.24 (q, J = 7.2 Hz, 2H), 2.54 (t, J =
7.6 Hz, 2H), 5.09 (t, J = 6.8 Hz, 1H), 5.54−5.61 (m, 1H), 6.04 (d, J =
15.4 Hz, 1H), 6.68 (d, J = 7.6 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 7.22−
7.37 (m, 10H); 13C NMR (CDCl3, 100 MHz) δ 153.5, 146.3, 135.7,
135.4, 134.4, 131.1, 129.5, 128.0, 127.1, 126.9, 124.0, 115.0, 79.1, 39.1,
35.0, 31.6, 29.9, 27.3, 15.8; HRMS (ESI) for C29H32NaO2 calcd for [M
+ Na]+ m/z 435.2300, found 435.2299.
General Procedure for the Intramolecular Friedel−Crafts
Reactions in Table 4. (E)-4-Styrylchroman (9a).1o Substrate 8a (13
mg, 0.05 mmol) was suspended in water (50 mL) and then the
mixture was heated under refluxing condition. After the reaction was
completed for 24 h, the reaction mixture was cooled to room
temperature and was extracted with EtOAc (3 × 75 mL). The organic
phase was dried over MgSO4, filtered and evaporated under reduced
pressure. The crude product was purified by flash column
chromatography on silica gel (EtOAc/petroleum ether = 1:20) to
1
give the desired product 9a (10 mg, 80% yield). Colorless oil: H
NMR (CDCl3, 400 MHz) δ 1.94−2.02 (m, 1H), 2.12−2.20 (m, 1H),
3.68 (q, J = 7.2 Hz, 1H), 4.16−4.21 (m, 1H), 4.24−4.29 (m, 1H), 6.24
(dd, J = 15.6, 8.0 Hz, 1H), 6.44 (d, J = 15.6 Hz, 1H), 6.83−6.87 (m,
2H), 7.11−7.23 (m, 3H), 7.28−7.37 (m, 4H); 13C NMR (CDCl3, 100
MHz) δ 154.5, 137.0, 133.1, 131.6, 130.1, 128.5, 127.9, 127.3, 126.2,
123.7, 120.2, 116.8, 64.0, 38.5, 29.0.
(2E,7E,11E)-14-(3,4-Dimethoxyphenyl)-7,11-dimethyl-1,1-diphe-
1
nyltetradeca-2,7,11-trien-1-ol (12). Colorless oil: H NMR (CDCl3,
400 MHz) δ 1.48−1.57 (m, 8H), 1.96−2.11 (m, 8H), 2.25−2.32 (m,
3H), 2.56−2.60 (m, 2H), 3.84 (s, 3H), 3.87 (s, 3H), 5.08 (t, J = 6.6
Hz, 1H), 5.17 (t, J = 6.7 Hz, 1H), 5.59−5.66 (m, 1H), 6.09 (d, J = 15.4
Hz, 1H), 6.71−6.78 (m, 3H), 7.22−7.38 (m, 10H); 13C NMR
(CDCl3, 100 MHz) δ 148.6, 147.0, 146.4, 135.8, 135.7, 135.0, 134.7,
130.9, 128.0, 127.0, 126.8, 124.4, 123.6, 120.2, 111.8, 111.1, 79.0, 55.9,
55.7, 39.7, 39.1, 35.6, 31.7, 30.1, 27.4, 26.6, 16.0, 15.8; HRMS (ESI)
for C36H44O3Na calcd for [M + Na]+ m/z 547.3188, found 547.3184.
General Procedure for the Polyene Cyclization Reactions in
Table 5. (1S,4aS,10aS)-1-(2,2-Diphenylvinyl)-6,7-dimethoxy-4a-
methyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene (11b). Sub-
strate 10b (44 mg, 0.1 mmol) was suspended in the mixed solution
of water and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) (5 mL,
VH2O:VHFIP = 3:1), and then the mixture was stirred in a 95 °C oil
bath. After the reaction was completed as determined by TLC, the
reaction mixture was cooled to room temperature and was extracted
with EtOAc (3 × 30 mL). The organic phase was dried over MgSO4
and then concentrated under vacuum. The crude product was purified
by flash column chromatography on silica gel (EtOAc/petroleum ether
= 1:6) to give the desired product 11b (33 mg, 78% yield). The dr
ratio was determined from the 1H NMR spectrum of the crude
(E)-6-Methoxy-4-styrylchroman (9b). Following general procedure
1
(12 mg, 90% yield). Colorless oil: H NMR (CDCl3, 400 MHz) δ
1.92−2.00 (m, 1H), 2.12−2.19 (m, 1H), 3.66 (q, J = 7.1 Hz, 1H), 3.71
(s, 3H), 4.12−4.17 (m, 1H), 4.20−4.26 (m, 1H), 6.24 (dd, J = 15.7,
8.1 Hz, 1H), 6.46 (d, J = 15.8 Hz, 1H), 6.68−6.79 (m, 3H), 7.21−7.24
(m, 1H), 7.29−7.38 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 153.2,
148.6, 137.0, 133.0, 131.6, 128.5, 127.4, 126.2, 124.3, 117.4, 114.6,
114.0, 64.0, 55.7, 38.9, 29.2; HRMS (ESI) for C18H18NaO2 calcd for
[M + Na]+ m/z 289.1204, found 289.1193.
