A concise route towards isoflavans

Article abstract of DOI:10.1002/jhet.4158

Isoflavans have gained considerable interest owing to their potential health benefits. Herein, we have presented a straightforward strategy for isoflavans synthesis. The strategy features an intermolecular [Cu]-catalyzed arylation of malonates and an intr

Full text of DOI:10.1002/jhet.4158

A Concise Route Towards Isoflavans
Basuli Suchand, Chinnabattigalla Sreenivasulu, Kshitija Gupta and Gedu Satyanarayana*
Dedication ((optional))
Department of Chemistry,
Indian Institute of Technology Hyderabad,
Kandi, Sangareddy,
502285, Telangana, India.
Ph. No: +91(40) 23016054,
E-mail: gvsatya@iith.ac.in
isoflavans isolated are sativan, vestitol, colutelol, lespedezol G1;
lespecyrtin D1, etc.14
Abstract: Isoflavans have gained considerable interest
owing to their potential health benefits. Herein, we have
presented a straightforward strategy for isoflavans synthesis.
The strategy features an intermolecular [Cu]-catalyzed arylation
of malonates and an intramolecular [Pd]-catalyzed Buchwald
coupling of hydroxy tethered bromoarenes as the key
transformations. This protocol enabled the synthesis of a variety
of isoflavan analogs.
Because of their unique structure and significant
biological activities, isoflavans have gained much recognition in
synthetic chemistry. Various research groups have put in many
efforts to develop numerous chemical routes to synthesize the
isoflavan/chroman frameworks.15 Most synthetic strategies
utilized the process of catalytic hydrogenation of isoflavenes,
under the action of a palladium catalyst in different solvents and
at pH conditions.16 A few of the approaches have mentioned.
The synthesis of Equol achieved from the reaction of the
racemic forms of formononetin and daidzein.17 An
enantioselective route to dimethoxy counterpart of (S)-Equol
was established by Ferreira and co-workers.18 Subsequently,
Heemstra et al. demonstrated a total synthesis of (S)-Equol by
employing enantioselective Evans' alkylation and intramolecular
Buchwald-Hartwig etherification, as key steps.19 Yang et al.
shown enantioselective hydrogenation reaction of a-arylcinnamic
acids under iridium-catalysis.20 They have extended a similar
strategy for the production of (S)-Equol.21 Recently, the research
group of Jingzhao Xia revealed asymmetric hydrogenation of
2H-chromenes via a catalytic action of Ir/In-BiphPHOX for the
synthesis of (S)-Equol with >95% ee.22 Gharpure et al. in his
work employed hetero-Diels-Alder reaction between olefin and
ortho-quinone methides.23
Introduction
Through the work of a couple of decades, chemists
have been able to develop broader transition-metal catalysts
based applications that catalyze cross-coupling reactions.1
Consequently, the implementation of these reactions in synthetic
organic chemistry has led to successful results.2 However, there
have been concerns regarding target specific cross-coupling
reactions, primarily involving C−heteroatom bond forming
techniques.3 Challenges in these sorts of transformations would
be due to particular side reactions, particularly, dehalogenation.4
In this context, isoflavans have gained much popularity with the
synthetic chemists. Isoflavans are oxygen-containing fused
bicyclic heterocycles featuring biological properties similar to
isoflavones5 and are C15 frameworks contemplated as
derivatives of 3-phenylchroman.6 Also, Isoflavans widely spread
and constitute isoflavonoid natural products.7 These compounds
showcase
prominent
biological
and
pharmacological
With this background, herein, we wish to disclose a
new protocol towards the synthesis of isoflavans. Carrying
forward our work on [TM]-catalysis,24 we have recently reported
effective synthetic strategies for flavans.25 In continuation of our
significance.8 Interestingly, the first isoflavan was an accidental
discovery, and it was named Equol. For the first time, Equol
isolated during an attempt to isolate estrogen from equine urine.9
After that, it was extracted from the urine of other animals and
humans, as well.10 Equol widely used as a dietary phytoestrogen
to decrease the prostate weight of rats.11 Apart from this, the
compounds belonging to this family have also reportedly seen to
possess anti-fungal, anticancer, and antioxidant properties.12
Also, it revealed that these compounds help prevent
osteoporosis, androgen, and inflammation and even slow down
the process of ageing.13 They also assist in brain mitochondrial
activities and prohibit prostrate growth. The various other
interests, we have demonstrated
a
protocol affording
neoflavans.26 Herein; we disclose a new strategy delivering
functionalized isoflavans. The synthetic route shows two key
transformations via transition-metal catalyzed reactions using
[Pd] and [Cu] metal catalysts.
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Figure 1: Retrosynthetic Analysis of Isoflavan 8/9.
Results and Discussion
The synthetic route to achieve isoflavans was initiated
with aryl malonate esters 2 and benzyl bromides 3. Thus, we
attempted the synthessis of aryl malonate esters 2 from
iodoarenes 1 and dimethyl malonate. The reaction was carried
out using CuI (5 mol%), picolinic acid (10 mol%), Cs2CO3 (1.5
equiv), in 1,4-dioxane as a solvent for 24 h at 100 °C.
Consequently, aryl malonate esters 2 were isolated in high
yields (Table 1).27 Benzylation reaction of aryl malonate esters 2
was performed using ortho-bromobenzyl bromides 3 at ambient
temperature, K2CO3, and in dry DMF. As a result, excellent
yields of the tethered ortho-Bromo-bis-aryl malonate esters 4
were obtained (Table 1). Next, the Krapcho decarboxylation
reaction was applied to the above-furnished compounds 4 using
NaCl in DMSO and water mixture (10:1) at 160 °C for 20 h. So,
ortho-Bromo-bis-aryl monoesters 5 were isolated in acceptable
From the retrosynthetic analysis, it was conceived that
isoflavans 8/9 could be accomplished utilizing an intramolecular
[Pd]-catalyzed Buchwald–Hartwig coupling of
hydroxy
bromoarenes 6/7 (Figure 1). Required primary and tertiary
alcohols 6/7 could be synthesized from aryl malonate esters 2
and ortho-bromobenzyl bromides 3. A suitable synthetic path in
achieving 6/7 would be benzylation, Krapcho decarboxylation,
and reduction/nucleophilic addition.
yields,
as
tabulated
in
Table
1.
Table 1: Scope for the formation of diaryl-monoesters 5aa-5ca.a
aIsolated yields of chromatographically pure products 2a-2c, 4aa-4ca and 5aa-5ca.
After achieving aryl benzyl esters 5, reduction of the
ester group was employed to furnish the corresponding alcohol,
which is
a
synthetic precursor for the metal-mediated
cyclizations. Consequently, the reduction reaction of the esters 5
2
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mediated by LiAlH4, afforded the corresponding primary alcohols
6a-6c in nearly quantitative yields without affecting the bromo-
substitution (Table 2). Furthermore, the reduction of the ester by
a Grignard reagent furnished the corresponding tertiary alcohols
7a-7h in very good to excellent yields (Table 2).
In this context, initially, we tested with our previously established
conditions in the synthesis of flavans and neo-flavans [i.e. CuI
(20 mol%)/2,2-bipyridyl (20 mol%), base KOtBu (3 equiv.) in dry
DMF (120 °C) for 24 h].25 However, unfortunately, these
conditions were not favorable in delivering the expected
isoflavan 8a (entries 1, Table 3). At this stage, we reckoned that
the use of excess base (KOtBu) might have hampered the
reaction. Thus we thought less amount of base (KOtBu) would
be more effective. Hence, the reaction was conducted using 2
and 1 equiv of KOtBu (entries 2 & 3, Table 3). However, the
attempts were futile in obtaining the isoflavan product 8a. Since
copper alone was not an optimum and general catalyst for the
C–O bond formation, we turned our focus towards utilizing [Pd]-
catalyst, which might also serve as more effective. Interestingly,
the commencing attempt alone showed effective results
[Pd(OAc)2 (10 mol%), JohnPhos (10 mol%), Cs2CO3 (2.0 equiv),
in dry toluene, at 90 °C for 24 h (entry 4, Table 3)].28 The final
product was predominantly the cyclized compound isoflavan 8a,
which isolated in a good yield of 80%. Additionally, to find the
most efficient operational conditions, the conditions were
modified by altering the temperature (entries 5 & 6, Table 3).
