One-Pot Synthesis of O-Heterocycles or Aryl Ketones Using an InCl3/Et3SiH System by Switching the Solvent

Article abstract of DOI:10.1021/acs.joc.9b00140

An efficient one-pot synthesis of O-heterocycles or aryl ketones has been achieved using Et₃SiH in the presence of InCl₃ via a sequential ionic hydrogenation reaction by switching the solvent. This methodology can be used to construct C-O bonds and to prepare conjugate reduction products, including chromans, tetrahydrofurans, tetrahydropyrans, dihydroisobenzofurans, dihydrochalcones, and 1,4-diones in a facile manner. In addition, a novel plausible mechanism involving a conjugate reduction and a tandem reductive cyclization was verified by experimental investigations.

Full text of DOI:10.1021/acs.joc.9b00140

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Article
One-Pot Synthesis of O-Heterocycles or Aryl Ketones
Using an InCl3/Et3SiH System by Switching the Solvent
Wenqiang Jia, Qiumu Xi, Tianqi Liu, Minjian Yang, Yonghui Chen, Dali Yin, and Xiaojian Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00140 • Publication Date (Web): 15 Apr 2019
Downloaded from http://pubs.acs.org on April 17, 2019
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The Journal of Organic Chemistry
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One-Pot Synthesis of O-Heterocycles or Aryl Ketones Using an
InCl3/Et3SiH System by Switching the Solvent
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Wenqiang Jia,† Qiumu Xi,† Tianqi Liu,† Minjian Yang,‡ Yonghui Chen,† Dali Yin†,‡ and Xiaojian
Wang*,†,‡
† State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica,
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
‡ Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Druggability
Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College,
Beijing 100050, China
Supporting Information
O
O
R3
R2
R2
R3 = H
R2
R1
R1
R3
OH
OH
O
CH3CN
Et2O
InCl3
Si-H
O
R2
O
O
n
R1
R1
O
R2
R1
R2
n = 0, 1
n = 0
n
O
up to 93% yields
(30 examples)
up to 87% yields
(9 examples)
ABSTRACT: An efficient one-pot synthesis of O-heterocycles or aryl ketones has been achieved using Et3SiH in the presence
of InCl3 via a sequential ionic hydrogenation reaction by switching the solvent. This methodology can be used to construct
C-O bonds and to prepare conjugate reduction products, including chromans, tetrahydrofurans, tetrahydropyrans,
dihydroisobenzofurans, dihydrochalcones and 1,4-diones in a facile manner. In addition, a novel plausible mechanism
involving a conjugate reduction and a tandem reductive cyclization was verified by experimental investigations.
these structures have been developed.5 However, most of
these strategies demand multiple steps that are conducted
under different reaction conditions. To date, there has been
INTRODUCTION
Chroman and tetrahydrofuran derivatives constitute the
core of many natural products and pharmaceutical
compounds with extensive biological and pharmacological
activities (Fig. 1).1 The most well-known chroman is -
tocopherol, which is an important member of the vitamin E
family that serves as a natural lipophilic antioxidant and
radical scavenger.2 Dihydrochalcones have been reported
to exhibit antibacterial and anticancer properties.3
Moreover, veraguensin, isolated from Virola surinamensis,
only one example for
a one-pot synthesis of 2-
phenylchroman, and this was achieved in 43% yield via a
tosylhydrazine-mediated reductive cyclization from 2-
hydroxychalcone, which is readily available and easy to
handle.6 Thus, an efficient methodology for the preparation
of chroman and tetrahydrofuran in a small number of steps
and in high yield is of great interest.
Ionic hydrogenation has become an efficient tool for the
reduction of certain functional groups.7 Recently, we
disclosed a facile Al(OTf)3-mediated cascade cyclization and
ionic hydrogenation to afford various N-heterocyclic
skeletons.8 In this context, we envisioned that it might be
possible to synthesize various O-heterocycles under the
same reaction conditions. Such a method has the potential
to be an extremely powerful synthetic tool, as it would offer
efficiency with both high atom and step economy. To the
best of our knowledge, no Lewis acid-promoted sequential
ionic hydrogenation for the synthesis of O-heterocycles has
been reported to date.
has been identified as
a potent inhibitor of the
trypomastigote Y strain of T. cruzi.4
O
HO
O
O
R'
R
O
O
O
C16H23
OH
O
Veraguensin
Dihydrochalcone
Vitamin E
Figure 1. Various O-containing bioactive compounds.
Given the importance of the chroman and tetrahydrofuran
motifs, in the last decade, many strategies for accessing
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Scheme 1. Synthesis of O-heterocycles and aryl ketones same reaction in Et2O as the solvent, and the two reactions
1
2
3
4
5
6
7
8
using the same Lewis acid and hydrosilane and
different solvents
exhibited excellent chemoselectivity (Scheme 1). Notably,
this intramolecular reaction can be carried out between a
hydroxyl or carbonyl moiety and an -unsaturated keto
carbonyl or carbonyl moiety, giving a variety of O-
heterocycles under mild reaction conditions.
O
O
R3
R2
R2
R3 = H
R3
OH
O
O
R2
OH
CH3CN
Et2O
InCl3
Ar1
Si-H
O
RESULTS AND DISCUSSION
O
Ar2
Ar2
Ar1
Ar1
Ar2
Initially, the sequential ionic hydrogenation reaction of 2-
hydroxychalcone (1a) with Et3SiH in the presence of 0.5
equiv of Al(OTf)3 was studied as a model reaction (Table 1).
We were encouraged to find that the reaction in
dichloromethane gave the desired cyclized product, 2-
phenylchroman (2a), in 52% yield (entry 1). However,
when the reaction was conducted in methanol or toluene,
desired product 2a was not obtained (entries 2 and 3).
Gratifyingly, the reaction in acetonitrile gave a higher yield
(entry 5). On the other hand, a screening of Lewis acid
revealed that InCl3 performed best and afforded 2a in 80%
yield (entries 5 vs 6-9). Then, running the reaction with a
lower loading of InCl3 (entry 10) or with Et3SiH (entry 11)
led to a dramatic decrease in the yield. Notably, in the
absence of a Lewis acid or Et3SiH, no product 2a was
observed (entries 12 and 13). Surprisingly, conjugate
reduction product 3a was isolated from the reaction
conducted in ether (entry 14). Consequently, the
combination of 0.5 equiv of InCl3 and 4 equiv of Et3SiH in
acetonitrile was found to give the best result for this
reaction.
O
O
R
R1
O
9
R1
R2
10
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intramolecular reaction:
O
R2
O
R
OH
R1
HO
O
O
O
O
Ar
Ar
R2 R3
Ar
O
Ar
R
R
O
O
InCl3
Si-H
O
R
new bond
R
O
Wide substrate scope
Mild reaction conditions
High chemoselectivity
Detailed mechanism studies
Table 1. Examination of the reaction conditions a
O
O
LA (0.5 equiv)
Et3SiH (4 equiv)
Ph
Ph
+
Ph
Solvent, rt, 15 h
O
2a
OH
OH
3a
1a
Yield (%)b
Entry
Lewis acid
Solvent
2a
52
-
3a
To generalize this reaction, various 2-hydroxychalcones
were subjected to the optimized reaction conditions
(Scheme 2, conditions A). It was found that both electron-
donating (X = 4-Me, 4-MeO, and 4-OH) and electron-
withdrawing groups (X = 4-Cl and 4-NO2) were well
tolerated and gave the desired 2-arylchromans (2b−2f) in
moderate to good yields. Notably, functional groups such as
a nitro and hydroxyl, which are sensitive to conventional
reductive conditions, were unaffected by our standard
reaction conditions. Meta substitution (X = 3-MeO) was also
tolerated in the reaction, and corresponding product 2g was
obtained in good yield. Replacement of the phenyl
substituent with a 2-naphthyl (2h) or 2-thienyl (2i) unit had
little effect on the reaction results but resulted in slightly
decreased yields. Substrate 1j, which was derived from
propiophenone, was tolerated and gave disubstituted
chroman 2j (C2-C3 cis) in a low yield, but only the C2-C3
isomer was observed.9 Furthermore, substrates derived
from salicylaldehydes with various substitution patterns
proceeded efficiently, giving the desire products (2k-2m) in
good yields. Remarkably, a special chroman (2n) was also
obtained in good yield. In addition, tetracyclic chromans
(2o and 2p) were prepared in 63% and 82% yields with
complete trans selectivity.10 Unfortunately, attempts to use
a hydrogen atom (2q) or methyl group (2r) in place of the
phenyl ring failed under the optimized conditions.
