“Haliranium Ion”-Induced Intermolecular Friedel-Crafts Alkylation in HFIP: Synthesis of β,β-Diaryl α-Halo carbonyl Compounds

Article abstract of DOI:10.1002/ejoc.202100823

Here reports a highly regio- and diastereoselective haliranium ion-induced intermolecular Friedel-Crafts reaction of α,β-unsaturated carbonyl compounds in HFIP. The operationally simple and mild method affords the synthetically useful β,β-diarylated α-hal

Full text of DOI:10.1002/ejoc.202100823

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: “Haliranium ion”-induced Intermolecular Friedel-Crafts Alkylation
in HFIP: Synthesis of β,β-Diaryl α-Halo carbonyl Compounds
Authors: Aditya Bhattacharya, Pushpendra mani Shukla, and Biswajit
Maji
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100823
Link to VoR: https://doi.org/10.1002/ejoc.202100823
01/2020

10.1002/ejoc.202100823
European Journal of Organic Chemistry
FULL PAPER
“Haliranium ion”-induced Intermolecular Friedel-Crafts Alkylation
in HFIP: Synthesis of β,β-Diaryl α-Halo carbonyl Compounds
Aditya Bhattacharya,[a] Pushpendra mani Shukla[a] and Biswajit Maji*[a]
[a]
Mr. Aditya Bhattacharya, Mr. Pushpendra mani Shukla, Dr. Biswajit Maji
Department of Chemistry
Indira Gandhi National Tribal University
Amarkantak, Anuppur-484886, India
E-mail: biswajit.maji@igntu.ac.in
Supporting information for this article is given via a link at the end of the document.
Abstract: Highly regio- and diastereoselective haliranium ion-
induced intermolecular Friedel-Crafts reaction of α,β-unsaturated
carbonyl compounds in HFIP is reported. The operationally
simple and mild method affords the synthetically useful β,β-
diarylated α-halo carbonyl compounds in good yields after a very
short reaction time. As an application, a few examples of β,β-
diarylated olefins are prepared in excellent yields. Based on the
experimental results and a qualitative study of 1D-NMR-
experiments, a plausible reaction mechanism is proposed.
by “haliranium ion” intermediate has been reported by Hajra
Group (Scheme 1c).[13]
Ar
X+
(a)
Ar
"haliranium ion"
(Intra- and inter-)
X
P
Intramolecular
P
Q
Q
P
BA
Ar
Q
X
or
Ar
Ar
LA
OX
(b)
XB
X+
X
Introduction
P = CH2, O, NR
Q = O; X = Br, I, etc.
LA = Lewis acid, BA = Brønsted acid
XB = Halogen-Bonding cat, OX = Oxidant
The Friedel-Crafts alkylation—an old textbook reaction has
recently become one of the leading chemical transformations for
aromatic compounds.[1,2] Owing to the outmost importance of
arene-alkylated products in numerous areas of science, a wide
variety of contemporary electrophilic alkylating agents alongside
with novel catalyst/reagent systems have been employed.[2]
Particularly, the Friedel-Crafts alkylation with reactive alkylating
species three-membered “haliranium ion”-generated in situ from
alkene, provided halo-functionalized arene alkylated products
(Scheme 1a).[3] These halo-functionalized compounds can
further be transferred to non-halogen-functionalized products
which often helpful to construct the desired molecules in total
synthesis.[4] The seminal works by Finch[5[ and Barluenga[6] and
subsequently, numerous reports on intramolecular-type arene-
alkene cyclization via in situ generated “haliranium ion”
intermediate have been successfully accomplished.[7] A wide
variety of halogenating sources and catalytic conditions/reagent
systems were successfully employed to achieve the desired
Intermolecular: Single report
via
Ar
LA
R
O
N
O
NBS
Ar1
(c)
Ar
Sm(OTf)3
Br
R
Ar1
CH3CN, MS 4
Å
R = COAr, CO2R
Br
Only Br-functionalization
In the presence of Lewis acid and additive
This work:
Ar
R
NXS
via substrate and
NXS activation
by hydrogen bonding
Ar1
Ar
(d)
HFIP
R
Ar1
X
X = Br, I
R = COAr, CO2R
Metal- and oxidant-free
Short reaction time (<5-10 min)
Additive-free
Scheme 1. Existing and current approaches for the “haliranium ion”-triggered
Friedel-Crafts alkylation reaction.
halo-functionalized
annulated
arene
heterocycles
and
In other means, judging by the recent development, the
Friedel-Crafts reactions promoted by the unique fluorinated
carbocycles (Scheme 1b). Moreover, most of these developed
methods truly suffer by the use of excess reagents/catalysts
including oxidants. In addition, over halogenation to the arene
part or poor diastereo-selectivity in the arene-alkylated products,
and long reaction time including generality of the substrates
scope are another challenge. In a logical extension of the
intramolecular-version of Friedel-Crafts alkylation, the polyene
cyclizations triggered by haliranium ion intermediates have been
also executed for the synthesis of complex halogenated-
polycyclic scaffolds. Ishihara,[8] Snyder,[9] Yamamoto,[10]
Gulder[11] and Hennecke[12[ groups, individually, described the
stereoselective polyene cyclizations noticeably using various
novel reagents/catalytic systems. In contrast, a single report on
the intermolecular version of Friedel-Crafts alkylation triggered
solvent
[TFE
(2,2,2-trifluoroethanol)/HFIP
(1,1,1,3,3,3-
hexafluoro-2-propanol)] have gained a substantial interest.[14] In
HFIP, Mayr,[15] Paquin,[16] Khaledi,[17[ Xiao[18] and Moran[19]
groups reported the Friedel-Crafts benzylations to access 1,1-
diarylalkanes or Polyarylated alkanes without using any
externally added catalyst. However, Moran employed a catalytic
amount of triflic acid in HFIP to activate electronically
deactivated benzyl alcohols. Both inter- and intramolecular
Friedel-Crafts acylations in HFIP, have been disclosed by Aubé
group at room temperature.[20] The stable three-membered
epoxide can also be utilized as an alkylating agent by Mayr and
Qu groups, in TFE and HFIP, respectively.[21] Later, the Qu
group established
a polyene cyclization in HFIP/Ph4PBF4
(additive), initiated by epoxide and terminated by arene-π-
1
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10.1002/ejoc.202100823
European Journal of Organic Chemistry
FULL PAPER
nucleophiles.[21c] Even, an another class of SN1-type reactions
including polyene cyclization activating by π-activated alcohols
were successfully realized by Shao & Xiao,[22] Baeza & Nájera[23]
and Qu[24] groups, independently, in TFE or HFIP. Further, Chi[25]
and MacMillan[26] groups, individually, described Friedel-Crafts
alkylation of indoles with oxyallyl cations generated in situ from
α-haloketones and α-tosyloxyketones, respectively, in TFE. In
addition, nitroalkenes can also be realized as effective
electrophiles for Friedel-Crafts alkylations.[27] Furthermore, the
polyene cyclizations in HFIP triggered by alkene-derived
haliranium ion and thiiranium ion intermediates have also been
demonstrated, independently, by Gulder[11] and Denmark[28]
research groups, respectively. Indeed, the use of fluorinated
solvents (TFE/HFIP) in these established methods is significant
to increase the substrate reactivity and manage a high level of
stereoselectivity and yield in the products. A weak non-covalent
hydrogen-bonding cluster between HFIP and Lewis basic center
present in the substrate/reagent/catalyst and stability of the
reactive cationic species is responsible to achieve this excellent
reactivity and selectivity. Compared to intramolecular versions of
Table 1. Optimization of the reaction conditions.[a]
OMe
MeO
O
O
MeO
MeO
MeO
MeO
Br
3a
Me
Me
1a
[Br+]-source
Solvent, °C, t
OMe
OMe
OMe
OMe
O
Br
2a
MeO
Br
Br
4a
MeO
Me
Entry
1
[Br+]-Source
(equiv)
Solvent
Time
(min.)
Temp.
(°C)
Yield of
3a:4a (%)[b]
(ratio)[c]
NBS(1.5)
HFIP
<5
25
38 (5:1)
2
NBS (1.5)
DCM/HFIP
Toluene/HFIP
ACN/HFIP
DCM/HFIP
Toluene/HFIP
DCM/HFIP
HFIP
30
25
25
25
0
31 (5:1)[d]
18 (5:1)[d]
<5
3
NBS (1.5)
30
haliranium
ion-induced
Friedel-Crafts
alkylations,
the
intermolecular version is generally less experienced, regardless
the high potency of halo-functionalized products. In fact, the
assemble of three separate molecular units (alkene, arene and
halogen source) to access arene-alkylated products is extremely
challenging and the reason by other competitive side reactions
such as arene halogenation, dibromo formation of alkene, over
halogenation in the Friedel-Crafts alkylated products etc. Thus,
keeping this in mind and our own interest towards the Friedel-
Crafts reactions,[29, 3] we report herein, a mild and efficient metal-,
additive- and oxidant-free intermolecular Friedel-Crafts alkylation
with chalcone and ester substrates using a simple inexpensive
and commercially available N-halosuccinimide (NXS) as the
halogenating agent in HFIP (Scheme 1d).
4
NBS (1.5)
10
5
NBS (1.5)
60
36 (5:1)[d]
27 (5:1)[d]
NR
6
NBS (1.5)
60
0
7
NBS (1.5)
120
<5
<5
<5
<5
60
-20
0
8
NBS (1.5)
NBS (1.05)
NBS (1.05)
NBS (1.05)
NBA (1.05)
NBP (1.05)
DBDMH (1.05)
DBDMH (0.65)
DBDMH (2.0)
NBS (1.05)
NBS (1.05)
NBS (1.05)
NBS (1.05)
69 (>10:1)
73 (>30:1)
43 (>30:1)
Trace
9
HFIP
0
10[e]
11[f]
12
13
14
15
16
17
18
19
20[g]
HFIP
0
HFIP
0
HFIP
0
15 (ND)
20 (ND)
48 (1:1)
33 (3:1)
69 (1:>99)
18
HFIP
60
0
HFIP
<5
<5
<5
60
0
HFIP
0
Results and Discussion
HFIP
0
At the outset, we studied the Friedel-Crafts alkylation of 1,2-
dimethoxybenzene 2a (1.5 equiv) with chalcone substrate 1a
(1.0 equiv) in the presence of N-bromosuccinimide (1.5 equiv)
as a brominating reagent in HFIP (Table 1). The desired Friedel-
Crafts alkylated product, α-bromo β,β-diaryl carbonyl compound
3a, was obtained in 38% yield along with non-separable
aromatic ring-bromination of β,β-diaryl-α-bromo-carbonyl
compound 4a in a 5:1 ratio (Entry 1). In addition, chalcone
related undesired compounds and ring-bromination of 1,2-
dimethoxybenzebne were also observed in a minor amount.
Most significantly, the reaction reached its full conversion,
instantaneously, after just final addition of NBS. We envisaged
that the high reactivity of the reaction might be controlled either
by using HFIP as an additive along with other appropriate
solvent or simply by lowering the temperature of the reaction.
