Terminal-Selective C(sp3)-H Arylation: NiH-Catalyzed Remote Hydroarylation of Unactivated Internal Olefins

Article abstract of DOI:10.1021/acs.organomet.0c00819

A terminal-selective migratory hydroarylation of unactivated olefins has been developed though a NiH-catalyzed alkene isomerization-hydroarylation relay process. This sp³C-H arylation was achieved with a simple pyrox ligand under mild conditions. The practicality and synthetic flexibility of the method is highlighted by the successful regioconvergent conversion of isomeric mixtures of alkenes to value-added linear arylation products on a gram scale.

Full text of DOI:10.1021/acs.organomet.0c00819

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Terminal-Selective C(sp3)−H Arylation: NiH-Catalyzed Remote
Hydroarylation of Unactivated Internal Olefins
Yuli He, Bo Han, and Shaolin Zhu*
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ABSTRACT: A terminal-selective migratory hydroarylation of
unactivated olefins has been developed though a NiH-catalyzed
alkene isomerization−hydroarylation relay process. This sp3 C−H
arylation was achieved with a simple pyrox ligand under mild
conditions. The practicality and synthetic flexibility of the method is
highlighted by the successful regioconvergent conversion of isomeric
mixtures of alkenes to value-added linear arylation products on a gram
scale.
hydrofunctionalization.5−12 Encouraged by the recent progress
on NiH-catalyzed remote hydrofunctionalization (Figure
1b),9−12 we wondered if the migratory arylation site9e could
be located at the least sterically hindered terminal C(sp3)−H
position, thus producing the linear arylation product (Figure
1c).13 In this case, the reaction would serve as a useful addition
to the current remote hydroarylation methods and broaden
their applications, including the retrosynthesis of complex
molecules or late-stage functionalization in drug discovery.
Herein, we report a nickel hydride catalyst modified by a pyrox
ligand which delivers distal terminal arylation products with
high functional group compatibility under mild conditions.
Details of the presumed mechanism for this terminal-
selective migratory hydroarylation reaction are shown in Figure
2. It is envisioned that the nickel(I) hydride (I)4 generated in
situ could promote a rapid and reversible isomerization
between a series of alkylnickel intermediates (II, IV, V, etc.)
along the alkyl chain through an iterative β-hydride
elimination/β-migratory reinsertion process. With a suitable
ligand, selective cross-coupling of the least sterically hindered
linear alkylnickel(I) intermediate (V) generated in this way
with aryl iodide (2) would be favored over other branched
alkylnickel(I) intermediates and regiocontrol would thus be
possible. The desired formal terminal C(sp3)−H arylation
product (3) would be formed and the nickel hydride species
could be regenerated in situ in the presence of a fluoride salt
INTRODUCTION
■
Alkyl−aryl cross-coupling catalyzed by transition metals is a
valuable process in a wide variety of C−C bond formation
reactions and enables the production of valuable alkyl−aryl
structural motifs (Figure 1a).1,2 In these couplings, however,
Figure 1. Design plan: terminal-selective migratory hydroarylation
enabled by alkene isomerization and sequential hydroarylation.
reaction sites are limited to the preactivated ipso positions. A
further difficulty is that the synthesis of the preformed
organometallic nucleophiles used in these processes is
nontrivial and these nucleophiles can be highly reactive and
unstable. Selective remote functionalization of hydrocarbons
has the potential to assist in chemical synthesis but often
suffers from the difficulty of discriminating between C(sp3)−H
bonds in both the starting material and product. A powerful
alternative approach is the use of an unsaturated alkene or its
precursor alkyl halide, abundant feedstock starting materials, to
undergo metal hydride3,4 catalyzed site-selective remote
Special Issue: Organometallic Solutions to Challenges
in Cross-Coupling
Received: December 31, 2020
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© XXXX American Chemical Society
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alkyl group of L1 are critical (entries 4−6). Modification of the
dihydrooxazole ring led to lower yields (entries 4 and 5). The
use of ligand L4 without an o-methyl substituent or
replacement of the pyrox ligand (L1) with bipyridine type
ligands (L5−L7) resulted in no desired product (entry 6). An
evaluation of other silanes showed that polymethylhydrosilox-
ane (PMHS) was less effective (entry 7). The replacement of
KF with CsF resulted in almost a complete loss of reactivity
(entry 8). Less polar solvents such as THF, toluene, and
acetonitrile were found to be unsuitable (entries 9−11), and
the polar solvent DMA was less effective (entry 12).
Conducting the reaction at 40 °C instead of at room
temperature (rt) also led to a lower yield (entry 13). When
a less reactive aryl bromide was used, cross-coupling happened
with considerably lower yield and regioselectivity in compar-
ison to that of aryl iodide (entry 14). Use of only 1.5 equiv of
the aryl iodide (2a) also led to a reduced yield (entry 15).
Control experiments revealed that all of the reaction
parameters were important for the success of the reaction.
With this protocol in hand, we sought to demonstrate the
generality of this transformation. As shown in Table 2, a variety
Figure 2. Proposed pathway of terminal-selective remote hydro-
arylation.
and hydrosilane to complete a net catalytic cycle. Here we
present our achievement of this reaction under mild conditions
with high functional group compatibility.
a b
,
Table 2. Scope of Alkene Coupling Partners
RESULTS AND DISCUSSION
■
We began by studying the coupling of trans-4-octene (1a) with
1-iodo-4-(trifluoromethyl)benzene (2a). An investigation of
various parameters showed that the desired terminal-selective
arylation product (3a) could be obtained in 80% yield by using
a combination of NiBr2·glyme and a suitable pyrox ligand
(L1). The reaction showed excellent regioselectivity (rr (linear
isomer:all other isomers) = 98:2) (Table 1, entry 1). Use of
other nickel sources led to diminished yields (entries 2 and 3).
The pyrox ligand (L1) is easily prepared and is stable in air
(see the Supporting Information for details). Screening of
ligands revealed that both the dihydrooxazole ring and the 6-
Table 1. Variation of Reaction Parameters
a
b
Isolated yields on a 0.50 mmol scale (average of two runs). rr refers
to regioisomeric ratio and represents the ratio of the major (terminal
arylation) product to the sum of all other isomers as determined by
c
GC analysis. 10 mol % of NiBr2·glyme and 11 mol % of L1 used.
of unactivated internal aliphatic alkenes undergo alkene
isomerization−hydroarylation smoothly. Both E (1b) and Z
(1c,h,l) alkenes, as well as E/Z mixtures (1d−g,i−k), were
well-tolerated, and high terminal-selective arylation was
observed, regardless of the starting position of the CC
double bond (1c vs 1d). Furthermore, a wide variety of
functional groups (1e−l) are well-tolerated, demonstrating the
high chemo- and regioselectivity of the reaction. For example,
a
Yields were determined by GC using dodecane as the internal
standard. The yield in parentheses is the isolated yield of purified
product and is an average of two experiments (0.5 mmol scale). rr
refers to regioisomeric ratio and represents the ratio of the major
(terminal arylation) product to the sum of all other isomers as
determined by GC analysis (see Supporting Information for
experimental details).
b
B
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a b
,
Table 3. Scope of Aryl Iodide Coupling Partners
a
b
Isolated yields on a 0.50 mmol scale (average of two runs). rr refers to regioisomeric ratio and represents the ratio of the major (terminal
1
arylation) product to the sum of all other isomers as determined by GC analysis; ratios reported as >95:5 were determined by a crude H NMR
analysis. 10 mol % of NiBr2·glyme and 11 mol % L1 used. 4.5 equiv of (EtO)3SiH used. 0.2 mmol of 2z used.
c
d
e
even with a heteroatomic substituent at the other terminus of
the alkyl chain, including carbamates (1e−g) or ethers (1h−j),
migration toward the terminal position and the subsequent
linear adduct is still preferred. Of particular interest, good
terminal chemo- and regioselectivity is still observed for olefins
bearing a remote phenyl group14 (1k) or a perfluoroalkyl-
substituted electron-withdrawing substituent (1l). In addition,
the isomerization−hydroarylation could be extended to a more
sterically hindered trisubstituted alkene (1l), although the
linear product was formed in a lower yield.
Next, we explored the scope of the aryl iodide coupling
partner. As shown in Table 3a, we found that aryl iodides
bearing either electron-deficient (2b−l) or electron-donating
(2n,o) groups were competent substrates with excellent
regioselectivity.15 Under these exceptionally mild conditions,
not only were ethers (2b,e,l), a nitrile (2c), an ester (2d), and
amides (2e,f) tolerated, even normally easily reduced func-
tional groups such as a ketone (2g) and an aldehyde (2h)
remained intact. The reaction is orthogonal to aryl chloride
(2i), aryl triflates (2j), and boronates (2k), which could be
used for further derivatization. Notably, various acidic and
basic functional groups, including a N−H-bearing amide (2f),
a primary alcohol (2n), and a primary aniline (2o), were
compatible with the current protocol.
Heterocyclic arenes products are common scaffolds in
pharmaceutically relevant targets, and with respect to
heteroaromatic iodide coupling partners (Table 3b), we
found that a range of pyridines (2p−t) were suitable
substrates. Extended aromatic systems such as a pyrrole-
substituted pyridine (2t) and quinoline (2u) were also
effective electrophiles in this transformation. Finally, multi-
nitrogen-containing heterocycles including 2-pyrimidinamine
(2v) and imidazo[1,2-a]pyridine (2w) were also competent
coupling partners, making this an attractive method for
preparing potential biochemically active agents.
