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Lactone Enolates of Isochroman-3-ones and 2‑Coumaranones:

Quantification of Their Nucleophilicity in DMSO and Conjugate
Additions to Chalcones
Mohammad Sadeq Mousavi, Antonia Di Mola, Giovanni Pierri, Consiglia Tedesco,
Magenta J. Hensinger, Aijia Sun, Yilan Wang, Peter Mayer, Armin R. Ofial,* and Antonio Massa*
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sı Supporting Information
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ABSTRACT: Owing to stereoelectronic effects, lactones often deviate in reactivity from their open-chain ester analogues as
demonstrated by the CH acidity (in DMSO) of 3-isochromanone (pKa = 18.8) and 2-coumaranone (pKa = 13.5), which is higher
than that of ethyl phenylacetate (pKa = 22.6). We have now characterized the reactivity of the lactone enolates derived from 3-
isochromanone and 2-coumaranone by following the kinetics of their Michael reactions with p-quinone methides and
arylidenemalonates (reference electrophiles) in DMSO at 20 °C. Evaluation of the experimentally determined second-order rate
constants k2 by the Mayr−Patz equation, lg k2 = sN(N + E), furnished the nucleophilicity parameters N (and sN) of the lactone
enolates. By localizing their position on the Mayr nucleophilicity scale, the scope of their electrophilic reaction partners becomes
predictable, and we demonstrate a novel catalytic methodology for a series of carbon−carbon bond-forming reactions of lactone
enolates with chalcones under phase transfer conditions in toluene.

■ INTRODUCTION
The development of new applications of well-known reaction
ammonium enolates.3 The observed reactivity of arylacetates
in organic syntheses can be ascribed to the relatively low
Brønsted acidity of alkyl phenylacetates. For example, a pKa of
modes is of paramount importance in organic chemistry, which
22.6 (in DMSO) has been estimated for ethyl phenylacetate 1
usually stems from the identification of new nucleophiles or
(Figure 1).4
electrophiles. When there is the necessity to develop catalytic
Differently, the structurally related lactones 3-isochroma-
reactions, a pronucleophile should have suitable Brønsted
none (2a) and 2-coumaranone [3a, also known as benzofuran-
acidity to be deprotonated under relatively mild conditions to
2(3H)-one] have pKa(DMSO) values of 18.8 and 13.5,
guarantee turnover during the reaction. At the same time, the
respectively, close to the C−H acidity level of methyl p-
deprotonated species should be sufficiently nucleophilic to
nitrophenylacetate 1′ (pKa = 15.1 in DMSO2b ). The
react at a reasonable rate with the electrophilic reaction surprisingly high CH acidities of 2a and 3a, which are by 4
partner. In this context, monoesters, such as ethyl phenyl- and 9 orders of magnitude stronger CH acids than 1, were
acetate 1, have rarely been applied as pronucleophiles and
required mostly the use of stoichiometric amounts of strong
bases to undergo reactions.1 If additional strong electron- Received: January 31, 2024
withdrawing groups (EWGs) are present on the aromatic ring Revised: March 28, 2024
in the ortho or para position to stabilize the formed ester Accepted: April 6, 2024
enolate ion, 2-arylacetate esters become suitable for organo- Published: April 30, 2024
catalytic reactions.2 Another viable strategy includes the
addition of isothiourea to activate the 2-phenylacetates as C1

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Figure 1. C−H acidities (pKa in DMSO, data from ref 4) of the ester
1 and the lactones 2a and 3a.

rationalized as being a consequence of the locked s-(E)

conformation of the alkoxy group, which is linked to the
carbonyl carbon of the ester (or lactone) moiety. The s-(E)
conformation causes ineffective nO → σ*CO interactions that
can operate in the better-stabilized s-(Z) conformation of open
chain esters.5
A limited number of catalytic reactions of 3-substituted 2-
coumaranones 3 have been reported.6 However, to our Figure 2. Reference electrophiles used for the characterization of the
knowledge, the use of 3-isochromanones (2) as pronucleo- nucleophilic lactone enolates 4 and 5. Electrophilicity parameters E
philes has so far almost been neglected. While SN2 alkylations are from refs 13a,14,16.
at C-4 of 2a as well as Knoevenagel-type condensations with
aldehydes have occasionally been studied,7,8 only one example products, which were formed in exemplary reactions of the
for a conjugate addition to a Michael acceptor has been lactone enolates with selected reference electrophiles. As
reported to date. Flintoft and co-workers generated the lithium shown in Scheme 1, all selected combinations of lactones and
enolate of lactone 2a, which reacted with nitroethene in THF electrophiles reacted in the presence of different bases and
(−78 °C to r.t., 30 min, 75% yield).9 This void of synthetic solvents to the expected Michael adducts. Diastereomeric
application is surprising since applications of benzolactones 2 mixtures of the Michael adducts 7a−7c and 8, isolated with
and 3 can be correlated to natural products modification10,11 low diastereoselectivity, were obtained after aqueous workup.
and are, thus, synthetically valuable. As a consequence of the selective and uniform product
As part of our research interest in the development of new formations, we assumed the occurrence of analogous Michael
methodologies for the synthesis of heterocyclic compounds,12 additions for all further combinations of lactone enolates with
the aim of this work is the determination of nucleophilicity other electrophiles, which were studied in the kinetic
parameters of the lactone enolates of 2a and 3a in the experiments.
framework of the Mayr reactivity scales13,14 and the The kinetics of adduct formation between 4 or 5 and the
investigation of their synthetic utility in Michael reactions. In reference electrophiles 6 in DMSO (20 °C) were followed
particular, chalcones attracted our attention as Michael spectrophotometrically by utilizing stopped-flow techniques.
acceptors because they are an often-met motif in natural The nucleophiles were used in at least 10-fold excess to achieve
products and relevant in medicinal chemistry.15 pseudo-first-order conditions, which enabled us to derive the
first-order rate constants kobs (s−1) by least-squares fitting of
■ RESULTS AND DISCUSSION
Nucleophilicity of Lactone Enolates. The more than 5
the function At = A0 exp(−kobst) + C to the experimentally
observed decay of the time-dependent absorbances of 6. Only
orders of magnitude different pKa(DMSO) values of the for the reaction of 4 with 6a, the kinetic experiments were
lactones 2a and 3a already indicate that significantly different carried out by using the electrophile 6a in excess (>10 equiv).
nucleophilic reactivities have to be expected for the For each nucleophile−electrophile combination, kobs was
corresponding lactone enolate species 4 and 5. Consequently, determined at four or five different concentrations of the excess
different sets of reference electrophiles 6 were chosen as the reaction partner, which made it possible to calculate the
reaction partners for 4 and 5 in the kinetic measurements second-order rate constants k2 (M−1 s−1) from the slope of the
(Figure 2), which were carried out to quantify the nucleophilic linear relationships of kobs with the nucleophile concentration
reactivities of the lactone enolates in DMSO solution. The (or electrophile concentration for the reaction of 4 with 6a).
selected quinone methides and arylidenemalonates qualify as Details of all kinetics experiments are given in the Supporting
reference electrophiles because of their reliably determined Information, and the determined second-order rate constants
electrophilic reactivity E on the Mayr scale16 and their k2 are listed in Table 1.
favorable UV−vis absorbance ranges, which enabled us to The second-order rate constants k2 were then evaluated by
follow the kinetics of their reactions with the lactone enolates 4 the Mayr−Patz eq 1.
and 5 by photometric methods. lg k 2 (20 °C) = s N(N + E) (1)
The lactone enolate 4 (counterion: Na+) was quantitatively
generated in DMSO solution by deprotonation of 2a with In eq 1, the decadic logarithm of a second-order rate
sodium hydride (1.1 equiv).17 The more acidic lactone 3a was constants k2 for a nucleophile−electrophile reaction is
quantitatively deprotonated by the milder Brønsted base DBU expressed by the three parameters E, N, and sN. Given that
(2.2 equiv) to generate DMSO solutions of the lactone enolate the electrophilicities E of the reference electrophiles 6 were
5 (counterion: DBU-H+). In a first step, we investigated the reported before, and the second-order rate constants k2 were
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Scheme 1. Michael Adducts of Reactions of Lactones 2a and 3a with Quinone Methides 6 under Basic Conditions

Table 1. Second-Order Rate Constants k2 (M−1 s−1) for the Reactions of Lactone Enolate Ions 4 and 5 with Reference
Electrophiles 6 (in DMSO at 20 °C)
lactone enolates electrophiles E k2 (M−1 s−1) N (sN)a
4 (enolate of 2a) 6a −20.55 3.79 × 102 25.39 (0.54)
6b −17.90 1.40 × 104
6c −17.29 2.04 × 104
6d −16.38 6.68 × 104
5 (enolate of 3a) 6c −17.29 5.19 × 101 19.60 (0.75)
6e −16.11 3.60 × 102
6f −15.03 3.06 × 103
6g −14.36 1.31 × 104
6h −13.39 3.28 × 104
enolate of 1 6c −17.29 5.51 × 105b 27.54 (0.57)b
enolate of 1′ 6c −17.29 7.21 × 101b 20.00 (0.71)b
a
Calculated by using eq 1. bWith data from ref 18.

experimentally determined in this work, the remaining

parameters N and sN, which are characteristic for the reactivity
of a nucleophile in a specific solvent, can be calculated. Thus,
the quantitative descriptors N (and sN) for the nucleophilicities
of 4 (N = 25.39, sN = 0.54) and 5 (N = 19.60, sN = 0.75) were
derived from the linear correlations of lg k2 with the E
parameters of the electrophilic reaction partners (Figure 3).
Interestingly, the determined N parameters for the
carbanions derived from 1, 1′, 2a, and 3a correlate linearly
with the Brønsted acidities pKa of these CH acids. The scatter
in Figure 4a (R2 = 0.9565) is rationalized by the fact that the
slope parameters sN, which vary between 0.54 and 0.75 for this
set of nucleophiles (see Table 1), were neglected when Figure 3. Determination of N and sN for the lactone enolates 4 and 5
from the linear correlations of lg k2 with the electrophilicity
constructing the graph. Linear correlations of higher precision parameters E of the reference electrophiles 6.
can be expected if rate constants for reactions of the enolates
with a common electrophile are plotted against the pKa values
of 1, 1′, 2a, and 3a.
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Scheme 2. Michael Adducts of Reactions of Lactones 2a and

3a with (a) Carbon Disulfide, (b) Methyl Acrylate (9), (c)
But-3-enone (11), and (d) Chalcone (13a)a