Thus we explored with a variety of reaction conditions such as
the use of binary solvent mixture DCM/HFIP, acetonitrile/HFIP
and toluene/HFIP ~ 1:1 (v/v) at different temperatures (Entries 2-
7). Although, the reaction temperature maintained at both 25°C
and 0°C, the chalcone substrate 2a in solvent mixture
DCM/HFIP and Toluene/HFIP, completely consumed after 30
min, the yield of the desired compound 3a was not further
TFE
0
PFTB
180
180
180
0
Trace
HFIPMe
DCM
0
No Reaction
Trace
25
[a] Condition: 1a (0.18 mmol), 2a (0.27 mmol), [Br+]-source (1.5/1.05 equiv as
mentioned) and solvent concentration (0.5 mL, 0.35 M); [b] Isolated yield; [c]
Ratio was determined from 1H NMR; [d] In a mixed solvents, a substantial
amount of a mixture of dibromo-, bromohydrin and some uncharacterized
products of corresponding chalcone 1a and arene bromination of 2a was
obtained (30-40%), where in neat HFIP, the amount is less (<15%); [e]
-
Additive Ph4+BF4 (1.0 equiv) was used; [f] Morpholine was added (1.0 equiv);
[g] XB catalyst (I & II) used in 20 mol%. DCM = 1,2-Dichloromethane, ACN =
Acetonitrile, NBS = N-Bromosuccinimide, NBA = N-Bromoacetamide, NBP =
N-Bromophthalimide, DBDMH = 1,3-Dibromo-5,5-dimethylhydantoin, HFIP =
Hexafluoro-2-propanol, TFE = Trifluoroethanol, PFTB = Perfluoro-tert-butanol,
HFIPMe = O-Methylhexafluoroisopropanol, NR = No Reaction, ND = Not
Determined.
N
N
Oct
N
N
I
Oct
F3C
I
OTf
OTf
F3C
XB-II
XB-I
2
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10.1002/ejoc.202100823
European Journal of Organic Chemistry
FULL PAPER
improved (Entries 2-3 and 5-6). Again, the reaction in a solvent
mixture acetonitrile/HFIP at 0°C afforded the mixture of dibromo-,
halohydrin and other undesired and uncharacterized products of
corresponding chalcone 1a was obtained (Entry 4). It is worth to
mention that the reaction in the presence of catalytic amount of
HFIP (10 mol%) or using 1.0 equiv. of HFIP in DCM also studied,
a very low yield of the product 3a was observed (10 mol% HFIP:
<5%; 1.0 equiv HFIP: 12%). The reaction at further low
temperature i.e. -20°C, no reaction took place might be due to
low nucleophilicity of arene. The starting substrate 1a was fully
recovered (Entry 7). With these results, we next performed the
reaction in neat HFIP at 0°C. Gratifyingly, the desired α-bromo-
functionalized-β,β-diarylcarbonyl compound 3a was isolated as a
major one (3a:4a = ~10:1) in a good yield of 69%, as a single
diastereoisomer (Entry 8). Next, by lowering the amount of NBS
with slightly excess of stoichiometric amount i.e. 1.05 equiv, the
formation of over ring-brominated Friedel-Crafts alkylated
product i.e. 4a almost prohibited and the desired product 3a was
obtained in 73% yield (3a:4a = >30:1, entry 9). Furthermore, the
Ar
R
R
NBS (1.05 equiv)
Ar1
Ar
2
Ar1
Br
°
HFIP, 0 C
<5 min
1
3
OMe
OMe
OMe
MeO
MeO
O
O
MeO
O
MeO
MeO
MeO
MeO
MeO
Br
Br
Br
3c, 60%
OMe
Me MeO
Me
Me
3a, 73%
3b, 70%
OMe
MeO
MeO
MeO
MeO
O
Br
O
O
MeO
MeO
MeO
MeO
MeO
Br
Me
Br
Br
3d, 51%
MeO
OMe
Me
3e, 63%
3f, 78%
OMe
MeO
OMe
OMe
O
O
additive effect using Ph4 BF4 (1.0 equiv)[22] and morpholine (1.0
equiv)[11] also tested for the same set of reaction in HFIP solvent
at 0°C, but not as such improvement of the yield of 3a was
observed (Entries 10 and 11). Continued searching to increase
the yield of 3a, other various brominating reagents such as NBA
(N-bromoacetamide), NBP (N-bromophthalimide) and more
reactive DBDMH (1,3-dibromo-5,5-dimethylhydantoin) were also
examined. Both NBA and NBP furnished the desired product in
low yields, 15% and 20%, respectively (Entries 12 and 13),
whereas, the brominating agent DBDMH (1.2 equiv) afforded a
mixture of 3a and 4a in almost ~1:1 ratio with 48% yield (Entry
14). Interestingly, even with the use of DBDMH in a less than
stoichiometric amount (0.65 equiv), the formation of 4a could not
be controlled; a mixture of 3a and 4a obtained in 33% with a 3:1
ratio and noticeably, the alkene substrate 1a was not fully
consumed (Entry 15). However, the use of 2.0 equiv of DBDMH,
the chalcone substrate 1a fully converted and afforded,
exclusively, the ring-brominated Friedel-Crafts alkylated product,
4a in a good yield of 69% in less than 5 min at 0°C (entry 16).
On the other hand, the possibility in other fluorinated solvents
such as trifluoroethanol (TFE), perfluoro-tert-butanol (PFTB) by
substituting the HFIP was also evaluated, albeit, the results were
not satisfactory (entries 17-18). In TFE solvent, only 18% of 3a
was isolated at 0°C and in PFTB, a trace amount of desired
product 3a was observed even after 3 hours. It is significance
also to mention that unlike the Yeung’s observation, the same
set of reaction did not provide any product (3a/4a) in the
presence of halogen-bonding organocatalyst XB-(I) and XB-
(II).[7i] Finally, we set out the optimized reaction condition in HFIP
at 0°C in presence of NBS/DBDMH, separately, which afforded
+
-
Me
O
MeO
MeO
Br
MeO
MeO
MeO
OMe
R
Br
3i: R = H, 73%
3j: R = Me, 76%
3k: R = OMe, 75%
3l: R = Cl, 70%
OMe
Br
3g, 79%
OMe
O
3h, 52%
OMe
OMe
OMe
MeO
MeO
MeO
O
O
O
MeO
OMe
MeO
MeO
Me
OMe
OMe
MeO
Br
Br
Br
MeO
Br
3o, 65%
MeO
3p, 68%
3m, 58%
3n, 71%
Me
F3C
CF3
F3C
CF3
Me
Me
O
O
O
O
O
MeO
MeO
MeO
MeO
MeO
MeO
OMe
Br
5, (80-90%)
Br
3q, 86%*
OMe
Br
6, (76-88%)
OMe
°
0
C to rt, 10 min
°
0
C to rt, 20 min
* = inseparable mixture
of 3q and 5 with a 3:1 ratio
Scheme 2. Substrates scope with NBS.
bromo-1,2,3-trimethoxybenezene afforded the corresponding
desired products 3c and 3d with slightly in lower yields (60 and
51%, respectively).2-Methoxynaphthalene also furnished the
bromo-functionalized desired product 3e through its α-position in
a moderate yield, 63%. Next, the electronic tuning at the ketone-
aryl part in the chalcones was evaluated. In all the cases, the
Friedel-Crafts alkylated products were obtained (3f-3l) in a
moderate to good yields (52-79%). Even, the enone, 4-(4-
methoxy-phenyl)-but-3-en-2-one afforded the desired product
3m in 58% yield. Further, the ester substrates were checked to
this transformation and in each cases, the corresponding α-
bromo β,β-diaryl carbonyl compounds, esters 3n-3p were
obtained in a moderate to good yields (65-71%). Noticeably, the
regioselectivity of chalcones or cinnamate esters and arenes is
excellent (>99:1). The alkene-regioselectivity could be explained
by the fact that the benzylic position of the in situ generated
bromiranium ion intermediate is more electrophilic as δ+ charge
at the β-carbon center is stabilized by the conjugation of the aryl
ring. The arenes such as anisole, 1,2- dimethoxybenzene and
1,2,3- trimethoxybenezene exclusively afforded the para-
alkylated
the desired Friedel-Crafts product α-bromo β,β-diaryl carbonyl
׳
compound 3a and it s ring-brominated product 4a, in good yields
73% and 69%, respectively.
Then, we investigated the scope of the Friedel-Crafts alkylations
with a wide range of chalcone and a few ester substrates using
NBS and DBDMH as brominating reagents, separately (Scheme
2 and Scheme 3, respectively). The reactions between a variety
of electron-rich arene and chalcones/esters were examined
using NBS (1.05 equiv) which is depicted in Scheme 2. 1,2-
Dimethoxybenzene and anisole gave the desired products 3a
and 3b in good yields. Even, the more sterically demanding
arene substrates such as 1,2,3-trimethoxybenzene and 5-
3
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10.1002/ejoc.202100823
European Journal of Organic Chemistry
FULL PAPER
OMe
OMe
OMe
Ar Br
OMe
O
R
R
DBDMH (2.0 equiv)
Ar1
Ar
2
A or B
HFIP
Br
O
Br Ar1
Br
°
0 C
HFIP,
MeO
MeO
MeO
MeO
<5 min
1
4
Br
Br
Br
Me
Me
OMe
OMe
OMe
3a
4a
Br
A: NBS (2.1 equiv), 0
B: DBDMH (1.5 equiv), 0 C, 10 min. 87%
°
C, 30 min, 63%
OMe
O
Br
°
OMe
O
MeO
Br
O
MeO
MeO
MeO
Me MeO
Scheme 4. Bromine-rich Friedel-Crafts alkylated product synthesis.
Br
Br
Br
Br
Me
Br
4c, 55%
OMe
MeO
4b, 61%
4a, 69%
O
OMe
MeO
MeO
OMe
OMe
OMe
O
Br
OMe
O
Br
NBS (1.05 equiv)
HFIP
Me
OMe
Br
O
O
MeO
MeO
MeO
Br
Br
°
0 C, 5 min
Br
MeO
Br
Br
Br
4f, 60%
OMe
Br
Me
MeO
Cl
MeO
Me
Me
3a
(One-pot and sequential)
4d, 58%
4e, 66%
Not isolated
OMe
OMe
DBDMH
(1.5 equiv)
Br
OMe
OMe
O
Br
O
Br
O
4a
(69%)
Br
Br
4g, 60%
Br
4h, 63%
Br
4i, 35%
MeO
Me
Me
OMe
Scheme 5. One-pot and sequential reaction.
Scheme 3. Substrates scope with DBDMH.
It seems that the reaction in the presence of DBDMH (2.0
equiv), first, arene attacks to the in situ generated bromiranium-
products. In case of 1,2,3-trimethoxybenezene, it seems that the
electronic factor predominates over steric factor (3c).
ion intermediate to afford bromo-functionalized
alkylated
product 3 and next, the additional ring bromination at the
activated arene part affords bromo-enriched Friedel-Crafts
alkylated products 4. In order to check the sequence of the
transformation of 4, a few reactions including one-pot sequential
reactions were performed (Schemes 4 and 5). First, the isolated
α-bromo β,β-diaryl ketone product 3a was subjected to react
with NBS (2.1 equiv) and DBDMH (1.5 equiv), separately, in
HFIP, and both the brominating reagent gave the desired
bromo-enriched ketone product 4a in a good yields, 63% and
87%, respectively. Secondly, a tandem reaction that is initially,
the chalcone 1a was reacted with 1,2-dimethoxybenezene using
NBS (1.05 equiv) and next, after 5 minutes, additional DBDMH
(1.5 equiv) was added in the same flask, the ring-brominated
alkylated ketone product 4a obtained in 69%.
Encouraged by these results we ensured the scope of the
NIS-promoted Friedel-Crafts alkylations under the optimized
condition (Scheme 6). The desired β,β-diaryl-α-iodo-carbonyl
compound ketone or ester 7 were obtained in good to excellent
yields with excellent regio- and diastereoselectivities, regardless,
the reaction time (5 vs 30 min; Scheme 2 vs 6).
Furthermore, attempts have been made to the comparatively
less electronically activated arenes such as toluene, xylene and
including N-analogue of methoxybenzene i.e. N,N-dimethyl
aniline to this method. Unfortunately, none of these among
arenes was furnished the desired Friedel-Crafts alkylated
product in a substantial amount; a trace amount (<5%) product
was formed. In such cases, O-nucleophilic attack of HFIP to the
generated bromiranium ion intermediate was observed and
afforded 5 and 6 in a good to excellent range of yields (5: 80-
90%; 6: 76-88%). Heteroarenes such as indole and 1-
methylindoles also studied, a messy reaction mixture was
formed. However, the slightly higher activated arene i.e.
mesitylene participated to this transformation, albeit, an
inseparable (by column chromatography) mixture of desired
product 3q and 5 were obtained in 86% with a 3:1 ratio.