However, the reaction could be scaled up without loss of
yield. For example, the desired chroman 2a could be
obtained in high yield (1.17 g, 80%) when the reaction was
scaled up with 7 mmol of chalcone 1a using
1
Al(OTf)3
Al(OTf)3
Al(OTf)3
Al(OTf)3
InCl3
DCM
-
-
2
MeOH
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Et2O
3
-
-
4
55
80
48
45
53
-
-
5
-
6
BF3 Et2O
Bi(OTf)3
Cu(OTf)2
In(OAc)3
InCl3
-
7
-
8
-
9
-
10 c
11 d
12 e
13 f
14
73
70
-
-
InCl3
-
-
-
InCl3
-
-
InCl3
-
80
a Reaction conditions: 1a (0.25 mmol, 1 equiv), Et3SiH
b
(4 equiv), Lewis acid (0.5 equiv), solvent (1.25 mL).
Yield of isolated product. c 0.3 equiv of Lewis acid was
used. d 3 equiv of Et3SiH was used. e No Lewis acid was
used. f No Et3SiH was used.
Herein, we report an InCl3-promoted, one-pot ionic
hydrogenation cascade cyclization comprising a two-step or
four-step sequence to construct a C-O bond to generate
chromans, tetrahydrofurans, tetrahydropyrans and
dihyroisbenzofurans. Additionally, we disclose a divergent
synthesis for accessing conjugate reduction products, such
as dihydrochalcones and 1,4-diaryl-1,4-diones, from the
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Scheme 2. Preparations of a variety of chromans and
Table 2. Substrates scope for tetrahydrofurans and
dihydrochalcones a
1
2
3
4
5
6
7
8
1,4-dionesa
O
O
O
O
Condition B
R1
Condition A
R1
2 Condition B
2 Condition A
Ar
Ar
Ar1
Ar1
Ar1
Ar2
R
R
O
R = H
R1
OH
O
O
O
OH
6
5
4
1
2
3
Yield (%)
Conditons A:
Entry
Ar1
Ar2
Ph
Product
b
2a
, X = H, 80% (80%)
(trans:cis)b,c
85% (1:0.70)
66% (1:0.95)
63% (1:1.00)
72% (1:0.98)
72% (1:0.75)
69%
2b
, X= 4-Me, 93%
2c
2d
, X = 4-MeO, 74%
, X = 4-OH, 42%
1
2
3
4
5
6d
7
8
9
Ph
5a
5b
5c
5d
5e
6f
9
O
O
X
10
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2e
4-MePh
4-EtPh
4-FPh
Ph
4-MePh
4-EtPh
4-FPh
4-MePh
Mes
, X = 4-Cl, 80%
2h
, 54%
2f
, X = 4-NO2, 48%
2g
,X = 3-MeO, 71%
R
S
O
O
O
Ph
2k
, R = 7-MeO, 71%
2i
, 42%
2j
, 54% (cis only)
2l
, R = 6-Cl, 64%
Mes
MeO
Ph
Ph
6a
6g
6h
61%
4-MeOPh
4-MeOPh
68%
O
O
O
4-BrPh
4-BrPh
85%
OH
c
2m
, 63%
2n
, 74%
a Reaction conditions A: 4 (0.5 mmol, 1 equiv), Et3SiH (6 equiv)
and InCl3 (0.5 equiv) in CH3CN (2.5 mL) at rt. Reaction
conditions B: 4 (0.5 mmol, 1 equiv), Et3SiH (6 equiv) and InCl3
O
O
Y
O
b
2q
, Y = H, N. D.
2r
, Y = Me, N.D.
(0.5 equiv) in Et2O (2.5 mL) at reflux. Yield of isolated
2o
, 63% (trans only)
2p
, 82% (trans only)
c
product.
Product ratios were judged by 1H NMR
d
spectroscopic analysis of the crude reaction mixture. The
reaction condition is the same as condition A. Mes = mesityl.
Conditons B:
O
3a
, X = H, 80%
3b
, X = 4-Me, 80%
, X = 4-Cl, 87%
, X= 4-Br, 76%
, X =3-Br, 70%
3e
3s
X
OH
3t
a
Reaction conditions A: 1 (0.5 mmol, 1 equiv), Et3SiH (4
equiv) and InCl3 (0.5 equiv) in CH3CN (2.5 mL) at rt.
Reaction conditions B: 1 (1 equiv), Et3SiH (4 equiv) and
InCl3 (0.5 equiv) in Et2O (2.5 mL) at rt. The yields shown are
of isolated products. b Gram-scale reaction: 2a (1.17 g, 80%)
was obtained. c 2 equiv of InCl3 and 16 equiv of Et3SiH were
used at reflux.
The extension of the sequential reductive cyclization
system to keto carbonyls with an -unsaturation was
investigated starting with the reaction of trans-1,2-
dibenzoylethylene (4a) with 0.5 equiv of InCl3 and 6 equiv
of Et3SiH (Table 2, conditions A). To our delight, cyclized
product 5a11 and 1,4-reduction product 6a were generated
in good yields from the reactions in different solvents
(Table 2, entries 1 and 7). Aryl rings with either electron-
donating groups (4-Me and 4-Et) or with an electron-
withdrawing group (4-F) were all well tolerated and gave
the desired cyclized products (Table 2, entries 2-4) in good
yields (63-72%). Asymmetrical substrate 4e also reacted
under the optimized conditions and afforded cyclized
product 5e (Table 2, entry 5). However, potentially due to
steric hindrance, the mesityl substituted -unsaturated
dicarbonyl substrate (4f) failed to afford the cyclized
product under the current reaction conditions, but
conjugate reduction product 6f was observed in 69% yield.
the standard condition. These results proved that the
InCl3/Et3SiH system worked as a relatively mild reducing
system. This sequential reductive cyclization resulted in
bond formation between the hydroxyl moiety of
a
substituted phenol and an -unsaturated keto carbonyl,
and all cases showed total diastereoselectivity (>99:1).
During the optimization of the sequential ionic
hydrogenation reaction, 1,4-reduction product 3a was
generated in 80% yield when ether was used as the solvent,
which may have poor solubility than acetonitrile(Table 1,
entry 14). Compared with other reduction systems, such as
H2/Pd/C or NaBH4, our system exhibited excellent
chemoselectivity, and no over-reduction products were
observed. Substrates 1b and 1e were suitable for this
reation (Scheme 2, conditions B), giving the conjugate
reduction products (3b and 3e) in good yields. In addition,
substrates with either para-bromo or meta-bromo groups
were compatible and were converted into the 1,4-reduction
products (3s and 3t) in 76% and 70% yields, respectively.
At the same time, when the solvent was changed from
acetonitrile to ether, as expected, the 1,4-reduction
products were generated in good yields (Table 2, conditions
B). A range of -unsaturated 1,4-dicarbonyl substrates
with electron-donating (4-MeO) and electron-withdrawing
groups (4-Br) on their aryl rings reacted smoothly under
conditions B to give the conjugate reduction products (6g
and 6h) in 68% and 85% yields.
To assess whether the protocol was applicable across a
range of keto phenols, the conversion of substrates 7 into
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substituted 6H-benzo[c]chromenes 8 was studied (Scheme reductions. Second, cyclization product 2a was obtained
1
2
3
4
5
6
7
8
3). The reaction scope was further examined, and both
under the standard reaction conditions when both
conjugate reduction product 3a and over-reduction product
16a were used as
Scheme 3. Extension to various keto phenols
Scheme 5. Mechanistic studies
O
R1
R1
(a) Control experiment
InCl3 (0.5 equiv)
Et3SiH (2 equiv)
R
R2
R2
O
O
OH
Ph
InCl3 (0.5 equiv)
Et3SiH (4 equiv)
CH3CN, reflux
Ph
Ph
+
O
R
HO
CH3CN, rt
O
9
O
, R= Ph, R1 = R2 = H
O
7a
8a
, 72%
, R= Ph, R1 = MeO, R2 = H
, 78%
, 70%
, 65%
13
14
, 51%
15
, 11%
7b
7c
8b
8c
10
11
12
13
14
15
16
17
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60
, R= Ph, R1 = H, R2 = Me
(b) Reactions of the plausible reaction intermediates
, R = Me, R1 = R2 = H
7d
8d
InCl3 (0.5 equiv)
Et3SiH (4 equiv)
O
Ph
CH3CN, rt
Scheme 4. Synthesis of tetrahydropyrans
OH
O
Ph
2a
, 88%
3a
O
O
InCl3 (0.5 equiv)
Et3SiH (4 equiv)
InCl3 (0.5 equiv)
Et3SiH (4 equiv)
OH
Ph
O
cis only
CH3CN, rt
CH3CN, rt
R
R
R
R
9a
, R = H
10a
10b
10c
, 89%
, 91%
, 85%
O
Ph
OH
16a
9b
, R = Me
2a
, 67%
9c
, R = Cl
OH
Ph
InCl3 (0.5 equiv)
CH3CN, rt
Et3SiH (4 equiv)
N.R.
methyl- and methoxy-substituted aryl rings were tolerated
(7b-7c). Moreover, substituted methyl aryl ketone 7d also
performed well, delivering corresponding product 8d in
65% yield.