(E)-5,7-Dimethoxy-4-styrylchroman (9c). Following general pro-
1
cedure (12 mg, 85% yield). White solid: mp = 49−50 °C; H NMR
(CDCl , 400 MHz) δ 1.87−1.91 (m, 1H), 2.08−2.17 (m, 1H), 3.73
3
(s, 3H), 3.76−3.78 (m, 4H), 4.07−4.13 (m, 1H), 4.19−4.23 (m, 1H),
6.06−6.08 (m, 2H), 6.15 (d, J = 16.0 Hz, 1H), 6.32 (dd, J = 15.8, 6.0
Hz, 1H), 7.15−7.19 (m, 1H), 7.25−7.33 (m, 4H); 13C NMR (CDCl3,
100 MHz) δ 159.8, 158.9, 155.8, 137.6, 133.2, 130.4, 128.4, 126.9,
126.1, 104.7, 93.2, 91.4, 62.2, 55.5, 55.2, 31.2, 27.3; HRMS (ESI) for
C19H20NaO3 calcd for [M + Na]+ m/z 319.1310, found 319.1302.
(E)-4-Styrylchroman-6-ol (9d). Substrate 8d (54 mg, 0.2 mmol)
was suspended in water (20 mL), and then the mixture was heated
under refluxing condition. After the reaction was completed, the
reaction mixture was cooled to room temperature and was extracted
with EtOAc (3 × 30 mL). The organic phase was dried over MgSO4,
filtered, and evaporated under reduced pressure. The crude product
was purified by flash column chromatography on silica gel (EtOAc/
petroleum ether = 1:7) to give the desired product 9d (33 mg, 65%
yield). White solid: mp = 79−82 °C (decomp); 1H NMR (CDCl3, 400
MHz) δ 1.91−2.17 (m, 2H), 3.59−3.65 (m, 1H), 4.10−4.26 (m, 2H),
4.55 (br s, 1H), 6.20 (dd, J = 15.8, 8.2 Hz, 1H), 6.46 (d, J = 15.8 Hz,
1H), 6.62−6.64 (m, 2H), 6.72 (d, J = 8.4 Hz, 1H), 7.21−7.25 (m,
1H), 7.29−7.38 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 148.9,
148.5, 136.9, 132.8, 131.7, 128.6, 127.4, 126.2, 124.6, 117.5, 116.0,
115.2, 64.2, 38.8, 29.1; HRMS (ESI) for C17H15O2 calcd for [M − H]−
m/z 251.1072, found 251.1075.
1
product. Colorless oil: H NMR (CDCl3, 400 MHz) δ 0.93 (s, 3H),
1.23−1.27 (m, 1H), 1.38−1.45 (m, 3H), 1.52−1.58 (m, 1H), 1.65−
1.74 (m, 2H), 1.94−1.99 (m, 1H), 2.14−2.32 (m, 2H), 2.68−2.81 (m,
2H), 3.82 (s, 3H), 3.83 (s, 3H), 5.86 (d, J = 10.0 Hz, 1H), 6.53 (s,
1H), 6.76 (s, 1H), 7.16−7.40 (m, 10H); 13C NMR (CDCl3, 100
MHz) δ 146.8, 146.8, 142.6, 141.0, 140.5, 134.0, 134.9, 129.7, 128.1,
128.0, 127.0, 126.8, 126.7, 111.6, 108.1, 56.0, 55.7, 47.4, 38.2, 38.0,
36.7, 33.5, 29.4, 23.2, 22.6, 21.5; HRMS (ESI) for C31H35O2 calcd for
[M + H]+ m/z 439.2637, found 439.2635.
