Chromium(III)-Catalyzed Addition of Water and Alcohol to α,β-Unsaturated Ketones for the Synthesis of β-Hydroxyl and β-Alkoxyl Ketones in Aqueous Media

Article abstract of DOI:10.1021/acs.joc.8b01584

An efficient chromium(III) chloride-catalyzed Michael-type reaction of water or alcohol with α,β-unsaturated ketones is developed. A variety of α,β-unsaturated ketones effectively reacted with either water or alcohols to give the corresponding β-hydroxyl ketones or β-alkoxyl ketones in modest to high yields with excellent compatibility to various functional groups. The approach was further utilized for the preparation of synthetically useful compounds containing tetrahydrofuran skeleton.

Full text of DOI:10.1021/acs.joc.8b01584

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Article
Chromium(III)-Catalyzed Addition of Water and Alcohol
to #,#-Unsaturated Ketones for The Synthesis of #-
Hydroxyl and #-Alkoxyl Ketones in Aqueous Media
Jin-Jin Yun, Xuan-Yu Liu, Wei Deng, Xue-Qiang Chu, Zhi-Liang Shen, and Teck-Peng Loh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01584 • Publication Date (Web): 15 Aug 2018
Downloaded from http://pubs.acs.org on August 15, 2018
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Chromium(III)ꢀCatalyzed Addition of Water and Alcohol to α,βꢀUnsaturated Ketones for
The Synthesis of βꢀHydroxyl and βꢀAlkoxyl Ketones in Aqueous Media
8
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JinꢀJin Yun,a XuanꢀYu Liu,a Wei Deng,a XueꢀQiang Chu,a ZhiꢀLiang Shen,a,* and TeckꢀPeng
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Loha,b,
*
a Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National
Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing 211816,
China
Eꢀmail: ias_zlshen@njtech.edu.cn
b Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371, Singapore
Eꢀmail: teckpeng@ntu.edu.sg
Abstract: An efficient chromium(III) chlorideꢀcatalyzed Michaelꢀtype reaction of water or alcohol
with α,βꢀunsaturated ketones is developed. A variety of α,βꢀunsaturated ketones effectively reacted with
either water or alcohols to give the corresponding βꢀhydroxyl ketones or βꢀalkoxyl ketones in modest
to high yields with excellent compatibility to various functional groups. The approach was further
utilized for the preparation of synthetically useful compounds containing tetrahydrofuran skeleton.
INTRODUCTION
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βꢀHydroxyl carbonyl compounds are not only pivotal building blocks in synthetic organic chemistry,
but also structural units which are ubiquitously present in natural and unnatural products.1,2 Among the
various methods developed so far, the aldolꢀtype reaction of aldehyde with ketone2 serves as a practical
strategy for the production of βꢀhydroxyl carbonyl compound. Alternatively, this type of compound
could also be synthesized by using a twoꢀstep sequence involving enone epoxidation and reductive
ringꢀopening of the thusꢀformed epoxide.3 In contrast, the direct conjugate addition of water to
α,βꢀunsaturated carbonyl compound should represent one of the most straightforward methods for the
production of βꢀhydroxyl carbonyl compound, which is also a common transformation in biological
systems. However, in most cases, this type of addition reaction is very difficult to achieve by synthetic
chemistry because water as an uncharged nucleophile is too unreactive to undergo Michaelꢀtype
reaction, which is in sharp contrast to the commonly used more reactive carbon and nitrogen
nucleophiles.4 In addition, the reaction between water and α,βꢀunsaturated carbonyl compound is
believed to be an equilibrium and the balance predominantly resides at the side of reactant, because the
in situ formed βꢀhydroxyl carbonyl compound tends to eliminate a molecule of water to regenerate
thermodynamically more stable α,βꢀunsaturated carbonyl compound, even when the reaction is
performed in aqueous media. Therefore, the direct preparation of βꢀhydroxyl carbonyl compound by
means of the conjugate addition of water to electronꢀdeficient alkene has not been widely investigated
and remains to be a big challenge. For a representative example, Bergman and Toste had pioneeringly
reported a phosphineꢀinduced conjugate addition reaction of α,βꢀunsaturated carbonyl compound with
water and alcohol, where the formation of a strong base as reaction catalyst has been proposed.5
However, in their reaction system, most of the reported cases employing alcohol instead of water as
nucleophile, and only one example of conjugate addition using water as Michael donor has been
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reported. Later, enantioselective versions of the Michaelꢀtype reactions involving water and very
special substrates of α,βꢀunsaturated 2ꢀacyl imidazole/pyridine by using DNAꢀbased copper catalyst or
artificial metalloenzymes were revealed by Feringa and Roelfes.6 In recent years, Hanefeld and
coꢀworkers have made considerable efforts to develop enzymeꢀ and amino acidꢀcatalyzed conjugate
additions of water to cyclic enones or lactones, but mostly in poor to moderate yields, which further
demonstrate the challenge of the reactions.7,8 Very recently, our group reported a direct method for
accessing βꢀhydroxyl ketones via the oxyꢀMichael addition of water to enones in the coꢀexistence of a
catalytic amount of indium triflate (20 mol%) in waterꢀcontaining solvent.9
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In recent decades, the use of Cr(II) salt as single electron transfer reagent in organic synthesis has
been widely investigated.10 In comparison, the utilization of Cr(III) salt as Lewis acid catalyst for
organic reactions are rather limited.11 In continuation of our endeavours in developing organic reactions
in aqueous media,12,13 herein we report that a catalytic amount of CrCl3 (20 mol%) serves as an
efficient catalyst which is capable of catalyzing the direct conjugate addition reaction of water with
α,βꢀunsaturated ketones in waterꢀcontaining solvent system, providing an easy entry to βꢀhydroxyl
ketones in reasonable yields. In addition, an array of alcohols were also proven to be suitable Michael
donor for the transformation, which reacted with α,βꢀunsaturated ketones to give the corresponding
βꢀalkoxyl ketones in modest to high yields. The approach was also successfully utilized for the
preparation of synthetically versatile compounds containing tetrahydrofuran skeleton.
RESULTS AND DISCUSSION
Preliminary studies were carried out to optimize the reaction conditions for the synthesis of
βꢀhydroxyl ketone 2a by employing 1ꢀphenylpropꢀ2ꢀenꢀ1ꢀone (1a) as a substrate in CH3CN/H2O. As
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listed in Table 1, a wide variety of metallic salts (e.g., CuCl2, CeCl3, ZnCl2, MnCl2, PbCl2, FeCl3) were
employed as Lewis acid catalyst for the hydration (entries 1ꢀ12). Of the various catalysts screened,
CrCl3 emerged to be a suitable catalyst for the addition reaction, leading to the desired βꢀhydroxyl
carbonyl compound 2a in 73% NMR yield (71% isolated yield) when the reaction was performed in
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o
CH3CN/H2O (1:2) at 80 C for 24 h (entry 12). Subsequently, several chromium salts, including
Cr(NO3)3, Cr(acac)3, Cr(OAc)3, and CrPO4, were introduced into the reaction system to explore their
catalytic activity for the Michaelꢀtype reaction (entries 13ꢀ17). It was found that, except Cr(NO3)3
which was capable of catalyzing the reaction with similarly high performance (72% NMR yield, entry
14), the use of all the other chromium catalysts gave rise to the target product in relatively low yield.
Thus, chromium trichloride was utilized as the catalyst for the addition reaction of water molecule to
α,βꢀunsaturated ketones in the following reactions.
Table 1. Optimization of Reaction Conditionsa
entry
1
catalyst
CuCl2
yield (%)b
31
38
2
CeCl3
3
ZnCl2
51
4
MnCl2
22
5
PbCl2
15
6
SnCl2
57
7
FeCl3
54
8
Ni(OTf)2
Fe(OTf)3
Fe(OTf)2
Fe(ClO4)3
CrCl3
13
9
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12
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14
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14
10
73 (71)c
CrCl2
57
Cr(NO3)3
Cr(acac)3
Cr(OAc)3
72
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17
Unless otherwise noted, the reactions were
performed at 80 oC for 24
by using
CrPO4
27
a
h
1ꢀphenylꢀpropꢀ2ꢀenꢀ1ꢀone (1a, 1 mmol) and Lewis
acid catalyst (0.20 mmol) in CH3CN/H2O (1 mL/2
b
mL). Yield was determined by NMR analysis of
the
crude
reaction
mixture
by
using
c
1,4ꢀdimethoxyꢀbenzene as an internal standard.
Isolated yield of analytically pure product.
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Encouraged by the above results, we subsequently investigated the general applicability of the
method for the preparation of βꢀhydroxyl ketones by utilizing various enones as substrates. As
summarized in Table 2, in most cases, moderate to good yields of the desired products 2bꢀr were
obtained. Aromatic enones containing either electronꢀwithdrawing or electronꢀdonating groups could
be well amenable to the mild reaction conditions (entries 1ꢀ11). Functional groups, such as NO2, CN,
CO2Me, and halogen, could be well tolerated under optimized reaction conditions (entries 1ꢀ7). The
reactions worked equally well with aromatic enones bearing methoxy substituent on its para, meta, and
ortho position, leading to the corresponding βꢀhydroxyl ketones 2jꢀl in 58ꢀ90% yields (entries 9ꢀ11).