a
Yields of isolated product after chromatographic purification.
Figure 4. (a) Correlation of enolate nucleophilicities N with pKa of
the corresponding CH acids 1, 1′, 2a, and 3a. (b) The Brønsted plot Interestingly, the parent chalcone 13a (E = −19.39)21 and
shows a linear relationship between the enolate reactivities (lg k2) lactone 2a under basic conditions in MeCN formed product
toward 6c and the acidity constants pKa of the corresponding CH 14a in good yield. The 4-monofunctionalized lactone 14a
acids 1, 1′, 2a, and 3a. corresponds to the 1:1-Michael adduct and was isolated as a
1:1 mixture of diastereomers (Scheme 2d).
Base-Catalyzed Michael Additions of Lactones to
Accordingly, the Brønsted correlation in Figure 4b illustrates Chalcones. Aiming to develop a catalytic process, we
that the nucleophilic reactivities (lg k2) of the ester and lactone optimized the adduct formation of 2a with the parent chalcone
enolates in reactions with quinone methide 6c correlate 13a under phase transfer conditions. In entry 1 of Table 2,
excellently with the Brønsted basicities of the CH acids 1, 1′,
2a, and 3a in DMSO (R2 = 0.9740). The slope of 0.476 in
Table 2. Optimization of the Michael Adduct Formation
Figure 4b is similar to the one reported for an analogous
between Chalcone (13a) and Lactone 2a
correlation for a series of benzyl anions stabilized by
ethoxycarbonyl, nitro, cyano, and sulfonyl groups (slope =
0.438, n = 11),18 which covered 14 orders of magnitude on the
pKa scale but showed much higher uncertainties (R2 = 0.74)
owing to the structurally more diverse set of carbanions that
undergo reactions via variable intrinsic barriers.18
By using the Mayr nucleophilicity parameters N and sN, it is
now possible to rationalize published synthetic procedures that NBu4Br molarity time yield
involve the investigated lactone enolates. For example, entry (equiv) base (equiv) [2a] (h) (%)a
Tominaga and co-workers reported that a mixture of 2- 1 K2CO3 (1.0) 0.337 24 -b
coumaranone 3a, sodium hydroxide, and carbon disulfide in 2 0.20 K2CO3 (1.0) 0.337 2 90
DMSO reacted at 10−15 °C to form an anionic adduct, which 3 0.05 K2CO3 (1.0) 0.337 2 88
was trapped by methylation with iodomethane to form 3- 4 0.05 K2CO3 (0.10) 0.337 2.5 86
bis(methylthio)methylene-2-coumaranone (Scheme 2a).19 5 0.01 K2CO3 (0.01) 0.675 48 88
This procedure is in good agreement with a moderately 6 0.10 K2CO3 (0.10) 0.675 5 97
rapid reaction that can be expected from a second-order rate 7 0.10 Li2CO3 (0.10) 0.675 36 80
constant of k2 = 27 M−1 s−1 (at 20 °C), which is calculated by a
Isolated yield. bStarting materials recovered.
using eq 1, the N (and sN) parameter of 5 in DMSO, and the
electrophilicity E = −17.70 for CS2.20
On the fundament of their nucleophilicity parameters, we lactone 2a and chalcone 13a were mixed in toluene in the
attempted to further explore the synthetic scope of 2a and 3a presence of K2CO3 (1 equiv.). Not unexpectedly, the starting
and investigated their reactivity toward prototypical Michael materials were recovered completely after 24 h at ambient
acceptors, such as methyl acrylate (9) or the α,β-unsaturated temperature (Table 1, entry 1) because of the insufficient
ketones 11 and 13a. The reactions of 3a with the β- solubility of potassium carbonate in toluene. The use of the
unsubstituted electrophiles 9 (E = −18.84)21 and 11 (E = phase transfer catalyst tetra-n-butyl ammonium bromide
−16.76),21 both gave the 1:2 adducts 10 and 12, respectively (TBAB) led to 14a in 90% yield within 2 h (entry 2), which
(Scheme 2b,c). was both a significantly shorter reaction time and a higher yield
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of 14a than from the analogous reaction performed in the synthesized several substituted 3-isochromanones with a range
more polar solvent acetonitrile but without the phase transfer of electronic properties incorporated on the aromatic ring
catalyst (Scheme 2d). Comparable yields of 14a were obtained [2b−2f, Supporting Information]. Several chalcones 13
even when decreasing the amounts of both TBAB and K2CO3 reacted with differently substituted 3-isochromanones 2a−2f
to 0.05 and 0.1 equiv, respectively (compare with entries 3 and with both reactants bearing halogens, electron-donating groups
4). The catalysts amount was further decreased to 0.01 equiv and EWGs in different positions on the aromatic rings,
with a concomitant scale up at 1 mmol, leading to high yield as showing variable reaction time as detected by thin-layer
well but requiring a longer reaction time (entry 5). However, chromatography (TLC) (used to monitor the disappearance of
the conditions were adjusted for practical reasons using 0.1 2), obtaining 14 in moderate to excellent yields (Table 3). In
equiv of both TBAB and K2CO3, providing product formation the case of (E)-3-(2-chlorophenyl)-1-phenylprop-2-en-1-one
in almost quantitative yield over 5 h (entry 6). These 13d, a high reaction temperature was required, probably
conditions can also be scaled up to 1 mmol with minimal because of the increased steric hindrance (entry 4), while at
impact on product yield (89% yield). The use of Li2CO3 room temperature, we did not observe any reaction. 7-
proved to be less effective, probably because of the lower Nitroisochroman-3-one 2d was not reactive at room temper-
counteranion exchange rate with TBAB (entry 7). On the ature, and a higher reaction temperature (110 °C) was
other hand, when the significantly less Brønsted acidic ethyl 2- necessary to achieve a moderate yield in the Michael addition
phenylacetate 1 was subjected to the same conditions, even with the parent chalcone 13a (entry 13). In this case, the nitro
after mixing for 24 h, we recovered the starting materials group leads to a decrease of the pKa, stabilizing the carbanion
unreacted. This demonstrates the importance of the pKa of the by resonance, and its nucleophilicity is lower than that of 4,
pronucleophiles’ C−H bonds for the development of effective explaining the observed reactivity. On the chalcone side, even
catalytic reactions (Scheme 3). (E)-3-(furan-2-yl)-1-phenylprop-2-en-1-one (13j), the pre-
sumably least electrophilic Michael acceptor in Table 3, gave
Scheme 3. Open-Chain Ester 1 Did Not React with a good yield in the reaction with 2a to give product 14j (entry
Chalcone 13a under the Optimal Conditions of Table 2, 10).
Entry 6 Low diastereoselectivity was usually observed, but the
majority of diastereomeric mixtures were easily separated by
chromatography or crystallization. In the case of the chloro-
substituted 14b, crystals suitable for single-crystal X-ray
analysis were obtained by slow evaporation of a solution of
14b (5 mg) in a dichloromethane/hexane mixture (1 mL, v/v
= 1:5) allowing for determination of the relative configuration
The scope of the lactone−chalcone adduct formation was as (S*,S*) (Figure 5). This was extended to all the series,
further explored under the optimized conditions of entry 6 of considering the similarity of the 1H NMR spectra and of the
Table 2. To assess the full extent of this reaction, we retention factors observed in chromatography.

Table 3. Scope Analysis for the Base-Catalyzed Michael Addition of Lactones 2 and Chalcones 13

entry lactones chalcones Ar Ar′ time (h) yield (%)a drb

1 2a, R = H 13a Ph Ph 5 14a, 97 50/50
2 2a, H 13b 4-ClC6H4 Ph 5 14b, 97 50/50
3 2a, H 13c 2-NO2C6H4 Ph 7 14c, 68 56/44
4c 2a, H 13d 2-ClC6H4 Ph 18 14d, 62 60/40
5 2a, H 13e 4-FC6H4 Ph 7 14e, 91 53/47
6 2a, H 13f 4-MeOC6H4 Ph 9 14f, 82 55/45
7 2a, H 13g Ph 3-CF3C6H4 6 14g, 76 53/47
8 2a, H 13h Ph 4-NO2C6H4 8 14h, 77 52/48
9 2a, H 13i Ph 4-MeOC6H4 10 14i, 73 53/47
10 2a, H 13j 2-furyl Ph 10 14j, 65 58/42
11 2b, 7-Br 13a Ph Ph 6 14k, 81 54/46
12 2c, 6-OMe 13a Ph Ph 3 14l, 96 50/50
13d 2d, 7-NO2 13a Ph Ph 12 14m, 58 53/47
14 2e, 6-Cl 13a Ph Ph 9 14n, 94 52/48
15 2c, 6-OMe 13f 4-MeOC6H4 Ph 3 14o, 93 51/49
16 2f, 8-F 13a Ph Ph 7 14p, 90 59/41

a
Isolated yield. bDetermined by 1H NMR spectroscopic analysis of the crude material. cReaction temperature at 60 °C. dReaction temperature at
110 °C.

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Figure 6. ORTEP diagram of 15d-1.22 Crystals of 15d-1 were

obtained by slow evaporation of a solution of 15d (10 mg) in a
Figure 5. ORTEP diagram of 14b-1.22 Crystals of 14b-1 were diethyl ether/isopropanol mixture (1 mL, v/v = 1:4).
obtained by slow evaporation of a solution of 14b-1 (5 mg) in a
dichloromethane/hexane mixture (1 mL, 1:5).
parameters N (sN) of the corresponding lactone enolates 4 and
Although the enolate of 2-coumaranone 3a is less 5 in DMSO were determined to be 25.39 (0.54) and 19.60
nucleophilic than that of 3-isochromanone 2a, it reacted (0.75), respectively. Considering the higher Brønsted acidity of
successfully with chalcones 13 under the conditions of entry 6 isochroman-3-one and 2-coumaranone in comparison to their
from Table 2. Several substituted 2-coumaranones were noncyclic structurally analogous alkyl phenylacetates, along
reacted with chalcones bearing different substituents on both with their high level of nucleophilic reactivity, an efficient
the aromatic rings as well, leading from good to high yields and catalytic method for Michael additions was developed. In
from moderate to low diastereoselectivity (Table 4). Of note, particular, series of substituted isochroman-3-ones and 2-
5-chloro-coumaranone 3c required a higher temperature and coumaranones were synthesized and then shown to react with
longer reaction time (Table 4, entry 8). Only 5-nitro- chalcones. In combination with the phase transfer catalyst
coumaranone 3d did not react at all, even at 80 °C, because tetra-n-butylammonium bromide (0.1 equiv), the low-cost
of the decrease of its nucleophilicity (entries 9 and 10) by the Brønsted base K2CO3 (0.1 equiv) could be used in catalytic
electron-withdrawing and, therefore, anion-stabilizing proper- amounts to activate the lactones in toluene and, thus, widen
ties of the nitro group (Hammett substituent constant σm = the scope of this carbon−carbon bond-forming reaction. Based
0.7123). In this series, the separation of the diastereomers was on these findings, further studies about the development of
more problematic and only in the case of 15d did attempts at asymmetric versions of the investigated Michael additions and
crystallization yield crystals suitable for X-ray analysis, depicted other applications in reactions with carbon-carbon and carbon-
in Figure 6, allowing for the determination of the relative heteroatom bond formation are ongoing.
configuration as (S*,R*).

■ CONCLUSIONS
■ EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all chemicals,
In this article, we explored the reactivity of isochroman-3-ones reagents, and solvents for the performed reactions are commercially
available. Isochroman-3-one was purchased from fluorochem, and
and 2-coumaranones as nucleophiles in Michael reactions. substituted isochroman-3-ones were prepared according to literature
Based on the Mayr−Patz eq 1 and by following the kinetics of procedures (see the Supporting Information for further details). All
the reactions of the respective lactone enolates with a series of the reactions were monitored by TLC on precoated silica gel plates
reference electrophiles (quinone methides and arylidenemal- (0.25 mm) and visualized by fluorescence quenching at 254 nm. Flash
onates) with known electrophilicity E, the nucleophilicity chromatography was carried out using silica gel 60 (70−230 mesh,

Table 4. Analysis of the Scope with 2-Coumaranones 3 and Chalcones 13

entry lactones chalcones Ar Ar′ time (h) yield (%)a d.rb

1 3a, R = H 13a Ph Ph 4 15a, 81 64/36
2 3a, H 13b 4-ClC6H4 Ph 5.5 15b, 83 53/47
3 3a, H 13f 4-MeOC6H4 Ph 5 15c, 87 54/46
4 3b, 5-OAc 13a Ph Ph 2.5 15d, 89 59/41
5 3a, H 13i Ph 4-MeOC6H4 5 15e, 83 62/38
6 3a, H 13d 2-ClC6H4 Ph 8.5 15f, 81 54/46
7 3a, H 13e 4-FC6H4 Ph 6.5 15g, 79 64/36
8c 3c, 5-Cl 13a Ph Ph 36 15h, 75 63/37
9d 3d, 5-NO2 13a Ph Ph 24 -e -
10d 3d, 5-NO2 13f 4-MeOC6H4 Ph 40 -e -

a
Isolated yield. bDetermined by 1H NMR on the crude material. cReaction temperature at 50 °C. dReaction temperature at 80 °C. eStarting
materials recovered.