The attempt has not found to be effective in increasing the yield.
Moving ahead, we increased the base to 3 equiv and observed
the undesired products at the expense of the desired product 8a
(entry 7, Table 3). While running the reaction in solvent DMF at
90 C for 14 h, we afforded isoflavan 8a in 60% yield (entry 8,
Table 3). Ultimately, by increasing the catalyst loading and
decreasing the reaction times to 12 h, we managed to improve
the yield to 85% (entry 9, Table 3). Delightfully, the same results
obtained by using 3 mol% of a palladium catalyst and 5 mol% of
ligand (entry 10, Table 3).
Table 2: Scope for the formation of alcohols 6a-6c/7a-7h.a,b,c,d
aIsolated yields of chromatographically pure products 6a-6c and 7a-7h.
bTertiary alcohols 7a-7h were prepared from bromo-esters 5aa-5ca using
alkyl/aryl Grignard reaction. cFor Lithium Aluminium Hydride (LAH) reduction
and methyl Grignard reaction, dry diethyl ether (Et2O) was used as solvent.
dFor ethyl/propyl/phenyl Grignard reaction dry tetrahydrofuran (THF) was used
as a solvent.
After obtaining bromo alcohols 6a-6c/7a-7h, we went ahead with
the key transformation step. It was an intramolecular reaction
leading to the construction of a C-O bond facilitated by a
transition metal catalyst to generate the corresponding isoflavan.
Table 3: Screening studies for the formation of isoflavan 8a.a,b,c
3
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Entry
Catalyst (mol%)
Ligand (mol%)
Base (equiv)
Solvent
(mL)
Temp
(°C)
Time
(h)
% of
Yield
(8a)b
c
1
2
CuI (20)
2,2’-bipyridyl (20)
2,2’-bipyridyl (20)
2,2’-bipyridyl (20)
JohnPhos (20)
JohnPhos (20)
JohnPhos (20)
JohnPhos (10)
JohnPhos (20)
JohnPhos (20)
JohnPhos (5)
KOtBu (3)
KOtBu (2)
DMF
DMF
120
120
120
90
24
24
24
24
12
20
12
14
12
12
CuI (20)
SM
SM
79
80
73
64
60
85
85
3
CuI (20)
KOtBu (1)
DMF
4
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (20)
Pd(OAc)2 (3)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (3)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Toluene
Toluene
toluene
toluene
DMF
5
110
70
6
7
90
8
90
9
toluene
toluene
90
10
90
aUnless then stated, all reactions were conducted by using 58.0 mg (0.20 mmol) of 6a, in 2 mL dry solvent. bYields of isolated product 8a.
cNo significant spot was observed on TLC.
Table 4: Scope for the formation of isoflavans 8a-8c/9a-9h.a,b
Moving forward, we examined the generality of the
scheme by implementing it on other substrates and applying the
above optimal conditions (entry 10, Table 3). The various
precursor alcohols 6a-6c subjected to the CO bond formation
intramolecularly. To our delight, the experimental conditions
verified to be practical in furnishing cyclized isoflavans 8a-8c
efficiently (Table 4). Furthermore, to test the scope and
limitations of the strategy, we employed the same protocol for
the production of tertiary alcohols. Thus, concluding the scheme,
we investigated the critical step constructing C–O bond
intramolecularly from bromo tertiary alcohols 7a-7h catalyzed
using palladium. As expected, the synthetic strategy worked well
on tertiary alcohols 7a-7h and afforded functionalized isoflavans
aChromatographically isolated yields of pure compounds 8a-8c & 9a-
9a-9h in good to excellent yields (Table 4).
9h. bReaction carried out on alcohols 6a-7h (0.20 mmol) in dry
toluene (2 mL).
Conclusion
4
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In conclusion, a straightforward synthetic route about
the synthesis of functionalized isoflavans devised. An
intermolecular CC and intramolecular CO bonds formation
were facilitated by [Cu] and [Pd], as the key transformations of
the strategy, respectively. This method is practical and flexible in
enabling the synthesis of different isoflavan derivatives.
acetate (3 × 20 mL) and saturated aqueous NH4Cl (40 mL). The
separated organic layers were dried using Na2SO4, filtered and
concentrated by rotary evaporator under reduced pressure.
Purification of the crude mixture using silica gel column
chromatography, furnished α-aryl malonate products 2a-2c (89-
92%).
General Procedure-2 for the synthesis of alkylated malonate
esters (4aa-4ca): Potassium carbonate (1.14 gm, 8.18 mmol,
3.0 equiv) was suspended in dry DMF (10 mL) at room
temperature. A solution containing aryl malonates 2 (2.72 mmol,
1.0 equiv) in 5 mL dry DMF was added to it dropwise. After 30
Experimental Section
General procedure:
A Bruker Tensor 37 (FT-IR) spectrophotometer was used to
record the IR spectra. Bruker Avance 400 (400 MHz)
min stirring at room temperature,
a solution of ortho-
1
spectrometer was used to record H-NMR spectra at 295 K in
bromobenzyl bromides 3 (3.27 mmol, 1.2 equiv) in dry DMF (5
mL) was added, and stirring was continued for further 12-15 h.
The reaction mixture was quenched with saturated aqueous
NH4Cl solution (40 mL), and extracted with EtOAc (3 × 20 mL).
Then the organic layers were washed with brine solution (30 mL)
and dried using anhydrous Na2SO4, filtered and the organic
layer was concentrated in rotary evaporator under reduced
pressure. Silica gel column chromatography of the residue,
generated the products, ortho-bromobenzyl malonates 4aa-4ca
(87-95%).
CDCl3; chemical shifts (δ in ppm) and coupling constants (J in
Hz) are reported in standard manner with reference to either
internal standard tetramethylsilane (TMS) (δH = 0.00 ppm) or
CHCl3 (δH = 7.25 ppm). Bruker Avance 400 (100 MHz)
spectrometer was used to record 13C-NMR spectra at RT in
CDCl3; chemical shifts (δ in ppm) are reported relative to CDCl3
[δC = 77.00 ppm (central line of triplet)]. The various initials
1
notations used in the H-NMR are: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet. 1H, 13C CPD and DEPT spectra
were useful to validate the assignment of signals. For accurate
mass measurements, Agilent 6538 UHD Q-TOF was used to
record High-resolution mass spectra (HR-MS) through the
multimode source. TLC monitored the progress of reactions on
silica gel coated on alumina plate or glass plate. The eluents
employed were a mixture of petroleum ether and ethyl acetate.
Reactions were conducted under nitrogen atmosphere in order
to maintain the inert condition.
General Procedure-3 for the synthesis of aryl mono esters
(5aa-5ca): A mixture of the alkylated malonate esters 4 (1.53
mmol), sodium chloride (178.0 mg, 3.07 mmol, 2.0 equiv) in
DMSO:H2O (10:1) (12 mL) was placed in a sealed tube. The
o
reaction mixture was heated at a temperature of 160 C for 18-
20 h. The mixture was cooled to room temperature and poured
into EtOAc (60 mL), washed using brine solution (2 × 30 mL),
dried by Na2SO4 and concentrated using rotary evaporator
under reduced pressure. The crude reaction mixture was
purified by silica gel column chromatography to afford the
products (5aa-5ca) as an oil (69-75%).
