Utility of Organoboron Reagents in Arylation of Cyclopropanols via Chelated Pd(II) Catalysis: Chemoselective Access to β-Aryl Ketones

Article abstract of DOI:10.1021/acs.joc.0c00160

Organoborane reagents were investigated as coupling partners to cyclopropanol-derived β-ketone enolates in the presence of a chelated Pd(II) catalyst. Efficient coupling of a range of electronically and sterically diverse cyclopropanols and aryl/alkenyl boronic derivatives (39 examples, 65-94% yield) could be achieved with the generation of synthetically important β-aryl ketone intermediates in a chemoselective fashion. This reactivity paradigm, which broadens the scope of aryl donor partners to homoenolates, allows open-flask conditions, water as a cosolvent, and preparation of halogen-bearing β-aryl ketones that are distinct from previous methods. This chelated Pd(II) catalysis appears to be different from the Pd(0) pathway, as evident from deuterium scrambling studies that could reveal differentiating protonolysis of an α-keto carbopalladium complex in the terminal step.

Full text of DOI:10.1021/acs.joc.0c00160

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Utility of Organoboron Reagents in Arylation of Cyclopropanols via
Chelated Pd(II) Catalysis: Chemoselective Access to β‑Aryl Ketones
Thangeswaran Ramar, Murugaiah A. M. Subbaiah,* and Andivelu Ilangovan*
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ABSTRACT: Organoborane reagents were investigated as cou-
pling partners to cyclopropanol-derived β-ketone enolates in the
presence of a chelated Pd(II) catalyst. Efficient coupling of a range
of electronically and sterically diverse cyclopropanols and aryl/
alkenyl boronic derivatives (39 examples, 65−94% yield) could be
achieved with the generation of synthetically important β-aryl
ketone intermediates in a chemoselective fashion. This reactivity
paradigm, which broadens the scope of aryl donor partners to
homoenolates, allows open-flask conditions, water as a cosolvent, and preparation of halogen-bearing β-aryl ketones that are distinct
from previous methods. This chelated Pd(II) catalysis appears to be different from the Pd(0) pathway, as evident from deuterium
scrambling studies that could reveal differentiating protonolysis of an α-keto carbopalladium complex in the terminal step.
generality assumes significance in the context of tactical
applications of halogen functionality on an aromatic ring by
medicinal chemists for late-stage diversification in the lead
optimization phase in a library synthesis mode through well-
known C−C and C−X (X = N, O, S) cross-couplings, for
example, Suzuki, Buchwald−Hartwig, and Ullmann protocols.
Nevertheless, reported Pd(0)-catalyzed reactions, which
require inert atmospheric conditions to prevent the oxidation
of Pd(0) by molecular oxygen, do not provide the advantage of
performing reactions under open-flask conditions. Also, the
feasibility of using water as an environmentally friendly solvent
or cosolvent has not been disclosed in the arylation of
cyclopropanols.
These constraining factors encouraged us to search for an
alternative disconnection approach, which would potentially
replace the oxidative addition of an aryl halide or triflate bond
to a Pd(0) complex with an equivalent yet different protocol.
Accordingly, we contemplated making use of a transmetalation
approach, which would allow the generation of the ArPd(II)
addition product, from a Pd(II) center and an organometallic
reagent in order to promote a selective process in which the
halogen functionality is sustained (Scheme 2).
INTRODUCTION
■
Because of the unique function of cyclopropanols as precursors
of ketone homoenolates, there has been an emerging interest
in the cyclopropanol-derived formation of new C−C, C−N,
C−O, C−S, and C−X (X = halogen) bonds in recent years.1,2
They can serve as a structurally distinct class of umpolung
three-carbon synthons or β-aryl carbonyl equivalents that
could provide fast access to diverse and valuable organic
molecules via unusual retrosynthetic disconnection ap-
proaches.3 This synthetic versatility of cyclopropanols has led
to the development of several protocols for facile access from a
variety of readily available starting materials.4 Notably,
cyclopropanols can be readily prepared from carboxylic esters
via the Kulinkovich reaction, involving Ti(OiPr)4-catalyzed
cross-coupling with ethyl Grignard reagents.4
In a seminal and elegant work, silyl-protected cyclo-
propanols were shown to couple to an aryl electrophile (aryl
triflate) by Nakamura and Kuwajima, involving Pd(0)-
catalyzed β-arylation of cyclopropanol-derived ketone homo-
enolates.5 Subsequently, Molander et al. demonstrated that
potassium trifluoroboratohomoenolates could readily undergo
Pd(0)-promoted Suzuki−Miyaura arylation, leading to facile
access of β-functionalized carbonyl derivatives.6 Recently, it
was shown that protection-free cyclopropanols could also
undergo Pd(0)-mediated C−C bond formation under mild
conditions with aryl halides via cyclopropanol-derived ketone
or aldehyde homoenolates (Scheme 1).7−10 However, the
observation of a mixture of products in certain cases arising out
of the formation of the competitive β-elimination byproduct
may constitute as a potential limiting factor from the
chemoselectivity perspective. Moreover, these studies do not
offer a preparative scope to synthesize halogen-appended
(specifically, Br and I) β-aryl aldehydes or ketones. This lack of
This strategy relied on the precedence of transmetalation-
based intermolecular Pd(II)-catalyzed oxidative Heck coupling
of olefins with organometallic reagents, which has recently
Received: January 21, 2020
https://dx.doi.org/10.1021/acs.joc.0c00160
© XXXX American Chemical Society
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A

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Scheme 1. Comparison of the Present Methodology with Previous Work
available with wide commercial supply, easy to synthesize,
relatively less toxic, and mostly stable to air and moisture.
Importantly, the catalytic transition metal-mediated or metal-
free direct C−H borylation of a range of substrates (for
example, arenes and heteroarenes) has greatly expanded the
synthetic scope of this class of reagents.15 We earlier reported
direct C−H functionalization of quinones via a radical strategy
using arylborornic acids and cyclopropanols that delivered
arylated quinones,16 and γ-carbonyl quinones,17 respectively.
As an extension of our research interest in exploiting
cyclopropanols as synthetically useful three-carbon homoeno-
Scheme 2. An Antithetic Approach That Would Impart Aryl
Nucleophiles as Synthons
emerged as one of the most reliable and efficient methods for
C−C bond formation.11−14 One of the elegant features of this
chemistry is the exploitation of organoboronic acids or their
derivatives as the powerful arylation resources that are readily
Figure 1. Select examples of pharmaceutically important β-aryl ketone derivatives.
B
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a
Table 1. Screening of Reaction Conditions to Identify an Efficient Protocol
b
entry
Pd source
Pd(OAc)2
ligand
DPPE
solvent
DMSO
additive (equiv)
air/O2
O2
% yield (3a)
1
none
49
58
44
57
73
78
83
85
93
91
93
94
93
32
47
70
59
88
84
86
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
neocuproine
bipyridyl
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO + H2O
DMSO + H2O
DMSO + H2O
dioxane + H2O
toluene + H2O
CuCl (0.2)
CuBr (0.2)
CuCl (0.2) + KOAc (1.0)
CuCl (1.0)
CuCl (1.5)
O2
O2
O2
O2
O2
O2
O2
O2
open air
open air
open air
open air
open air
open air
open air
open air
open air
open air
open air
O2
CuCl (2.0)
CuCl (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
c
c
c
c
c
c
DMSO + H2O
DMSO + H2O
DMSO + H2O
DMSO
DMSO
DMSO
c
PdCl2(MeCN)2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
c
d
85
87
60
e
O2
O2
f
a
Until otherwise stated, the reactions were carried out with 1a (1 equiv), 2a (entries 1−10, 3.0 equiv; entry 11, 2.5 equiv; entries 12−20, 2.0
equiv), Pd source (entries 1−10, 0.2 equiv; entries 11−20, 0.1 equiv), ligand (0.2 equiv), and an additive in DMSO solvent (3.0 mL) under an
b
c
oxygen atmosphere using an O2 balloon or open-air atmosphere at 70 °C for 2 h. Isolated yields DMSO (2.5 mL) + H2O (0.5 mL) (ratio 5:1).
d
e
f
Reaction temperature: 60 °C. Reaction temperature: 80 °C. 1.0 equiv of 2a.
late synthons and development of synthetic protocols for β-aryl
carbonyl derivatives,13,18 we report for the first time that
arylboronic acids can effectively serve as the cross-coupling
partners with the cyclopropanol-derived metal homoenolates
to generate dihydrochalcones and related analogues in a
chemoselective mode. Besides, this high yielding new method-
ology has afforded selective access to halogen-bearing β-aryl
ketones, which were not possible by previously reported
arylation of cyclopropanols. Moreover, homoenolates, as
reverse-polarity synthons of a Michael acceptor, can be
construed as precursors of enones, thereby imparting a general
synthetic utility that would represent an alternative to the well-
precedented conjugate addition of organometallic reagents,
including boronic acids, to unsaturated ketones.19−21
carbonyl derivatives, various synthetic methodologies have
recently been reported.30−35 This is illustrated in our recent
report that offers mild and regioselective access to β-aryl
aldehydes and ketones, from readily accessible allyl alcohols via
a ligated Pd(II)-mediated arylative isomerization approach.13,18
The present methodology, which is an addition to the
compendium of existing methodologies, attempts to broaden
the scope of starting materials, especially organoboronic
derivatives. Importantly, carboxylic esters, which can be
converted to β-aryl ketones via sequential application of the
titanium-promoted cyclopropanation and palladium-mediated
arylation, can further expand the substrate scope and utility in
organic synthesis.
The “β-aryl carbonyl” motif that includes the privileged
dihydrochalcone moiety is an active area of synthetic interest
because of the widespread prevalence in natural products of
medicinal importance and occurrence in the structures of
marketed drugs (Figure 1).22−29 Applications of β-aryl alkyl
carbonyl compounds as useful starting points/intermediates in
(a) pharmaceutical chemistry to generate diverse scaffolds
and/or drug-like compounds and (b) agricultural chemistry are
well-documented. Reflecting the importance of β-aryl alkyl
RESULTS AND DISCUSSION
■
The 1,1-disubstituted cyclopropanol 1a and 4-methoxyphe-
nylboronic acid 2a were selected as the model substrates to test
our hypothesis. While keeping Pd(OAc)2 as the source of
transition metal, bis(diphenylphosphino)ethane (DPPE) as the
chelating ligand, and DMSO as the solvent, our initial study
focused on the impact of additives under an oxygen
atmosphere (balloon) at 70 °C (Table 1). To our delight,
C
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Scheme 3. Preparative Scope of the Coupling of Cyclopropanol 1a with Diverse Arylboronic Acids That Vary in Electronic and
Steric Properties
we were able to observe a 49% yield of the desired product 3a
in the absence of any additive, a profile that offered the hope to
further enhance the productivity by suppressing the formation
of ring-opened byproduct 4a or 5a (entry 1). The addition of
0.2 equiv of CuCl resulted in a slight improvement in the yield
(58%, entry 2). This prompted an investigation of another
copper salt, such as CuBr (entry 3), which resulted in a slightly
lower yield. However, a gradual increase in the amount of
CuCl was associated with a corresponding proportional yield
enhancement, eventually achieving an 85% yield in the
presence of 3.0 equiv of CuCl (entries 4−8). Replacement
of CuCl (3.0 equiv) with Cu(OAc)2 (3.0 equiv) was found to
be beneficial to augment the yield further to 93%, which was
consistent with the reaction profile with an almost complete
suppression of formation of byproducts 4a and 5a (entry 9).
