Concise Synthesis of a Potential 5-Lipoxygenase Activating Protein (FLAP) Inhibitor and Its Analogs through Late-Stage Alkene Dicarbofunctionalization

Article abstract of DOI:10.1021/acs.oprd.9b00199

We report a five-step synthesis of the biologically important 1,1-diarylalkane 1, a potential 5-lipoxygenase activating protein (FLAP) inhibitor that was synthesized previously in 12 steps. In this synthesis, we apply a three-component alkene dicarbofunct

Full text of DOI:10.1021/acs.oprd.9b00199

Communication
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Concise Synthesis of a Potential 5‑Lipoxygenase Activating Protein
(FLAP) Inhibitor and Its Analogs through Late-Stage Alkene
Dicarbofunctionalization
Shekhar KC, Roshan K. Dhungana, Vivek Aryal, and Ramesh Giri*
Department of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, New Mexico 87131, United States
S
* Supporting Information
retrosynthetic disconnection to synthesize concisely a potential
5-lipoxygenase activating protein (FLAP) inhibitor (1), its
analogs, and regioisomers.
Molecules based on 1,1-diarylalkane scaffolds, such as
compounds 1 and 2, have been reported to show strong
bioactivity against membrane protein FLAP (Scheme 2).8 For
ABSTRACT: We report a five-step synthesis of the
biologically important 1,1-diarylalkane 1, a potential 5-
lipoxygenase activating protein (FLAP) inhibitor that was
synthesized previously in 12 steps. In this synthesis, we
apply a three-component alkene dicarbofunctionalization
reaction as a key final step to assemble the potential FLAP
inhibitor 1 from commercially available starting materials.
In addition, we also report the synthesis of a variety of
new analogs of the inhibitor 1 and its regioisomer.
Scheme 2. 1,1-Diarylalkanes as Potential 5-Lipoxygenase
Activating Protein (FLAP) Inhibitors and Anti-Breast,
-Lung, and -Brain Cancer Agents
KEYWORDS: alkenes, alkylarylation, 1,1-diarylalkanes,
dicarbofunctionalization, FLAP inhibitor, three-component
INTRODUCTION
■
Difunctionalization of alkenes with two carbon-based coupling
partners, termed dicarbofunctionalization (Scheme 1),1 offers
Scheme 1. Alkene Dicarbofunctionalization
an expeditious route for the synthesis of complex molecules
from readily available starting materials.2 A number of such
reactions have been developed over the years, which have
enabled the synthesis of complex carbo- and heterocycles
through cyclization/coupling.3 Recently, a number of reports
have appeared to demonstrate the difunctionalization of
alkenes in a three-component process through cross-coupling,4
reductive coupling,5 and C−H bond functionalization.6
Despite growing interest in recent years in developing such
reactions, their application as a new retrosynthetic disconnec-
tion to construct natural products and biologically active
molecules is scarce. The known but limited examples have
utilized the cyclization/coupling approach in which tethered
alkenes are dicarbofunctionalized to synthesize a select number
of lignan natural products3l,m and sesquiterpenes.7 In contrast,
the application of three-component alkene dicarbofunctional-
ization reactions in the synthesis of biologically important
target molecules largely remains unknown.4i In this article, we
report the application of a Ni-catalyzed alkylarylation of
alkenes, a reaction that we recently developed,4h as a new
example, Chu and co-workers from the Merck Research
Laboratory reported that the compound 1 showed FLAP
binding activity with IC50 at 3.0 nM.8 Similar structural
frameworks (3 and 4) have also been shown to be active
against breast cancer (MCF-7), lung cancer (H-460), and
brain cancer (SF-268).9 In 2012, Chu and co-workers reported
the synthesis of the potential FLAP inhibitor 1 in 12 steps.8
The synthesis relied upon a four-step construction of the key
intermediate 6 from 1,5-dimethoxybenzaldehyde (5), which
involved a sequence of the Grignard reaction with PhMgBr, the
Special Issue: Honoring 25 Years of the Buchwald-Hartwig
Amination
Received: May 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00199
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Scheme 3. Merck Synthesis of the Potential FLAP Inhibitor 1
Scheme 4. Retrosynthesis of Compound 1 with Alkene Dicarbofunctionalization as a Key Step
Scheme 5. Attempted Synthesis of Intermediate 11 and the Formation of the Anthracenone Derivative 12
Swern oxidation, the Grignard reaction with tBuCH2MgBr,
and the reduction of the resultant alcohol with Et3SiH/
trifluoroacetic acid (TFA) (Scheme 3). Herein, we apply a Ni-
catalyzed alkene dicarbofunctionalization reaction on a vinyl-
arene derivative to install both the tBu and the Ph groups in
one step and construct the α-phenyl-β-tert-butylethylaryl core
of the potential FLAP inhibitor 1.
1010 followed by the Pd-catalyzed Suzuki−Miyaura vinylation
of the triflate 10 with the Molander reagent (Scheme 5).11 The
vinylarene 8 was then subjected to dicarbofunctionalization
with tBuI and PhZnI in the presence of 5 mol % NiCl2(PPh3)2
as a catalyst in NMP at room temperature.4h The reaction
furnished the intermediate 7 in 62% yield. The intermediate 7
was then reacted with BCl3 for selective demethylation of the
ether MeO group in the presence of the ester group.12
However, the reaction did not furnish the expected product 11.
Instead, BCl3 promoted the intramolecular Friedel−Crafts
acylation of the phenyl group with the ortho-ester and
generated the anthracenone derivative 12 in 86% yield. Further
attempts to selectively demethylate the ether MeO group
under other reaction conditions, such as with PhSH/K2CO3,13
MgI2/ionic liquid,14 Cu2O/NaOMe,15 and AlCl3,16 also failed
to furnish the desired product.
RESULTS AND DISCUSSION
■
We envisioned that the potential FLAP inhibitor 1 could be
derived from the intermediate 7, which can be readily accessed
in one step by alkylarylation of the alkene moiety in 4-
methoxy-2-vinylbenzoic acid methyl ester (8) (Scheme 4).
Therefore, we first synthesized the intermediate 8 from the
commercially available 2-hydroxy-4-methoxybenzoic acid
methyl ester 9 in two steps by converting 9 to its triflate
B
DOI: 10.1021/acs.oprd.9b00199
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
It became evident from the formation of the anthracenone
derivative 12 that the Lewis acidic reaction condition for
selective demethylation was incompatible with the 1,1-diaryl
backbone bearing an ortho-ester group. Therefore, we revised
our synthetic route in which the alkylarylation of a vinylarene
would be conducted in the last step only after the
quinolinylmethyl group was installed on the vinylarene (15)
(Scheme 6). The vinylarene 15 could be expected to be
substituents on the aryl ring (Scheme 8). These new analogs
are formed in good yields (48−65%).21
Scheme 8. Synthesis of the Analogs of Compound 1
Scheme 6. Revised Retrosynthesis of Compound 1 with
Alkene Dicarbofunctionalization as the Last Step
derived from the commercially available 2-bromo-4-nitro-
benzoic acid methyl ester (16). We first converted the nitro
compound 16 to the hydroxyl compound 18 in two steps
17
involving the reduction of the NO2 group to NH2 by SnCl2
Encouraged by the result of the late-stage alkene
alkylarylation, we also synthesized a 5-quinolinylmethoxy
regioisomer 29 of the potential FLAP inhibitor 1 in four
steps (Scheme 9) from the commercially available 2-bromo-5-
methoxybenzoic acid methyl ester (25). The ether MeO group
in 25 was selectively demethylated in the presence of the ester
group with BCl3 to obtain the hydroxy compound 26.12 The
hydroxy compound 26 was then vinylated by the Pd-catalyzed
Suzuki−Miyaura coupling with the Molander reagent followed
by quinolinylmethylation of the hydroxyl group to generate the
vinylarene intermediate 28. The Ni-catalyzed alkylarylation of
the vinylarene 28 with tBuI and PhZnI furnished the 5-
quinolinylmethoxy regioisomer 29 in 56% yield.21
followed by diazotization with NaNO2/conc. H2SO4 and
hydrolysis (Scheme 7).18 The hydroxyl compound 18 was then
vinylated by a Pd-catalyzed Suzuki−Miyaura coupling with the
Molander reagent to form the hydroxyvinylarene compound
19.11 The hydroxyvinylarene 19 was then arylmethylated with
2-(chloromethyl)quinoline hydrochloride19 to generate the
vinylarene intermediate 15. The vinylarene 15 was then
subjected to Ni-catalyzed alkylarylation with tBuI and PhZnI.