Next, the DBDMH-promoted Friedel-Crafts alkylation of a
variety of chalcone substrates with electron-rich arenes was
investigated. The result is illustrated in Scheme 3. The use of
DBDMH in 2.0 equivalents, the additional ring-brominated
Friedel-Crafts alkylated products (4a-4g) were obtained in good
yields. In comparison, a less activated aryl substituted chalcone
substrates i.e. 4-Me- and Ph- arene at the enone part also
subjected to optimized conditions and afford the desired
products 4h-4i in moderate yields (35-63%). Interestingly, the
additional ring bromination observed at the electron-rich arene
part only. However, the product 4c was not brominated in the
aromatic ring of the original chalcone (4-OMe substituted Ar). In
this example, highly activated arene 1,3,5-trimethoxybenzene
was used and a substantial amount of ring-brominated arene
product 2-bromo-1,3,5-trimethoxybenzene was observed.
Finally, the Friedel-Crafts alkylated products (3, 4 & 7) can
be used as a handle for further structural diversification as
desired and significant (Scheme 7). As
a representative
examples, the halo-functionalized carbonyl compounds 3a, 4f,
7a and 7e could easily be transformed to symmetrical β,β-
diarylated olefins 8a-8c in excellent yields (87-95%) in the
presence of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) in THF
under refluxing condition. Whereas, the unsymmetrical α-bromo
β,β-diaryl carbonyl compound 4h afforded the corresponding
alkene 8d with a mixture of diastereoisomers (Z:E
4
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10.1002/ejoc.202100823
European Journal of Organic Chemistry
FULL PAPER
Crousse et al first time realized the NBS-activation by HFIP
which can facilitate for regioselective arene halogenations and
which was confirmed by 1H-NMR study.[33] However, in our
method, three separate molecular units i.e. alkene (α,β-
Ar
R
R
NIS (1.05 equiv)
Ar1
Ar
2
Ar1
°
HFIP,
0
C
I
1
30 min
7
unsaturated carbonyl
compounds; chalcones or esters),
R = COAr, CO2R
electron-rich arenes and NXS are added together in HFIP to
afford Friedel-Crafts alkylated products. In order to understand
the potential hydrogen-bond interactions between–OH of HFIP
and Lewis basic centres present in all used reacting components
OMe
OMe
OMe
O
MeO
MeO
O
MeO
MeO
MeO
MeO
i.e. alkenes (chalcones), NXS (NBS) and
arene (1,2-
dimethoxybenzene), a few sets of NMR-experiments (1H- and
13C NMR) were performed (Figure 1-6). Initially, the 1H- and 13C-
NMR experiments with individual components (HFIP, chalcone
1a, arene 2a and brominating agent NBS) were recorded using
CDCl3 as NMR solvent. Next, the 1H- and 13C-NMR of binary
components i.e. HFIP and every single species (chalcone 1a,
arene 2a and NBS) were also recorded (see supporting
information for details) separately. The downfield shifting of –OH
protons in HFIP and carbonyl carbons of NBS confirms the
hydrogen-bonded interactions between the HFIP and
brominating agent NBS, which most probably helps to form in
situ generated three membered bromiranium-ion intermediates
from the corresponding alkenes. Similarly, the binary mixture of
HFIP and chalcone 1a, a distinct and a sharp downfield shifting
for –OH proton in HFIP and carbonyl carbon of chalcone
substrate 1a was observed; however, the alkene protons of 1a
appeared in a same δ-values [δ 7.75 and 7.39] in the absence or
presence of HFIP. Interestingly, the aryl protons in chalcone
substrate 1a, as designated in figure 3, resonated at slightly
higher δ-value i.e. δ 7.29 (in absence of HFIP) increased to δ
7.35 (in the presence of HFIP). This might be due to weak
interaction between CF3-groups in HFIP and meta-protons (with
respect to carbonyl group) in chalcone substrate 1a through
weak hydrogen-bonding-network. After the clinical analysis of
the 13C-NMR-spectra of a binary mixture between HFIP and
chalcone 1a (Figure 4), the downfield shifting of carbonyl carbon
(δ 191.20 and 195.30 vs 190.20) and the β-carbon (δ 145.37
and 148.60 vs 144.70) of α,β-unsaturated carbonyl compound
1a strongly exemplified by the significant interaction between
HFIP and chalcone 1a. Further, the 1H- and 13C-NMR-
experiments of a binary mixture of HFIP and arene 1,2-
dimethoxybenzene were carried out and the results indicate a
possible interaction between heteroatom oxygen in –OMe group
of 1,2-dimethoxybenzene and –OH in HFIP. We believe that
such interactions between HFIP and nucleophilic arene may
play some role for the high level of para-selectivity (arene-
regioisomers). These 1D-NMR-experiment results, particularly,
the strong interactions between a binary mixture of chalcone and
HFIP, lead us to think about the reaction mechanism. The
reaction proceeds either through a reactive haliranium ion
intermediate or by a Michael addition and followed by a
halogenation sequence. The alkenes utilized in this study were
not simple electron-rich olefins, rather α, β-unsaturated carbonyl
compounds by means of electrophilic Michael systems. An
electrophilic Michael system (chalcone or ester) readily forms
three member haliranium ion intermediate in the presence of an
electrophilic halogenating agent like NXS, it seems to be
unusual. To probe the more mechanistic insights, we conducted
a control reaction between alkene 1a and arene 2a without using
NBS in HFIP at 0°C, whether a 1,4-Michael addition product
formed or not (Scheme 8). The reaction did not provide any
I
I
Me
Me
7a, 75%
7b, 82%
OMe
OMe
OMe
MeO
MeO
O
O
O
MeO
MeO
OMe
OMe
I
I
I
MeO
Cl
MeO
7e, 68%
7d, 67%
7c, 80%
Scheme 6. NIS-promoted Friedel-Crafts alkylations.
Ar'
O
Ar'
O
R
DBU, THF
Ar
R
Ar
°
X
70 C
H
X = Br, I
R = COAr, CO2R
8
OMe
OMe
OMe
Br
O
O
MeO
MeO
Br
H
H
Me
MeO
Me
8a, 91%
3a (X = Br)
7a (X = I)
4f (X = Br)
OMe
8b, 92%
8a, 95%
OMe
OMe
Br
O
O
OMe
H
MeO
Me
H
Z:E = 6:1
4h (X = Br)
MeO
7e (X = I)
8c, 87%
8d, 93%
Scheme 7. Applications towards the synthesis of β,β-diarylated olefins.
= 6:1). These β,β-diarylated olefins (8a-8d) were mostly be
prepared by Pd-catalyzed Matsuda−Heck Reactions.[30]
It has been proven that HFIP activates the carbonyl group
(C=O) of the various carbonyl compounds by establishing the
hydrogen-bond-network. In general, several most reactive
carbonyl compounds such as acid chloride (Friedel-Crafts
acylation and thioesterification),[20] azadicarboxylate (arene
amination),[31] o- aminobenzaldehyde derivatives (Tert-amino
effect/1,5-H-transfer reaction),[32]
N-halosuccinimide (arene
halogenation,[33] polyene-cyclization[11]), and other carbonyl
substrates[34] have been successfully employed. The significant
role of HFIP in these reactions has also been demonstrated by
taking into account the results of Nuclear Magnetic Resonance
(NMR)-experiments.
5
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10.1002/ejoc.202100823
European Journal of Organic Chemistry
FULL PAPER
Figure 1: 1H-NMR experiment of NBS & HFIP (400 MHz, CDCl3)
Figure 2: 13C-NMR experiment of NBS & HFIP (100 MHz, CDCl3)
(NBS + HFIP = 1:10)
C=O
(NBS + HFIP = 1:10)
Ha
d
3.68
d 176.1
O
O
N
O
N
O
Br
Br
d 173.2
C=O
F3C
F3C
F3C
Hb:
d
4.39
OHa
Hb
OHa
Hb
Ha
d
3.15
F3C
Figure 3: 1H-NMR experiment of 1a & HFIP (400 MHz, CDCl3)
(1a:HFIP = 1:10)
Figure 4: 13C-NMR experiment of 1a & HFIP (100 MHz, CDCl3)
(1a:HFIP = 1:10)
C
148.6
d
b
d 195.3
C=O
(1a:HFIP = 1:1)
Hd:
d
(1a:HFIP = 1:1)
5.33
191.2
d
C=O
Ha
O
Ha
O
C
144.7
1a
1a
d
b
MeO
He
MeO
MeO
He
d 190.2
C=O
Hb
Hb
Me
MeO
Me
He
He
1a
1a
Hc:
d
4.39
Hd: d
F3C
F3C
3.15
F3C
OHd
F3C Hc
OHd
Hc
Figure 5: 1H-NMR experiment of 2a & HFIP (400 MHz, CDCl3)
Figure 6: 13C-NMR experiment of 2a & HFIP (100 MHz, CDCl3)
(2a:HFIP = 1:5)
(2a:HFIP = 1:5)
H :
Hde
d
4.35
148.50
d
1
d 4.39
OCH3
OMe
1
c
4
149.03
1
d
2
120.90
d
OCH3
OMe
3
d
111.31
2
3
Ha
2a
2a
Hb
5
CF3
CF3
F3C
He:
d
4.39
F3C
He
6
Hd
d
3.15
OHd
OH
Figure 1-6. Qualitative 1D-NMR study to probe the reaction mechanism.
O
OMe
Michael-addition product, even after prolonged reaction time (3
h). This controlled experiment proves that the stated reaction
undoubtedly proceeds through three-membered non-isolable
haliranium ion intermediate.
MeO
MeO
OMe
HFIP
No Reaction
°
0 C, 3 h
1a
2a
Finally, based on the 1D-NMR-study, control experimental
observation and previous literatures,[11] a plausible reaction
mechanism is anticipated (Scheme 9). It seems that the overall
Scheme 8. Control experiment.
6
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10.1002/ejoc.202100823
European Journal of Organic Chemistry
FULL PAPER
Br
carried to insights more into the proposed reaction mechanism.
The reaction proceeds via a highly reactive three-membered
haliranium ion intermediate, a Friedel-Crafts-type alkylation.
Further, the importance of these halo-functionalized carbonyl
compounds can be exemplified towards the synthesis of β, β-
diarylated olefins.
O
O
N
N
Br
CF3
CF3
O
O
CF3
CF3
N
N
O
H
O
or
X
N
O
H
O
O
Br
N
X
O
Br
O
X = Br, I
OH
CF3
R
Ar1
O
H
CF3
1
F3C
CF3
R1
Ar1
R = COAr, CO2R
n(HFIP) OMe
Me
Experimental Section
O
(HFIP)n
OMe
CF3
CF3
2
O
H O
OMe
R
General reaction procedure I: “Bromiranium ion”-induced HFIP-
mediated Friedel-Crafts alkylations with chalcones and cinnamate esters:
preparation of 3.
CF3
H
O
or
N
O
O
d
H
R1
O
CF3
O
Ar1
X
Ar1
X
Br
R1 = OR, Ar
X = Br, I
To a stirred solution of chalcone or cinnamate ester 1 (1.0 equiv) in HFIP,
arene 2 (1.5 equiv) was added and cooled to 0 C and then NBS (1.05
N
CF3
CF3
N
°
O
H
O
N
n(HFIP)
O
equiv) was added and the reaction mixture was stirred at the same
temperature for 5-10 minutes. On completion, the reaction was quenched
with saturated aqueous Na2S2O3 solution. The resulting mixture was
extracted with dichloromethane and finally organic extract was washed
with brine solution. The organic extract was dried over Na2SO4 and the
solvent was evaporated under reduced pressure. The residue was then
subjected to purification by flash column chromatography using EtOAc
and petroleum-ether mixture as an eluent to yield the Friedel-Crafts
alkylated products 3.