1-(2,2-Diphenylvinyl)-6-methoxy-4a-methyl-1,2,3,4,4a,9,10,10a-
octahydrophenanthrene (11c). Following general procedure (31 mg,
1
76% yield). The single crystal of 11c was grown from EtOAc. H
NMR (CDCl3, 400 MHz) δ 0.99 (s, 3H), 1.24−1.35 (m, 1H), 1.43−
1.53 (m, 3H), 1.55−1.63 (m, 1H), 1.71−1.79 (m, 2H), 2.01−2.04 (m,
1H), 2.22−2.37 (m, 2H), 2.83−2.86 (m, 2H), 3.82 (s, 3H), 5.92 (d, J
= 10.1 Hz, 1H), 6.73 (dd, J = 8.3, 2.4 Hz, 1H), 6.87 (d, J = 2.4 Hz,
1H), 7.03 (d, J = 8.4 Hz, 1H), 7.16−7.45 (m, 10H); 13C NMR
(CDCl3, 100 MHz) δ 157.5, 149.2, 142.6, 141.0, 140.5, 134.9, 129.9,
129.7, 128.2, 128.1, 127.6, 127.0, 126.8, 110.8, 110.4, 55.2, 47.1, 38.4,
37.7, 37.2, 33.5, 28.8, 23.2, 22.6, 21.5; HRMS (ESI) for C30H33O calcd
for [M + H]+ m/z 409.2531, found 409.2524.
Preparation of Substrates 10a−d and 12. Substrates 10a−d,1o
121o were prepared according to previously reported procedures.
(2E,7E)-10-(3,4-Dimethoxyphenyl)-7-methyl-1,1-diphenyldeca-
1
2,7-dien-1-ol (10b). Colorless oil: H NMR (CDCl3, 400 MHz) δ
1.44−1.59 (m, 5H), 1.98 (t, J = 7.4 Hz, 2H), 2.06 (q, J = 7.4 Hz, 2H),
2.25−2.33 (m, 3H), 2.58 (t, J = 7.3 Hz, 2H), 3.83 (s, 3H), 3.85 (s,
3H), 5.14 (t, J = 7.4 Hz, 1H), 5.57−5.64 (m, 1H), 6.07 (d, J = 15.4 Hz,
1H), 6.67−6.81 (m, 3H), 7.23−7.37 (m, 10H); 13C NMR (CDCl3,
100 MHz) δ 148.6, 147.0, 146.4, 135.8, 135.4, 135.0, 130.9, 128.0,
127.0, 126.8, 123.9, 120.2, 111.7, 111.0, 79.0, 55.8, 55.7, 39.1, 35.6,
31.7, 30.0, 27.4, 15.9; HRMS (ESI) for C31H36NaO3 calcd for [M +
Na]+ m/z 479.2562, found 479.2558.
8-(2,2-Diphenylvinyl)-4b-methyl-4b,5,6,7,8,8a,9,10-octahydro-
phenanthren-3-ol (11d). Following general procedure (32 mg, 82%
1
yield). Colorless oil: H NMR (CDCl3, 400 MHz) δ 0.90 (s, 3H),
1.21−1.27 (m, 1H), 1.33−1.43 (m, 3H), 1.45−1.55 (m, 1H), 1.63−
1.73 (m, 2H), 1.94−1.96 (m, 1H), 2.05−2.10 (m, 1H), 2.27−2.45 (m,
1H), 2.75−2.77 (m, 2H), 4.74−4.80 (m, 1H), 5.85 (d, J = 10.0 Hz,
1H), 6.54−6.57 (m, 1H), 6.72 (d, J = 1.4 Hz, 1H), 6.90 (d, J = 8.2 Hz,
1H), 7.18−7.37 (m, 10H); 13C NMR (CDCl3, 100 MHz) δ 153.2,
149.4, 142.6, 141.0, 140.4, 134.9, 130.1, 129.7, 128.2, 128.1, 127.6,
127.0, 126.8, 126.8, 112.7, 111.3, 47.0, 38.3, 37.6, 37.0, 33.4, 28.8, 23.1,
(2E,7E)-10-(4-Methoxyphenyl)-7-methyl-1,1-diphenyldeca-2,7-
1
dien-1-ol (10c). Colorless oil: H NMR (CDCl3, 400 MHz) δ 1.44−
1.52 (m, 5H), 1.97 (t, J = 7.4 Hz, 2H), 2.05 (q, J = 7.3 Hz, 2H), 2.23−
G
DOI: 10.1021/jo502636d
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
22.6, 21.4; HRMS (ESI) for C29H31O calcd for [M + H]+ m/z
395.2375, found 395.2378.