Despite the presence of the ortho-ester group and the acidic
benzylic methylene group activated by both the oxygen and
quinoline, the alkylarylation reaction proceeded smoothly to
furnish the potential FLAP inhibitor 1 in 63% yield. The
reaction can also be conducted in a gram-scale quantity (5.0
mmol, 1.474 g) without compromising the product yield
(65%) (Scheme 7).20 In order to demonstrate the versatility of
the late-stage alkene alkylarylation reaction, we also synthe-
sized four additional analogs (21−24) of the potential FLAP
inhibitor 1 containing CF3, p-Me, o-Me, and p-OMe
CONCLUSION
■
In summary, we have demonstrated an application of the three-
component alkene dicarbofunctionalization reaction in the
five-step synthesis of a potential FLAP inhibitor 1, a bioactive
Scheme 7. Synthesis of Compound 1 Using Late-Stage Alkene Dicarbofunctionalization
C
DOI: 10.1021/acs.oprd.9b00199
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Scheme 9. Synthesis of 5-Quinolinylmethoxy Regioisomer 29 of the Potential FLAP Inhibitor 1
molecule containing a 1,1-diarylalkane scaffold that was
previously synthesized in 12 steps. Furthermore, we also
applied the alkene dicarbofunctionalization reaction in
generating four different analogs and a 5-quinolinylmethoxy
regioisomer of the potential FLAP inhibitor 1. In these
examples, the alkene dicarbofunctionalization reaction was
performed in the last step of the synthesis.
and the solvent was removed under vacuum. To the PhZnI
residue were added NiCl2(PPh3)2 (163.5 mg, 0.25 mmol),
methyl 4-(quinolin-2-ylmethoxy)-2-vinylbenzoate (15) (1595
mg, 5.0 mmol), and tertiary butyl iodide (1840 mg, 10 mmol).
The mixture was then dissolved in 25 mL of NMP. The vial
was tightly capped and removed from the glovebox, and the
reaction mixture was vigorously stirred at room temperature.
After 6 h, the reaction was diluted with EtOAc (50 mL) and
washed several times with water. The organic layers were
collected and dried. The compound 1 was purified by silica gel
column chromatography using THF/hexanes (1:10).
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all the
reactions and chemicals were handled under a nitrogen
atmosphere. All glassware were properly dried in an oven
before use. Solvents and reagents were purchased from
commercial sources. Organozinc reagents were prepared
according to a literature procedure.22 1H, 13C, and 19F NMR
spectra were recorded on a Bruker instrument (300 and 500,
75 and 126, and 282 and 470 MHz, respectively) at the
Department of Chemistry and Chemical Biology, the
University of New Mexico (UNM) and internally referenced
Methyl 4-Methoxy-2-(((trifluoromethyl)sulfonyl)oxy)-
benzoate (10). Compound 10 was prepared according to a
literature procedure.10 To a solution of methyl 2-hydroxy-4-
methoxybenzoate (1.8 g, 10 mmol) in CH2Cl2 (30 mL) in a
round-bottom flask, DIPEA (1.55 g, 12 mmol) was added and
stirred at 0 °C for 10 min. Triflic anhydride (3.66g, 13 mmol)
was added dropwise to the reaction mixture and stirred at
room temperature. After 12 h, CH2Cl2 (10 mL) and saturated
NaHCO3 (5 mL) were added to the reaction mixture. The
organic layer was separated, and the aqueous fraction was
further extracted with CH2Cl2 (15 mL). The organic layers
were collected, and the solvent was removed in a rotary
evaporator. The title compound 10 was obtained as a brown
solid (2.9 g, 95% yield) after purification by silica gel column
to the residual solvent signals of CDCl3 for H and 13C NMR
1
at 7.26 and 77.16 ppm, and externally referenced to C6F6 for
19F NMR at −164.9 ppm. The chemical shifts of NMR and the
coupling constants (J) for 1H, 13C, and 19F NMR are reported
in δ parts per millions (ppm) and in hertz, respectively. The
following conventions are used for multiplicities: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of
doublet; br, broad. High resolution mass spectra for new
compounds were recorded at the Mass Spectrometry facilities
at the Department of Chemistry and Chemical Biology, UNM.
General Procedure for Alkylarylation. In a glovebox, a
solution of phenylzinc iodide (0.60 mmol, 720 μL of 0.833 M
stock solution in THF) was taken in a 1-dram vial and the
solvent was removed under vacuum. To the PhZnI residue
were added NiCl2(PPh3)2 (9.81 mg, 0.015 mmol), methyl 4-
(quinolin-2-ylmethoxy)-2-vinylbenzoate (95.7 mg, 0.30
mmol), and tertiary butyl iodide (110.4 mg, 0.60 mmol).
The mixture was then dissolved in 1.5 mL of NMP. The vial
was tightly capped and removed from the glovebox, and the
reaction mixture was vigorously stirred at room temperature.
After 6 h, the reaction was diluted with EtOAc (10 mL) and
washed several times with water. The organic layers were
collected and dried. The products were purified by silica gel
column chromatography.
1
chromatography using ethyl acetate/hexanes (1:5). H NMR
(500 MHz, CDCl3): δ 3.88 (s, 3H), 3.93 (s, 3H), 6.77 (s, 1H),
6.95 (d, J = 6.0 Hz, 1H), 8.06 (d, J = 6.0 Hz, 1H); 13C NMR
(126 MHz, CDCl3): δ 52.4, 56.1, 109.0, 113.5, 116.4, 118.8 (q,
J = 320.8 Hz), 134.2, 149.7, 164.1; 19F NMR (282 MHz,
CDCl3) δ −73.2; IR (neat) cm−1: 1731, 1614, 1420, 1128,
1068; HRMS (ESI): Calcd for C10H10F3O6S (M + H)+
315.0150, found 315.0147.
Methyl 4-Methoxy-2-vinylbenzoate (8). Compound 8 was
prepared according to a literature procedure.11 Pd(OAc)2 (112
mg, 0.5 mmol), PPh3 (132 mg, 0.5 mmol), Cs2CO3 (4.9 g, 15
mmol), potassiumvinyltrifluoroborate (0.8 g, 6.0 mmol), and
methyl 2-bromo-4-hydroxybenzoate (1.57 g, 5.0 mmol) were
weighed in a sealed tube. 15 mL of THF and 1.3 mL of H2O
were added to the reaction mixture and heated at 85 °C. After
12 h, diethyl ether (20 mL) and water (5 mL) were added to
the reaction mixture. The organic layer was separated, and the
aqueous fraction was further extracted with diethyl ether (4 ×
20 mL). The organic layers were collected, and the solvent was
removed in a rotary evaporator. The title compound 8 was
obtained as a white solid (2.1 g, 75% yield) after purification
General Procedure for Large Scale Alkylarylation. In a
glovebox, a solution of phenylzinc iodide (10 mmol, 12.3 mL
of 0.81 M stock solution in THF) was taken in a sealed tube
D
DOI: 10.1021/acs.oprd.9b00199
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
by silica gel column chromatography using ethyl acetate/
hexanes (1:10). 1H NMR (500 MHz, CDCl3): δ 3.86 (s, 6H),
5.35 (d, J = 10.0 Hz, 1H), 5.62 (d, J = 15.0 Hz, 1H), 6.82 (dd,
J = 10.0 Hz, 3.0 Hz, 1H), 7.03 (d, J = 5.0 Hz, 1H), 7.55 (dd, J
= 20.0 Hz, 10.0 Hz, 1H), 7.91 (d, J = 10.0 Hz, 1H); 13C NMR
(126 MHz, CDCl3): δ 51.9, 55.4, 112.5, 112.9, 116.4, 120.8,
132.8, 136.5, 142.4, 162.6, 167.3; IR (neat) cm−1: 1708, 1598,
1433, 1232, 1125; HRMS (ESI): Calcd for C11H13O3 (M +
H)+ 193.0865, found 193.0866.