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Merck, Darmstadt, Germany). Preparative TLC (PrepTLC) was Procedure B. 3-Isochromanone 2a (42.5 mg, 0.287 mmol) and
carried out on silica gel plates (200 × 200 × 0.5 mm). The products sodium hydride (7.1 mg, 95% purity, 0.281 mmol) were dissolved in
were detected under UV light, extracted with ethyl acetate, and DMSO (5 mL) under an argon atmosphere at room temperature and
obtained after rotary evaporation. Yields are given for isolated stirred for 45 min. Then, a solution of pQM 6b (101 mg, 0.259
products showing one spot on a TLC plate. The NMR spectra were mmol) in a DMSO/dichloromethane mixture (4.5 mL/2.5 mL) was
recorded on Bruker DRX 600, 400, and 300 MHz spectrometers (600 added. The reaction mixture was stirred for 1 h and then poured on
MHz, 1H, 150 MHz, 13C; 400 MHz, 1H, 100.6 MHz; 13C, 300 MHz, 0.5% aq. acetic acid (50 mL). The layers were separated, and the aq.
1
H, 75.5 MHz, 13C, 250 MHz, 1H, 62.5 MHz, 13C). Internal reference phase was extracted with ethyl acetate (3 × 20 mL). The combined
was set to the residual solvent signals (δH 7.26 ppm, δC 77.16 ppm for organic phases were washed with brine (2 × 20 mL) and dried over
CDCl3).24 The 13C{1H} NMR spectra were recorded under broad- MgSO4. After filtration, volatiles were evaporated to obtain the crude
band proton-decoupling and reported Cq, CH, CH2, or CH3 product (146 mg). Purification by column chromatography (silica gel,
assignments were based on additional heteronuclear single quantum n-pentane/ethyl acetate = 7:1) furnished 7a (92.7 mg, yield: 67%); a
coherence (HSQC) and heteronuclear multiple bond correlation mixture of diastereomers, d.r. 1:1.6. NMR spectra of this sample were
(HMBC) experiments. 1H NMR and high-resolution mass spectrom- used to assign 1H and 13C resonances of 7a-minor.
etry (HRMS) data are reported for all compounds. IR and 13C NMR 7a-major: 1H NMR (400 MHz, CDCl3, δ) 7.23−7.19 (m, 1H),
data are given only for new compounds. The following abbreviations 7.10−7.07 (m, 1H), 7.04−7.02 (m, 1H), 6.84 (s, 2H), 6.72 (s, 2H),
are used to indicate the multiplicity in NMR spectra: s�singlet, d� 6.61−6.59 (m, 1H), 5.05 (s, 1H), 4.93 (d, J = 14.3 Hz, 1H), 4.54 (d, J
doublet, t�triplet, q�quartet, dd�doublet of doublets, m� = 14.1 Hz, 1H), 4.37 (d, J = 6.8 Hz, 1H), 4.30 (d, J = 7.0 Hz, 1H),
multiplet, brs�broad signal. High-resolution mass spectra were 3.10 (dd, J = 6.3 Hz, 5.0 Hz, 4H), 2.79−2.67 (m, 4H), 2.00−1.93 (m,
acquired by the Salerno team using a Bruker SolariX XR Fourier 4H), 1.28 (s, 18H). 13C{1H} NMR (101 MHz, CDCl3, δ) 172.4 (Cq),
transform ion cyclotron resonance mass spectrometer (Bruker 152.8 (Cq), 142.0 (Cq), 135.4 (Cq), 133.6 (Cq), 131.9 (Cq), 130.5
Daltonik GmbH, Bremen, Germany) equipped with a 7T refrigerated (Cq), 129.0 (CH), 127.7 (CH), 127.6 (Cq), 127.3 (CH), 127.2 (CH),
actively shielded superconducting magnet. For ionization of the 126.0 (CH), 124.0 (Cq), 121.5 (Cq), 69.9 (CH2), 54.4 (CH, Ar2CH),
samples electrospray ionization (ESI) or matrix-assisted laser 53.4 (CH), 50.2 (CH2), 34.3 (Cq), 30.3 (CH3), 27.8 (CH2), 22.3
desorption/ionization (MALDI) was applied. In Munich, HRMS (CH2). HRMS (ESI): m/z calcd for C36H44NO3+ (M + H+)
was performed by using a Thermo Finnigan LTQ FT (ESI) or a 538.3316; found: 538.3305.
Thermo Finnigan MAT 95 instrument (EI). IR spectra were recorded 7a-minor: 1H NMR (400 MHz, CDCl3, δ) 6.57 (s, 2H), 5.08 (s,
on a IR Bruker Vertex 70v spectrometer. 1H), 4.87 (d, J = 14.2 Hz, 1H), 4.23 (d, J = 5.6 Hz, 1H), 2.64−2.61
Kinetics. The kinetics of the reactions of the lactone enolates with (m, 4H), 1.37 (s, 18H); further resonances could not unequivocally
the reference electrophiles 6 were followed by UV/vis spectroscopy be assigned because of superimposition with resonances of 7a-major.
13
(Applied Photophysics SX20 stopped-flow spectrophotometer). A C{1H} NMR (101 MHz, CDCl3, δ) 172.0, 152.8, 142.0, 135.6,
constant temperature (20.0 ± 0.2 °C) was maintained through the 134.1, 132.2, 131.4, 128.9, 127.8, 127.7, 127.6, 127.2, 125.7, 123.7,
use of a circulating bath cryostat. All solutions were freshly prepared 121.3, 69.9, 56.2, 52.9, 50.2, 34.5, 30.4, 27.8, 22.3.
under an atmosphere of dry argon by using dry DMSO (over 4-((3,5-Di-tert-butyl-4-hydroxyphenyl)(4-(dimethylamino)-
molecular sieves, Acros Organics). Solutions of sodium 3-oxoisochro- phenyl)-λ3-methyl)-4λ3-isochroman-3-one (7b). The product
man-4-ide (4) in DMSO were prepared by deprotonation of 3- was obtained from 3-isochromanone 2a (29.6 mg, 0.200 mmol),
isochromanone (2a) with sodium hydride. Solutions of 2-oxo-2,3- pQM 6c (65.3 mg, 0.193 mmol), and potassium tert-butoxide (31.4
dihydrobenzofuran-3-ide (5) in DMSO were prepared by deproto- mg, 0.280 mmol) by analogously following Procedure A (cf. synthesis
nation of 2-coumaranone (3a) with DBU (2.2 equiv.). of 7a). Purification of the crude product by column chromatography
The kinetic measurements were initiated by mixing equal volumes (silica gel, pentane/ethyl acetate = 7:1) furnished 7b (17.1 mg, yield:
of DMSO solutions of the nucleophiles and electrophiles. Selected 18%); a mixture of diastereomers, d.r. 1:2.
1
reactions of 4 with the electrophiles 6 were measured with and H NMR (400 MHz, CDCl3, δ) 7.30−7.28 (m, 4H), 7.25−7.17
without added crown ether (15-crown-5, 1.1 equiv relative to the (m, 4H), 7.11−7.02 (m, 9H), 6.78−6.76 (m, 5H), 6.72−6.70 (m,
concentration of 4). In general, nucleophile concentrations were at 4H), 6.62−6.58 (m, 4H), 5.10 (s, 1 Hminor), 5.07 (s, 2 Hmajor), 4.94 (d,
least ten times higher than electrophile concentrations to achieve J = 14.2 Hz, 2 Hmajor), 4.89 (d, J = 14.3 Hz, 1 Hminor), 4.57 (d, J = 14.2
pseudo-first-order kinetics. Only for the reaction of 4 with 6a (Table Hz, 1 Hmajor), 4.46 (d, J = 6.2 Hz, 1 Hminor), 4.43 (br s, 4 Hmajor), 4.34
S1), the kinetic experiments were carried out by using the electrophile (d, J = 6.1 Hz, 1 Hminor), 4.39 (d, J = 14.0 Hz, 1 Hminor), 2.94 (s, 12
6a in excess (>10 equiv). The first-order rate constants kobs (s−1) Hmajor), 2.91 (s, 6 Hminor), 1.37 (s, 18 Hminor), 1.29 (s, 38 Hmajor);
could be obtained from the decay of the absorbance at or close to the reported integrals refer to 1H (=1.0) of the minor diastereomer.
13
absorption maximum of the reaction partner used in lower C{1H} NMR (101 MHz, CDCl3, δ) 172.2 (Cqmajor), 171.8 (Cqminor),
concentration by least-squares fitting of the equation At = A0 152.9 (Cqmajor+minor), 149.65 (Cqminor), 149.61 (Cqmajor), 135.7
exp(−kobst) + C to the exponential absorption decay curve. Plots of (Cqminor), 135.5 (Cqmajor), 134.1 (Cqminor), 133.6 (Cqmajor), 132.0
kobs (s−1) versus the nucleophile concentration (or electrophile (Cqminor), 131.8 (Cqmajor), 131.2 (Cqminor), 130.5 (Cqmajor), 129.7
concentration for the reaction of 4 with 6a) gave the second-order (CHminor), 129.4 (CHmajor), 128.91 (CHmajor), 128.88 (CHminor),
rate constants k2 (M−1 s−1) as slopes of the linear correlations. 128.84 (Cqminor), 128.4 (Cqmajor), 128.0 (CHminor), 127.9 (CHmajor),
4-((3,5-Di-tert-butyl-4-hydroxyphenyl)(julolidin-9-yl)-λ 3 - 127.29 (CHminor), 127.27 (CHmajor), 126.0 (CHmajor), 125.7
methyl)-4λ3-isochroman-3-one (7a). Procedure A. 3-Isochroma- (CHminor), 124.1 (CHmajor), 123.9 (CHminor), 112.7 (CHmajor), 112.5
none 2a (31.2 mg, 0.211 mmol), pQM 6b (77.5 mg, 0.199 mmol), (CHminor), 69.90 (CH2major), 69.88 (CH2minor), 55.9 (CH, lactone-
and potassium tert-butoxide (30.3 mg, 0.270 mmol) were mixed in CHminor or Ar2CHminor), 54.4 (CH, lactone-CHmajor or Ar2CHmajor),
DMSO (13 mL) and stirred for 10 min. Then, the reaction mixture 53.2 (CH, lactone-CHmajor or Ar2CHmajor), 52.6 (CH, (CH, lactone-
was poured on 0.5% aq. acetic acid (50 mL). The phases were CHminor or Ar2CHminor)), 40.75 (CH3minor), 40.74 (CH3major), 34.5
separated, and the aqueous phase was extracted with ethyl acetate (3 (Cqminor), 34.3 (Cqmajor), 30.4 (CH3minor), 30.3 (CH3major). HRMS
× 40 mL). The combined organic phases were washed with brine (2 (ESI): m/z calcd for C32H40NO3+ (M + H+): 486.3003; found:
× 40 mL), dried over sodium sulfate, and filtered. Partial 486.2995.
crystallization by slow diffusion of pentane into a dichloromethane 4-((4-Hydroxy-3,5-dimethoxyphenyl)(4-methoxyphenyl)-
solution of the diastereomeric mixture of 7a at 4 °C (fridge) delivered λ3-methyl)-4λ3-isochroman-3-one (7c). The product was ob-
a small amount of diastereomerically pure cubic crystals of 7a (13.9 tained from 3-isochromanone 2a (38.4 mg, 0.259 mmol), sodium
mg, yield: 13%), which were characterized by X-ray crystallography hydride (7.1 mg, 95% purity, 0.281 mmol), and pQM 6d (61.0 mg,
(bv020).22 A solution of the diastereomerically pure crystals in CDCl3 0.224 mmol) by analogously following Procedure B (cf. synthesis of
was used for the NMR spectroscopic characterization of 7a-major. 7a). Purification of the crude product by column chromatography

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The Journal of Organic Chemistry pubs.acs.org/joc Article