This methodology can also be used for the late-stage
functionalization of structurally complex and pharmaceutically
relevant intermediates (Table 3c). A variety of (hetero)aryl
iodides derived from commercially available pharmaceuticals,
such as empagliflozin (2x), as well as heteroaryl-containing
drugs, including canagliflozin (2y), apixaban (2z), indometha-
cin (2a′), and cloquintocet-mexyl (2b′), underwent migratory
cross-coupling. Interestingly, carbohydrate derivatives such as
the glucose (2c′) could also undergo the remote arylation
successfully.
C
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chromatography and eluted with hexanes to provide the title
compound as a colorless liquid in 80% yield (103.3 mg). IR (neat,
cm−1): 2926, 1323, 1118, 1018, 732. 1H NMR (400 MHz, CDCl3): δ
7.54 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 2.67 (t, J = 7.8 Hz,
2H), 1.68−1.61 (m, 2H), 1.33−1.30 (m, 10H), 0.91 (t, J = 6.8 Hz,
3H). 13C NMR (101 MHz, CDCl3): δ 147.2, 128.3, 128.2 (q, J = 32.3
Hz), 125.3 (q, J = 3.8 Hz), 124.6 (q, J = 271.6 Hz), 36.0, 32.1, 31.4,
29.9, 29.5, 29.4, 22.9, 14.2. 19F NMR (376 MHz, CDCl3): δ −62.3.
HRMS-EI (m/z): calcd for C15H21F3 [M]+ 258.1595, found 258.1598.
1-Hexyl-4-(trifluoromethyl)benzene (Table 2, 3b). The title
compound was prepared from (E)-hex-3-ene (62 μL, 0.50 mmol),
following the general procedure and using NiBr2·glyme (7.8 mg, 0.025
mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g,
1.25 mmol, 2.5 equiv), 4-iodobenzotrifluoride (272.0 mg, 150 μL, 1.0
mmol, 2.0 equiv), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and
DMF (3.75 mL). The reaction mixture was stirred for 24 h at rt. The
crude material was purified by flash column chromatography and
eluted with pentanes to provide the title compound as a colorless
liquid in 79% yield (90.8 mg). IR (neat, cm−1): 2929, 1618, 1322,
1116, 1066, 820. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 7.9 Hz,
2H), 7.31 (d, J = 7.9 Hz, 2H), 2.69 (t, J = 7.8 Hz, 2H), 1.70−1.62 (m,
2H), 1.40−1.31 (m, 6H), 0.93 (t, J = 6.4 Hz, 3H). 13C NMR (101
MHz, CDCl3): δ 147.2, 128.8, 128.1 (q, J = 32.3 Hz), 125.3 (q, J =
3.9 Hz), 124.6 (q, J = 272.7 Hz), 36.0, 31.9, 31.4, 29.1, 22.8, 14.2. 19F
NMR (376 MHz, CDCl3): δ −62.3. HRMS-EI (m/z): calcd for
C13H17F3 [M]+ m/z 230.1282, found 230.1279.
Isomeric mixtures of olefins derived directly from
petrochemical sources are substantially cheaper than pure
olefin isomers and their value-added regioconvergent con-
version is therefore of considerable interest. As a proof of
concept, equimolar mixtures of five isomeric octanes were
utilized on a 10 mmol scale and the linear arylation product
was obtained on a gram scale in a highly regioconvergent
manner (Scheme 1).
Scheme 1. Regioconvergent, 10 mmol Scale Benchtop
Experiment
CONCLUSION
■
A mild, regioconvergent, and terminal-selective nickel-
catalyzed migratory hydroarylation has been established.
Excellent regio- and chemoselectivities were observed with a
wide variety of both functionalized and unfunctionalized
alkenes and (hetero)aryl iodide partners. Research into remote
hydroarylation with branched selectivity is currently in
progress and will be reported in due course.
1-Octyl-4-(trifluoromethyl)benzene (Table 2, 3c). The title
compound was prepared from (E)-oct-3-ene (56.1 mg, 0.50 mmol),
following the general procedure and using NiBr2·glyme (7.8 mg, 0.025
mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g,
1.25 mmol, 2.5 equiv), 4-iodobenzotrifluoride (272.0 mg, 150 μL, 1.0
mmol, 2.0 equiv), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and
DMF (3.75 mL). The reaction mixture was stirred for 24 h at rt. The
crude material was purified by flash column chromatography and
eluted with hexanes to provide the title compound as a colorless liquid
in 78% yield (94.4 mg). IR (neat, cm−1): 2926, 1323, 1118, 1018,
EXPERIMENTAL SECTION
■
General Information. Commercial reagents were purchased from
commercial sources unless otherwise noted. Flash chromatography
was performed using glass columns with 230−400 mesh silica gel. 1H
NMR and 13C NMR spectra were recorded on Bruker 400 and 500
MHz spectrometers. IR spectra were obtained on a Bruker Alpha
spectrometer and are reported in terms of frequency of absorption
(cm−1). GC analysis was performed on an Agilent 7890B gas
chromatograph with an FID detector using a J&W DB-1 column (10
m, 0.1 mm I.D.). High-resolution mass spectra were obtained using a
Bruker Daltonics, Inc. APEXIII 7.0 TESLA FTMS instrument (ESI)
or a Waters Micromass GCT Premier Instrument (EI).
1
732. H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 8.0 Hz, 2H), 7.30
(d, J = 7.9 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 1.68−1.61 (m, 2H),
1.33−1.30 (m, 10H), 0.91 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 147.2, 128.3, 128.2 (q, J = 32.3 Hz), 125.3 (q, J = 3.8 Hz),
124.6 (q, J = 271.6 Hz), 36.0, 32.1, 31.4, 29.9, 29.5, 29.4, 22.9, 14.2.
19F NMR (376 MHz, CDCl3): δ −62.3. HRMS-EI (m/z): calcd for
C15H21F3 [M]+ 258.1595, found 258.1598.
1-Octyl-4-(trifluoromethyl)benzene (Table 2, 3d). The title
compound was prepared from oct-2-ene (56.1 mg, 0.50 mmol),
following the general procedure and using NiBr2·glyme (7.8 mg, 0.025
mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g,
1.25 mmol, 2.5 equiv), 4-iodobenzotrifluoride (272.0 mg, 150 μL, 1.0
mmol, 2.0 equiv), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and
DMF (3.75 mL). The reaction mixture was stirred for 24 h at rt. The
crude material was purified by flash column chromatography and
eluted with hexanes to provide the title compound as a colorless liquid
in 90% yield (116.2 mg). IR (neat, cm−1): 2926, 1323, 1118, 1018,
General Procedure for the NiH-Catalyzed Remote Hydro-
arylation. L1 (6.0 mol %), NiBr2·glyme (5.0 mol %), KF (2.5 equiv),
and anhydrous DMF (3.75 mL) were placed in an oven-dried 8 mL
screw-cap vial equipped with a magnetic stirring bar. The vial was
placed in a nitrogen-filled glovebox, and the mixture was stirred for 20
min, at which time (EtO)3SiH (2.5 equiv) (a mixture stirred not more
than 1 min), alkene (0.5 mmol, 1.0 equiv), and aryl iodide (1.0 mmol,
2.0 equiv) were added to the resulting mixture in that order. The tube
was sealed with a Teflon-lined screw cap, removed from the glovebox,
and stirred at rt (22−26 °C) for up to 24 h. The reaction mixture was
then directly filtered through a short pad of silica gel using EtOAc in
hexanes to give the crude product. Dodecane (50 μL) was added as
an internal standard for GC analysis. 1,1,2,2-Tetrachloroethane (41.0
1
732. H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 8.0 Hz, 2H), 7.30
(d, J = 7.9 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 1.68−1.61 (m, 2H),
1.33−1.30 (m, 10H), 0.91 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 147.2, 128.3, 128.2 (q, J = 32.3 Hz), 125.3 (q, J = 3.8 Hz),
124.6 (q, J = 271.6 Hz), 36.0, 32.1, 31.4, 29.9, 29.5, 29.4, 22.9, 14.2.
19F NMR (376 MHz, CDCl3): δ −62.3. HRMS-EI (m/z): calcd for
1
mg, 0.25 mmol) was added as an internal standard for H NMR
C15H21F3 [M]+ 258.1595, found 258.1598.
analysis of the crude material. The product was purified by
chromatography on silica gel for each substrate. The yields reported
are the average of at least two experiments, unless otherwise indicated.
1-Octyl-4-(trifluoromethyl)benzene (Table 2, 3a). The title
compound was prepared from (E)-oct-4-ene (87.5 μL, 62.4 mg,
0.50 mmol), following the general procedure and using NiBr2·glyme
(7.8 mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol
%), KF (73.0 g, 1.25 mmol, 2.5 equiv), 4-iodobenzotrifluoride (272.0
mg, 150 μL, 1.0 mmol, 2.0 equiv), (EtO)3SiH (230 μL, 1.25 mmol,
2.5 equiv), and DMF (3.75 mL). The reaction mixture was stirred for
24 h at rt. The crude material was purified by flash column
tert-Butyl (6-(4-(Trifluoromethyl)phenyl)hexyl)carbamate (Table
2, 3e). The title compound was prepared from tert-butyl hex-4-en-1-
ylcarbamate (100.0 mg, 0.50 mmol), following the general procedure
and using NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg,
0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol, 2.5 equiv), 4-
iodobenzotrifluoride (272.0 mg, 150 μL, 1.0 mmol, 2.0 equiv),
(EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75 mL).