However, 4,4′-dimethoxy-1,1′-biphenyl was observed as a
byproduct in small amounts (∼5% yield), which could be
attributed to Pd(II)-mediated homocoupling of 2a.36 Having
optimized the reaction yield to a satisfactory extent, attempts
were made to fine-tune reaction parameters on practical
considerations, for example, the feasibility of replacing
dioxygen gas with the atmospheric air in an open-vessel
fashion from the perspective of safety and cost factors.
Gratifyingly, the yield was found to be sustainable even upon
switching to open air (entry 10). Optimization of the
stoichiometry of the coupling partner 2a, Pd(II) catalyst, and
D
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Scheme 4. Preparative Scope of Cyclopropanols Bearing 1-Aryl, 1-Alkyl, 1-Cyclohexyl, and 1-Alkenyl Substituents
Cu(II) salt was next explored as part of an effort to increase the
catalytic efficiency of the transformation (entries 11 and 12).
It was observed that the amounts of arylboronic acid (by
33%), Pd(OAc)2 (by 50%), and Cu(OAc)2 (by 33%) could all
be substantially reduced without any significant impact on the
yield, resulting in the identification of a further efficient
condition (entry 12). Remarkably, the product 3a was
obtained in a similar yield (93%) even after blending DMSO
with water (0.5 mL), a green solvent, in a 5:1 ratio (entry 13)
in an attempt to enhance the eco-friendly character. A limited
ligand screening was undertaken involving the replacement of
the bidentate phosphine ligand DPPE by nitrogen-coordinat-
ing ligands, neocuproine, and bipyridyl, which are known to be
less prone to Pd(II)-catalyzed oxidation in the presence of O2
(entries 14 and 15). However, the nitrogenous ligands were
found to be less efficient with a significant reduction in the
yield.12 Solvent screening indicated that the polar aprotic
solvent DMSO was found to be more efficient than less-polar
solvents like dioxane and toluene (entries 16 and 17). While
the role of DMSO in promoting efficient catalysis in the
present reaction is not understood, it seems likely that DMSO
also serves as a ligand for Pd(II). Sulfoxides, which can bind to
metals in two ways through either sulfur or oxygen, are known
to be efficient ligands in transition metal-mediated catalysis.37
Especially, catalyst systems containing both PdII and DMSO
have been proven to be effective in promoting a wide range of
synthetic transformations.38 Replacement of Pd(OAc)2 with
different precatalysts like PdCl2, PdCl2(MeCN)2, and
Pd2(dba)3 was also investigated (entries 18−20). These
catalysts were also found to be effective (84−88% yield),
although they were slightly inferior to Pd(OAc)2. The reaction
was monitored by both LCMS and TLC from 15 min to 2 h at
70 °C. We could observe that the reaction required almost 2 h
for the complete consumption of the starting material. The
effect of temperature was studied with a minimal variation in
the range of 70 10 °C (entries 21 and 22). We could observe
that 70 °C was found to provide a better yield than other
temperatures (60 or 80 °C). The product yield was reduced to
60% with the increased formation of ring-opening byproduct
4a in the presence of 1 equiv of 2a (entry 23). Thus, use of
cyclopropanol (1.0 equiv), arylboronic acid (2.0 equiv),
PdOAc2 (0.1 equiv), Cu(OAc)2 (2.0 equiv), and DPPE (0.2
equiv) in DMSO−H2O (5:1 ratio) under the open-air
atmosphere at 70 °C was identified as the standard protocol
to investigate the substrate scope of both cyclopropanols and
organoboronic derivatives.
We began the preparative experiments by investigating the
scope of the transmetalation coupling partner with twenty-five
different arylboronic acids with a variation in electronic and/or
steric characteristics, and the results are summarized in Scheme
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Scheme 5. Preparative Scope of Boronic Acid Head Group Variation and Alkenyl Boronic Esters
3. The arylboronic acids, bearing electron-donating alkyl,
alkoxy, and amine functionalities, were found to couple
efficiently to obtain the corresponding products with the
yields in the range of 66−94% (examples 3a−3h). Interest-
ingly, the coupling of 1a with arylboronic acids, bearing
electron-withdrawing NO2, CN, CO2Me, and Ph groups, also
took place equally well and provided good to excellent yields
(65−94%; examples 3i−3m). These results are especially
encouraging, placed in the context of the reported sluggish
nature of insertion of electron-poor aryl groups in chelation-
controlled cationic Pd(II)-mediated transformations.11,12
Thus, the absence of significant disparity in reactivity between
the electronically distinct boron systems indicates the wide
applicability of the reaction. The simple and electronically
neutral phenylboronic acid (example 3n) also gave a superior
yield (92%).
addition step that was responsible for an increased and
unproductive formation of ring-opened byproduct.7 Heteroaryl
and fused aromatic systems, for example, indazole and 2-
naphthyl, were also found to react with 1a in high yields
(examples 3q−3r). Coupling of halogen-bearing arylboronic
acids delivered the corresponding dihydrochalcone products
(examples 3s−3y) in very high yields (80−93%), indicating
that the reaction outcome was undeterred by the presence of
highly susceptible Br and I functionalities. The reactions, as
exemplified by 3t−3x, were found to be chemoselective with
the absence of concomitant generation of byproducts from the
putative Pd(0) catalysis that would involve oxidative addition
across Ar−Br and Ar−I bonds. Moreover, this reaction profile
seems to suggest a mechanism that does not involve the
generation of LnPd(0) as a means of the reductive elimination
step.
A high level of productivity was even achieved upon
coupling of sterically demanding arylboronic acids with either
1 or 2 ortho-methyl substitutions, as exemplified in the case of
3o and 3p. These results imply an improved performance of
the present system over the cross-coupling of sterically
demanding aryl halides bearing 2 ortho-methyl substituents
with reduced yields, attributed to the sluggish oxidative
The preparative scope of the cyclopropyl coupling partner
was next investigated by varying the substitutions on the
phenyl group, keeping either 2a or 2e as the arylboronic acid
(Scheme 4). The coupling reactions in the case of examples
3aa−3ae afforded high yields (76−92%). The chemoselective
reaction profile was evident in the example 3ac, supporting
further the compatibility of oxidative-addition-susceptible
F
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a
Table 2. Controlled Reactions to Investigate the Mechanistic Aspects of the Catalysis
b
c
c
c
entry
Pd(OAc)2
Cu(OAc)2
LiCl
atm.
% yield (3a)
% yield (4a)
% yield (5a)
1
2
3
4
yes
no
yes
yes
no
yes
yes
yes
no
no
yes
open air
open air
open air
N2
45
0
24
90
40
0
43
0
0
81
0
no
0
a
b
c
The standard condition was modified as per the table. 3.0 equiv. Isolated yields.
halogen functionalities irrespective of their presence in either
the cyclopropanol (3ac) or organoboronic counterpart
[Scheme 3: 3u, 3v, and 3x (see 2u, 2v and 2x in the
supporting information)]. The cyclopropanols, which have
been employed in the above preparative examples, bear an aryl
group at 1-position of cyclopropanol. In an attempt to expand
the scope of the ketone homoenolates, the effect of replacing
the 1-aryl substitution with cycloalkyl, aralkyl, and aralkenyl
groups was investigated (examples 3af−3ak). Swapping the
phenyl group (3aa) with the cyclohexyl group (3af) or
inserting the alkyl substitution like methyl and propyl spacers
between the aryl and cyclopropyl ring (3ag−3aj) had no
deleterious impact on the productivity outcome, although this
structural modification involved a change of electronic
character (sp2 to sp3) of the attachment point at the
cyclopropyl ring. Arylation of cyclopropanol (3ak), bearing a
styrenyl moiety with a double bond, was also found to provide
an acceptable yield with a chemoselective coupling that was
not associated with the oxidative Heck arylation at the olefinic
bond. In order to determine the practical utility of this
methodology, a large-scale reaction, illustrated with the
cyclopropanol, for example, 3aa, was performed (1 g scale),
which was found to furnish an almost comparable yield to that
of the small-scale reaction.
To expand the scope of borane warheads of arylboronic
nucleophiles, organoboronic esters and organotrifluoroborate
salts (also known as Molander’s salts) were considered
(Scheme 5). While boronic acids can pose challenges with
cumbersome purification, less stability, and uncertain stoi-
chiometry due to the possibility of trimerization to the
corresponding boroxine, organoboronic esters, and organo-
trifluoroborate variants appear to have better advantages than
boronic acids like known stoichiometry, insensitivity to air and
moisture and/or ease of storage as crystalline solids.39,40 The
organoboronate esters can be readily accessed using a number
of methods, for example, iridium(I)-catalyzed C−H activation
of arenes with bis(pinacolato)diboron (Pin2B2)41 and trans-
metalation from reactive organometallics.
These results encouraged us to investigate the scope of
organoboronic esters containing both aryl and alkenyl
moieties, and the results are summarized in Scheme 5. Alkenyl
boron reagents have been emerging as versatile and important
synthons in organic synthesis.42,43 Substituted alkenyl boronic
esters are known for a variety of synthetic applications that
include facile metal-catalyzed transformations to obtain a series
of functionalities like C−C, C−O, C−N, and C−X (X = F, Cl,
Br, and I), the synthesis of tri- and tetra-substituted alkenes via
the Suzuki coupling, the total synthesis of natural products,
and the generation of medicinally useful agents. Coupling of 1a
with select substituted arylboronic esters was also found to be
efficient with the yields that were either similar (examples 3a,
3d, and 3n) or improved (example 3k) when compared to that
of the corresponding arylboronic acids. An intramolecular
cross-coupling of cyclopropanols and alkenyl halides or triflates
as part of a seven-membered ring annulation has been
disclosed by Cha et al.44 Surprisingly, the intermolecular
variant of coupling cyclopropanols with the alkenyl partners
(halides, triflates, or alkenyl boronic acid derivatives) has
received meager attention. Hence, there exists an opportunity
to expand the scope for alkenyl partners in an attempt to access
aryl pent-4-en-1-one systems. The investigated olefinic boronic
ester derivatives afforded β-substituted ethyl ketone derivatives
with good yields in the range of 79−93% (examples 3bf−3bh)
with no significant impact of variation in the cyclic moiety, for
example, carbocyclic (cyclohexenyl) or heterocyclic (dihydro-
pyranyl) groups.