Notably, α,βꢀunsaturated ketones possessing thienyl, furyl, and benzofuryl substituents, which were
more or less sensitive to acidic conditions, were also proven to be suitable candidates for the conjugate
addition reaction in aqueous media, producing the anticipated products 2nꢀp in moderate to good yields
(entries 13ꢀ15). In a same manner, aliphatic enones could also be effectively converted into the target
products 2qꢀr in acceptable yields under wellꢀestablished conditions (entries 16ꢀ17). Unfortunately, the
analogous reactions involving α,βꢀunsaturated ketones substituted by a methyl group in its β or α
position proceeded sluggishly to give the expected product 2s in 36% yield and product 2t in 0% yield
(entries 18ꢀ19).
Table 2. Substrate Scope Study by Using
Various Enonesa
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yield
(%)b
entry
substrate
product
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1
R = 4ꢀNO2
R = 3ꢀNO2
R = 4ꢀCN
R = 4ꢀCO2Me
R = 4ꢀF
2b
2c
2d
2e
2f
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61
90
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R = 4ꢀCl
2g
2h
2i
7
R = 4ꢀBr
8
R = 4ꢀMe
R = 4ꢀOMe
R = 3ꢀOMe
R = 2ꢀOMe
9
2j
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11
2k
2l
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2m
68
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2n
2o
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88
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16
2p
2q
51
56
17
18
2r
2s
2t
50
36
19
NR
a
o
The reactions were performed at 80 C for 24 h
by using enone 1 (1 mmol) and CrCl3 (0.20
mmol) in CH3CN/H2O (1 mL/2 mL). Isolated
yield of analytically pure product.
b
With the success of above reactions, next we attempted to expand the substrate scope of the reaction
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to encompass alcohols as starting materials.14 As outlined in Table 3, the reactions involving
1ꢀ(4ꢀmethoxyphenyl)propꢀ2ꢀenꢀ1ꢀone (1j) and a spectrum of alcohols 3 proceeded efficiently in the
presence of 20 mol% CrCl3 to deliver the desired products 4aꢀl in 46ꢀ99% yields. It was observed that
varying the substituent of aliphatic alcohols had little effect on the outcome of the reaction, leading to
the βꢀalkoxyl ketones 4aꢀd in excellent yields (entries 1ꢀ4). Alcohols containing alkenyl and alkynyl
moieties also reacted smoothly to furnish the corresponding products 4gꢀh in 80ꢀ90% yields (entries
7ꢀ8). In the case of benzyl alcohols, 82ꢀ84% yields of products 4iꢀj could also be produced under
wellꢀestablished conditions (entries 9ꢀ10). Moreover, substrates containing various important
functional groups, including halogen, cyano, and ester, effectively underwent the present
transformations under mild reaction conditions, giving rise to the products 4e, 4f, and 4j in good yields
ranging between 84% and 88% (entries 5, 6 and 10). Furthermore, sterically congested secondary
alcohols were also capable of efficiently participating in the reaction with acceptable performance
(entries 2, 11 and 12).
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Table 3. Substrate Scope Study by Using Various
Alcoholsa
yield
(%)b
entry
ROH
product
1
2
3
EtOHc
iꢀPrOHc
nꢀBuOHc
4a
4b
4c
99
95
98
4
4d
92
5
6
7
4e
4f
86
88
90
4g
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4h
4i
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4j
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4k
4l
57
46
a
Unless otherwise noted, the reactions were
performed at 80 oC for 24
by using
1ꢀ(4ꢀmethoxyphenyl)propꢀ2ꢀenꢀ1ꢀone (1j, 1 mmol),
alcohol 3 (6 mmol) and CrCl3 (0.20 mmol) in
CH3CN (1 mL). b Isolated yield of analytically pure
h
c
product. The reaction was directly performed in
alcohol (ROH, 3 mL) instead of in CH3CN.
In cases where the reactions were carried out in a mixture of water and alcohol, it was found that
alcohol exhibited better reactivity than water. As shown in Scheme 1, when substrate 1j was treated
with EtOH/H2O (volume ratio is 1:1) in the presence of 20 mol% CrCl3 at 80 oC for 12 h, a mixture of
products 2j and 4a (overall 75% yield) was obtained in the molar ratio of 1:2, further implying that
water was a relatively poor nucleophile for the conjugate addition reaction as compared to alcohol.
Scheme 1. Competitive Reaction Involving Substrate 1j in the Presence of Both Water and
Ethanol
It should be noted that the reactions of cyclic enones with water normally proceeded sluggishly,
presumably as a result of the ready retroꢀaldolꢀtype reaction of the in situ formed product under the
slightly acidic conditions. For instance, the reaction of 2ꢀcyclohexenꢀ1ꢀone (1u) with water proceeded
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poorly to deliver the corresponding product in 7% NMR yield and it completely decomposed upon
purification by silica gel column chromatography. In contrast, the identical reactions employing
sevenꢀmembered and eightꢀmembered enones 1vꢀw led to the corresponding products 2vꢀw with
remarkably improved yields of 47% and 72% (Scheme 2), indicating the relatively increased stability
of the generated βꢀhydroxyl ketones from sixꢀ to eightꢀmembered ring.
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Scheme 2. Substrate Scope Study by Using Cyclic
Enones and Water
The same trend, but with improved efficiency, was also observed when the above cyclic enones
reacted with alcohols (including ethanol, 3ꢀchloropropanꢀ1ꢀol, benzyl alcohol, and even isopropanol).
As shown in Table 4, the reactions involving 6ꢀ, 7ꢀ, and 8ꢀmembered enones with alcohols took place
with enhanced performance (as compared to water addition) in the presence of 20 mol% CrCl3 to
generate the corresponding βꢀalkoxyl ketones 4mꢀu in 27ꢀ95% yields, with the eightꢀmembered enone
1w being the most efficient substrate for the addition reaction.
Table 4. Substrate Scope Study by Using Cyclic
Enones and Various Alcoholsa
yield
(%)b
entry
substrate
ROH
product
1
2
1u
1v
EtOHc
EtOHc
4m
4n
27
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1v
1v
iꢀPrOHc
4o
4p
4q
4r
4s
4t
43
83
62
77
48
83
95
1v
1w
1w
1w
1w
EtOHc
iꢀPrOHc
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4u
a Unless otherwise noted, the reactions were performed
at room temperature for 24 h by using cyclic enones
1uꢀw (1 mmol), alcohol 3 (6 mmol) and CrCl3 (0.20
b
mmol) in CH3CN (1 mL).
Isolated yield of
c
analytically pure product. The reaction was directly
performed in alcohol (ROH, 3 mL) instead of in
CH3CN.
To further demonstrate the potential synthetic application of this method, several tetrahydrofuran
derivatives, which are widely featured in natural products and pharmaceutically active compounds,
were synthesized by using this strategy.15 As outlined in Scheme 3, the intermediates of βꢀalkoxyl
ketones 5aꢀc were isolated in moderate to good yields from the reactions of α,βꢀunsaturated ketones
with 2ꢀiodoethanol (3m) in the presence of a catalytic amount of chromium trichloride. Next, the
obtained βꢀalkoxyl ketones 5aꢀc were subjected to NaNH2ꢀpromoted intramolecular nucleophilic
annulation by means of an SN2ꢀtype reaction route, affording the corresponding tetrahydrofuran
derivatives 6aꢀc in 66ꢀ87% yields.
Scheme 3. Synthesis of Tetrahydrofuran Derivatives
Mechanistically, CrCl3 is believed to enhance the electrophilicity and reactivity of the
electronꢀdeficient CꢀC double bond of α,βꢀunsaturated ketones by coordinating with the carbonyl group,
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which effectively contributed to the subsequent conjugate addition with water or alcohol.
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CONCLUSION
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In summary, we have developed a chromium(III) chlorideꢀcatalyzed methodology to achieve the
straightforward preparation of synthetically important βꢀhydroxyl and βꢀalkoxyl ketones through the
hydration and hydroalkoxylation of α,βꢀunsaturated ketones with water and alcohols. The reactions
proceeded smoothly with wide substrate scope and broad functional group compatibility. As for the
reactivity of cyclic enones for undergoing the conjugate addition with water and alcohol, it follows the
order of 8ꢀmembered enone > 7ꢀmembered enone > 6ꢀmembered enone. A twoꢀstep sequence
encompassing the CrCl3ꢀcatalyzed reaction of 2ꢀiodoethanol with α,βꢀunsaturated ketones as well as
the ensuing baseꢀmediated intramolecular ring closure was designed for the ready access to
synthetically useful tetrahydrofuran derivatives.
EXPERIMENTAL SECTION
General information. Unless otherwise stated, all reagents were purchased from commercial
suppliers and used without further purification. The solvents used in the reactions were analytical grade
(≥ 98%), which were purchased from Sahn Chemical Technology (Shanghai) Co., Ltd. All reactions
were carried out under air using undistilled solvent, without the need of precautions to exclude air and
moisture unless otherwise noted. Melting points were recorded on an Electrothermal digital melting
1
point apparatus. IR spectra were recorded on a FTꢀIR spectrophotometer using KBr optics. H, 19F, and
13C NMR spectra were recorded in CDCl3 on Bruker Avance 400 MHz spectrometerss.