OH
16a
O
Ph
2a
, 69%
17a
(c) Reaction of the intermediate
OTES
OH
Ph
Moreover, this system was extended to the conversion of
1,5-dicarbonyl substrates (9) into 2,6-disubstituted
tetrahydropyrans (10) (Scheme 4).12 Substrates bearing
InCl3 (0.5 equiv)
CH3CN, rt
Ph
+
OH
17a
OH
16a
O
Ph
, 60%
2a
, 10%
electron-donating
and
electron-withdrawing
aryl
OTES
Ph
substituents (9b and 9c) gave similarly excellent yields
with complete cis selectivity.
InCl3 (0.5 equiv)
Et3SiH (4 equiv)
CH3CN, rt
OH
17a
O
Ph
To access products with a variety of skeletons, 1,2-
dibenzoylbenzene (11a) and 1,2-diformylbenzene (11b)
were investigated to give the corresponding 1,3-
dihydroisobenzofurans (12a and 12b).13 Under similar
reaction conditions, the reaction of 11a worked well (89%
yield) and gave trans:cis = 1.2:1 [eq. (1)]. The reaction of
11b afforded trace product using InCl3 as the Lewis acid.
Changing the Lewis acid to Al(OTf)3 led to a dramatic
improvement in both the reactivity and yield [eq. (2)].
2a
, 89%
Scheme 6. A tentative reaction pathway
InCl3
Et3SiH
O
Et3SiL
HInL2
Et3SiH
Ar
OH
InL3
Ph
OInL2
H
Ph
O
Ar
InCl3 (0.5 equiv)
Et3SiH (4 equiv)
O
O
Ar
O
(1)
OInL2
CH3CN, reflux
OH
I
Ph
Ar
Ph
11a
H
H
12a
, trans:cis=1.2:1, 89%
OH
III
O
H
LA (0.5 equiv)
Et3SiH (4 equiv)
InL3
HInL2
Ar
O
O
O
(2)
II
OH
CH3CN, rt
L = Cl, OH
12b
InCl3
H
11b
: trace
Al(OTf)3 : 41%
starting materials. These results indicated that a conjugate
sequential reduction may be involved in this ionic
hydrogenation. Furthermore, substrate 16a did not
undergo the cyclization in the presence of 0.5 equiv of InCl3.
Surprisingly, when 4 equiv of Et3SiH was added to the above
reaction system, cyclization product 2a was isolated in 69%
yield. This experiment confirmed that Et3SiH not only
served as the reductant but also played a vital role in the
To elucidate the mechanism of this sequential ionic
hydrogenation, several preliminary studies were carried
out. First, 2-methoxy chalcone 13 was prepared and
subjected to the previously described reaction conditions
(Scheme 5a). In the reaction, conjugate reduction product
14 and corresponding over-reduction product 15 were
observed, supporting a mechanism involving sequential
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cyclization (Scheme 5b). Finally, the transformation of 17a stirred solution of 1 (0.5 mmol, 1 equiv) and InCl3 (0.5
1
2
3
4
5
6
7
8
into 2a and 16a was observed in the presence of 0.5 equiv
of InCl3 only. Meanwhile, treatment of 17a under the
standard conditons could afford the cyclization product 2a
in 89% yield. These experiments could verify that the silyl
reagent was important for the cyclization (Scheme 5c).
equiv) in dry acetonitrile (2.5 mL) was added Et3SiH (4
equiv). The reaction mixture was stirred at room
temperature for 15 h. After completion of the reaction,
water was added to the reaction mixture, which was
extracted with dichloromethane. The combined organic
layers were washed with brine, dried over anhydrous
Na2SO4, concentrated in vacuo and purified by column
chromatography on silica gel (PE : EA = 50:1) to afford the
desired products (2).
On the basis of these mechanistic studies, we proposed a
tentative reaction pathway as shown in Scheme 6: (1)
transmetalation between Et3SiH and InCl3 forms an indium
hydride species (HInL2),14 (2) the Michael addition of the
hydride to a 2-hydroxychalcone affords the corresponding
indium enolate I,14b (3) isomerization of intermediate I
would lead to dihydrochalcone II, (4) 1,2-addition of the
hydride to a dihydrochalcone II leads to the intermediate
III, (5) intramolecular cyclization of intermediate III lead to
the expected chroman, (6) transmetalation between InL3
and Et3SiH regenerates HInL2.
9
2-phenylchroman (2a).6 Yield: 80% (86.1 mg), light yellow
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1
oil. Rf = 0.3 (petroleum ether/ethyl acetate, 30:1). H NMR
(400 MHz, CDCl3) δ 7.49 - 7.41 (m, 4H), 7.39 - 7.37 (m, 1H),
7.20 - 7.13 (m, 2H), 6.99 - 6.91 (m, 2H), 5.11 (d, J = 10.0 Hz,
1H), 3.08 - 3.00 (m, 1H), 2.86 - 2.81 (m, 1H), 2.28 - 2.22 (m,
1H), 2.19 - 2.11 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
155.2, 141.8, 129.6, 128.6, 127.9, 127.4, 126.1, 121.9, 120.4,
117.0, 77.8, 30.0, 25.1. HRMS (EI) m/z: [M]+ Calc. for:
C15H14O, 210.1045, Found 210.1042.
CONCLUSION
2-p-tolylchroman (2b). 6 Yield: 93% (104.1 mg), white solid,
mp: 79-81 o C. Rf = 0.3 (petroleum ether/ethyl acetate, 30:1).
1H NMR (400 MHz, ) δ 7.31 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 7.7
Hz, 2H), 7.13 - 7.07 (m, 2H), 6.90 - 6.84 (m, 2H), 5.03 (dd, J
= 9.9, 2.5 Hz, 1H), 3.03 - 2.95 (m, 1H), 2.82 - 2.76 (m, 1H),
2.36 (s, 3H), 2.22 - 2.16 (m, 1H), 2.11 - 2.04 (m, 1H). 13C{1H}
NMR (101 MHz, CDCl3) δ 155.3, 138.9, 137.6, 129.6, 129.3,
127.4, 126.1, 121.9, 120.3, 117.0, 77.8, 30.0, 25.3, 21.3.
HRMS (ESI) m/z: [M+H]+ Calc. for: C16H17O, 225.1274,
Found 225.1270.
In conclusion, we have developed an InCl3-promoted, one-
pot synthesis of O-heterocycles and aryl ketones via
sequential ionic hydrogenation by switching the solvent.
This reaction was compatible with a diverse range of
functions groups, including nitro, hydroxyl and bromo
groups, that are typically sensitive to reductive conditions.
A variety of chroman, tetrahydrofuran, tetrahydropyran
and dihydroisobenzofuran derivatives were obtained in
moderate to excellent yields. When the reaction was
conducted in Et2O as the solvent, the conjugate reduction
reaction occurred to generate the dihydrochalcone or 1,4-
dione as the sole product. This sequential ionic
hydrogenation was achieved by the reaction between a
hydroxyl or carbonyl moiety and an -unsaturated keto
carbonyl or a carbonyl and afforded various O-heterocycles.
In addition, detailed mechanistic studies involving
conjugate reduction, over-reduction and intramolecular
cyclization pathways were verified by control experiments.
The synthesis of other heterocycles via the sequential ionic
hydrogenation reaction is under way in our laboratory.
2-(4-methoxyphenyl)chroman (2c). 6 Yield: 74% (88.8 mg),
o
white solid, mp: 70-72 C. Rf = 0.3 (petroleum ether/ethyl
acetate, 30:1). 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.6
Hz, 2H), 7.14 - 7.08 (m, 2H), 6.94 - 6.85 (m, 4H), 5.01 (dd, J
= 10.1, 2.4 Hz, 1H), 3.82 (s, 3H), 3.04 - 2.96 (m, 1H), 2.84 -
2.78 (m, 1H), 2.21 - 2.14 (m, 1H), 2.12 - 2.05 (m, 1H). 13C{1H}
NMR (101 MHz, CDCl3) δ 159.4, 155.3, 134.0, 129.6, 127.5,
127.4, 121.9, 120.3, 117.0, 114.0, 77.6, 55.4, 29.9, 25.3.