Overall, the examples discussed above support the generality
of the transformation with the compatibility of various
functionalities like OBn, Boc, ester, halogens (Br and I),
nitrile, ketal, and olefin. In contrast to the reported propensity
of palladium homoenolates to undergo degradation to the
corresponding enone byproducts via β-hydride elimination in
few cases,7 the formation of such byproducts was not observed
in our examples, indicating the suppression of occurrence of
the associated side-reaction pathway.
While a probable mechanism in the case of Pd(0)-catalyzed
cross-coupling of cylcopropanols and aryl halides has been
postulated, the catalytic pathway based on detailed mechanistic
studies remains to be fully understood.2,7,8,10 This stimulated
us to gain insights into the mechanistic aspects of the catalytic
cycle that involved an alternate Pd(II) system as the active
catalyst with an arylboronic acid as the surrogate of an aryl
halide. Accordingly, controlled experiments were carried out
In a representative trial reaction, simple phenylboronic acid
(2n) was replaced with either potassium phenyltrifluoroborate
(2ba) or phenylboronic acid pinacol ester (2bb) for coupling
with the cyclopropanol 1a (example 3n). Like phenylboronic
acid, these surrogates were also found to efficiently couple, and
the yields were only slightly lower than that of coupling with
2n.
G
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subsequently promoting C−C bond formation to deliver 3a
in a manner that is independent of Cu(II). At the same time,
the Pd(II) ketone homoenolate intermediate is subject to an
alternative pathway that would involve competitive proto-
nolysis, thereby constituting a suboptimal system. In the
absence of Pd(II), Cu(II) is capable of opening the
cyclopropanol, resulting in the formation of β-hydride
elimination product 5a but could not promote C−C bond
formation between 5a and 2a further (Table 2, entry 2).
Reactions of Cu(II) salts with cyclopropanol substrates to
generate enone derivatives like 5a via β-hydride elimination of
the corresponding Cu(II) ketone homoenolates have been
well-documented.45−47 Unlike Pd(II) species, the Cu(II)
ketone homoenolate is not susceptible to protonolysis of the
side reaction, thereby promoting selective β-hydride elimi-
nation. Although the cyclopropyl ring-opening process can be
Cu(II)-mediated, catalytic Pd(II) would still be required to
promote the C−C bond formation between 5a and 2a to
obtain 3a (see later: Scheme 7). Additionally, it may be
inferred that Cu(II) plays the primary role in the ring-opening
step of the catalytic cycle under a standard protocol (Table 1,
entry 13) with the suppression of Pd(II)-mediated ring
cleavage. This is consistent with the negligible formation of
4a, a major byproduct in the Pd(II)-promoted catalytic
pathway.
Table 3. Competitive Experiments to Glean Insight into the
Involvement of the Pd(0) Complex, Involving Oxidative
Addition of an Aryl Iodide
a
b
c
c
entry
base
% yield (3a)
% yield (3b)
1
2
3
none
Et3N
K2CO3
71
61
34
0
8
30
a
Standard conditions were applied except that 2a and 2ca (1.0 equiv
b
c
of each) were used in a 1:1 ratio. 3.0 equiv. Isolated yields.
that have been depicted in Table 2, Table 3, Scheme 6, and
Scheme 7. Following submission of the model substrates 1a
and 2a to the standard condition in the absence of Cu(OAc)2,
it was observed that the desired product 3a could still be
obtained (Table 2, entry 1). However, the yield of the desired
product was reduced, a profile that can be attributed to an
almost equal propensity to the concurrent formation of ring-
opening protonolysis byproduct 4a. This result indicates that
Pd(II) is capable of opening the cyclopropanol and
The palladium(II) catalysis, which involves arylboronic acids
containing nonmetal-coordinating electropositive transmetala-
tion handles (e.g., −B(OH)2), has previously been proposed to
proceed via a cationic manifold in the presence of a bidentate
ligand and another ligand (for example, −OCOCF3, −OAc, or a
Scheme 6. Controlled Experiments to Study the Incorporation of Deuterium or H/D Exchange
H
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Scheme 7. Controlled Experiments to Study the Arylative Insertion of β-Hydride Elimination Intermediate 5a
solvent) that can readily dissociate.11,48 Experimentally,
mechanistic studies involving ESI-MS-(+) analysis of reaction
mixtures of bidentate ligand (for example, neocuproine and
dppp) controlled Pd(II)-catalyzed arylation of olefins could
reveal the involvement of cationic organopalladium inter-
mediates during the course of the reaction.49,50 Additionally,
the addition of the chloride ion to cationic palladium
complexes has been shown to substantially reduce the reaction
rate with olefins in the Heck−Mizoroki cross-coupling due to
the formation of neutral palladium chloride species.51 In the
reported Pd(0)-catalyzed β-arylation of homoenolates, silyl-
protected cyclopropanols have been shown to undergo
coupling with a cationic arylpalladium complex catalytically
generated from the oxidative addition of an aryl triflate.5
Moreover, the addition of stoichiometric LiCl or tetra-n-
butylammonium bromide to the reaction mixture was found to
almost completely inhibit the catalysis. In order to verify the
cationic nature of the arylation of the ketone homoenolate in
the present protocol, a neutral aryl-palladium(II) catalysis was
contemplated with the addition of LiCl (3.0 equiv) into the
reaction mixture. This additive resulted in a dramatic reduction
in the reaction rate with a substantial drop in the yield of 3a
from 93% to 24% after 2 h, indicating the suppression of the
reaction rate of arylation following the shift from cationic to
the neutral pathway (Table 2, entry 3). The chemoselectivity
was also destroyed, as apparent from the concomitant
generation of 4a with approximately a 2:1 ratio to the arylation
product 3a, an observation that could be attributed to the high
tendency of palladium keto homoenolate species under neutral
Pd(II) conditions to undergo the protonolysis side reaction
before arylative insertion.
would involve the steps that generate Pd(0) and require Pd(0)
to be oxidized back to the active catalyst Pd(II). However, the
reaction yield was not altered significantly, suggesting that
molecular oxygen does not play a major role in the catalytic
system (Table 2, entry 4). This result is largely consistent with
deuterium incorporation studies (vide infra) that reveal
protonolysis in the final step of the catalytic cycle, leading to
the regeneration of active Pd(II), a mechanistic profile that
does not require an oxidant for catalytic turn over.
Next, an intermolecular competition experiment between
the aryl nucleophile 2a and the aryl electrophile 2ca for
coupling with 1a was studied to further understand the kinetic
and mechanistic aspects behind LnPd(II) and LnPd(0) (Table
3). Pd(0) species can be expected to form from Pd(II) ketone
homoenolates in the reaction system through the operative
mechanisms like (a) β-hydride elimination to generate the
corresponding unsaturated ketone 5a19,52 and (b) reductive
elimination of the organopalladium complex upon arylative
insertion to generate 3a. Under the standard conditions, the
formation of the arylboronic acid-derived product (3a) was
only observed with no concomitant formation of Heck-type
product 3b (entry 1). This result, which is consistent with the
observed chemoselectivity in the preparative examples, does
not seem to support the possibility of either the presence or
involvement of Pd(0) in the reaction system. To gain further
insight, we also investigated the reaction profile after adding a
base into the reaction mixture. Among multiple roles that a
base can play in the catalysis, it can promote the selective
reduction of Pd(II) to Pd(0) or recycling of the Pd(0)
complex from the hydridopalladium(II) intermediate derived
via β-hydride elimination, thereby allowing accumulation of
Pd(0) species that is conducive to open alternative reaction
pathways like oxidative addition of aryl halides. The product
3b was obtained in 7:1 and 1:1 ratios, respectively, in the
presence of the organic base Et3N (Table 3, entry 2) and the
inorganic base K2CO3 (Table 3, entry 3). The formation of an
Because the standard reaction was conducted under the
open-flask condition, a controlled experiment was undertaken
under an inert atmosphere of N2 gas to study the influence of
dioxygen gas as an oxidant. Dioxygen would be expected to
positively impact the catalytic turn over, if the catalytic cycle
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aryl halide-based product was thus possible only upon
modifying the pH of the reaction via the addition of a base
that is conducive to the generation of Pd(0). Overall, these
results suggest that the possibility of the involvement of Pd(0)
in the catalytic cycle is limited, an assumption that is in
concordance with other experimental observations (for
example, protonolysis in the final step of catalysis and the
limited role of oxygen) that does not support the generation of
Pd(0).
product with the characteristic deuterium installation at the α-
position to the carbonyl of dihydrochalcone 3a (Scheme 7,
equation c). These observations lend support to the generation
and protonolysis of an α-keto carbopalladium complex (for
example, see G in Figure 2) in line with the mechanism of the
In order to understand whether the catalytic cycle would
encompass a protonolysis step in the presence of a proton
source, the possibility of deuterium incorporation was
investigated by subjecting the substrate 1a to standard reaction
conditions by replacing H2O with D2O as a cosolvent (Scheme
6, equation a). Interestingly, this resulted in the H/D exchange
of one of the two methylene protons at the α-position to the
carbonyl of dihydrochalcone 3a with the preferred formation
of the 3a-d compound in the absence of the formation of the
normal product 3a. In order to understand whether DMSO
can act as a protic source beyond its role as the solvent, a
reaction was conducted by replacing DMSO with DMSO-d6 in
the absence of D2O (Scheme 6, equation b). However, no
deuterium incorporation was observed, ruling out the
possibility of DMSO acting as a proton donor.
Analysis of ketone 3a by 1H NMR spectroscopy following a
24 h equilibration with DMSO-d6 and D2O did not show
either mono- or dideuterium incorporation at the α-position of
the carbonyl, suggesting that the normal product 3a is not
capable of H/D exchange with D2O (Scheme 6, equation c).
As a further step, the product 3a itself was subjected to the
standard catalytic conditions for 3 h in the absence (Scheme 6,
equation d) or presence of boronic acid 2a (Scheme 6,
equation e). These later two experiments were designed to
investigate the role of boronic acid as a strong Bronsted acid in
promoting either the incorporation of deuterium or H/D
exchange. However, 3a did not undergo any deuterium
incorporation, suggesting that the end product expelled from
the catalytic cycle was not susceptible to H/D exchange under
reaction conditions. On the basis of these key observations, it
can be suggested that incorporation of deuterium at the carbon
atom α to the ketone occurs as an inherent part of the catalytic
cycle, which is presumably an outcome of protonolysis of the
carbopalladium(II) complex in the final step of the catalysis
with the release of the parent and active Pd(II) catalyst.