OMe
Br
Br
OMe
O
OMe
R
N
N
OMe
R
O
(HFIP)n
Br
Br Ar1
Ar1
X
4
Br+
X
3
Scheme 9. Plausible reaction mechanism.
Spectral data of 3a-3q, 5 and 6
2-Bromo-3,3-bis(3,4-dimethoxyphenyl)-1-(p-tolyl)propan-1-one
(3a):
Prepared from (E)-3-(3,4-dimethoxyphenyl)-1-(p-tolyl)prop-2-en-1-one
(50 mg, 0.177 mmol, 1.0 equiv) and 1,2-dimethoxybenzene (0.27 mmol,
1.5 equiv) using general procedure I; White solid (65 mg, 73%); m.p. =
reaction is based on i) HFIP-promoted in situ generation of three
membered reactive haliranium ion intermediate from the
corresponding alkenes (chalcone or esters), and followed by ii)
electrophilic aromatic substitution reaction mechanism, affording
the halo-functionalized β,β-diarylcarbonyl compounds 3. The
three-member haliranium ion intermediate which probably
stabilized by the counter anion of HFIP or succinimide, can be
attacked by the electron-rich arene π-nucleophiles as similar in
Friedel-Crafts reactions. Finally, the re-aromatization of arene
ring successfully affords the β,β-diaryl α-halo carbonyl
compounds 3 (X = Br), 7 (X = I) by the loss of proton facilitated
by the conjugate base of HFIP. In case of halogen-rich product
formation using DBDMH (1.5 equiv) or NBS (2.1 equiv) as
brominating- agents, the Friedel-Crafts alkylated product 3
further attacks to the electrophiles Br+, affording the desired
bromo-enriched Friedel-Crafts alkylated products 4.
1
136-138 °C; Rf = 0.25 (25% EA/PE); H-NMR (CDCl3, 400 MHz): δ 7.85
(d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.2 Hz, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.89
(d, J = 8.8 Hz, 1H), 6.86 (s, 1H), 6.75-6.72 (m, 2H), 6.64 (d, J = 8.0 Hz,
1H), 5.79 (d, J = 11.6 Hz, 1H), 4.79 (d, J = 11.6 Hz, 1H), 3.90 (s, 3H),
3.86 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 2.40 (s, 3H); 13C-NMR (CDCl3,
100 MHz): δ 192.6, 149.0, 148.9, 148.2, 148.0, 144.9, 134.4, 133.7,
132.6, 129.7 (2C), 128.8 (2C), 120.3, 119.4, 112.3, 111.8, 111.3, 111.2,
56.1, 56.0, 55.9, 55.8, 52.9, 49.6, 21.8; HRMS (EI) calcd for C26H27BrO5,
523.0919 m/z (M+Na)+; Found, 523.0919 m/z.
2-Bromo-3-(3,4-dimethoxyphenyl)-3-(4-methoxyphenyl)-1-(p-tolyl)propan-
1-one (3b): Prepared from (E)-3-(3,4-dimethoxyphenyl)-1-(p-tolyl)prop-2-
en-1-one (50 mg, 0.177 mmol, 1.0 equiv) and anisole (0.27 mmol, 1.5
equiv) using general procedure I; White solid (62 mg, 70%); m.p. = 133-
135 °C; Rf = 0.25 (20% EA/PE); 1H-NMR (CDCl3, 400 MHz): δ 7.84 (d, J =
8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.99 (d, J =
8.4 Hz, 1H), 6.89-6.85 (m, 2H), 6.69 (d, J = 8.4 Hz, 2H), 5.81 (d, J = 11.6
Hz, 1H), 4.82 (d, J = 11.6 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.66 (s, 3H),
2.39 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 192.5, 158.5, 148.9, 148.1,
144.8, 134.6, 133.3, 132.5, 129.6 (2C), 128.9 (2C), 128.8 (2C), 120.2,
114.3 (2C), 112.3, 111.3, 56.1 (2C), 55.2, 52.6, 49.5, 21.8; HRMS (EI)
calcd for C25H25BrO4, 493.0813 m/z (M+Na)+; Found, 493.0812 m/z.
Conclusion
In a nutshell, a new protocol has been developed for halogen-
induced Friedel-Crafts alkylations in HFIP. The salient features
of this protocol is i) a very short reaction time and ii) a metal-,
oxidant- and additive-free method iii) a high diastereoselectivity
(>99:1) and regioselectivity (mostly, para-selective arene attack)
is maintained towards the synthesis of β,β-diaryl-α-halo carbonyl
compounds under mild reaction condition. In this protocol,
bromine-rich Friedel-Crafts alkylated products can also be
prepared by simple changing the halogenating reagents (NBS vs
DBDMH) under the same reaction conditions. More significantly,
the less reactive halogenating agent NIS also participated to this
method and successfully afforded iodo-functionalized β, β-diaryl
carbonyl compounds. Detailed mechanism investigations (a
qualitative 1D-NMR study and control experiments) have been
2-Bromo-3-(3,4-dimethoxyphenyl)-1-(p-tolyl)-3-(2,3,4-
trimethoxyphenyl)propan-1-one (3c): Prepared from (E)-3-(3,4-
dimethoxyphenyl)-1-(p-tolyl)prop-2-en-1-one (50 mg, 0.177 mmol, 1.0
equiv) and 1,2,3-trimethoxybenzene (0.27 mmol, 1.5 equiv) using general
°
procedure I; Off white solid (56 mg, 60%); m.p. = 68-70 C; Rf = 0.25
(35% EA/PE); 1H-NMR (CDCl3, 400 MHz): δ 7.88 (d, J = 8.0 Hz, 2H), 7.25
(d, J = 7.6 Hz, 2H), 6.98 (d, J = 4.0 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.45
(d, J = 8.8 Hz, 1H), 5.98 (d, J = 11.6 Hz, 1H), 5.06 (d, J = 11.6 Hz, 1H),
3.89 (s, 3H), 3.84 (s, 3H), 3.74 (s, 3H), 3.72 (s, 6H), 2.40 (s, 3H); 13C-
NMR (CDCl3, 100 MHz): δ 192.6, 152.8, 151.4, 148.7, 147.9, 144.6,
142.6, 134.4, 132.6, 129.6 (2C), 128.8 (2C), 127.9, 121.3, 120.7, 112.7,
7
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10.1002/ejoc.202100823
European Journal of Organic Chemistry
FULL PAPER
111.0, 107.0, 60.7, 60.6, 56.1, 55.9 (2C), 50.1, 47.7, 21.8; HRMS (EI)
calcd for C27H29BrO6, 553.1025 m/z (M+Na)+; Found, 553.1021 m/z.
129.8, 129.6, 128.4, 127.8, 120.7, 113.9 (2C), 112.5, 111.4, 111.0, 56.0,
55.8, 55.6, 55.4, 50.9, 50.6, 20.6; HRMS (EI) calcd for C26H27BrO5,
523.0919 m/z (M+Na)+; Found, 523.0916 m/z.
2-Bromo-3-(6-bromo-2,3,4-trimethoxyphenyl)-3-(3,4-dimethoxyphenyl)-1-
(p-tolyl)propan-1-one (3d): Prepared from (E)-3-(3,4-dimethoxyphenyl)-1-
(p-tolyl)prop-2-en-1-one (50 mg, 0.177 mmol, 1.0 equiv) and 5-bromo-
1,2,3-trimethoxybenzene (0.27 mmol, 1.5 equiv) using general procedure
I; White solid (55 mg, 51%); m.p. = 70-72 °C; Rf = 0.25 (35% EA/PE); 1H-
NMR (CDCl3, 400 MHz): δ 7.88 (d, J = 8.0 Hz, 2H), 7.24-7.18 (m, 4H),
6.86 (d, J = 7.6 Hz, 2H), 6.48 (d, J = 10.8 Hz, 1H), 5.36 (d, J = 10.8 Hz,
1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.74 (s, 3H), 3.53 (s, 3H), 3.48 (s, 3H),
2.38 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 192.9, 152.8, 152.0, 148.6,
148.0, 144.5, 141.5, 132.8, 132.6, 129.4 (3C), 128.9 (2C), 121.1, 119.6,
112.7, 112.4, 110.8, 61.2, 60.4, 56.1, 56.0, 55.9, 51.7, 48.6, 21.8; HRMS
(EI) calcd for C27H28Br2O6, 631.0130 m/z (M+Na)+; Found, 631.0124 m/z.
2-Bromo-3-(3,4-dimethoxyphenyl)-3-(4-methoxyphenyl)-1-phenylpropan-
1-one (3i): Prepared from (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-
one (50 mg, 0.209 mmol, 1.0 equiv) and 1,2-dimethoxybenzene (0.31
mmol, 1.5 equiv) using general procedure I; White solid (69 mg, 73 %);
1
m.p. = 54-56 °C; Rf = 0.25 (25% EA/PE); H-NMR (CDCl3, 400 MHz): δ
7.94 (d, J = 8.0 Hz, 2H), 7.59-7.57 (m, 1H), 7.46 (d, J = 7.6 Hz, 2H), 7.35
(d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 8.0 Hz, 2H), 6.64
(d, J = 8.0 Hz, 1H), 5.81 (d, J = 11.6 Hz, 1H), 4.81 (d, J = 11.6 Hz, 1H),
3.79 (s, 3H), 3.73 (s, 3H), 3.71 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ
193.1, 158.7, 149.0, 147.9, 135.2, 133.9, 133.8, 133.7, 129.4 (2C), 128.9
(2C), 128.6 (2C), 119.3, 114.1 (2C), 111.7, 111.3, 55.8 (2C), 55.3, 52.6,
49.7; HRMS (EI) calcd for C24H23BrO4, 479.0657 m/z (M+Na)+; Found,
479.0653 m/z.
2-Bromo-3-(3,4-dimethoxyphenyl)-3-(2-methoxynaphthalen-1-yl)-1-(p-
tolyl)propan-1-one (3e): Prepared from (E)-3-(3,4-dimethoxyphenyl)-1-(p-
tolyl)prop-2-en-1-one (50 mg, 0.177 mmol, 1.0 equiv) and 2-
methoxynaphthalene (0.27 mmol, 1.5 equiv) using general procedure I;
Off white solid (58 mg, 63%); m.p. = 80-82 °C; Rf = 0.25 (25% EA/PE);
1H-NMR (CDCl3, 400 MHz): δ 8.32 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.0 Hz,
2H), 7.66 (d, J = 8.8 Hz, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz,
1H), 7.25-7.20 (m, 4H), 7.06 (d, J = 9.2 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H),
6.62 (d, J = 10.4 Hz, 1H), 5.58 (d, J = 10.4 Hz, 1H), 3.86 (s, 3H), 3.82 (s,
3H), 3.55 (s, 3H), 2.40 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 192.0,
153.2, 148.6, 148.0, 144.2, 134.0, 132.6, 132.3, 129.8, 129.5 (3C), 128.8
(3C), 127.2, 123.7, 123.2, 122.4, 121.8, 112.8, 112.7, 110.9, 56.0, 55.9,
55.6, 52.8, 48.3, 21.8; HRMS (EI) calcd for C29H27BrO4, 543.0970 m/z
(M+Na)+; Found, 543.0970 m/z.