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Tetramethylsilane (TMS) served as internal standard for H NMR and 13C NMR. High resolution mass
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spectra (HRMS) were recorded on a Waters Q–TOF Permier Spectrometer (ESI or EI source).
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General procedure for the synthesis of α,βꢀunsaturated ketones.
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Method A: Synthesis of 1ꢀphenylpropꢀ2ꢀenꢀ1ꢀone (1a).16 To
a
stirred solution of
3ꢀchloropropiophenone (10.12 g, 60.0 mmol, 1.0 equiv.) in chloroform (100 mL) was dropwise added
triethylamine (20 mL, 144.0 mmol, 2.4 equiv.) for 30 min under argon atmosphere. The reaction
mixture was stirred for 18 h followed by washing with aq. HCl (0.1 M, 2 x 60 mL), distilled water (2 x
60 mL), saturated aq. NaHCO3 (60 mL), and brine (60 mL). The organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel
column chromatography using ethyl acetate/petroleum ether as eluent to give the corresponding
product 1a as colorless oil.
Method B: Synthesis of aryl vinyl ketone (1bꢀq).17 To a mixture of methyl aryl ketone (10.0 mmol,
1.0 equiv.) and paraformaldehyde (1.80 g, 60.0 mmol, 6.0 equiv.) in THF (20 mL) were added
diisopropylammonium trifluoroacetate (2.13 g, 10.0 mmol) and trifluoroacetic acid (0.11 g, 1.0 mmol,
10 mol%) in Schlenk tube. After the reaction mixture was refluxed for 36 h, the solvent was removed
under reduced pressure. The residue was dissolved in Et2O, and the ethereal solution was sequentially
washed with aq. HCl (1 M, 60 mL), NaOH (1 M, 60 mL), and brine (120 mL), respectively. The
organic phase was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product
was purified by silica gel column chromatography using ethyl acetate/petroleum ether as eluent to give
the corresponding aryl vinyl ketone 1bꢀq.
Method C: Synthesis of transꢀ1ꢀphenylbutꢀ2ꢀenꢀ1ꢀone (1s).18 2, 3ꢀtransꢀCrotonyl chloride (4.87 g,
46.6 mmol, 1.0 equiv.) was suspended in benzene (13.0 mL, 150 mmol, 3.2 equiv.), and AlCl3 (10.00 g,
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75.0 mmol, 1.6 equiv.) was added while the mixture was cooled at 0 oC. The mixture was stirred for 1 h
and it was quenched by slowly pouring into a mixture of aq. HCl (1 M, 200 mL) and iceꢀwater (150
mL). Extraction with dichloromethane (3 × 50 mL) followed by washing with aq. NaOH (1 M, 20 mL)
and drying over anhydrous Na2SO4 yielded the crude product after removal of the solvent. The residue
was purified by silica gel column chromatography using ethyl acetate/petroleum ether as eluent to give
the pure product 1s as colorless oil.
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Method D: Synthesis of 2ꢀmethylꢀ1ꢀphenylpropꢀ2ꢀenꢀone (1t).19 To a stirred solution of
propiophenone (1.34 g, 10.0 mmol, 1.0 equiv.) in DMF (25 mL) was sequentially added
paraformaldehyde (1.80 g, 60.0 mmol, 6.0 equiv.), piperidine (0.13 mL, 1.3 mmol, 0.13 equiv.) and
AcOH (0.13 mL, 2.2 mmol, 0.22 equiv.). The resulting mixture was heating at 90 °C for 24 h. After
cooling down, water (60 mL) was added to the residue and the mixture was extracted with Et2O (3 x 60
mL). The combined organic layers were washed with water (60 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under vacuum to yield the crude product. The residue was purified by silica
gel column chromatography using ethyl acetate/petroleum ether as eluent to give the pure product 1t as
colorless oil.
Method E: Synthesis of (Z)ꢀcyclooctꢀ2ꢀenꢀ1ꢀone (1w).20 To a solution of LDA (90.0 mmol, 3.0
equiv.) was added cyclooctanone (3.79 g, 30.0 mmol, 1.0 equiv.) which was dissolved in THF (60 mL)
at ꢀ78 °C. After stirring for 1 h, the solution was warmed to room temperature and stirred for an
additional 1 h at room temperature. After reꢀcooling to ꢀ78 °C, TMSCl (8.0 mL, 90.0 mmol, 3.0 equiv.)
was added, and stirring was continued for 1 h. Then the reaction solvent was removed in vacuo and the
residue was purified by neutral alumina column chromatography using petroleum ether as eluant to
give the TMS enol ether product (3.97 g, ~ 20 mmol). Subsequently, IBX (11.20 g, 40 mmol, 2.0
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equiv.) and MPO (5.01 g, 40 mmol, 2.0 equiv.) were dissolved in DMSO (0.4 M) in an equimolar ratio
at ambient temperature (the solvent used was not dried, and no precautions were taken to exclude
moisture or oxygen from the reaction vessel). The IBX·MPO solution was added in one portion at
ambient temperature to the TMS enol ether dissolved in a minimum of DMSO. In addition, a minimum
of CH2Cl2 was added dropwise to the suspension until the solution became clear. The solution was
stirred vigorously, and reaction progress was monitored by thinꢀlayer chromatography. Upon
completion, the reaction mixture was diluted with aqueous NaHCO3 (5%) and extracted with diethyl
ether (3 x 50 mL). The combined organic phase was washed with saturated aqueous NaHCO3, water,
and brine. After drying (Na2SO4), the solvent was removed in vacuo to yield the crude product, which
could be purified further by silica gel column chromatography using ethyl acetate/petroleum ether as
eluent to give the pure product 1w as colorless oil.
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General procedure for the hydration of α,βꢀunsaturated ketones. α,βꢀUnsaturated ketones 1 (1.0
mmol, 1.0 equiv.) and CrCl3·6H2O (0.0533 g, 0.20 mmol, 20 mol%) were stirred in CH3CN/H2O (1
o
mL/2 mL) at 80 C for 24 h. Upon completion of the reaction (as indicated by TLC), the reaction
mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with
brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The obtained crude residue
was purified by silica gel column chromatography using ethyl acetate and petroleum ether as eluant to
afford pure βꢀhydroxyl ketones 2aꢀw.
3ꢀHydroxyꢀ1ꢀphenylpropanꢀ1ꢀone (2a): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 3:10) to afford the desired product. Yield = 71% (106.6 mg). Light yellow oil.
IR (KBr): ν 3399, 3062, 2944, 1682, 1449, 1214, 748, 690 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.93–
7.91 (m, 2H), 7.56–7.51 (m, 1H), 7.44–7.40 (m, 2H), 3.99 (t, J = 5.5 Hz, 2H), 3.20 (brs, 1H), 3.19 (t, J
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= 5.5 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 200.2, 136.4, 133.3, 128.5, 127.9, 57.8, 40.4 ppm.
HRMS (m/z): calcd for C9H11O2 [M+H]+ 151.0759, found: 151.0756.
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3ꢀHydroxyꢀ1ꢀ(4ꢀnitrophenyl)propanꢀ1ꢀone (2b): Purification by silica gel column chromatography
(ethyl acetate/petroleum ether = 3:5) to afford the desired product. Yield = 41% (80.6 mg). Orange
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solid. M.p. 91.8–92.5 C. IR (KBr): ν 3548, 3110, 2910, 1684, 1516, 1340, 1046, 742 cmꢀ1. H NMR
(400 MHz, CDCl3): δ 8.32–8.28 (m, 2H), 8.13–8.09 (m, 2H), 4.05 (t, J = 5.4 Hz, 2H), 3.27 (t, J = 5.4
Hz, 2H), 2.70 (brs, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 198.6, 150.4, 140.9, 129.0, 123.8, 57.6,
41.1 ppm. HRMS (m/z): calcd for C9H10NO4 [M+H]+ 196.0610, found: 196.0604.
3ꢀHydroxyꢀ1ꢀ(3ꢀnitrophenyl)propanꢀ1ꢀone (2c): Purification by silica gel column chromatography
(ethyl acetate/petroleum ether = 3:5) to afford the desired product. Yield = 45% (88.7 mg). Light
yellow oil. IR (KBr): ν 3546, 3087, 2944, 1690, 1530, 1351, 919, 734 cmꢀ1. H NMR (400 MHz,
1
CDCl3): δ 8.79–8.78 (m, 1H), 8.44 (ddd, J = 8.2, 2.2, 1.3 Hz, 1H), 8.30 (dt, J = 7.8, 1.3 Hz, 1H), 7.71 (t,
J = 8.0 Hz, 1H), 4.08 (t, J = 5.3 Hz, 2H), 3.29 (t, J = 5.3 Hz, 2H), 2.58 (brs, 1H) ppm. 13C NMR (100
MHz, CDCl3): δ 198.0, 148.4, 137.8, 133.5, 130.0, 127.7, 123.0, 57.6, 40.8 ppm. HRMS (m/z): calcd
for C9H10NO4 [M+H]+ 196.0610, found: 196.0608.