(silica gel, n-pentane/ethyl acetate = 1:1) furnished a yellow oil (74.8 mixture was washed with sat. aq NH4Cl solution, and the aqueous
mg). The content of residual ethyl acetate in the sample was phase was extracted with ethyl acetate (3 × 30 mL). The combined
determined from the integrals in the 1H NMR spectrum (7.9 mg) and organic phases were dried over MgSO4 and filtered. Volatiles were
the yield of 7c calculated (66.8 mg, yield: 71%); a mixture of removed under vacuum, which left a colorful oily crude product.
diastereomers, d.r. 1:1.3. Purification by column chromatography (silica gel, hexane/CH2Cl2 =
1
H NMR (599 MHz, CDCl3, δ) 7.29−7.24 (m, 6.6H), 7.16−7.13 5:1) gave 10 (58.2 mg, yield: 51%) as a gray-green oil.
(m, 2.4H), 7.11−7.08 (m, 2.4H), 7.04−7.03 (m, 2 Hminor), 6.88−6.85 1
H NMR (599 MHz, CDCl3, δ) 7.33−7.31 (m, 1H), 7.20−7.12
(m, 2.7 Hmajor), 6.77−6.74 (m, 2 Hminor), 6.73−6.71 (m, 2.3H), 6.52 (m, 3H), 3.55 (s, 6H), 2.32−2.15 (m, 6H), 1.97 (ddd, J = 16.0, 10.7,
(s, 2 Hminor), 6.27 (s, 2.6 Hmajor), 5.04 (d, J = 14.2 Hz, 1.3 Hmajor), 5.02 5.0 Hz, 2H). 13C{1H} NMR (151 MHz, CDCl3, δ) 178.7 (Cq), 172.6
(d, J = 14.1 Hz, 1 Hminor), 4.84 (d, J = 14.3 Hz, 1.3 Hmajor), 4.77 (d, J (Cq), 153.4 (Cq), 129.6 (CH), 128.1 (Cq), 124.8 (CH), 123.8 (CH),
= 14.3 Hz, 1 Hminor), 4.51−4.49 (m, 2.3 Hmajor+minor), 4.39−4.37 (m, 111.2 (CH), 51.9 (CH3), 50.9 (Cq), 33.0 (CH2), 29.4 (CH2). IR
2.3 Hmajor+minor), 3.81 (s, 6 Hminor), 3.80 (s, 4.0 Hmajor), 3.77 (s, 3 (ATR, neat): 2953, 1798, 1733, 1477, 1461, 1435, 1226, 1196, 1170,
Hminor), 3.69 (s, 7.9 Hmajor); reported integrals refer to 1H (=1.0) of 1128, 1089, 1032, 868, 753 cm−1. HRMS (EI): m/z calcd for
the minor diastereomer. 13C{1H} NMR (151 MHz, CDCl3, δ) 171.5 C16H18O6•+ [M•+]: 306.1098; found: 306.1097.
(Cqmajor), 171.3 (Cqminor), 158.8 (Cqmajor), 158.7 (Cqminor), 147.0 4,4′-(2-Oxo-2,3-dihydrobenzofuran-3,3-diyl)bis(butan-2-
(Cqminor), 146.8 (Cqmajor), 134.0 (Cqminor), 133.8 (Cqmajor), 133.50 one) (12). The product was obtained from 2-coumaranone 3a (100
(Cqmajor), 133.48 (Cqminor), 132.5 (Cqminor), 132.3 (Cqmajor), 131.65 mg, 0.746 mmol) and methyl vinyl ketone (11) (52 mg, 0.742 mmol)
(Cqminor), 131.61 (Cqmajor), 131.5 (Cqminor), 131.3 (Cqmajor), 129.9 by analogously following Procedure C (cf. synthesis of 10). Purification
(CHminor), 129.6 (CHmajor), 128.73 (CHminor), 128.71 (CHmajor), by column chromatography (silica gel, hexane/CH2Cl2 = 5:1) gave 12
128.3 (CHmajor), 128.2 (CHminor), 127.61 (CHminor), 127.57 (88.7 mg, yield: 87%) as a yellow-brown oil.
1
(CHmajor), 124.33 (CHmajor), 124.26 (CHminor), 114.0 (CHmajor), H NMR (599 MHz, CDCl3, δ) 7.34−7.31 (m, 1H), 7.18−7.10
113.8 (CHminor), 105.8 (CHmajor), 105.7 (CHminor), 70.1 (CH2minor), (m, 3H), 2.32−2.28 (m, 2H), 2.26−2.13 (m, 4H), 2.10−2.00 (m,
70.0 (CH2major), 56.5 (CH3, 2 × OMeminor), 56.3 (CH3, 2 × 2H), 1.98 (s, 6H). 13C{1H} NMR (151 MHz, CDCl3, δ) 206.9 (Cq,
OMemajor), 55.36 (CH3, OMemajor), 55.34 (CH3, OMeminor), 54.7 ketone C�O), 179.1 (Cq, lactone C�O), 153.1 (Cq), 129.4 (CH),
(CHminor), 54.4 (CHmajor), 52.3 (CHmajor), 52.1 (CHminor); additional 128.8 (Cq), 124.9 (CH), 123.8 (CH), 111.0 (CH), 50.4 (Cq), 38.4
resonances at δ 171.6, 60.6, 21.2, and 14.3 are caused by residual ethyl (CH2), 31.6 (CH2), 30.1 (CH3). IR (ATR, neat): 2927, 1798, 1712,
acetate, which could not be removed from the sample. HRMS (EI): 1478, 1461, 1362, 1225, 1164, 1129, 1038, 880, 754, 733 cm−1.
m/z calcd for C25H22O6•+ [M − H2]•+: 418.1411; found: 418.1415. HRMS (EI): m/z calcd for C16H18O4•+ [M•+]: 274.1200; found:
3-((3,5-Di-tert-butyl-4-hydroxyphenyl)(4-methoxyphenyl)- 274.1199.
methyl)benzofuran-2(3H)-one (8). Under an atmosphere of dry K2CO3-Promoted Michael Reaction of 2a with Chalcone 13a
N2, 2-coumaranone 3a (100 mg, 0.746 mmol) and potassium (Scheme 2d). Isochroman-3-one 2 (30 mg, 0.20 mmol), potassium
carbonate (206 mg, 1.49 mmol) were mixed in acetonitrile (2 mL). carbonate (28 mg, 0.20 mmol), and chalcone 13a (46 mg, 0.22
Then, pQM 6e (242 mg, 0.746 mmol, solution in 8 mL MeCN) was mmol) were stirred in MeCN (0.4 mL) for 30 h at room temperature.
added dropwise. The reaction mixture was stirred for 1.5 h at room Purification was carried out directly by chromatography on a silica gel
temperature. The resulting purple solution was filtered and column with eluent hexane/ethyl acetate (95/5 → 70/30) to elute
neutralized with sat. aq NH4Cl solution (ca. 25 mL). The aq phase 14a (50 mg, 70% yield) as a mixture of diastereomers.
was extracted with ethyl acetate (3 × 25 mL), and the combined Catalytic Michael Reactions of 2 or 3 with Chalcones.
organic phases were dried (MgSO4) and filtered. Evaporation of Procedure D. Isochroman-3-one 2 or 3-coumaranone 3 (0.135
volatiles and drying under vacuum yielded a foamy, orange solid (360 mmol), potassium carbonate (10 mol %), tetrabutyl ammonium
mg). The content of residual ethyl acetate in the sample was bromide (TBAB, 10 mol %), and chalcone (0.148 mmol, 1.1 equiv)
determined from the integrals in the 1H NMR spectrum (25 mg) and were stirred in toluene (0.2 mL) for 5 h at room temperature.
the yield of 8 calculated (335 mg, yield: 98%); a mixture of Purification was carried out by chromatography on a short pad of
diastereomers, d.r. 1:1.6. silica gel column with eluent hexane/ethyl acetate (95/5 → 70/30) to
1
H NMR (400 MHz, CDCl3, δ) 7.24−7.19 (m, 5.2 Hmajor+minor), elute the mixture of diastereomers. Where possible, the diastereomers
7.02−6.96 (m, 9.7 Hmajor+minor), 6.90−6.87 (m, 3.3 Hmajor), 6.77−6.72 were separated by PrepTLC using hexane/ethyl acetate (90/10) as
(m, 6.3 Hmajor+minor), 6.68−6.63 (m, 2.0 Hminor), 5.15 (s, 1 Hminor), the eluent.
5.06 (s, 1.6 Hmajor), 4.81 (d, J = 4.8 Hz, 1 Hminor), 4.78 (d, J = 5.3 Hz, 4-(3-Oxo-1,3-diphenylpropyl)isochroman-3-one (14a) was purified by
1.6 Hmajor), 4.52−4.49 (m, 2.6 Hmajor+minor), 3.82 (s, 4.7 Hmajor), 3.76 flash chromatography (silica gel, hexane/ethyl acetate = 8:2), isolated
(s, 3.0 Hminor), 1.36 (s, 18.0 Hminor), 1.26 (s, 29.4 Hmajor); reported in a total yield of 97%, and analyzed by HRMS. Subsequently,
integrals refer to 1H (=1.0) of the minor diastereomer. 13C{1H} PrepTLC (silica gel, hexane/ethyl acetate = 85:15) was used to
NMR (101 MHz, CDCl3, δ) 175.7 (Cqminor), 175.6 (Cqmajor), 158.7 separate the diastereomers of 14b (dr = 50/50). HRMS (MALDI-FT
(Cqminor), 158.5 (Cqmajor), 154.18 (Cqminor), 154.16 (Cqmajor), 153.0 ICR): m/z calcd. for C24H21O3 [M + H]+: 357.1485; found:
(Cqmajor), 152.8 (Cqminor), 135.8 (Cqminor), 135.6 (Cqmajor), 133.1 357.1475.
(Cqmajor), 131.6 (Cqminor), 130.7 (CHminor), 130.4 (CHmajor), 129.6 The reaction was also scaled up to 1 mmol scale of isochroman-3-
(CHmajor), 129.2 (CHminor or Cqminor), 129.1 (CHminor or Cqminor), one 2a. Product 14a was isolated as a mixture of diastereomers after
129.0 (Cqmajor), 126.50 (Cqmajor), 126.47 (Cqminor), 126.1 (CHmajor), flash chromatographic purification on silica gel (hexane/ethyl acetate
125.5 (CHmajor), 125.4 (CHminor), 125.2 (CHminor), 123.81 (CHmajor), = 8:2) in a total yield of 89% (317 mg).
123.75 (CHminor), 113.9 (CHmajor), 113.8 (CHminor), 110.71 (R*)-4-((R*)-3-Oxo-1,3-diphenylpropyl)isochroman-3-one (14a-
(CHminor), 110.69 (CHmajor), 55.4 (CH3major), 55.3 (CH3minor), 51.6 1): white solid (23 mg); mp 143−145 °C. 1H NMR (400 MHz,
(CH, C−Hminor), 51.4 (CH, C−Hmajor), 49.54 (CH, C−Hminor), 49.52 CDCl3, δ) 8.01 (dd, J = 8.4, 1.3 Hz, 2H), 7.65 (d, J = 6.1 Hz, 2H),
(CH, C−Hmajor), 34.6 (Cqminor), 34.3 (Cqmajor), 30.4 (CH3minor), 30.3 7.56 (t, J = 7.5 Hz, 2H), 7.49 (t, J = 7.6 Hz, 1H), 7.37−7.28 (m, 2H),
(CH3major). HRMS (EI): m/z calcd for C30H32O4•+ [M − H2]•+: 7.24 (t, J = 7.3 Hz, 2H), 6.99 (d, J = 6.9 Hz, 2H), 6.95 (d, J = 7.7 Hz,
456.2295; found: 456.2292. 1H), 4.76 (d, J = 14.4 Hz, 1H), 4.40 (dd, J = 18.3, 9.4 Hz, 1H), 4.22
Dimethyl 3,3′-(2-oxo-2,3-dihydrobenzofuran-3,3-diyl)- (d, J = 3.8 Hz, 1H), 4.03−3.94 (m, 1H), 3.60 (d, J = 15.3 Hz, 1H),
dipropionate (10). Procedure C. Under an atmosphere of dry N2, 3.54 (dd, J = 18.3, 4.4 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3, δ)
2-coumaranone 3a (100 mg, 0.746 mmol) was added to a solution of 200.0, 172.5, 140.6, 138.5, 135.2, 134.7, 132.4, 131.1, 130.09, 130.06,
potassium carbonate (206 mg, 1.49 mmol) in acetonitrile (5 mL). 129.9, 129.7, 129.5, 129.1, 128.8, 124.7, 71.1, 51.0, 48.4, 42.9. IR
Subsequently, methyl acrylate (9) (67 μL, 0.739 mmol) was added (neat): 2926, 1727, 1679, 1595 cm−1.
dropwise, and the reaction mixture was stirred at room temperature (R*)-4-((S*)-3-Oxo-1,3-diphenylpropyl)isochroman-3-one (14a-
for 30 h (TLC showed complete consumption of 3a). Then, the 2): white solid (23 mg); mp 137−139 °C. 1H NMR (400 MHz,

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The Journal of Organic Chemistry pubs.acs.org/joc Article