Furthermore, the deuterium incorporation eliminates the
possibility of reductive elimination as the final step of the
catalytic cycle and generation of Pd(0) species.
The Cu(II)-promoted formation of vinyl ketone 5a (see
Table 2, entry 2) stimulated an interest to probe whether the
generated enone would undergo arylative insertion with the
arylboronic reagent (Scheme 7). As discussed previously, the
formation of vinyl ketones by Cu(II)-mediated ring opening of
hydroxycyclopropanes, involving the generation of metal keto
enolates and subsequent β-hydride elimination, is well-
precedented.45,47,53 In this direction, vinyl ketone 5a was
isolated following treatment of the cyclopropanol 1a with
Cu(OAc)2 and was then subjected to the standard condition.
Interestingly, this reaction furnished the 1,4-addition product
3a (Scheme 7, equation a) but did not provide the Heck-type
vinylation product (equation b), suggesting an absence of the
β-hydride elimination mechanistic pathway. Additionally, the
coupling of 5a and 2a was conducted under standard
conditions by replacing H2O with D2O that afforded an end
Figure 2. Proposed mechanism for cationic Pd(II)-assisted C−C
cross-coupling of cyclopropanol with organoboronic acid.
well-precedented conjugate addition of organoboronic acids to
α,β-unsaturated ketones.20 Two additional experiments were
designed to examine the metal-catalyzed conjugate addition
process in the presence of only Pd(II) or only Cu(II) to gain
an understanding of the metal that could be responsible for the
C−C bond-forming step. The product 3a was not obtained
with Cu(II) salt alone in the absence of a Pd(II) source
(Scheme 7, equation d). In contrast, 3a could be obtained in
the presence of Pd(II) even after excluding Cu(II) salt, albeit
in a modest yield (Scheme 7, equation e). These observations
corroborate with the earlier findings (Table 2, entries 1 and 2)
that Pd(II), but not Cu(II), is responsible for the C−C bond
formation step.
On the basis of observations from the controlled experi-
ments, the proposed catalytic cycle that can be analogous to
the palladium(II)-catalyzed conjugate addition of organo-
boronic acids to an enone involves key steps of trans-
metalation, insertion, and hydrolytic carbon-Pd bond cleavage,
as illustrated in Figure 2.54 This involves the generation of the
cationic aryl/alkenylpalladium(II) complex (B) in the fore-
most step of the putative catalytic cycle, resulting from
transmetalation of the aryl/alkenyl organoborane reagent with
the DPPE-chelated palladium(II) complex (A).3,11,49,50 The
vinyl ketone intermediate (E) is generated by Cu(II)-mediated
ring opening of hydroxycyclopropane (C), involving the
generation of copper keto enolate and subsequent β-hydride
elimination.45−47 Subsequently, the vinyl ketone substrate E
coordinates to the metal center of the Pd(II)-aryl/alkenyl
species through the vacant site to form the olefin-Pd π-complex
(F). Migratory insertion of the aryl/alkenyl group from the
metal center into the olefinic bond via syn addition results in
the generation of α-keto carbopalladium complex G.20 This
species undergoes protonolysis in the presence of a proton
source to liberate β-arylethyl ketone product (H) and the
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active catalyst A that can initiate the next catalytic cycle. As
discussed earlier, experimental observation of the insertion of
the deuterium atom at the α-methylene position to the keto
group of 3a in the presence of D2O under standard condition
supports the protonolysis event of the α-keto carbopalladium
complex G (Scheme 6). In the Pd(0)-promoted cross-coupling
of cyclopropanol-derived homoenolates, it is hypothesized that
the reductive elimination of an arylpalladium(II) homoenolate
constitutes the final step of the catalytic process in order to
furnish the arylated ketone product and active Pd(0) species.1,3
In contrast to the Pd(0) mechanism, our mechanistic studies
reveal a differentiated catalytic cycle for the cationic Pd(II)
pathway that would require the arylpalladium(II) homoenolate
to undergo the carbopalladation and protonolysis after the
migratory insertion of the aryl moiety, corroborated by the
deuterium incorporation studies.
In line with entry 1 in Table 2, a minor pathway may involve
the role of the palladium complex alone with the initial steps of
the catalytic cycle that are expected to be similar to that of
previously reported direct arylation of siloxycylopropanes by
the aryl triflate via cationic arylpalladium complex.4,5 It seems
likely that the initial step involves the coordination of the
cyclopropanol substrate C to the palladium(II) intermediate
(B) to generate the cyclopropyloxypalladium(II) intermediate,
which subsequently undergoes C−C bond cleavage of the
highly strained cyclopropyl ring and aryl/alkenyl insertion to
provide the metal ketone homoenolate J. This intermediate
rearranges to provide the enol-coordinated palladium(II)
intermediate K. This later species can undergo tautomeric
equilibrium with carbo-palladium intermediate G in the
solution state with high susceptibility of these tautomers for
hydrolytic cleavage. The C-bound tautomer G is subjected to
protonolysis in the presence of a protic source like water to
selectively deliver the 1,4-addition product H without the
formation of the competitive Heck-type coupling product via
β-hydride elimination.55
pentanols as substrates, and (c) developing applications toward
the synthesis of natural products, are currently under progress
in these laboratories.
EXPERIMENTAL SECTION
■
Materials and General Methods. All anhydrous reactions were
performed under an atmosphere of N2 or Ar gas with magnetic
stirring. Reagents and solvents were purchased from commercial
suppliers and used without further purification, unless otherwise
stated. Reactions were monitored by thin-layer chromatography
(TLC). TLC was performed using E. Merck precoated silica plates
(60F-254) with a 0.25 mm thickness and visualized using short-wave
UV light or developing agents (KMnO4, phosphomolybdic acid, or p-
anisaldehyde). Purifications were performed using flash column
chromatography with 60−120 mesh silica gel as the stationary
phase and a gradient of ethyl acetate in petroleum ether as the mobile
phase.
Known compounds were characterized by comparing their 1H
NMR spectra to the previously reported data. New compounds were
characterized by 1H NMR, 13C NMR, and MS, and copies of H and
1
13C NMR spectra have been included at the end of the Supporting
Information. Proton nuclear magnetic resonance (1H NMR) spectra
1
were recorded on Bruker 300 and 400 MHz instruments. H NMR
chemical shifts are reported in ppm (δ) relative to the internal
standard tetramethylsilane (TMS, δ 0.00 ppm). 13C NMR chemical
shifts are reported in ppm with respect to solvent resonance as the
internal standard (CDCl3 at 77.0 ppm). NMR data are reported as
follows: chemical shift (multiplicity [singlet (s), doublet (d), triplet
(t), quartet (q), pentet (p), multiplet (m), and broad singlet (br. s)],
coupling constant [Hz], and integration). For LC/MS character-
ization of the purified compounds, reversed-phase analytical HPLC/
MS experiments were performed on an Agilent 1200 Series system
coupled with a single quadrupole instrument using the electrospray
ionization (ESI) method or Waters Aquity system coupled with a
Waters Micromass SQ mass spectrometer. High-resolution mass
spectrometry (HRMS) data were obtained from an Orbitrap
(Thermofisher) mass spectrometer using a heated ESI method in
positive or negative ion detection mode.
Experimental Procedures. General Procedure for the Synthesis
of Cyclopropanols via the Kulinkovich Reaction. To a solution of
ester (25 mmol, 1 equiv) and titanium tetraisopropoxide (35 mmol,
1.4 equiv) in anhydrous THF (25 mL; 1 M solution) was added
dropwise 1 M solution of ethylmagnesium bromide in THF (70
mmol, 2.8 equiv) over 30 min at 0 °C. The reaction mixture was
stirred at room temperature for 14 h. Then the solution was cooled to
0 °C and slowly quenched with ice water. The precipitate was filtered
and washed with ethyl acetate. The filtrate was partitioned between
ethyl acetate and water. The organic layer was washed with brine,
dried over anhydrous sodium sulfate, filtered, and concentrated under
a vacuum to afford the residue. The crude product was purified by
flash column chromatography using a gradient of ethyl acetate and
petroleum ether to afford the product.
1-(3,4-Difluorophenyl)cyclopropan-1-ol (1ad). Following a 5.0 g
(29 mmol, 1 equiv) scale reaction, the crude product was purified by
flash column chromatography using a gradient of ethyl acetate and
petroleum ether (ratio = 10:90) to afford the title product as a light
yellow oil (3.9 g, 79%): 1H NMR (400 MHz, chloroform-d) δ 7.19−
7.05 (m, 2H), 7.02−6.93 (m, 1H), 2.47−2.22 (br s., 1H), 1.32−1.25
(m, 2H), 1.05−0.97 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
150.8 (dd, JC−F = 130 Hz, 13 Hz), 148.4 (dd, JC−F = 129 Hz, 13 Hz),
141.6 (d, JC−F = 8 Hz), 120.1 (dd, JC−F = 7, 3 Hz), 117.0 (d, JC−F = 17
Hz), 113.9 (d, JC−F = 19 Hz), 56.0, 18.1; HRMS (ESI/Orbitrap) m/z
[M + H]+ calcd for C9H9F2O 171.0616, found 171.0658.
1-(3-Chloro-4-methoxyphenyl)cyclopropan-1-ol (1ae). Following
a 5.0 g (25 mmol, 1 equiv) scale reaction, the crude product was
purified by flash column chromatography using a gradient of ethyl
acetate and petroleum ether (ratio = 15:85) to afford the title product
as a colorless oil (3.6 g, 73%): 1H NMR (400 MHz, chloroform-d) δ
0.34 (d, J = 2.3 Hz, 1H), 7.19 (dd, J = 2.3, 8.6 Hz, 1H), 6.89 (d, J =
CONCLUSION
■
In conclusion, we took advantage of widely available
organoboronic reagents as the new and efficient coupling
partners to the homoenolate equivalents for forging C−C
bonds. The design strategy relied on the selective engagement
of these aryl agents with electrophilic Pd(II) over Pd(0),
thereby exploiting the mechanistic differences in the catalysis
between these Pd systems to promote chemoselectivity.
Preparative capabilities over a range of structurally diverse
aryl and alkenyl boronic acids/esters and substituted cyclo-
propanols indicate the broad scope of this new methodology.