Methyl 2-Bromo-4-hydroxybenzoate (18). Compound 18
was prepared according to a literature procedure.18 In a round-
bottom flask, methyl 4-amino-2-bromobenzoate (7.786 g, 30
mmol) was weighed, the flask was cooled to 0 °C and H2SO4
(13.6 mL in 92 mL H2O) was added dropwise. After the
resulting solution was stirred at 0 °C for 20 min, NaNO2 (3.5
g, 51 mmol) in 35 mL water was added dropwise and the
reaction mixture was allowed to stir for an additional 30 min at
0 °C before refluxing at 100 °C for 45 min. The reaction
mixture was brought to room temperature, CHCl3 (100 mL)
was added. The organic layer was separated, and the remaining
aqueous fraction was extracted with CHCl3 (4 × 100 mL). The
organic layer was collected, and the solvent was removed in a
rotary evaporator. The title compound 18 was obtained as a
white solid (56% yield, 3.847 g) after purification by silica gel
column chromatography using ethyl acetate/hexanes (1:10).
1H NMR (300 MHz, CDCl3): δ 3.87 (s, 3H), 4.94 (br.s, 1H),
6.82 (d, J = 9.0 Hz, 1H), 7.13 (s, 1H), 7.77 (d, J = 9.0 Hz,
1H); 13C NMR (75 MHz, CDCl3): δ 52.4, 115.3, 122.2, 123.0,
124.1, 134.4, 162.5, 167.6; IR (neat) cm−1: 3333, 1684, 1261,
1031; HRMS (ESI): Calcd for C8H8BrO3 (M + H)+ 230.9657,
found 230.9663.
Methyl 2-(3,3-Dimethyl-1-phenylbutyl)-4-methoxy-
benzoate (7). The title compound 7 was obtained as a
colorless liquid from a 3 mmol scale reaction (606 mg, 62%
yield) after purification by silica gel column chromatography
1
using ether/hexanes (1:10). H NMR (300 MHz, CDCl3): δ
0.87 (s, 9H), 2.10 (d, J = 9.0 Hz, 2H), 3.81 (s, 3H), 3.91 (s,
3H), 5.54 (t, J = 7.5 Hz, 1H), 6.69 (dd, J = 9.0 Hz, 2.7 Hz,
1H), 7.08 (d, J = 3.0 Hz, 1H), 7.14−7.17 (m, 1H), 7.26 (t, J =
7.5 Hz, 2H), 7.42 (d, J = 9.0 Hz, 2H), 7.82 (d, J = 9.0 Hz, 1H);
13C NMR (75 MHz, CDCl3): δ 30.3, 31.8, 41.0, 50.1, 51.9,
55.3, 110.1, 114.9, 121.8, 125.9, 128.0, 128.3, 132.9, 146.7,
150.8, 162.2, 168.2; IR (neat) cm−1: 1711, 1601, 1432, 1232,
1124; HRMS (ESI): Calcd for C21H27O3 (M + H)+ 327.1960,
found 327.1947.
Methyl 4-Hydroxy-2-vinylbenzoate (19). Compound 19
was prepared according to a literature procedure.11 Pd(OAc)2
(336 mg, 1.5 mmol), PPh3 (393 mg, 1.5 mmol), Cs2CO3
(14.625 g, 45 mmol), potassiumvinyltrifluoroborate (2.41 g, 18
mmol), and methyl 2-bromo-4-hydroxybenzoate (3.435 g, 15
mmol) were weighed in a sealed tube. 45 mL of THF (45 mL)
and H2O (4 mL) were added to the reaction mixture and
heated at 85 °C. After 12 h, diethyl ether (50 mL) and water
(25 mL) were added to the reaction mixture. The organic layer
was separated, and the remaining aqueous fraction was
extracted with diethyl ether (4 × 50 mL). The organic layer
was collected, and the solvent was removed in a rotary
evaporator. The title compound 19 was obtained as a white
solid (76% yield, 2.03 g) after purification by silica gel column
chromatography in ether/hexanes (1:5). 1H NMR (300 MHz,
CDCl3): δ 3.88 (s, 3H), 5.32 (d, J = 9.0 Hz, 1H), 5.57 (d, J =
15.0 Hz, 1H), 5.89 (s, 1H), 6.78 (dd, J = 9.0 Hz, 3.0 Hz, 1H),
7.00 (d, J = 3.0 Hz, 1H), 7.50 (dd, J = 18.0 Hz, 12.0 Hz, 1H),
7.86 (d, J = 9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 52.2,
114.2, 114.7, 116.8, 120.4, 133.2, 136.0, 142.8, 159.6, 168.2; IR
(neat) cm−1: 3291, 1677, 1560, 1438, 1138; HRMS (ESI):
Calcd for C10H11O3 (M + H)+ 179.0708, found 179.0713.
Methyl 4-(Quinolin-2-ylmethoxy)-2-vinylbenzoate (15).
Compound 15 was prepared according to a literature
procedure.19 In a round-bottom flask, methyl 4-hydroxy-2-
vinylbenzoate (1.78 g, 10 mmol) was weighed and dissolved in
DMF (30 mL). K2CO3 (3.450 g, 25 mmol) and KI (2.49 g, 15
mmol) were added, and the reaction mixture was allowed to
stir at room temperature. 2-(Chloromethyl)quinolin-1-ium
chloride (2.556 g, 12 mmol) was added to the reaction
suspension and stirred at room temperature. After 12 h, EtOAc
(30 mL) and water (15 mL) were added to the reaction
mixture. The aqueous fraction was removed, and the organic
layer was further washed with water (3 × 10 mL). The organic
layer was collected, and the solvent was removed in a rotary
evaporator. The title compound 15 was obtained as a white
solid (85% yield, 2.711 g) after purification by silica gel column
3-Methoxy-10-neopentylanthracen-9(10H)-one (12).
Compound 7 (326 mg, 0.5 mmol) was weighed in a round-
bottom flask, dissolved in CH2Cl2 (10 mL), and the reaction
mixture was cooled to −78 °C. BCl3 (1 mL of 1 M solution in
hexanes) was then added dropwise over 10 min, and the
reaction mixture was stirred for additional 30 min at −78 °C
before allowing it to warm up to room temperature. After 2 h,
the reaction was quenched with water (5 mL), and the reaction
mixture was extracted with CH2Cl2 (2 × 10 mL). The organic
layers were collected, and the solvent was removed in a rotary
evaporator. The title compound 12 was obtained as a white
solid (126.4 mg, 86% yield) after purification by silica gel
column chromatography using ethyl acetate/hexanes (1:5). 1H
NMR (300 MHz, CDCl3): δ 0.65 (s, 9H), 1.95−2.07 (m, 2H),
3.89 (s, 3H), 4.31 (t, J = 6.0 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H),
6.98 (s, 1H), 7.36−7.41 (m, 1H), 7.50 (d, J = 3.0 Hz, 2H),
8.22 (t, J = 7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ 30.7,
32.5, 41.6, 55.2, 55.5, 112.8, 113.1, 126.1, 126.8, 127.5, 128.3,
130.1, 132.1, 132.6, 146.5, 149.3, 162.9, 184.1; IR (neat) cm−1:
1651, 1598, 1456, 1274, 1241, 1091, 931; HRMS (ESI): Calcd
for C20H23O2 (M + H)+ 295.1698, found 295.1702.