HRMS (ESI) m/z: [M+H]+ Calc. for: C16H17O2, 241.1223,
Found 241.1220.
4-(chroman-2-yl)phenol (2d). Yield: 42% (47.4 mg), white
solid, mp: 85-87 o C. Rf = 0.3 (petroleum ether/ethyl acetate,
5:1). 1H NMR (400 MHz, CDCl3) δ 7.31 - 7.29 (m, 2H), 7.11 -
7.07 (m, 2H), 6.89 - 6.82 (m, 4H), 4.99 (dd, J = 10.1, 2.5 Hz,
1H), 3.01 - 2.94 (m, 1H), 2.82 - 2.76 (m, 1H), 2.19 - 2.13 (m,
1H), 2.12 - 2.02 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
155.3, 155.3, 134.1, 129.6, 127.7, 127.4, 121.9, 120.4, 117.0,
115.4, 77.6, 29.9, 25.3. HRMS (ESI) m/z: [M+H] + Calc. for:
C15H15O2, 227.1067, Found 227.1062.
EXPERIMENTAL SECTION
General. Unless otherwise indicated, all reactions were
carried out under anhydrous, air-free conditions. All
solvents and chemicals were obtained from commercial
sources and used without further purification. Flash column
chromatography was performed with silica gel 300 - 400
mesh on Biotage Isolera one. NMR spectra were recorded
on a Mercury-400 or Mercury-500 spectrometer, with
tetramethylsilane as an internal standard and reported in
ppm (δ). ESI-HRMS data were measured on Thermo
Exactive Orbitrap plus spectrometer. Melting points were
determined on Yanaco MP-J3 microscope melting point
apparatus. 2-hydroxychalcones (1)5b, (E)-1,4-enediones
2-(4-chlorophenyl)chroman (2e).6 Yield: 80% (97.6 mg),
o
white solid, mp: 73-75 C. Rf = 0.3 (petroleum ether/ethyl
acetate, 30:1). 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 4H), 7.14
- 7.07 (m, 2H), 6.90 - 6.85 (m, 2H), 5.04 (dd, J = 10.0, 2.6 Hz,
1H), 3.02 - 2.94 (m, 1H), 2.81 - 2.75 (m, 1H), 2.22 - 2.16 (m,
1H), 2.09 - 1.98 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
154.9, 140.3, 133.6, 129.6, 128.8, 127.5, 127.5, 121.7, 120.6,
117.0, 77.1, 30.0, 25.0. HRMS (EI) m/z: [M]+ Calc. for:
C15H13ClO, 244.0655, Found 244.0659.
(4)15,
1,5-dicarbonyl
compounds
(9)16,
1,2-
Dibenzoylbenzene (11a)17, 135b, 1518 and 16a5b were
prepared according to the literatures.
2-(4-nitrophenyl)chroman (2f). Yield: 48% (61.2 mg), yellow
o
solid, mp: 115-117 C. Rf = 0.3 (petroleum ether/ethyl
Typical procedure for sequential ionic hydrogenation
using 2-hydroxychalcone (1), InCl3 and Et3SiH: To a
1
acetate, 30:1). H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.7
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The Journal of Organic Chemistry
Page 6 of 10
Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.16 - 7.13 (m, 1H), 7.09 (d, 6-chloro-2-phenylchroman (2l). Yield: 64% (78.1 mg), white
solid, mp: 58-60 o C. Rf = 0.3 (petroleum ether/ethyl acetate,
30:1). 1H NMR (400 MHz, CDCl3) δ 7.41 - 7.36 (m, 4H), 7.34
- 7.30 (m, 1H), 7.08 - 7.05 (m, 2H), 6.87 - 6.76 (m, 1H), 5.04
(dd, J = 10.0, 2.5 Hz, 1H), 2.99 - 2.91 (m, 1H), 2.79 - 2.72 (m,
1H), 2.23 - 2.17 (m, 1H), 2.11 - 2.01 (m, 1H). 13C{1H} NMR
(101 MHz, CDCl3) δ 153.8, 141.3, 129.1, 128.7, 128.1, 127.4,
126.0, 125.1, 123.5, 118.3, 78.0, 29.6, 25.0. HRMS (EI) m/z:
[M]+ Calc. for: C15H13ClO, 244.0655, Found 244.0652.
1
2
3
4
5
6
7
8
J = 7.3 Hz, 1H),6.93 - 6.88 (m, 2H), 5.17 (dd, J = 9.9, 2.6 Hz,
1H), 3.05 - 2.97 (m, 1H), 2.82 - 2.76 (m, 1H), 2.29 - 2.22 (m,
1H), 2.09 - 1.98 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
154.4, 149.2, 129.7, 127.7, 126.8, 123.9, 121.6, 121.0, 117.0,
76.6, 30.1, 24.8. HRMS (EI) m/z: [M]+ Calc. for: C15H13NO3,
255.0895, Found 255.0894.
2-(3-methoxyphenyl)chroman (2g).6 Yield: 71% (85.2 mg),
transparent oil. Rf = 0.3 (petroleum ether/ethyl acetate,
1
30:1). H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 8.2 Hz, 1H),
4-(6-methoxychroman-2-yl)phenol (2m). Yield: 63% (80.6
9
o
7.16 - 7.12 (m, 1H), 7.10 (d, J = 7.3 Hz, 1H), 7.03 - 7.01 (m,
2H), 6.94 (d, J = 8.2 Hz, 1H), 6.91 - 6.86 (m, 2H), 5.06 (dd, J =
10.1, 2.4 Hz, 1H), 3.83 (s, 3H), 3.05 - 2.96 (m, 1H), 2.84 - 2.78
(m, 1H), 2.28 - 2.20 (m, 1H), 2.15 -2.05 (m, 1H). 13C{1H} NMR
(101 MHz, CDCl3) δ 159.8, 155.1, 143.4, 129.6, 127.4, 121.9,
120.4, 118.4, 117.0, 113.3, 111.7, 77.7, 55.3, 30.0, 25.1.
HRMS (ESI) m/z: [M+H]+ Calc. for: C16H17O2, 241.1223,
Found 241.1219.
mg), yellow solid, mp: 150-152 C, Rf = 0.3 (petroleum
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ether/ethyl acetate, 5:1). 1H NMR (400 MHz, CDCl3) δ 7.30 -
7.27 (m, 2H), 6.84 - 6.80 (m, 3H), 6.69 (dd, J = 8.9, 3.1 Hz,
1H), 6.62 (d, J = 3.0 Hz, 1H), 4.92 (dd, J = 10.1, 2.6 Hz, 1H),
3.75 (s, 3H), 2.98 - 2.93 (m, 1H), 2.80 – 2.73 (m, 1H), 2.17 -
2.11 (m, 1H), 2.10 - 2.00 (m, 1H). 13Cc NMR (101 MHz, CDCl3)
δ 155.4, 153.4, 149.4, 134.2, 127.7, 122.4, 117.6, 115.4,
+
114.1, 113.4, 77.5, 55.9, 29.9, 25.6. HRMS (EI) m/z: [M]
Calc. for: C16H16O3, 256.1099, Found 256.1098.
2-(naphthalen-2-yl)chroman (2h). Yield: 54% (70.2 mg),
transparent oil. Rf = 0.3 (petroleum ether/ethyl acetate,
30:1). 1H NMR (500 MHz, CDCl3) δ 7.97 - 7.96 (m, 1H), 7.94
- 7.92 (m, 3H), 7.62 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 3.4 Hz, 2H),
7.24 - 7.23 (m, 1H), 7.19 (d, J = 7.0 Hz, 1H), 7.06 (d, J = 7.7
Hz, 1H), 6.99 (t, J = 6.8 Hz, 1H), 5.31 (d, J = 7.9 Hz, 1H), 3.14
- 2.89 (m, 1H), 2.92 - 2.89 (m, 1H),2.38 - 2.35 (m, 1H),2.27-
2.25 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.2, 133.4,
133.1, 129.6, 128.4, 128.1, 127.8, 127.5, 126.2, 126.0, 124.9,
124.1, 121.9, 120.5, 117.0, 77.9, 30.0, 25.2. HRMS (EI) m/z:
[M]+ Calc. for: C19H16O, 260.1201, Found 260.1204.