Importantly, this protocol has paved the way for new substrate
classes like halogen-appended dihydrochalcones, which cannot
be accessed by previously reported methods. Furthermore, it
has been demonstrated that this operationally simple reaction
can be performed under open-flask conditions with water as
the green cosolvent and is capable of producing β-aryl ketones
on the gram scale. The deuterium incorporation studies, which
were conducted as part of a mechanistic investigation to gain
insight into the catalytic pathway of cationic Pd(II), provided
critical information on the occurrence of α-keto carbopallada-
tion and subsequent protonolysis in the terminal step. Further
investigations for (a) optimizing the catalytic efficiency of the
reaction in terms of the stoichiometry of Cu(OAc)2 and
ArB(OH)2, (b) expanding the scope of this transformation to
1,2-disubstituted cyclopropanols, cyclobutanols, and cyclo-
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8.5 Hz, 1H), 3.90 (s, 3H), 2.48 (br. s, 1H), 1.27−1.21 (m, 2H),
1.03−0.96 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.7,
137.4, 127.1, 124.2, 122.4, 112.0, 56.2, 17.2; HRMS (ESI/Orbitrap)
m/z [M + H]+ calcd for C10H12ClO2 199.0520, found 199.0560.
General Procedure for the Reaction of Cyclopropanols with
Organoboronic Acids, Organoboronic Esters, or Organotrifluor-
oborates. A mixture containing cyclopropanol (1 mmol, 1 equiv),
organoboronic acid (2 mmol, 2 equiv)/organoboronic acid pinacol
ester (2 mmol, 2 equiv)/potassium organotrifluoroborate (2 mmol, 2
equiv), Pd(OAc)2 (0.1 mmol, 0.1 equiv), Cu(OAc)2 (2 mmol, 2
equiv), and DPPE (0.2 mmol, 0.2 equiv) in a solvent mixture (0.33 M
solution) of DMSO (2.5 mL) and water (0.5 mL) was stirred at 70 °C
in an oil bath for 2 h under open air. The reaction mixture was
monitored by TLC. After completion of the reaction, the mixture was
partitioned between ethyl acetate and water (note that, if there was no
separation of layers, the mixture was filtered through a Celite bed, and
the bed was washed with ethyl acetate). After filtration, the separation
of layers was observed). The organic layer was washed with water and
brine solution, dried over anhydrous sodium sulfate, and concentrated
under reduced pressure to get the crude product, which was purified
by column chromatography.
1-(4-Methoxyphenyl)-3-(p-tolyl)propan-1-one (3d). Following a
200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude product was
purified by flash column chromatography using a gradient of ethyl
acetate and petroleum ether (ratio = 10:90) to afford the title product
1
as an off-white solid (282 mg, yield: 91%): H NMR (400 MHz,
chloroform-d) δ 8.00−7.91 (m, 2H), 7.15 (q, J = 8.1 Hz, 4H), 6.98−
6.90 (m, 2H), 3.88 (s, 3H), 3.29−3.20 (m, 2H), 3.08−2.99 (m, 2H),
2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.9, 163.4,
138.4, 135.6, 130.3, 130.0, 129.2, 128.3, 113.7, 55.5, 40.3, 29.9, 21.0;
LCMS (ES) m/z 255.3 [M + H]+; HRMS (ESI/Orbitrap) m/z [M +
H]+ calcd for C17H19O2 255.1380, found 255.1387.
3-(3,4-Dimethoxyphenyl)-1-(4-methoxyphenyl)propan-1-one
(3e). Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the
crude product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 20:80) to afford
the title product as an off-white solid (296 mg, yield: 81%): 1H NMR
(400 MHz, chloroform-d) δ 7.94−7.92 (m, 2H), 6.92−6.90 (m, 2H),
6.78−6.76 (m, 3H), 3.85 (s, 9H), 3.23−3.3.19 (m, 2H), 3.01- 2.97
(m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.9, 163.5, 148.9,
147.5, 134.1, 130.3, 130.0, 120.2, 113.7, 111.9, 111.4, 56.0, 55.9, 55.5,
40.4, 30.0; LCMS (ES) m/z 301.3 [M + H]+; HRMS (ESI/Orbitrap)
m/z [M + H]+ calcd for C18H21O4 301.1434, found 301.1444.
3-(Benzo[d][1,3]dioxol-5-yl)-1-(4-methoxyphenyl)propan-1-one
(3f). Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the
crude product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 15:85) to afford
1,3-Bis(4-methoxyphenyl)propan-1-one (3a).56 Following a 200.0
mg (1.2 mmol, 1 equiv) scale reaction, the crude product was purified
by flash column chromatography using a gradient of ethyl acetate and
petroleum ether (ratio = 15:85) to afford the title product as an off-
1
white solid (306 mg, 93%): H NMR (400 MHz, chloroform-d) δ
1
the title product as a light brown solid (298 mg, yield: 86%): H
8.03−7.94 (m, 2H), 7.26−7.17 (m, 2H), 6.98−6.92 (m, 2H), 6.90−
6.84 (m, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.32−3.20 (m, 2H), 3.11−
2.99 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.0, 163.5,
158.0, 133.5, 130.3, 130.1, 130.1, 129.3, 114.0, 113.7, 55.5, 55.3, 40.4,
29.5; LCMS (ES) m/z 271.3 [M + H]+
NMR (400 MHz, chloroform-d) δ 7.97−7.94 (m, 2H), 6.95−6.92
(m, 2H), 6.77−6.72 (m, 3H), 5.93 (s, 2H), 3.88 (s, 3H), 3.24−3.19
(m, 2H), 3.01−2.96 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
197.8, 163.5, 147.6, 145.8, 135.3, 130.3, 130.0, 121.1, 113.7, 108.9,
108.3, 100.8, 55.5, 40.3, 30.1; LCMS (ES) m/z 285.1 [M + H]+;
HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for C17H17O4 285.1121,
found 285.1129.
1-(4-Methoxyphenyl)-3-(4-morpholinophenyl)propan-1-one
(3g). Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the
crude product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 15:85) to afford
the title product as an off-white solid (372 mg, yield: 94%): 1H NMR
(400 MHz, chloroform-d) δ 8.00−7.90 (m, 2H), 7.18 (d, J = 8.3 Hz,
2H), 6.96−6.90 (m, 2H), 6.90−6.84 (m, 2H), 3.91−3.83 (m, 7H),
3.27−3.17 (m, 2H), 3.17−3.10 (m, 4H), 3.10−2.90 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 198.0, 163.4, 150.0, 130.8,
.
1,3-Bis(4-methoxyphenyl)propan-1-one-2-d (2[H]-3a). Following
a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, while using 2.5 mL of
DMSO and 0.5 mL of D2O (0.33 M solution), the crude product was
purified by flash column chromatography using a gradient of ethyl
acetate and petroleum ether (ratio = 15:85) to afford the title product
as an off-white solid (301 mg, 91%): 1H NMR (400 MHz,
chloroform-d) δ 8.01−7.92 (m, 2H), 7.22−7.16 (m, 2H), 6.99−
6.90 (m, 2H), 6.90−6.66 (m, 2H), 3.89 (s, 3H), 3.70 (s, 3H), 3.27−
3.16 (m, 1H), 3.05−2.98 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 198.0, 163.4, 158.0, 133.5, 130.3, 130.0, 129.4, 113.9, 113.7,
55.5, 55.3, 40.4, 40.2, 40.0, 29.5; LCMS (ES) m/z 272.3 [M + H]+;
HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for C17H18DO3
272.1391, found 272.1386.
130.3, 130.1, 129.1, 116.1, 113.7, 66.9, 55.5, 49.7, 40.3, 29.5; LCMS
(ES) m/z 326.1 [M + H]+; HRMS (ESI/Orbitrap) m/z [M + H]+
calcd for C20H24NO3 326.1751, found 326.1751.
3-(4-(Benzyloxy)phenyl)-1-(4-methoxyphenyl)propan-1-one
(3b). Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the
crude product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 15:85) to afford
the title product as an off-white solid (358 mg, 85%): 1H NMR (400
MHz, chloroform-d) δ 7.99−7.93 (m, 2H), 7.51−7.31 (m, 5H),
7.23−7.16 (m, 2H), 7.00−6.89 (m, 4H), 5.06 (s, 2H), 3.88 (s, 3H),
3.28−3.19 (m, 2H), 3.07−2.98 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 198.0, 163.4, 157.2, 137.2, 133.8, 130.3, 130.0, 129.4, 128.6,
127.9, 127.5, 114.9, 113.7, 70.1, 55.5, 40.5, 29.5; LCMS (ES) m/z
347.3 [M + H]+; HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for
C23H23O3 347.1642, found 347.1633.
3-(4-Isobutylphenyl)-1-(4-methoxyphenyl)propan-1-one (3h).
Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude
product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 15:85) to afford
the title product as an off-white solid (327 mg, yield: 90%): 1H NMR
(400 MHz, chloroform-d) δ 7.99−7.93 (m, 2H), 7.17 (d, J = 7.8 Hz,
2H), 7.12−7.06 (m, 2H), 6.97−6.91 (m, 2H), 3.90 (s, 3H), 3.28−
3.22 (m, 2H), 3.07−3.00 (m, 2H), 2.46 (d, J = 7.1 Hz, 2H), 1.85
(dquin, J = 13.5, 6.8 Hz, 1H), 0.91 (d, J = 6.6 Hz, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 198.0, 163.4, 139.4, 138.6, 130.3, 130.0,
129.2, 128.1, 113.7, 55.4, 45.0, 40.2, 30.2, 30.0, 22.4; LCMS (ES) m/z
297.2 [M + H]+; HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for
C20H25O2 297.1849, found 297.1848.
tert-Butyl (4-(3-(4-Methoxyphenyl)-3-oxopropyl)phenyl)-
carbamate (3c). Following a 200.0 mg (1.2 mmol, 1 equiv) scale
reaction, the crude product was purified by flash column
chromatography using a gradient of ethyl acetate and petroleum
ether (ratio = 15:85) to afford the title product as an off-white solid
1-(4-Methoxyphenyl)-3-(4-nitrophenyl)propan-1-one (3i). Fol-
lowing a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude
product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 20:80) to afford
1
(286 mg, yield: 66%): H NMR (400 MHz, chloroform-d) δ 7.97−
1
7.91 (m, 2H), 7.32−7.25 (m, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.96−
6.90 (m, 2H), 6.43 (br s, 1H), 3.87 (s, 3H), 3.25−3.17 (m, 2H),
3.05−2.97 (m, 2H), 1.52 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3)
δ 197.9, 163.4, 153.5, 136.4, 136.2, 130.3, 128.9, 118.9, 113.7, 80.1,
55.4, 40.2, 29.7, 28.3; LCMS (ES) m/z 300.1 [M-tert-butyl]+; HRMS
(ESI/Orbitrap) m/z [M + H]+ calcd for C21H26NO4 356.1856, found
356.1847.
the title product as a yellow solid (275 mg, yield: 79%): H NMR
(400 MHz, chloroform-d) δ 8.19−8.13 (m, 2H), 7.98−7.92 (m, 2H),
7.43 (d, J = 8.5 Hz, 2H), 6.98−6.92 (m, 2H), 3.89 (s, 3H), 3.36−3.29
(m, 2H), 3.23−3.15 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
196.6, 163.7, 149.4, 146.5, 130.3, 129.4, 123.7, 113.9, 55.5, 39.0, 29.9;
LCMS (ES) m/z 286.1 [M + H]+; HRMS (ESI/Orbitrap) m/z [M +
H]+ calcd for C16H16NO4 286.1074, found 286.1073.
