Bioinspired Diastereoconvergent Synthesis of the Tricyclic Core of Palodesangrens via Diels-Alder Reaction, LiAlH4-Mediated Isomerization, and Acid-Mediated Cyclization

Article abstract of DOI:10.1021/acs.joc.8b00668

The cyclohexene moiety of the tricyclic 6,7-diaryl-tetrahydro-6H-benzo[c]chromene core of palodesangrens could be assembled in a biomimetic and step-economical fashion by the Diels-Alder reaction between the electron-rich (E)-1,3-butadienylarenes as the diene and the electron-deficient chalcones as the dienophile. During the reduction of ketone to the corresponding alcohol by LiAlH₄, the mixture of endo and exo isomers underwent a novel diastereoconvergent LiAlH₄-mediated isomerization to install the desired stereochemistry at C10a. Subsequent pyran ring closure under acidic conditions installed the stereochemistry at the remaining C6. Overall, the tricyclic core of palodesangrens could be prepared in three steps and up to 38% yield.

Full text of DOI:10.1021/acs.joc.8b00668

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Bio-inspired diastereoconvergent synthesis of the tricyclic
core of palodesangrens via Diels-Alder reaction, LiAlH4-
mediated isomerization, and acid-mediated cyclization
Poramate Songthammawat, Sirilak Wangngae, Koki Matsumoto,
Chuthamat Duangkamol, Somsak Ruchirawat, and Poonsakdi Ploypradith
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00668 • Publication Date (Web): 16 Apr 2018
Downloaded from http://pubs.acs.org on April 16, 2018
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Bio-inspired diastereoconvergent synthesis of the tricyclic core of palodesangrens via Diels-
Alder reaction, LiAlH
4
-mediated isomerization, and acid-mediated cyclization
†
‡
‡
‡
Poramate Songthammawat, Sirilak Wangngae, Koki Matsumoto, Chuthamat Duangkamol,
†,‡,§,¶
†,‡,§,¶*
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Somsak Ruchirawat,
Poonsakdi Ploypradith
†
Program in Chemical Biology, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, 54
Kamphaeng Phet 6 Road, Laksi, Bangkok, Thailand 10210
‡
Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6
Road, Laksi, Bangkok, Thailand 10210
§
Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, Thailand
73170
¶
Centre of Excellence on Environmental Health and Toxicology, Commission on Higher
Education (CHE), Ministry of Education, Thailand
E-mail: poonsakdi@cri.or.th
Abstract
The cyclohexene moiety of the tricyclic 6,7-diaryl-tetrahydro-6H-benzo[c]chromene core of
palodesangrens could be assembled in a biomimetic and step-economical fashion by the Diels-
Alder reaction between the electron-rich (E)-1,3-butadienylarenes as the diene and the electron-
deficient chalcones as the dienophile. During the reduction of ketone to the corresponding
alcohol by LiAlH , the mixture of endo and exo isomers underwent a novel diastereoconvergent
4
LiAlH
4
-mediated isomerization to install the desired stereochemistry at C10a. Subsequent pyran
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ring closure under acidic conditions installed the stereochemistry at the remaining C6. Overall,
the tricyclic core of palodesangrens could be prepared in 3 steps and up to 38% yield.
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Introduction
Palodesangrens A-E (1-5, Figure 1) are tetracyclic benzo[c]pyranochromenones isolated from
1
the bark of Brosimum rubescens Taubert, a plant also commonly known as blood wood found in
the Amazon and Guianas as well as in Panama and Brazilian Atlantic forest. Due to their
relatively small amount from natural sources (0.0005-0.0019%), their biological activities have
1
not been fully investigated except for their moderate antiandrogenic activity. Some
palodesangrens were found to inhibit testosterone 5-reductase as well as the formation of 5-
1
dihydrotestosterone (DHT) binding with an androgen receptor. Such DHT-receptor complex has
been implicated as causes of some androgen-dependent diseases such as prostatic hypertrophy,
2
prostate cancer, male pattern baldness, and hirsutism. Since their isolation, palodesangrens were
proposed to be the first natural Diels-Alder adducts arising biosynthetically from the [4+2]-
cycloaddition reactions between the corresponding prenylcoumarin (6) and chalcones (7) while
other related natural Diels-Alder adducts such as kuwanons biosynthetically came from stilbenes,
prenylchalcones, prenylflavonoids, or prenylbenzofurans. Recently, based on their biosynthesis,
several synthetic studies and/or total syntheses of some of these natural products, except those of
3
-9
palodesangrens, have been reported.
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Figure 1. Structures of palodesangrens (1-5), proposed biosynthetic precursors (6 and 7)
During the past few years, our research group has been involved with the generation of ortho-
quinone methides (o-QMs) and their [4+2]-cycloaddition reactions with various activated olefins
under catalysis or mediation by Lewis/-acid (PtCl
4
) or Brønsted acid (p-toluenesulfonic acid
immobilized on silica; PTS-Si) to furnish the corresponding 2-arylchromans as well as the
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tricyclic 6,7-diaryl-tetrahydro-6H-benzo[c]chromene (Scheme 1).
With the proposed
biosynthesis of palodesangrens from an aryldiene such as 6 and chalcone 7 in mind, we have
now developed a biosynthesis-inspired step-economy strategy for the tricyclic core of
palodesangrens.
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Scheme 1. Two strategies for the synthesis of the tricyclic core of palodesangrens
In our previously developed route, the o-QM precursor 8 and electron-rich chalcone 7a bearing
1
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electron-donating group(s) as Ar and/or Ar were employed in the Pt(IV)-catalyzed inverse
electron demand [4+2]-cycloaddition reaction to provide the chroman ketone 9 which
subsequently underwent the Kursanov reduction to install H stereoselectively and then Ru(II)-
7
catalyzed ring closing metathesis (RCM) to install the cyclohexene ring of the tricyclic core
10e
1
0. However, the relative stereochemistry of 10 at C6-C10a, C6a-C7, and C6a-C10a did not
match that of the tricyclic core 11 at those identical positions on the general structure of natural
palodesangren 12. Thus, our new synthetic approach was designed to overcome this issue. Since
chalcones (e.g. 7) were biosynthetically proposed to be the dienophiles for the Diels-Alder
reactions, we anticipated that the trans geometry of electron-poor chalcone 7b bearing electron-
1
2
withdrawing substituents as Ar and/or Ar , upon its Diels-Alder reaction with the aryldiene 13,
would confer the desired trans relationship between H6a and H in the cyclohexene ketone
7
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3-9
product 14. In addition, we also anticipated that the subsequent steps including the acid-
mediated cyclization of 14 would proceed to furnish the tricyclic product 15 with the desired
stereochemistry at the remaining C6 and C10a positions (vide infra).