2-Bromo-3-(3,4-dimethoxyphenyl)-3-(4-methoxyphenyl)-1-(p-tolyl)propan-
1-one (3j): Prepared from (E)-3-(4-methoxyphenyl)-1-(p-tolyl)prop-2-en-1-
one (50 mg, 0.198 mmol, 1.0 equiv) and 1,2-dimethoxybenzene (0.29
mmol, 1.5 equiv) using general procedure I; White solid (71 mg, 76%);
1
m.p. = 57-59 °C; Rf = 0.25 (25% EA/PE); H-NMR (CDCl3, 400 MHz): δ
7.85 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H),
6.89 (d, J = 8.4 Hz, 2H), 6.74-6.71 (m, 2H), 6.63 (d, J = 8.4 Hz, 1H), 5.82
(d, J = 11.6 Hz, 1H), 4.81 (d, J = 11.6 Hz, 1H), 3.79 (s, 3H), 3.73 (s, 3H)
3.71 (s, 3H), 2.40 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 192.7, 158.6,
149.0, 147.9, 144.8, 134.0, 133.9, 132.6, 129.7 (2C), 129.4 (2C), 128.8
(2C), 119.3, 114.0 (2C), 111.7, 111.3, 55.8 (2C), 55.3, 52.6, 49.6, 21.8;
HRMS (EI) calcd for C25H25BrO4, 493.0813 m/z (M+Na)+; Found,
493.0812 m/z.
2-Bromo-3,3-bis(3,4-dimethoxyphenyl)-1-(4-methoxyphenyl)propan-1-
one
(3f):
Prepared
from
(E)-3-(3,4-dimethoxyphenyl)-1-(4-
2-Bromo-3-(3,4-dimethoxyphenyl)-1,3-bis(4-methoxyphenyl)propan-1-
one (3k): Prepared from (E)-1,3-bis(4-methoxyphenyl)prop-2-en-1-one
(50 mg, 0.186 mmol, 1.0 equiv) and 1,2-dimethoxybenzene (0.28 mmol,
1.5 equiv) using general procedure I; White solid (68 mg, 75%); m.p. =
60-62 °C; Rf = 0.25 (30% EA/PE); 1H-NMR (CDCl3, 400 MHz): δ 7.94 (d,
J = 8.8 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 6.93-6.88 (m, 4H), 6.74-6.71 (m,
2H), 6.63 (d, J = 8.4 Hz, 1H), 5.81 (d, J = 11.6 Hz, 1H), 4.81 (d, J = 11.6
Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.72 (s, 6H); 13C-NMR (CDCl3, 100
MHz): δ 191.5, 164.1, 158.6, 148.9, 147.9, 134.1, 134.0, 131.1 (2C),
129.4 (2C), 127.9, 119.3, 114.2 (2C), 114.0 (2C), 111.7, 111.3, 55.8 (2C),
55.6, 55.3, 52.6, 49.6; HRMS (EI) calcd for C25H25BrO5, 509.0763 m/z
(M+Na)+; Found, 509.0762 m/z.
methoxyphenyl)prop-2-en-1-one (50 mg, 0.168 mmol, 1.0 equiv) and 1,2-
dimethoxybenzene (0.25 mmol, 1.5 equiv) using general procedure I;
White solid (67 mg, 78%); m.p. = 60-62 °C; Rf = 0.25 (30% EA/PE); H-
1
NMR (CDCl3, 400 MHz): δ 7.94 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.0 Hz,
1H), 6.93-6.90 (m, 3H), 6.87-6.85 (m, 1H), 6.73-6.72 (m, 2H), 6.64 (d, J =
8.0 Hz, 1H), 5.79 (d, J = 11.6 Hz, 1H), 4.80 (d, J = 11.6 Hz, 1H), 3.90 (s,
3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H); 13C-NMR
(CDCl3, 100 MHz): δ 191.5, 164.1, 148.9 (2C), 148.1, 148.0, 134.5, 133.8,
131.1 (2C), 127.9, 120.3, 119.3, 114.2 (2C), 112.3, 111.8, 111.3, 111.2,
56.1, 55.9 (2C), 55.8, 55.6, 52.9, 49.5; HRMS (EI) calcd for C26H27BrO6,
539.0868 m/z (M+Na)+; Found, 539.0862 m/z.
2-Bromo-3-(3,4-dimethoxyphenyl)-1,3-bis(4-methoxyphenyl)propan-1-
2-Bromo-1-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)-3-(4-
one
(3g):
Prepared
from
(E)-3-(3,4-dimethoxyphenyl)-1-(4-
methoxyphenyl)propan-1-one (3l): Prepared from (E)-1-(4-chlorophenyl)-
3-(4-methoxyphenyl)prop-2-en-1-one (50 mg, 0.183 mmol, 1.0 equiv) and
1,2-dimethoxybenzene (0.28 mmol, 1.5 equiv) using general procedure I;
Off white solid (63 mg, 70%); m.p. = 48-50 °C; Rf = 0.25 (25% EA/PE);
1H-NMR (CDCl3, 400 MHz): δ 7.87 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.4 Hz,
2H), 7.33 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 6.8 Hz, 2H), 6.70-6.69 (m, 2H),
6.64 (d, J = 8.4 Hz, 1H), 5.75 (d, J = 11.6 Hz, 1H), 4.78 (d, J = 11.6 Hz,
1H), 3.79 (s, 3H), 3.73 (s, 6H); 13C-NMR (CDCl3, 100 MHz): δ 191.9,
158.7, 149.1, 148.1, 140.3, 133.7 (2C), 133.4, 130.1 (2C), 129.4 (2C),
129.3 (2C), 119.1, 114.1 (2C), 111.8, 111.3, 55.9 (2C), 55.4, 52.6, 49.5;
HRMS (EI) calcd for C24H22BrClO4, 513.0267 m/z (M+Na)+ ; Found,
513.0265 m/z.
methoxyphenyl)prop-2-en-1-one (50 mg, 0.168 mmol, 1.0 equiv) and
anisole (0.25 mmol, 1.5 equiv) using general procedure I; White solid (65
mg, 79%); m.p. = 58-60 °C; Rf = 0.25 (25% EA/PE); 1H-NMR (CDCl3, 400
MHz): δ 7.93 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8
Hz, 2H), 6.89-6.85 (m, 3H), 6.69 (d, J = 8.4 Hz, 2H), 5.80 (d, J = 11.6 Hz,
1H), 4.81 (d, J = 11.2 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 6H), 3.66 (s, 3H);
13C-NMR (CDCl3, 100 MHz): δ 191.4, 164.1, 158.4, 148.9, 148.1, 134.7,
133.3, 131.1 (2C), 128.9 (2C), 127.9, 120.2, 114.2 (2C), 114.1, 113.9,
112.2, 111.2, 56.1, 55.9, 55.6, 55.2, 52.6, 49.5; HRMS (EI) calcd for
C25H25BrO5, 509.0763 m/z (M+Na)+; Found, 509.0759 m/z,
2-Bromo-3-(3,4-dimethoxyphenyl)-3-(4-methoxy-2-methylphenyl)-1-(4-
methoxyphenyl)propan-1-one
(3h):
Prepared
from
(E)-3-(3,4-
3-Bromo-4-(3,4-dimethoxyphenyl)-4-(4-methoxyphenyl)butan-2-one (3m):
Prepared from methyl (E)-4-(4-methoxyphenyl)but-3-en-2-one (50 mg,
0.283 mmol, 1.0 equiv) and 1,2-dimethoxybenzene (0.42 mmol, 1.5
equiv) using general procedure I; gummy liquid (65 mg, 58%); Rf = 0.25
(15% EA/PE); 1H-NMR (CDCl3, 400 MHz): δ 7.28 (d, J = 8.4 Hz, 2H), 6.88
(d, J = 8.4 Hz, 2H), 6.83-6.74 (m, 3H), 4.98 (d, J = 12.0 Hz, 1H), 4.46 (d,
J = 11.6 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 2.23 (s, 3H);
13C-NMR (CDCl3, 100 MHz): δ 200.9, 158.5, 149.0, 148.1, 133.1, 133.0,
128.9 (2C), 119.3, 114.0 (2C), 111.3, 111.2, 56.6, 55.9, 55.8, 55.2, 53.3,
dimethoxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (50 mg, 0.168
mmol, 1.0 equiv) and 1-methoxy-3-methylbenzene (0.25 mmol, 1.5
equiv) using general procedure I; gummy liquid (44 mg, 52%); Rf = 0.25
(30% EA/PE); 1H-NMR (CDCl3, 400 MHz): δ 7.98 (d, J = 8.4 Hz, 2H),
7.07-7.03 (m, 2H), 6.97-6.92 (m, 3H), 6.86-6.81 (m, 2H), 6.60 (d, J = 8.4
Hz, 1H), 6.21 (d, J = 11.2 Hz, 1H), 4.94 (d, J = 10.8 Hz, 1H), 3.89 (s, 3H),
3.85 (s, 3H), 3.84 (s, 3H), 3.61 (s, 3H), 2.14 (s, 3H); 13C-NMR (CDCl3,
100 MHz): δ 191.5, 163.8, 154.1, 148.6, 147.9, 134.7, 131.0 (2C), 130.1,
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100823
European Journal of Organic Chemistry
FULL PAPER
26.6; HRMS (EI) calcd for C19H21BrO4, 417.0500 m/z (M+Na)+; Found,
417.0497 m/z.
1H), 6.85 (d, J = 7.6 Hz, 1H), 5.80 (d, J = 10.0 Hz, 1H), 4.37 (d, J = 10.0
Hz, 1H), 4.07-4.01 (m, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H); 13C-
NMR (CDCl3, 100 MHz): δ 168.4, 150.7, 149.7, 125.4, 122.8, 110.7,
110.1, 84.7, 74.5 (hept, CH(CF3)2), 56.0 (2C), 53.3, 46.0; HRMS (EI)
calcd for C15H15BrF6O5, 492.9984 m/z (M+Na)+; Found, 492.9981 m/z.
Methyl
2-bromo-3,3-bis(3,4-dimethoxyphenyl)propanoate
(3n):[13]
Prepared from methyl (E)-3-(3,4-dimethoxyphenyl)acrylate (50 mg, 0.224
mmol, 1.0 equiv) and 1,2-dimethoxybenzene (0.33 mmol, 1.5 equiv)
using general procedure I; White solid (70 mg, 71%); m.p. = 42-43 °C; Rf
= 0.25 (25% EA/PE); 1H-NMR (CDCl3, 400 MHz): δ 6.89-6.74 (m, 6H),
4.83 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 11.6 Hz, 1H), 3.86 (s, 3H), 3.84 (s,
3H), 3.82 (s, 3H), 3.81 (s, 3H), 3.60 (s, 3H); 13C-NMR (CDCl3, 100 MHz):
δ 169.7, 149.0 (2C), 148.4, 148.2, 133.3, 132.9, 119.9, 119.6, 111.7,
111.4, 111.3, 111.2, 56.0 (2C), 55.9 (2C), 54.5, 53.0, 48.7; HRMS (EI)
calcd for C20H23BrO6, 463.0555 m/z (M+Na)+; Found, 463.0551 m/z.
General reaction procedure II: “Bromiranium ion”-induced HFIP-
mediated Friedel–Crafts alkylation reaction followed by ring bromination:
Preparation of 4
To a stirred solution of chalcone or cinnamate ester 1 (1.0 equiv) in HFIP,
arene 2 (1.5 equiv) was added and cooled to 0 °C and then DBDMH (2.0
equiv) was added and the reaction mixture was stirred at the same
temperature for 5-10 minutes. On completion, the reaction was quenched
with saturated aqueous Na2S2O3 solution. The resulting mixture was
extracted with dichloromethane and finally organic extract was washed
with brine solution. The organic extract was dried over Na2SO4 and the
solvent was evaporated under reduced pressure. The residue was then
subjected to purification by flash column chromatography using EtOAc
and petroleum-ether mixture as an eluent to yield 4.