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Article
Methyl 4-(3-(4-Methoxyphenyl)-3-oxopropyl)benzoate (3j). Fol-
lowing a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude
product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 15:85) to afford
the title product as an off-white solid (342 mg, yield: 94%): 1H NMR
(400 MHz, chloroform-d) δ 7.99−7.93 (m, 4H), 7.35−7.28 (m, 2H),
6.95−6.92 (m, 2H), 3.96 (s, 3H), 3.88 (s, 3H), 3.28−3.20 (m, 2H),
3.15−3.12 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.2,
167.0, 163.6, 147.0, 130.3, 129.8, 128.5, 128.1, 127.2, 113.8, 55.5,
52.0, 39.4, 30.2; LCMS (ES) m/z 299.3 [M + H]+; HRMS (ESI/
Orbitrap) m/z [M + H]+ calcd for C18H19O4 299.1278, found
299.1270.
LCMS (ES) m/z 255.3 [M + H]+; HRMS (ESI/Orbitrap) m/z [M +
H]+ calcd for C17H19O2 255.1380, found 255.1385
3-Mesityl-1-(4-methoxyphenyl)propan-1-one (3p). Following a
200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude product was
purified by flash column chromatography using a gradient of ethyl
acetate and petroleum ether (ratio = 10:90) to afford the title product
1
as an off-white solid (306 mg, yield: 89%): H NMR (400 MHz,
chloroform-d) δ 7.96 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H),
6.89 (s, 2H), 3.88 (s, 3H), 3.12−2.98 (m, 4H), 2.32 (s, 6H), 2.28 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.2, 163.5, 136.1, 135.4,
135.0, 130.3, 130.0, 129.0, 113.8, 55.5, 37.6, 23.9, 20.8, 19.7; LCMS
(ES) m/z 283.3 [M + H]+; HRMS (ESI/Orbitrap) m/z [M + H]+
calcd for C19H23O2 283.1693, found 283.1701.
3-(3-(4-Methoxyphenyl)-3-oxopropyl) benzonitrile (3k). Follow-
ing a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude product
was purified by flash column chromatography using a gradient of ethyl
acetate and petroleum ether (ratio = 15:85) to afford the title product
1-(4-Methoxyphenyl)-3-(1-methyl-1H-indazol-5-yl)propan-1-one
(3q). Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the
crude product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 25:75) to afford
1
as an off-white solid (211 mg, yield: 65%): H NMR (400 MHz,
1
chloroform-d) δ 7.95 (d, J = 9.0 Hz, 2H), 7.57 (s, 1H), 7.55−7.48 (m,
2H), 7.45−7.37 (m, 1H), 6.95 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H),
3.33−3.25 (m, 2H), 3.16−3.08 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 196.8, 163.7, 142.9, 133.2, 132.0, 130.3, 129.9, 129.7, 129.3,
118.9, 113.8, 112.5, 55.5, 39.2, 29.6; LCMS (ES) m/z 266.3 [M +
H]+; HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for C17H16NO2
266.1176, found 266.1180.
2-Fluoro-4-(3-(4-methoxyphenyl)-3-oxopropyl)benzonitrile (3l).
Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude
product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 15:85) to afford
the title product as an off-white solid (276 mg, yield: 80%): 1H NMR
(400 MHz, chloroform-d) δ 7.99−7.90 (m, 2H), 7.55 (t, J = 7.3 Hz,
1H), 7.21−7.10 (m, 2H), 6.95 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H),
3.34−3.25 (m, 2H), 3.19−3.10 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 196.4, 163.8, 163.2 (d, JC−F = 250 Hz), 150.6 (d, JC−F = 8
Hz), 133.3, 130.3, 129.5, 125.1, 116.5 (d, JC−F = 15 Hz), 114.1, 113.9,
99.0 (d, JC−F = 16 Hz), 55.5, 38.6, 30.0; LCMS (ES) m/z 284.2 [M +
H]+; HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for C17H15FNO2
284.1081, found 284.1074.
the title product as a brown solid (269 mg, yield: 75%): H NMR
(400 MHz, chloroform-d) δ 8.00−7.90 (m, 3H), 7.60 (s, 1H), 7.38−
7.30 (m, 2H), 6.97−6.90 (m, 2H), 4.08 (s, 3H), 3.90 (s, 3H), 3.35−
3.28 (m, 2H), 3.22−3.15 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 197.8, 163.5, 138.9, 133.6, 132.2, 130.3, 130.0, 127.7, 124.3,
119.8, 113.7, 108.9, 55.5, 40.5, 35.5, 30.2; LCMS (ES) m/z 295.3 [M
+ H]+; HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for C18H19N2O2
295.1441, found 295.1448.
1-(4-Methoxyphenyl)-3-(naphthalen-2-yl)propan-1-one (3r).
Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude
product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 10:90) to afford
the title product as an off-white solid (329 mg, yield: 93%): 1H NMR
(400 MHz, chloroform-d) δ 8.03−7.95 (m, 2H), 7.87−7.78 (m, 3H),
7.72 (s, 1H), 7.53−7.38 (m, 3H), 6.99−6.92 (m, 2H), 3.89 (s, 3H),
3.42−3.33 (m, 2H), 3.29−3.21 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 197.8, 163.5, 139.0, 133.7, 132.1, 130.3, 130.0, 128.1, 127.6,
127.5, 127.2, 126.5, 126.0, 125.3, 113.8, 55.5, 40.0, 30.45; LCMS (ES)
m/z 291.0 [M + H]+; HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for
C20H19O2 291.1380, found 291.1380.
3-([1,1′-Biphenyl]-3-yl)-1-(4-methoxyphenyl) propan-1-one
(3m). Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the
crude product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 15:85) to afford
the title product as an off-white solid (288 mg, yield: 75%): 1H NMR
(400 MHz, chloroform-d) δ 7.98 (d, J = 8.8 Hz, 2H), 7.64−7.59 (m,
2H), 7.49−7.34 (m, 6H), 7.31−7.25 (m, 1H), 6.95 (d, J = 8.8 Hz,
2H), 3.89 (s, 3H), 3.37−3.29 (m, 2H), 3.19−3.12 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 197.8, 163.5, 142.0, 141.5, 141.2, 130.3,
130.0, 128.9, 128.7, 127.4, 127.4, 127.3, 127.2, 125.0, 113.8, 55.5,
40.1, 30.5; LCMS (ES) m/z 317.1 [M + H]+; HRMS (ESI/Orbitrap)
m/z [M + H]+ calcd for C22H21O2, 317.1536, found 317.1537.
1-(4-Methoxyphenyl)-3-phenylpropan-1-one (3n). Following a
200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude product was
purified by flash column chromatography using a gradient of ethyl
acetate and petroleum ether (ratio = 10:90) to afford the title product
3-(4-Fluorophenyl)-1-(4-methoxyphenyl)propan-1-one (3s). Fol-
lowing a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude
product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 10:90) to afford
the title product as a white solid (291 mg, yield: 92%): 1H NMR (400
MHz, chloroform-d) δ 7.95 (d, J = 8.8 Hz, 2H), 7.21 (dd, J = 8.4, 5.5
Hz, 2H), 7.04−6.88 (m, 4H), 3.88 (s, 3H), 3.29−3.19 (m, 2H),
3.10−2.99 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.6,
163.5, 161.8 (d, JC−F = 242 Hz), 137.1 (d, JC−F = 3 Hz), 130.3, 129.9,
129.8 (d, JC−F = 7 Hz), 115.2 (d, JC−F = 21 Hz), 113.8, 55.5, 40.1,
29.5; LCMS (ES) m/z 259.1 [M + H]+; HRMS (ESI/Orbitrap) m/z
[M + H]+ calcd for C16H16FO2 259.1129, found 259.1139.
3-(4-Chlorophenyl)-1-(4-methoxyphenyl)propan-1-one (3t). Fol-
lowing a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude
product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 10:90) to afford
the title product as an off-white solid (311 mg, yield: 93%): 1H NMR
(400 MHz, chloroform-d) δ 7.99−7.92 (m, 2H), 7.31−7.24 (m, 2H),
7.23−7.17 (m, 2H), 6.99−6.90 (m, 2H), 3.89 (s, 3H), 3.29−3.21 (m,
2H), 3.10−3.01 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.4,
163.5, 139.9, 131.8, 130.3, 129.8, 128.6, 113.8, 55.5, 39.8, 29.6; LCMS
(ES) m/z 275.0 [M + H]+; HRMS (ESI/Orbitrap) m/z [M + H]+
calcd for C16H16ClO2 275.0833, found 275.0829.
1
as an off-white solid (269 mg, yield: 92%): H NMR (400 MHz,
chloroform-d) δ 7.98 (d, J = 7.3 Hz, 2H), 7.62−7.54 (m, 1H), 7.52−
7.44 (m, 2H), 7.20 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 3.81
(s, 3H), 3.34−3.26 (m, 2H), 3.08−3.00 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 199.4, 158.0, 136.9, 133.3, 133.0, 129.3, 128.6,
128.0, 114.0, 55.3, 40.7, 29.3; LCMS (ES) m/z 241.3 [M + H]+;
HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for C16H17O2 241.1223,
found 241.1228.
3-(4-Bromophenyl)-1-(4-methoxyphenyl)propan-1-one (3u).
Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude
product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 10:90) to afford
the title product as an off-white solid (332 mg, yield: 85%): 1H NMR
(400 MHz, chloroform-d) δ 7.86−7.79 (m, 2H), 7.63−7.58 (m, 2H),
7.20−7.15 (m, 2H), 6.89−6.83 (m, 2H), 3.81 (s, 3H), 3.28−3.21 (m,
2H), 3.05−2.99 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.3,
158.1, 135.6, 133.1, 131.9, 129.6, 129.3, 128.2, 114.0, 55.3, 40.7, 29.2;
1-(4-Methoxyphenyl)-3-(o-tolyl)propan-1-one (3o). Following a
200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude product was
purified by flash column chromatography using a gradient of ethyl
acetate and petroleum ether (ratio = 10:90) to afford the title product
1
as an off-white solid (279 mg, yield: 90%): H NMR (400 MHz,
chloroform-d) δ 8.00−7.93 (m, 2H), 7.23−7.10 (m, 4H), 6.97−6.90
(m, 2H), 3.88 (s, 3H), 3.25−3.17 (m, 2H), 3.09−3.01 (m, 2H), 2.36
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.0, 163.5, 139.6,
136.0, 130.3, 130.0, 128.7, 126.3, 126.2, 113.8, 55.5, 38.8, 27.7, 19.4;
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LCMS (ES) m/z 320.1 [M + H]+; HRMS (ESI/Orbitrap) m/z [M +
H]+ calcd for C16H16BrO2 319.0328, found 319.0329.