The reaction mixture was stirred for 24 h at rt. The crude material was
purified by flash column chromatography and eluted with 2% EtOAc
in hexanes to provide the title compound as a colorless liquid in 55%
D
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yield (95.6 mg). IR (neat, cm−1): 2931, 1691, 1510, 1323, 1116, 1017,
842. H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 7.9 Hz, 2H), 7.18
4-(5-(4-(Trifluoromethyl)phenyl)pentyl)tetrahydro-2H-pyran
(Table 2, 3i). The title compound was prepared from 4-(pent-1-en-1-
yl)tetrahydro-2H-pyran (77.0 mg, 0.50 mmol), following the general
procedure and using NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0 mol %),
L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol, 2.5
equiv), 4-iodobenzotrifluoride (272.0 mg, 150 μL, 1.0 mmol, 2.0
equiv), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75
mL). The reaction mixture was stirred for 24 h at rt. The crude
material was purified by flash column chromatography and eluted
with 1% EtOAc in hexanes to provide the title compound as a
colorless liquid in 44% yield (65.8 mg). IR (neat, cm−1): 2926, 1324,
1119, 1067, 842. 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 7.9 Hz,
2H), 7.20 (d, J = 9.2 Hz, 2H), 3.89−3.85 (m, 2H), 3.35−3.23 (m,
2H), 2.58 (t, J = 6.8 Hz, 2H), 1.58−1.47 (m, 4H), 1.28−1.11 (m,
9H). 13C NMR (101 MHz, CDCl3): δ 147.0, 128.8, 128.1 (q, J = 32.2
Hz), 125.3 (q, J = 3.9 Hz), 124.5 (q, J = 271.7 Hz), 68.3, 37.0, 35.9,
35.1, 33.3, 31.3, 29.5, 26.3. 19F NMR (376 MHz, CDCl3): δ −62.3.
HRMS-EI (m/z): calcd for C17H23F3O [M]+ 300.1701, found
300.1709.
1
(d, J = 7.8 Hz, 2H), 4.50 (s, 1H), 3.02 (q, J = 6.8 Hz, 2H), 2.57 (t, J =
7.7 Hz, 2H), 1.58−1.50 (m, 2H), 1.40−1.33 (m, 11H), 1.27−1.24
(m, 4H). 13C NMR (101 MHz, CDCl3): δ 156.1, 146.9, 128.8, 128.1
(q, J = 32.3 Hz), 125.3 (q, J = 3.8 Hz), 124.5 (q, J = 271.8 Hz), 79.1,
40.6, 35.8, 31.2, 30.1, 28.9, 28.5, 26.7. 19F NMR (376 MHz, CDCl3):
δ −62.3. HRMS-ESI (m/z): calcd for C18H26F3NNaO2 [M + Na]+
368.1808, found 368.1805.
Benzyl Benzyl(6-(4-(trifluoromethyl)phenyl)hexyl)carbamate
(Table 2, 3f). The title compound was prepared from benzyl
benzyl(hex-3-en-1-yl)carbamate (161.5 mg, 0.50 mmol), following
the general procedure and using NiBr2·glyme (7.8 mg, 0.025 mmol,
5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25
mmol, 2.5 equiv), 4-iodobenzotrifluoride (272.0 mg, 150 μL, 1.0
mmol, 2.0 equiv), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and
DMF (3.75 mL). The reaction mixture was stirred for 24 h at rt. The
crude material was purified by flash column chromatography and
eluted with 5% EtOAc in hexanes to provide the title compound as a
colorless liquid in 62% yield (145.1 mg). IR (neat, cm−1): 2931, 1696,
1418, 1323, 1116, 1028, 631. 1H NMR (400 MHz, CDCl3): δ 7.57 (d,
J = 7.9 Hz, 2H), 7.53−7.01 (m, 12H), 5.22 (s, 2H), 4.54 (s, 2H),
3.32−3.25 (m, 2H), 2.66 (t, J = 6.8 Hz, 2H), 1.64−1.54 (m, 4H),
1.38−1.27 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 156.9 and 156.3
(due to rotamers), 146.9, 138.1, 137.0, 128.8, 128.6, 128.5, 128.3,
128.0, 127.9, 127.7, 127.6, 127.4, 127.3, 125.3 (q, J = 3.9 Hz), 124.5
(q, J = 271.6 Hz), 67.25, 50.6, and 50.3 (due to rotamers), 47.3 and
46.3 (due to rotamers), 35.7, 31.1, 28.9, 28.1, and 27.7 (due to
rotamers), 26.7. 19F NMR (376 MHz, CDCl3): δ −62.2. HRMS-ESI
(m/z): calcd for C28H30F3NNaO2 [M + Na]+ 492.2121, found
492.2125.
1-(11-Methoxy-7,11-dimethyldodecyl)-4-(trifluoromethyl)-
benzene (Table 2, 3j). The title compound was prepared from 11-
methoxy-7,11-dimethyldodec-4-ene (108.1 mg, 0.50 mmol), following
the general procedure and using NiBr2·glyme (7.8 mg, 0.025 mmol,
5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25
mmol, 2.5 equiv), 4-iodobenzotrifluoride (272.0 mg, 150 μL, 1.0
mmol, 2.0 equiv), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and
DMF (3.75 mL). The reaction mixture was stirred for 24 h at rt. The
crude material was purified by flash column chromatography and
eluted with hexanes to provide the title compound as a colorless liquid
in 60% yield (108.7 mg). IR (neat, cm−1): 2928, 1323, 1121, 1066,
1
842. H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 8.0 Hz, 2H), 7.20
(d, J = 8.0 Hz, 2H), 3.10 (s, 3H), 2.58 (t, J = 7.8 Hz, 2H), 1.58−1.51
(m, 2H), 1.37−1.18 (m, 15H), 1.06 (s, 6H), 0.78 (d, J = 6.5 Hz, 3H).
13C NMR (101 MHz, CDCl3): δ 147.2, 128.8, 128.1 (q, J = 32.2 Hz),
125.3 (q, J = 3.9 Hz), 124.5 (q, J = 272.7 Hz), 74.8, 49.2, 40.3, 37.8,
37.2, 36.0, 32.9, 31.4, 30.0, 29.4, 27.1, 25.2, 21.5, 19.8. 19F NMR (376
MHz, CDCl3): δ −62.3. HRMS-EI (m/z): calcd for C21H32F3O [M −
15]+ 357.2405, found 357.2403.
tert-Butyl 4-(5-(4-(Trifluoromethyl)phenyl)pentyl)piperidine-1-
carboxylate (Table 2, 3g). The title compound was prepared from
tert-butyl 4-(pent-2-en-1-yl)piperidine-1-carboxylate (127.0 mg, 0.50
mmol), following the general procedure and using NiBr2·glyme (7.8
mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %),
KF (73.0 g, 1.25 mmol, 2.5 equiv), 4-iodobenzotrifluoride (272.0 mg,
150 μL, 1.0 mmol, 2.0 equiv), (EtO)3SiH (230 μL, 1.25 mmol, 2.5
equiv), and DMF (3.75 mL). The reaction mixture was stirred for 24
h at rt. The crude material was purified by flash column
chromatography and eluted with 2% EtOAc in hexanes to provide
the title compound as a colorless liquid in 60% yield (119.7 mg). IR
5-(2-Methyl-7-(4(Trifluoromethyl)phenyl)heptyl)benzo[d][1,3]-
dioxole (Table 2, 3k). The title compound was prepared from 5-(2-
methylhept-3-en-1-yl)benzo[d][1,3]dioxole (123.2 mg, 0.50 mmol),
following the general procedure and using NiBr2·glyme (7.8 mg, 0.025
mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g,
1.25 mmol, 2.5 equiv), 4-iodobenzotrifluoride (272.0 mg, 150 μL, 1.0
mmol, 2.0 equiv), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and
DMF (3.75 mL). The reaction mixture was stirred for 24 h at rt. The
crude material was purified by flash column chromatography and
eluted with 2% EtOAc in hexanes to provide the title compound as a
colorless liquid in 42% yield (82.3 mg). IR (neat, cm−1): 2926, 1488,
1322, 1116, 770. 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 8.0 Hz,
2H), 7.20 (d, J = 7.6 Hz, 2H), 6.64 (d, J = 7.9 Hz, 1H), 6.55 (s, 1H),
6.51−6.48 (m, 1H), 5.84 (s, 2H), 2.57 (t, J = 7.7 Hz, 2H), 2.45 (dd, J
= 13.5, 6.2 Hz, 1H), 2.21 (dd, J = 13.5, 8.0 Hz, 1H), 1.55−1.50 (m,
4H), 1.26−1.18 (m, 4H), 1.08−0.99 (m, 1H), 0.76 (d, J = 6.6 Hz,
3H). 13C NMR (126 MHz, CDCl3): δ 147.5, 147.1, 145.6, 135.6,
128.8, 128.1 (q, J = 32.2 Hz), 125.3 (q, J = 3.8 Hz), 124.6 (q, J =
271.6 Hz), 122.0, 109.6, 108.0, 100.8, 43.6, 36.5, 35.9, 35.3, 31.3,
29.6, 27.0, 19.5. 19F NMR (471 MHz, CDCl3): δ −62.2. HRMS-EI
(m/z): calcd for C22H25F3O2 [M]+ 378.1808, found 378.1807.