Methyl 4-Amino-2-bromobenzoate (17). Compound 17
was prepared according to a literature procedure.17 Methyl 2-
bromo-4-nitrobenzoate (10 g, 38.0 mmol) and SnCl2·2H2O
(35.9 g, 190 mmol) were weighed in a round-bottom flask and
dissolved in EtOAc (190 mL). After the reaction was stirred
for 12 h at 50 °C, EtOAc (150 mL) and saturated aqueous
NaHCO3 (100 mL) were added to the reaction mixture. The
organic layer was separated, and the remaining aqueous
fraction was extracted with EtOAc (3 × 100 mL). The organic
layer was collected, and the solvent was removed in a rotary
evaporator. The title compound 17 was obtained as an
analytically pure light-yellow solid (7.97 g, 92% yield), which
1
was used for the next step without further purification. H
NMR (500 MHz, CDCl3): δ 3.84 (s, 3H), 4.13 (br.s, 2H),
6.54 (dd, J = 10.0 Hz, 2.5 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H),
7.73 (d, J = 2.0 Hz, 1H); 13C NMR (126 MHz, CDCl3): δ
51.9, 112.9, 119.5, 119.8, 124.1, 133.7, 150.7, 166.1; IR (neat)
cm−1: 3324, 1704, 1586, 1428, 1240, 1032; HRMS (ESI):
Calcd for C8H9BrNO2 (M + H)+ 229.2817, found 229.9809.
1
chromatography using ethyl acetate/hexanes (1:5). H NMR
(300 MHz, CDCl3): δ 3.86 (s, 3H), 5.34 (d, J = 12.0 Hz, 1H),
5.45 (s, 2H), 5.60 (d, J = 18.0 Hz, 1H), 6.95 (dd, J = 9.0 Hz,
3.0 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.48−7.59 (m, 2H),
E
DOI: 10.1021/acs.oprd.9b00199
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
7.65 (d, J = 12.0 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.87 (dd, J
= 18.0 Hz, 9.0 Hz, 2H), 8.08 (d, J = 9.0 Hz, 1H), 8.20 (d, J =
9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 51.9, 71.4, 113.6,
113.7, 116.7, 119.1, 121.4, 126.7, 127.7, 127.8, 129.0, 130.0,
132.9, 136.2, 137.2, 142.4, 147.6, 157.1, 161.3, 167.2; IR
(neat) cm−1: 1709, 1564, 1426, 1258, 1138, 1091; HRMS
(ESI): Calcd for C20H18NO3 (M + H)+ 320.1287, found
320.1293.
Methyl 2-(3,3-Dimethyl-1-phenylbutyl)-4-(quinolin-2-
ylmethoxy)benzoate (1). The title compound 1 was obtained
as a light yellow liquid from a 5 mmol scale reaction (1.474 g,
65% yield) after purification by silica gel column chromatog-
raphy using THF/hexanes (1:10). 1H NMR (500 MHz,
CDCl3): δ 0.75 (s, 9H), 1.98 (dd, J = 6.0 Hz, 3.0 Hz, 2H), 3.88
(s, 3H), 5.42 (s, 2H), 5.45 (t, J = 4.5 Hz, 1H), 6.82 (dd, J = 3.0
Hz, 1.5 Hz, 1H), 7.05−7.11 (m, 3H), 7.18 (d, J = 3.0 Hz, 1H),
7.29 (d, J = 3.0 Hz, 2H), 7.57−7.61 (m, 2H), 7.76−7.78 (m,
2H), 7.83 (d, J = 6.0 Hz, 1H), 8.14 (dd, J = 12.0 Hz, 6.0 Hz,
2H); 13C NMR (126 MHz, CDCl3): δ 30.2, 31.7, 41.0, 50.0,
52.0, 71.4, 112.3, 114.9, 119.2, 122.2, 125.8, 126.8, 127.7,
127.8, 127.9, 128.3, 129.1, 130.0, 132.8, 137.2, 146.6, 147.7,
151.0, 157.4, 160.9, 168.2; IR (neat) cm−1: 2949, 1711, 1598,
1430, 1234, 1124, 1041; HRMS (ESI): Calcd for C30H32NO3
(M + H)+ 454.2382, found 454.2397.
Methyl (E)-2-(3,3-Dimethylbut-1-en-1-yl)-4-(quinolin-2-
ylmethoxy)benzoate. Along with the title compound 1, this
Heck product was obtained as a colorless liquid (50.6 mg, 27%
yield) after purification by silica gel column chromatography
using THF/hexanes (1:10) from a 0.5 mmol scale reaction. 1H
NMR (500 MHz, CDCl3): δ 1.12 (s, 9H), 3.85 (s, 3H), 5.45
(s, 2H), 6.07 (d, J = 15.0 Hz, 1H), 6.88 (dd, J = 5.0 Hz, J =
10.0 Hz, 1H), 7.15−7.19 (m, 2H), 7.56 (t, J = 7.5 Hz, 1H),
7.68 (d, J = 10.0 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.84 (d, J =
10.0 Hz, 1H), 7.88 (d, J = 10.0 Hz, 1H), 8.09 (d, J = 15.0 Hz,
1H), 8.21 (d, J = 10.0 Hz, 1H); 13C NMR (126 MHz, CDCl3):
δ 29.6, 33.8, 51.8, 71.4, 113.0, 113.3, 119.2, 121.1, 124.1,
126.8, 127.7, 127.8, 129.0, 130.0, 133.0, 137.3, 143.0, 144.9,
147.6, 157.3, 161.2, 167.5; HRMS (ESI): Calcd for
C24H26NO3 (M + H)+ 376.1913, found 376.1916.
5.40−5.45 (m, 3H), 6.82 (d, J = 9.0 Hz, 1H), 6.92 (d, J = 9.0
Hz, 2H), 7.19−7.22 (m, 2H), 7.54−7.61 (m, 2H), 7.76−7.84
(m, 3H), 8.14 (dd, J = 9.0 Hz, J = 3.0 Hz, 2H); 13C NMR (126
MHz, CDCl3): δ 21.0, 30.2, 31.6, 40.6, 50.0, 51.9, 71.4, 112.2,
114.8, 119.2, 122.1, 126.7, 127.7, 127.8, 129.0, 129.1, 130.0,
132.8, 135.2, 137.2, 143.6, 147.7, 151.3, 157.4, 160.9, 168.2; IR
(neat) cm−1: 2948, 1712, 1599, 1429, 1123; HRMS (ESI):
Calcd for C31H34NO3 (M + H)+ 468.2539, found 468.2536.
Methyl 2-(3,3-Dimethyl-1-(o-tolyl)butyl)-4-(quinolin-2-
ylmethoxy)benzoate (23). The title compound 23 was
obtained as a colorless viscous liquid (91 mg, 58% yield)
after purification by silica gel column chromatography using
THF/hexanes (1:10). 1H NMR (300 MHz, CDCl3): δ 0.79 (s,
9H), 1.79 (dd, J = 15.0 Hz, J = 6.0 Hz, 1H), 1.95 (dd, J = 15.0
Hz, J = 9.0 Hz, 1H), 2.30 (s, 3H), 3.85 (s, 3H), 5.37 (s, 2H),
5.50 (t, J = 7.5 Hz, 1H), 6.82 (dd, J = 9.0 Hz, J = 3.0 Hz, 1H),
6.94−7.01 (m, 2H), 7.04−7.08 (m, 2H), 7.25−7.27 (m, 1H),
7.54−7.60 (m, 2H), 7.73−7.79 (m, 2H), 7.83 (d, J = 9.0 Hz,
1H), 8.10 (d, J = 9.0 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H); 13C
NMR (126 MHz, CDCl3): δ 20.2, 30.7, 31.9, 38.1, 49.5, 52.0,
71.3, 112.0, 116.3, 119.2, 122.8, 125.5, 125.9, 126.8, 127.6,
127.7, 127.8, 129.0, 130.0, 130.7, 132.8, 136.3, 137.2, 143.1,
147.6, 149.4, 157.4, 160.7, 168.2; IR (neat) cm−1: 2919, 1714,
1598, 1430, 1236, 1122; HRMS (ESI): Calcd for C31H34NO3
(M + H)+ 468.2539, found 468.2560.