δ 157.9, 143.7, 134.4, 133.4, 129.3, 129.2, 129.2, 128.1, 113.9, 55.2,
40.5, 29.3, 21.6; LCMS (ES) m/z 255.3 [M + H]+; HRMS (ESI/
Orbitrap) m/z [M + H]+ calcd for C17H19O2 255.1380, found
255.1386.
3-(4-Iodophenyl)-1-(4-methoxyphenyl)propan-1-one (3v). Fol-
lowing a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude
product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 10:90) to afford
the title product as an off-white solid (382 mg, yield: 86%): 1H NMR
(400 MHz, chloroform-d) δ 7.96−7.91 (m, 2H), 7.64−7.59 (m, 2H),
7.04−7.00 (m, 2H), 6.96−6.91 (m, 2H), 3.89 (s., 3H), 3.26−3.21 (m,
2H), 3.04−2.99 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.3,
163.5, 141.1, 137.4, 130.5, 130.2, 129.8, 113.7, 91.0, 55.4, 39.6, 29.6;
LCMS (ES) m/z 367.1 [M + H]+; HRMS (ESI/Orbitrap) m/z [M +
H]+ calcd for C16H16IO2 367.0189, found 367.0191.
3-(3-Chlorophenyl)-1-(4-methoxyphenyl)propan-1-one (3w).
Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude
product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 10:90) to afford
the title product as an off-white solid (304 mg, yield: 91%): 1H NMR
(400 MHz, chloroform-d) δ 8.01−7.92 (m, 2H), 7.28−7.25 (m, 1H),
7.25−7.14 (m, 3H), 6.99−6.93 (m, 2H), 3.89 (s, 3H), 3.30−3.23 (m,
2H), 3.11−3.01 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.3,
163.6, 143.5, 134.2, 130.3, 130.2, 129.8, 129.8, 128.6, 126.7, 126.3,
113.8, 113.8, 113.7, 55.5, 39.7, 29.9; LCMS (ES) m/z 275.2 [M +
H]+; HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for C16H16ClO2
275.0833, found 275.0833.
3-(3-Bromophenyl)-1-(4-methoxyphenyl)propan-1-one (3x). Fol-
lowing a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude
product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 10:90) to afford
the title product as an off-white solid (341 mg, yield: 88%): 1H NMR
(400 MHz, chloroform-d) δ 8.00−7.92 (m, 2H), 7.46−7.40 (m, 1H),
7.35 (dt, J = 7.3, 1.9 Hz, 1H), 7.23−7.15 (m, 2H), 6.98−6.92 (m,
2H), 3.89 (s, 3H), 3.29−3.22 (m, 2H), 3.14−2.97 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 197.3, 163.6, 143.9, 131.5, 130.5, 130.2,
129.8, 129.2, 128.5, 127.2, 122.5, 113.8, 55.5, 39.7, 29.8; LCMS (ES)
m/z 321.0 [M + H]+; HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for
C16H16BrO2 319.0328, found 319.0323.
3-(2-Fluoro-5-methoxyphenyl)-1-(4-methoxyphenyl)propan-1-
one (3y). Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction,
the crude product was purified by flash column chromatography using
a gradient of ethyl acetate and petroleum ether (ratio = 15:85) to
afford the title product as an off-white solid (282 mg, yield: 80%): 1H
NMR (400 MHz, chloroform-d) δ 7.99−7.91 (m, 2H), 6.99−6.91
(m, 3H), 6.80 (dd, J = 6.1, 3.2 Hz, 1H), 6.70 (dt, J = 8.9, 3.5 Hz, 1H),
3.88 (s, 3H), 3.78 (s, 3H), 3.28−3.22 (m, 2H), 3.09−3.01 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 197.5, 163.5, 155.6, 154.1 (d,
1-(4-Bromophenyl)-3-(4-methoxyphenyl)propan-1-one (3ac).
Following a 200.0 mg (1.0 mmol, 1 equiv) scale reaction, the crude
product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 10:90) to afford
the title product as an off-white solid (271 mg, yield: 90%): 1H NMR
(400 MHz, chloroform-d) δ 7.98−7.91 (m, 2H), 7.42 (dd, J = 8.2, 1.8
Hz, 2H), 7.17−7.11 (m, 2H), 6.94 (dd, J = 8.7, 1.8 Hz, 2H), 3.90 (s,
3H), 3.28−3.19 (m, 2H), 3.07−2.99 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ 197.4, 163.5, 140.5, 131.5, 130.3, 130.3, 129.8, 128.6,
119.8, 113.8, 55.5, 39.7, 29.6; LCMS (ES) m/z 321.0 [M + H]+;
HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for C16H16BrO2
319.0328, found 319.0329.
1-(3,4-Difluorophenyl)-3-(4-methoxyphenyl)propan-1-one
(3ad). Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the
crude product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 10:90) to afford
the title product as an off-white solid (247 mg, yield: 76%): 1H NMR
(400 MHz, chloroform-d) δ 7.83−7.76 (m, 1H), 7.76−7.70 (m, 1H),
7.30−7.20 (m, 1H), 7.19−7.14 (m, 2H), 6.89−6.83 (m, 2H), 3.80 (s,
3H), 3.26−3.20 (m, 2H), 3.05−2.98 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ 196.7, 158.0, 153.4 (dd, JC−F = 155, 13 Hz), 150.2
(dd, JC−F = 149, 13 Hz), 133.9 (d, JC−F = 8 Hz), 132.8, 129.2, 124.9
(dd, JC−F = 11, 3 Hz), 117.4 (d, JC−F = 14 Hz), 117.2 (d, JC−F = 12
Hz), 114.0, 55.2, 40.5, 29.1; LCMS (ES) m/z 277.2 [M + H]+;
HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for C16H15F2O2
277.1035, found 277.1038.
1-(3-Chloro-4-methoxyphenyl)-3-(4-methoxyphenyl)propan-1-
one (3ae). Following a 200.0 mg (1.0 mmol, 1 equiv) scale reaction,
the crude product was purified by flash column chromatography using
a gradient of ethyl acetate and petroleum ether (ratio = 15:85) to
afford the title product as an off-white solid (282 mg, yield: 92%): 1H
NMR (400 MHz, chloroform-d) δ 7.99 (s, 1H), 7.90−7.84 (m, 1H),
7.17 (d, J = 8.8 Hz, 2H), 6.99−6.93 (m, 1H), 6.88−6.80 (m, 2H),
3.97 (s, 3H), 3.82 (s, 3H), 3.24−3.16 (m, 2H), 3.05−2.96 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 197.0, 158.7, 158.0, 133.2,
130.6, 129.3, 128.4, 122.9, 114.0, 111.3, 56.4, 55.3, 40.4, 29.3; LCMS
(ES) m/z 305.2 [M + H]+; HRMS (ESI/Orbitrap) m/z [M + H]+
calcd for C17H18ClO3 305.0939, found 305.0940.
1-Cyclohexyl-3-(4-methoxyphenyl)propan-1-one (3af). Follow-
ing a 200.0 mg (1.4 mmol, 1 equiv) scale reaction, the crude product
was purified by flash column chromatography using a gradient of ethyl
acetate and petroleum ether (ratio = 10:90) to afford the title product
as a colorless oil (302 mg, yield: 86%): 1H NMR (400 MHz,
chloroform-d) δ 7.15−7.09 (m, 2H), 6.88−6.81 (m, 2H), 3.80 (s,
3H), 2.88−2.80 (m, 2H), 2.78−2.71 (m, 2H), 2.37−2.27 (m, 1H),
1.87−1.74 (m, 4H), 1.71−1.60 (m, 1H), 1.39−1.13 (m, 5H);
13C{1H} NMR (100 MHz, CDCl3) δ 213.3, 158.0, 133.5, 129.3,
113.9, 55.3, 51.0, 42.5, 28.9, 28.4, 25.9, 25.7; LCMS (ES) m/z 247.1
[M + H]+; HRMS (ESI/Orbitrap) m/z [M + Na]+ calcd for
C16H22NaO2 269.1512, found 269.1515.
JC−F = 153 Hz), 130.3, 129.9, 129.0 (d, JC−F = 23 Hz), 115.9 (d, JC−F
= 6 Hz), 115.6 (d, JC−F = 32 Hz), 113.7, 112.5 (d, JC−F = 11 Hz),
55.7, 55.4, 38.5, 24.5, LCMS (ES) m/z 289.3 [M + H]+; HRMS
(ESI/Orbitrap) m/z [M + H]+ calcd for C17H18FO3 289.1234, found
289.1239.
3-(4-Methoxyphenyl)-1-phenylpropan-1-one (3aa). Following a
200.0 mg (1.5 mmol, 1 equiv) scale reaction, the crude product was
purified by flash column chromatography using a gradient of ethyl
acetate and petroleum ether (ratio = 10:90) to afford the title product
4-(3,4-Dimethoxyphenyl)-1-phenylbutan-2-one (3ag). Following
a 200.0 mg (1.4 mmol, 1 equiv) scale reaction, the crude product was
purified by flash column chromatography using a gradient of ethyl
acetate and petroleum ether (ratio = 15:85) to afford the title product
1
as an off-white solid (326 mg, yield: 91%): H NMR (400 MHz,
chloroform-d) δ 7.98 (d, J = 7.3 Hz, 2H), 7.34−7.20 (m, 5H), 6.92
(d, J = 8.5 Hz, 2H), 3.81 (s, 3H), 3.34−3.26 (m, 2H), 3.08−3.00 (m,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.4, 158.0, 136.9, 133.3,
133.0, 129.3 128.6, 128.0, 113.7, 114.0, 55.3, 40.7, 29.3; LCMS (ES)
m/z 241.1 [M + H]+; HRMS (ESI/Orbitrap) m/z [M]+ calcd for
C16H16O2 240.1223, found 240.1230.