1-(9,9,10,10,11,11,12,12,13,13,14,14,14-Tridecafluorotetradecyl)-
4-(trifluoromethyl)benzene (Table 2, 3l). The title compound was
prepared from 1-perfluorohexyl-1-octene (215.1 mg, 0.50 mmol),
following the general procedure and using NiBr2·glyme (7.8 mg, 0.025
mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g,
1.25 mmol, 2.5 equiv), 4-iodobenzotrifluoride (272.0 mg, 150 μL, 1.0
mmol, 2.0 equiv), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and
DMF (3.75 mL). The reaction mixture was stirred for 24 h at rt. The
crude material was purified by flash column chromatography and
eluted with hexanes to provide the title compound as a colorless liquid
in 54% yield (155.4 mg). IR (neat, cm−1): 2932, 1325, 1119, 1019,
1
(neat, cm−1): 2928, 1988, 1418, 1324, 1119, 843. H NMR (400
MHz, CDCl3): δ 7.44 (d, J = 7.9 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H),
3.99 (d, J = 13.1 Hz, 2H), 2.61−2.55 (m, 4H), 1.57−1.53 (m, 4H),
1.38 (s, 9H), 1.25−1.23 (m, 5H), 1.16−1.11 (m, 2H), 1.00−0.96 (m,
2H). 13C NMR (101 MHz, CDCl3): δ 155.1, 147.0, 128.8, 128.1 (q, J
= 32.1 Hz), 125.3 (q, J = 3.9 Hz), 124.5 (q, J = 271.7 Hz), 79.3, 44.2,
36.6, 36.1, 35.9, 32.4, 31.3, 29.5, 28.6, 26.6. 19F NMR (376 MHz,
CDCl3): δ −62.3. HRMS-ESI (m/z): calcd for C22H32F3NNaO2 [M +
Na]+ 422.2277, found 422.2278.
1-(6-(Benzyloxy)hexyl)-4-(trifluoromethyl)benzene (Table 2, 3h).
The title compound was prepared from (Z)-((hex-3-en-1-yloxy)-
methyl)benzene (95.1 mg, 0.50 mmol), following the general
procedure and using NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0 mol
%), L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol, 2.5
equiv), 4-iodobenzotrifluoride (272.0 mg, 150 μL, 1.0 mmol, 2.0
equiv), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75
mL). The reaction mixture was stirred for 24 h at rt. The crude
material was purified by flash column chromatography and eluted
with hexanes to provide the title compound as a colorless liquid in
66% yield (111.0 mg). IR (neat, cm−1): 2932, 2856, 1322, 1114, 1018,
696. 1H NMR (400 MHz, CDCl3): δ 7.42 (d, J = 7.9 Hz, 2H), 7.29−
7.10 (m, 7H), 4.40 (s, 2H), 3.37 (t, J = 6.5 Hz, 2H), 2.55 (t, J = 7.7
Hz, 2H), 1.56−1.49 (m, 4H), 1.35−1.24 (m, 4H). 13C NMR (101
MHz, CDCl3): δ 147.0, 138.8, 128.8, 128.5, 128.1 (q, J = 32.3 Hz),
127.7, 127.6, 125.3 (q, J = 3.8 Hz), 124.6 (q, J = 271.8 Hz), 73.0,
70.5, 35.8, 31.2, 29.8, 29.1, 26.2. 19F NMR (376 MHz, CDCl3): δ
−62.2. HRMS-EI (m/z): calcd for C20H23F3O [M]+ 336.1701, found
336.1707.
E
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696. 1H NMR (400 MHz, CDCl3): δ 7.5 (d, J = 7.9 Hz, 2H), 7.2 (d, J
= 7.9 Hz, 2H), 2.6 (t, J = 7.7 Hz, 2H), 2.03−1.89 (m, 2H), 1.57−1.47
(m, 4H), 1.31−1.24 (m, 8H). 13C NMR (101 MHz, CDCl3): δ 147.1,
128.8, 128.3 (q, J = 32.3 Hz), 125.4 (q, J = 3.7 Hz), 124.6 (q, J =
271.5 Hz), 118.8−110.1 (13C−19F coupling from C6F13), 35.9, 31.3,
31.0 (t, J = 22.5 Hz), 29.4, 29.3, 29.2, 29.2, 20.2. 19F NMR (376 MHz,
CDCl3): δ −62.4 (s, 3F), −80.9 (t, J = 9.9 Hz, 3F), −114.5 to −114.5
(m, 2F), −121.9 to −122.1 (m, 2F), −122.9 to −123.1 (m, 2F),
−123.6 to −123.8 (m, 2F), −126.2 to −126.4 (m, 2F). HRMS-EI
(m/z): calcd for C21H20F16 [M]+ 576.1310, found 576.1317.
1-(3-Ethylpentyl)-4-(trifluoromethyl)benzene (Table 2, 3m). The
title compound was prepared from 3-ethyl-2-pentene (68 μL, 0.5
mmol), following the general procedure and using NiBr2·glyme (15.6
mg, 0.05 mmol, 5.0 mol %), L1 (8.8 mg, 0.055 mmol, 11.0 mol %),
KF (73.0 g, 1.25 mmol, 2.5 equiv), 4-iodobenzotrifluoride (272.0 mg,
150 μL, 1.0 mmol, 2.0 equiv), (EtO)3SiH (230 μL, 1.25 mmol, 2.5
equiv), and DMF (3.75 mL). The reaction mixture was stirred for 24
h at rt. The crude material was purified by flash column
chromatography and eluted with pentanes to provide the title
compound as a colorless liquid in 37% yield (45.2 mg). IR (neat,
cm−1): 2962, 2925, 1618, 1322, 1119, 1018, 835. 1H NMR (400
MHz, CDCl3): δ 7.44 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H),
2.55 (t, J = 6.8 Hz, 2H), 1.52−1.45 (m, 2H), 1.28−1.24 (m, 5H),
0.79 (t, J = 7.4 Hz, 6H). 13C NMR (101 MHz, Chloroform-d): δ
147.6, 128.8, 128.1 (q, J = 32.3 Hz), 125.3 (q, J = 3.7 Hz), 124.6 (q, J
= 271.6 Hz), 40.1, 34.7, 33.2, 25.4, 11.0. 19F NMR (376 MHz,
CDCl3): δ −62.3. HRMS-EI (m/z): calcd for C14H19F3 [M]+
244.1439, found 244.1445.
1-Octyl-4-(trifluoromethoxy)benzene (Table 3a, 4b). The title
compound was prepared from 1-iodo-4-(trifluoromethoxy)benzene
(288.0 mg, 1.0 mmol, 2.0 equiv), following the general procedure and
using NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg,
0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol, 2.5 equiv), (E)-oct-
4-ene (87.5 μL, 62.4 mg, 0.50 mmol), (EtO)3SiH (230 μL, 1.25
mmol, 2.5 equiv), and DMF (3.75 mL). The reaction mixture was
stirred for 24 h at rt. The crude material was purified by flash column
chromatography and eluted with hexanes to provide the title
compound as a colorless liquid in 66% yield (90.1 mg). IR (neat,
cm−1): 2926, 1508, 1254, 1115, 812. 1H NMR (400 MHz, CDCl3): δ
7.10 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 2.52 (t, J = 7.6 Hz,
2H), 1.56−1.46 (m, 2H), 1.28−1.13 (m, 10H), 0.80 (t, J = 6.8 Hz,
3H). 13C NMR (101 MHz, CDCl3): δ 147.4, 141.8, 129.7, 121.0,
120.7 (q, J = 256.4 Hz), 35.5, 32.0, 31.6, 29.8, 29.6, 29.4, 22.8, 14.2.
19F NMR (376 MHz, CDCl3): δ −58.0. HRMS-EI (m/z): calcd for
C15H21F3O [M]+ 274.1542, found 274.1544.
colorless liquid in 82% yield (105.3 mg). IR (neat, cm−1): 2924, 1716,
1610, 1270, 1104, 761. H NMR (400 MHz, CDCl3): δ 7.95 (d, J =
1
8.3 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 2.65
(t, J = 7.8 Hz, 2H), 1.65−1.58 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H),
1.34−1.21 (m, 10H), 0.87 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 166.9, 148.5, 129.7, 128.5, 128.0, 60.9, 36.1, 32.0, 31.3,
29.6, 29.4, 29.4, 22.8, 14.5, 14.2. HRMS-ESI (m/z): calcd for
C17H26NaO2 [M + Na]+ 285.1825, found 285.1817.
Morpholino(3-octylphenyl)methanone (Table 3a, 4e). The title
compound was prepared from (3-iodophenyl)(morpholino)-
methanone (317.1 mg, 1.0 mmol, 2.0 equiv), following the general
procedure and using NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0 mol %),
L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol, 2.5
equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg, 0.50 mmol), (EtO)3SiH
(230 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75 mL). The reaction
mixture was stirred for 24 h at rt. The crude material was purified by
flash column chromatography and eluted with 10% EtOAc in hexanes
to provide the title compound as a colorless liquid in 56% yield (84.6
1
mg). IR (neat, cm−1): 2922, 1605, 1490, 1242, 1120, 942, 808. H
NMR (400 MHz, CDCl3): δ 7.25−7.20 (m, 1H), 7.18−7.10 (m, 3H),
3.78−3.30 (m, 8H), 2.55 (t, J = 7.6 Hz, 2H), 1.58−1.48 (m, 2H),
1.29−1.15 (m, 10H), 0.80 (t, J = 6.9 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 170.8, 143.6, 135.3, 130.1, 128.5, 127.1, 124.4, 67.0, 48.4,
and 42.6 (due to rotamers), 35.9, 32.0, 31.4, 29.6, 29.4, 29.4, 22.8,
14.2. HRMS-ESI (m/z): calcd for C19H30NO2 [M + H]+ 304.2271,
found 304.2271.