1,3-di(chroman-2-yl)benzene (2n). Yield: 74% (126.5 mg),
yellow solid, mp: 91-93 o C. Rf = 0.3 (petroleum ether/ethyl
acetate, 10:1). 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.50
(s, 3H), 7.25 - 7.18 (m, 4H), 7.03 - 6.96 (m, 4H), 5.17 (d, J =
10.2 Hz, 2H), 3.14 - 3.06 (m, 2H), 2.90 (d, J = 16.3 Hz, 2H),
2.34 - 2.30 (m, 2H), 2.24 - 2.14 (m, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 155.1, 142.1, 129.6, 128.85, 128.84, 127.4,
125.6, 125.5, 123.8, 123.7, 121.9, 120.4, 117.03, 117.02,
77.87, 77.81, 30.16, 30.13, 25.2. HRMS (ESI) m/z: [M+H]+
Calc. for: C24H23O2, 343.1693, Found 343.1700.
2-(thiophen-2-yl)chroman (2i). Yield: 42% (45.3 mg),
transparent oil. Rf = 0.3 (petroleum ether/ethyl acetate,
30:1). 1H NMR (400 MHz, CDCl3) δ 7.30 - 7.28 (m, 1H), 7.13
- 7.07 (m, 3H), 7.01 - 6.99 (m, 1H), 6.90 - 6.85 (m, 2H), 5.34
- 5.31 (m, 1H), 3.03 - 2.94 (m, 1H), 2.87 - 2.81 (m, 1H), 2.37
- 2.30 (m, 1H), 2.26 - 2.18 (m, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 154.7, 144.8, 129.6, 127.5, 126.7, 125.1, 124.5,
121.6, 120.7, 117.1, 73.7, 30.0, 24.8. HRMS (EI) m/z: [M]+
Calc. for: C13H12OS, 216.0609, Found 216.0610.
4b,10,10a,11-tetrahydroindeno[1,2-b]chromene (2o). Yield:
o
63% (69.9 mg), white solid, mp: 125-127 C. Rf = 0.3
1
(petroleum ether/ethyl acetate, 30:1). H NMR (400 MHz,
CDCl3) δ 7.55 - 7.53 (m, 1H), 7.29 - 7.27 (m, 3H), 7.16 - 7.13
(m, 2H), 7.01 (dd, J = 8.1, 1.1 Hz, 1H), 6.92 (td, J = 7.4, 1.3 Hz,
1H), 4.91 (d, J = 10.0 Hz, 1H), 3.17 - 3.10 (m, 1H), 3.07 - 2.97
(m, 2H), 2.63 - 2.56 (m, 1H), 2.50 - 2.42 (m, 1H). 13C{1H} NMR
(101 MHz, CDCl3) δ 155.6, 141.7, 141.6, 130.6, 127.9, 127.6,
126.8, 125.1, 123.3, 122.7, 120.9, 117.8, 84.1, 44.3, 34.4,
32.1. HRMS (EI) m/z: [M]+ Calc. for: C16H14O, 222.1045,
Found 222.1046.
3-methyl-2-phenylchroman (2j). Yield: 54% (60.4 mg),
transparent oil. Rf = 0.3 (petroleum ether/ethyl acetate,
30:1). 1H NMR (400 MHz, CDCl3) δ 7.41 - 7.36 (m, 4H), 7.31
- 7.29 (m, 1H), 7.16 - 7.12 (m, 1H), 7.09 (d, J =7.3 Hz, 1H),
6.94 (d, J = 8.2 Hz, 1H), 6.92 - 6.88 (m, 1H), 5.19 (d, J = 2.2
Hz, 1H), 3.22 (dd, J = 16.2, 5.8 Hz, 1H), 2.59 (dd, J = 16.3, 3.3
Hz, 1H), 2.41 - 2.36 (m, 1H), 0.80 (d, J = 7.0 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 154.6, 140.4, 130.2, 128.2, 127.3,
127.3, 126.0, 120.9, 120.6, 116.7, 79.7, 33.0, 31.8, 12.6.
6,6a,7,12a-tetrahydro-5H-benzo[c]xanthene (2p). Yield:
o
82% (96.7 mg), yellow solid, mp: 69-71 C. Rf = 0.3
1
(petroleum ether/ethyl acetate, 30:1). H NMR (400 MHz,
CDCl3) δ 7.77 (d, J = 7.6 Hz, 1H), 7.28 (t, J = 7.2 Hz, 1H), 7.23
(d, J = 5.9 Hz, 1H), 7.15 - 7.09 (m, 3H), 6.99 - 6.97 (m, 1H),
6.88 (td, J = 7.4, 1.1 Hz, 1H), 4.79 (d, J = 9.9 Hz, 1H), 3.04 -
2.96 (m, 1H), 2.88 (dd, J = 16.0, 4.9 Hz, 2H), 2.69 (dd, J = 16.2,
11.7 Hz, 1H), 2.15 - 2.05 (m, 2H), 1.70 - 1.59 (m, 1H). 13C{1H}
NMR (101 MHz, CDCl3) δ 155.3, 136.5, 135.8, 129.7, 128.8,
127.5, 127.3, 126.6, 126.2, 122.4, 120.5, 117.2, 78.0, 34.6,
32.8, 28.9, 27.8. HRMS (ESI) m/z: [M+H]+ Calc. for: C17H17O,
237.1274, Found 237.1271.
+
HRMS (EI) m/z: [M] Calc. for: C16H16O, 224.1201, Found
224.1200.
7-methoxy-2-phenylchroman (2k).6 Yield: 71% (85.2 mg),
transparent oil. Rf = 0.3 (petroleum ether/ethyl acetate,
30:1). 1H NMR (400 MHz, CDCl3) δ 7.47 - 7.39 (m, 4H), 7.37
- 7.33 (m, 1H), 7.02 - 6.99 (m, 1H), 6.53 - 6.50 (m, 2H), 5.07
(dt, J = 10.1, 2.5 Hz, 1H), 3.79 - 3.78 (m, 3H), 2.99 - 2.90 (m,
1H), 2.79 - 2.72 (m, 1H), 2.25 - 2.18 (m, 1H), 2.15 - 2.05 (m,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.1, 155.8, 141.7,
130.0, 128.6, 127.9, 126.1, 114.0, 107.5, 101.6, 78.0, 55.4,
30.2, 24.4. HRMS (ESI) m/z: [M+H]+ Calc. for: C16H17O2,
241.1223, Found 241.1219.
3-(2-hydroxyphenyl)-1-phenylpropan-1-one (3a).6 Yield:
o
80% (90.4 mg), white solid, mp: 83-85
C. Rf = 0.3
(petroleum ether/ethyl acetate, 5:1). 1H NMR (400 MHz,
CDCl3) δ 7.97 (dd, J = 8.4, 1.3 Hz, 2H), 7.87 (s, 1H), 7.58 - 7.54
(m, 1H), 7.46 - 7.42 (m, 2H), 7.12 - 7.10 (m, 2H), 6.90 (d, J =
7.5 Hz, 1H), 6.84 (td, J = 7.4, 1.3 Hz, 1H), 3.46 - 3.43 (m, 2H),
3.05 - 3.02 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 202.1,
154.6, 136.2, 133.9, 130.7, 128.8, 128.4, 128.1, 127.9, 120.8,
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The Journal of Organic Chemistry
117.6, 40.5, 23.4. HRMS (ESI) m/z: [M+H]+ Calc. for:
C15H15O2, 227.1067, Found 227.1065.
125.1, 81.26, 35.6, 21.27. HRMS (EI) m/z: [M] Calc. for:
C18H20O, 252.1514, Found 252.1510. Cis: two isomers
mixture (trans:cis=1.08:1) 1H NMR (400 MHz, CDCl3) δ 7.32
(d, J = 8.0 Hz, 4H), 7.16 (d, J = 7.2 Hz, 4H), 5.00 (t, J = 5.2 Hz,
2H), 2.45 - 2.37 (m, 2H), 2.34 (s, 6H), 1.98 - 1.95 (m, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 140.1, 137.0, 129.12,
126.1, 81.23, 34.5, 21.26. HRMS (ESI) m/z: [M]+ Calc. for:
C18H20O, 252.1514, Found 252.1516.
+
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3
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7
8
3-(2-hydroxyphenyl)-1-p-tolylpropan-1-one (3b).6 Yield:
o
80% (96.0 mg), white solid, mp: 130-132 C. Rf = 0.3
(petroleum ether/ethyl acetate, 5:1). 1H NMR (400 MHz,
CDCl3) δ 8.09 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.0
Hz, 2H), 7.12 – 7.08 (m, 2H), 6.91 (d, J = 7.5 Hz, 1H), 6.86 -
6.82 (m, 1H), 3.43 - 3.40 (m, 2H), 3.03 – 3.01 (m, 2H), 2.39
(s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 201.7, 154.6, 144.8,
133.6, 130.6, 129.3, 128.4, 127.9, 127.9, 120.6, 117.5, 40.3,
23.4, 21.7. HRMS (ESI) m/z: [M+H]+ Calc. for: C16H17O2,
241.1223, Found 241.1215.