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Results and discussion
As shown retrosynthetically in Scheme 2, the coumarin moiety of palodesangrens 12 was
anticipated to be installed at a late stage; the key intermediate tricyclic 6,7-diaryl-tetrahydro-6H-
benzo[c]chromene 15 would arise from the corresponding cyclohexene ketone 14 which, in turn,
would be furnished by the intermolecular Diels-Alder reactions between aryldiene 13 and
chalcone 7b. The diene moiety of 13 would be installed via the Claisen-Schmidt condensation of
the aldehyde 16 and acetone followed by the Wittig methylenation. Chalcones 7b could be
prepared straightforwardly from the corresponding acetophenone and benzaldehyde derivatives.
Scheme 2. Retrosynthetic analysis of palodesangrens
11a
As a model, we first used 2-methoxyphenyldiene 17 and chalcone 18 for the Diels-Alder
reactions. The results were summarized in Table 1. In the absence of Lewis acid, the reaction
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required either conventional or microwave heating. The best isolated yield of 19 (45%) as a 10:1
mixture of endo:exo isomers could be obtained from conventional heating at 130 °C for 48 h
6
a,7c
(entry 1).
requiring shorter reaction time (entry 2). In addition, reactions employing catalytic amount (up to
0 mol%) of Cu(OAc) , copper-2-thiophene carboxylate (CuTC), In(OTf) , or hydroquinone in
conjunction with microwave heating either did not proceed or gave 19 in low to moderate yields
up to 41%; entries 3-15). Catalytic amount of Cu(OAc) in MeCN, 1,4-dioxane, or DMF as
solvent with conventional heating at different temperatures gave the product only in 18-34%
yields (entries 3-5). Microwave irradiation at 200 °C for the reactions using Cu(OAc) as catalyst
in MeCN, 1,4-dioxane, DMF, and water gave similar results, providing 19 in 27-33% yields
entries 6-9). Interestingly, using a mixed solvent system of water and 1,4-dioxane (1:1 v/v)
Microwave heating gave lower yields of 19 of a similar endo:exo ratio, albeit
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(
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gave better yield (40%; entry 10). When catalytic amount of CuTC was employed either in
MeCN or DMF, the reactions proceeded to furnish 19 in 33-40% yields (entries 11-12). Use of
catalytic amount of hydroquinone in MeCN gave the product 19 in 41% yield (entry 13);
however, no reaction occurred when 1,4-dioxane was employed as solvent at different
temperatures (entry 14). At 50 °C, catalytic amount of In(OTf)
decomposition of the diene 17 (entry 15). In addition, when other Lewis acids (AlCl
Sc(OTf) , PtCl , AgOTf, and BF ·Et O) were employed as catalyst, even at low temperatures (-
8 to 0 °C), only the decomposition of the diene 17 was detected. Thus, from this model study,
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in 1,4-dioxane gave only the
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, Me Al,
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conventional heating at 130 °C for 48 h using toluene as solvent was the best condition for the
requisite Diels-Alder reaction.
a
Table 1. Optimization of reaction conditions for the Diels-Alder reactions of 17 and 18
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entry solvent
additive (mol%)
none
temp (°C) time (h) yield (%)
c
d
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PhMe
130
48
45
30
PhMe
none
150-200
0.33-1
18-48
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c
MeCN
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
2
2
(20)
(20)
(20)
(20)
(20)
(20)
(20)
(20)
70
18-21
34
c
1,4-dioxane
DMF
110
c
150
18
31
MeCN
200
0.33
0.33
0.33
0.33
0.33
0.33
0.33
0.33
0.33
0.33
33
e
1,4-dioxane
DMF
200
32
50-200
200
27
H
2
2
O
27
H
O:1,4-dioxane (1:1) Cu(OAc)
200
40
1
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MeCN
CuTC (20)
CuTC (20)
200
40
DMF
200
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MeCN
hydroquinone (20) 200
41
1,4-dioxane
1,4-dioxane
hydroquinone (20) 50-100
no reaction
In(OTf)
3
(20)
50
decomposed
a
Unless otherwise noted, the reactions were performed using microwave irradiation at the
specified duration (h) and temperature (°C) in sealed reaction vessels. Temperature was
b
1
monitored by an external surface sensor. Yields were estimated based on H NMR of the crude
c
product using 1,3,5-trimethoxybenzene as an internal standard. Conventional heating was
d
e
employed. Isolated yield. No reaction occurred at temperatures lower than 200 °C.
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With the optimal condition, we proceeded to investigate similar reactions with other aryldienes
and chalcones. Starting from 2-hydroxy-4-methoxybenzadehyde 20, the corresponding
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aryldienes 21a-b could be prepared smoothly in 56-67% yield over 3 steps (Scheme 3).
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number of different chalcones were prepared accordingly from the corresponding benzaldehyde
and acetophenone derivatives in good to excellent yields. It should be noted that better yields of
the aldol condensation between the acetophenones 22 and hydroxybenzaldehyde derivatives 23
under basic conditions could be obtained when the hydroxy groups were protected as the
12
corresponding MOM ethers (24 and 25). The MOM ethers could be readily cleaved in the
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subsequent step using 10% sulfuric acid in refluxing ethanol. Since the ensuing Diels-Alder
reactions would require the dienophiles (chalcones) to be electron-deficient, the free hydroxy
groups were then converted to the corresponding acetate group (chalcones 26b-l).
Scheme 3. Synthesis of aryldienes 21a-b and chalcones 26b-l
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The aryldienes 21a-b reacted with chalcones 26b-l via the Diels-Alder reactions to provide the
corresponding adducts (27a-p) in 50-89% yields as 1.1:1 to 3.3:1 (endo:exo) inseparable
1
3
mixtures (Figure 2). Generally, the electronic nature of the chalcones as well as the presence of
bromine atom on the aryldiene 21b only slightly affected the yields or the stereoselectivity of the
reactions. Chalcone 18 with electronically neutral phenyl groups gave 27a in 52% yield as a
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.4:1 mixture upon reacting with 21a; 27m was obtained from 18 and 21b in similar yield (59%)
and stereoselectivity (2.2:1). While keeping the aromatic ring of the ketone as 4-methoxyphenyl,
we observed the effect of different positions of the acetate group of chalcones on the yields (27b-
d and 27e-g) but not on the stereoselectivity. When 21b was employed, 27n was obtained in
yield and stereoselectivity similar to those obtained for 27g. The presence of the methylenedioxy
group on the ketone of chalcones increased the stereoselectivity in 27j-k to 3.3:1. The Diels-
Alder adduct 27o was obtained in similar stereoselectivity when 21b was employed for the
reaction albeit in lower yield (50%) when compared with those of 27j-k (62%). When the
aromatic ring of the ketone contained an electron-withdrawing acetate group, the adducts (27h,
2
7l, and 27p) were obtained in good to excellent yields (64-89%) but only in low
stereoselectivity (1.1:1 to 1.5:1).