Materials: Solvents were distilled/dried before use. Petroleum
ether, dichloromethane (DCM), ethyl acetate and dry DMSO
were employed as solvents. Petroleum ether has a boiling range
of 60 to 80 °C and dry DMSO has a boiling range of 160 to 170
°C with purity 99%. They were bought from Sigma Aldrich as
well as local commercial sources. For chromatography, Acme’s
silica gel (100-200 mesh) was used.
General Procedure-4 for reduction of malonate esters (5aa-
5ca): Under N2 atmosphere, in a dry round-bottomed flask
bromo malonate esters 5 (0.50 mmol) in dry Et2O (25 mL) was
taken, to which LiAlH4 (1.50 mmol) was slowly added in portion
wise at 0 ˚C. Then the reaction mixture was allowed to stirrer for
2 h at 0 ˚C. Then quenched with ethyl acetate ( 30 mL), and the
resultant mixture was separated using ethyl acetate (2 × 30 mL)
and brine solution (60 mL). The separated organic layers were
dried by Na2SO4 and concentrated using rotary evaporator
under reduced pressure. Then the reaction mixture was purified
by silica gel column chromatography to furnish the primary
alcohols 6a-6c (93-97%).
General Procedure-1 for the synthesis of aryl malonate
esters (2a-2c): To an oven-dried round-bottomed flask charged
with a Teflon-coated magnetic stirrer bar, were added aryl
iodides 1 (5.0 mmol), CuI (5.0 mol%), 2-picolinic acid (10.0
mol%), Cs2CO3 (10.0 mmol), and distilled diethyl malonate (7.5
mmol) and purged with nitrogen gas (3 cycles). Anhydrous 1,4-
dioxane (10 mL) was added to the reaction mixture heated in a
preheated oil bath at 80 °C. After the designated time, the
completed reaction (judged by TLC analysis) was allowed to
reach room temperature. The mixture was separated using ethyl
5
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General Procedure-5 for the synthesis of tertiary alcohol
(7a-7h): In a round-bottomed flask magnetically stirred esters 5
(0.50 mmol) in 5 mL of dry ether/THF was taken, to which
methylmagnesium iodide (2.5 mmol) or ethyl/ propyl/ phenyl
magnesium bromide (2.5 mmol) [prepared from magnesium (2.5
mmol) and methyl iodide (4.00 mmol) in dry ether or
ethyl/propyl/phenyl bromide (4.00 mmol) in dry THF and a
catalytic amount of iodine] was added at 10 C. The reaction
mixture was stirred for 3-5 h 10 C to rt. Then quenched by
aqueous NH4Cl (50 mL) and extracted using ethyl acetate (2 ×
30 mL). The organic layers were dried by Na2SO4 and
concentrated in rotary evaporator. The crude products were
purified by using silica gel column chromatography to furnish the
tertiary alcohols 7a-7h (71–95%).
85:15), furnished 4ab (964 mg, 87%) as colourless viscus liquid.
[TLC monitor (PE/EA 90:10), Rf(2a) = 0.30, Rf(3b) = 0.70, UV
1
detection]. H NMR (400 MHz, CDCl3) δ = 7.34 – 7.21 (m, 6H),
6.60 (dd, J = 8.8, 3.1 Hz, 1H), 6.48 (d, J = 3.1 Hz, 1H), 3.82 (s,
2H), 3.77 (s, 6H), 3.57 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3)
δ = 170.4, 158.2, 136.6, 136.1, 132.9, 128.3, 128.0, 127.6,
117.0, 116.2, 114.7, 63.4, 55.1, 52.9, 41.5 ppm. HRMS (ESI)
calculated [M+Na]+ for C19H19BrNaO5 : 429.0308, found:
+
429.0305.
Dimethyl 2-(2-bromobenzyl)-2-(m-tolyl)malonate (4ba): GP-2
was followed with potassium carbonate (1.14 gm, 8.18 mmol,
3.0 equiv) in dry DMF (10 mL), aryl malonate 2b (604 mg, 2.72
mmol, 1.0 equiv) was added with ortho-bromobenzyl bromides
3a (814 mg, 3.27 mmol, 1.2 equiv) in 5 mL dry DMF, and stirred
for 14 h. The column chromatography purification (PE/EA, 95:05
to 90:10), furnished 4ba (968 mg, 91%) as colourless viscus
liquid. [TLC monitor (PE/EA 95:05), Rf(2b) = 0.30, Rf(3a) = 0.70,
General Procedure-6 for the Synthesis of Isoflavans (8a-
8c/9a-9h): Alcohol 6 or 7 (0.20 mmol), Pd(OAc)2 (3 mol%),
JohnPhos (5 mol%), Cs2CO3 (0.40 mmol) were added to a dried
Schlenk tube under N2 atmosphere. Then 2 mL dry toluene was
added to the mixture and stirred at 90 C for 12-14 h. After
completion of the reaction, the reaction mixture was quenched
by aq. NH4Cl (30 mL) and extracted with ethyl acetate (3 × 20
1
UV detection]. H NMR (400 MHz, CDCl3) δ = 7.45 (dd, J = 7.8,
1.3 Hz, 1H), 7.15 – 7.11 (m, 2H), 7.11 – 7.04 (m, 3H), 7.00 (ddd,
J = 14.3, 7.6, 1.8 Hz, 2H), 3.85 (s, 2H), 3.73 (s, 6H), 2.32 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3) δ = 170.6, 137.5, 136.0, 135.9,
132.6, 131.0, 129.0, 128.4, 128.2, 127.9, 126.9, 126.6, 125.2,
63.4, 52.9, 41.2, 21.6 ppm. HRMS (ESI) calculated [M+H]+ for
mL).
The organic layers were dried by Na2SO4 and
concentrated in rotary evaporator under reduced pressure. The
purification of crude mixture using silica gel column
chromatography, furnished the isoflavan products 8a-8c/9a-9h
(79-94%).
+
C19H20BrO4 : 391.0539, found: 391.0535
Dimethyl 2-(2-bromobenzyl)-2-(p-tolyl)malonate (4ca): GP-2
was followed with potassium carbonate (1.14 gm, 8.18 mmol,
3.0 equiv) in dry DMF (10 mL), aryl malonate 2c (604 mg, 2.72
mmol, 1.0 equiv) was added with ortho-bromobenzyl bromides
3a (814 mg, 3.27 mmol, 1.2 equiv) in 5 mL dry DMF, and stirred
for 14 h. The column chromatography purification (PE/EA, 95:05
to 90:10), furnished 4ca (947 mg, 89%) as colourless viscus
liquid. [TLC monitor (PE/EA 95:05), Rf(2c) = 0.30, Rf(3a) = 0.70,
Dimethyl 2-(2-bromobenzyl)-2-phenylmalonate (4aa): GP-2
was followed with potassium carbonate (1.14 gm, 8.18 mmol,
3.0 equiv) in dry DMF (10 mL), aryl malonate 2a (566 mg, 2.72
mmol, 1.0 equiv), ortho-bromobenzyl bromides 3a (814 mg, 3.27
mmol, 1.2 equiv) in 5 mL dry DMF (5 mL), and stirred for 12 h.