2,5-bis(4-ethylphenyl)tetrahydrofuran (5c). Yield: 63%
(88.2 mg) (trans:cis = 1:1.0), yellow waxy. Rf = 0.3
(petroleum ether/ethyl acetate, 30:1). Trans: two isomers
mixture (trans:cis=1:0.98) 1H NMR (400 MHz, CDCl3) δ 7.33
(d, J = 7.9 Hz, 4H), 7.19 (d, J = 6.7 Hz, 4H), 5.22 (t, J = 6.6 Hz,
2H), 2.68 - 2.62 (m, 4H), 2.46 - 2.38 (m, 2H), 2.02 - 1.97 (m,
2H), 1.26 - 1.22 (m, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ
143.31, 141.0, 127.95, 125.7, 81.25, 35.6, 28.69, 15.79.
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1-(4-chlorophenyl)-3-(2-hydroxyphenyl)propan-1-one (3e).6
Yield: 87% (113.1 mg), white solid, mp: 145-147 o C. Rf = 0.3
(petroleum ether/ethyl acetate, 5:1). 1H NMR (400 MHz,
CDCl3) δ 7.92 - 7.88 (m, 2H), 7.60 (s, 1H), 7.42 - 7.40 (m, 2H),
7.12 - 7.08 (m, 2H), 6.90 - 6.88 (m, 1H), 6.85 (td, J = 7.4, 1.0
Hz, 1H), 3.43 - 3.40 (m, 2H), 3.04 - 3.01 (m, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ 200.8, 154.5, 140.4, 134.5, 130.7, 129.8,
129.1, 128.1, 127.6, 120.9, 117.4, 40.4, 23.6. HRMS (ESI)
m/z: [M+H]+ Calc. for: C15H14ClO2, 261.0677, Found
261.0673.
1-(4-bromophenyl)-3-(2-hydroxyphenyl)propan-1-one (3s).6
Yield: 76% (115.9 mg), white solid, mp: 135-137 o C. Rf = 0.3
(petroleum ether/ethyl acetate, 5:1). 1H NMR (400 MHz,
CDCl3) δ 7.83 - 7.81 (m, 2H), 7.59 - 7.56 (m, 2H), 7.55 (s, 1H),
7.12 - 7.08 (m, 2H), 6.88 (dd, J = 8.5, 1.2 Hz, 1H), 6.84 (td, J =
7.4, 1.2 Hz, 1H), 3.40 - 3.37 (m, 2H), 3.03 – 3.00 (m, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 201.0, 154.5, 134.9, 132.1,
130.7, 129.9, 129.1, 128.1, 127.6, 120.9, 117.4, 40.4, 23.5.
HRMS (ESI) m/z: [M+H]+ Calc. for: C15H14BrO2, 305.0172,
Found 305.0188.
+
HRMS (ESI) m/z: [M+H] Calc. for: C20H25O, 281.1900,
Found 281.1896. Cis: 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.35
(m, 4H), 7.20 - 7.18 (m, 4H), 5.04 - 5.01 (m, 2H), 2.66 (q, J =
7.2 Hz, 4H), 2.42 – 2.37 (m, 2H), 1.99 - 1.97 (m, 2H), 1.27 -
1.22 (m, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 143.38,
140.3, 127.91, 126.1, 81.24, 34.5, 28.70, 15.76. HRMS (ESI)
m/z: [M+H]+ Calc. for: C20H25O, 281.1900, Found 281.1895.
2,5-bis(4-fluorophenyl)tetrahydrofuran (5d). Yield: 72%
(93.6 mg) (trans:cis = 1:0.98), yellow waxy. Rf = 0.3
(petroleum ether/ethyl acetate, 30:1). Trans: 1H NMR (400
MHz, CDCl3) δ 7.37 - 7.34 (m, 4H), 7.05 - 7.01 (m, 4H), 5.21
(t, J = 6.6 Hz, 2H), 2.48 - 2.42 (m, 2H), 1.99 - 1.93 (m, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 162.2 (d, J = 243 Hz), 139.2
(d, J = 3 Hz), 127.3 (d, J = 8 Hz), 115.3 (d, J = 21 Hz), 80.9,
+
35.8. HRMS (ESI) m/z: [M+H]
Calc. for: C16H15F2O,
261.1086, Found 261.1079. Cis: 1H NMR (400 MHz, CDCl3) δ
7.39 - 7.36 (m, 4H), 7.05 - 7.01 (m, 4H), 5.00 (t, J = 5.3 Hz,
2H), 2.45 - 2.37 (m, 2H), 1.97 - 1.88 (m, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ 162.3 (d, J = 244 Hz), 138.5 (d, J = 3 Hz),
127.7 (d, J = 8 Hz), 115.3 (d, J = 22 Hz), 80.7, 34.4. HRMS (EI)
m/z: [M]+ Calc. for: C16H14F2O, 260.1013, Found 260.1015.
1-(3-bromophenyl)-3-(2-hydroxyphenyl)propan-1-one (3t).6
o
Yield: 70% (106.7 mg), white solid, mp: 80-82 C. Rf = 0.3
(petroleum ether/ethyl acetate, 5:1). 1H NMR (400 MHz,
CDCl3) δ 8.08 (t, J = 1.8 Hz, 1H), 7.88 - 7.85 (m, 1H), 7.66
(ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.55 (s, 1H), 7.30 (t, J = 7.9 Hz,
1H), 7.13 - 7.09 (m, 2H), 6.92 - 6.89 (m, 1H), 6.86 (td, J = 7.4,
1.2 Hz, 1H), 3.39 - 3.36 (m, 2H), 3.04 - 3.01 (m, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 200.6, 154.3, 137.9, 136.5, 131.4,
130.6, 130.3, 128.1, 127.5, 126.9, 123.0, 120.9, 117.3, 40.3,
23.7. HRMS (ESI) m/z: [M+H]+ Calc. for: C15H14BrO2,
305.0172, Found 305.0167.
2-phenyl-5-p-tolyltetrahydrofuran (5e). Yield: 72% (85.6
mg) (trans:cis = 1:0.75), yellow waxy. Rf = 0.3 (petroleum
ether/ethyl acetate, 30:1). Trans: 1H NMR (400 MHz, CDCl3)
δ 7.42 - 7.41 (m, 3H), 7.37 - 7.34 (m, 3H), 7.31 - 7.26 (m, 2H),
7.16 (d, J = 7.9 Hz, 1H), 5.28 - 5.23 (m, 2H), 2.49 - 2.45 (m,
2H), 2.35 (s, 3H), 2.03 - 1.96 (m, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 143.8, 143.7, 140.7, 136.93, 129.16, 128.49, 127.3,
125.7, 81.47, 81.39, 35.7, 35.6, 21.27. HRMS (EI) m/z: [M] +
2,5-diphenyltetrahydrofuran (5a).11 Yield: 80% (89.6 mg)
(trans:cis = 1:0.7), yellow waxy. Rf = 0.3 (petroleum
ether/ethyl acetate, 30:1). Trans: 1H NMR (400 MHz, CDCl3)
δ 7.41 (d, J = 7.3 Hz, 4H), 7.35 (t, J = 7.6 Hz, 4H), 7.28 - 7.24
(m, 2H), 5.26 (t, J = 6.6 Hz, 2H), 2.52 – 2.44 (m, 2H), 2.03 -
1.97 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 143.7, 128.5,
1
Calc. for: C17H18O, 238.1358, Found 238.1362. Cis: H NMR
(400 MHz, CDCl3) δ 7.46 - 7.43 (m, 3H), 7.37 - 7.32 (m, 3H),
7.29 -7.25 (m, 2H), 7.17 (d, J = 7.9 Hz, 1H), 5.07 - 5.02 (m,
2H), 2.45 - 2.39 (m, 2H), 2.35 (s, 3H), 1.99 - 1.95 (m, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 143.1, 143.0, 140.0,
137.05, 129.14, 128.47, 127.4, 126.1, 81.38, 81.31, 34.6,
34.5, 21.29. HRMS (ESI) m/z: [M+H]+ Calc. for: C17H19O,
239.1430, Found 239.1434.
1
127.3, 125.7, 81.4, 35.7. Cis: H NMR (400 MHz, CDCl3) δ
7.45 (d, J = 7.2 Hz, 4H), 7.38 - 7.34 (m, 4H), 7.30 - 7.25 (m,
2H), 5.06 (t, J = 5.3 Hz, 2H), 2.47 - 2.40 (m, 2H), 2.02 - 1.97
(m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 143.0, 128.4,
127.4, 126.1, 81.3, 34.5.