CDCl3, δ) 8.03 (dd, J = 7.1, 1.3 Hz, 2H), 7.50 (tt, J = 7.4, 1.3 Hz, CDCl3, δ) 197.6, 197.4, 171.9, 171.1, 138.8, 137.6, 136.8, 136.7,
1H), 7.39 (t, J = 7.8 Hz, 1H), 7.24−7.09 (m, 4H), 7.08 (d, J = 7.3 Hz, 135.1, 134.9, 133.37, 133.32, 132.9, 132.5, 132.0, 130.8, 129.9, 129.7,
1H), 7.00 (t, J = 7.6 Hz, 1H), 6.90 (dd, J = 7.4, 2.1 Hz, 2H), 6.42 (d, J 129.1, 128.9, 128.7, 128.6, 128.6, 128.3, 128.1, 128.0, 127.8, 127.8,
= 7.7 Hz, 1H), 5.18 (d, J = 14.1 Hz, 1H), 5.01 (d, J = 14.1 Hz, 1H), 127.7, 127.5, 127.4, 127.1, 124.5, 124.0, 69.9, 52.6, 50.3, 42.3, 42.0,
3.91 (ddd, J = 9.1, 7.2, 5.2 Hz, 1H), 3.87 (d, J = 9.1 Hz, 1H), 3.79 40.4, 36.8. HRMS (MALDI-FT ICR): m/z calcd. for C24H20ClO3 [M
(dd, J = 17.8, 7.3 Hz, 1H), 3.42 (dd, J = 17.7, 5.3 Hz, 1H). 13C{1H} + H]+: 391.1095; found: 391.1072.
NMR (101 MHz, CDCl3, δ) 197.8, 172.4, 140.7, 136.8, 133.3, 132.6, 4-(1-(4-Fluorophenyl)-3-oxo-3-phenylpropyl)isochroman-3-one (14e)
131.7, 128.7, 128.6, 128.5, 128.3, 128.1, 127.7, 127.48, 127.43, 124.5, was purified by flash chromatography (silica gel, hexane/ethyl acetate
69.6, 52.7, 42.6, 42.1. IR (neat): 2994, 1731, 1685, 1597 cm−1. = 9:1), isolated in a total yield of 91%, and analyzed by HRMS.
4-(1-(4-Chlorophenyl)-3-oxo-3-phenylpropyl)isochroman-3-one (14b) Subsequently, PrepTLC (silica gel, hexane/ethyl acetate = 92:8) was
was purified by flash chromatography (silica gel, hexane/ethyl acetate used to separate the diastereomers (dr = 53/47).
= 8:2), isolated in a total yield of 97%, and analyzed by HRMS. HRMS (MALDI-FT ICR): m/z calcd. for C24H19FO3K [M + K]+:
Subsequently, PrepTLC (silica gel, hexane/ethyl acetate = 85:15) was 413.0950; found: 413.0982.
used to separate the diastereomers of 14b (dr = 50/50). (R*)-4-((R*)-1-(4-fluorophenyl)-3-oxo-3-phenylpropyl)-
HRMS (MALDI-FT ICR): m/z calcd. for C24H20ClO3 [M + H]+: isochroman-3-one (14e-1): white solid (24 mg); mp 137−139 °C. 1H
391.1095; found: 391.1091. NMR (400 MHz, CDCl3, δ) 8.02 (dd, J = 7.2, 1.4 Hz, 2H), 7.63 (tt, J
(R*)-4-((R*)-1-(4-Chlorophenyl)-2-oxo-2-phenylethyl)- = 7.4, 1.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.30 (dd, J = 7.5, 1.2 Hz,
isochroman-3-one (14b-1): white solid (26 mg); mp 174−176 °C. 1H 1H), 7.23 (d, J = 6.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.01−6.93 (m,
NMR (400 MHz, CDCl3, δ) 8.11 (dd, J = 7.1, 1.5 Hz, 2H), 7.65 (d, J 4H), 6.54 (d, J = 6.4 Hz, 1H), 5.37 (d, J = 14.2 Hz, 1H), 5.17 (d, J =
= 6.1 Hz, 2H), 7.56 (t, J = 7.5 Hz, 2H), 7.49 (t, J = 7.6 Hz, 1H), 14.3 Hz, 1H), 4.07−4.00 (m, 1H), 3.93 (dd, J = 7.1, 6.5 Hz, 1H), 3.87
7.36−7.29 (m, 2H), 7.24 (t, J = 7.3 Hz, 2H), 6.99 (d, J = 6.9 Hz, 2H), (d, J = 7.1 Hz, 1H), 3.54 (dd, J = 17.8, 5.9 Hz, 1H). 13C{1H} NMR
6.95 (d, J = 7.7 Hz, 1H), 4.76 (d, J = 14.4 Hz, 1H), 4.40 (dd, J = 18.3, (101 MHz, CDCl3, δ) 197.5, 172.0, 161.8 (d, JC,F = 246.4 Hz), 136.5
9.4 Hz, 1H), 4.22 (d, J = 3.8 Hz, 1H), 4.04−3.94 (m, 1H), 3.60 (d, J (d, JC,F = 13.2 Hz), 133.2, 132.3, 131.4, 129.7 (d, JC,F = 7.9 Hz),
= 15.3 Hz, 1H), 3.54 (dd, J = 18.3, 4.4 Hz, 1H). 13C{1H} NMR (63 128.5, 128.4, 128.0, 127.7, 127.4, 124.5, 115.5, 115.2, 69.5, 52.6, 42.1,
MHz, CDCl3, δ) 198.1, 170.7, 137.6, 136.7, 133.5, 133.3, 133.2, 41.6. 19F{1H} NMR (376 MHz, CDCl3, δ) −114.21. IR (neat): 2924,
130.6, 129.4, 128.6, 128.0, 127.4, 123.4, 69.7, 49.3, 46.2, 41.3. IR 1725, 1686, 1597 cm−1.
(neat): 2925, 1744, 1685, 1590 cm−1. (R*)-4-((S*)-1-(4-Fluorophenyl)-3-oxo-3-phenylpropyl)-
(R*)-4-((S*)-1-(4-Chlorophenyl)-2-oxo-2-phenylethyl)- isochroman-3-one (14e-2): white solid (22 mg); mp 134−136 °C. 1H
isochroman-3-one (14b-2): white solid (26 mg); mp 164−166 °C. 1H NMR (400 MHz, CDCl3, δ) 8.12 (dd, J = 7.1, 1.3 Hz, 2H), 7.64 (t, J
NMR (400 MHz, CDCl3, δ) 7.95 (dd, J = 7.2, 1.5 Hz, 2H), 7.57 (t, J = 7.6 Hz, 2H), 7.56 (t, J = 7.6 Hz, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.33
= 7.3 Hz, 1H), 7.46 (t, J = 7.4 Hz, 2H), 7.25 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 7.01−6.92 (m, 5H), 4.84 (d, J = 14.5 Hz, 1H),
(d, J = 6.1 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 4.34 (dd, J = 18.2, 9.1 Hz, 1H), 4.19 (d, J = 3.9 Hz, 1H), 3.98 (dt, J =
6.48 (d, J = 7.6 Hz, 2H), 5.36 (d, J = 14.1 Hz, 1H), 5.13 (d, J = 14.3 8.9, 4.4 Hz, 1H), 3.79 (d, J = 14.5 Hz, 1H), 3.52 (dd, J = 18.2, 4.8 Hz,
Hz, 1H), 3.97−3.79 (m, 3H), 3.47 (dd, J = 17.6, 5.6 Hz, 1H). 1H). 13C{1H} NMR (101 MHz, CDCl3, δ) 198.3, 170.9, 162.3 (d, JC,F
13
C{1H} NMR (101 MHz, CDCl3, δ) 197.4, 171.9, 139.3, 136.7, = 246.7 Hz), 137.0, 135.0, 133.5, 133.4, 130.8, 129.8 (d, JC,F = 7.7
133.4, 133.2, 132.4, 131.6, 129.7, 128.7, 128.5, 128.0, 127.9, 127.6, Hz), 128.8, 128.7, 128.1, 127.5, 123.5, 115.6, 115.4, 69.8, 49.5, 46.3,
127.1, 124.7, 69.6, 52.6, 41.9, 36.2. IR (neat): 2924, 1725, 1685, 1582 41.7. 19F{1H} NMR (376 MHz, CDCl3, δ) −114.21. IR (neat): 2925,
cm−1. 1744, 1681, 1511 cm−1.
4-(1-(2-Nitrophenyl)-3-oxo-3-phenylpropyl)isochroman-3-one (14c) 4-(1-(4-Methoxyphenyl)-3-oxo-3-phenylpropyl)isochroman-3-one
was purified by flash chromatography (silica gel, hexane/ethyl acetate (14f) was purified by flash chromatography (silica gel, hexane/ethyl
= 7:3) and isolated as a white solid (36 mg, yield: 68%), a mixture of acetate = 8:2), isolated in a total yield of 82%, and analyzed by
diastereomers (dr = 56/44). 1H NMR (400 MHz, CDCl3, δ) 7.99major HRMS. Subsequently, PrepTLC (silica gel, hexane/ethyl acetate =
(dd, J = 7.1, 1.4 Hz, 2H), 7.94major (dd, J = 7.1 Hz, 1.4 Hz, 2H), 7.77− 85:15) was used to separate the diastereomers (dr = 55/45).
7.70 (m, 3H), 7.68 (d, J = 3.9 Hz, 3H), 7.60 (d, J = 7.4 Hz, 2H), 7.48 HRMS (MALDI-FT ICR): m/z calcd. for C25H21KO4 [M + K]+:
(t, J = 9.3 Hz, 5H), 7.45−7.40 (m, 4H), 7.29 (d, J = 5.0 Hz, 2H), 7.15 425.1149; found: 425.1155.
(d, J = 7.3 Hz, 1H), 7.04 (dt, J = 8.4, 4.4 Hz, 1H), 6.37minor (d, J = 7.6 (R*)-4-((R*)-1-(4-Methoxyphenyl)-3-oxo-3-phenylpropyl)-
Hz, 1H), 6.02minor (d, J = 14.2 Hz, 1H), 5.35major (d, J = 14.2 Hz, 1H), isochroman-3-one (14f-1): white solid (23 mg); mp 138−141 °C. 1H
5.08minor (d, J = 14.2 Hz, 1H), 5.01−4.83 (m, 2H), 4.26minor (d, J = 7.6 NMR (400 MHz, CDCl3, δ) 8.13 (dd, J = 7.1, 1.5 Hz, 2H), 7.68−7.61
Hz, 1H), 4.05−3.90 (m, 3H), 3.72major (dd, J = 18.4, 7.3 Hz, 1H), (m, 2H), 7.55 (t, J = 7.5 Hz, 2H), 7.48 (t, J = 7.5 Hz, 1H), 7.36−7.29
3.54minor (dd, J = 18.0, 6.7 Hz, 1H), 3.45 (d, J = 2.6 Hz, 1H), 13C{1H} (m, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.77 (d, J
NMR (63 MHz, CDCl3, δ) 196.6, 196.5, 171.3, 170.3, 150.4, 150.2, = 8.8 Hz, 2H), 4.79 (d, J = 14.4 Hz, 1H), 4.34 (dd, J = 18.2, 9.3 Hz,
136.3, 136.2, 136.0, 134.4, 133.3, 132.7, 132.7, 131.9, 131.8, 131.0, 1H), 4.18 (d, J = 3.8 Hz, 1H), 3.93 (dt, J = 8.8, 4.2 Hz, 1H), 3.82 (s,
129.4, 129.2, 128.7, 128.6, 128.5, 128.1, 128.0, 127.9, 127.8, 127.7, 3H), 3.74 (d, J = 14.3 Hz, 1H), 3.50 (dd, J = 18.2, 4.6 Hz, 1H).
13
127.2, 124.8, 124.5, 124.4, 69.9, 69.6, 52.6, 50.3, 42.2, 42.0, 37.2, 33.8. C{1H} NMR (101 MHz, CDCl3, δ) 198.7, 171.2, 159.2, 137.2,
HRMS (MALDI-FT ICR): m/z calcd. for C26H24NaO5 [M + Na]+: 134.0, 133.3, 131.2, 131.0, 129.3, 128.7, 128.6, 128.1, 127.3, 123.4,
439.1516; found: 439.1525. 113.9, 69.9, 55.2, 49.7, 46.3, 41.8. IR (neat): 3065, 1744, 1679, 1513
4-(1-(2-Chlorophenyl)-3-oxo-3-phenylpropyl)isochroman-3-one cm−1.
(14d). The reaction mixture was heated at 60 °C (oil bath). The (R*)-4-((S*)-1-(4-Methoxyphenyl)-3-oxo-3-phenylpropyl)-
crude product was purified by flash chromatography (silica gel, isochroman-3-one (14f-2): white solid (19 mg); mp 121−124 °C. 1H
hexane/ethyl acetate = 85:15) and isolated as a white solid (32 mg, NMR (400 MHz, CDCl3, δ) 8.02 (dd, J = 7.1, 1.5 Hz, 2H), 7.62 (t, J
yield: 62%), a mixture of diastereomers (dr = 60/40). 1H NMR (400 = 7.3 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.37−7.26 (m, 1H), 7.22−
MHz, CDCl3, δ) 8.03minor (d, J = 4.4 Hz, 2H), 8.02major (d, J = 4.2 Hz, 7.16 (m, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 6.62
2H), 7.65−7.56 (m, 2H), 7.55−7.48 (m, 4H), 7.39 (d, J = 7.3 Hz, (d, J = 7.9 Hz, 1H), 5.20 (d, J = 14.2 Hz, 1H), 5.11 (d, J = 14.3 Hz,
2H), 7.27 (td, J = 16.1, 8.1 Hz, 6H), 7.19 (d, J = 6.8 Hz, 1H), 7.09− 1H), 4.06−3.95 (m, 1H), 3.87 (d, J = 7.3 Hz, 1H), 3.82 (s, 3H), 3.78
7.01 (m, 2H), 6.36minor (d, J = 7.6 Hz, 1H), 6.03minor (d, J = 14.1 Hz, (d, J = 7.3 Hz, 1H), 3.51 (dd, J = 17.7, 5.5 Hz, 1H). 13C{1H} NMR
1H), 5.34minor (d, J = 14.2 Hz, 1H), 4.95minor (d, J = 14.4 Hz, 1H), (101 MHz, CDCl3, δ) 197.9, 172.4, 158.9, 136.9, 133.2, 132.6, 132.6,
4.75−4.66major (m, 1H), 4.40 (d, J = 14.6 Hz, 1H), 4.25 (d, J = 5.6 Hz, 131.7, 129.3, 128.7, 128.6, 128.1, 127.7, 127.4, 124.5, 113.9, 69.7,
1H), 4.15 (dd, J = 18.1, 8.2 Hz, 1H), 4.03 (dd, J = 18.3, 6.7 Hz, 1H), 55.2, 52.7, 42.3, 42.1. IR (neat): 3061, 1741, 1669, 1523 cm−1.
3.96 (d, J = 10.9 Hz, 1H), 3.63major (dd, J = 18.3, 6.0 Hz, 1H), 4-(3-Oxo-1-phenyl-3-(3-(trif luoromethyl)phenyl)propyl)isochroman-
3.50minor (dd, J = 18.1, 5.5 Hz, 1H). 13C{1H} NMR (101 MHz, 3-one (14g) was purified by flash chromatography (silica gel, hexane/

6923 https://doi.org/10.1021/acs.joc.4c00277
J. Org. Chem. 2024, 89, 6915−6928
The Journal of Organic Chemistry pubs.acs.org/joc Article