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Figure 2. Diels-Alder cycloadducts 27a-p
With the cyclohexene ketone adducts in hand, we next considered the ensuing cyclization of the
chroman moiety of the tricyclic core of palodesangrens. The adduct 27a was used as a model for
this cyclization. We anticipated that 27a could be directly converted to the corresponding
hemiketal 28a upon treating with acids which would simultaneously mediate both the cleavage
1
4
of the aromatic MOM ether and the cyclization on the ketone moiety. Various Brønsted acids
were screened under different conditions ((a) 0.5-0.6 equivalents of p-TsOH or p-TsOH
1
5
immobilized on silica (PTS-Si) in toluene or CH
2
Cl at rt to 80 °C for 6-18 h and (b) 10% or
2
8
3
M H
2
SO
4
in EtOH at rt for 48 h ); however, none furnished 28a. It was noted that even under
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these acidic conditions the MOM group was not cleaved (Scheme 4). Thus, we considered
reducing the ketone moiety of 27a to the corresponding alcohol which, upon subsequent acid-
mediated cleavage of MOM ether as well as cyclization, would furnish the desired chroman 29a.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
However, reducing this ketone proved to be non-trivial; NaBH as well as hydrosilane reduction
4
16
(
BF
3
·Et
2
O or TFA in conjunction with Et
3
SiH) failed to reduce the ketone completely. After
some experimentation, it was found that LiAlH
4
was required for this reduction, giving the
17
corresponding alcohol, which, upon treating with 10% H
2
SO
4
for 48 h at rt, furnished the
18
tricyclic chroman 29a as a single diastereomer but only as a minor product. To our delight,
however, the cyclohexene ketones 27b, 27e, 27i, and 27o, upon undergoing a similar reaction
sequence, smoothly provided the corresponding tricyclic chromans 29b-e, each as a single
diastereomer in 59-65% yields over two steps. Relative stereochemistry at all four contiguous
stereogenic centers was established spectroscopically, especially by nOe studies, and it was
found to be in good accordance with that reported for naturally-occurring palodesangrens.
Scheme 4. Synthesis of tricyclic chromans 29a-e
The apparent diastereoconvergence for the final two steps of converting 27b, 27e, 27i, and 27o to
the corresponding tricyclic 29b-e as single diastereomers was, to the best of our knowledge,
unprecedented. A plausible mechanism to account for this observation was proposed in Scheme
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1
1
1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
with the following supporting evidence. If one equivalent of LiAlH was employed, only the
4
corresponding phenol product was obtained from cleaving the acetate group; the ketone was left
intact (A). With LiAlH in excess, reduction of the ketone occurred with concomitant LiAlH
mediated isomerization at C10a to generate the products with C10a cis to the adjacent C6a (B).
10a is prone to undergo such reaction because of its relatively high acidity from its
4
4
-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
19
allylic/benzylic electronic nature. In order to determine whether other basic species (i.e.
ethoxide, a by-product generated from the cleavage of the acetate group by LiAlH ) may mediate
this isomerization, when compound 27a was treated with stoichiometric or excessive amount of
ethoxide (from Cs CO and EtOH or its sodium salt) at room temperature, no isomerization was
detected. Therefore, LiAlH was required to mediate this isomerization. However, it remains
4
2
3
4
unclear whether the reduction of the ketone preceded the isomerization or vice versa. As shown
in Scheme 5, the two possible intermediates A1 and A2 would be generated from the
isomerization at C10a following the cleavage of the acetate group but assumingly still retaining
their ketone functional groups. The intermediate A1 would be more thermodynamically stable
than A2 due to the presence of the 1,3-diaxial interaction of the aromatic rings at C7 and C10a in
1
A2. For 27a, 27b, and 27i, the crude H NMR of the LiAlH
4
reduction clearly showed the signal
OMe of the MOM group as
-mediated isomerization during
of one olefin (C10; ca. 5.50 ppm) and one set of signals of the OCH
2
a major component and further supported this uncommon LiAlH
4
20
this step (see Supporting Information for the spectra). Thus, the relative stereochemistry at all
three stereocenters (C6a, C7, and C10a) in the tricyclic products now matched those found in
natural palodesangrens. Whether the LiAlH reduction of the ketone was stereoselective was
4
irrelevant because the ensuing acid-mediated ring closure of the pyran moiety would ionize the
alcohol, thereby generating the corresponding carbocation (C) for the stereoselective cyclization.
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For compound 29c, the corresponding nOe values were found for H10a and H6a (2.35% and
3
.01%) as well as H
7
and H
6
(0.49%); this further confirmed the cis relationships between H10a
and H
and H6a as well as that between H
7
6
.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. A proposed plausible mechanism for the diastereoconvergent generation of 29c
Conclusion
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In summary, a concise bio-inspired synthesis of the tricyclic 6,7-diaryl-tetrahydro-6H-
benzo[c]chromene core of palodesangrens has been successfully developed. The cyclohexene
moiety was first constructed via the key Diels-Alder reactions between the aryldienes 21a or 21b
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
0
1
2
3
4
5
6
7
8
9
0
and electron-deficient chalcones 18 or 26b-l. The required trans relationship between H6a and H
7
of the tricyclic core in palodesangrens was conferred by the trans geometry of chalcones.
Despite only modest stereoselectivity (1.1-10:1 endo:exo ratios) obtained from the Diels-Alder
reactions for the cyclohexene adducts 19 and 27a-p, the desired cis relationship between H6a and
H
10a was successfully installed via the subsequent novel LiAlH
thereby converting both endo and exo isomers, in a diastereoconvergent manner, to the endo
products during this step. The ensuing acid-mediated cyclization by using 10% H SO generated
4
-mediated isomerization of H10a,
2
4
the carbocation which underwent the stereoselective cyclization/MOM cleavage to provide the
pyran ring with the desired stereochemistry at the remaining C6 stereocenter. Thus, unlike other
approaches which normally employed acid-mediated cyclization either separately on one of the
two endo/exo isomers or directly on the mixture containing both endo and exo isomers of the
cyclohexene ketones to form the remaining ring(s), our bio-inspired diastereoconvergent strategy
for the palodesangrens employed LiAlH as a reagent not only to reduce the ketone to the
4
corresponding alcohol but also, more importantly, to affect the C10a isomerization. Overall, the
tricyclic core 29b-e with stereochemistry at all four contiguous stereogenic centers which
matched that in natural palodesangrens could be obtained in 30-38% yield over 3 steps from
appropriate chalcones and dienes.