Methyl
2-bromo-3-(3,4-dimethoxyphenyl)-3-(4-
methoxyphenyl)propanoate (3o):[13] Prepared from methyl (E)-3-(4-
methoxyphenyl)acrylate (50 mg, 0.260 mmol, 1.0 equiv) and 1,2-
dimethoxybenzene (0.39 mmol, 1.5 equiv) using general procedure I;
1
White solid (69 mg, 65%); m.p. = 54-56 °C; Rf = 0.25 (20% EA/PE); H-
NMR (CDCl3, 400 MHz): δ 7.23 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz,
2H), 6.81-6.73 (m, 3H), 4.85 (d, J = 12.0 Hz, 1H), 4.48 (d, J = 12.0 Hz,
1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 3.61 (s, 3H); 13C-NMR
(CDCl3, 100 MHz): δ 169.7, 158.7, 149.0, 148.3, 133.1, 132.9, 129.0 (3C),
119.6, 114.1 (2C), 111.3, 56.0, 55.9, 55.3, 54.2, 53.0, 48.7; HRMS (EI)
calcd for C19H21BrO5, 433.0450 m/z (M+Na)+; Found, 433.0443 m/z.
Spectral data of 4a-4i
2-Bromo-3,3-bis(2-bromo-4,5-dimethoxyphenyl)-1-(p-tolyl)propan-1-one
(4a): Prepared from (E)-3-(3,4-dimethoxyphenyl)-1-(p-tolyl)prop-2-en-1-
one (50 mg, 0.177 mmol, 1.0 equiv) and 1,2-dimethoxybenzene (0.27
mmol, 1.5 equiv) using general procedure II; Off white solid (80 mg,
69%); m.p. = 79-81 °C; Rf = 0.25 (25% EA/PE); 1H-NMR (CDCl3, 400
MHz): δ 7.89 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.03 (s, 1H),
7.02 (s, 1H), 6.96 (s, 1H), 6.88 (s, 1H), 6.09 (d, J = 10.0 Hz, 1H), 5.54 (d,
J = 10.0 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 3.57 (s, 3H),
2.40 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 191.9, 148.7, 148.5, 148.2,
147.9, 144.9, 132.2, 131.4, 130.5, 129.7 (3C), 128.8 (3C), 116.6, 116.0,
115.1, 112.6, 56.2, 56.1 (2C), 56.0, 51.0, 50.7, 21.8; HRMS (EI) calcd for
C26H25Br3O5, 680.9109 m/z (M+Na)+; Found, 680.9094 m/z.
Methyl 2-bromo-3,3-bis(3,4-dimethoxyphenyl)propanoate (3p): Prepared
from Methyl (E)-3-(3,4-dimethoxyphenyl)acrylate (50 mg, 0.224 mmol,
1.0 equiv) and anisole (0.33 mmol, 1.5 equiv) using general procedure I;
1
white solid (63 mg, 68%); m.p. = 43-45 °C; Rf = 0.25 (25% EA/PE); H-
NMR (CDCl3, 400 MHz): δ 7.18 (d, J = 8.4 Hz, 2H), 6.90-6.78 (m, 5H),
4.86 (d, J = 11.6 Hz, 1H), 4.49 (d, J = 11.6 Hz, 1H), 3.86 (s, 3H), 3.84 (s,
3H), 3.73 (s, 3H), 3.59 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 169.6,
158.7, 148.9, 148.0, 133.3, 132.3, 128.8 (2C), 119.6, 114.2 (2C), 111.4,
111.0, 56.0, 55.9, 55.3, 54.1, 52.9, 48.6; HRMS (EI) calcd for C19H21BrO5,
433.0450 m/z (M+Na)+ ; Found, 433.0449 m/z.
2-Bromo-3-(2-bromo-4,5-dimethoxyphenyl)-3-(3-bromo-4-
2-Bromo-3-(3,4-dimethoxyphenyl)-3-mesityl-1-(4-methoxyphenyl)propan-
methoxyphenyl)-1-(p-tolyl)propan-1-one (4b): Prepared from (E)-3-(3,4-
dimethoxyphenyl)-1-(p-tolyl)prop-2-en-1-one (50 mg, 0.177 mmol, 1.0
equiv) and anisole (0.27 mmol, 1.5 equiv) using general procedure II; Off
1-one
(3q):
Prepared
from
(E)-3-(3,4-dimethoxyphenyl)-1-(4-
methoxyphenyl)prop-2-en-1-one (50 mg, 0.168 mmol, 1.0 equiv) and
mesitylene (0.25 mmol, 1.5 equiv) using general procedure I; Non-
separable mixture (ratio = 3:1) (72 mg, 86%); Rf = 0.25 (20% EA/PE);
1H-NMR (CDCl3, 400 MHz; Major): δ 7.84 (d, J = 8.8 Hz, 2H), 7.03 (d, J =
8.8 Hz, 1H), 6.95 (s, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.4 Hz,
2H), 6.26 (d, J = 10.8 Hz, 1H), 5.31 (d, J = 11.2 Hz, 1H), 3.86 (s, 3H),
3.84 (s, 6H), 2.65 (s, 3H), 2.10 (s, 6H); 13C-NMR (CDCl3, 100 MHz;
Major): δ 191.2, 163.9, 148.5, 147.5, 136.4, 135.7, 132.3, 131.4, 130.8
(3C), 127.5, 121.0, 114.2, 114.0 (3C), 112.8, 110.6, 56.0, 55.9, 55.5,
48.1, 47.7, 20.7 (3C); HRMS (EI) calcd for C27H29BrO4, 521.1126 m/z
(M+Na)+; Found, 521.1119 m/z.
1
white solid (68 mg, 61%); m.p. = 78-80 °C; Rf = 0.25 (20% EA/PE); H-
NMR (CDCl3, 400 MHz): δ 7.86 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H), 7.26-
7.18 (m, 3H), 7.05 (s, 1H), 6.97 (s, 1H), 6.68 (d, J = 8.8 Hz, 1H), 5.80 (d,
J = 11.2 Hz, 1H), 5.45 (d, J = 11.6 Hz, 1H), 3.95 (s, 3H), 3.85 (s, 3H),
3.75 (s, 3H), 2.40 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 191.6, 154.9,
148.9, 148.7, 145.0, 133.2, 133.0, 132.2, 129.7 (3C), 129.0 (3C), 128.9,
128.6, 116.0, 111.8 (2C), 56.7, 56.2 (2C), 50.3, 48.4, 21.8; HRMS (EI)
calcd for C25H23Br3O4, 650.9003 m/z (M+Na)+; Found, 650.9001 m/z.
2-Bromo-3-(3-bromo-2,4,6-trimethoxyphenyl)-3-(4-methoxyphenyl)-1-
phenylpropan-1-one (4c): Prepared from (E)-3-(4-methoxyphenyl)-1-
phenylprop-2-en-1-one (50 mg, 0.209 mmol, 1.0 equiv) and 1,3,5-
trimethoxybenzene (0.31 mmol, 1.5 equiv) using general procedure II;
2-Bromo-3-(3,4-dimethoxyphenyl)-3-((1,1,1,3,3,3-hexafluoropropan-2-
yl)oxy)-1-(4 methoxyphenyl)propan-1-one (5): Prepared from methyl (E)-
3-(3,4-dimethoxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (50 mg,
0.168 mmol, 1.0 equiv) using general procedure I; White solid (81 mg,
90%); Rf = 0.20 (20% EA/PE); 1H-NMR (CDCl3, 400 MHz): δ 8.03 (d, J =
8.0 Hz, 2H), 7.03-6.89 (m, 5C), 5.41 (d, J = 9.6 Hz, 1H), 5.23 (d, J = 9.6
Hz, 1H), 4.26-4.20 (m, 1H), 3.91 (s, 6H), 3.87 (s, 3H); 13C-NMR (CDCl3,
100 MHz): δ 190.5, 164.4, 150.3, 149.3, 131.4 (2C), 127.6, 127.2, 122.2,
114.2 (2C), 110.8, 110.6, 83.9, 74.5 (hept, CH(CF3)2), 56.1, 55.9, 55.6,
46.6; HRMS (EI) calcd for C21H19BrF6O5, 569.0197 m/z (M+Na)+; Found,
569.0193 m/z.
1
White solid (65 mg, 55%); m.p. = 77-79 °C; Rf = 0.25 (30% EA/PE); H-
NMR (CDCl3, 400 MHz): δ 7.98 (d, J = 8.0 Hz, 2H), 7.57-7.55 (m, 1H),
7.49-7.45 (m, 4H), 6.84 (dd, J = 6.8 Hz, 2.4 Hz, 2H), 6.40 (d, J = 10.8 Hz,
1H), 6.08 (s, 1H), 5.15 (d, J = 10.8 Hz, 1H), 3.98 (s, 3H), 3.75 (s, 6H),
3.54 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 193.0, 158.6, 156.5, 156.4,
156.1; 134.9, 133.9, 133.4, 129.9 (3C), 128.8 (3C), 128.6 (3C), 118.1,
113.8 (2C), 92.6, 60.9, 56.4, 55.3 (2C); HRMS (EI) calcd for C25H24Br2O5,
586.9868 m/z (M+Na)+; Found, 586.9865 m/z.
2-Bromo-3,3-bis(3-bromo-4-methoxyphenyl)-1-(4-chlorophenyl)propan-1-
Methyl-2-bromo-3-(3,4-dimethoxyphenyl)-3-((1,1,1,3,3,3-
one
(4d):
Prepared
from
(E)-1-(4-chlorophenyl)-3-(4-
hexafluoropropan-2-yl)oxy)propanoate (6): Prepared from methyl (E)-3-
(3,4-dimethoxyphenyl)acrylate (50 mg, 0.224 mmol, 1.0 equiv) using
general procedure I; Off white solid (92 mg, 88%); Rf = 0.20 (20%
methoxyphenyl)prop-2-en-1-one (50 mg, 0.183 mmol, 1.0 equiv) and
anisole (0.27 mmol, 1.5 equiv) using general procedure II; White solid (65
mg, 58%); m.p. = 70-72 °C; Rf = 0.25 (25% EA/PE); 1H-NMR (CDCl3, 400
MHz): δ 7.89 (d, J = 8.0 Hz, 2H), 7.54 (s, 1H), 7.44 (d, J = 8.0 Hz, 2H),
1
EA/PE); H-NMR (CDCl3, 400 MHz): δ 6.93 (d, J = 8.4 Hz, 1H), 6.88 (s,
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100823
European Journal of Organic Chemistry
FULL PAPER
7.37 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.89 (d, J
= 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 5.68 (d, J = 12.0 Hz, 1H), 4.75 (d,
J = 12.0 Hz, 1H), 3.88 (s, 3H), 3.76 (s, 3H); 13C-NMR (CDCl3, 100 MHz):
δ 191.2, 155.2, 155.1, 140.6, 134.7, 134.1, 133.0, 132.9, 132.7, 130.1
(2C), 129.4 (2C), 128.6, 127.6, 112.2 (2C), 112.0 (2C), 56.4, 56.3, 51.5,
48.5; HRMS (EI) calcd for C23H18Br3ClO3, 640.8351 m/z (M+Na)+; Found,
640.8343 m/z.
5.85 (d, J = 11.6 Hz, 1H), 5.25 (d, J = 11.6 Hz, 1H), 3.86 (s, 3H), 3.74 (s,
3H), 3.53 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 191.1, 164.2, 148.4,
148.3, 140.0, 132.4, 131.1 (2C), 129.0 (2C), 128.5 (2C), 127.8, 127.4,
116.6, 115.4, 114.3 (2C), 110.1, 56.1, 56.0, 55.7, 52.1, 49.7; HRMS (EI)
calcd for C24H22Br2O4, 556.9762 m/z (M+Na)+ ; Found, 556.9761 m/z.
Bromine-rich Friedel-Crafts alkylated product synthesis: Reaction
Procedures A & B.