Methyl 2-(1-(4-Methoxyphenyl)-3,3-dimethylbutyl)-4-
(quinolin-2-ylmethoxy)benzoate (24). The title compound
24 was obtained as a colorless viscous liquid (91.2 mg, 63%
yield) after purification by silica gel column chromatography
1
using THF/hexanes (1:10). H NMR (300 MHz, CDCl3): δ
0.74 (s, 9H), 1.94 (d, J = 6.0 Hz, 2H), 3.70 (s, 3H), 3.87 (s,
3H), 5.37 (t, J = 7.5 Hz, 1H), 5.42 (s, 2H), 6.62 (d, J = 9.0 Hz,
1H), 6.80 (dd, J = 9.0 Hz, J = 2.7 Hz, 1H), 7.16−7.21 (m,
3H), 7.55−7.62 (m, 2H), 7.75−7.79 (m, 2H), 7.84 (d, J = 6.0
Hz, 1H), 8.14 (dd, J = 12.0 Hz, J = 9.0 Hz, 2H); 13C NMR
(126 MHz, CDCl3): δ 30.2, 31.7, 40.2, 50.2, 51.9, 52.2, 71.4,
112.3, 113.7, 114.7, 119.3, 122.0, 126.8, 127.7, 127.8, 128.8,
129.1, 130.0, 132.8, 137.2, 138.8, 147.7, 151.5, 157.5, 157.6,
160.9, 168.2; IR (neat) cm−1: 2950, 1712, 1508, 1237, 1038;
HRMS (ESI): Calcd for C31H34NO4 (M + H)+ 484.2488,
found 484.2476.
Methyl 2-Bromo-5-hydroxybenzoate (26). Compound 26
was prepared according to a literature procedure.12 The methyl
2-bromo-5-methoxybenzoate 25 (326 mg, 5.0 mmol) was
weighed in a round-bottom flask, dissolved in dichloroethane
(50 mL), and the reaction mixture was cooled to −78 °C. BCl3
(5 mL solution of 1 M BCl3 solution) was then added
dropwise over 20 min, and the reaction mixture was stirred for
30 min at −78 °C before allowing it to slowly warm to room
temperature. After stirring for 2 h at room temperature, the
reaction mixture was quenched with water (20 mL). The
solution was extracted with CH2Cl2 (2 × 30 mL), the organic
layers were collected, and the solvent was removed in a rotary
evaporator. The title compound 26 was obtained as a white
solid (954 mg, 83% yield) after purification by silica gel
column chromatography using ethyl acetate/hexanes (1:20).
The 1H NMR and 13C NMR values match the reported values
in the literature.18 1H NMR (500 MHz, CDCl3): δ 3.92 (s,
3H), 6.12 (br.s, 1H), 6.86 (dd, J = 10.0 Hz, J = 3.0 Hz, 1H),
7.31 (d, J = 5.0 Hz, 1H), 7.47 (d, J = 10.0 Hz, 1H); 13C NMR
(126 MHz, CDCl3): δ 52.9, 111.8, 118.4, 120.5, 132.6, 135.4,
135.4, 155.1, 167.1; IR (neat) cm−1: 3333, 1684, 1261, 1031.
Methyl 2-(3,3-Dimethyl-1-(4-(trifluoromethyl)phenyl)-
butyl)-4-(quinolin-2-ylmethoxy)benzoate (21). The title
compound 21 was obtained as a colorless viscous liquid (75
mg, 48% yield) after purification by silica gel column
1
chromatography using THF/hexanes (1:10). H NMR (500
MHz, CDCl3): δ 0.74 (s, 9H), 1.93−2.01 (m, 2H), 3.87 (s,
3H), 5.44 (m, 2H), 5.54 (t, J = 7.5 Hz, 1H), 6.85 (dd, J = 9.0
Hz, J = 2.5 Hz, 1H), 7.14 (d, J = 2.5 Hz, 1H), 7.25 (d, J = 10.0
Hz, 1H), 7.36 (d, J = 10.0 Hz, 1H), 7.57−7.60 (m, 2H), 7.76−
7.85 (m, 3H), 8.14 (dd, J = 11.5 Hz, J = 9.0 Hz, 2H); 13C
NMR (126 MHz, CDCl3): δ 30.2, 31.7, 40.8, 49.9, 52.1, 71.5,
112.9, 114.5, 119.2, 119.3, 121.9, 122.3 (q, J = 257.7 Hz),
123.2, 125.2 (q, J = 3.8 Hz), 126.9, 127.8, 127.9, 128.1 (q, J =
3.8 Hz), 129.0 (q, J = 3.8 Hz), 130.2, 133.1, 137.3, 147.7,
150.1, 150.7, 157.3, 161.0, 167.9; 19F NMR (282 MHz,
CDCl3) δ −62.7; IR (neat) cm−1: 2951, 1712, 1600, 1323,
1110; HRMS (ESI): Calcd for C31H31F3NO3 (M + H)+
522.2256, found 522.2275.
Methyl 2-(3,3-Dimethyl-1-(p-tolyl)butyl)-4-(quinolin-2-
ylmethoxy)benzoate (22). The title compound 22 was
obtained as a colorless viscous liquid (91 mg, 65% yield)
after purification by silica gel column chromatography using
THF/hexanes (1:10). 1H NMR (300 MHz, CDCl3): δ 0.76 (s,
9H), 1.98 (d, J = 3.0 Hz, 2H), 2.23 (s, 3H), 3.88 (s, 3H),
F
DOI: 10.1021/acs.oprd.9b00199
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Methyl 5-hydroxy-2-vinylbenzoate (27). Compound 27
was prepared according to a literature procedure.11 Pd(OAc)2
(112 mg, 0.5 mmol), PPh3 (132 mg, 0.5 mmol), Cs2CO3 (4.9
g, 15 mmol), potassiumvinyltrifluoroborate (0.8 g, 6 mmol),
and methyl 2-bromo-4-hydroxybenzoate (1.15 g, 5 mmol)
were weighed in a sealed tube. THF (15 mL) and H2O (1.3
mL) were added to the reaction mixture and heated at 85 °C.
After 12 h, diethyl ether (20 mL) and water (5 mL) were
added to the reaction mixture. The organic layer was separated,
and the remaining aqueous fraction was extracted with diethyl
ether (4 × 20 mL). The organic layer was collected and the
solvent was removed in a rotary evaporator. The title
compound 27 was obtained as a white solid (660 mg, 75%
yield) after purification by silica gel column chromatography
using ethyl acetate/hexanes (1:10). 1H NMR (500 MHz,
CDCl3): δ 3.89 (s, 3H), 5.24 (d, J = 10.0 Hz, 1H), 5.54 (d, J =
15.0 Hz, 1H) 6.13 (s, 1H), 7.00 (dd, J = 10.0 Hz, 5.0 Hz, 1H),
7.33 (dd, J = 20.0 Hz, 10.0 Hz, 1H), 7.37 (d, J = 3.0 Hz, 1H),
7.47 (d, J = 10.0 Hz, 1H); 13C NMR (126 MHz, CDCl3): δ
52.5, 115.0, 116.8, 119.8, 128.9, 129.5, 132.2, 135.2, 155.2,
168.3; IR (neat) cm−1: 3367, 1693, 1606, 1434, 1297, 1211,
1069; HRMS (ESI): Calcd for C10H9O3 (M + H)+ 177.0552,
found 177.0551.