Experimental
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General Experimental Methods. Unless otherwise noted, reactions were run in oven-dried
round-bottomed flasks. For microwave reactions, sealed reaction vessels were employed and the
temperature was monitored by an external surface sensor. Tetrahydrofuran (THF) was distilled
from sodium benzophenone ketyl or purified by the solvent purification system while
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
dichloromethane (CH
2
Cl ) was also purified by the solvent purification system prior to use. All
2
other compounds were used as received from the suppliers; PTS-Si (p-TsOH immobilized on
2
silica) employed in these experiments possessed the surface area of 500 m /g as indicated by the
supplier. The crude reaction mixtures were concentrated under reduced pressure by removing
organic solvents on rotary evaporator. Column chromatography was performed using silica gel
60 (particle size 0.06-0.2 mm; 70-230 mesh ASTM). Analytical thin-layer chromatography
1
(
TLC) was performed with silica gel 60 F254 aluminum sheets. Chemical shifts for H nuclear
magnetic resonance (NMR) spectra were reported in parts per million (ppm, ) downfield from
tetramethylsilane. Splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet
(
q), multiplet (m), broad (br), doublet of doublet (dd), doublet of triplet (dt), and doublet of
doublet of doublet (ddd). Resonances for infrared (IR) spectra were reported in wavenumbers
-1
(cm ). Low resolution (LRMS) mass spectra were obtained either using electron ionization (EI)
or time-of-flight (TOF) while high resolution (HRMS) mass spectra were obtained using time-of-
flight (TOF) via the atmospheric-pressure chemical ionization (APCI) or electrospray ionization
(ESI). Melting points were uncorrected.
General procedure for the synthesis of aryldiene 21a-b.
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Claisen–Schmidt condensation. To a stirred solution of MOM-protected benzaldehyde (1.0
equiv) and acetone (5.0 equiv) in a mixture of MeOH:H O (1:1 v/v) (10 mL/mmol) was added
2
NaOH (3.5 equiv) and then the reaction mixture was stirred at room temperature overnight. The
reaction mixture was extracted with EtOAc (3 x 10 mL). The combined organic phases were
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
washed with brine (10 mL), dried over Na
2
SO , and concentrated under reduced pressure to give
4
the crude product. The product was obtained following purification by column chromatography
on silica (25% EtOAc/hexane).
(
E)-4-(4-Methoxy-2-(methoxymethoxy)phenyl)but-3-en-2-one (20a2). Following the General
Procedure for the Claisen–Schmidt condensation described above, the desired product was
1
obtained as a yellow oil (2.0 g, 8.47 mmol, 73 %). H NMR (300 MHz, CDCl
3
): δ 2.37 (s, 3H),
3
6
.51 (s, 3H), 3.82 (s, 3H), 5.25 (s, 2H), 6.58 (dd, J = 8.7, 2.4 Hz, 1H), 6.67 (d, J = 16.5 Hz, 1H),
1
3
.73 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 16.5 Hz, 1H). C NMR (75 MHz,
): δ 27.1, 55.4, 56.2, 94.5, 101.0, 107.4, 116.7, 125.3, 129.2, 138.4, 157.5, 162.7, 198.9. IR
CDCl
3
-
1
(
(
UATR): max 2956, 2839, 1665, 1591, 1503 cm . LRMS (EI): m/z (rel intensity) 161 (21), 175
+
+
100), 176 (16), 191 (21), 236 (11), 237 (M , 2). TOF-HRMS: calcd for C13
H
16NaO (M + Na )
4
259.0942, found 259.0941.
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(
E)-4-(5-Bromo-4-methoxy-2-(methoxymethoxy)phenyl)but-3-en-2-one (20b2). Following
the General Procedure for the Claisen–Schmidt condensation described above, the desired
1
product was obtained as a yellow solid (1.0 g, 3.17 mmol, 81%). Mp 85.5–86.5 °C. H NMR
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
300 MHz, CDCl
3
): δ 2.37 (s, 3H), 3.52 (s, 3H), 3.92 (s, 3H), 5.27 (s, 2H), 6.65 (d, J = 16.4 Hz,
13
1
H), 6.79 (s, 1H), 7.73 (s, 1H), 7.77 (d, J = 16.4 Hz, 1H). C NMR (75 MHz, CDCl
3
): δ 27.7,
56.4, 95.0, 99.5, 104.3, 117.9, 126.0, 131.8, 136.7, 156.9, 158.4, 198.4. IR (UATR): max 2961,
-1
2
943, 1658, 1593, 1489 cm . LRMS (EI): m/z (rel intensity) 76 (15), 161 (14), 239 (20), 241
+
79
+
(
19), 253 (100), 255 (90), 316 (M , 12). TOF-HRMS: calcd for C13
H
15 BrNaO
4
(M + Na )
8
1
+
337.0046, found 337.0039; calcd for C13
H
15 BrNaO (M + Na ) 339.0027, found 339.0023.
4
Wittig methylenation. To a stirred solution of methyltriphenylphosphonium bromide (2.3
equiv) in dry THF (10 mL/1 mmol) at -78 °C under argon was added n-BuLi (2.0 equiv) and the
mixture was slowly warmed up to rt at which it was stirred for 1 h. At that time, the reaction
mixture was cooled to -78 °C before a solution of the MOM-protected (E)-benzylideneacetones
(
1.0 equiv) in THF (5 mL) was added. The reaction was then further stirred at -78 °C, slowly
warmed up to room temperature at which it was stirred for 3 h. The reaction was quenched with
O, extracted with EtOAc (3 x 10 mL), dried over Na SO and concentrated under reduced
H
2
2
4
pressure. The crude mixture was purified by column chromatography on silica (20%
EtOAc/hexane) to give the desired product.
(
E)-4-Methoxy-2-(methoxymethoxy)-1-(3-methylbuta-1,3-dien-1-yl)benzene
(21a).
Following the General Procedure for the Wittig methylenation described above, the desired
1
product was obtained as a colorless oil (1.4 g, 5.89 mmol, 75 %). H NMR (300 MHz, CDCl
3
): δ
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
2
.98 (s, 3H), 3.47 (s, 3H), 3.75 (s, 3H), 5.02 (d, J = 15.6 Hz, 2H), 5.18 (s, 2H), 6.53 (dd, J = 8.7,
1
3
.4 Hz, 1H), 6.68 (d, J = 2.4, 1H), 6.80 (d, J = 6.6 Hz, 2H), 7.43 (d, J = 8.7 Hz, 1H). C NMR
): δ 18.8, 55.3, 56.1, 94.9, 101.7, 107.2, 116.0, 120.2, 123.0, 126.9, 130.2,
(75 MHz, CDCl
3
-1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
42.7, 155.6, 160.2. IR (UATR): max 2936, 2837, 1726, 1677, 1606, 1505, 1464, 1442 cm .
+
LRMS (EI): m/z (rel intensity) 55 (73), 57 (100), 69 (64), 71 (54), 234 (M , 11). TOFHRMS
+
calcd for C14
H18NaO
5
(M + Na +O
2
) 289.1045, found 289.1046.
(
E)-1-Bromo-2-methoxy-4-(methoxymethoxy)-5-(3-methylbuta-1,3-dien-1-yl)benzene (21b).