2-Bromo-3-(2-bromo-4,5-dimethoxyphenyl)-3-(3-bromo-4-
methoxyphenyl)-1-(p-tolyl)propan-1-one (4e): Prepared from (E)-3-(4-
methoxyphenyl)-1-(p-tolyl)prop-2-en-1-one (50 mg, 0.198 mmol, 1.0
equiv) and 1,2-dimethoxybenzene (0.30 mmol, 1.5 equiv) using general
procedure II; White solid (82 mg, 66%); m.p. = 75-77 °C; Rf = 0.25 (25%
EA/PE); 1H-NMR (CDCl3, 400 MHz): δ 7.88 (d, J = 8.4 Hz, 2H), 7.56 (d, J
= 2.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 7.6 Hz, 2H), 6.95 (s,
1H), 6.87 (d, J = 8.4 Hz, 1H), 6.64 (s, 1H), 5.80 (d, J = 11.2 Hz, 1H), 5.16
(d, J = 11.6 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.75 (s, 3H), 2.41 (s, 3H);
13C-NMR (CDCl3, 100 MHz): δ 192.0, 155.1, 148.5, 148.4, 145.2, 133.5,
133.3, 132.3, 131.9, 129.8 (3C), 128.7 (3C), 116.7, 115.3, 111.6, 109.9,
56.3, 56.1, 56.0, 51.1, 49.8, 21.8; HRMS (EI) calcd for C25H23Br3O4,
648.9024 m/z (M+Na)+; Found, 648.9022 m/z.
Procedure A: To a stirred solution of 3a (50 mg, 0.1 mmol, 1.0 equiv) in
HFIP, NBS (2.1 equiv) was added and the resultant mixture was stirred
at 0 oC for 30 minutes. On completion, the reaction was quenched with
saturated aqueous Na2S2O3 solution. The resulting mixture was extracted
with dichloromethane and finally organic extract was washed with brine
solution. The organic extract was dried over Na2SO4 and the solvent was
evaporated under reduced pressure. The residue was then subjected to
purification by flash column chromatography using EtOAc and petroleum-
ether mixture as an eluent to yield 4a (41 mg, 63%).
Procedure B: To a stirred solution of 3a (50 mg, 0.1 mmol, 1.0 equiv) in
HFIP, DBDMH (1.5 equiv) was added and the resultant mixture was
stirred at 0 oC for 10 minutes. On completion, the reaction was quenched
with saturated aqueous Na2S2O3 solution. The resulting mixture was
extracted with dichloromethane and finally organic extract was washed
with brine solution. The organic extract was dried over Na2SO4 and the
solvent was evaporated under reduced pressure. The residue was then
subjected to purification by flash column chromatography using EtOAc
and petroleum- ether mixture as an eluent to yield 4a (57 mg, 87%).
2-Bromo-3,3-bis(3-bromo-4-methoxyphenyl)-1-(p-tolyl)propan-1-one (4f):
Prepared from (E)-3-(4-methoxyphenyl)-1-(p-tolyl)prop-2-en-1-one (50
mg, 0.198 mmol, 1.0 equiv) and anisole (0.30 mmol, 1.5 equiv) using
general procedure II; Off white solid (71 mg, 60%); m.p. = 73-75 °C; Rf =
0.25 (20% EA/PE); 1H-NMR (CDCl3, 400 MHz): δ 7.85 (d, J = 8.0 Hz, 2H),
7.54 (s, 1H), 7.36 (s, 1H), 7.32-7.25 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H),
6.89 (d, J = 8.8 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 5.73 (d, J = 11.6 Hz,
1H), 4.77 (d, J = 11.6 Hz, 1H), 3.88 (s, 3H), 3.76 (s, 3H), 2.41 (s, 3H);
13C-NMR (CDCl3, 100 MHz): δ 191.9, 155.1, 155.0, 145.2, 135.1, 134.4,
133.0, 132.8 132.2, 129.8 (2C), 129.7, 128.9 (2C), 128.6, 127.7, 112.2,
112.0 (2C), 56.4, 56.3, 51.5, 48.6, 21.9; HRMS (EI) calcd for C24H21Br3O3,
618.8918 m/z (M+Na)+; Found, 618.8909 m/z.
One-pot and sequential reaction
To a stirred solution of chalcone 1 (50 mg, 0.177 mmol, 1.0 equiv) in
o
HFIP, arene 2 (1.5 equiv) was added and cooled to 0 C and then NBS
(1.05 equiv) was added and the reaction mixture was stirred at the same
temperature for 5-10 minutes. Then DBDMH (1.5 equiv) was added and
the mixture was stirred for next 10 minutes. On completion, the reaction
was quenched with saturated aqueous Na2S2O3 solution. The resulting
mixture was extracted with dichloromethane and finally organic extract
was washed with brine solution. The organic extract was dried over
Na2SO4 and the solvent was evaporated under reduced pressure. The
residue was then subjected to purification by flash column
chromatography using EtOAc and petroleum- ether mixture as an eluent
to yield the title compound 4a (80 mg, 69%).
2-Bromo-3,3-bis(3-bromo-4-methoxyphenyl)-1-phenylpropan-1-one (4g):
Prepared from (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (50 mg,
0.209 mmol, 1.0 equiv) and anisole (0.31 mmol, 1.5 equiv) using general
procedure II; White solid (72 mg, 60%); m.p. = 75-77 °C; Rf = 0.25 (20%
EA/PE); 1H-NMR (CDCl3, 400 MHz): δ 7.95 (d, J = 7.6 Hz, 2H), 7.57 (d, J
= 8.8 Hz, 2H), 7.48-7.46 (m, 2H), 7.38 (s, 1H), 7.32 (d, J = 8.8 Hz,
1H),7.12 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 8.4 Hz,
1H), 5.75 (d, J = 11.6 Hz, 1H), 4.78 (d, J = 11.6 Hz, 1H), 3.88 (s, 3H),
3.75 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 192.3, 155.1, 155.0, 134.9,
134.7, 134.2, 134.0, 133.0, 132.8, 129.0 (2C), 128.7 (3C), 128.6, 127.7,
112.1, 112.0, 111.9, 56.4, 56.2, 51.5, 48.7; HRMS (EI) calcd for
C23H19Br3O3, 604.8761 m/z (M+Na)+; Found, 604.8758 m/z.
General reaction procedure III: “Iodiranium ion”-induced HFIP-
mediated Friedel-Crafts alkylation reaction with chalcone and cinnamate
esters: preparation of 7
2-Bromo-3-(2-bromo-4,5-dimethoxyphenyl)-1,3-di-p-tolylpropan-1-one
(4h): Prepared from (E)-1,3-di-p-tolylprop-2-en-1-one (50 mg, 0.211
mmol, 1.0 equiv) and 1,2-dimethoxybenzene (0.31 mmol, 1.5 equiv)
using general procedure II; White solid (71 mg, 63%); m.p. = 91-93 °C; Rf
To a stirred solution of chalcone or cinnamate ester 1 (1.0 equiv) in HFIP,
arene 2 (1.5 equiv) was added and cooled to 0 °C and then NIS (1.05
equiv) was added and the reaction mixture was stirred at the same
temperature for 30 minutes. On completion, the reaction was quenched
with saturated aqueous Na2S2O3 solution. The resulting mixture was
extracted with dichloromethane and finally organic extract was washed
with brine solution. The organic extract was dried over Na2SO4 and the
solvent was evaporated under reduced pressure. The residue was then
subjected to purification by flash column chromatography using EtOAc
and petroleum-ether mixture as an eluent to yield the Friedel-Crafts
alkylated products 7.
1
= 0.30 (25% EA/PE); H-NMR (CDCl3, 400 MHz): δ 7.89 (d, J = 8.0 Hz,
2H), 7.38 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.6 Hz, 2H), 7.15 (d, J = 8.0 Hz,
2H), 6.93 (s, 1H), 6.71 (s, 1H), 5.90 (d, J = 11.2 Hz, 1H), 5.24 (d, J = 11.6
Hz, 1H), 3.72 (s, 3H), 3.52 (s, 3H), 2.39 (s, 3H), 2.31 (s, 3H); 13C-NMR
(CDCl3, 100 MHz): δ 192.2, 148.3 (2C), 145.0, 137.0, 136.9, 132.5, 132.4,
129.7 (2C), 129.2 (2C), 128.7 (4C), 116.5, 115.2, 110.1, 56.0, 55.9, 51.6,
49.9, 21.8, 21.2; HRMS (EI) calcd for C25H24Br2O3, 554.9969 m/z
(M+Na)+; Found, 554.9963 m/z.
Spectral data of 7a-7e
2-Bromo-3-(2-bromo-4,5-dimethoxyphenyl)-1-(4-methoxyphenyl)-3-
phenylpropan-1-one (4i): Prepared from (E)-1-(4-methoxyphenyl)-3-
phenylprop-2-en-1-one (50 mg, 0.209 mmol, 1.0 equiv) and 1,2-
dimethoxybenzene (0.31 mmol, 1.5 equiv) using general procedure II; Off
white gummy liquid (39 mg, 35%); Rf = 0.25 (20% EA/PE); 1H-NMR
(CDCl3, 400 MHz): δ 7.97 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 7.6 Hz, 2H),
7.36-7.32 (m, 2H), 7.28-7.25 (m, 1H), 6.94-6.92 (m, 3H), 6.70 (s, 1H),
3,3-Bis(3,4-dimethoxyphenyl)-2-iodo-1-(p-tolyl)propan-1-one
(7a):
Prepared from (E)-3-(3,4-dimethoxyphenyl)-1-(p-tolyl)prop-2-en-1-one
(50 mg, 0.177 mmol, 1.0 equiv) and 1,2-dimethoxybenzene (0.27 mmol,
1.5 equiv) using general procedure III; Off white solid (73 mg, 75%); m.p.
= 122-124 °C; Rf = 0.25 (25% EA/PE); 1H-NMR (CDCl3, 400 MHz): δ 7.86
10
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European Journal of Organic Chemistry
FULL PAPER
(d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.80
(d, J = 8.0 Hz, 2H), 6.75 (d, J = 6.8 Hz, 2H), 6.64 (d, J = 8.0 Hz, 1H), 6.02
(d, J = 12.0 Hz, 1H), 4.83 (d, J = 12.0 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H),
3.73 (s, 6H), 2.41 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 193.8, 148.8,
148.1, 147.8, 144.7, 133.5, 129.6, 128.6, 120.5 (4C), 118.8 (3C), 111.9,
111.4, 111.1, 111.0, 56.1 (2C), 55.9, 55.8, 53.7, 31.5, 21.8; HRMS (EI)
calcd for C26H27IO5, 569.0801 m/z (M+Na)+; Found, 569.0798 m/z.
Spectral data of 8a-8d
3,3-Bis(3,4-dimethoxyphenyl)-1-(p-tolyl)prop-2-en-1-one (8a): Prepared
from 2-Bromo-3,3-bis(3,4-dimethoxyphenyl)-1-(p-tolyl)propan-1-one (3a)
(50 mg, 0.1 mmol, 1.0 equiv) and DBU (0.12 mmol, 1.2 equiv) using
general procedure IV; Yellow solid (38 mg, 91%); m.p. = 80-82 °C; Rf =
0.25 (25% EA/PE); 1H-NMR (CDCl3, 400 MHz): δ 7.82 (d, J = 7.6 Hz, 2H),
7.18 (d, J = 8.0 Hz, 2H), 6.95-6.93 (m, 3H), 6.87 (d, J = 8.0 Hz, 1H), 6.76
(d, J = 6.0 Hz, 2H), 6.69 (s, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H),
3.72 (s, 3H), 2.38 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 193.0, 154.2,
150.2, 149.2, 148.7, 148.3, 143.4, 136.0, 134.4, 131.7, 129.2 (2C), 128.9
(2C), 123.1, 122.6, 122.2, 113.2, 111.5, 110.6, 110.5, 56.1, 56.0, 55.9,
55.8, 21.8; HRMS (EI) calcd for C26H26O5, 419.1859 m/z (M+H)+; Found,
419.1854 m/z.