(neat) cm−1: 2918, 1719, 1600, 1492, 1207, 1071; HRMS
(ESI): Calcd for C30H32NO3 (M + H)+ 454.2382, found
454.2390.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.9b00199.
■
S
NMR spectra of the products (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: rgiri@unm.edu.
■
ORCID
Ramesh Giri: 0000-0002-8993-9131
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of New Mexico (UNM) for financial
support, and upgrades to the NMR (NSF Grants CHE08-
40523 and CHE09-46690) and MS Facilities. The Bruker X-
ray diffractometer was purchased via an NSF CRIF:MU award
to UNM (CHE04-43580).
Methyl 5-(Quinolin-2-ylmethoxy)-2-vinylbenzoate (28).
Compound 28 was prepared according to a literature
procedure.19 In a round-bottom flask, methyl 5-hydroxy-2-
vinylbenzoate (920 mg, 4 mmol) was weighed and dissolved in
DMF (10 mL). K2CO3 (828 mg, 6 mmol) and KI (996 mg, 6
mmol) were then added, and the reaction mixture was stirred
at room temperature. 2-(Chloromethyl)quinolin-1-ium chlor-
ide (1.02 g, 4.8 mmol) was added to the reaction mixture and
stirred at room temperature. After 12 h, EtOAc (20 mL) and
water (15 mL) were added to the reaction mixture. The
organic layer was separated and washed with water (3 × 5
mL). The organic layer was collected, and the solvent was
removed in a rotary evaporator. The title compound 28 was
obtained as a white solid (1.12 g, 88% yield) after purification
by silica gel column chromatography using ethyl acetate/
REFERENCES
■
(1) For reviews, see: (a) Giri, R.; Kc, S. Strategies toward
Dicarbofunctionalization of Unactivated Olefins by Combined Heck
Carbometalation and Cross-Coupling. J. Org. Chem. 2018, 83, 3013.
(b) Dhungana, R. K.; KC, S.; Basnet, P.; Giri, R. Transition Metal-
Catalyzed Dicarbofunctionalization of Unactivated Olefins. Chem. Rec.
2018, 18, 1314. (c) Derosa, J. T.; van der Puyl, V. A.; Tran, V. T.;
Engle, K. M. Carbon−Carbon π-Bonds as Conjunctive Reagents in
Cross-Coupling. Aldrichimica Acta 2018, 51, 21.
(2) For dicarbofunctionalization of activated alkenes, see: (a) Qin,
T.; Cornella, J.; Li, C.; Malins, L. R.; Edwards, J. T.; Kawamura, S.;
Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. A general alkyl-alkyl
cross-coupling enabled by redox-active esters and alkylzinc reagents.
Science 2016, 352, 801. (b) Guo, H.-C.; Ma, J.-A. Catalytic
Asymmetric Tandem Transformations Triggered by Conjugate
Additions. Angew. Chem., Int. Ed. 2006, 45, 354. (c) Zhang, L.;
Lovinger, G. J.; Edelstein, E. K.; Szymaniak, A. A.; Chierchia, M. P.;
Morken, J. P. Catalytic conjunctive cross-coupling enabled by metal-
induced metallate rearrangement. Science 2016, 351, 70.
(3) (a) Stadtmueller, H.; Lentz, R.; Tucker, C. E.; Stuedemann, T.;
Doerner, W.; Knochel, P. Palladium-catalyzed iodine-zinc exchange
reactions. A new palladium-mediated intramolecular carbozincation of
alkenes. J. Am. Chem. Soc. 1993, 115, 7027. (b) Wakabayashi, K.;
Yorimitsu, H.; Oshima, K. Cobalt-Catalyzed Tandem Radical
Cyclization and Cross-Coupling Reaction: Its Application to
Benzyl-Substituted Heterocycles. J. Am. Chem. Soc. 2001, 123, 5374.
1
hexanes (1:5). H NMR (500 MHz, CDCl3): δ 3.87 (s, 3H),
5.25 (d, J = 10.0 Hz, 1H), 5.40 (s, 2H), 5.54 (d, J = 15.0 Hz,
1H), 7.14 (dd, J = 10.0 Hz, 5.0 Hz, 1H), 7.38 (dd, J = 15.0 Hz,
J = 10.0 Hz, 1H), 7.50−7.56 (m, 3H), 7.64 (d, J = 10.0 Hz,
1H), 7.71−7.74 (m, 1H), 7.81 (d, J = 10.0 Hz, 1H), 8.08 (d, J
= 10.0 Hz, 1H), 8.17 (d, J = 5.0 Hz, 1H); 13C NMR (126
MHz, CDCl3): δ 52.2, 71.5, 115.1, 116.2, 119.1, 126.7, 127.7,
127.8, 128.6, 129.0, 129.7, 129.9, 132.8, 135.1, 137.2, 147.6,
157.3, 157.6, 167.5; IR (neat) cm−1: 1711, 1598, 1496, 1427,
1218, 1050; HRMS (ESI): Calcd for C20H18NO3 (M + H)+
320.1287, found 320.1286.
Methyl 2-(3,3-Dimethyl-1-phenylbutyl)-5-(quinolin-2-
ylmethoxy)benzoate (29). The title compound 29 was
obtained as a colorless viscous liquid (76 mg, 56% yield)
after purification by silica gel column chromatography using
THF/hexanes (1:10). 1H NMR (300 MHz, CDCl3): δ 0.81 (s,
9H), 2.05 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H), 5.17 (t, J = 6.0 Hz,
1H), 5.35 (s, 2H), 7.08−7.13 (m, 2H), 7.20−7.25 (m, 2H),
7.34 (d, J = 6.0 Hz, 2H), 7.40 (d, J = 3.0 Hz, 1H), 7.45 (d, J =
9.0 Hz, 1H), 7.55 (m, J = 7.5 Hz, 1H), 7.64 (d, J = 9.0 Hz,
1H), 7.74 (t, J = 7.5 Hz, 1H), 7.82 (d, J = 4.5 Hz, 1H), 8.06 (d,
J = 9.0 Hz, 1H), 8.18 (d, J = 9.0 Hz, 1H); 13C NMR (126
MHz, CDCl3): δ 30.3, 31.7, 40.9, 50.1, 52.3, 71.5, 116.0, 118.6,
119.2, 125.8, 126.6, 127.7, 127.8, 128.0, 128.4, 129.0, 129.9,
130.9, 137.2, 140.3, 147.0, 147.7, 155.9, 157.7, 168.6; IR
́
(c) Phapale, V. B.; Bunuel, E.; García-Iglesias, M.; Cardenas, D. J. Ni-
̃
Catalyzed Cascade Formation of C(sp3)-C(sp3) Bonds by Cyclization
and Cross-Coupling Reactions of Iodoalkanes with Alkyl Zinc
Halides. Angew. Chem., Int. Ed. 2007, 46, 8790. (d) Cong, H.; Fu,
G. C. Catalytic Enantioselective Cyclization/Cross-Coupling with
Alkyl Electrophiles. J. Am. Chem. Soc. 2014, 136, 3788. (e) You, W.;
Brown, M. K. Diarylation of Alkenes by a Cu-Catalyzed Migratory
Insertion/Cross-Coupling Cascade. J. Am. Chem. Soc. 2014, 136,
14730. (f) McMahon, C. M.; Renn, M. S.; Alexanian, E. J. Manganese-
Catalyzed Carboacylations of Alkenes with Alkyl Iodides. Org. Lett.
2016, 18, 4148. (g) Dhungana, R. K.; Shrestha, B.; Thapa-Magar, R.;
Basnet, P.; Giri, R. Pd-Catalyzed Regioselective 1,2-Dicarbofunction-
alization of Unactivated Olefins by a Heck Reaction/Enolate
Cyclization Cascade. Org. Lett. 2017, 19, 2154. (h) Thapa, S.;
G
DOI: 10.1021/acs.oprd.9b00199
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Basnet, P.; Giri, R. Copper-Catalyzed Dicarbofunctionalization of
Unactivated Olefins by Tandem Cyclization/Cross-Coupling. J. Am.