2,2,2-Trifluoro-N-(4-octylphenyl)acetamide (Table 3a, 4f). The
title compound was prepared from 2,2,2-trifluoro-N-(4-iodophenyl)-
acetamide (315.2 mg, 1.0 mmol, 2.0 equiv), following the general
procedure and using NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0 mol %),
L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol, 2.5
equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg, 0.50 mmol), (EtO)3SiH
(230.0 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75 mL). The reaction
mixture was stirred for 24 h at rt. The crude material was purified by
flash column chromatography and eluted with 2% EtOAc in hexanes
to provide the title compound as a white solid in 58% yield (91.4 mg).
1
Mp: 84−86 °C. IR (neat, cm−1): 3295, 2917, 1702, 1147, 831. H
NMR (400 MHz, CDCl3): δ 7.97 (s, 1H), 7.38 (d, J = 8.5 Hz, 2H),
7.10 (d, J = 8.4 Hz, 2H), 2.51 (t, J = 7.6 Hz, 2H), 1.57−1.45 (m, 2H),
1.27−1.16 (m, 10H), 0.80 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 155.0 (q, J = 37.4 Hz), 141.5, 132.8, 129.3, 120.7, 116.0
(q, J = 288.4 Hz), 35.6, 32.0, 31.5, 29.6, 30.0, 29.4, 22.8, 14.2. 19F
NMR (376 MHz, CDCl3): δ −75.7. HRMS-ESI (m/z): calcd for
C16H22F3NNaO [M + Na]+ 324.1546, found 324.1542.
1-(4-Octylphenyl)ethan-1-one (Table 3a, 4g). The title com-
pound was prepared from 1-(4-iodophenyl)ethan-1-one (246.1 mg,
1.0 mmol, 2.0 equiv), following the general procedure and using
NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg, 0.030
mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol, 2.5 equiv), (E)-oct-4-ene
(87.5 μL, 62.4 mg, 0.50 mmol), (EtO)3SiH (230 μL, 1.25 mmol, 2.5
equiv), and DMF (3.75 mL). The reaction mixture was stirred for 24
h at rt. The crude material was purified by flash column
chromatography and eluted with hexanes to provide the title
compound as a colorless liquid in 72% yield (83.5 mg). IR (neat,
4-Octylbenzonitrile (Table 3a, 4c). The title compound was
prepared from 4-iodobenzonitrile (229.0 mg, 1.0 mmol, 2.0 equiv),
following the general procedure and using NiBr2·glyme (7.8 mg, 0.025
mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g,
1.25 mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg, 0.50 mmol),
(EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75 mL).
The reaction mixture was stirred for 24 h at rt. The crude material was
purified by flash column chromatography and eluted with hexanes to
provide the title compound as a colorless liquid in 56% yield (60.2
1
cm−1): 2923, 1681, 1605, 1356, 1285, 596. H NMR (400 MHz,
1
mg). IR (neat, cm−1): 2954, 2854, 2227, 1607, 1413, 819, 560. H
CDCl3): δ 7.79 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 2.57 (t, J
= 7.6 Hz, 2H), 2.49 (s, 3H), 1.56−1.50 (m, 2H), 1.26−1.14 (m,
10H), 0.80 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ
197.9, 148.9, 135.0, 128.7, 128.6, 36.1, 32.0, 31.3, 29.5, 29.4, 29.3,
26.7, 22.8, 14.2. HRMS-ESI (m/z): calcd for C16H25O [M + H]+
233.1900, found 233.1897.
4-Octylbenzaldehyde (Table 3a, 4h). The title compound was
prepared from 4-iodobenzaldehyde (232.0 mg, 1.0 mmol, 2.0 equiv),
following the general procedure and using NiBr2·glyme (7.8 mg, 0.025
mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g,
1.25 mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg, 0.50 mmol),
(EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75 mL).
The reaction mixture was stirred for 24 h at rt. The crude material was
purified by flash column chromatography and eluted with hexanes to
provide the title compound as a white solid in 71% yield (77.3 mg).
NMR (400 MHz, CDCl3): δ 7.48 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.1
Hz, 2H), 2.58 (d, J = 7.8 Hz, 2H), 1.57−1.50 (m, 2H), 1.23−1.18 (m,
10H), 0.80 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ
148.7, 132.2, 129.3, 119.3, 109.6, 36.2, 32.0, 31.1, 29.5, 29.4, 29.3,
22.8, 14.2. HRMS-ESI (m/z): calcd for C15H21NNa [M + Na]+
238.1566, found 238.1559.
Ethyl 4-Octylbenzoate (Table 3a, entry 4d). The title compound
was prepared from ethyl 4-iodobenzoate (276.1 mg, 1.0 mmol, 2.0
equiv), following the general procedure and using NiBr2·glyme (7.8
mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %),
KF (73.0 g, 1.25 mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg,
0.50 mmol), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and DMF
(3.75 mL). The reaction mixture was stirred for 24 h at rt. The crude
material was purified by flash column chromatography and eluted
with 1% EtOAc in hexanes to provide the title compound as a
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Mp: 34−35 °C. IR (neat, cm−1): 2923, 1698, 1605, 1167, 824. H
NMR (400 MHz, CDCl3): δ 9.96 (s, 1H), 7.79 (d, J = 8.1 Hz, 2H),
7.33 (d, J = 8.0 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 1.70−1.54 (m, 2H),
1.30−1.26 (m, 10H), 0.87 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 192.2, 150.6, 134.5, 130.0, 129.2, 36.4, 32.0, 31.2, 29.5,
29.4, 29.3, 22.8, 14.2. HRMS-ESI (m/z): calcd for C15H23O [M + H+]
219.1743, found 219.1746.
1-Chloro-3-octylbenzene (Table 3a, 4i). The title compound was
prepared from 1-chloro-3-iodobenzene (238.5 mg, 1.0 mmol, 2.0
equiv), following the general procedure and using NiBr2·glyme (7.8
mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %),
KF (73.0 g, 1.25 mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg,
0.50 mmol), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and DMF
(3.75 mL). The reaction mixture was stirred for 24 h at rt. The crude
material was purified by flash column chromatography and eluted
with hexanes to provide the title compound as a colorless liquid in
84% yield (93.8 mg). IR (neat, cm−1): 2923, 1597, 1466, 1078, 777.
1H NMR (400 MHz, CDCl3): δ 7.27−7.16 (m, 3H), 7.09 (d, J = 7.2
Hz, 1H), 2.62 (t, J = 7.6 Hz, 2H), 1.68−1.60 (m, 2H), 1.41−1.27 (m,
10H), 0.93 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ
145.1, 134.1, 129.6, 128.7, 126.8, 125.9, 35.8, 32.0, 31.4, 29.6, 29.4,
29.3, 22.8, 14.3. HRMS-EI (m/z): calcd for C14H21Cl [M]+ 224.1332,
found 224.1327.
1.25−1.17 (m, 10H), 0.80 (t, J = 6.6 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 159.7, 144.8, 129.3, 121.0, 114.3, 110.9, 55.3, 36.2, 32.1,
31.6, 29.7, 29.5, 29.4, 22.9 14.3. HRMS-EI (m/z): calcd for C15H24O
[M]+ 220.1827, found 220.1828.
1
Octylbenzene (Table 3a, 4m). The title compound was prepared
from iodobenzene (204 mg, 1.0 mmol, 2.0 equiv), following the
general procedure and using NiBr2·glyme (15.6 mg, 0.05 mmol, 10.0
mol %), L1 (8.8 mg, 0.055 mmol, 11.0 mol %), KF (73.0 g, 1.25
mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg, 0.50 mmol),
(EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75 mL).
The reaction mixture was stirred for 24 h at rt. The crude material was
purified by flash column chromatography and eluted with pentanes to
provide the title compound as a colorless liquid in 54% yield (51.3
1
mg). IR (neat, cm−1): 2923, 2853, 1454, 743, 696. H NMR (400
MHz, CDCl3): δ 7.42−7.36 (m, 2H), 7.32−7.26 (m, 3H), 2.73 (t, J =
7.8 Hz, 2H), 1.78−1.70 (m, 2H), 1.52−1.40 (m, 10H), 1.02 (t, J =
6.2 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 143.1, 128.6, 128.4,
125.7, 36.2, 32.1, 31.8, 29.7, 29.6, 29.5, 22.9, 14.3. HRMS-EI (m/z):
calcd for C14H22 [M]+ 190.1722, found 190.1724.
(4-Octylphenyl)methanol (Table 3a, 4n). The title compound was
prepared from (4-iodophenyl)methanol (234.0, 1.0 mmol, 2.0 equiv),
following the general procedure and using NiBr2·glyme (15.6 mg, 0.05
mmol, 10.0 mol %), L1 (8.8 mg, 0.055 mmol, 11.0 mol %), KF (73.0
g, 1.25 mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg, 0.50
mmol), (EtO)3SiH (414.0 μL, 2.25 mmol, 4.5 equiv), and DMF (3.75
mL). The reaction mixture was stirred for 24 h at rt.
4-Octylphenyl Trifluoromethanesulfonate (Table 3a, entry 4j).