Following the General Procedure for the Wittig methylenation described above, the desired
1
product was obtained as a yellow solid (170.0 mg, 0.54 mmol, 74 %). Mp 75.3–77.5 °C °C. H
NMR (300 MHz, CDCl
3
): δ 1.97 (s, 3H), 3.51 (s, 3H), 3.88 (s, 3H), 5.04 (br s, 1H), 5.09 (br s,
13
1
H), 5.21 (s, 2H), 6.74 (s, 1H), 6.75 (s, 2H), 7.67 (s, 1H). C NMR (75 MHz, CDCl ): δ 18.6,
3
56.2, 56.3, 95.2, 100.1, 104.2, 116.9, 121.4, 121.5, 129.9, 131.2, 142.3, 154.8, 155.7. IR
-1
(
UATR): max 2944, 1595, 1489, 1382, 1288 cm . LRMS (EI): m/z (rel intensity) 57 (100), 69
+
79
+
(
84), 71 (69), 83(41), 313 (M , 2). TOFHRMS calcd for C14
H
18 BrNaO
3
(M + H ) 313.0434,
8
1
+
found 313.0437; calcd for C14
H
18 BrNaO (M + H ) 315.0415, found 315.0408.
3
General procedure for the synthesis of chalcones 23b-l.
Claisen–Schmidt condensation. To a stirred solution of the MOM-protected acetophenone (1.0
equiv) and MOM-protected aryl aldehyde (1.0 equiv) in a mixture of MeOH:H O (1:1 v/v) (10
2
mL/mmol) was added NaOH (3.5 equiv). The reaction mixture was stirred at room temperature
overnight. After completion, the mixture was extracted with EtOAc (3 x 15 mL) and washed
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once with brine. After being dried over Na
2
SO , the combined organic layers were evaporated
4
under reduced pressure to give the crude product which was further purified by column
chromatography using 25% EtOAc/hexane as eluent to furnish the desired product.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(E)-3-(4-(Methoxymethoxy)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I1b). Following
the General Procedure for the Claisen–Schmidt condensation described above, the desired
1
product was obtained as a yellow oil (1.2 g, 4.02 mmol, 90 %). H NMR (400 MHz, CDCl
3
): δ
3
.49 (s, 3H), 3.89 (s, 3H), 5.22 (s, 2H), 6.99 (d, J = 12.0 Hz, 2H), 7.08 (d, J = 12.0 Hz, 2H), 7.45
(d, J = 20.0 Hz, 1H), 7.59 (d, J = 12.0 Hz, 2H), 7.78 (d, J = 20.0 Hz, 1H), 8.04 (d, J = 12.0 Hz,
13
2
H). C NMR (100 MHz, CDCl
3
): δ 55.5, 56.2, 94.2, 113.8, 116.5, 119.9, 128.8, 130.0, 130.7,
-1
1
31.3, 143.6, 159.1, 163.3, 188.7. IR (UATR): max 2902, 2935, 1656, 1597, 1508, 1422 cm .
+
LRMS (EI): m/z (rel intensity) 121 (23), 135 (51), 253 (62), 267 (11), 298 (M , 100). TOF-
+
HRMS: calcd for C18
H18NaO
4
(M + Na ) 321.1097, found 321.1097.
(
E)-3-(2-(Methoxymethoxy)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I1c). Following
the General Procedure for the Claisen–Schmidt condensation described above, the desired
1
product was obtained as a yellow oil (1.1 g, 3.69 mmol, 78%). H NMR (400 MHz, CDCl
3
): δ
3
.51 (s, 3H), 3.89 (s, 3H), 5.28 (s, 2H), 6.98 (d, J = 9.2 Hz, 2H), 7.05 (t, J = 7.6 Hz, 1H), 7.18 (d,
J = 8.4 Hz, 1H), 7.35 (t, J = 1.6, 1.2 Hz, 1H), 7.61 (d, J = 15.6 Hz, 1H), 7.68 (d, J = 6.0 Hz, 1H),
1
3
8.05 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 16.0 Hz, 1H). C NMR (100 MHz, CDCl ): δ 55.4, 56.3,
3
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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6
9
4.6, 113.7, 114.8, 121.9, 122.5, 124.8, 128.3, 130.7, 131.3, 131.5, 139.1, 156.3, 163.3, 189.0. IR
−
1
(
UATR): νmax 3072, 2935, 1655, 1596, 1484, 1165, 982 cm . LRMS (EI): m/z (rel intensity) 77
+
+
(5), 118 (13), 135 (90), 237 (100), 298 (M , 1).TOF-HRMS: calcd for C18
H
18NaO (M + Na )
4
2
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
21.1097, found 321.1106. These spectroscopic data matched those reported previously.
(
E)-3-(3-(Methoxymethoxy)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I1d). Following
the General Procedure for the Claisen–Schmidt condensation described above, the desired
1
product was obtained as a yellow solid (1.7 g, 5.70 mmol, 82 %). Mp 75.2–77.4 °C. H NMR
(
400 MHz, CDCl
3
): δ 3.51 (s, 3H), 3.89 (s,3H), 5.22 (s, 2H), 6.99 (d, J = 8.4 Hz, 2H), 7.09 (d, J
=
=
7.5 Hz, 1H), 7.28–7.36 (m, 3H), 7.52 (d, J = 15.6 Hz, 1H), 7.76 (d, J = 15.6 Hz, 1H), 8.04 (d, J
1
3
8.4 Hz, 2H). C NMR (100 MHz, CDCl ): δ 55.5, 56.1, 94.5, 113.9, 115.7, 118.2, 122.2,
3
122.3, 129.9, 130.9, 131.1, 136.6, 143.7, 157.7, 163.5, 188.7. IR (UATR): νmax 2956, 2903,
−
1
1
659, 1598, 1311, 1244 cm . LRMS (EI): m/z (rel intensity) 121 (59), 135 (54), 237 (36), 253
+
+
(
51), 298 (M , 100). TOF-HRMS: calcd for C18
H
19
O (M + H ) 299.1278, found 299.1266.
4
(
E)-3-(3-Methoxy-4-(methoxymethoxy)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I1e).
Following the General Procedure for the Claisen–Schmidt condensation described above, the
desired product was obtained as a yellow solid (800 mg, 2.44 mmol, 76 %). Mp 91.5–92.5 °C.
1
H NMR (300 MHz, CDCl ): δ 3.53 (s, 3H), 3.89 (s,3H), 3.96 (s, 3H), 5,29 (s, 2H), 6.99 (d, J =
3
9
.0 Hz, 2H), 7.24–7.17 (m, 3H), 7.42 (d, J = 15.6 Hz, 1H), 7.76 (d, J = 15.6 Hz, 1H), 8.04 (d, J =
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.0 Hz, 1H). C NMR (75 MHz, CDCl
3
): δ 55.2, 56.7, 56.1, 94.9, 110.6, 113.5, 115.5, 119.9,
1
22.2, 129.1, 130.9, 130.5, 143.6, 148.3,149.5, 163.0, 188.3. IR (UATR): νmax 2936, 2939, 1655,
−
1
1598, 1507, 1464, 1420, 1338 cm . LRMS (EI): m/z (rel intensity) 57(19), 77(19), 135(100),
+
+
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
83(13), 328 (M , 30). TOF-HRMS: calcd for C19
H20NaO
5
(M + Na ) 351.1197, found
3
51.1203.
(
E)-3-(4-Methoxy-3-(methoxymethoxy)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I1f).