Chem. Soc. 2017, 139, 5700. (i) Xu, T.; Dong, G. Rhodium-Catalyzed
Regioselective Carboacylation of Olefins: A C-C Bond Activation
Approach for Accessing Fused-Ring Systems. Angew. Chem., Int. Ed.
2012, 51, 7567. (j) Walker, J. A.; Vickerman, K. L.; Humke, J. N.;
Stanley, L. M. Ni-Catalyzed Alkene Carboacylation via Amide C−N
Bond Activation. J. Am. Chem. Soc. 2017, 139, 10228. (k) Xiao, J.;
Cong, X.-W.; Yang, G.-Z.; Wang, Y.-W.; Peng, Y. Stereoselective
synthesis of a Podophyllum lignan core by intramolecular reductive
nickel-catalysis. Chem. Commun. 2018, 54, 2040. (l) Kc, S.; Basnet, P.;
Thapa, S.; Shrestha, B.; Giri, R. Ni-Catalyzed Regioselective
Dicarbofunctionalization of Unactivated Olefins by Tandem Cycliza-
tion/Cross-Coupling and Application to the Concise Synthesis of
Lignan Natural Products. J. Org. Chem. 2018, 83, 2920. (m) Kuang,
Y.; Wang, X.; Anthony, D.; Diao, T. Ni-catalyzed two-component
reductive dicarbofunctionalization of alkenes via radical cyclization.
Chem. Commun. 2018, 54, 2558. (n) Nakamura, M.; Ito, S.; Matsuo,
K.; Nakamura, E. Iron-Catalyzed Chemoselective Cross-Coupling of
Primary and Secondary Alkyl Halides with Arylzinc Reagents. Synlett
2005, 2005, 1794. (o) Jin, Y.; Wang, C. Ni-catalysed reductive
arylalkylation of unactivated alkenes. Chem. Sci. 2019, 10, 1780.
(p) Wang, K.; Ding, Z.; Zhou, Z.; Kong, W. Ni-Catalyzed
Enantioselective Reductive Diarylation of Activated Alkenes by
Domino Cyclization/Cross-Coupling. J. Am. Chem. Soc. 2018, 140,
12364.
(4) (a) Nakamura, M.; Hirai, A.; Nakamura, E. Iron-Catalyzed
Olefin Carbometalation. J. Am. Chem. Soc. 2000, 122, 978. (b) Terao,
J.; Saito, K.; Nii, S.; Kambe, N.; Sonoda, N. Regioselective Double
Alkylation of Styrenes with Alkyl Halides Using a Titanocene
Catalyst. J. Am. Chem. Soc. 1998, 120, 11822. (c) Liao, L.; Jana, R.;
Urkalan, K. B.; Sigman, M. S. A Palladium-Catalyzed Three-
Component Cross-Coupling of Conjugated Dienes or Terminal
Alkenes with Vinyl Triflates and Boronic Acids. J. Am. Chem. Soc.
2011, 133, 5784. (d) Wu, X.; Lin, H.-C.; Li, M.-L.; Li, L.-L.; Han, Z.-
Y.; Gong, L.-Z. Enantioselective 1,2-Difunctionalization of Dienes
Enabled by Chiral Palladium Complex-Catalyzed Cascade Arylation/
Allylic Alkylation Reaction. J. Am. Chem. Soc. 2015, 137, 13476.
(e) Mizutani, K.; Shinokubo, H.; Oshima, K. Cobalt-Catalyzed Three-
Component Coupling Reaction of Alkyl Halides, 1,3-Dienes, and
Trimethylsilylmethylmagnesium Chloride. Org. Lett. 2003, 5, 3959.
(f) Urkalan, K. B.; Sigman, M. S. Palladium-Catalyzed Oxidative
Intermolecular Difunctionalization of Terminal Alkenes with Organo-
stannanes and Molecular Oxygen. Angew. Chem., Int. Ed. 2009, 48,
3146. (g) Kuang, Z.; Yang, K.; Song, Q. Pd-Catalyzed Regioselective
1,2-Difunctionalization of Vinylarenes with Alkenyl Triflates and Aryl
Boronic Acids at Ambient Temperature. Org. Lett. 2017, 19, 2702.
(h) Kc, S.; Dhungana, R. K.; Shrestha, B.; Thapa, S.; Khanal, N.;
Basnet, P.; Lebrun, R. W.; Giri, R. Ni-Catalyzed Regioselective
Alkylarylation of Vinylarenes via C(sp3)−C(sp3)/C(sp3)−C(sp2)
Bond Formation and Mechanistic Studies. J. Am. Chem. Soc. 2018,
140, 9801. (i) Gao, P.; Chen, L.-A.; Brown, M. K. Nickel-Catalyzed
Stereoselective Diarylation of Alkenylarenes. J. Am. Chem. Soc. 2018,
140, 10653. (j) Anthony, D.; Lin, Q.; Baudet, J.; Diao, T. Nickel-
Catalyzed Asymmetric Reductive Diarylation of Vinylarenes. Angew.
Chem., Int. Ed. 2019, 58, 3198. (k) Klauck, F. J. R.; Yoon, H.; James,
M. J.; Lautens, M.; Glorius, F. Visible-Light-Mediated Deaminative
Three-Component Dicarbofunctionalization of Styrenes with Benzylic
Radicals. ACS Catal. 2019, 9, 236. (l) Yong, X.; Han, Y.-F.; Li, Y.;
Song, R.-J.; Li, J.-H. Alkylarylation of styrenes via direct C(sp3)−Br/
C(sp2)−H functionalization mediated by photoredox and copper
cooperative catalysis. Chem. Commun. 2018, 54, 12816. (m) Basnet,
P.; Dhungana, R. K.; Thapa, S.; Shrestha, B.; Kc, S.; Sears, J. M.; Giri,
R. Ni-Catalyzed Regioselective β,δ-Diarylation of Unactivated Olefins
in Ketimines via Ligand-Enabled Contraction of Transient Nickella-
cycles: Rapid Access to Remotely Diarylated Ketones. J. Am. Chem.
Soc. 2018, 140, 7782. (n) Li, W.; Boon, J. K.; Zhao, Y. Nickel-
catalyzed difunctionalization of allyl moieties using organoboronic
acids and halides with divergent regioselectivities. Chem. Sci. 2018, 9,
600. (o) Shrestha, B.; Basnet, P.; Dhungana, R. K.; Kc, S.; Thapa, S.;
Sears, J. M.; Giri, R. Ni-Catalyzed Regioselective 1,2-Dicarbofunction-
alization of Olefins by Intercepting Heck Intermediates as Imine-
Stabilized Transient Metallacycles. J. Am. Chem. Soc. 2017, 139,
10653. (p) Thapa, S.; Dhungana, R. K.; Magar, R. T.; Shrestha, B.;
Kc, S.; Giri, R. Ni-catalysed regioselective 1,2-diarylation of
unactivated olefins by stabilizing Heck intermediates as pyridylsilyl-
coordinated transient metallacycles. Chem. Sci. 2018, 9, 904.
(q) Basnet, P.; Kc, S.; Dhungana, R. K.; Shrestha, B.; Boyle, T. J.;
Giri, R. Synergistic Bimetallic Ni/Ag and Ni/Cu Catalysis for
Regioselective γ,δ-Diarylation of Alkenyl Ketimines: Addressing β-H
Elimination by in Situ Generation of Cationic Ni(II) Catalysts. J. Am.
Chem. Soc. 2018, 140, 15586. (r) Gu, J.-W.; Min, Q.-Q.; Yu, L.-C.;
Zhang, X. Tandem Difluoroalkylation-Arylation of Enamides
Catalyzed by Nickel. Angew. Chem., Int. Ed. 2016, 55, 12270.