The title compound was prepared from 4-iodophenyl trifluorometha-
nesulfonate (352.1 mg, 1.0 mmol, 2.0 equiv), following the general
procedure and using NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0 mol %),
L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol, 2.5
equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg, 0.50 mmol), (EtO)3SiH
(230 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75 mL). The reaction
mixture was stirred for 24 h at rt. The crude material was purified by
flash column chromatography and eluted with 0.5% EtOAc in hexanes
to provide the title compound as a colorless liquid in 62% yield (104.6
The workup procedure was modified and is detailed below. After
completion, the reaction mixture was transferred to a 25 mL round-
bottom flask and the volatiles were removed under reduced pressure,
A MeOH solution of NH4F (10 mL, saturated) was added, and the
reaction mixture was stirred at room temperature for 30 min. EtOAc
(30 mL) and water were added, and the aqueous layer was extracted
with EtOAc (10 mL × 3). The combined organic layers were dried
over Na2SO4 and concentrated in vacuo. The crude material was
purified by flash column chromatography and eluted with 2% EtOAc
in hexanes to provide the title compound as a colorless liquid in 59%
1
mg). IR (neat, cm−1): 2926, 1500, 1422, 1205, 1135, 883, 607. H
NMR (400 MHz, CDCl3): δ 7.16 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 8.7
Hz, 2H), 2.54 (t, J = 7.6 Hz, 2H), 1.58−1.48 (m, 2H), 1.24−1.18 (m,
10H), 0.80 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ
147.8, 143.7, 130.2, 121.1, 118.9 (q, J = 320.8 Hz), 35.5, 32.0, 31.45,
29.6, 29.5, 29.4, 22.8, 14.2. 19F NMR (376 MHz, CDCl3): δ −72.9.
HRMS-EI (m/z): calcd for C15H21F3O3S [M]+ 338.1163, found
338.1165.
4,4,5,5-Tetramethyl-2-(3-octylphenyl)-1,3,2-dioxaborolane
(Table 3a, 4k). The title compound was prepared from 2-(3-
iodophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (330.1 mg, 1.0
mmol, 2.0 equiv), following the general procedure and using NiBr2·
glyme (7.8 mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0
mol %), KF (73.0 g, 1.25 mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL,
62.4 mg, 0.50 mmol), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and
DMF (3.75 mL). The reaction mixture was stirred for 24 h at rt. The
crude material was purified by flash column chromatography and
eluted with 2% EtOAc in hexanes to provide the title compound as a
colorless liquid in 52% yield (82.3 mg). IR (neat, cm−1): 2924, 1357,
1144, 708. 1H NMR (400 MHz, CDCl3): δ 7.58−7.52 (m, 2H),
7.24−7.20 (m, 2H), 2.53 (t, J = 7.6 Hz, 2H), 1.56−1.50 (m, 2H),
1.30−1.27 (m, 12H), 1.23−1.18 (m, 10H), 0.81 (t, J = 6.7 Hz, 3H).
13C NMR (101 MHz, CDCl3): δ 142.4, 134.9, 132.2, 131.6, 127.8,
83.89, 36.1, 32.1, 31.9, 29.7, 29.6, 29.4, 25.1, 22.8, 14.3. HRMS-ESI
(m/z): calcd for C20H33BNaO2 [M + Na]+ 339.2466, found 339.2474.
1-Methoxy-3-octylbenzene (Table 3a, 4l). The title compound
was prepared from 1-iodo-3-methoxybenzene (234 mg, 1.0 mmol, 2.0
equiv), following the general procedure and using NiBr2·glyme (7.8
mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %),
KF (73.0 g, 1.25 mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg,
0.50 mmol), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and DMF
(3.75 mL). The reaction mixture was stirred for 24 h at rt. The crude
material was purified by flash column chromatography and eluted
with hexanes to provide the title compound as a colorless liquid in
40% yield (44.1 mg). IR (neat, cm−1): 2923, 1584, 1259, 1151, 694.
1H NMR (400 MHz, CDCl3): δ 7.11 (t, J = 7.7 Hz, 1H), 6.70−6.63
(m, 3H), 3.72 (s, 3H), 2.50 (t, J = 7.8 Hz, 2H), 1.56−1.49 (m, 2H),
1
yield (65 mg). IR (neat, cm−1): 3320, 2922, 1463, 1027, 755. H
NMR (400 MHz, CDCl3): δ 7.29 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.8
Hz, 2H), 4.67 (s, 2H), 2.63 (t, J = 7.6 Hz, 2H), 1.84 (s, 1H), 1.68−
1.58 (m, 2H), 1.37−1.29 (m, 10H), 0.92 (t, J = 6.7 Hz, 3H). 13C
NMR (101 MHz, CDCl3): δ 142.7, 138.3, 128.8, 127.3, 65.4, 35.8,
32.0, 31.7, 29.6, 29.5, 29.4, 22.8, 14.3. HRMS-EI (m/z): calcd for
C15H24O [M]+ 220.1827, found 220.1825.
2-Fluoro-4-octylaniline (Table 3a, 4o). The title compound was
prepared from 2-fluoro-4-iodoaniline (237.0 mg, 1.0 mmol, 2.0
equiv), following the general procedure and using NiBr2·glyme (7.8
mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %),
KF (73.0 g, 1.25 mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg,
0.50 mmol), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and DMF
(3.75 mL). The reaction mixture was stirred for 24 h at rt. The crude
material was purified by flash column chromatography and eluted
with 1% EtOAc in hexanes to provide the title compound as a
colorless liquid in 70% yield (78 mg). IR (neat, cm−1): 3383, 2923,
1519, 896, 618. 1H NMR (400 MHz, CDCl3): δ 6.75−6.71 (m, 1H),
6.69−6.57 (m, 2H), 3.38 (s, 2H), 2.41 (t, J = 7.6 Hz, 2H), 1.52−1.41
(m, 2H), 1.23−1.16 (m, 10H), 0.80 (t, J = 6.6 Hz, 3H). 13C NMR
(101 MHz, chloroform-d): δ 151.9 (d, J = 238.5 Hz), 134.3 (d, J = 5.8
Hz), 131.8 (d, J = 13.3 Hz), 124.3 (d, J = 3.2 Hz), 117.1 (d, J = 3.7
Hz), 115.2 (d, J = 18.2 Hz), 35.1, 32.0, 31.7, 29.7, 29.4, 29.3, 22.8,
14.3. 19F NMR (471 MHz, CDCl3): δ −135.4. HRMS-ESI (m/z):
calcd for C14H23FN [M + H]+ 224.1809, found 224.1807.
2-Chloro-4-octylpyridine (Table 3b, 4p). The title compound was
prepared from 2-chloro-4-iodopyridine (239.4 mg, 1.0 mmol, 2.0
equiv), following the general procedure and using NiBr2·glyme (7.8
mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %),
KF (73.0 g, 1.25 mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg,
0.50 mmol), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and DMF
(3.75 mL). The reaction mixture was stirred for 24 h at rt. The crude
material was purified by flash column chromatography and eluted
with 1% EtOAc in hexanes to provide the title compound as a pale
G
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1
yellow liquid in 65% yield (73.1 mg). IR (neat, cm−1): 2924, 1591,
1384, 1085, 717. 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 5.0 Hz,
1H), 7.07 (s, 1H), 6.95 (d, J = 5.0 Hz, 1H), 2.51 (t, J = 7.6 Hz, 2H),
1.59−1.48 (m, 2H), 1.28−1.15 (m, 10H), 0.80 (t, J = 6.8 Hz, 3H).
13C NMR (101 MHz, CDCl3): δ 155.4, 151.6, 149.5, 124.3, 122.9,
35.1, 31.9, 30.2, 29.4, 29.3, 29.2, 22.8, 14.2. HRMS-ESI (m/z): calcd
for C13H21ClN [M + H]+ 226.1357, found 226.1358.
2-Fluoro-5-octylpyridine (Table 3b, 4q). The title compound was
prepared from 2-fluoro-5-iodopyridine (223.0 mg, 1.0 mmol, 2.0
equiv), following the general procedure and using NiBr2·glyme (7.8
mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %),
KF (73.0 g, 1.25 mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg,
0.50 mmol), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and DMF
(3.75 mL). The reaction mixture was stirred for 24 h at rt. The crude
material was purified by flash column chromatography and eluted
with 1% EtOAc in hexanes to provide the title compound as a
colorless liquid in 73% yield (76.2 mg). IR (neat, cm−1): 2925, 1592,
1482, 1393, 1247, 829. 1H NMR (400 MHz, CDCl3): δ 7.93 (s, 1H),
7.53−7.48 (m, 1H), 6.76 (dd, J = 8.3, 2.9 Hz, 1H), 2.51 (t, J = 7.6 Hz,
2H), 1.57−1.46 (m, 2H), 1.24−1.16 (m, 10H), 0.80 (t, J = 6.8 Hz,
3H). 13C NMR (101 MHz, chloroform-d): δ 162.3 (d, J = 236.5 Hz),
147.0 (d, J = 14.1 Hz), 141.1 (d, J = 7.6 Hz), 135.7 (d, J = 4.5 Hz),
109.0 (d, J = 37.3 Hz), 32.1, 31.9, 31.3, 29.5, 29.3, 29.2, 22.8, 14.2. 19F
NMR (376 MHz, CDCl3): δ −72.7. HRMS-ESI (m/z): calcd for
C13H21FN [M + H]+ 210.1653, found 210.1650.
(70.0 mg). IR (neat, cm−1): 2923, 1645, 1481, 1405, 754. H NMR
(400 MHz, CDCl3): δ 8.33 (d, J = 2.1 Hz, 1H), 7.54 (dd, J = 8.1, 2.5
Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 5.80 (s, 2H), 2.59 (t, J = 7.6 Hz,
2H), 2.03 (s, 6H), 1.65−1.54 (m, 2H), 1.33−1.16 (m, 10H), 0.81 (t, J
= 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 150.0, 149.3, 137.8,
137.0, 128.7, 121.7, 106.7, 32.7, 32.0, 31.2, 29.5, 29.4, 29.4, 22.8, 14.3,
13.2. HRMS-ESI (m/z): calcd for C19H29N2 [M + H]+ 285.2325,
found 285.2326.