ethyl acetate = 85:15), isolated in a total yield of 76%, and analyzed (d, J = 7.9 Hz, 1H), 5.20 (d, J = 14.2 Hz, 1H), 5.11 (d, J = 14.2 Hz,
by HRMS. Subsequently, PrepTLC (silica gel, hexane/ethyl acetate = 1H), 4.09−3.95 (m, 1H), 3.87 (d, J = 7.3 Hz, 1H), 3.82 (s, 3H), 3.78
9:1) was used to separate the diastereomers (dr = 53/47). (t, J = 6.7 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3, δ) 197.9,
HRMS (MALDI-FT ICR): m/z calcd. for C25H19F3KO3 [M + K]+: 172.5, 158.9, 136.9, 133.3, 132.65, 132.62, 131.8, 129.3, 128.7, 128.6,
463.0918; found: 463.0945. 128.1, 127.8, 127.4, 124.5, 113.9, 69.7, 55.3, 52.7, 42.3, 42.1. IR
(R*)-4-((R*)-2-Oxo-1-phenyl-2-(3-(trifluoromethyl)phenyl)- (neat): 2991, 1740, 1681, 1599 cm−1.
ethyl)isochroman-3-one (14g-1): white solid (22 mg); mp 133−135 ((Furan-2-yl)-3-oxo-3-phenylpropyl)isochroman-3-one (14j) was pu-
°C. 1H NMR (400 MHz, CDCl3, δ) 8.35 (dd, J = 18.0, 7.9 Hz, 2H), rified by flash chromatography (silica gel, hexane/ethyl acetate =
7.91 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 7.6 Hz, 80:20) and isolated as a white solid (30 mg, yield: 65%), a mixture of
1H), 7.50 (t, J = 7.6 Hz, 1H), 7.33 (q, J = 7.0 Hz, 2H), 7.25 (t, J = 7.4 diastereomers (dr = 58/42). 1H NMR (400 MHz, CDCl3, δ) 8.10major
Hz, 2H), 6.99 (d, J = 7.3 Hz, 2H), 6.95 (d, J = 7.5 Hz, 1H), 4.77 (d, J (dd, J = 7.1, 1.4 Hz, 2H), 8.04minor (dd, J = 7.1, 1.4 Hz, 2H), 7.64 (d, J
= 14.4 Hz, 1H), 4.43 (dd, J = 18.4, 9.5 Hz, 1H), 4.21 (d, J = 3.8 Hz, = 7.3 Hz, 2H), 7.58−7.51 (m, 5H), 7.45 (t, J = 7.4 Hz, 2H), 7.40−
1H), 3.99 (dt, J = 9.4, 4.2 Hz, 1H), 3.62 (d, J = 14.4 Hz, 1H), 3.54 7.33 (m, 3H), 7.31−7.16 (m, 3H), 7.08major (d, J = 7.7 Hz, 1H),
(dd, J = 18.4, 4.3 Hz, 1H), 13C{1H} NMR (101 MHz, CDCl3, δ) 6.70minor (d, J = 7.7 Hz, 1H), 6.30major (dd, J = 3.2, 1.9 Hz, 1H),
197.4, 171.2, 138.9, 137.6, 133.6, 131.4 (q, JC,F = 32.5 Hz), 131.4, 6.26minor (dd, J = 3.2, 1.9 Hz, 1H), 5.89minor (d, J = 3.2 Hz, 1H),
131.1, 129.8, 129.8, 129.4, 128.7, 128.3, 128.1, 127.9, 127.5, 125.0 (q, 5.84major (d, J = 3.2 Hz, 1H), 5.54minor (d, J = 14.3 Hz, 1H), 5.38major
JC,F = 3.7 Hz), 123.5, 69.8, 49.4, 46.9, 41.7. 19F{1H} NMR (376 MHz, (s, 1H), 5.24minor (d, J = 14.3 Hz, 1H), 5.02major (d, J = 14.5 Hz, 1H),
CDCl3, δ) −62.76. IR (neat): 2924, 1725, 1685, 1582 cm−1. 4.31major (d, J = 13.4 Hz, 1H), 4.19−4.07 (m, 3H), 3.86−3.77major (m,
(R*)-4-((S*)-2-Oxo-1-phenyl-2-(3-(trifluoromethyl)phenyl)- 1H), 3.63−3.51 (m, 3H), 13C{1H} NMR (75 MHz, CDCl3, δ) 198.6,
ethyl)isochroman-3-one (14g-2): white solid (20 mg); mp 114−116 197.8, 171.7, 170.5, 140.6, 138.9, 137.0, 136.7, 133.8, 133.5, 133.4,
°C. 1H NMR (400 MHz, CDCl3, δ) 8.21 (s, 1H), 8.16 (d, J = 8.0 Hz, 133.1, 133.0, 131.9, 130.9, 130.2, 129.9, 128.8, 128.8, 128.7, 128.6,
1H), 7.82 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.28−7.08 (m, 128.3, 128.2, 128.1, 128.0, 127.8, 127.7, 127.7, 126.5, 121.4, 121.2,
5H), 7.04 (t, J = 7.4 Hz, 1H), 6.98 (dd, J = 6.5, 3.1 Hz, 2H), 6.39 (d, J 68.9, 68.8, 52.3, 49.0, 47.1, 42.6, 42.1, 41.4. HRMS (MALDI-FT
= 7.5 Hz, 1H), 5.45 (d, J = 14.2 Hz, 1H), 5.14 (d, J = 14.2 Hz, 1H), ICR): m/z calcd. for C22H18NaO4 [M + Na]+: 369.1097; found:
3.97−3.90 (m, 2H), 3.46 (dd, J = 13.5, 6.5 Hz, 1H). 13C{1H} NMR 369.1093.
(101 MHz, CDCl3, δ) 196.6, 172.4, 140.7, 137.4, 132.7, 131.6, 131.4 7-Bromo-4-(3-oxo-1,3-diphenylpropyl)isochroman-3-one (14k) was
(q, JC,F = 32.8 Hz), 131.3, 129.7 (q, JC,F = 3.9 Hz), 129.3, 128.6, purified by flash chromatography (silica gel, hexane/ethyl acetate =
128.6, 128.3, 127.8, 127.6, 127.5, 125.0, 124.9, 124.6, 69.6, 52.8, 42.5. 80:20) and isolated as a white solid (47 mg, yield: 81%), a mixture of
19 1
F{ H} NMR (376 MHz, CDCl3, δ) −62.64. IR (neat): 2935, 1727, diastereomers (dr = 54/46). 1H NMR (400 MHz, CDCl3, δ) 8.14major
1689, 1612 cm−1. (dd, J = 7.1, 1.4 Hz, 2H), 8.03minor (d, J = 7.1, 1.4, 2H), 7.71−7.48 (m,
(R*)-4-((R*)-3-(4-Nitrophenyl)-3-oxo-1-phenylpropyl)isochroman-3- 8H), 7.41−7.21 (m, 9H), 7.12−6.97 (m, 5H), 6.36minor (d, J = 7.9 Hz,
one (14h) was purified by flash chromatography (silica gel, hexane/ 1H), 5.35minor (d, J = 14.3 Hz, 1H), 5.10 minor (d, J = 14.3 Hz, 1H),
ethyl acetate = 7:3) and isolated as a white solid (21 mg, yield: 77%); 4.69major (d, J = 14.5 Hz, 1H), 4.43major (dd, J = 18.4, 9.8 Hz, 1H),
mp 183−186 °C. 1H NMR (400 MHz, CDCl3, δ) 8.35 (d, J = 8.9 Hz, 4.19major (d, J = 3.5 Hz, 1H), 4.02−3.88 (m, 3H), 3.55−3.45 (m, 4H).
13
2H), 8.23 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 7.7 Hz, 1H), 7.44 (t, J = 7.5 C{1H} NMR (75 MHz, CDCl3, δ) 198.6, 197.8, 171.7, 170.5, 140.6,
Hz, 1H), 7.26 (t, J = 5.8 Hz, 2H), 7.18 (t, J = 7.2 Hz, 2H), 6.90 (t, J = 138.9, 137.0, 136.7, 133.8, 133.5, 133.4, 133.1, 133.0, 131.9, 130.9,
6.6 Hz, 3H), 4.71 (d, J = 14.5 Hz, 1H), 4.39 (dd, J = 18.5, 9.5 Hz, 130.2, 129.9, 128.8, 128.8, 128.7, 128.6, 128.3, 128.2, 128.1, 128.0,
1H), 4.13 (d, J = 3.8 Hz, 1H), 3.91 (dt, J = 8.7, 4.0 Hz, 1H), 3.57− 127.8, 127.74, 127.7, 126.5, 121.4, 121.2, 68.9, 68.8, 52.3, 49.0, 47.1,
3.43 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3, δ) 197.3, 171.1, 42.6, 42.1, 41.4. HRMS (MALDI-FT ICR): m/z calcd. for
150.6, 141.5, 138.6, 133.4, 131.1, 129.3, 128.8, 128.7, 128.2, 128.1, C24H19BrNaO3 [M + Na]+: 457.0410; found: 457.0419.
128.0, 127.6, 124.0, 123.5, 69.8, 49.3, 46.9, 42.1. IR (neat): 2944, 6-Methoxy-4-(3-oxo-1,3-diphenylpropyl)isochroman-3-one (14l) was
1729, 1682, 1597 cm−1. HRMS (MALDI-FT ICR): m/z calcd. for purified by flash chromatography (silica gel, hexane/ethyl acetate =
C24H19NNaO5 [M + Na]+: 424.1155; found: 424.1177. The other 75:25), isolated in a total yield of 96%, and analyzed by HRMS.
diastereomer was isolated with an unsuitable purity. Therefore, we Subsequently, PrepTLC (silica gel, hexane/ethyl acetate = 80:20) was
were not able to perform a full characterization. The overall yield and used to separate the diastereomers (dr = 50/50).
the dr were determined on the integration of crude NMR. HRMS (MALDI-FT ICR): m/z calcd. For C25H21KO4 [M + K]+:
4-(3-(4-Methoxyphenyl)-3-oxo-1-phenylpropyl)isochroman-3-one 425.1149; found: 425.1189.
(14i) was purified by flash chromatography (silica gel, hexane/ethyl (R*)-6-Methoxy-4-((S*)-3-oxo-1,3-diphenylpropyl)isochroman-3-
acetate = 8:2), isolated in a total yield of 73%, and analyzed by one (14l-1): white solid (25 mg); mp 157−159 °C. 1H NMR (400
HRMS. Subsequently, PrepTLC (silica gel, hexane/ethyl acetate = MHz, CDCl3, δ) 8.13 (dd, J = 7.0, 1.5 Hz, 2H), 7.65 (t, J = 7.4 Hz,
85:15) was used to separate the diastereomers (dr = 53/47). 2H), 7.33−7.29 (m, 1H), 7.24 (t, J = 7.3 Hz, 2H), 7.14 (s, 1H), 7.04
HRMS (MALDI-FT ICR): m/z calcd. for C25H22NaO4 [M + Na]+: (d, J = 6.9 Hz, 2H), 6.86 (s, 2H), 4.38 (dd, J = 18.3, 9.4 Hz, 1H), 4.16
409.1410; found: 409.1417. (d, J = 3.9 Hz, 1H), 4.01 (dt, J = 9.1, 4.2 Hz, 1H), 3.95 (s, 3H), 3.59
(R*)-4-((R*)-3-(4-Methoxyphenyl)-3-oxo-1-phenylpropyl)- (d, J = 13.9 Hz, 1H), 3.53 (dd, J = 18.3, 4.4 Hz, 1H). 13C{1H} NMR
isochroman-3-one (14i-1): white solid (20 mg); mp 146−148 °C. 1H (101 MHz, CDCl3, δ) 198.6, 171.2, 159.9, 139.3, 137.1, 135.3, 133.3,
NMR (400 MHz, CDCl3, δ) 8.13 (d, J = 9.0 Hz, 2H), 7.64 (dd, J = 128.7, 128.6, 128.4, 128.2, 127.8, 124.7, 123.4, 114.1, 112.3, 69.5,
13.2, 7.2 Hz, 2H), 7.55 (t, J = 7.5 Hz, 2H), 7.48 (t, J = 7.5 Hz, 1H), 55.5, 50.0, 46.8, 41.5. IR (neat): 3061, 1734, 1685, 1598 cm−1.
7.32 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, (R*)-6-Methoxy-4-((S*)-3-oxo-1,3-diphenylpropyl)isochroman-3-
2H), 6.77 (d, J = 8.8 Hz, 2H), 4.79 (d, J = 14.4 Hz, 1H), 4.34 (dd, J = one (14l-2): white solid (25 mg); mp 146−148 °C. 1H NMR (400
18.2, 9.3 Hz, 1H), 4.18 (d, J = 3.8 Hz, 1H), 3.93 (dt, J = 8.8, 4.2 Hz, MHz, CDCl3, δ) 8.03 (dd, J = 7.1, 1.5 Hz, 2H), 7.51 (t, J = 7.6 Hz,
1H), 3.82 (s, 3H), 3.74 (d, J = 14.3 Hz, 1H), 3.50 (dd, J = 18.2, 4.6 2H), 7.30−7.26 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 3.6
Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3, δ) 198.7, 171.3, 159.2, Hz, 2H), 6.81 (dd, J = 8.4, 2.6 Hz, 1H), 5.95 (d, J = 2.6 Hz, 1H),
137.2, 134.0, 133.3, 131.2, 131.1, 129.3, 128.7, 128.7, 128.2, 127.4, 5.39−5.29 (m, 1H), 5.11 (d, J = 13.8 Hz, 1H), 3.99 (d, J = 7.9 Hz,
123.4, 113.9, 69.9, 55.3, 49.7, 46.4, 41.8. IR (neat): 2994, 1744, 1679, 1H), 3.93 (d, J = 7.9 Hz, 1H), 3.88 (d, J = 12.4 Hz, 1H), 3.58 (d, J =
1513 cm−1. 4.7 Hz, 1H), 3.53 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3, δ)
(R*)-4-((S*)-3-(4-Methoxyphenyl)-3-oxo-1-phenylpropyl)- 197.9, 172.4, 159.0, 141.0, 136.9, 134.2, 133.3, 128.7, 128.6, 128.5,
isochroman-3-one (14i-2): white solid (18 mg); mp 141−143 °C, 1H 128.1, 127.4, 125.7, 123.7, 114.0, 113.1, 69.4, 55.2, 53.1, 42.5, 42.2. IR
NMR (400 MHz, CDCl3, δ) 8.02 (d, J = 8.9 Hz, 2H),7.62 (t, J = 7.3 (neat): 3065, 1724, 1681, 1612 cm−1.
Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 8.3 Hz, 1H), 7.18 (t, J = 7-Nitro-4-(3-oxo-1,3-diphenylpropyl)isochroman-3-one (14m). The
7.7 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 6.62 reaction mixture was heated at 110 °C (oil bath). The crude product

6924 https://doi.org/10.1021/acs.joc.4c00277
J. Org. Chem. 2024, 89, 6915−6928
The Journal of Organic Chemistry pubs.acs.org/joc Article

was purified by flash chromatography (silica gel, hexane/ethyl acetate (R*)-8-Fluoro-4-((R*)-3-oxo-1,3-diphenylpropyl)isochroman-3-