3-(4-Methoxyphenyl)-1-(p-tolyl)propan-1-one (3ab). Following a
200.0 mg (1.4 mmol, 1 equiv) scale reaction, the crude product was
purified by flash column chromatography using a gradient of ethyl
acetate and petroleum ether (ratio = 10:90) to afford the title product
as a white solid (312 mg, yield: 91%): 1H NMR (400 MHz,
chloroform-d) δ 7.91−7.86 (m, 2H), 7.27 (d, J = 7.8 Hz, 2H), 7.22−
7.17 (m, 2H), 6.89−6.84 (m, 2H), 3.81 (s, 3H), 3.29−3.23 (m, 2H),
3.06−3.00 (m, 2H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
1
as an off-white solid (331 mg, yield: 86%): H NMR (400 MHz,
chloroform-d) δ 7.41−7.25 (m, 3H), 7.24−7.13 (m, 2H), 6.78 (d, J =
8.0 Hz, 1H), 6.73−6.64 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.68 (s,
2H), 2.91−2.81 (m, 2H), 2.81−2.74 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ 207.5, 148.9, 147.4, 134.1, 133.6, 129.4, 128.7, 127.0,
120.1, 111.8, 111.4, 56.0, 55.8, 50.4, 43.7, 29.5; LCMS (ES) m/z
285.1 [M + H]+; HRMS (ESI/Orbitrap) m/z [M + Na]+ calcd for
C18H20NaO3 307.1305, found 307.1313.
4-(3,4-Dimethoxyphenyl)-1-(p-tolyl)butan-2-one (3ah). Follow-
ing a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude product
was purified by flash column chromatography using a gradient of ethyl
acetate and petroleum ether (ratio = 20:80) to afford the title product
N
https://dx.doi.org/10.1021/acs.joc.0c00160
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
as a light yellow solid (324 mg, yield: 88%): H NMR (400 MHz,
chloroform-d) δ 7.18−7.11 (m, 2H), 7.10−7.04 (m, 2H), 6.82−6.75
(m, 1H), 6.72−6.64 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.64 (s, 2H),
2.87−2.80 (m, 2H), 2.80−2.72 (m, 2H), 2.35 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 207.8, 148.9, 147.4, 136.6, 133.7, 131.0, 129.4,
129.3, 120.1, 111.8, 111.4, 56.0, 55.8, 50.1, 43.6, 29.5, 21.0; LCMS
(ES) m/z 299.1 [M + H]+; HRMS (ESI/Orbitrap) m/z [M + Na]+
calcd for C19H22NaO3 321.1461, found 321.1470.
3-(3,6-Dihydro-2H-pyran-4-yl)-1-(4-methoxyphenyl)propan-1-
one (3bh). Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction,
the crude product was purified by flash column chromatography using
a gradient of ethyl acetate and petroleum ether (ratio = 20:80) to
afford the title product as an off-white solid (279 mg, yield: 93%): 1H
NMR (400 MHz, chloroform-d) δ 8.02−7.89 (m, 2H), 7.01−6.86
(m, 2H), 5.51−5.42 (m, 1H), 4.11 (d, J = 2.3, 4.5 Hz, 2H), 3.92 (s,
3H), 3.84−3.74 (m, 2H), 3.12−2.98 (m, 2H), 2.50−2.36 (m, 2H),
2.14−2.06 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.3,
163.5, 134.7, 130.3, 130.0, 120.0, 113.8, 65.5, 64.3, 55.5, 36.0, 35.9,
35.7, 35.5, 31.4, 28.7; LCMS (ES) m/z 247.1 [M + H]+; HRMS
(ESI/Orbitrap) m/z [M + H]+ calcd for C15H19O3 247.1329, found
247.1329.
Procedure for the Cross-Coupling of 5a with 2a. A mixture
containing vinyl ketone 5a (1 mmol, 1 equiv), 2a (2 mmol, 2 equiv),
Pd(OAc)2 (0.1 mmol, 0.1 equiv), Cu(OAc)2 (2 mmol, 2 equiv), and
DPPE (0.2 mmol, 0.2 equiv) in a solvent mixture (0.33 M solution) of
DMSO (2.5 mL) and water (0.5 mL) was stirred at 70 °C in an oil
bath for 2 h under open air. The reaction mixture was monitored by
TLC. After completion of the reaction, the mixture was partitioned
between ethyl acetate and water. The organic layer was washed with
water and brine solution, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure to get the crude product, which
was purified by flash column chromatography using a gradient of ethyl
acetate and petroleum ether (ratio = 15:85) to afford the product 3a
as an off-white solid (263 mg, 80%).
1,4-Bis(4-methoxyphenyl)butan-2-one (3ai). Following a 200.0
mg (1.1 mmol, 1 equiv) scale reaction, the crude product was purified
by flash column chromatography using a gradient of ethyl acetate and
petroleum ether (ratio = 15:85) to afford the title product as an off-
white solid (287 mg, yield: 90%): 1H NMR (400 MHz, chloroform-d)
δ 7.39−7.24 (m, 3H), 7.18 (d, J = 7.8 Hz, 2H), 6.78 (d, J = 8.0 Hz,
1H), 6.73−6.64 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.68 (s, 2H),
2.89−2.74 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 207.5,
148.9, 147.4, 134.1, 133.6, 129.4, 128.7, 127.0, 120.1, 111.8, 111.4,
56.0, 55.8, 50.4, 43.7, 29.5; LCMS (ES) m/z 285.1 [M + H]+; HRMS
(ESI/Orbitrap) m/z [M + Na]+ calcd for C18H20NaO3 307.1305,
found 307.1312.
1-(3,4-Dimethoxyphenyl)-6-phenylhexan-3-one (3aj). Following
a 200.0 mg (1.1 mmol, 1 equiv) scale reaction, the crude product was
purified by flash column chromatography using a gradient of ethyl
acetate and petroleum ether (ratio = 20:80) to afford the title product
1
as an off-white solid (306 mg, yield: 86%): H NMR (400 MHz,
chloroform-d) δ 7.34−7.27 (m, 2H), 7.24−7.15 (m, 3H), 6.83−6.78
(m, 1H), 6.77−6.71 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 2.90−2.83
(m, 2H), 2.75−2.68 (m, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.42 (t, J = 7.4
Hz, 2H), 1.99−1.88 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
209.9, 149.0, 147.5, 141.6, 133.8, 128.5, 128.4, 126.0, 120.2, 111.9,
111.5, 56.0, 55.9, 44.5, 42.2, 35.1, 29.4, 25.2; LCMS (ES) m/z 313.3
[M + H]+; HRMS (ESI/Orbitrap) m/z [M + Na]+ calcd for
C20H24NaO3 335.1618, found 335.1624.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c00160.
■
sı
1H NMR and 13C{1H} NMR spectra of new compounds
(E)-5-(4-Methoxyphenyl)-1-phenylpent-1-en-3-one (3ak). Fol-
lowing a 200.0 mg (1.3 mmol, 1 equiv) scale reaction, the crude
product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 15:85) to afford
the title product as an off-white solid (234 mg, yield: 70%): 1H NMR
(400 MHz, chloroform-d) δ 7.62−7.47 (m, 3H), 7.44−7.35 (m, 3H),
7.17 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.76 (s, 1H), 6.72
(s, 1H), 3.80 (s, 3H), 3.04−2.92 (m, 4H); 13C{1H} NMR (100 MHz,
CDCl3) δ 199.5, 158.0, 142.7, 140.1, 134.5, 133.2, 130.5, 129.3, 128.9,
128.3, 126.2, 114.0, 55.3, 42.7, 29.3; LCMS (ES) m/z 267.2 [M +
H]+; HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for C18H19O2
267.1380, found 267.1372.
3-(Cyclohex-1-en-1-yl)-1-(4-methoxyphenyl)propan-1-one (3bf).
Following a 200.0 mg (1.2 mmol, 1 equiv) scale reaction, the crude
product was purified by flash column chromatography using a
gradient of ethyl acetate and petroleum ether (ratio = 10:90) to afford
the title product as a white solid (251 mg, yield: 84%): 1H NMR (400
MHz, chloroform-d) δ 8.00−7.95 (m, 2H), 6.99−6.91 (m, 2H),
5.49−5.43 (m, 1H), 3.89 (s, 3H), 3.07−3.01 (m, 2H), 2.37 (t, J = 7.8
Hz, 2H), 2.04−1.96 (m, 4H), 1.69−1.54 (m, 4H); 13C{1H} NMR
(100 MHz, CDCl3) δ 198.9, 163.3, 136.7, 130.3, 130.2, 121.3, 113.7,
55.5, 36.8, 32.6, 28.5, 25.2, 22.9, 22.5; LCMS (ES) m/z 245.2 [M +
H]+; HRMS (ESI/Orbitrap) m/z [M + H]+ calcd for C16H21O2
245.1536, found 245.1530.
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Andivelu Ilangovan − Department of Chemistry, Bharathidasan
University, Palkalaiperur, Thiruchirapalli 620024, India;
orcid.org/0000-0001-7240-7166; Phone: +91-
9865436093; Email: ilangovan@bdu.ac.in
Murugaiah A. M. Subbaiah − Department of Chemistry,
Bharathidasan University, Palkalaiperur, Thiruchirapalli
620024, India; orcid.org/0000-0001-5707-966X;
Phone: +91-9731600213; Email: murugaiah.andappan@
syngeneintl.com
Author
Thangeswaran Ramar − Discovery Chemistry, BBRC, Syngene,
Bangalore 560099, India; Department of Chemistry,
Bharathidasan University, Palkalaiperur, Thiruchirapalli
620024, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c00160
1-(4-Methoxyphenyl)-3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-
propan-1-one (3bg). Following a 200.0 mg (1.2 mmol, 1 equiv) scale
reaction, the crude product was purified by flash column
chromatography using a gradient of ethyl acetate and petroleum
ether (ratio = 25:75) to afford the title product as a white solid (290
mg, yield: 79%): 1H NMR (400 MHz, chloroform-d) δ 8.00−7.94 (m,
2H), 6.98−6.93 (m, 2H), 5.41−5.37 (m, 1H), 4.06−3.99 (m, 4H),
3.89 (s, 3H), 3.11−3.03 (m, 2H), 2.55−2.39 (m, 2H), 2.32−2.22 (m,
4H), 1.84−1.77 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.5,
163.4, 136.5, 130.3, 130.0, 118.4, 113.7, 108.0, 64.4, 55.5, 36.6, 35.6,
31.5, 31.1, 27.9; LCMS (ES) m/z 303.2 [M + H]+; HRMS (ESI/
Orbitrap) m/z [M + H]+ calcd for C18H23O4 303.1591, found
303.1590.
Author Contributions
The manuscript was written through the contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors express deep gratitude to Sanjeev Sukumaran, Dr.
Anjan Chakrabarti, Dr. Sathya Sanker, Dr. Manickam
■
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https://dx.doi.org/10.1021/acs.joc.0c00160
J. Org. Chem. XXXX, XXX, XXX−XXX

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