3-Octylquinoline (Table 3b, 4u). The title compound was
prepared from 3-iodoquinoline (255.0 mg, 1.0 mmol, 2.0 equiv),
following the general procedure and using NiBr2·glyme (7.8 mg, 0.025
mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g,
1.25 mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg, 0.50 mmol),
(EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75 mL).
The reaction mixture was stirred for 24 h at rt. The crude material was
purified by flash column chromatography and eluted with 5% EtOAc
in hexanes to provide the title compound as a colorless liquid in 54%
1
yield (65.1 mg). IR (neat, cm−1): 2923, 1494, 748, 723. H NMR
(400 MHz, CDCl3): δ 8.79 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 8.4 Hz,
1H), 7.90 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.70−7.60 (m, 1H), 7.51
(t, J = 7.5 Hz, 1H), 2.78 (t, J = 7.7 Hz, 2H), 1.77−1.66 (m, 2H),
1.40−1.24 (m, 10H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 152.2, 146.8, 135.5, 134.2, 129.2, 128.6, 128.3, 127.4,
126.6, 33.3, 31.9, 31.3, 29.5, 29.3, 29.3, 22.8, 14.2. HRMS-ESI (m/z):
calcd for C17H24N [M + H]+ 242.1903, found 242.1902.
N,N-Dimethyl-5-octylpyrimidin-2-amine (Table 3b, 4v). The title
compound was prepared from 5-iodo-N,N-dimethylpyrimidin-2-
amine (249.0 mg, 1.0 mmol, 2.0 equiv), following the general
procedure and using NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0 mol %),
L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol, 2.5
equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg, 0.50 mmol), (EtO)3SiH
(230 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75 mL). The reaction
mixture was stirred for 24 h at rt. The crude material was purified by
flash column chromatography and eluted with 5% EtOAc in hexanes
to provide the title compound as a pale yellow liquid in 72% yield
(84.6 mg). IR (neat, cm−1): 2922, 1602, 1526, 1403, 974, 797, 523.
1H NMR (400 MHz, CDCl3): δ 8.08 (s, 2H), 3.09 (s, 6H), 2.32 (t, J
= 7.6 Hz, 2H), 1.48−1.39 (m, 2H), 1.24−1.16 (m, 10H), 0.80 (t, J =
6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 161.4, 157.5, 122.2,
37.3, 32.0, 31.5, 29.5, 29.5, 29.4, 29.1, 22.8, 14.2. HRMS-ESI (m/z):
calcd for C14H26N3 [M + H]+ 236.2121, found 236.2128.
2-Methoxy-5-octylpyridine (Table 3b, 4r). The title compound
was prepared from 5-iodo-2-methoxypyridine (235.2 mg, 1.0 mmol,
2.0 equiv), following the general procedure and using NiBr2·glyme
(7.8 mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol
%), KF (73.0 g, 1.25 mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4
mg, 0.50 mmol), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and
DMF (3.75 mL). The reaction mixture was stirred for 24 h at rt. The
crude material was purified by flash column chromatography and
eluted with 1% EtOAc in hexanes to provide the title compound as a
colorless liquid in 62% yield (68.5 mg). IR (neat, cm−1): 2923, 1607,
1490, 1285, 1028, 826. 1H NMR (400 MHz, CDCl3): δ 7.88 (s, 1H),
7.30 (dd, J = 8.4, 2.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H),
2.42 (t, J = 7.7 Hz, 2H), 1.53−1.42 (m, 2H), 1.25−1.13 (m, 10H),
0.79 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 162.7,
146.0, 139.0, 130.7, 110.4, 53.3, 32.2, 32.0, 31.5, 29.5, 29.4, 29.2, 22.8,
14.2. HRMS-ESI (m/z): calcd for C14H23NNaO [M + Na]+
244.1672, found 244.1669.
4-(5-Octylpyridin-2-yl)morpholine (Table 3b, 4s). The title
compound was prepared from 4-(5-iodopyridin-2-yl)morpholine
(290.0 mg, 1.0 mmol, 2.0 equiv), following the general procedure
and using NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg,
0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol, 2.5 equiv), (E)-oct-
4-ene (87.5 μL, 62.4 mg, 0.50 mmol), (EtO)3SiH (230 μL, 1.25
mmol, 2.5 equiv), and DMF (3.75 mL). The reaction mixture was
stirred for 24 h at rt. The crude material was purified by flash column
chromatography and eluted with 2% EtOAc in hexanes to provide the
title compound as a colorless liquid in 60% yield (82.8 mg). IR (neat,
cm−1): 2922, 1605, 1490, 1242, 1120, 942, 808. 1H NMR (400 MHz,
CDCl3): δ 7.96 (d, J = 2.4 Hz, 1H), 7.28 (dd, J = 8.6, 2.5 Hz, 1H),
6.53 (d, J = 8.5 Hz, 1H), 3.76 (t, J = 4.8 Hz, 4H), 3.40 (t, J = 4.8 Hz,
4H), 2.41 (t, J = 7.6 Hz, 2H), 1.53−1.42 (m, 2H), 1.24−1.17 (m,
10H), 0.80 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ
158.3, 147.4, 138.1, 128.2, 107.1, 67.0, 46.2, 32.2, 32.0, 31.6, 29.6,
29.4, 29.2, 22.8, 14.3. HRMS-ESI (m/z): calcd for C17H28N2NaO [M
+ Na]+ 299.2094, found 299.2092.
2-(tert-Butyl)-6-octylimidazo[1,2-a]pyridine (Table 3b, 4w). The
title compound was prepared from 2-(tert-butyl)-6-iodoimidazo[1,2-
a]pyridine (300.1 mg, 1.0 mmol, 2.0 equiv), following the general
procedure and using NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0 mol %),
L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol, 2.5
equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg, 0.50 mmol), (EtO)3SiH
(230 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75 mL). The reaction
mixture was stirred for 24 h at rt. The crude material was purified by
flash column chromatography and eluted with 2% EtOAc in hexanes
to provide the title compound as a colorless liquid in 54% yield (77.2
1
mg). IR (neat, cm−1): 2923, 1507, 1235, 803, 686. H NMR (400
MHz, CDCl3): δ 7.73 (s, 1H), 7.42 (d, J = 9.2 Hz, 1H), 7.18 (s, 1H),
6.90 (dd, J = 9.2, 1.7 Hz, 1H), 2.46 (t, J = 7.6 Hz, 2H), 1.56−1.45 (m,
2H), 1.32 (s, 9H), 1.24−1.17 (m, 10H), 0.80 (t, J = 6.8 Hz, 3H). 13C
NMR (101 MHz, CDCl3): δ 157.0, 144.3, 126.4, 126.3, 123.1, 116.7,
106.7, 32.7, 32.4, 32.0, 30.9, 30.4, 29.5, 29.4, 29.3, 22.8, 14.2. HRMS-
ESI (m/z): calcd for C19H30N2Na [M + Na]+ 309.2301, found
309.2300.
(S)-3-(4-(2-Chloro-5-octylbenzyl)phenoxy)tetrahydrofuran
(Table 3c, 4x). The title compound was prepared from (S)-3-(4-(2-
chloro-5-iodobenzyl)phenoxy)tetrahydrofuran (414.7 mg, 1.0 mmol,
2.0 equiv), following the general procedure and using NiBr2·glyme
(7.8 mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol
%), KF (73.0 g, 1.25 mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4
mg, 0.50 mmol), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and
DMF (3.75 mL). The reaction mixture was stirred for 24 h at rt. The
crude material was purified by flash column chromatography and
eluted with 1% EtOAc in hexanes to provide the title compound as a
colorless liquid in 78% yield (155.8 mg). IR (neat, cm−1): 2923, 1611,
2-(2,5-Dimethyl-1H-pyrrol-1-yl)-5-octylpyridine (Table 3b, 4t).
The title compound was prepared from 2-(2,5-dimethyl-1H-pyrrol-1-
yl)-5-iodopyridine (298.0 mg, 1.0 mmol, 2.0 equiv), following the
general procedure and using NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0
mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol,
2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg, 0.50 mmol), (EtO)3SiH
(230 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75 mL). The reaction
mixture was stirred for 24 h at rt. The crude material was purified by
flash column chromatography and eluted with 2% EtOAc in hexanes
to provide the title compound as a pale yellow liquid in 50% yield
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1507, 1238, 817. H NMR (400 MHz, CDCl3): δ 7.15 (s, 1H), 7.01
(d, J = 8.5 Hz, 2H), 6.90−6.83 (m, 2H), 6.69 (d, J = 8.6 Hz, 2H),
4.82−4.75 (m, 1H), 3.94−3.84 (m, 5H), 3.82−3.74 (m, 1H), 2.42 (t,
J = 7.6 Hz, 2H), 2.13−2.00 (m, 2H), 1.47−1.40 (m, 2H), 1.21−1.15
(m, 10H), 0.79 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ
155.9, 141.8, 138.5, 132.3, 131.3, 131.2, 130.0, 129.3, 127.8, 115.4,
77.4, 73.3, 67.3, 38.5, 35.4, 33.2, 32.0, 31.5, 29.6, 29.4, 29.4, 22.8,
14.3. HRMS-ESI (m/z): calcd for C25H33ClNaO2 [M + Na]+
423.2061, found 423.2058.