1,4-diphenylbutane-1,4-dione (6a). Yield: 61% (72.6 mg),
white solid, mp: 151-153 o C. Rf = 0.3 (petroleum ether/ethyl
acetate, 5:1). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.3 Hz,
4H), 7.59 - 7.55 (m, 2H), 7.47 (t, J = 7.8 Hz, 4H), 3.46 (s, 4H).
13C{1H} NMR (101 MHz, CDCl3) δ 198.8, 136.9, 133.3, 128.7,
128.2, 32.7. HRMS (ESI) m/z: [M+H]+ Calc. for: C16H15O2,
239.1067, Found 239.1066.
2,5-dip-tolyltetrahydrofuran (5b). Yield: 66% (83.1 mg)
(trans:cis = 1:0.95), yellow waxy. Rf = 0.3 (petroleum
ether/ethyl acetate, 30:1). Trans: 1H NMR (400 MHz, CDCl3)
δ 7.29 (d, J = 8.0 Hz, 4H), 7.15 (d, J = 7.9 Hz, 4H), 5.21 (t, J =
6.6 Hz, 2H), 2.45 - 2.40 (m, 2H), 2.34 (s, 6H), 2.00 - 1.94 (m,
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 140.8, 136.8, 129.14,
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1,4-dimesitylbutane-1,4-dione (6f). Yield: 69% (111.1 mg), 2,6-diphenyltetrahydro-2H-pyran (10a). Yield: 89% (105.9
white solid, mp: 128-130 o C. Rf = 0.3 (petroleum ether/ethyl
acetate, 5:1). 1H NMR (400 MHz, CDCl3) δ 6.85 (s, 4H), 3.12
(s, 4H), 2.28 (s, 6H), 2.26 (s, 12H). 13C{1H} NMR (101 MHz,
CDCl3) δ 208.6, 139.2, 138.5, 132.9, 128.6, 38.1, 21.1, 19.2.
HRMS (ESI) m/z: [M+H]+ Calc. for: C22H27O2, 323.2006,
Found 323.1996.
mg), transparent oil. Rf = 0.3 (petroleum ether/ethyl
acetate, 30:1). Cis: H NMR (400 MHz, CDCl3) δ 7.46 (d, J =
7.8 Hz, 4H), 7.38 -7.34 (m, 4H), 7.29 - 7.25 (m, 2H), 4.59 (d,
J = 11.2 Hz, 2H), 2.09 - 2.05 (m, 1H), 1.95 -1.92 (m, 2H), 1.91
- 1.83 (m, 1H), 1.68 - 1.59 (m, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 143.6, 128.3, 127.3, 125.9, 80.3, 34.0, 24.6. HRMS
(EI) m/z: [M]+ Calc. for: C17H18O, 238.1358, Found 238.1355.
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3
4
5
6
7
8
1
1,4-bis(4-methoxyphenyl)butane-1,4-dione (6g). Yield: 68%
(101.3 mg), white solid, mp: 151-153 o C. Rf = 0.3 (petroleum
2,6-di-p-tolyltetrahydro-2H-pyran (10b). Yield: 91% (121.0
1
o
ether/ethyl acetate, 5:1). H NMR (400 MHz, CDCl3) δ 8.01
mg), white solid, mp: 38-40 C. Rf = 0.3 (petroleum
9
(d, J = 8.8 Hz, 4H), 6.94 (d, J = 8.8 Hz, 4H), 3.86 (s, 6H), 3.39
(s, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 197.5, 163.6, 130.5,
130.0, 113.8, 55.6, 32.4. HRMS (ESI) m/z: [M+H]+ Calc. for:
C18H19O4, 299.1278, Found 299.1277.
ether/ethyl acetate, 10:1). Cis: 1H NMR (400 MHz, CDCl3) δ
7.32 (d, J = 8.0 Hz, 4H), 7.15 - 7.13 (m, 4H), 4.53 (dd, J = 11.3,
1.5 Hz, 2H), 2.33 (s, 6H), 2.05 - 2.00 (m, 1H), 1.90 - 1.79 (m,
3H), 1.64 - 1.55 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ
140.7, 136.8, 128.9, 125.9, 80.18, 33.9, 24.6, 21.2. HRMS
(ESI) m/z: [M+H]+ Calc. for: C19H23O, 267.1743, Found
267.1743.
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1,4-bis(4-bromophenyl)butane-1,4-dione (6h). Yield: 85%
(167.4 mg), white solid, mp: 175-177 o C. Rf = 0.3 (petroleum
1
ether/ethyl acetate, 5:1). H NMR (400 MHz, CDCl3) δ 7.88
(d, J = 8.6 Hz, 4H), 7.63 - 7.60 (m, 4H), 3.40 (s, 4H). 13C{1H}
NMR (101 MHz, CDCl3) δ 197.6, 135.5, 132.1, 129.7, 128.5,
32.5. HRMS (EI) m/z: [M]+ Calc. for: C16H12Br2O2, 393.9204,
Found 393.9196.
2,6-bis(4-chlorophenyl)tetrahydro-2H-pyran (10c). Yield:
o
85% (130.0 mg), white solid, mp: 95-97 C. Rf = 0.3
(petroleum ether/ethyl acetate, 30:1). Cis: 1H NMR (400
MHz, CDCl3) δ 7.36 - 7.33 (m, 4H), 7.32 - 7.29 (m, 4H), 4.55 -
4.51 (m, 2H), 2.06 - 2.02 (m, 1H), 1.90 - 1.79 (m, 3H), 1.59 -
1.50 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 141.8, 133.0,
128.5, 127.3, 79.6, 33.8, 24.3. HRMS (EI) m/z: [M]+ Calc. for:
C17H16Cl2O, 306.0578, Found 306.0580.
6-phenyl-6H-benzo[c]chromene (8a). Yield: 72% (92.9 mg),
o
white solid, mp: 73-75 C. Rf = 0.3 (petroleum ether/ethyl
1
acetate, 10:1). H NMR (400 MHz, CDCl3) δ 7.78 - 7.74 (m,
2H), 7.41 - 7.32 (m, 6H), 7.24 - 7.19 (m, 2H), 7.04 (td, J = 7.6,
1.3 Hz, 1H), 6.99 (dd, J = 8.0, 1.2 Hz, 1H), 6.85 (d, J = 7.6 Hz
1H), 6.16 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.7,
139.6, 134.0, 130.1, 129.7, 128.6, 128.6, 128.5, 128.2, 127.7,
126.3, 123.2, 122.9, 122.2, 118.0, 79.7. HRMS (EI) m/z: [M]+
Calc. for: C19H14O, 258.1045, Found 258.1043.
1,3-diphenyl-1,3-dihydroisobenzofuran (12a).13 Yield: 89%
(121.0 mg), yellow waxy. Rf = 0.3 (petroleum ether/ethyl
acetate, 30:1). two isomers mixture (trans:cis=1.2:1) 1H
NMR (500 MHz, Acetone) δ 7.54 - 7.50 (m, 4.8H), 7.47 - 7.38
(m, 6.3H), 7.36 -7.35 (m, 1H), 7.32 - 7.31 (m, 2.6H), 7.22 -
7.20 (m, 1.2H, trans isomer), 7.08 - 7.06 (m ,1H, cis isomer),
6.52 (s, 1.2H, trans isomer), 6.20 (s, 1H, cis isomer). 13C{1H}
NMR (101 MHz, Acetone) δ 144.12, 143.62, 142.91, 142.78,
129.30, 128.91, 128.70, 128.61, 128.58, 128.40, 127.38,
123.06, 122.86, 86.70, 85.85.
1,3-dihydroisobenzofuran (12b).19 Yield: 41% (24.0 mg),
transparent oil. Rf = 0.3 (petroleum ether/ethyl acetate,
30:1). 1H NMR (400 MHz, CDCl3) δ 7.27 - 7.22 (m, 4H), 5.11
(s, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 139.1, 127.3, 121.0,
73.7.
8-methoxy-6-phenyl-6H-benzo[c]chromene (8b). Yield: 78%
o
(112.3 mg), white solid, mp: 91-93 C. Rf = 0.3 (petroleum
ether/ethyl acetate, 10:1). 1H NMR (500 MHz, CDCl3) δ 7.71
- 7.67 (m, 2H), 7.39 - 7.32 (m, 5H), 7.16 (t, J = 7.6 Hz, 1H),
7.02 (t, J = 7.5 Hz, 1H), 6.98 - 6.93 (m, 2H), 6.40 (d, J = 2.6 Hz,
1H), 6.12 (s, 1H), 3.75 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 159.4, 152.9, 139.5, 135.6, 128.7, 128.6, 128.5,
128.2, 123.7, 123.1, 122.9, 122.5, 122.2, 117.9, 113.9, 112.1,
79.78, 55.46. HRMS (EI) m/z: [M]+ Calc. for: C20H16O2,
288.1150, Found 288.1154.