The column chromatography purification (PE/EA, 95:05 to
90:10), furnished the isolflavan 4aa (975 mg, 95%) as colourless
viscus liquid. [TLC monitor (PE/EA 95:05), Rf(2a)= 0.30, Rf(3a) =
0.70, UV detection]. 1H NMR (400 MHz, CDCl3) δ = 7.44 (dd, J =
7.9, 1.4 Hz, 1H), 7.29 – 7.19 (m, 5H), 7.09 (td, J = 7.5, 1.4 Hz,
1H), 7.01 (ddd, J = 16.9, 7.6, 1.8 Hz, 2H), 3.87 (s, 2H), 3.76 (s,
6H) ppm. 13C NMR (100 MHz, CDCl3) δ = 170.5, 136.0, 135.8,
132.6, 131.0, 128.3, 128.3, 128.0, 127.6, 127.0, 126.6, 63.4,
1
UV detection]. H NMR (400 MHz, CDCl3) δ = 7.45 (dd, J = 7.8,
1.3 Hz, 1H), 7.16 – 7.11 (m, 2H), 7.11 – 7.05 (m, 3H), 7.01 (ddd,
J = 13.1, 7.5, 1.8 Hz, 2H), 3.86 (s, 2H), 3.73 (s, 6H), 2.32 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3) δ = 170.6, 137.4, 136.0, 133.1,
132.6, 131.0, 128.7, 128.2, 128.1, 126.9, 126.5, 63.0, 52.8, 41.0,
+
21.0 ppm. HRMS (ESI) calculated [M+H]+ for C19H20BrO4 :
391.0539, found: 391.0533
Methyl 3-(2-bromophenyl)-2-phenylpropanoate (5aa): GP-3
was followed with alkylated malonate esters 4aa (1.53 mmol),
sodium chloride (178.0 mg, 3.07 mmol, 2.0 equiv) in DMSO:H2O
(10:1) (12 mL) in sealed tube and stirred at 160 oC for 18 h. The
column chromatography purification (PE/EA, 97:03 to 95:05),
afforded 5aa (366 mg, 75%) as colourless viscus liquid. [TLC
monitor (PE/EA 95:05), Rf(4aa) = 0.30, Rf(5aa) = 0.70, UV
+
52.9, 41.2 ppm. HRMS (ESI) calculated [M+H]+ for C18H18BrO4 :
377.0383, found: 377.0378.
Dimethyl2-(2-bromo-5-methoxybenzyl)-2-phenylmalonate
(4ab): GP-2 was followed with potassium carbonate (1.14 gm,
8.18 mmol, 3.0 equiv) in dry DMF (10 mL), aryl malonate 2a
(566 mg, 2.72 mmol, 1.0 equiv), ortho-bromobenzyl bromides 3b
(915 mg, 3.27 mmol, 1.2 equiv) in 5 mL dry DMF, and stirred for
15 h. The column chromatography purification (PE/EA, 90:10 to
1
detection]. H NMR (400 MHz, CDCl3) δ = 7.52 (dd, J = 7.8, 1.2
6
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Hz, 1H), 7.34 – 7.22 (m, 5H), 7.13 – 7.01 (m, 3H), 4.04 (dd, J =
13.0, 10.3 Hz, 1H), 3.60 (s, 3H), 3.50 (dd, J = 13.6, 9.0 Hz, 1H),
3.13 (dd, J = 13.6, 6.3 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3)
δ = 173.6, 138.5, 138.1, 132.8, 131.5, 128.7, 128.2, 127.8,
127.4, 127.2, 124.6, 52.0, 51.0, 40.2 ppm. HRMS (ESI)
1H), 7.22 (d, J = 8.1, 2H), 7.18 – 7.08 (m, 4H), 7.05 (ddd, J =
7.9, 3.0, 2.3 Hz, 1H), 4.01 (dd, J = 13.0, 6.2 Hz, 1H), 3.60 (s,
3H), 3.50 (dd, J = 13.6, 9.0 Hz, 1H), 3.12 (dd, J = 13.7, 6.2 Hz,
1H), 2.33 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 173.7,
138.3, 137.1, 135.5, 132.8, 131.5, 129.3, 128.1, 127.6, 127.2,
124.7, 51.9, 50.7, 40.1, 21.0 ppm. HRMS (ESI) calculated
calculated [M+H]+ for C16H16Br79O2 : 319.0328, found: 319.0324
+
and [M+H]+ for C16H16Br81O2 : 321.0308, found: 321.0305.
[M+H]+ for C17H18Br79O2 : 333.0485, found: 333.0482 and
+
+
[M+H]+ for C17H18Br81O2 : 335.0464, found: 335.0460.
+
Methyl-3-(2-bromo-5-methoxyphenyl)-2-phenylpropanoate
(5ab): GP-3 was followed with alkylated malonate esters 4ab
(1.53 mmol), sodium chloride (178.0 mg, 3.07 mmol, 2.0 equiv)
in DMSO:H2O (10:1) (12 mL) in sealed tube and stirred at 160
oC for 20 h. The column chromatography purification (PE/EA,
97:03 to 93:07), afforded 5ab (379 mg, 71%) as colourless
viscus liquid. [TLC monitor (PE/EA 93:07), Rf(4ab) = 0.30,
3-(2-Bromophenyl)-2-phenylpropan-1-ol (6a): GP-4 was
followed with bromo malonateester 5aa (0.50 mmol) in dry ether
(25 mL), was added slowly LiAlH4 (1.50 mmol) in portion wise 0
˚C and the resultant reaction mixture was stirred for at 0 ˚C for 2
h to get compound 6a. The column chromatography purification
(PE/EA, 93:07 to 90:10), gave 6a (138 mg, 95%) as colourless
viscus liquid. [TLC monitor (PE/EA 95:05), Rf(5aa) = 0.70, Rf(6a)
1
Rf(5ab) = 0.70, UV detection]. H NMR (400 MHz, CDCl3) δ =
1
7.39 (d, J = 8.5 Hz, 1H), 7.34 – 7.22 (m, 5H), 6.64 – 6.58 (m,
2H), 4.00 (dd, J = 8.7, 6.5 Hz, 1H), 3.65 (s, 3H), 3.62 (s, 3H),
3.47 (dd, J = 13.6, 8.8 Hz, 1H), 3.08 (dd, J = 13.6, 6.5 Hz, 1H)
ppm. 13C NMR (100 MHz, CDCl3) δ = 173.5, 158.5, 139.0, 138.4,
133.2, 128.7, 127.8, 127.4, 116.7, 115.0, 114.3, 55.3, 52.0, 51.0,
= 0.30, UV detection]. H NMR (400 MHz, CDCl3) δ = 7.50 (d,
J=8.4 Hz, 1H), 7.31 – 7.25 (m, 2H), 7.20 (t, J = 6.6 Hz, 3H), 7.10
– 7.05 (m, 1H), 6.98 (ddd, J = 14.6, 7.5, 1.8 Hz, 2H), 3.77 (dd, J
= 5.9, 2.9 Hz, 2H), 3.21 – 3.14 (m, 2H), 2.93 (ddd, J = 16.5, 9.1,
4.3 Hz, 1H), 1.63 (br.s, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ
= 141.6, 139.1, 132.7, 131.3, 128.5, 128.0, 127.7, 127.0, 126.8,
124.6, 65.9, 48.1, 38.8 ppm. HRMS (ESI) calculated [(M+H)+(-
+
40.3 ppm. HRMS (ESI) calculated [M+H]+ for C17H18Br79O3 :
+
349.0434, found: 349.0421 and [M+H]+ for C17H18Br81O3 :
351.0413, found: 351.0408.
H2O)]+ for C15H14Br79+
:
273.0273, found: 273.0271 and
Methyl 3-(2-bromophenyl)-2-(m-tolyl)propanoate (5ba): GP-3
was followed with alkylated malonate esters 4ba (1.53 mmol),
sodium chloride (178.0 mg, 3.07 mmol, 2.0 equiv) in DMSO:H2O
(10:1) (12 mL) in sealed tube and stirred at 160 oC for 19 h. The
column chromatography purification (PE/EA, 97:03 to 95:05),
afforded 5ba (403 mg, 79%) as colourless viscus liquid. [TLC
monitor (PE/EA 95:05), Rf(4ba) = 0.30, Rf(5ba) = 0.70, UV
[(M+H)+(-H2O)]+ for C15H14Br81+: 275.0254, found: 275.0251.