Following the General Procedure for the Claisen–Schmidt condensation described above, the
desired product was obtained as a yellow solid (996 mg, 3.03 mmol, 85 %). Mp 74.2–76.6 °C.
1
H NMR (300 MHz, CDCl
3
): δ 3.55 (s, 3H), 3.90 (d, J = 12.9 Hz, 6H), 5.28 (s, 2H), 6.91 (d, J =
8
.4 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 7.28 (dd, J = 8.1, 2.1 Hz, 1H), 7.40 (d, J = 15.6 Hz, 1H),
1
3
7.47 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 15.6 Hz, 1H), 8.03 (d, J = 8.7 Hz, 2H). C NMR (75 MHz,
CDCl
3
): δ 55.5, 55.9, 56.3, 95.6, 111.7, 113.8, 115.4, 120.1, 124.3, 128.2, 130.7, 131.3, 143.9,
−1
1
46.8, 151.9, 163.3, 188.7. IR (UATR): νmax 2935, 1599, 1509, 1258 cm . LRMS (EI): m/z (rel
+
intensity) 121 (34), 135 (100), 283 (79), 328 (53, M ). TOF-HRMS: calcd for C19
H20NaO
5
(M +
+
Na ) 351.1203, found 351.1210.
(
E)-3-(3,4-Bis(methoxymethoxy)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one
(I1g).
Following the General Procedure for the Claisen–Schmidt condensation described above, the
desired product was obtained as a yellow solid (920 mg, 2.57 mmol, 73 %). Mp 64.6–66.1 °C.
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4
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5
5
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6
1
H NMR (400 MHz, CDCl
3
): δ 3.53 (s, 3H), 3.56 (s, 3H), 3.89 (s, 3H), 5.29 (s, 2H), 5.30 (s, 2H),
6
.99 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.28–7.25 (m, 1H), 7.42 (d, J = 15.6 Hz, 1H),
13
7.48 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 15.6 Hz, 1H), 8.04 (d, J = 8.8 Hz, 2H). C NMR (100
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MHz, CDCl
3
): 55.4, 56.3, 95.1, 95.5, 113.7, 115.9, 116.1, 120.5, 123.8, 129.5, 130.7, 131.2,
−1
1
43.7, 147.3, 149.2, 163.3, 188.7. IR (UATR): νmax 2935, 2839, 1598, 1507, 1252 cm . LRMS
+
(
EI): m/z (rel intensity) 267 (16), 281 (49), 282 (100), 358 (32, M ). TOF-HRMS: calcd for
+
C
20
H22NaO
6
(M + Na ) 381.1309, found 381.1312.
(
(
E)-3-(3,4-Bis(methoxymethoxy)phenyl)-1-(4-(methoxymethoxy)phenyl)prop-2-en-1-one
I1h). Following the General Procedure for the Claisen–Schmidt condensation described above,
the desired product was obtained as a yellow solid (694 mg, 1.94 mmol, 58 %). Mp 81.3–83.5
1
°C. H NMR (400 MHz, CDCl
3
): δ 3.50 (s, 3H), 3.53 (s, 3H), 3.56 (s, 3H), 5.26 (s, 2H), 5.29 (s,
2
H), 5.29 (s, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.25–7.28 (m, 1H), 7.40 (d,
J = 15.6 Hz, 1H), 7.47 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 15.6 Hz, 1H), 8.01 (d, J = 8.8 Hz, 2H).
1
3
C NMR (100 MHz, CDCl
29.5, 130.7, 131.2, 132.2, 143.9, 147.4, 149.3, 160.9, 189.0. LRMS (EI): m/z (rel intensity) 165
100), 251 (36), 267 (69), 312 (87), 388 (M+, 66). IR (UATR): νmax 2955, 1599, 1507, 1253,
3
): δ 56.3, 56.3, 94.1, 95.1, 95.6, 115.8, 116.0, 116.2, 120.6, 123.9,
1
(
−
1
+
1
151, 1076 cm . TOF-HRMS: calcd for C21
H
24NaO (M + Na ) 411.1414, found 411.1420.
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(
E)-1-(3,4-Dimethoxyphenyl)-3-(4-(methoxymethoxy)phenyl)prop-2-en-1-one
(I1i).
Following the General Procedure for the Claisen–Schmidt condensation described above, the
1
desired product was obtained as a yellow oil (1.1 g, 3.35 mmol, 77 %). H NMR (400 MHz,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl
3
): δ 3.49 (s, 3H), 3.97 (s, 3H), 3.98 (s, 3H), 5.22 (s, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.08 (d,
J = 8.8 Hz, 2H), 7.46 (d, J = 15.6 Hz, 1H), 7.59 (s, 1H), 7.62 (t, J = 2.0 Hz, 2H), 7.68 (dd, J =
1
3
2
9
.0, 1.6 Hz, 1H), 7.79 (d, J = 15.6 Hz, 1H). C NMR (100 MHz, CDCl ): δ 56.0, 56.1, 56.1,
3
4.2, 109.9, 110.8, 116.5, 119.8, 122.8, 128.8, 130.0, 131.5, 143.6, 149.2, 153.1, 159.0, 188.6.
+
LRMS (EI): m/z (rel intensity) 151 (15), 165 (39), 182 (37), 283 (78), 328 (M , 100). TOF-
+
HRMS: calcd for C19
H20NaO
5
(M + Na ) 351.1203, found 351.1215.
(
E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(4-(methoxymethoxy)phenyl)prop-2-en-1-one
(I1j).
Following the General Procedure for the Claisen–Schmidt condensation described above, the
desired product was obtained as a yellow solid (996 mg, 3.19 mmol, 95 %). Mp 95.4–96.8 °C.
1
H NMR (300 MHz, CDCl ): δ 3.49 (s, 3H), 5.22 (s, 2H), 6.06 (s, 2H), 6.89 (d, J = 8.1 Hz, 1H),
3
7.07 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 15.6 Hz, 1H), 7.53 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 8.7 Hz,
13
2
5
1
H), 7.64 (dd, J = 8.1, 1.5 Hz, 1H), 7.77 (d, J = 15.6 Hz, 1H). C NMR (75 MHz, CDCl
3
): δ
6.1, 94.2, 101.8, 107.8, 108.4, 116.4, 119.8, 124.4, 128.7, 130.0, 133.1, 143.8, 148.2, 151.5,
−
1
59.1, 188.2. IR (UATR): νmax 2901, 1654, 1589, 1508, 1440, 1239, 985 cm . LRMS (EI): m/z
+
(rel intensity) 84 (10), 149 (37), 174 (11), 267 (66), 312 (100, M ). TOF-HRMS: calcd for
+
C
18
H16NaO
5
(M + Na ) 335.0889, found 335.0893.
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(
E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(3,4-bis(methoxymethoxy)phenyl)prop-2-en-1-one (I1k).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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0
Following the General Procedure for the Claisen–Schmidt condensation described above, the
desired product was obtained as a yellow solid (996 mg, 2.68 mmol, 74 %). Mp 97.3–99.8 °C.