4ꢀ(3ꢀHydroxypropanoyl)benzonitrile (2d): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 3:5) to afford the desired product. Yield = 58% (101.6 mg). White solid. M.p.
71.7–73.6 C. IR (KBr): ν 3531, 2937, 2228, 1683, 1348, 1208, 1045, 792 cmꢀ1. H NMR (400 MHz,
CDCl3): δ 8.06–8.03 (m, 2H), 7.79–7.76 (m, 2H), 4.04 (t, J = 5.4 Hz, 2H), 3.23 (t, J = 5.4 Hz, 2H), 2.56
(brs, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 198.8, 139.4, 132.6, 128.4, 117.8, 116.7, 57.6, 40.8
ppm. HRMS (m/z): calcd for C10H10NO2 [M+H]+ 176.0712, found: 176.0711.
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Methyl 4ꢀ(3ꢀhydroxypropanoyl)benzoate (2e): Purification by silica gel column chromatography
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(ethyl acetate/petroleum ether = 3:5) to afford the desired product. Yield = 62% (129.7 mg). White
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solid. M.p. 96.5–97.7 C. IR (KBr): ν 3414, 2960, 1722, 1675, 1284, 1111, 759, 698 cmꢀ1. H NMR
(400 MHz, CDCl3): δ 8.15–8.12 (m, 2H), 8.03–8.00 (m, 2H), 4.05 (t, J = 5.3 Hz, 2H), 3.95 (s, 3H),
3.26 (t, J = 5.3 Hz, 2H), 2.63 (brs, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 199.8, 166.1, 139.7, 134.2,
129.9, 127.9, 57.8, 52.5, 40.8 ppm. HRMS (m/z): calcd for C11H13O4 [M+H]+ 209.0814, found:
209.0815.
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1ꢀ(4ꢀFluorophenyl)ꢀ3ꢀhydroxypropanꢀ1ꢀone (2f): Purification by silica gel column chromatography
(ethyl acetate/petroleum ether = 2:5) to afford the desired product. Yield = 63% (105.9 mg). Light
yellow oil. IR (KBr): ν 3404, 2946, 1682, 1598, 1232, 1039, 836 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ
8.01–7.97 (m, 2H), 7.16–7.12 (m, 2H), 4.02 (t, J = 5.3 Hz, 2H), 3.20 (t, J = 5.3 Hz, 2H), 2.78 (brs, 1H)
ppm. 19F NMR (376 MHz, CDCl3): δ ꢀ104.4 ppm. 13C NMR (100 MHz, CDCl3): δ 198.8, 165.9 (d, JCꢀF
= 253.9 Hz), 133.0 (d, JCꢀF = 3.0 Hz), 130.7 (d, JCꢀF = 9.4 Hz), 115.8 (d, JCꢀF = 21.8 Hz), 57.9, 40.3 ppm.
HRMS (m/z): calcd for C9H10FO2 [M+H]+ 169.0665, found: 169.0668.
1ꢀ(4ꢀChlorophenyl)ꢀ3ꢀhydroxypropanꢀ1ꢀone (2g): Purification by silica gel column chromatography
(ethyl acetate/petroleum ether = 2:5) to afford the desired product. Yield = 53% (98.5 mg). Yellow oil.
IR (KBr): ν 3404, 2952, 1678, 1585, 1397, 1070, 998, 816 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.82–
7.79 (m, 2H), 7.61–7.58 (m, 2H), 4.01 (t, J = 5.4 Hz, 2H), 3.17 (t, J = 5.4 Hz, 2H), 2.79 (brs, 1H) ppm.
13C NMR (100 MHz, CDCl3): δ 199.2, 135.3, 131.9, 129.5, 128.7, 57.8, 40.4 ppm. HRMS (m/z): calcd
for C9H1035ClO2 [M+H]+ 185.0369, found: 185.0370.
1ꢀ(4ꢀBromophenyl)ꢀ3ꢀhydroxypropanꢀ1ꢀone (2h): Purification by silica gel column chromatography
(ethyl acetate/petroleum ether = 2:5) to afford the desired product. Yield = 64% (145.5 mg). Yellow
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solid. M.p. 30.9–31.4 C. IR (KBr): ν 3363, 2947, 1681, 1590, 1401, 1093, 820, 530 cmꢀ1. H NMR
(400 MHz, CDCl3): δ 7.88–7.84 (m, 2H), 7.42–7.39 (m, 2H), 3.99 (t, J = 5.4 Hz, 2H), 3.16 (t, J = 5.4
Hz, 2H), 3.00 (brs, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 199.0, 139.8, 134.8, 129.4, 128.9, 57.7,
40.4 ppm. HRMS (m/z): calcd for C9H1079BrO2 [M+H]+ 228.9864, found: 228.9864.
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3ꢀHydroxyꢀ1ꢀ(pꢀtolyl)propanꢀ1ꢀone (2i): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 2:5) to afford the desired product. Yield = 61% (99.6 mg). Light yellow oil.
IR (KBr): ν 3419, 2946, 1679, 1607, 1362, 1180, 1039, 811 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.82
(d, J = 7.9 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 3.98 (t, J = 5.5 Hz, 2H), 3.17 (brs, 1H), 3.15 (t, J = 5.5 Hz,
2H), 2.37 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 199.8, 144.1, 134.0, 129.1, 128.0, 57.9, 40.2,
21.5 ppm. HRMS (m/z): calcd for C10H13O2 [M+H]+ 165.0916, found: 165.0912.
3ꢀHydroxyꢀ1ꢀ(4ꢀmethoxyphenyl)propanꢀ1ꢀone (2j): Purification by silica gel column chromatography
(ethyl acetate/petroleum ether = 3:5) to afford the desired product. Yield = 90% (162.3 mg). Yellow
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solid. M.p. 31.4–32.3 C. IR (KBr): ν 3494, 2938, 1666, 1600, 1261, 1018, 803 cmꢀ1. H NMR (400
MHz, CDCl3): δ 7.93 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 4.00 (t, J = 5.3 Hz, 2H), 3.86 (s,
3H), 3.17 (t, J = 5.3 Hz, 2H), 2.82 (brs, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 199.0, 163.7, 130.3,
129.7, 113.7, 58.1, 55.4, 39.9 ppm. HRMS (m/z): calcd for C10H13O3 [M+H]+ 181.0865, found:
181.0864.
3ꢀHydroxyꢀ1ꢀ(3ꢀmethoxyphenyl)propanꢀ1ꢀone (2k): Purification by silica gel column
chromatography (ethyl acetate/petroleum ether = 3:5) to afford the desired product. Yield = 58% (103.7
1
mg). Yellow oil. IR (KBr): ν 3416, 2942, 1679, 1266, 1050, 784, 687 cmꢀ1. H NMR (400 MHz,
CDCl3): δ 7.53–7.50 (m, 1H), 7.46–7.45 (m, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.12–7.09 (m, 1H), 4.00 (t, J
= 5.4 Hz, 2H), 3.83 (s, 3H), 3.20 (t, J = 5.4 Hz, 2H), 2.95 (brs, 1H) ppm. 13C NMR (100 MHz, CDCl3):
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δ 200.1, 159.7, 137.8, 129.6, 120.7, 119.8, 112.1, 57.9, 55.3, 40.5 ppm. HRMS (m/z): calcd for
C10H13O3 [M+H]+ 181.0865, found: 181.0865.
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3ꢀHydroxyꢀ1ꢀ(2ꢀmethoxyphenyl)propanꢀ1ꢀone (2l): Purification by silica gel column chromatography
(ethyl acetate/petroleum ether = 3:5) to afford the desired product. Yield = 63% (113.0 mg). Yellow oil.
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IR (KBr): ν 3416, 2944, 1667, 1486, 1286, 1023, 758 cmꢀ1. H NMR (400 MHz, CDCl3): δ 7.76–7.73
(m, 1H), 7.49–7.44 (m, 1H), 7.00–6.94 (m, 2H), 3.95 (t, J = 5.3 Hz, 2H), 3.89 (s, 3H), 3.24 (t, J = 5.3
Hz, 2H), 2.94 (brs, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 202.3, 158.9, 134.1, 130.2, 127.2, 120.5,
111.5, 58.3, 55.4, 45.8 ppm. HRMS (m/z): calcd for C10H13O3 [M+H]+ 181.0865, found: 181.0864.
1ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ3ꢀhydroxypropanꢀ1ꢀone (2m): Purification by silica gel column
chromatography (ethyl acetate/petroleum ether = 3:5) to afford the desired product. Yield = 68% (133.0
mg). Yellow solid. M.p. 79.7–81.4 oC. IR (KBr): ν 3515, 2907, 1675, 1444, 1259, 1030, 924, 817 cmꢀ1.