3-(2-Bromophenyl)-2-(m-tolyl)propan-1-ol (6b): GP-4 was
followed with bromo malonateester 5ba (0.50 mmol) in dry ether
(25 mL), was added slowly LiAlH4 (1.50 mmol) in portion wise 0
˚C and the resultant reaction mixture was stirred for at 0 ˚C for 2
h. The column chromatography purification (PE/EA, 93:07 to
90:10), gave 6b (148 mg, 97%) as colourless viscus liquid. [TLC
monitor (PE/EA 95:05), Rf(5ba) = 0.70, Rf(6b) = 0.30, UV
1
detection]. H NMR (400 MHz, CDCl3) δ = 7.53 (dd, J = 7.9, 1.0
1
Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.17 – 7.02 (m, 6H), 4.00 (dd, J
= 9.2, 5.9 Hz, 1H), 3.60 (s, 3H), 3.49 (dd, J = 13.6, 9.2 Hz, 1H),
3.12 (dd, J = 13.6, 5.9 Hz, 1H), 2.33 (s, 3H) ppm. 13C NMR (100
MHz, CDCl3) δ = 173.6, 138.4, 138.3, 138.3, 132.8, 131.5,
128.5, 128.4, 128.2, 128.2, 127.2, 124.8, 124.7, 52.0, 51.0, 40.1,
detection]. H NMR(400 MHz, CDCl3) δ = 7.52 (dd, J = 8.4, 1.2
Hz, 1H), 7.24 – 7.17 (m, 1H), 7.12 (td, J = 7.4, 1.3 Hz, 1H), 7.08
– 6.99 (m, 5H), 3.86 – 3.74 (m, 2H), 3.23 – 3.13 (m, 2H), 3.03 –
2.92 (m, 1H), 2.33 (s, 3H), 1.39 (br.s, 1H) ppm. 13C NMR (100
MHz, CDCl3) δ = 141.5, 139.3, 138.2, 132.8, 131.3, 128.8,
128.5, 127.8, 127.7, 127.1, 125.0, 124.7, 66.0, 48.1, 38.8, 21.5
ppm. HRMS (ESI) calculated [M+NH4]+ for C16H21Br79NO+:
322.0801, found: 322.0799 and [M+NH4]+ for C16H21Br81NO+:
324.0781, found: 324.0780.
21.4 ppm. HRMS (ESI) calculated [M+H]+ for C17H18Br79O2 :
+
333.0485, found: 333.0484 and [M+H]+ for C17H18Br81O2 :
+
335.0464, found: 335.0463.
Methyl 3-(2-bromophenyl)-2-(p-tolyl)propanoate (5ca): GP-3
was followed with alkylated malonate esters 4ca (1.53 mmol),
sodium chloride (178.0 mg, 3.07 mmol, 2.0 equiv) in DMSO:H2O
(10:1) (12 mL) in sealed tube and stirred at 160 oC for 18 h. The
column chromatography purification (PE/EA, 97:03 to 95:05),
afforded 5ca (352 mg, 69%) as colourless viscus liquid. [TLC
monitor (PE/EA 95:05), Rf(4ca) = 0.30, Rf(5ca) = 0.70, UV
detection]. 1H NMR (400 MHz, CDCl3) δ = 7.53 (dd, J = 7.9, 1.1,
3-(2-Bromophenyl)-2-(p-tolyl)propan-1-ol (6c): GP-4 was
followed with bromo malonate ester 5ca (0.50 mmol) in dry ether
(25 mL), was added slowly LiAlH4 (1.50 mmol) in portion wise 0
˚C and the resultant reaction mixture was stirred for at 0 ˚C for 2
h. The column chromatography purification (PE/EA, 93:07 to
90:10), gave 6c (142 mg, 93%) as colourless viscus liquid. [TLC
control PE/EA 95:05), Rf(5ba) = 0.70, Rf(6c) = 0.30, UV
7
This article is protected by copyright. All rights reserved.

1
detection]. H NMR (400 MHz, CDCl3) δ = 7.52 (d, J = 8.0 Hz,
CDCl3 δ = 146.2, 145.4, 139.5, 139.1, 132.5, 131.5, 130.3,
130.0, 128.2, 127.7, 127.6, 127.2, 126.8, 126.6, 126.4, 126.3,
126.1, 125.7, 124.6, 80.9, 53.2, 36.7 ppm. HRMS (ESI)
calculated [(M+H)+(-H2O)]+ for C27H22Br79+: 425.0899, found:
425.0896 and [(M+H)+(-H2O)]+ for C27H22Br81+: 427.0883,
found: 427.0879.
1H), 7.15 – 7.09 (m, 5H), 7.03 (dd, J = 12.1, 4.7 Hz, 2H), 3.79 (s,
2H), 3.18 (dt, J = 11.1, 6.2 Hz, 2H), 3.02 – 2.90 (m, 1H), 2.32 (s,
3H), 1.42 (br. s, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ = 139.3,
138.4, 136.4, 132.8, 131.3, 129.3, 127.9, 127.7, 127.1, 124.7,
66.1, 47.7, 38.9, 21.0 ppm. HRMS (ESI) calculated [M+NH4]+ for
C16H21Br79NO+: 322.0801, found: 322.0797 and [M+NH4]+ for
C16H21Br81NO+: 324.0782, found: 324.0777.
4-(2-Bromo-5-methoxyphenyl)-2-methyl-3-phenylbutan-2-ol
(7d): GP-5 was followed to obtain title compound 7d from ester
5ab (0.50 mmol). The column chromatography purification
(PE/EA, 90:10 to 85:15), delivered 7d (157 mg, 90%) as
colourless viscus liquid. [TLC monitor PE/EA 90:10), Rf(5ab) =
0.70, Rf(7d) = 0.30, UV detection]. 1H NMR (400 MHz, CDCl3) δ
= 7.29 (d, J = 8.7 Hz, 1H), 7.25 – 7.13 (m, 5H), 6.47 (dd, J = 8.7
and 3.1 Hz, 1H), 6.23 (d, J = 3.1 Hz, 1H), 3.45 (s, 3H), 3.42 (d, J
= 1.9 Hz, 1H), 3.12 – 2.87 (m, 2H), 1.46 (s, 1H), 1.36 (s, 3H),
1.24 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 158.1, 140.8,
140.4, 132.9, 129.7, 128.0, 126.7, 116.4, 114.9, 113.8, 73.2,
56.7, 55.1, 36.7, 28.5, 28.2 ppm. HRMS (ESI) calculated
[(M+H)+(-H2O)]+ for C18H20Br79O+: 331.0692, found: 331.0688
4-(2-Bromophenyl)-2-methyl-3-phenylbutan-2-ol (7a): GP-5
was followed to obtain title compound 7a from ester 5aa (0.50
mmol). The column chromatography purification (PE/EA, 93:07
to 90:10), delivered 7a (152 mg, 95%) as colourless viscus
liquid. [TLC monitor PE/EA 95:05), Rf(5aa) = 0.70, Rf(7a) = 0.30,
1
UV detection]. H NMR (400 MHz, CDCl3) δ = 7.48 – 7.37 (m,
1H), 7.24 – 7.12 (m, 5H), 6.96 – 6.84 (m, 2H), 6.78 – 6.70 (m,
1H), 3.46 (dd, J = 12.8, 2.2 Hz, 1H), 3.17 – 3.00 (m, 2H), 1.49
(br. s, 1H), 1.36 (s, 3H), 1.24 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3) δ = 140.3, 139.9, 132.6, 131.4, 129.7, 127.9, 127.3,
126.7, 126.6, 124.5, 73.1, 56.6, 36.4, 28.4, 28.2 ppm. HRMS
(ESI) calculated [(M+H)+(-H2O)]+ for C17H18Br79+: 301.0586,
and
333.0668.