(s) Yahiaoui, S.; Fardost, A.; Trejos, A.; Larhed, M. Chelation-
Mediated Palladium(II)-Catalyzed Domino Heck−Mizoroki/Suzuki−
Miyaura Reactions Using Arylboronic Acids: Increasing Scope and
Mechanistic Understanding. J. Org. Chem. 2011, 76, 2433. (t) Derosa,
J.; Tran, V. T.; Boulous, M. N.; Chen, J. S.; Engle, K. M. Nickel-
Catalyzed β,γ-Dicarbofunctionalization of Alkenyl Carbonyl Com-
pounds via Conjunctive Cross-Coupling. J. Am. Chem. Soc. 2017, 139,
10657. (u) Derosa, J.; Kleinmans, R.; Tran, V. T.; Karunananda, M.
K.; Wisniewski, S. R.; Eastgate, M. D.; Engle, K. M. Nickel-Catalyzed
1,2-Diarylation of Simple Alkenyl Amides. J. Am. Chem. Soc. 2018,
140, 17878. (v) Zhao, X.; Tu, H.-Y.; Guo, L.; Zhu, S.; Qing, F.-L.;
Chu, L. Intermolecular selective carboacylation of alkenes via nickel-
catalyzed reductive radical relay. Nat. Commun. 2018, 9, 3488.
(5) García-Domínguez, A.; Li, Z.; Nevado, C. Nickel-Catalyzed
Reductive Dicarbofunctionalization of Alkenes. J. Am. Chem. Soc.
2017, 139, 6835.
(6) (a) Ma, Y.; Zhang, D.; Yan, Z.; Wang, M.; Bian, C.; Gao, X.;
Bunel, E. E.; Lei, A. Iron-Catalyzed Oxidative C−H/C−H Cross-
Coupling between Electron-Rich Arenes and Alkenes. Org. Lett. 2015,
17, 2174. (b) Ouyang, X.-H.; Li, Y.; Song, R.-J.; Hu, M.; Luo, S.; Li, J.-
H. Intermolecular dialkylation of alkenes with two distinct C(sp3)−H
bonds enabled by synergistic photoredox catalysis and iron catalysis.
Science Advances 2019, 5, No. eaav9839.
(7) Balme, G.; Bouyssi, D. Total synthesis of the triquinane marine
sesquiterpene ( )Δ9(12) capnellene using a palladium-catalyzed bis-
cyclization step. Tetrahedron 1994, 50, 403.
(8) Chu, L.; Armstrong, H. M.; Chang, L. L.; Cheng, A. F.; Colwell,
L.; Cui, J.; Evans, J.; Galka, A.; Goulet, M. T.; Hayes, N.; Lo, J.;
Menke, J.; Ok, H. O.; Ondeyka, D. L.; Patel, M.; Quaker, G. M.;
Sings, H.; Witkin, S. L.; Zhao, A.; Ujjainwalla, F. Evaluation of endo-
and exo-aryl-substitutions and central scaffold modifications on
diphenyl substituted alkanes as 5-lipoxygenase activating protein
inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 4133.
(9) (a) Sanchez, L. A.; Olmedo, D.; Lopez-Perez, J. L.; Williams, T.
D.; Gupta, M. P. Two new alkylresorcinols from Homalomena
wendlandii and their cytotoxic activity. Nat. Prod. Commun. 2012, 7,
1043. (b) Yonova, I. M.; Johnson, A. G.; Osborne, C. A.; Moore, C.
E.; Morrissette, N. S.; Jarvo, E. R. Stereospecific Nickel-Catalyzed
Cross-Coupling Reactions of Alkyl Grignard Reagents and Identi-
fication of Selective Anti-Breast-Cancer Agents. Angew. Chem., Int. Ed.
2014, 53, 2422.
(10) Smyth, L. A.; Phillips, E. M.; Chan, V. S.; Napolitano, J. G.;
Henry, R.; Shekhar, S. Pd-Catalyzed Synthesis of Aryl and Heteroaryl
Triflones from Reactions of Sodium Triflinate with Aryl (Heteroaryl)
Triflates. J. Org. Chem. 2016, 81, 1285.
(11) Molander, G. A.; Brown, A. R. Suzuki−Miyaura Cross-
Coupling Reactions of Potassium Vinyltrifluoroborate with Aryl and
Heteroaryl Electrophiles. J. Org. Chem. 2006, 71, 9681.
(12) Yanagisawa, A.; Taga, M.; Atsumi, T.; Nishimura, K.; Ando, K.;
Taguchi, T.; Tsumuki, H.; Chujo, I.; Mohri, S.-i. Process Develop-
ment of the PDE4 Inhibitor K-34. Org. Process Res. Dev. 2011, 15, 376.
(13) Chakraborti, A. K.; Sharma, L.; Nayak, M. K. Demand-Based
Thiolate Anion Generation under Virtually Neutral Conditions:
Influence of Steric and Electronic Factors on Chemo- and
H
DOI: 10.1021/acs.oprd.9b00199
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Regioselective Cleavage of Aryl Alkyl Ethers. J. Org. Chem. 2002, 67,
6406.
(14) Lee, K. S.; Kim, K. D. A convenient and efficient method for
demethylation of aryl methyl ethers with magnesium iodide in ionic
liquid. Bull. Korean Chem. Soc. 2010, 31, 3842.
(15) Liu, L.; Li, Z.; Chen, C.; Li, H.; Xu, L.; Yu, Z. Efficient
dealkylation of aryl alkyl ethers catalyzed by Cu2O. Tetrahedron 2018,
74, 2447.
(16) Suzuki, T.; Miyajima, Y.; Suzuki, K.; Iwakiri, K.; Koshimizu, M.;
Hirai, G.; Sodeoka, M.; Kobayashi, S. Unexpected Diels−Alder/
Carbonyl-ene Cascade toward the Biomimetic Synthesis of Chlor-
opupukeananin. Org. Lett. 2013, 15, 1748.
(17) Jung, K.-Y.; Vanommeslaeghe, K.; Lanning, M. E.; Yap, J. L.;
Gordon, C.; Wilder, P. T.; MacKerell, A. D.; Fletcher, S. Amphipathic
α-Helix Mimetics Based on a 1,2-Diphenylacetylene Scaffold. Org.
Lett. 2013, 15, 3234.
̈
̈
(18) Ueberschaar, N.; Xu, Z.; Scherlach, K.; Metsa-Ketela, M.;
̈
Bretschneider, T.; Dahse, H.-M.; Gorls, H.; Hertweck, C. Synthetic
Remodeling of the Chartreusin Pathway to Tune Antiproliferative and
Antibacterial Activities. J. Am. Chem. Soc. 2013, 135, 17408.
(19) Kolasa, T.; Gunn, D. E.; Bhatia, P.; Woods, K. W.; Gane, T.;
Stewart, A. O.; Bouska, J. B.; Harris, R. R.; Hulkower, K. I.; Malo, P.
E.; Bell, R. L.; Carter, G. W.; Brooks, C. D. W. Heteroarylmethox-
yphenylalkoxyiminoalkylcarboxylic Acids as Leukotriene Biosynthesis
Inhibitors. J. Med. Chem. 2000, 43, 690.
(20) The mass balance is accounted for by the formation of a Heck
product (27%) and the remaining starting material (5%).
(21) The alkylarylation reaction typically generates 10−25% Heck
products and contains 5−15% unreacted starting materials.
(22) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Efficient Synthesis of Functionalized Organozinc Compounds by the
Direct Insertion of Zinc into Organic Iodides and Bromides. Angew.
Chem., Int. Ed. 2006, 45, 6040.
I
DOI: 10.1021/acs.oprd.9b00199
Org. Process Res. Dev. XXXX, XXX, XXX−XXX