1H NMR (400 MHz, CDCl3): δ 7.53 (dd, J = 8.2, 1.7 Hz, 1H), 7.39 (d, J = 1.7 Hz, 1H), 6.83 (d, J = 8.2
Hz, 1H), 6.03 (s, 2H), 3.98 (t, J = 5.4 Hz, 2H), 3.12 (t, J = 5.4 Hz, 2H), 2.96 (brs, 1H) ppm. 13C NMR
(100 MHz, CDCl3): δ 198.3, 152.0, 148.1, 131.4, 124.4, 107.8, 107.6, 101.8, 58.0, 40.0 ppm. HRMS
(m/z): calcd for C10H11O4 [M+H]+ 195.0657, found: 195.0657.
3ꢀHydroxyꢀ1ꢀ(thiophenꢀ2ꢀyl)propanꢀ1ꢀone (2n): Purification by silica gel column chromatography
(ethyl acetate/petroleum ether = 1:2) to afford the desired product. Yield = 89% (139.4 mg). Orange oil.
IR (KBr): ν 3404, 3092, 2888, 1655, 1416, 1259, 1054, 852, 727 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ
7.69 (dd, J = 3.9, 1.2 Hz, 1H), 7.60 (dd, J = 5.0, 1.2 Hz, 1H), 7.07 (dd, J = 5.0, 3.9 Hz, 1H), 3.95 (t, J =
5.7 Hz, 2H), 3.25 (brs, 1H), 3.11 (t, J = 5.7 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 192.8, 143.7,
134.0, 132.4, 128.1, 57.8, 41.1 ppm. HRMS (m/z): calcd for C7H9O2S [M+H]+ 157.0323, found:
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1ꢀ(Furanꢀ2ꢀyl)ꢀ3ꢀhydroxypropanꢀ1ꢀone (2o): Purification by silica gel column chromatography
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(ethyl acetate/petroleum ether = 3:5) to afford the desired product. Yield = 88% (122.8 mg). Light
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yellow oil. IR (KBr): ν 3404, 3131, 2890, 1667, 1468, 1396, 1042, 768 cmꢀ1. H NMR (400 MHz,
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CDCl3): δ 7.59 (t, J = 1.9 Hz, 1H), 7.22 (d, J = 3.5 Hz, 1H), 6.54 (dq, J = 3.5, 1.9 Hz, 1H), 3.98 (t, J =
5.4 Hz, 2H), 3.08 (t, J = 5.4 Hz, 2H), 2.76 (brs, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 189.1, 152.4,
146.7, 117.6, 112.3, 57.8, 40.3 ppm. HRMS (m/z): calcd for C7H9O3 [M+H]+ 141.0552, found:
141.0549.
1ꢀ(Benzofuranꢀ2ꢀyl)ꢀ3ꢀhydroxypropanꢀ1ꢀone (2p): Purification by silica gel column chromatography
(ethyl acetate/petroleum ether = 3:5) to afford the desired product. Yield = 51% (96.2 mg). Orange
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solid. M.p. 59.9–61.6 C. IR (KBr): ν 3443, 3133, 2922, 1688, 1564, 1368, 1157, 1069, 747 cmꢀ1. H
NMR (400 MHz, CDCl3): δ 7.69 (d, J = 7.9 Hz, 1H), 7.57–7.53 (m, 2H), 7.47 (t, J = 7.9 Hz, 1H), 7.30
(t, J = 7.5 Hz, 1H), 4.07 (t, J = 5.5 Hz, 2H), 3.22 (t, J = 5.5 Hz, 2H), 2.92 (brs, 1H) ppm. 13C NMR
(100 MHz, CDCl3): δ 190.1, 155.5, 152.1, 128.4, 126.8, 123.9, 123.3, 113.4, 112.3, 57.7, 40.9 ppm.
HRMS (m/z): calcd for C11H11O3 [M+H]+ 191.0708, found: 191.0708.
1ꢀCyclohexylꢀ3ꢀhydroxypropanꢀ1ꢀone (2q): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 2:5) to afford the desired product. Yield = 56% (87.4 mg). Light yellow oil.
IR (KBr): ν 3400, 2930, 1704, 1450, 1145, 1048, 895 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 3.79 (t, J =
5.4 Hz, 2H), 2.81 (brs, 1H), 2.66 (t, J = 5.4 Hz, 2H), 2.34–2.27 (m, 1H), 1.84–1.79 (m, 2H), 1.76–1.72
(m, 2H), 1.66–1.60 (m, 1H), 1.34–1.13 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3): δ 214.9, 57.7, 51.0,
42.1, 28.2, 25.6, 25.4 ppm. HRMS (m/z): calcd for C9H17O2 [M+H]+ 157.1229, found: 157.1229.
1ꢀHydroxyoctanꢀ3ꢀone (2r): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 2:5) to afford the desired product. Yield = 50% (71.9 mg). Light yellow oil.
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IR (KBr): ν 3409, 2932, 1709, 1378, 1051 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 3.82 (t, J = 5.4 Hz, 2H),
2.69 (brs, 1H), 2.65 (t, J = 5.4 Hz, 2H), 2.41 (t, J = 7.5 Hz, 2H), 1.60–1.52 (m, 2H), 1.34–1.20 (m, 4H),
0.87 (t, J = 6.9 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 212.0, 57.8, 44.2, 43.3, 31.2, 23.3, 22.4,
13.8 ppm. HRMS (m/z): calcd for C8H17O2 [M+H]+ 145.1229, found: 145.1229.
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3ꢀHydroxyꢀ1ꢀphenylbutanꢀ1ꢀone (2s): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 2:5) to afford the desired product. Yield = 36% (58.5 mg). Yellow oil. IR
(KBr): ν 3421, 2971, 1682, 1449, 1213, 1002, 754, 690 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.96–7.93
(m, 2H), 7.60–7.56 (m, 1H), 7.48–7.44 (m, 2H), 4.40 (ddq, J = 8.8, 6.3, 2.9 Hz, 1H), 3.42 (brs, 1H),
3.17 (dd, J = 17.7, 2.9 Hz, 1H), 3.04 (dd, J = 17.7, 8.8 Hz, 1H), 1.29 (d, J = 6.3 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3): δ 200.8, 136.6, 133.5, 128.6, 128.0, 63.9, 46.4, 22.4 ppm. HRMS (m/z): calcd for
C10H13O2 [M+H]+ 165.0916, found: 165.0916.
3ꢀHydroxycycloheptanꢀ1ꢀone (2v): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 1:2) to afford the desired product. Yield = 47% (60.2 mg). Yellow oil. IR
(KBr): ν 3412, 2932, 1698, 1450, 1264, 1043 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 4.07–4.02 (m, 1H),
2.87 (brs, 1H), 2.75 (d, J = 5.0 Hz, 2H), 2.50–2.36 (m, 2H), 1.88–1.71 (m, 5H), 1.59–1.51 (m, 1H) ppm.
13C NMR (100 MHz, CDCl3): δ 212.8, 67.3, 51.6, 44.2, 38.5, 24.2, 23.6 ppm. HRMS (m/z): calcd for
C7H13O2 [M+H]+ 129.0916, found: 129.0916.
3ꢀHydroxycyclooctanꢀ1ꢀone (2w): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 1:2) to afford the desired product. Yield = 72% (101.8 mg). Yellow oil. IR
(KBr): ν 3412, 2934, 1698, 1469, 1239, 1058, 783 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 4.04–3.98
(m, 1H), 3.03 (brs, 1H), 2.75–2.66 (m, 2H), 2.35–2.32 (m, 2H), 2.03–1.93 (m, 1H), 1.91–1.79 (m,
2H), 1.62–1.43 (m, 4H), 1.23–1.13 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 214.4, 70.5,
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47.6, 44.3, 34.4, 28.0, 22.6, 19.8 ppm. HRMS (m/z): calcd for C8H15O2 [M+H]+ 143.1072, found:
143.1075.
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General
procedure
for
the
hydroalkoxylation
of
α,βꢀunsaturated
ketones.
1ꢀ(4ꢀMethoxyphenyl)propꢀ2ꢀenꢀ1ꢀone (1j, 0.1622 g, 1.0 mmol, 1.0 equiv.), alcohols 3 (6.0 mmol, 6
equiv.) and CrCl3·6H2O (0.0533 g, 0.20 mmol, 20 mol%) were stirred in CH3CN (1 mL) at 80 oC for 24
h. Upon completion of the reaction (as indicated by TLC), the reaction mixture was directly
concentrated in vacuo. The obtained crude residue was purified by silica gel column chromatography
using ethyl acetate and petroleum ether as eluant to afford the pure βꢀalkoxyl ketones 4aꢀl. In cases
where EtOH, iPrOH, and nBuOH were used as substrates, the reactions were directly performed in this
alcohol (3 mL) instead of in CH3CN.
3ꢀEthoxyꢀ1ꢀ(4ꢀmethoxyphenyl)propanꢀ1ꢀone (4a): Purification by silica gel column chromatography
(ethyl acetate/petroleum ether = 1:5) to afford the desired product. Yield = 99% (206.2 mg). Colorless
oil. IR (KBr): ν 2975, 1676, 1601, 1259, 1171, 844 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.97–7.93 (m,
2H), 6.95–6.91 (m, 2H), 3.86 (s, 3H), 3.85 (t, J = 6.8 Hz, 2H), 3.53 (q, J = 7.0 Hz, 2H), 3.22 (t, J = 6.8
Hz, 2H), 1.20 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 196.9, 163.5, 130.4, 130.1,
113.7, 66.5, 65.9, 55.4, 38.5, 15.1 ppm. HRMS (m/z): calcd for C12H17O3 [M+H]+ 209.1178, found:
209.1178.