[(M+H)+(-H2O)]+
for C18H20Br81O+: 333.0673, found:
found: 301.0582 and
[(M+H)+(-H2O)]+
for C17H18Br81+
:
303.0567, found: 303.0562.
4-(2-Bromophenyl)-2-methyl-3-(m-tolyl)butan-2-ol (7e): GP-5
was followed to obtain compound 7e from ester 5ba (0.50
mmol). The column chromatography purification (PE/EA, 93:07
to 90:10), delivered 7e (150 mg, 90%) as colourless viscus
liquid. [TLC monitor PE/EA 93:07), Rf(5ba) = 0.70, Rf(7e) = 0.30,
1-(2-Bromophenyl)-3-ethyl-2-phenylpentan-3-ol (7b): GP-5
was followed to obtain title compound 7b from ester 5aa (0.50
mmol). The column chromatography purification (PE/EA, 93:07
to 90:10), delivered 7b (160 mg, 92%) as colourless viscus
liquid. [TLC monitor PE/EA 95:05), Rf(5aa) = 0.70, Rf(7b) = 0.30,
1
UV detection]. H NMR(400 MHz, CDCl3) δ = 7.43 (dd, J = 7.6
1
UV detection]. H NMR (400 MHz, CDCl3) δ = 7.45 – 7.36 (m,
and 1.7 Hz, 1H), 7.11 (t, J = 7.7 Hz, 1H), 7.02 – 6.86 (m, 5H),
6.77 (dd, J = 7.2 and 2.1 Hz, 1H), 3.44 (dd, J = 13.4 and 2.8 Hz,
1H), 3.15 – 3.05 (m, 1H), 3.00 (dd, J = 11.8 and 2.8 Hz, 1H),
1H), 7.23 – 7.10 (m, 5H), 6.94 – 6.81 (m, 2H), 6.72 – 6.62 (m,
1H), 3.40 (dd, J = 11.8, 1.5 Hz, 1H), 3.17 – 3.07 (m, 2H), 1.89 –
1.73 (m, 2H), 1.33 – 1.27 (m, 2H), 1.05 – 0.94 (m, 3H), 0.87 –
0.75 (m, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 140.7, 140.0,
132.4, 131.7, 129.9, 127.8, 127.2, 126.5, 126.3, 124.5, 51.6,
36.2, 29.5, 28.2, 8.2, 7.7 ppm. HRMS (ESI) calculated [(M+H)+(-
2.27 (s, 3H), 1.47 (s, 1H), 1.34 (s, 3H), 1.26 (s, 3H) ppm. 13
C
NMR (100 MHz, CDCl3) δ = 140.1, 134.0, 137.4, 132.6, 131.3,
130.5, 127.8, 127.4, 127.3, 126.7, 126.7, 124.6, 73.2, 56.5, 36.3,
28.2, 21.5 ppm. HRMS (ESI) calculated [(M+H)+(-H2O)]+ for
C18H20Br79+: 315.0743, found: 315.0738 and [(M+H)+(-H2O)]+
for C18H20Br81+: 317.0724, found: 317.0719.
H2O)]+ for C19H22Br79+
:
329.0899, found: 329.0889 and
[(M+H)+(-H2O)]+ for C19H22Br81+: 331.0881, found: 331.0875.
3-(2-Bromophenyl)-1,1,2-triphenylpropan-1-ol (7c): GP-5 was
followed to obtain title compound 7c from ester 5aa (0.50 mmol).
The column chromatography purification (PE/EA, 93:07 to
90:10), delivered 7c (197 mg, 89%) as colourless viscus liquid.
[TLC monitor PE/EA 95:05), Rf(5aa) = 0.70, Rf(7c) = 0.30, UV
1-(2-Bromophenyl)-3-ethyl-2-(m-tolyl)pentan-3-ol (7f): GP-5
was followed to obtain title compound 7f from ester 5ba (0.50
mmol). The column chromatography purification (PE/EA, 93:07
to 90:10), delivered 7f (161 mg, 89%) as colourless viscus liquid.
[TLC monitor PE/EA 93:07), Rf(5ba) = 0.70, Rf(7f) = 0.30, UV
detection]. 1H NMR (400 MHz, CDCl3) δ = 7.41 (dd, J = 7.4 and
1.7 Hz, 1H), 7.18 – 6.80 (m, 7H), 6.75 – 6.66 (m, 1H), 3.47 –
3.29 (m, 1H), 3.18 – 3.07 (m, 2H), 2.26 (s, 3H), 1.81 (dt, J = 13.9
and 7.1 Hz, 2H), 1.31 (dd, J = 15.1 and 7.3 Hz, 2H), 0.98 (t, J =
7.5 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H) ppm. 13C NMR (100 MHz,
CDCl3) δ = 140.4, 140.1, 137.2, 132.4, 131.6, 130.6, 127.6,
1
detection]. H NMR (400 MHz, CDCl3) δ = 7.77 (dd, J = 8.4 and
1.0 Hz, 2H), 7.51 – 7.46 (m, 1H), 7.39 – 7.33 (m, 4H), 7.25 –
7.21 (m, 2H), 7.18 – 7.06 (m, 4H), 7.03 – 6.98 (m, 3H), 6.84
(dddd, J = 26.7, 17.2, 7.4 and 1.6 Hz, 3H), 4.32 (dd, J = 11.6
and 3.8 Hz, 1H), 3.26 (dd, J = 14.2 and 11.7 Hz, 1H), 3.15 (dd, J
= 14.3 and 3.7 Hz, 1H), 2.67 (s, 1H) ppm. 13C NMR (100 MHz,
8
This article is protected by copyright. All rights reserved.

127.1, 127.1, 126.9, 126.5, 124.5, 76.9, 51.5, 36.0, 29.4, 28.1,
21.5, 8.2, 7.8 ppm. HRMS (ESI) calculated [(M+H)+(-H2O)]+ for
C20H24Br79+: 343.1056, found: 343.1048 and [(M+H)+(-H2O)]+
for C20H24Br81+: 345.1034, found: 345.1030.
mol%), Cs2CO3 (0.40 mmol), 2 mL toluene(dry) was added and
allowed to stirrer at 90 C for 12 h. The column chromatography
purification (PE/EA, 98:02 to 95:05), furnished 9a (45 mg, 94%)
as colourless viscus liquid. [TLC monitor PE/EA 95:05), Rf(7a) =
1
4-(2-Bromophenyl)-2-methyl-3-(p-tolyl)butan-2-ol (7g): GP-5
was followed to obtain title compound 7g from ester 5ca (0.50
mmol). The column chromatography purification (PE/EA, 93:07
to 90:10), delivered 7g (152 mg, 91%) as colourless viscus
liquid. [TLC monitor PE/EA 93:07), Rf(5ca) = 0.70, Rf(7g) = 0.30,
0.20, Rf(9a) = 0.70, UV detection]. H NMR(400 MHz, CDCl3) δ
= 7.33 – 7.24 (m, 5H), 7.17 – 7.07 (m, 2H), 6.91 – 6.80 (m, 2H),
3.20 (dd, J = 16.2 and 10.5 Hz, 1H), 3.06 (dd, J = 10.5 and 5.3
Hz, 1H), 2.96 (dd, J = 16.2 and 5.3 Hz, 1H), 1.30 (s, 3H), 1.22
(s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 153.5, 141.5,
129.3, 128.8, 128.2, 127.4, 126.9, 121.6, 120.0, 117.2, 77.2,
47.8, 29.1, 28.1, 21.3 ppm. HRMS (ESI) calculated [M+H]+ for
C17H19O+: 239.1430, found: 239.1426.