= 7:3) to afford a white solid (31 mg, yield: 58%), a mixture of one (14p-1): white solid (30 mg); mp 119−121 °C. 1H NMR (400
diastereomers (dr = 53/47). 1H NMR (400 MHz, CDCl3, δ) 8.15major MHz, CDCl3, δ) 8.07 (dd, J = 7.1, 1.5 Hz, 2H), 7.59 (t, J = 7.4 Hz,
(d, J = 6.5 Hz, 2H), 8.04minor (d, J = 7.7 Hz, 2H), 7.94major (t, J = 10.2 1H), 7.54−7.41 (m, 2H), 7.43−7.38 (m, 2H), 7.25 (d, J = 7.3 Hz,
Hz, 2H), 7.87minor (s, 1H), 7.67major (dt, J = 14.7, 7.2 Hz, 2H), 7.59− 1H), 7.19 (t, J = 7.9 Hz, 2H), 6.99−6.92 (m, 1H), 6.91 (d, J = 7.0 Hz,
7.51 (m, 3H), 7.26−7.38 (m, 7H), 7.05 (d, J = 3.6 Hz, 2H), 6.98 (d, J 2H), 4.95 (d, J = 15.0 Hz, 1H), 4.35 (dd, J = 18.4, 9.7 Hz, 1H), 4.18
= 7.2 Hz, 2H), 6.58minor (d, J = 8.4 Hz, 1H), 5.66major (d, J = 14.3 Hz, (d, J = 3.6 Hz, 1H), 3.89 (dt, J = 9.7, 3.8 Hz, 1H), 3.44 (dd, J = 18.4,
1H), 5.32major (d, J = 14.6 Hz, 1H), 4.84 (d, J = 14.9 Hz, 1H), 4.51 4.1 Hz, 1H), 3.36 (d, J = 15.0 Hz, 1H). 13C NMR (63 MHz, CDCl3,
(dd, J = 18.9, 10.3 Hz, 1H), 4.37 (d, J = 3.4 Hz, 1H), 4.11−3.95 (m, δ) 198.4, 170.3, 157.2 (d, JC,F = 247.2 Hz), 138.7, 136.8, 136.5, 136.4,
4H), 3.53−3.46 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3, δ) 133.3, 130.0 (d, JC,F = 8.1 Hz), 128.6, 128.1, 128.0, 127.9, 123.5 (d,
199.9, 199.1, 172.2, 171.0, 148.6, 142.9, 139.9, 138.2, 135.0, 135.0, JC,F = 3.3 Hz), 118.7 (d, JC,F = 16.6 Hz), 113.7 (d, JC,F = 20.2 Hz),
134.0, 131.1, 131.0, 130.4, 130.4, 130.2, 130.1, 129.7, 129.6, 129.5, 64.2 (d, JC,F = 3.7 Hz), 48.8, 47.1, 41.2. 19F{1H} NMR (376 MHz,
129.4, 125.2, 124.1, 121.4, 120.3, 70.2, 70.0, 54.4, 50.6, 48.8, 44.0, CDCl3, δ) −120.74. IR (neat): 2947, 1755, 1656, 929 cm−1.
43.5, 42.7. HRMS (MALDI-FT ICR): m/z calcd for C24H19NNaO5 (R*)-8-Fluoro-4-((S*)-3-oxo-1,3-diphenylpropyl)isochroman-3-
[M + Na]+: 424.1155; found: 424.1180. one (14p-2): white solid (21 mg); mp 113−115 °C. 1H NMR (300
6-Chloro-4-(3-oxo-1,3-diphenylpropyl)isochroman-3-one (14n) was MHz, CDCl3, δ) 7.97 (dd, J = 7.0, 1.5 Hz, 2H), 7.57 (tt, J = 7.4, 1.5
purified by flash chromatography (silica gel, hexane/ethyl acetate = Hz, 1H), 7.46 (t, J = 7.4 Hz, 2H), 7.24−7.19 (m, 3H), 7.09−7.01 (m,
85:15), isolated in a total yield of 94%, and analyzed by HRMS. 1H), 6.99−6.89 (m, 3H), 6.29 (d, J = 7.6 Hz, 1H), 5.40 (d, J = 13.8
Subsequently, PrepTLC (silica gel, hexane/ethyl acetate = 90:10) was Hz, 1H), 5.03 (d, J = 14.8 Hz, 1H), 4.00−3.95 (m, 2H), 3.85 (ddd, J
used to separate the diastereomers (dr = 52/48). = 17.6, 5.0, 2.7 Hz, 1H), 3.45 (ddd, J = 17.5, 3.4, 1.3 Hz, 1H). 13C
HRMS (MALDI-FT ICR): m/z calcd. For C24H19ClNaO3 [M + NMR (63 MHz, CDCl3, δ) 197.6, 171.6, 157.8 (d, JC,F = 247.4 Hz),
Na]+: 413.0914; found: 413.0919. 140.3, 136.6, 135.2, 133.2, 129.1 (d, JC,F = 8.2 Hz), 128.55, 128.50,
(R*)-6-Chloro-4-((R*)-3-oxo-1,3-diphenylpropyl)isochroman-3- 128.1, 127.9, 127.5, 124.1, 119.1 (d, JC,F = 16.3 Hz), 114.0 (d, JC,F =
one (14n-1): white solid (25 mg); mp 146−148 °C. 1H NMR (400 20.4 Hz), 63.4 (d, JC,F = 3.7 Hz), 52.0, 42.8, 41.8. 19F{1H} NMR (376
MHz, CDCl3, δ) 8.14 (dd, J = 7.0, 1.5 Hz, 2H), 7.69 (d, J = 2.1 Hz, MHz, CDCl3, δ) −119.96. IR (neat): 2942, 1749, 1627, 925 cm−1.
1H), 7.65 (dt, J = 7.4, 1.4 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 7.33− 3-(3-Oxo-1,3-diphenylpropyl)benzof uran-2(3H)-one (15a) was puri-
7.28 (m, 2H), 7.25 (t, J = 7.3 Hz, 2H), 7.02 (s, 1H), 7.00 (d, J = 1.6 fied by flash chromatography (silica gel, hexane/ethyl acetate =
Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 4.71 (d, J = 14.5 Hz, 1H), 4.42 75:25) and isolated as a white solid (37 mg, yield: 81%), a mixture of
(dd, J = 18.4, 9.8 Hz, 1H), 4.19 (d, J = 3.7 Hz, 1H), 3.96 (dt, J = 9.8, diastereomers (dr = 64/36).
3.8 Hz, 1H), 3.54−3.50 (m, 1H), 3.48 (d, J = 4.0 Hz, 1H). 13C{1H} 1
H NMR (400 MHz, CDCl3, δ) 8.11major (dd, J = 7.0, 1.5 Hz, 2H),
NMR (101 MHz, CDCl3, δ) 198.6, 171.2, 159.9, 139.3, 137.1, 135.3, 8.02minor (dd, J = 7.0, 1.5 Hz, 2H) 7.64 (q, J = 8.1 Hz 2H), 7.52−7.56
133.4, 128.7, 128.6, 128.4, 128.2, 127.8, 124.7, 123.4, 114.1, 112.3, (m, 4H), 7.44major (d, J = 7.2 Hz, 1H), 7.31 (d, J = 7.7 Hz, 4H), 7.17−
69.5, 55.5, 50.0, 46.8, 41.5. IR (neat): 3029, 1766, 1680, 1600 cm−1. 7.25 (m, 9H), 7.06 (d, J = 7.9 Hz, 1H), 6.92major (d, J = 7.9 Hz, 1H),
(R*)-6-Chloro-4-((S*)-3-oxo-1,3-diphenylpropyl)isochroman-3- 6.76minor (d, J = 7.9 Hz, 1H), 4.24−4.28 (m, 4H), 4.20major (d, J = 7.3
one (14n-2): white solid (23 mg); mp 129−132 °C. 1H NMR (400 Hz, 1H), 4.04−4.07 (m, 1H), 4.00minor (d, J = 6.6 Hz, 1H), 3.71minor
MHz, CDCl3, δ) 8.03 (dd, J = 7.1, 1.5 Hz, 2H), 7.63 (t, J = 7.4 Hz, (d, J = 6.7 Hz, 1H), 3.57−3.68 (m, 2H). 13C{1H} NMR (75 MHz,
1H), 7.52 (t, J = 7.6 Hz, 2H), 7.33−7.29 (m, 3H), 7.26 (dd, J = 8.1, CDCl3, δ) 198.3, 197.5, 176.1, 175.5, 153.7, 153.4, 139.9, 138.7,
2.0 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 7.02 136.7, 136.6, 133.4, 133.2, 129.0, 128.7, 128.6, 128.5, 128.3, 128.05,
(d, J = 3.7 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H), 5.35 (d, J = 14.3 Hz, 128.00, 127.7, 127.5, 127.3, 126.0, 125.7, 125.1, 124.5, 123.9, 123.7,
1H), 5.13 (d, J = 14.3 Hz, 1H), 4.02−3.97 (m, 1H), 3.94−3.89 (m, 110.6, 110.3, 47.9, 47.5, 42.8, 41.9, 41.4, 39.5. HRMS (MALDI-FT
2H), 3.53 (dd, J = 12.8, 4.4 Hz, 1H). 13C{1H} NMR (75 MHz, ICR) m/z: calcd for C23H18NaO3 [M + Na]+: 365.1148, found:
CDCl3, δ) 197.7, 171.5, 140.3, 136.6, 134.6, 133.5, 133.3, 130.0, 365.1140.
128.6, 128.1, 128.0, 127.6, 127.4, 125.7, 68.8, 52.5, 42.4, 41.8. IR 3-(1-(4-Chlorophenyl)-2-oxo-2-phenylethyl)benzof uran-2(3H)-one
(neat): 3029, 1734, 1685, 1598 cm−1. (15b) was purified by flash chromatography (silica gel, hexane/ethyl
6-Methoxy-4-(1-(4-methoxyphenyl)-3-oxo-3-phenylpropyl)- acetate = 75:25) and isolated as a white solid (42 mg, yield: 83%), a
isochroman-3-one (14o) was purified by flash chromatography (silica mixture of diastereomers (dr = 53/47). 1H NMR (400 MHz, CDCl3,
gel, hexane/ethyl acetate = 8:2) and isolated as a white solid (52 mg, δ) 8.10major (d, J = 7.1 Hz, 2H), 8.00minor (d, J = 7.1 Hz, 1H), 7.66major
yield: 93%), a mixture of diastereomers (dr = 51/49). 1H NMR (400 (q, J = 7.6 Hz, 2H), 7.58−7.51 (m, 4H), 7.45 (d, J = 7.5 Hz, 1H),
MHz, CDCl3, δ) 8.11 (dd, J = 7.1 Hz, 1.5 Hz, 2H), 8.02 (dd, J = 7.1 7.39−7.30minor (m, 2H), 7.27major (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.6
Hz, 1.5 Hz, 2H), 7.68−7.57 (m, 2H), 7.52 (dt, J = 14.5, 7.5 Hz, 4H), Hz, 1H), 7.19−7.12major (m, 4H), 7.12−7.07minor (m, 3H), 6.96 (d, J =
7.12 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.96−6.92 (m, 5H), 6.87 (m, 8.1 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 4.31−4.15 (m, 4H), 4.08minor
2H), 6.85−6.69 (m, 5H), 5.18 (d, J = 13.8 Hz, 1H), 5.06 (d, J = 13.9 (q, J = 7.4 Hz, 1H), 3.93major (dd, J = 17.3, 6.3 Hz, 1H), 3.72−3.56
Hz, 1H), 4.73 (d, J = 13.9 Hz, 1H), 4.32 (dd, J = 18.3, 9.3 Hz, 1H), (m, 2H). 13C{1H} NMR (75 MHz, CDCl3, δ) 197.9, 197.1, 175.8,
4.12 (d, J = 3.8 Hz, 1H), 4.05−3.95 (m, 1H), 3.94 (s, 3H), 3.90 (dd, J 175.2, 153.7, 153.3, 138.2, 137.1, 136.5, 136.4, 133.5, 133.4, 133.1,
= 8.2, 2.7 Hz, 1H), 3.85 (d, J = 7.9 Hz, 1H), 3.80 (s, 6H), 3.69 (d, J = 129.7, 129.3, 129.2, 128.9, 128.6, 128.5, 128.0, 127.9, 125.7, 125.2,
14.0 Hz, 1H), 3.58 (s, 3H), 3.53 (dd, J = 7.0, 5.1 Hz, 1H), 3.48 (dd, J 124.9, 124.3, 124.0, 123.8, 110.8, 110.5, 47.9, 47.5, 42.2, 41.3, 41.1,
= 7.7, 5.2 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3, δ) 198.7, 198.0, 39.5. HRMS (MALDI-FT ICR) m/z: calcd for C23H17ClNaO3 [M +
172.5, 171.3, 159.9, 159.2, 159.0, 158.9, 137.2, 136.9, 135.4, 134.1, Na]+: 399.0758, found: 399.0762.
133.3, 133.3, 132.7, 131.2, 129.4, 129.3, 128.7, 128.7, 128.2, 128.1, 3-(1-(4-Methoxyphenyl)-2-oxo-2-phenylethyl)benzof uran-2(3H)-one
125.6, 124.8, 123.8, 123.3, 114.0, 113.9, 113.3, 112.3, 69.7, 69.4, 55.5, (15c) was purified by flash chromatography (silica gel, hexane/ethyl
55.3, 55.3, 55.2, 53.0, 50.1, 46.0, 42.3, 42.0, 41.8. HRMS (MALDI-FT acetate = 70:30) and isolated as a white solid (43 mg, yield: 87%), a
ICR): m/z calcd. for C26H24NaO5 [M + Na]+: 439.1516; found: mixture of diastereomers (dr = 54/46). 1H NMR (400 MHz, CDCl3,
439.1525. δ) 8.11major (dd, J = 7.0, 1.4 Hz, 2H), 8.01minor (dd, J = 7.0, 1.4 Hz,
8-Fluoro-4-(-3-oxo-1,3-diphenylpropyl)isochroman-3-one (14p) was 2H), 7.64 major (q, J = 8.4 Hz, 2H), 7.54 (q, J = 8.4 Hz, 4H), 7.45 (d, J
purified by flash chromatography (silica gel, hexane/ethyl acetate = = 7.3 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 7.20
80:20), isolated in a total yield of 90%, and analyzed by HRMS. (td, J = 7.6, 1.2 Hz, 1H), 7.09 (dd, J = 15.9, 8.8 Hz, 6H), 6.94 minor (d,
Subsequently, PrepTLC (silica gel, hexane/ethyl acetate = 85:15) was J = 9.2 Hz, 1H), 6.87−6.80 (m, 3H), 6.73 (d, J = 8.8 Hz, 2H), 4.30−
used to separate the diastereomers (dr = 59/41). 4.20 (m, 3H), 4.17 (d, J = 7.4 Hz, 1H), 4.06−3.91 (m, 2H), 3.82minor
HRMS (MALDI-FT ICR): m/z calcd. For C24H20FO3 [M + H]+: (s, 3H), 3.76 major (s, 3H), 3.65major (dd, J = 16.9, 7.3 Hz, 1H),
375.1391; found: 375.1386. 3.58minor (d, J = 12.6 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3, δ)

6925 https://doi.org/10.1021/acs.joc.4c00277
J. Org. Chem. 2024, 89, 6915−6928
The Journal of Organic Chemistry pubs.acs.org/joc Article