3ꢀIsopropoxyꢀ1ꢀ(4ꢀmethoxyphenyl)propanꢀ1ꢀone (4b): Purification by silica gel column
chromatography (ethyl acetate/petroleum ether = 1:5) to afford the desired product. Yield = 95% (211.2
mg). Yellow oil. IR (KBr): ν 2971, 1675, 1601, 1259, 1171, 839 cmꢀ1. H NMR (400 MHz, CDCl3): δ
1
7.96–7.92 (m, 2H), 6.93–6.89 (m, 2H), 3.84 (s, 3H), 3.83 (t, J = 6.9 Hz, 2H), 3.64–3.58 (m, 1H), 3.19 (t,
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J = 6.9 Hz, 2H), 1.15 (d, J = 6.1 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3): δ 197.0, 163.4, 130.3,
130.1, 113.6, 71.7, 63.5, 55.3, 38.9, 22.0 ppm. HRMS (m/z): calcd for C13H19O3 [M+H]+ 223.1334,
found: 223.1333.
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3ꢀButoxyꢀ1ꢀ(4ꢀmethoxyphenyl)propanꢀ1ꢀone (4c): Purification by silica gel column chromatography
(ethyl acetate/petroleum ether = 1:5) to afford the desired product. Yield = 98% (232.7 mg). Yellow oil.
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IR (KBr): ν 2958, 1675, 1601, 1259, 1171, 1030, 842 cmꢀ1. H NMR (400 MHz, CDCl3): δ 7.94–7.90
(m, 2H), 6.91–6.88 (m, 2H), 3.83 (s, 3H), 3.81 (t, J = 6.7 Hz, 2H), 3.43 (t, J = 6.7 Hz, 2H), 3.17 (t, J =
6.7 Hz, 2H), 1.55–1.48 (m, 2H), 1.36–1.27 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H) ppm. 13C NMR (100 MHz,
CDCl3): δ 196.9, 163.3, 130.3, 130.0, 113.5, 70.9, 66.1, 55.3, 38.4, 31.6, 19.2, 13.8 ppm. HRMS (m/z):
calcd for C14H21O3 [M+H]+ 237.1491, found: 237.1490.
3ꢀ(Cyclohexylmethoxy)ꢀ1ꢀ(4ꢀmethoxyphenyl)propanꢀ1ꢀone (4d): Purification by silica gel column
chromatography (ethyl acetate/petroleum ether = 1:6) to afford the desired product. Yield = 92% (254.7
1
mg). Colorless oil. IR (KBr): ν 2922, 1675, 1601, 1259, 1170, 1031, 842 cmꢀ1. H NMR (400 MHz,
CDCl3): δ 7.93–7.91 (m, 2H), 6.90–6.88 (m, 2H), 3.82 (s, 3H), 3.79 (t, J = 6.7 Hz, 2H), 3.23 (d, J = 6.6
Hz, 2H), 3.17 (t, J = 6.7 Hz, 2H), 1.71–1.60 (m, 5H), 1.57–1.48 (m, 1H), 1.24–1.06 (m, 3H), 0.90–0.81
(m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 197.0, 163.3, 130.3, 130.0, 113.5, 77.1, 66.3, 55.3, 38.4,
37.8, 29.9, 26.5, 25.7 ppm. HRMS (m/z): calcd for C17H25O3 [M+H]+ 277.1804, found: 277.1801.
3ꢀ(3ꢀChloropropoxy)ꢀ1ꢀ(4ꢀmethoxyphenyl)propanꢀ1ꢀone (4e): Purification by silica gel column
chromatography (ethyl acetate/petroleum ether = 1:5) to afford the desired product. Yield = 86% (220.8
1
mg). Colorless oil. IR (KBr): ν 2871, 1675, 1601, 1259, 1170, 1030, 842 cmꢀ1. H NMR (400 MHz,
CDCl3): δ 7.92–7.90 (m, 2H), 6.90–6.88 (m, 2H), 3.82 (s, 3H), 3.82 (t, J = 6.5 Hz, 2H), 3.58–3.55 (m,
4H), 3.15 (t, J = 6.5 Hz, 2H), 1.99–1.93 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 196.6, 163.3,
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130.2, 129.9, 113.5, 67.2, 66.1, 55.2, 41.8, 38.1, 32.4 ppm. HRMS (m/z): calcd for C13H1835ClO3
[M+H]+ 257.0944, found: 257.0944.
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3ꢀ(3ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀoxopropoxy)propanenitrile (4f): Purification by silica gel column
chromatography (ethyl acetate/petroleum ether = 3:5) to afford the desired product. Yield = 88% (205.3
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mg). White solid. M.p. 31.2–32.2 C. IR (KBr): ν 2907, 2248, 1673, 1601, 1264, 1174, 984, 801 cmꢀ1.
1H NMR (400 MHz, CDCl3): δ 7.93–7.90 (m, 2H), 6.92–6.88 (m, 2H), 3.88 (t, J = 6.4 Hz, 2H), 3.83 (s,
3H), 3.66 (t, J = 6.3 Hz, 2H), 3.18 (t, J = 6.4 Hz, 2H), 2.56 (t, J = 6.3 Hz, 2H) ppm. 13C NMR (100
MHz, CDCl3): δ 196.3, 163.5, 130.3, 129.8, 117.8, 113.6, 66.4, 65.5, 55.4, 38.0, 18.7 ppm. HRMS
(m/z): calcd for C13H16NO3 [M+H]+ 234.1130, found: 234.1130.
(E)ꢀ3ꢀ(butꢀ2ꢀenꢀ1ꢀyloxy)ꢀ1ꢀ(4ꢀmethoxyphenyl)propanꢀ1ꢀone (4g): Purification by silica gel column
chromatography (ethyl acetate/petroleum ether = 1:4) to afford the desired product. Yield = 90% (209.8
mg). Yellow oil. IR (KBr): ν 2916, 1675, 1601, 1258, 1170, 968, 844 cmꢀ1. H NMR (400 MHz,
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CDCl3): δ 7.93 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 5.71 (dq, J = 12.9, 6.4 Hz, 1H), 5.57 (dq, J
= 12.9, 6.4 Hz, 1H), 3.93 (d, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.83 (t, J = 6.8 Hz, 2H), 3.20 (t, J = 6.8 Hz,
2H), 1.69 (d, J = 6.4 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 196.8, 163.4, 130.3, 130.0, 129.7,
127.3, 113.6, 71.8, 65.3, 55.4, 38.5, 17.7 ppm. HRMS (m/z): calcd for C14H19O3 [M+H]+ 235.1334,
found: 235.1334.
3ꢀ(Butꢀ2ꢀynꢀ1ꢀyloxy)ꢀ1ꢀ(4ꢀmethoxyphenyl)propanꢀ1ꢀone (4h): Purification by silica gel column
chromatography (ethyl acetate/petroleum ether = 1:4) to afford the desired product. Yield = 80% (186.2
o
mg). Light yellow solid. M.p. 31.1–31.6 C. IR (KBr): ν 2914, 1669, 1601, 1253, 1183, 985, 799, 606
cmꢀ1. H NMR (400 MHz, CDCl3): δ 7.96–7.93 (m, 2H), 6.94–6.91 (m, 2H), 4.14 (q, J = 2.3 Hz, 2H),
1
3.92 (t, J = 6.7 Hz, 2H), 3.86 (s, 3H), 3.23 (t, J = 6.7 Hz, 2H), 1.84 (t, J = 2.3 Hz, 3H) ppm. 13C NMR
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(100 MHz, CDCl3): δ 196.6, 163.5, 130.3, 130.0, 113.7, 82.5, 75.0, 65.3, 58.9, 55.4, 38.3, 3.6 ppm.
HRMS (m/z): calcd for C14H17O3 [M+H]+ 233.1178, found: 233.1176.
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3ꢀ(Benzyloxy)ꢀ1ꢀ(4ꢀmethoxyphenyl)propanꢀ1ꢀone (4i): Purification by silica gel column
chromatography (ethyl acetate/petroleum ether = 1:5) to afford the desired product. Yield = 82% (221.7
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mg). Colorless oil. IR (KBr): ν 2865, 1675, 1601, 1259, 1170, 1029, 739, 699 cmꢀ1. H NMR (400
MHz, CDCl3): δ 7.94–7.91 (m, 2H), 7.32 (d, J = 4.4 Hz, 4H), 7.29–7.23 (m, 1H), 6.92–6.88 (m, 2H),
4.54 (s, 2H), 3.90 (t, J = 6.6 Hz, 2H), 3.81 (s, 3H), 3.22 (t, J = 6.6 Hz, 2H) ppm. 13C NMR (100 MHz,
CDCl3): δ 196.7, 163.4, 138.1, 130.3, 130.0, 128.2, 127.6, 127.5, 113.6, 73.2, 65.7, 55.3, 38.4 ppm.