6948. (f) Kumar, R.; Van der Eycken, E. V. Chem. Soc. Rev. 2013, 42,
1121−1146. For recent representative examples, see: (g) Shirakawa,
General Procedure for the Tricyclization Reactions in Table
6. Allylic alcohol 12 (52 mg, 0.1 mmol) was suspended in 1,1,1,3,3,3-
hexafluoro-2-propanol (HFIP) (5 mL), and then the mixture was
stirred under refluxing condition. After the reaction was completed as
determined by TLC, the solvent was removed under reduced pressure,
and the residue was purified by flash chromatography on silica gel
(CH2Cl2/petroleum ether = 2:5) to give the crude tetracyclic products
13 and 14 and mono- and dicyclized byproducts. The crude tetracyclic
products were further purified by preparative HPLC on ODS-C18
(flow: 10 mL/min; 26.08 min (14), 28.31 min (13); 99% CH3CN, 1%
H2O, 25 °C).
(1S,4aS,4bR,10bR,12aS)-1-(2,2-Diphenylvinyl)-8,9-dimethoxy-
4a,10b-dimethyl-1,2,3,4,4a,4b,5,6,10b,11,12,12a-dodecahydrochry-
sene (13). White solid (20 mg, 39% yield): mp = 82−89 °C; 1H NMR
(CDCl3, 600 MHz) δ 0.67 (s, 3H), 0.88 (td, J = 12.4, 5.2 Hz, 1H),
0.99−1.03 (m, 1H), 1.16 (s, 3H), 1.18−1.22 (m, 1H), 1.26−1.28 (m,
1H), 1.34 (qd, J = 13.2, 2.7 Hz, 1H), 1.42−1.54 (m, 3H), 1.60−1.66
(m, 2H), 1.77−1.79 (m, 2H), 1.83−1.87 (m, 1H), 2.16 (qd, J = 10.9,
3.6 Hz, 1H), 2.27 (dt, J = 12.7, 3.0 Hz, 1H), 2.73−2.86 (m, 2H), 3.82
(s, 3H), 3.83 (s, 3H), 5.80 (d, J = 10.1 Hz, 1H), 6.51 (s, 1H), 6.74 (s,
1H), 7.17−7.24 (m, 7H), 7.29−7.39 (m, 3H); 13C NMR (CDCl3, 150
MHz) δ 147.0, 146.7, 142.7, 142.5, 140.6, 140.5, 135.4, 129.7, 128.1,
128.0, 127.2, 127.0, 126.7, 126.8, 111.2, 107.8, 56.0, 55.7, 53.3, 52.4,
39.9, 38.8, 37.8, 37.5, 36.8, 33.8, 30.3, 25.8, 23.5, 20.7, 18.1, 13.6;
HRMS (ESI) for C36H42O2Na calcd for [M + Na]+ m/z 529.3083,
found 529.3079.
(1S,4aS,4bS,10bR,12aS)-1-(2,2-Diphenylvinyl)-8,9-dimethoxy-
4a,10b-dimethyl-1,2,3,4,4a,4b,5,6,10b,11,12,12a-dodecahydrochry-
sene (14). White solid (6 mg, 13% yield): mp = 91−96 °C; 1H NMR
(CDCl3, 600 MHz) δ 0.98 (s, 3H), 1.16−1.20 (m, 3H), 1.23−1.30 (m,
1H), 1.33−1.37 (m, 1H), 1.47 (s, 3H), 1.48−1.72 (m, 7H), 1.80−1.83
(m, 1H), 2.08−2.14 (m, 2H), 2.60−2.70 (m, 2H), 3.83 (s, 6H), 5.75
(d, J = 10.1 Hz, 1H), 6.47 (s, 1H), 6.77 (s, 1H), 7.15−7.24 (m, 7H),
7.30−7.39 (m, 3H); 13C NMR (CDCl3, 150 MHz) δ 147.1, 146.4,
142.7, 140.7, 140.6, 135.4, 129.7, 128.6, 128.1, 128.0, 126.9, 126.7,
110.7, 110.4, 56.1, 55.7, 54.3, 44.9, 39.3, 38.6, 38.3, 37.6, 36.9, 33.6,
32.0, 31.3, 24.4, 22.6, 21.5, 21.1; HRMS (ESI) for C36H42O2Na calcd
for [M + Na]+ m/z 529.3083, found 529.3074.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of the products listed in Tables 1−6.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: qujin@nankai.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the NSFC (21072098,
21372119), the National Natural Science Foundation of China
Innovation Group (21121002), and the Tianjin Natural Science
Foundation (14JCYBJC20200). We thank Professor Chi Zhang
at Nankai University for helpful discussions.
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REFERENCES
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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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1
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DOI: 10.1021/jo502636d
J. Org. Chem. XXXX, XXX, XXX−XXX