1
H NMR (400 MHz, CDCl ): δ 3.52 (s, 3H), 3.55 (s, 3H), 5.28 (s, 2H), 5.29 (s, 2H), 6.05 (s, 2H),
3
6.89 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.25 (dd, J = 8.4, 2.0 Hz, 1H), 7.35 (d, J =
1
5.6 Hz, 1H), 7.45 (d, J = 2 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 8.4, 1.6 Hz, 1H), 7.72
13
(
d, J = 15.6 Hz, 1H). C NMR (100 MHz, CDCl
3
): δ 56.3, 95.1, 95.5, 101.8, 107.8, 108.4,
1
15.9, 116.2, 120.4, 123.8, 124.6, 129.5, 133.1, 143.9, 147.4, 148.2, 149.4, 151.6, 188.3. IR
−
1
(UATR): νmax 2956, 2902, 2827, 1654, 1588, 1504, 1439 cm . LRMS (EI): m/z (rel intensity)
+
1
49(74), 174(27), 295(36), 296 (100), 372(M , 37). TOF-HRMS: calcd for C20
H
20NaO (M +
7
+
Na ) 395.1101, found 395.1114.
(
E)-3-(2-Methoxy-4-(methoxymethoxy)phenyl)-1-(4-(methoxymethoxy)phenyl)prop-2-en-1-
one (I1l). Following the General Procedure for the Claisen–Schmidt condensation described
above, the desired product was obtained as a yellow solid (504 mg, 1.41 mmol, 69 %). Mp 97.5–
1
9
6
9.1 °C. H NMR (300 MHz, CDCl
3
): δ 3.49 (s, 6H), 3.89 (s, 3H), 5.20 (s, 2H), 5.24 (s, 2H),
.61 (d, J = 2.1 Hz, 1H), 6.67 (dd, J = 8.7, 2.1 Hz, 1H), 7.10 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 3.3,
13
1H), 8.00–8.07 (m, 3H). C NMR (75 MHz, CDCl
3
): δ 55.4, 56.1, 93.9, 94.2, 99.9, 107.8, 115.6,
117.9, 120.5, 130.9, 130.5, 132.4, 139.5, 160.1, 160.3, 160.6, 189.4. IR (UATR): νmax 2955,
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902, 1654, 1599, 1502, 1149 cm . LRMS (EI): m/z (rel intensity) 135(14), 165(14), 327(100),
+
+
28(19), 358(M , 7). TOF-HRMS: calcd for C20
H
22NaO (M + Na ) 381.1308, found 381.1300.
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
Deprotection of MOM ether. To a solution of MOM-protected chalcones (1.0 mmol) in ethanol
8 mL) was slowly added a solution of HCl (10% aqueous solution, 3.5 mL). The mixture was
refluxed for 30 min. After cooling down to room temperature, the mixture was diluted with water
20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over
Na SO and concentrated under reduced pressure to give the crude product in good purity which
was used in the next step without further purification.
(
(
2
4
(
E)-3-(4-Hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I2b). Following the General
Procedure for the deprotection of the MOM ether described above, the desired product was
1
obtained as a yellow solid (705 mg, 2.77 mmol, 89 %). Mp 158.6–160.5 °C. H NMR (300
MHz, acetone-d
6
): δ 3.84 (s, 3H), 6.79 (d, J = 9.0 Hz, 2H), 7.01 (d, 9.0 Hz, 2H), 7.55 (d, J = 15.5
1
3
Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 15.5 Hz, 1H), 8.04 (d, J = 9.0 Hz, 2H). C NMR
(
75 MHz, acetone-d
6
): δ 56.1, 114.9, 116.9, 119.4, 127.8, 131.8, 131.9, 132.3, 146.1, 161.5,
-1
1
65.2, 191.1. IR (UATR): max 3158, 2935, 2129, 1642, 1599, 1578, 1556 cm . TOF-HRMS:
+
calcd for C16
H
15
O (M + H ) 255.1016, found 255.1010. These spectroscopic data matched those
3
1
2
reported previously.
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2
2
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2
2
2
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3
3
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(
E)-3-(2-Hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I2c). Following the General
Procedure for the deprotection of the MOM ether described above, the desired product was
1
obtained as a yellow solid (286 mg, 1.12 mmol, 70 %). Mp 148.2−149.0 °C. H NMR (400 MHz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
acetone-d
6
) δ 3.91 (s, 3H), 6.94 (t, J = 7.6, 1H), 7.02 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 8.8 Hz,
2
H), 7.27–7.31 (m, 1H), 7.81 (dd, J = 7.6, 1.6 Hz, 1H), 7.91 (d, J = 16.0 Hz, 1H), 8.15 (d, J = 8.8
1
3
Hz, 2H), 8.18 (d, J = 15.6 Hz, 1H), 9.19 (s, 1H). C NMR (100 MHz, acetone-d
6
): δ 55.1, 113.8,
1
16.2, 120.0, 121.5, 122.3, 128.8, 130.6, 131.4, 131.5, 138.7, 156.9, 163.4, 187.7. IR (UATR):
−1
+
ν
max 3167, 2923, 1641, 1582, 1457, 1171, 1020 cm . LRMS (EI): m/z (rel intensity) 254 (M , 6),
+
2
37 (54), 135 (100), 108 (45), 77 (15), 57 (13). TOF-HRMS: calcd for C16
H14NaO
3
(M + Na )
1
2
277.0835, found 277.0844. These spectroscopic data matched those reported previously.
(
E)-3-(3-Hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I2d). Following the General
Procedure for the deprotection of the MOM ether described above, the desired product was
1
obtained as a pale yellow solid (1.33 g, 5.23 mmol, 96 %). Mp 150.5−152.8 °C. H NMR (400
MHz, acetone-d
6
): δ 3.92 (s, 3H), 6.95 (br d, J = 5.6 Hz, 1H), 7.09 (d, 8.0 Hz, 2H), 7.29 (d, J =
1
3
1
3.6 Hz, 3H), 7.69 (d, J = 15.6 Hz, 1H), 7.81 (d, J = 15.6 Hz, 1H), 8.17 (d, J = 8.0 Hz, 2H). C
NMR (100 MHz, acetone-d
6
): δ 55.1, 114.8, 117.3, 119.9, 121.9, 129.9, 130.7, 131.1, 136.7,
-1
1
43.2, 157.8, 163.6, 187.3. IR (UATR): max 3328, 2969, 1650, 1584, 1447, 1262 cm . LRMS
+
(EI): m/z (rel intensity) 71 (18), 91 (14), 135 (100), 237 (23), 254 (M , 86). TOF-HRMS: calcd
+
for C16
H
15
O
3
(M + H ) 255.1016, found 255.1010. These spectroscopic data are in good
12
accordance with those reported previously.