HRMS (m/z): calcd for C17H19O3 [M+H]+ 271.1334, found: 271.1333.
Methyl4ꢀ((3ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀoxopropoxy)methyl)benzoate (4j): Purification by silica gel
column chromatography (ethyl acetate/petroleum ether = 3:10) to afford the desired product. Yield = 84%
(275.8 mg). Yellow solid. M.p. 31.3–31.5 oC. IR (KBr): ν 2899, 1723, 1668, 1264, 1169, 987, 752 cmꢀ1.
1H NMR (400 MHz, CDCl3): δ 8.02–7.94 (m, 4H), 7.40–7.38 (m, 2H), 6.96–6.92 (m, 2H), 4.61 (s, 2H),
3.94 (t, J = 6.5 Hz, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.26 (t, J = 6.5 Hz, 2H) ppm. 13C NMR (100 MHz,
CDCl3): δ 196.6, 166.8, 163.5, 143.5, 130.3, 130.0, 129.6, 129.2, 127.1, 113.6, 72.6, 66.1, 55.4, 52.0,
38.4 ppm. HRMS (m/z): calcd for C19H21O5 [M+H]+ 329.1389, found: 329.1389.
1ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀ(1ꢀphenylethoxy)propanꢀ1ꢀone (4k): Purification by silica gel column
chromatography (ethyl acetate/petroleum ether = 1:8) to afford the desired product. Yield = 57% (162.1
mg). Colorless oil. IR (KBr): ν 2974, 1676, 1601, 1259, 1170, 701 cmꢀ1. 1H NMR (400 MHz, CDCl3):
δ 7.96–7.92 (m, 2H), 7.38–7.24 (m, 5H), 6.95–6.91 (m, 2H), 4.47 (q, J = 6.5 Hz, 1H), 3.87 (s, 3H),
3.79–3.68 (m, 2H), 3.29–3.12 (m, 2H), 1.43 (d, J = 6.5 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ
196.9, 163.4, 143.7, 130.4, 130.1, 128.4, 127.4, 126.1, 113.6, 78.4, 64.2, 55.4, 38.8, 24.0 ppm. HRMS
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(m/z): calcd for C18H21O3 [M+H]+ 285.1491, found: 285.1491.
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3ꢀ(((1R,2S,5R)ꢀ2ꢀisopropylꢀ5ꢀmethylcyclohexyl)oxy)ꢀ1ꢀ(4ꢀmethoxyphenyl)propanꢀ1ꢀone
(4l):
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Purification by silica gel column chromatography (ethyl acetate/petroleum ether = 1:10) to afford the
desired product. Yield = 46% (146.5 mg). Light yellow oil. IR (KBr): ν 2954, 1679, 1601, 1259, 1170,
1032, 843 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.94–7.92 (m, 2H), 6.92– 6.90 (m, 2H), 4.02 (ddd, J =
9.2, 7.4, 5.9 Hz, 1H), 3.85 (s, 3H), 3.71 (ddd, J = 9.2, 7.4, 6.5 Hz, 1H), 3.26–3.03 (m, 3H), 2.11 (dddd,
J = 18.3, 11.3, 5.4, 3.2 Hz, 2H), 1.65–1.54 (m, 2H), 1.40–1.27 (m, 1H), 1.16 (ddt, J = 13.4, 10.3, 3.2
Hz, 1H), 0.99–0.70 (m, 12H) ppm. 13C NMR (100 MHz, CDCl3): δ 197.2, 163.3, 130.3, 130.1, 113.5,
79.5, 64.0, 55.4, 48.1, 40.2, 38.9, 34.5, 31.4, 25.4, 23.2, 22.3, 20.9, 16.1 ppm. HRMS (m/z): calcd for
C20H31O3 [M+H]+ 319.2273, found: 319.2275.
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General procedure for the hydroalkoxylation of cyclic enones. Cyclic enones (1uꢀw, 1.0 mmol,
1.0 equiv.), alcohols 3 (6 equiv.), and CrCl3·6H2O (0.0533 g, 0.20 mmol, 20 mol%) were stirred in
CH3CN (1 mL) at room temperature for 24 h. Upon completion of the reaction (as indicated by TLC),
the reaction mixture was directly concentrated in vacuo. The crude residue obtained was purified by
silica gel column chromatography using ethyl acetate and petroleum ether as eluant to afford the pure
i
βꢀalkoxyl ketones 4mꢀu. In cases where EtOH and PrOH were used as substrates, the reactions were
directly performed in this alcohol (3 mL) instead of in CH3CN.
3ꢀEthoxycyclohexanꢀ1ꢀone (4m): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 1:20) to afford the desired product. Yield = 27% (38.4 mg). Light yellow oil.
IR (KBr): ν 2945, 1716, 1221, 1105 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 3.74–3.69 (m, 1H), 3.46 (q, J
= 7.0 Hz, 2H), 2.59 (dd, J = 14.1, 4.1 Hz, 1H), 2.43 (dd, J = 14.1, 7.4 Hz, 1H), 2.29 (t, J = 6.6 Hz, 2H),
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2.06–1.92 (m, 2H), 1.80–1.73 (m, 1H), 1.68–1.59 (m, 1H), 1.15 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (100
MHz, CDCl3): δ 209.7, 76.4, 63.5, 47.6, 41.0, 30.1, 20.6, 15.4 ppm. HRMS (m/z): calcd for C8H15O2
[M+H]+ 143.1072, found: 143.1073.
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3ꢀEthoxycycloheptanꢀ1ꢀone (4n): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 1:20) to afford the desired product. Yield = 68% (106.2 mg). Light yellow oil.
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IR (KBr): ν 2931, 1701, 1447, 1008 cmꢀ1. H NMR (400 MHz, CDCl3): δ 3.58 (t, J = 7.9 Hz, 1H),
3.51–3.38 (m, 2H), 2.79 (dd, J = 14.4, 8.1 Hz, 1H), 2.68 (d, J = 14.4 Hz, 1H), 2.43 (qdd, J = 16.7, 8.2,
3.8 Hz, 2H), 1.96–1.88 (m, 1H), 1.81–1.66 (m, 4H), 1.59–1.52 (m, 1H), 1.13 (t, J = 7.0 Hz, 3H) ppm.
13C NMR (100 MHz, CDCl3): δ 212.1, 74.1, 63.7, 48.9, 44.1, 35.7, 24.5, 23.8, 15.3 ppm. HRMS (m/z):
calcd for C9H17O2 [M+H]+ 157.1229, found: 157.1230.
3ꢀIsopropoxycycloheptanꢀ1ꢀone (4o): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 1:20) to afford the desired product. Yield = 43% (73.2 mg). Yellow oil. IR
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(KBr): ν 2931, 1701, 1367, 1123, 1057 cmꢀ1. H NMR (400 MHz, CDCl3): δ 3.70–3.61 (m, 2H), 2.80
(dd, J = 14.2, 8.4 Hz, 1H), 2.66 (ddd, J = 14.2, 2.3, 0.8 Hz, 1H), 2.50 (ddd, J = 16.8, 8.4, 4.0 Hz, 1H),
2.40 (ddd, J = 16.8, 8.4, 4.0 Hz, 1H), 1.92–1.65 (m, 5H), 1.60–1.52 (m, 1H), 1.10 (dd, J = 6.1, 3.6 Hz,
6H) ppm. 13C NMR (100 MHz, CDCl3): δ 212.6, 71.4, 68.8, 49.7, 44.2, 36.5, 24.7, 23.8, 22.5, 22.2 ppm.
HRMS (m/z): calcd for C10H19O2 [M+H]+ 171.1385, found: 171.1385.
3ꢀ(3ꢀChloropropoxy)cycloheptanꢀ1ꢀone (4p): Purification by silica gel column chromatography
(ethyl acetate/petroleum ether = 1:20) to afford the desired product. Yield = 83% (169.0 mg). Light
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yellow oil. IR (KBr): ν 2932, 1701, 1448, 1100 cmꢀ1. H NMR (400 MHz, CDCl3): δ 3.61–3.54 (m,
3H), 3.50 (t, J = 5.8 Hz, 2H), 2.76 (dd, J = 14.4, 7.8 Hz, 1H), 2.67 (dd, J = 14.4, 2.3 Hz, 1H), 2.41–2.37
(m, 2H), 1.98–1.88 (m, 3H), 1.78–1.54 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3): δ 211.8, 74.3, 64.5,
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48.7, 44.1, 41.8, 35.1, 32.6, 24.3, 23.7 ppm. HRMS (m/z): calcd for C10H1835ClO2 [M+H]+ 205.0995,
found: 205.0994.
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3ꢀ(Benzyloxy)cycloheptanꢀ1ꢀone (4q): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 1:20) to afford the desired product. Yield = 62% (135.3 mg). Light yellow oil.