1
UV detection]. H NMR (400 MHz, CDCl3) δ = 7.43 (dd, J = 7.5
and 1.7 Hz, 1H), 7.05 (dd, J = 23.6 and 7.9 Hz, 4H), 6.95 – 6.87
(m, 2H), 6.78 (dd, J = 7.2 and 2.0 Hz, 1H), 3.43 (dd, J = 13.1
and 2.3 Hz, 1H), 3.16 – 2.93 (m, 2H), 2.27 (s, 3H), 1.33 (s, 3H),
1.25 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 134.0, 137.0,
136.1, 132.5, 131.3, 129.5, 128.7, 127.3, 126.7, 124.5, 73.2,
56.2, 36.3, 28.2, 28.1, 21.0 ppm. HRMS (ESI) calculated
[(M+H)+(-H2O)]+ for C18H20Br79+: 315.0743, found: 315.0738 and
[(M+H)+(-H2O)]+ for C18H20Br81+: 317.0724, found: 317.0719.
4-(2-(2-Bromophenyl)-1-(p-tolyl)ethyl)heptan-4-ol (7h): GP-5
was followed to obtain title compound 7h from ester 5ca (0.50
mmol). The column chromatography purification (PE/EA, 93:07
to 90:10), delivered 7h (138 mg, 71%) as colourless viscus
liquid. [TLC monitor PE/EA 93:07), Rf(5ca) = 0.70, Rf(7h) = 0.30,
2,2-Diethyl-3-phenylchromane (9b): GP-6 was carried out with
alcohol 7b (0.20 mmol), Pd(OAc)2 (3 mol%), JohnPhos (5
mol%), Cs2CO3 (0.40 mmol), 2 mL toluene(dry) was added and
allowed to stirrer at 90 C for 13 h. The column chromatography
purification (PE/EA, 98:02 to 95:05), furnished 9b (47 mg, 89%)
as colourless viscus liquid. [TLC monitor PE/EA 95:05), Rf(7b) =
0.20, Rf(9b) = 0.70, UV detection]. 1H NMR (400 MHz, CDCl3) δ
= 7.27 – 7.10 (m, 6H), 7.08 – 7.01 (m, 1H), 6.95 – 6.78 (m, 2H),
3.25 – 3.06 (m, 2H), 2.96 (dd, J = 16.9 and 6.1 Hz, 1H), 1.77 –
1.67 (m, 2H), 1.58 (dq, J = 14.6 and 7.4 Hz, 1H), 1.38 (dq, J =
14.6 and 7.4 Hz, 1H), 0.92 (t, J = 7.4 Hz, 3H), 0.84 (t, J = 7.5 Hz,
3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 153.8, 142.5, 129.4,
128.7, 128.3, 127.3, 126.6, 121.5, 120.0, 117.3, 80.3, 43.1, 29.4,
26.6, 25.6, 7.5, 7.3 ppm. HRMS (ESI) calculated [M+H]+ for
C19H23O+: 267.1743, found: 267.1742.
1
UV detection]. H NMR (400 MHz, CDCl3) δ = 7.41 (d, J = 7.4
Hz, 1H), 7.10 – 7.04 (m, 2H), 6.98 (d, J = 7.6 Hz, 2H), 6.89 (q, J
= 7.2 Hz, 2H), 6.72 (d, J = 7.1 Hz, 1H), 3.37 (d, J = 8.7 Hz, 1H),
3.17 – 3.03 (m, 2H), 2.26 (s, 3H), 1.83 – 1.60 (m, 2H), 1.39 –
1.18 (m, 6H), 0.96 (t, J = 7.2 Hz, 3H), 0.78 (t, J = 6.7 Hz, 3H)
ppm. 13C NMR (100 MHz, CDCl3) δ = 140.2, 137.3, 135.7, 132.4,
131.6, 128.6, 127.1, 126.6, 124.5, 76.6, 51.9, 39.9, 38.8, 35.9,
21.0, 17.1, 16.7, 14.7, 14.5 ppm.
2,2,3-Triphenylchromane (9c): GP-6 was followed with alcohol
7c (0.20 mmol), Pd(OAc)2 (3 mol%), JohnPhos (5 mol%),
Cs2CO3 (0.40 mmol), 2 mL toluene(dry) was added and allowed
to stirrer at 90 C for 14 h. The column chromatography
purification (PE/EA, 98:02 to 95:05), furnished 9c (63 mg, 87%)
as colourless viscus liquid. [TLC monitor PE/EA 95:05), Rf(7c) =
3-(m-Tolyl)chromane (8b): GP-6 was followed with alcohol 6b
(0.20 mmol), Pd(OAc)2 (3 mol%), JohnPhos (5 mol%), Cs2CO3
(0.40 mmol), 2 mL toluene(dry) was added and allowed to stirrer
at 90 C for 12 h. The column chromatography purification
(PE/EA, 98:02 to 95:05), furnished 8b (37 mg, 82%) as
colourless viscus liquid. [TLC monitor PE/EA 95:05), Rf(6b) =
0.20, Rf(8b) = 0.70, UV detection]. 1H NMR (400 MHz, CDCl3) δ
= 7.28 (t, J = 7.5 Hz, 1H), 7.22 – 7.04 (m, 5H), 6.96 – 6.87 (m,
2H), 4.39 (ddd, J = 10.6, 3.6 and 2.2 Hz, 1H), 4.05 (t, J = 10.6
Hz, 1H), 3.34 – 3.19 (m, 1H), 3.18 – 2.93 (m, 2H), 2.40 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3) δ = 154.3, 141.2, 138.4, 129.7,
128.6, 128.1, 127.8, 127.4, 124.3, 122.0, 120.3, 116.5, 70.9,
38.5, 32.4, 21.4 ppm. HRMS (ESI) calculated [M+H]+ for
C16H17O+: 225.1274, found: 225.1272.
1
0.20, Rf(9c) = 0.70, UV detection]. H NMR (400 MHz, CDCl3) δ
= 7.66 (dd, J = 8.4 and 1.1 Hz, 2H), 7.37 – 7.25 (m, 4H), 7.24 –
7.14 (m, 3H), 7.14 – 7.05 (m, 2H), 7.07 – 6.90 (m, 7H), 6.90 –
6.81 (m, 1H), 4.24 (dd, J = 7.0 and 1.3 Hz, 1H), 3.32 (dd, J =
17.0 and 7.1 Hz, 1H), 2.90 (d, J = 16.2 Hz, 1H) ppm. 13C NMR
(100 MHz, CDCl3) δ = 154.1, 144.8, 144.0, 141.5, 129.5, 129.2,
128.5, 127.7, 127.5, 127.3, 127.0, 126.3, 126.3, 126.1, 125.8,
121.4, 121.0, 117.4, 83.4, 44.4, 30.1 ppm. HRMS (ESI)
calculated [M+H]+ for C27H23O+: 363.1743, found: 363.1737.
6-Methoxy-2,2-dimethyl-3-phenylchromane (9d): GP-6 was
followed with alcohol 7d (0.20 mmol), Pd(OAc)2 (3 mol%),
JohnPhos (5 mol%), Cs2CO3 (0.40 mmol), 2 mL toluene(dry)
was added and allowed to stirrer at 90 C for 14 h. The column
chromatography purification (PE/EA,, 98:02 to 93:07), furnished
2,2-Dimethyl-3-phenylchromane (9a): GP-6 was carried out
with alcohol 7a (0.20 mmol), Pd(OAc)2 (3 mol%), JohnPhos (5
9
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9d (42 mg, 79%) as colourless viscus liquid. [TLC monitor
= 0.20, Rf(9g) = 0.70, UV detection]. 1H NMR (400 MHz, CDCl3)
δ = 7.18 – 7.08 (m, 6H), 6.88 (dd, J = 11.6, 4.4 Hz, 2H), 3.19
(dd, J = 16.2 and 10.8 Hz, 1H), 3.04 (dd, J = 10.7 and 5.3 Hz,
1H), 2.93 (dd, J = 16.3 and 5.3 Hz, 1H), 2.35 (s, 3H), 1.31 (s,
3H), 1.22 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 153.5,
138.4, 136.5, 129.3, 128.9, 128.6, 127.3, 121.7, 119.9, 117.1,
77.3, 47.4, 29.2, 28.1, 21.1, 21.0 ppm. HRMS (ESI) calculated
[M+H]+ for C18H21O+: 253.1587, found: 253.1585.