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The Journal of Organic Chemistry
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(
E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I2e). Following
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the General Procedure for the deprotection of the MOM ether described above, the desired
1
product was obtained as a yellow oil (85.1 mg, 0.29 mmol, 98 %). H NMR (300 MHz, CDCl
3
):
δ 3.86 (s, 3H), 3.91 (s, 3H), 6.35 (br s, OH), 6.93−6.97 (m, 3H), 7.11 (d, J = 1.5 Hz, 1H),
7.17−7.20 (m, 1H), 7.39 (d, J = 15.6 Hz, 1H), 7.74 (d, J = 15.6 Hz, 1H), 8.02 (d, J = 8.7 Hz, 2H).
1
3
C NMR (75 MHz, CDCl ): δ 55.4, 55.9, 110.0, 113.7, 114.9, 119.3, 123.1, 127.5, 130.7, 131.1,
3
-1
1
44.4, 146.8, 148.2, 163.2. 188.8. IR (UATR): max 3371, 2937, 1596, 1508, 1252, 1166 cm .
+
LRMS (EI): m/z (rel intensity) 55 (50), 57 (74), 69 (42), 149 (41), 284 (M , 100). TOF-HRMS:
+
calcd for C17
H
17
O
4
(M + H ) 285.1130, found 285.1121.
(
E)-3-(3-Hydroxy-4-methoxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I2f). Following
the General Procedure for the deprotection of the MOM ether described above, the desired
1
product was obtained as a brown solid (601 mg, 2.12 mmol, 99 %). Mp 126.6−128.2 °C. H
NMR (400 MHz, CDCl
3
): δ 3.92 (d, J = 0.8 Hz, 6H), 7.03 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 9.2
Hz, 2H), 7.26 (dd, J = 2.4, 2.4 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 3.2 Hz, 2H), 7.85
1
3
(
s, 1H), 8.18 (d, J = 9.2 Hz, 2H). C NMR (100 MHz, CDCl ): δ 55.0, 55.4, 111.4, 113.8, 113.8,
3
119.6, 122.1, 128.6, 130.6, 131.4, 143.4, 146.9, 149.8, 163.4, 187.2. IR (UATR): νmax 3384,
−1
2
2
840, 1600, 1508, 1259, 1169, 1023 cm . LRMS (EI): m/z (rel intensity) 124 (24), 135 (100),
+
+
69 (54), 284 (M , 92). TOF-HRMS: calcd for C17
H
17
O (M + H ) 285.1121, found 285.1124.
4
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The Journal of Organic Chemistry
Page 28 of 65
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(
E)-3-(3,4-Dihydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (I2g). Following the
0
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General Procedure for the deprotection of the MOM ether described above, the desired product
1
was obtained as a yellow solid (464 mg, 1.72 mmol, 87 %). Mp 74.2−76.6 °C. H NMR (400
MHz, acetone-d
8.4, 2.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 2H), 7.51 (d, J = 2.4 Hz, 2H), 8.00 (d, J = 8.8 Hz, 2H). C
NMR (100 MHz, acetone-d ): δ 55.9, 114.6, 115.6, 116.3, 119.6, 122.9, 128.4, 131.4, 132.3,
44.6, 146.3, 148.8, 164.2, 188.1. IR (UATR): νmax 3329, 29842, 1646, 1598, 1510, 1257, 1169
6
): δ 3.77 (s, 3H), 6.76 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 7.05 (dd, J =
13
6
1
−
1
cm . LRMS (EI): m/z (rel intensity) 57 (100), 71 (82), 97 (60), 149 (56), 178 (27), 221 (16), 270
+
+
(
M , 10). TOF-HRMS: calcd for C16
H
15
O (M + H ) 271.0962, found 271.0963.
4
(E)-3-(3,4-Dihydroxyphenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one (I2h). Following the
General Procedure for the deprotection of the MOM ether described above, the desired product
1
was obtained as a red solid (408 mg, 1.59 mmol, 98 %). Mp 189.7−191.7 °C. H NMR (400
MHz, acetone-d
6
): δ 6.77 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 2.0 Hz, 2H), 7.05 (dd, J = 8.2, 2.2 Hz,
1
3
H), 7.18 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 2.4 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 8.49 (br s,
13
OH). C NMR (100 MHz, acetone-d ): δ 114.8, 115.3, 115.5, 118.9, 122.1, 127.6, 130.6,
6
-1
130.9, 143.6, 145.4, 147.9, 161.7, 187.3. IR (UATR): max 3256, 1578, 1508, 1368, 1238 cm .
+
LRMS (EI): m/z (rel intensity) 57 (100), 71 (86), 83 (71), 97 (85), 127 (32), 256 (M , 9). TOF-
+
HRMS: calcd for C15
H
13
O
4
(M + H ) 257.0810, found 257.0808. These spectroscopic data are in
1
2
good accordance with those reported previously.
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Page 29 of 65
The Journal of Organic Chemistry
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(E)-1-(3,4-Dimethoxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (I2i). Following the
General Procedure for the deprotection of the MOM ether described above, the desired product
1
was obtained as a yellow solid (458 mg, 1.61 mmol, 88 %). Mp 143.0−144.1 °C. H NMR (400
MHz, acetone-d
6
): δ 3.91(s, 3H), 3.92 (s, 3H), 6.92 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 1H),
7
.67 (d, J = 2 Hz, 1H), 6.69 (d, J = 8.8 Hz, 2H), 7.72 (s, 2H), 7.85 (dd, J = 8.4, 2.0 Hz, 1H), 9.04
13
(
br s, 1H). C NMR (100 MHz, acetone-d
6
): δ 55.2, 55.3, 110.6, 111.0, 115.8, 118.7, 122.8,
1
1
27.0, 130.5, 131.5, 143.3, 149.4, 153.5, 159.7, 187.2. IR (UATR): νmax 3272, 2935, 1643, 1560,
−
1
509, 1257, 1020 cm . LRMS (EI): m/z (rel intensity) 57 (31), 84 (27), 149 (33), 165 (26), 253
+
+
(
44), 269 (22), 284 (M , 100). TOF-HRMS: calcd for C17
H
17
O (M + H ) 285.1121, found
4
2
85.1117.
(
E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(4-hydroxyphenyl)prop-2-en-1-one (I2j). Following the
General Procedure for the deprotection of the MOM ether described above, the desired product
1
was obtained as a yellow solid (677 mg, 2.52 mmol, 99 %). Mp 161.3−163.3 °C. H NMR (400
MHz, acetone-d
6
): δ 6.15 (s, 2H), 6.93 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 1H), 7.60 (d, J =
1
.6 Hz, 1H), 7.72 (d, J = 6.0 Hz, 3H), 7.74 (s, 1H), 7.83 (dd, J = 8.0, 1.6 Hz, 1H), 8.94 (s, OH).
1
3
C NMR (100 MHz, acetone-d ): δ 102.1, 107.8, 107.8, 115.8, 124.4, 126.9, 130.6, 131.8,
6
1
33.3, 143.7, 148.4, 151.6, 159.9, 186.8. LRMS (EI): m/z (rel intensity) 57(43), 84 (100), 149
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