198.5, 197.8, 176.2, 175.7, 158.9, 158.7, 153.9, 153.6, 136.9, 136.8, 3-(1-(4-Fluorophenyl)-3-oxo-3-phenylpropyl)benzof uran-2(3H)-one
133.4, 133.3, 131.9, 130.8, 129.5, 129.1, 128.8, 128.7, 128.2, 128.1, (15g). The reaction mixture was heated at 50 °C (oil bath). The
126.4, 125.9, 125.3, 124.6, 124.0, 123.8, 113.9, 113.8, 110.8, 110.5, crude product was purified by flash chromatography (silica gel,
55.2, 55.1, 48.3, 47.9, 42.3, 41.8, 41.4, 39.9. HRMS (MALDI-FT ICR) hexane/ethyl acetate = 75:25) and isolated as a white solid (38 mg,
m/z: calcd for C24H20NaO4 [M + Na]+: 395.1234, found: 395.1253. yield: 79%), a mixture of diastereomers (dr = 64/36). 1H NMR (400
2-Oxo-3-(2-oxo-1,2-diphenylethyl)-2,3-dihydrobenzof uran-5-yl acetate MHz, CDCl3, δ) 8.11major (dd, J = 7.2, 1.3 Hz, 2H), 8.01minor (dd, J =
(15d) was purified by flash chromatography (silica gel, hexane/ethyl 7.2, 1.3 Hz, 2H), 7.65major (q, J = 7.8 Hz, 2H), 7.58−7.51 (m, 3H),
acetate = 75:25) and isolated as a white solid (48 mg, yield: 89%), a 7.46major (d, J = 6.5 Hz, 1H), 7.34minor (t, J = 7.9 Hz, 1H), 7.26 (d, J =
mixture of diastereomers (dr = 59/41). 1H NMR (400 MHz, CDCl3, 8.6 Hz, 1H), 7.22 (dd, J = 7.5, 1.2 Hz, 1H), 7.17minor (dd, J = 8.9, 5.4
δ) 8.10major (dd, J = 7.1, 1.5 Hz, 2H), 8.02 (dd, J = 7.1, 1.5 Hz, 2H), Hz, 1H), 7.12major (dd, J = 9.0, 5.4 Hz, 3H), 7.07minor (d, J = 8.0 Hz,
7.64major (q, J = 7.5 Hz, 2H), 7.59−7.50 (m, 3H), 7.42minor (d, J = 7.0 1H), 6.98 (t, J = 8.7 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.88 (t, J = 8.7
Hz, 1H), 7.38−7.28 (m, 2H), 7.26−7.20 (m, 5H), 7.18 (d, J = 7.9 Hz, Hz, 3H), 4.33−4.21 (m, 4H), 4.18 (d, J = 7.2 Hz, 1H), 4.09minor (q, J
2H), 7.04−6.99 (m, 1H), 6.96 (dd, J = 8.6, 2.4 Hz, 1H), 6.90 (d, J = = 7.3 Hz, 1H), 3.94major (dd, J = 17.3, 6.4 Hz, 1H), 3.73−3.55 (m,
8.6, 1H), 6.55 (m, 1H), 4.36−4.23major (m, 3H), 4.21minor (d, J = 8.8 2H). 13C{1H} NMR (101 MHz, CDCl3, δ) 198.2, 197.4, 176.0, 175.5,
Hz, 1H), 4.07minor (q, J = 7.1 Hz, 1H), 3.97minor (dd, J = 17.1, 6.9 Hz, 163.2, 160.7, 153.9, 153.5, 136.8, 136.7, 135.6, 134.5, 133.6, 133.5,
1H), 3.68minor (dd, J = 17.2, 7.0 Hz, 1H), 3.59major (dd, J = 17.1, 3.8 130.1 (d, JC,F = 7.7 Hz), 129.7 (d, JC,F = 7.7 Hz), 129.3, 129.0, 128.8
Hz, 1H), 2.38major (s, 3H), 2.31minor (s, 3H). 13C{1H} NMR (75 MHz, (2C), 128.2, 128.1, 126.1, 125.5, 125.1, 124.5, 124.2, 123.9, 115.5 (d,
CDCl3, δ) 198.3, 197.6, 175.9, 175.6, 169.6, 169.5, 151.3, 150.9, JC,F = 21.2 Hz), 115.3 (d, JC,F = 21.2 Hz), 110.9, 110.6, 48.2, 47.9,
146.9, 146.6, 139.6, 138.5, 136.8, 136.7, 133.5, 133.4, 130.0, 129.4, 42.3, 41.5, 41.5, 39.8. 19F{1H} NMR (376 MHz, CDCl3, δ) −114.53,
128.77, 128.74, 128.6, 128.5, 128.2, 128.2, 127.8, 127.6, 127.2, 126.7, −114.84. HRMS (MALDI-FT ICR) m/z: calcd for C23H17FNaO3 [M
122.3, 121.9, 119.2, 118.6, 111.2, 111.0, 48.5, 48.2, 43.0, 42.1, 41.4, + Na]+: 383.1053, found: 383.1055.
39.5, 21.1, 21.0. HRMS (MALDI-FT ICR) m/z: calcd for C25H20KO5 5-Chloro-3-(3-oxo-1,3-diphenylpropyl)benzofuran-2(3H)-one (15h).
[M + K]+: 439.0942, found: 439.0967. The reaction mixture was heated at 50 °C (oil bath). The crude
One diastereomer was separated by crystallization from a mixture product was purified by flash chromatography (silica gel, hexane/ethyl
acetate = 80:20) and isolated as a white solid (38 mg, yield: 75%), a
of isopropanol/ether = 1:5 (1 mL):
mixture of diastereomers (dr = 63/37). 1H NMR (300 MHz, CDCl3,
(R*)-2-Oxo-3-((S*)-3-oxo-1,3-diphenylpropyl)-2,3-dihydrobenzo-
δ) 8.04major (d, J = 8.1 Hz, 2H), 7.95minor (d, J = 8.2 Hz, 2H), 7.73minor
furan-5-yl acetate: white solid (28 mg); mp 116.5−117.7 °C. 1H
(d, J = 8.1 Hz, 1H), 7.58major (d, J = 6.7 Hz, 2H), 7.49major (t, J = 7.8
NMR (400 MHz, CDCl3, δ) 8.10 (dd, J = 7.1, 1.5 Hz, 2H), 7.66 (q, J
Hz, 3H), 7.38major (d, J = 6.6 Hz, 3H), 7.25 (d, J = 7.6 Hz, 4H), 7.19−
= 7.4, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.26−7.16 (m, 6H), 6.96 (dd, J =
7.07 (m, 8H), 7.03 (d, J = 7.3 Hz, 2H), 6.87minor (d, J = 8.0 Hz, 2H),
8.6, 2.4 Hz, 1H), 4.34−4.21 (m, 3H), 3.59 (dd, J = 17.2, 4.0 Hz, 1H),
6.79−6.67major (m, 1H), 4.29−4.11 (m, 4H), 3.98major (d, J = 3.9 Hz,
2.38 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3, δ) 197.3, 171.2, 150.6, 1H), 3.92minor (d, J = 6.5 Hz, 1H), 3.67−3.49 (m, 2H). 13C{1H}
141.5, 138.6, 133.4, 131.0, 129.3, 128.8, 128.7, 128.2, 128.1, 128.0, NMR (75 MHz, CDCl3, δ) 198.3, 197.5, 176.0, 175.5, 153.7, 153.4,
127.6, 124.0, 123.5, 69.8, 49.3, 46.9, 42.1. IR (KBr): 2923, 1786, 139.9, 138.7, 136.7, 136.6, 133.3, 133.2, 129.2, 129.0, 128.6, 128.5,
1769, 1688, 1643, 1487 cm−1. HRMS (MALDI-FT ICR) m/z: calcd 128.3, 127.5, 127.3, 126.0, 125.7, 125.1, 124.5, 123.9, 123.7, 110.6,
for C25H20KO5 [M + K]+: 439.0942, found: 439.0967. 110.3, 47.9, 47.6, 42.9, 41.9, 41.5, 39.5. HRMS (MALDI-FT ICR) m/
3-(3-(4-Methoxyphenyl)-3-oxo-1-phenylpropyl)benzof uran-2(3H)- z: calcd for C23H17ClNaO3 [M + Na]+: 399.0758, found: 399.0771.
one (15e) was purified by flash chromatography (silica gel, hexane/
ethyl acetate = 70:30) and isolated as a white solid (41 mg, yield: 83%
yield), a mixture of diastereomers (dr = 62/38). 1H NMR (400 MHz,
CDCl3, δ) 8.09major (d, J = 9.0 Hz, 2H), 8.00minor (d, J = 8.9 Hz, 2H),
■ ASSOCIATED CONTENT
Data Availability Statement
7.44major (d, J = 7.3 Hz, 1H), 7.35−7.25 (m, 3H), 7.24−7.14 (m, 8H), The data underlying this study are available in the published
7.10−7.04major (m, 1H), 7.00 (t, J = 9.5 Hz, 3H), 6.91major (d, J = 8.7 article and its Supporting Information.
Hz, 1H), 6.84minor (d, J = 7.4 Hz, 1H), 4.32−4.23 (m, 3H), 4.21major *
sı Supporting Information
(d, J = 8.6 Hz, 1 H), 4.07minor (q, J = 7.1 Hz, 1H), 3.93major (s, 3H),
3.92minor (s, 3H), 3.63minor (dd, J = 17.0, 7.3 Hz, 1H), 3.54major (dd, J =
The Supporting Information is available free of charge at
16.6, 4.1 Hz, 1H), 13C{1H} NMR (75 MHz, CDCl3, δ) 196.9, 196.1, https://pubs.acs.org/doi/10.1021/acs.joc.4c00277.
176.2, 175.7, 163.8, 163.7, 153.9, 153.6, 140.1, 139.0, 130.5, 130.4, Evaluated kinetic data, procedures for the preparation of
130.0, 129.9, 129.1, 128.8, 128.6, 128.5, 128.4, 128.1, 127.6, 127.4, starting materials, crystallographic data, and copies of
126.3, 125.9, 125.3, 124.7, 124.0, 123.8, 113.9, 110.7, 110.4, 55.6, NMR spectra of all new compounds (PDF)
48.1, 47.8, 43.2, 42.3, 41.1, 39.2. HRMS (MALDI-FT ICR) m/z:
calcd for C24H20KO4 [M + K]+: 411.0993, found: 411.0973. Primary kinetic data (ZIP)
3-(1-(2-Chlorophenyl)-3-oxo-3-phenylpropyl)benzof uran-2(3H)-one Accession Codes
(15f) was purified by flash chromatography (silica gel, hexane/ethyl
CCDC 2314553, 2314554, and 2320508 contain the
acetate = 75:25) and isolated as a white solid (41 mg, yield: 81%
yield), a mixture of diastereomers (dr = 54/46). 1H NMR (400 MHz,
supplementary crystallographic data for this paper. These
CDCl3, δ) 8.02major (dd, J = 7.1, 1.4 Hz, 2H), 7.96minor (d, J = 7.1, 1.4 data can be obtained free of charge via www.ccdc.cam.ac.uk/
Hz, 2H), 7.62 (q, J = 8.0 Hz, 2H), 7.54−7.46 (m, 4H), 7.40 (dd, J = data_request/cif, or by emailing [email protected].
5.8, 3.7 Hz, 1H), 7.37−7.31 (m, 3H), 7.29 (dd, J = 8.5, 5.0 Hz, 3H), uk, or by contacting The Cambridge Crystallographic Data
7.24−7.06 (m, 5H), 7.03 (d, J = 8.2 Hz, 1H), 6.84minor (d, J = 7.0 Hz, Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1H), 5.01major (td, J = 7.4, 4.8 Hz, 1H), 4.59minor (q, J = 7.4 Hz, 1H), 1223 336033.
4.45major (d, J = 4.8 Hz, 1H), 3.97major (dd, J = 18.0, 7.7 Hz, 1H),
3.81minor (dd, J = 17.6, 8.8 Hz, 1H), 3.69minor (dd, J = 17.7, 5.0 Hz,
1H), 3.48major (dd, J = 18.0, 6.9 Hz, 1H). 13C{1H} NMR (75 MHz,
CDCl3, δ) 197.5, 197.0, 176.2, 175.2, 153.6, 153.4, 137.8, 137.3,
■ AUTHOR INFORMATION
Corresponding Authors
136.4, 134.3, 134.1, 133.3, 133.2, 130.1, 130.0, 129.2, 128.9, 128.6, Armin R. Ofial − Department Chemie, Ludwig-Maximilians-
128.5, 128.4, 128.0, 127.9, 127.6, 127.03, 127.00, 125.9, 125.2, 125.0, Universität München, 81377 München, Germany;
124.7, 124.1, 123.7, 110.6, 110.3, 46.4, 46.2, 39.1, 39.0, 37.1. HRMS orcid.org/0000-0002-9600-2793; Email: [email protected]
(MALDI-FT ICR) m/z: calcd for C23H17ClKO3 [M + K]+: 415.0497, Antonio Massa − Dipartimento di Chimica e Biologia “A.
found: 415.0499. Zambelli”, Università degli Studi di Salerno, 84084 Fisciano,
6926 https://doi.org/10.1021/acs.joc.4c00277
J. Org. Chem. 2024, 89, 6915−6928
The Journal of Organic Chemistry pubs.acs.org/joc Article

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■ ACKNOWLEDGMENTS
A.M. thanks the University of Salerno and MUR for financial
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