3-(3,4-Dimethoxyphenyl)-2-iodo-1-(p-tolyl)-3-(2,3,4-
trimethoxyphenyl)propan-1-one (7b): Prepared from (E)-3-(3,4-
dimethoxyphenyl)-1-(p-tolyl)prop-2-en-1-one (50 mg, 0.177 mmol, 1.0
equiv) and 1,2,3-trimethoxybenzene (0.27 mmol, 1.5 equiv) using general
procedure III; Off white solid (84 mg, 82%); m.p. = 130-132 °C; Rf = 0.25
(30% EA/PE); 1H-NMR (CDCl3, 400 MHz): δ 7.91 (d, J = 8.0 Hz, 2H), 7.26
(d, J = 8.0 Hz, 2H), 7.01-6.99 (m, 2H),6.89-6.83 (m, 2H), 6.47 (d, J = 8.4
Hz, 1H), 6.23 (d, J = 12.0 Hz, 1H), 5.13 (d, J = 12.0 Hz, 1H), 3.93 (s, 3H),
3.87 (s, 3H), 3.81 (s, 3H), 3.75 (s, 3H), 3.72 (s, 3H), 2.41 (s, 3H); 13C-
NMR (CDCl3, 100 MHz): δ 193.6, 152.6, 151.2, 148.4, 147.7, 144.4,
142.4, 135.6, 131.9, 129.5 (2C), 128.5 (2C), 127.6, 120.4 (2C), 112.3,
110.8, 106.8, 60.7, 60.5, 56.0, 55.8, 55.7, 48.2, 31.9, 21.8; HRMS (EI)
calcd for C27H29IO6, 599.0907 m/z (M+Na)+; Found, 599.0905 m/z.
3,3-Bis(3,4-dimethoxyphenyl)-1-(p-tolyl)prop-2-en-1-one (8a): Prepared
from 3,3-Bis(3,4-dimethoxyphenyl)-2-iodo-1-(p-tolyl)propan-1-one (7a)
(50 mg, 0.09 mmol, 1.0 equiv) and DBU (0.1 mmol, 1.2 equiv) using
general procedure IV; Yellow solid (36 mg, 95%); m.p. = 80-82 °C; Rf =
0.25 (25% EA/PE); All spectroscopic are in accordance with 8a obtained
from 3a.
1-(4-Chlorophenyl)-2-iodo-3,3-bis(4-methoxyphenyl)propan-1-one (7c):
Prepared from (E)-1-(4-chlorophenyl)-3-(4-methoxyphenyl)prop-2-en-1-
one (50 mg, 0.183 mmol, 1.0 equiv) and anisole (0.27 mmol, 1.5 equiv)
using general procedure III; Off white solid (74 mg, 80%); m.p. = 80-
82 °C; Rf = 0.25 (20% EA/PE); 1H-NMR (CDCl3, 400 MHz): δ 7.88 (d, J =
8.0 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.15 (d, J =
8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 8.0 Hz, 2H), 6.02 (d, J =
12.0 Hz, 1H), 4.85 (d, J = 11.6 Hz, 1H), 3.80 (s, 3H), 3.67 (s, 3H); 13C-
NMR (CDCl3, 100 MHz): δ 193.0, 158.6, 158.3, 140.0, 135.4, 133.0,
132.8, 129.9 (2C), 129.2 (2C), 129.1 (2C), 128.4 (2C), 114.2 (2C), 114.0
(2C), 55.3, 55.2, 53.0, 31.4; HRMS (EI) calcd for C23H20ClIO3, 529.0043
m/z (M+Na)+; Found, 529.0039 m/z.
3,3-Bis(3-bromo-4-methoxyphenyl)-1-(p-tolyl)prop-2-en-1-one
Prepared from 2-Bromo-3,3-bis(3-bromo-4-methoxyphenyl)-1-(p-
(8b):
tolyl)propan-1-one (4f) (50 mg, 0.084 mmol, 1.0 equiv) and DBU (0.1
mmol, 1.2 equiv) using general procedure IV; Yellow solid (39 mg, 92%);
°
m.p. = 85-87 C; Rf = 0.3 (25% EA/PE); 1H-NMR (CDCl3, 400 MHz): δ
7.81 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H), 7.33 (s, 1H), 7.26-7.20 (m, 3H),
7.13 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.80 (d, J
= 8.4 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 2.40 (s, 3H); 13C-NMR (CDCl3,
100 MHz): δ 191.7, 156.9, 156.1, 151.4, 143.8, 135.8, 135.2, 134.5,
133.3, 132,3, 130.4, 129.33, 129.30 (2C), 128.9, (2C), 123.3, 111.9,
111.5, 111.4, 111.3, 56.5, 56.3, 21.8; HRMS (EI) calcd for C24H20Br2O3,
516.9837 m/z (M+H)+; Found, 516.9833 m/z.
Methyl 3,3-bis(4-methoxyphenyl)acrylate (8c):[30c] Prepared from Methyl
2-iodo-3,3-bis(4-methoxyphenyl)propanoate (7e) (50 mg, 0.12 mmol, 1.0
equiv) and DBU (0.14 mmol, 1.2 equiv) using general procedure IV; red
Methyl
3-(3,4-dimethoxyphenyl)-2-iodo-3-(2,3,4-
(7d): Methyl (E)-3-(3,4-
trimethoxyphenyl)propanoate
dimethoxyphenyl)acrylate (50 mg, 0.224 mmol, 1.0 equiv) and 1,2,3-
trimethoxybenzene (0.34 mmol, 1.5 equiv) using general procedure III;
Off white solid (78 mg, 67%); m.p. = 132-134 °C; Rf = 0.25 (25% EA/PE);
1H-NMR (CDCl3, 400 MHz): δ 6.97 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.0 Hz,
2H), 6.80 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 5.10 (d, J = 12.4
Hz, 1H), 4.83 (d, J = 12.4 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H),
3.80 (s, 6H), 3.59 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 171.2, 152.9,
151.2, 148.5, 147.9, 142.3, 134.6, 126.8, 120.4. 120.1, 111.6, 110.8,
107.0, 60.8, 60.6, 55.9 (2C), 55.8, 52.9, 48.8, 56.7; HRMS (EI) calcd for
C21H25IO7, 539.0543 m/z (M+Na)+; Found, 539.0539 m/z.
1
solid (32 mg, 87%); m.p. = 60-61 °C; Rf = 0.25 (20% EA/PE); H-NMR
(CDCl3, 400 MHz): δ 7,24 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H),
6.91 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.23 (s, 1H), 3.84 (s,
3H), 3.81 (s, 3H), 3.63 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 166.9,
160.8, 159.7, 157.1, 133.8, 131.1, 130.9 (2C), 130.1 (2C), 114.2, 113.7
(2C), 113.2 (2C), 55.4, 55.3, 51.3; HRMS (EI) calcd for C18H18O4,
299.1283 m/z (M+H)+; Found, 299.1277 m/z.
3-(2-Bromo-4,5-dimethoxy-phenyl)-1,3-di-p-tolyl-propenone
(8d):
Prepared from Methyl 2-iodo-3,3-bis(4-methoxyphenyl)propanoate (4h)
(80 mg, 0.15 mmol, 1.0 equiv) and DBU (0.18 mmol, 1.2 equiv) using
general procedure IV; greenish yellow gummy liquid (63 mg, 93%)
formed as a mixture of two diastereoisomers (Z:E = 6:1); Rf = 0.20 (10%
EA/PE); 1H-NMR (CDCl3, 500 MHz) of major diastereoisomer: δ 7.86 (d, J
= 7.9 Hz, 2H), 7.39 (s, 1H), 7.30 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 7.9 Hz,
2H), 7.18 (d, J = 7.9 Hz, 2H), 7.02 (s, 1H), 6.66 (s, 1H), 3.87 (s, 3H), 3.76
(s, 3H), 2.38 (s, 6H).; 13C-NMR (CDCl3, 125 MHz): δ 190.6, 152.4, 148.9,
148.1, 143.3, 139.8, 136.5, 135.8, 132.0, 129.3 (2c), 129.0 (2c), 128.6
(2c), 127.5 (2c), 123.2, 115.3, 113.3, 112.9, 59.9 (2c), 21.6, 21.3 HRMS
(EI) calcd for C25H23BrNaO3, 473.0728 m/z (M+Na)+; Found, 473.0731
m/z.
Methyl 2-iodo-3,3-bis(4-methoxyphenyl)propanoate (7e): Prepared from
Methyl (E)-3-(4-methoxyphenyl)acrylate (50 mg, 0.260 mmol, 1.0 equiv)
and Anisole (0.39 mmol, 1.5 equiv) using general procedure III; White
solid (74 mg, 68%); m.p. = 105-107 °C; Rf = 0.25 (20% EA/PE); 1H-NMR
(CDCl3, 400 MHz): δ 7.20-7.16 (m, 4H), 6.85 (d, J = 8.4 Hz, 2H), 6.76 (d,
J = 8.4 Hz, 2H), 4.96 (d, J = 12.4 Hz, 1H), 4.49 (d, J = 12.4 Hz, 1H), 3.76
(s, 3H), 3.71 (s, 3H), 3.57 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 171.2,
158.6 (2C), 134.5, 132.5, 128.7 (2C), 128.4 (2C), 114.2 (2C), 114.0 (2C),
55.3, 55.2, 54.6, 52.9, 26.5; HRMS (EI) calcd for C18H19IO4, 449.0226
m/z (M+Na)+; Found, 449.0226 m/z.
General reaction procedure IV: Synthesis of β,β-diarylated olefins 8
To a stirred solution of α-halo-functionalized β,β-diarylated alkane (0.1
mmol, 1.0 equiv) in anhydrous THF (1.0 ml) was added DBU (0.12 mmol,
1.2 equiv) and the resultant mixture was heated at 70 °C for 2 hours
under nitrogen atmosphere. After completion, the reaction mixture was
cooled and concentrated in vaccuo. The crude mixture was purified by
flash column chromatography using EtOAc and petroleum-ether mixture
as an eluent to afford the desired β,β-diarylated olefins 8.
Acknowledgements
Financial support from DST, New Delhi, India [DST-INSPIRE
program, IFA-CH12-79] and SERB, DST, India [File No:
CRG/2020/001295]
are
gratefully
acknowledged.
A.
11
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10.1002/ejoc.202100823
European Journal of Organic Chemistry
FULL PAPER
[12] C. Ascheberg, J. Bock, C. F. Buß, Mück-Lichtenfeld, C. G. Daniliuc, K.
Bergander, F. Dielmann, U. Hennecke, Chem. Eur. J. 2017, 23, 11578–
11586.
Bhattacharya thanks to DST-INSPIRE programme for his
Fellowship. P. M. Shukla thanks to IGNTU for his fellowship.
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Keywords: • Arene • β,β-Diaryl α-halo carbonyl compound •
Diastereoselectivity • Friedel-Crafts alkylation • Haliranium ion
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10.1002/ejoc.202100823
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Ar
R
via substrate and
NXS activation
by hydrogen bonding
Ar1
Ar
NXS
HFIP
R
Ar1
X
R = COAr, CO2R
X = Br, I
dr = >99:1
>30 examples
Highly regio-, chemo- and diastereoselective
Metal- and oxidant-free
Short reaction time
Additive-free
Both bromo- and iodo-functionalization
β,β-Diaryl α-halo carbonyl compounds are versatile building blocks and common targets in organic synthesis. Herein we present
metal-, oxidant- and additive free a mild method to access such halo-functionalized building blocks in excellent selectivities via
haliranium ion-triggered Friedel-Crafts-type alkylation with a broad range of chalcones and cinnamate esters in HFIP.
13
This article is protected by copyright. All rights reserved.