IR (KBr): ν 2932, 1701, 1454, 1069, 738, 698 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.36–7.25 (m, 5H),
4.54 (q, J = 11.8 Hz, 2H), 3.75 (tt, J = 7.1, 2.1 Hz, 1H), 2.92 (dd, J = 14.4, 7.1 Hz, 1H), 2.78 (dd, J =
14.4, 2.1 Hz, 1H), 2.50 (qdd, J = 16.7, 8.3, 3.6 Hz, 2H), 2.09–2.02 (m, 1H), 1.91–1.77 (m, 3H), 1.76–
1.61 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 212.1, 138.2, 128.3, 127.5, 127.4, 73.4, 70.1, 48.7,
44.2, 35.4, 24.4, 23.8 ppm. HRMS (m/z): calcd for C14H19O2 [M+H]+ 219.1385, found: 219.1384.
3ꢀEthoxycyclooctanꢀ1ꢀone (4r): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 1:20) to afford the desired product. Yield = 77% (131.0 mg). Light yellow oil.
IR (KBr): ν 2935, 1698, 1358, 1071, 738, 698 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 3.55–3.39 (m, 3H),
2.73 (t, J = 10.8 Hz, 1H), 2.59 (ddd, J = 11.2, 4.2, 1.5 Hz, 1H), 2.36 (ddd, J = 15.5, 6.6, 3.3 Hz, 1H),
2.26 (ddd, J = 15.3, 11.8, 3.3 Hz, 1H), 2.02 (tdt, J = 15.3, 11.8, 4.2 Hz, 1H), 1.89 (dddt, J = 14.4, 10.8,
3.8, 1.8 Hz, 1H), 1.82–1.74 (m, 1H), 1.61–1.49 (m, 2H), 1.47–1.38 (m, 2H), 1.12 (t, J = 7.0 Hz, 3H),
1.09–0.99 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 213.1, 78.4, 63.9, 45.4, 44.1, 32.2, 28.0, 22.6,
20.2, 15.4 ppm. HRMS (m/z): calcd for C10H19O2 [M+H]+ 171.1385, found: 171.1385.
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3ꢀIsopropoxycyclooctanꢀ1ꢀone (4s): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 1:20) to afford the desired product. Yield = 48% (88.5 mg). Yellow oil. IR
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(KBr): ν 2933, 1698, 1332, 1124, 1066 cmꢀ1. H NMR (400 MHz, CDCl3): δ 3.70–3.61 (m, 1H), 3.52
(tt, J = 10.4, 4.1 Hz, 1H), 2.77 (t, J = 10.8 Hz, 1H), 2.50 (ddd, J = 11.2, 4.2, 1.4 Hz, 1H), 2.36 (ddd, J =
15.4, 6.4, 3.2 Hz, 1H), 2.25 (ddd, J = 15.3, 12.2, 2.9 Hz, 1H), 2.03 (tdd, J = 12.1, 9.4, 6.0 Hz, 1H),
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1.88–1.74 (m, 2H), 1.55 (dddd, J = 15.0, 10.6, 7.7, 4.4 Hz, 2H), 1.47–1.38 (m, 2H), 1.09 (dd, J = 6.1,
4.7 Hz, 6H), 1.06–0.97 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 213.2, 76.0, 69.2, 46.3, 44.2, 33.0,
28.0, 22.8, 22.5, 22.4, 20.3 ppm. HRMS (m/z): calcd for C11H21O2 [M+H]+ 185.1542, found: 185.1541.
3ꢀ(3ꢀChloropropoxy)cyclooctanꢀ1ꢀone (4t): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 1:20) to afford the desired product. Yield = 83% (181.5 mg). Yellow oil. IR
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(KBr): ν 2934, 1698, 1359, 1094 cmꢀ1. H NMR (400 MHz, CDCl3): δ 3.65–3.46 (m, 5H), 2.76–2.69
(m, 1H), 2.62 (ddq, J = 9.1, 3.4, 1.7 Hz, 1H), 2.41–2.24 (m, 2H), 2.06–1.76 (m, 5H), 1.63–1.40 (m, 4H),
1.08 (dddd, J = 10.1, 6.3, 4.1, 2.1 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 212.9, 78.6, 64.7, 45.2,
44.1, 41.8, 32.7, 32.0, 28.0, 22.6, 20.1 ppm. HRMS (m/z): calcd for C11H2035ClO2 [M+H]+ 219.1152,
found: 219.1153.
3ꢀ(Benzyloxy)cyclooctanꢀ1ꢀone (4u): Purification by silica gel column chromatography (ethyl
acetate/petroleum ether = 1:20) to afford the desired product. Yield = 95% (221.4 mg). Light yellow oil.
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IR (KBr): ν 2933, 1698, 1355, 1104 cmꢀ1. H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 4.4 Hz, 4H),
7.31–7.24 (m, 1H), 4.61–4.51 (m, 2H), 3.68 (tt, J = 10.0, 4.2 Hz, 1H), 2.86 (t, J = 10.8 Hz, 1H), 2.73
(ddd, J = 11.4, 4.2, 1.4 Hz, 1H), 2.41 (ddd, J = 15.4, 6.7, 3.1 Hz, 1H), 2.31 (ddd, J = 15.4, 11.6, 3.1 Hz,
1H), 2.11–1.96 (m, 2H), 1.88–1.79 (m, 1H), 1.66–1.54 (m, 3H), 1.52–1.43 (m, 1H), 1.19–1.08 (m, 1H)
ppm. 13C NMR (100 MHz, CDCl3): δ 212.9, 138.2, 128.2, 127.4, 127.4, 78.1, 70.5, 45.3, 44.1, 32.1,
27.9, 22.7, 20.1 ppm. HRMS (m/z): calcd for C15H21O2 [M+H]+ 233.1542, found: 233.1544.
General procedure for the synthesis of tetrahydrofuran derivatives. α,βꢀUnsaturated ketones 1
(1.0 mmol, 1.0 equiv.), 2ꢀiodoethanol (3m, 1.0318 g, 6.0 mmol, 6 equiv.) and CrCl3·6H2O (0.0533 g,
o
0.20 mmol, 20 mol%) were stirred in CH3CN (1 mL) at 80 C for 24 h. Upon completion of the
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reaction (as indicated by TLC), the reaction mixture was directly concentrated in vacuo. The crude
residue obtained was purified by silica gel column chromatography using ethyl acetate and petroleum
ether as eluant to afford the pure intermediates 5aꢀc. To the stirred solution of the intermediates 5aꢀc
(0.5 mmol, 1.0 equiv.) was added NaNH2 (0.0390 g, 1.0 mmol, 2 equiv.) and DMF (2 mL) under
nitrogen atmosphere, and the reaction was stirred at room temperature for 24 h. Then the reaction
mixture was carefully quenched with water (20 mL), extracted with ethyl acetate (3 x 20 mL). The
combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4 and
concentrated in vacuo. The crude residue obtained was purified by silica gel column chromatography
using ethyl acetate and petroleum ether as eluant to give the pure products 6aꢀc.
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3ꢀ(2ꢀIodoethoxy)ꢀ1ꢀ(4ꢀmethoxyphenyl)propanꢀ1ꢀone (5a): Purification by silica gel column
chromatography (ethyl acetate/petroleum ether = 1:6) to afford the desired product. Yield = 67% (223.9
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mg). Yellow solid. M.p. 30.9–31.4 C. IR (KBr): ν 2897, 1669, 1601, 1255, 1174, 980, 798 cmꢀ1. H
NMR (400 MHz, CDCl3): δ 7.97–7.93 (m, 2H), 6.95–6.91 (m, 2H), 3.92 (t, J = 6.5 Hz, 2H), 3.86 (s,
3H), 3.74 (t, J = 6.8 Hz, 2H), 3.24 (t, J = 6.8 Hz, 2H), 3.22 (t, J = 6.5 Hz, 2H) ppm. 13C NMR (100
MHz, CDCl3): δ 196.6, 163.5, 130.4, 129.9, 113.7, 71.6, 66.1, 55.4, 38.3, 3.0 ppm. HRMS (m/z): calcd
for C12H16IO3 [M+H]+ 335.0144, found: 335.0143.
3ꢀ(2ꢀIodoethoxy)ꢀ1ꢀ(thiophenꢀ2ꢀyl)propanꢀ1ꢀone (5b): Purification by silica gel column
chromatography (ethyl acetate/petroleum ether = 1:6) to afford the desired product. Yield = 71% (220.2
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mg). Yellow oil. IR (KBr): ν 2871, 1660, 1416, 1234, 1104, 726 cmꢀ1. H NMR (400 MHz, CDCl3): δ
7.74 (dd, J = 3.8, 1.2 Hz, 1H), 7.64 (dd, J = 5.0, 1.2 Hz, 1H), 7.13 (dd, J = 5.0, 3.8 Hz, 1H), 3.90 (t, J =
6.4 Hz, 2H), 3.72 (t, J = 6.7 Hz, 2H), 3.22 (t, J = 6.7 Hz, 2H), 3.19 (t, J = 6.4 Hz, 2H) ppm. 13C NMR
(100 MHz, CDCl3): δ 190.8, 144.2, 133.9, 132.3, 128.1, 71.6, 65.8, 39.4, 2.9 ppm. HRMS (m/z): calcd
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