2-methyl-6-phenyl-6H-benzo[c]chromene (8c). Yield: 70%
3-(2-methoxyphenyl)-1-phenylpropan-1-one (14). Yield:
51% (61.2 mg), transparent oil. Rf = 0.3 (petroleum
ether/ethyl acetate, 10:1). 1H NMR (400 MHz, CDCl3) δ 7.98
- 7.96 (m, 2H), 7.56 - 7.52 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H),
7.21 - 7.18 (m, 2H), 6.91 - 6.84 (m, 2H), 3.82 (s, 3H), 3.28 -
3.24 (m, 2H), 3.06 - 3.04 (m, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 200.1, 157.6, 137.1, 133.0, 130.3, 129.6, 128.6,
128.2, 127.6, 120.6, 110.3, 55.3, 39.0, 25.8. HRMS (ESI) m/z:
[M+H]+ Calc. for: C16H17O2, 241.1223, Found 241.1221.
(95.2 mg), transparent oil. Rf = 0.3 (petroleum ether/ethyl
1
acetate, 10:1). H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.9
Hz, 1H), 7.56 (s, 1H), 7.41 - 7.32 (m, 6H), 7.25 - 7.21 (m, 1H),
7.03 (d, J = 8.3 Hz, 1H), 6.91 (dd, J = 8.4, 1.9 Hz, 1H), 6.86 (d,
J = 7.4 Hz, 1H), 6.13 (s, 1H), 2.36 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 151.5, 139.7, 134.2, 131.3, 130.4, 130.3,
128.5, 128.5, 128.4, 128.2, 127.5, 126.3, 123.6, 122.5, 122.1,
117.7, 79.7, 21.0. HRMS (EI) m/z: [M]+ Calc. for: C20H16O,
272.1201, Found 272.1205.
3-(2-methoxyphenyl)-1-phenylpropan-1-ol (15). Yield: 11%
(13.3 mg), transparent oil. Rf = 0.3 (petroleum ether/ethyl
acetate, 5:1). 1H NMR (400 MHz, CDCl3) δ 7.35 - 7.33 (m, 4H),
7.27 - 7.24 (m, 1H), 7.21 - 7.14 (m, 2H), 6.90 (t, J = 7.3 Hz,
1H), 6.86 (d, J = 8.2 Hz, 1H), 4.63 (dd, J = 8.3, 4.8 Hz, 1H),
3.83 (s, 3H), 2.78 - 2.73 (m, 2H), 2.08 - 1.97 (m, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 157.4, 144.7, 130.2, 130.1, 128.5,
127.4, 127.3, 126.0, 120.8, 110.4, 73.6, 55.4, 39.5, 26.5.
HRMS (ESI) m/z: [M-H2O+H]+ Calc. for: C16H17O, 225.1274,
Found 225.1269.
6-methyl-6H-benzo[c]chromene (8d). Yield: 65% (63.7 mg),
yellow oil. Rf = 0.3 (petroleum ether/ethyl acetate, 30:1). 1H
NMR (400 MHz, CDCl3) δ 7.76 - 7.71 (m, 2H), 7.38 (td, J = 7.6,
1.4 Hz, 1H), 7.31 (td, J = 7.4, 1.4 Hz, 1H), 7.28 - 7.23 (m, 1H),
7.19 - 7.16 (m, 1H), 7.06 (td, J = 7.5, 1.3 Hz, 1H), 7.01 (dd, J =
8.0, 1.3 Hz, 1H), 5.29 (q, J = 6.6 Hz, 1H), 1.64 (d, J = 6.6 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.5, 135.9, 129.5,
129.4, 128.2, 127.9, 124.1, 123.2, 122.7, 122.2, 121.9, 117.9,
73.7, 20.3. HRMS (ESI) m/z: [M]+ Calc. for: C14H12O,
196.0888, Found 196.0887.
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The Journal of Organic Chemistry
(5) For selected examples of synthesis of chromans, see: (a)
Nakamura, S.; Uchiyama, M.; Ohwada, T. 4H-1,2-Benzoxazines with
Electron-Withdrawing Substituents on the Benzene Ring:ꢀ
Synthesis and Application as Potent Intermediates for Oxygen-
Functionalized Aromatic Compounds. J. Am. Chem. Soc. 2003, 125,
5282-5283. (b) Mazimba, O.; Masesane, I. B.; Majinda, R. R. An
efficient synthesis of flavans from salicylaldehyde and
acetophenone derivatives. Tetrahedron Lett. 2011, 52, 6716-6718.
(c) Shee, S.; Paul, B.; Panja, D.; Roy, B. C.; Chakrabarti, K.; Ganguli,
K.; Das, A.; Das, G. K.; Kundu, S. Tandem Cross Coupling Reaction of
Alcohols for Sustainable Synthesis of β-Alkylated Secondary
Alcohols and Flavan Derivatives. Adv. Synth. Catal. 2017, 359,
3888-3893. For selected examples of synthesis of
tetrahydrofurans, see: (d) Shibata, T.; Fujiwara, R.; Ueno, Y.
Cationic platinum-catalyzed etherification by intra-and
intermolecular dehydration of alcohols. Synlett 2005, 152-154. (e)
Chan, C.-K.; Tsai, Y.-L.; Chang, M.-Y. Bi(OTf)3 catalyzed
disproportionation reaction of cinnamyl alcohols. Tetrahedron
2017, 73, 3368-3376. For selected examples of synthesis of
chromene, see: (f) Wang, B.; Xu, M.; Li, S.; Song, H.; Wang, B. A
General Synthetic Route to 6,6-Substituted-6H-dibenzo[b,d]pyrans
from Dibenzofuran. J. Org. Chem. 2006, 71, 8291-8293. (g) Zhang,
J.; Ajitha, M. J.; Liu, L. He, K.; Dai, B.; Huang, K.-W. Enantioselective
2-(3-hydroxy-3-phenylpropyl)phenol (16a). Yield: 60% (68.4
o
1
2
3
4
5
6
7
8
mg), white solid, mp: 85-87
C. Rf = 0.3 (petroleum
1
ether/ethyl acetate, 2:1). H NMR (400 MHz, d6-DMSO) δ
9.12 (s, 1H), 7.29 - 7.27 (m, 4H), 7.20 - 7.15 (m, 1H), 6.97 (d,
J = 7.4 Hz, 1H), 6.93 (td, J = 7.7, 1.7 Hz, 1H), 6.71 (d, J = 7.9
Hz, 1H), 6.65 (t, J = 7.4 Hz, 1H), 5.15 (s, 1H), 4.48 (t, J = 6.5
Hz, 1H), 2.61 - 2.54 (m, 1H), 2.43 - 2.39 (m, 1H), 1.83 - 1.77
(m, 2H). 13C{1H} NMR (101 MHz, d6-DMSO) δ 155.0, 146.3,
129.5, 128.1, 127.9, 126.6, 126.5, 125.8, 118.8, 114.8, 72.1,
39.2, 26.2. HRMS (EI) m/z: [M]+ Calc. for: C15H16O2,
228.1150, Found 228.1154.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
1H and 13C{1H} NMR spectra for all products (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: wangxiaojian@imm.ac.cn
Notes
The authors declare no competing financial interest.
Organocatalyzed
Oxa-Michael-Aldol
Cascade
Reactions:
Construction of Chiral 4H-Chromenes with a Trifluoromethylated
Tetrasubstituted Carbon Stereocenter. Adv. Synth. Catal. 2015, 57,
967-973. (h) Yang, L.; Neuburger, M.; Baudoin, O. Chiral
Bifunctional Phosphine-Carboxylate Ligands for Palladium(0)-
Catalyzed Enantioselective C-H Arylation. Angew. Chem. Int. Ed.
2018, 57, 1394-1398. For selected examples of synthesis of
tetrahydropyrans, see: (i) Jiang, X.; London, E. K.; Morris, D. J.;
Clarkson, G. J.; Wills, M. Gold-catalysed cyclic ether formation from
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ACKNOWLEDGMENT
This research is supported by the National Natural Science
Foundation of China (Nos. 81473096 and 81602949) and
and CAMS Collaborative Innovation Project (No. 2017-I2M-
3-011). We thank Prof. Hui Lv (Wuhan University), Prof.
Xueliang Huang (FJIRSM) and Dr. Xiangyu Chen for helpful
discussions and valuable suggestions.
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