1
PE/EA 93:07), Rf(7d) = 0.20, Rf(9d) = 0.70, UV detection]. H
NMR (400 MHz, CDCl3) δ = 7.26 – 7.12 (m, 5H), 6.71 (d, J = 8.8
Hz, 1H), 6.65 (dd, J = 8.9 and 3.0 Hz, 1H), 6.56 (d, J = 2.9 Hz,
1H), 3.67 (s, 3H), 3.07 (dd, J = 16.1 and 9.9 Hz, 1H), 2.95 (dd, J
= 9.9 and 5.4 Hz, 1H), 2.86 (dd, J = 16.1 and 5.4 Hz, 1H), 1.20
(s, 3H), 1.11 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ = 153.1,
147.5, 141.5, 128.7, 128.2, 126.9, 122.1, 117.7, 113.7, 113.5,
76.8, 55.6, 47.7, 29.5, 27.9, 21.4 ppm. HRMS (ESI) calculated
2,2-Dipropyl-3-(p-tolyl)chromane (9h): GP-6 was carried out
with alcohol 7h (0.20 mmol), Pd(OAc)2 (3 mol%), JohnPhos (5
mol%), Cs2CO3 (0.40 mmol), 2 mL toluene(dry) was added and
allowed to stirrer at 90 C for 14 h. The column chromatography
purification (PE/EA, 98:02 to 95:05), furnished 9h (50 mg, 81%)
as colourless viscus liquid. [TLC monitor (PE/EA 95:05), Rf(7h) =
0.20, Rf(9h) = 0.70, UV detection]. 1H NMR (400 MHz, CDCl3) δ
= 7.19 – 7.11 (m, 1H), 7.12 – 7.00 (m, 5H), 6.94 – 6.79 (m, 2H),
3.15 (t, J = 6.6 Hz, 1H), 3.03 (ddd, J = 41.2, 16.7, 6.5 Hz, 2H),
2.32 (s, 3H), 1.73 – 1.59 (m, 2H), 1.54 – 1.28 (m, 6H), 0.88 (t, J
= 7.1 Hz, 3H), 0.80 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz,
CDCl3) δ = 153.8, 139.3, 136.1, 129.4, 128.9, 128.5, 127.2,
121.5, 119.9, 117.2, 80.2, 43.3, 37.3, 35.7, 29.5, 21.0, 16.5,
16.3, 14.5 ppm. HRMS (ESI) calculated [M+H]+ for C22H29O+:
309.2213, found: 309.2205.
[M+H]+ for C18H21O2 : 269.1536, found: 269.1539.
+
2,2-Dimethyl-3-(m-tolyl)chromane (9e): GP-6 was followed
with alcohol 7e (0.20 mmol), Pd(OAc)2 (3 mol%), JohnPhos (5
mol%), Cs2CO3 (0.40 mmol), 2 mL toluene(dry) was added and
allowed to stirrer at 90 C for 14 h. The column chromatography
purification (PE/EA, 98:02 to 95:05), furnished 9e (46 mg, 92%)
as colourless viscus liquid. [TLC monitor PE/EA 95:05), Rf(7e) =
0.20, Rf(9e) = 0.70, UV detection]. 1H NMR (400 MHz, CDCl3) δ
= 7.24 – 7.16 (m, 1H), 7.17 – 7.11 (m, 1H), 7.11 – 7.01 (m, 4H),
6.87 (dd, J = 11.8, 4.5 Hz, 2H), 3.20 (dd, J = 16.3, 10.9 Hz, 1H),
3.03 (dd, J = 10.9, 5.3 Hz, 1H), 2.92 (dd, J = 16.3, 5.3 Hz, 1H),
2.35 (s, 3H), 1.30 (s, 3H), 1.22 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3) δ = 153.5, 141.4, 137.7, 129.6, 129.3, 128.1, 127.6,
127.3, 125.8, 121.7, 119.9, 117.1, 77.3, 47.8, 29.1, 28.2, 21.5,
21.1 ppm. HRMS (ESI) calculated [M+H]+ for C18H21O+:
253.1587, found: 253.1584.
Acknowledgments
2,2-Diethyl-3-(m-tolyl)chromane (9f): GP-6 was followed with
alcohol 7f (0.20 mmol), Pd(OAc)2 (3 mol%), JohnPhos (5 mol%),
Cs2CO3 (0.40 mmol), 2 mL toluene(dry) was added and allowed
to stirrer at 90 C for 14 h. The column chromatography
purification (PE/EA, 98:02 to 95:05), furnished 9f (48 mg, 85%)
as colourless viscus liquid. [TLC monitor PE/EA 95:05), Rf(7f) =
0.20, Rf(9f) = 0.70, UV detection]. 1H NMR (400 MHz, CDCl3) δ
= 7.20 – 7.10 (m, 2H), 7.08 – 6.96 (m, 4H), 6.93 – 6.81 (m, 2H),
3.17 (t, J = 6.7 Hz, 1H), 3.09 (dd, J = 17.0 and 6.5 Hz, 1H), 2.98
(dd, J = 17.0 and 6.9 Hz, 1H), 2.30 (s, 3H), 1.74 (dqd, J = 14.8,
7.5 and 2.4 Hz, 2H), 1.65 – 1.50 (m, 2H), 1.41 (dq, J = 14.6 and
7.4 Hz, 1H), 0.93 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 7.5 Hz, 3H)
ppm. 13C NMR (100 MHz, CDCl3) δ = 153.8, 142.3, 137.6, 129.5,
129.4, 128.2, 127.3, 127.3, 125.6, 121.6, 119.9, 117.3, 80.3,
43.1, 29.4, 26.7, 25.4, 21.5, 7.5, 7.3 ppm. HRMS (ESI)
calculated [M+H]+ for C20H25O+: 281.1900, found: 281.1899.
2,2-Dimethyl-3-(p-tolyl)chromane (9g): GP-6 was followed with
alcohol 7g (0.20 mmol), Pd(OAc)2 (3 mol%), JohnPhos (5
mol%), Cs2CO3 (0.40 mmol), 2 mL toluene(dry) was added and
allowed to stirrer at 90 C for 14 h. The column chromatography
purification (PE/EA, 98:02 to 95:05), furnished 9g (45 mg, 90%)
as colourless viscus liquid. [TLC monitor (PE/EA 95:05), Rf(7g)
We thankful to DST-SERB [No.EMR/2017/005312], New Delhi,
for financial support. S.B. thankful to MHRD and C.B.S thankful
to UGC for the research fellowship.
Keywords: Isoflavans
1
•
Intramolecular arylation
2
•
Iodobenzene 3 • malonates 4 • ortho-bromobenzylbromide 5
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Insert text for Table of Contents here. We have presented a straightforward strategy for isoflavans synthesis. The strategy features
an intermolecular [Cu]-catalyzed arylation of malonates and an intramolecular [Pd]-catalyzed Buchwald coupling of hydroxyl tethered
bromoarenes, as the key transformations. This method is practical and flexible in enabling the synthesis of different isoflavan
derivatives.
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