CDCl3): δ 171.6, 169.6, 155.9, 148.8, 136.2, 132.9, 131.2, 130.6,
130.1, 128.9, 127.5, 115.1, 111.9, 111.5, 101.1, 55.8, 52.2, 36.2, 36.1
31.2, 30.3, 29.5, 29.4, 22.8, 14.2, 13.4. HRMS-ESI (m/z): calcd for
C28H36NO4 [M + H]+ 450.2639, found 450.2636.
Heptan-2-yl 2-((5-Chloro-3-octylquinolin-8-yl)oxy)acetate (Table
3c, 4b′). The title compound was prepared from heptan-2-yl 2-((5-
chloro-3-iodoquinolin-8-yl)oxy)acetate (461.0 mg, 1.0 mmol, 2.0
equiv), following the general procedure and using NiBr2·glyme (7.8
mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg, 0.030 mmol, 6.0 mol %),
KF (73.0 g, 1.25 mmol, 2.5 equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg,
0.50 mmol), (EtO)3SiH (230 μL, 1.25 mmol, 2.5 equiv), and DMF
(3.75 mL). The reaction mixture was stirred for 24 h at rt. The crude
material was purified by flash column chromatography and eluted
with 10% EtOAc in hexanes to provide the title compound as a yellow
liquid in 71% yield (158.3 mg). IR (neat, cm−1): 2925, 1754, 1491,
(5-(4-Fluorophenyl)thiophen-2-yl)(2-methyl-5-octylphenyl)-
methanone (Table 3c, 4y). The title compound was prepared from
(5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)-
methanone (422.3 mg, 1.0 mmol, 2.0 equiv), following the general
procedure and using NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0 mol %),
L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol, 2.5
equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg, 0.50 mmol), (EtO)3SiH
(230 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75 mL). The reaction
mixture was stirred for 24 h at rt. The crude material was purified by
flash column chromatography and eluted with 2% EtOAc in hexanes
to provide the title compound as a colorless liquid in 51% yield (103.3
1
1203, 1107, 728. H NMR (400 MHz, CDCl3): δ 8.82 (s, 1H), 8.24
(s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 5.00 (q, J =
6.3 Hz, 1H), 4.91 (s, 2H), 2.82 (t, J = 7.8 Hz, 2H), 1.75−1.67 (m,
2H), 1.59−1.44 (m, 2H), 1.36−1.15 (m, 19H), 0.89−0.76 (m, 6H).
13C NMR (126 MHz, CDCl3): δ 168.3, 153.0, 151.6, 139.1, 137.3,
mg). IR (neat, cm−1): 2923, 1634, 1410, 1206, 807. H NMR (400
1
131.1, 127.2, 126.0, 123.0, 108.4, 72.7, 66.4, 35.7, 33.4, 31.9, 31.6,
31.2, 29.4, 29.3, 29.2, 25.0, 22.7, 22.5, 19.9, 14.1, 14.0. HRMS-ESI
(m/z): calcd for C26H39ClNO3 [M + H]+ 448.2613, found 448.2616.
(3aR,5R,6S,6aR)-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl 4-Octylbenzoate
(Table 3c, 4c′). The title compound was prepared from
(3aR,5R,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl 4-iodobenzoate (490.3
mg, 1.0 mmol, 2.0 equiv), following the general procedure and using
NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0 mol %), L1 (4.8 mg, 0.030
mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol, 2.5 equiv), (E)-oct-4-ene
(87.5 μL, 62.4 mg, 0.50 mmol), (EtO)3SiH (230 μL, 1.25 mmol, 2.5
equiv), and DMF (3.75 mL). The reaction mixture was stirred for 24
h at rt. The crude material was purified by flash column
chromatography and eluted with 2% EtOAc in hexanes to provide
the title compound as a colorless oil in 81% yield (192.9 mg). IR
MHz, CDCl3): δ 7.57−7.51 (m, 2H), 7.28 (d, J = 3.9 Hz, 1H), 7.18
(s, 1H), 7.14 (d, J = 4.0 Hz, 1H), 7.11 (d, J = 1.8 Hz, 2H), 7.05−6.97
(m, 2H), 2.52 (t, J = 7.6 Hz, 2H), 2.27 (s, 3H), 1.57−1.46 (m, 2H),
1.23−1.15 (m, 10H), 0.81−0.74 (m, 3H). 13C NMR (101 MHz,
CDCl3): δ 190.6, 163.4 (d, J = 249.8 Hz), 152.6, 143.8, 140.0, 138.2,
136.5, 133.7, 131.4, 130.6, 129.8 (d, J = 3.5 Hz), 128.2 (d, J = 8.3
Hz), 128.1, 124.1, 116.3 (d, J = 22.0 Hz), 35.5, 32.0, 31.6, 29.6, 29.4,
29.4, 22.8, 19.4, 14.2. 19F NMR (376 MHz, CDCl3): δ −111.7.
HRMS-ESI (m/z): calcd for C26H29FNaOS [M + Na]+ 431.1815,
found 431.1813.
Ethyl 1-(4-Methoxyphenyl)-5-(4-octylphenyl)-4-oxo-4,5,6,7-tet-
rahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (Table 3c, 4z).
The title compound was prepared from ethyl 5-(4-iodophenyl)-1-(4-
methoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]-
pyridine-3-carboxylate (103.5 mg, 0.4 mmol, 2.0 equiv), following the
general procedure and using NiBr2·glyme (3.1 mg, 0.01 mmol, 5.0
mol %), L1 (1.9 mg, 0.012 mmol, 6.0 mol %), KF (29.2 g, 0.5 mmol,
2.5 equiv), (E)-oct-4-ene (35.0 μL, 0.2 mmol), (EtO)3SiH (92 μL,
0.5 mmol, 2.5 equiv), and DMF (1.5 mL). The reaction mixture was
stirred for 24 h at rt. The crude material was purified by flash column
chromatography and eluted with 10% EtOAc in hexanes to provide
the title compound as a colorless liquid in 51% yield (51.3 mg). IR
1
(neat, cm−1): 2926, 1723, 1610, 1263, 1017, 732. H NMR (400
MHz, CDCl3): δ 7.86 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H),
5.87 (d, J = 3.6 Hz, 1H), 5.41 (d, J = 2.7 Hz, 1H), 4.54 (d, J = 3.7 Hz,
1H), 4.33−4.22 (m, 2H), 4.03 (dd, J = 5.1, 3.2 Hz, 2H), 2.58 (t, J =
7.6 Hz, 2H), 1.60−1.46 (m, 2H), 1.48 (s, 3H), 1.34 (s, 3H), 1.22 (d, J
= 17.7 Hz, 16H), 0.80 (t, J = 6.5 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 165.4, 149.4, 129.9, 128.7, 127.1, 112.5, 109.5, 105.3, 83.5,
80.1, 76.6, 72.8, 67.3, 36.2, 32.0, 31.3, 29.5, 29.4, 29.3, 27.0, 26.9,
26.3, 25.4, 22.8, 14.2. HRMS-ESI (m/z): calcd for C27H41NaO7 [M +
Na]+ 499.2666, found 499.2666.
(neat, cm−1): 2924, 1712, 1672, 1511, 1247, 1085, 789. H NMR
1
(400 MHz, CDCl3): δ 7.40 (d, J = 8.9 Hz, 2H), 7.16−7.06 (m, 4H),
6.82 (d, J = 8.8 Hz, 2H), 4.38 (q, J = 7.0 Hz, 2H), 4.02 (t, J = 6.6 Hz,
2H), 3.72 (s, 3H), 3.23 (t, J = 6.6 Hz, 2H), 2.49 (t, J = 7.6 Hz, 2H),
1.55−1.44 (m, 2H), 1.35 (t, J = 7.0 Hz, 3H), 1.22−1.16 (m, 10H),
0.80 (t, J = 6.5 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 168.3,
153.0, 151.6, 139.1, 137.3, 131.1, 127.2, 126.0, 123.0, 108.4, 72.7,
66.4, 35.7, 33.4, 31.9, 31.6, 31.2, 29.4, 29.3, 29.2, 25.0, 22.7, 22.5,
19.9, 14.1, 14.0. HRMS-ESI (m/z): calcd for C30H38N3O4 [M + H]+
504.2857, found 504.2856.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.0c00819.
■
sı
Experimental procedures and characterization data for
all compounds (PDF)
Methyl 2-(5-Methoxy-2-methyl-1-(4-octylbenzoyl)-1H-indol-3-
yl)acetate (Table 3c, 4a′). The title compound was prepared from
methyl 2-(1-(4-iodobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-
acetate (463.3 mg, 1.0 mmol, 2.0 equiv), following the general
procedure and using NiBr2·glyme (7.8 mg, 0.025 mmol, 5.0 mol %),
L1 (4.8 mg, 0.030 mmol, 6.0 mol %), KF (73.0 g, 1.25 mmol, 2.5
equiv), (E)-oct-4-ene (87.5 μL, 62.4 mg, 0.50 mmol), (EtO)3SiH
(230 μL, 1.25 mmol, 2.5 equiv), and DMF (3.75 mL). The reaction
mixture was stirred for 24 h at rt. The crude material was purified by
flash column chromatography and eluted with 15% EtOAc in hexanes
to provide the title compound as a white solid in 45% yield (101.1
mg). Mp: 72−73 °C. IR (neat, cm−1): 2925, 1731, 1667, 1605, 1323,
AUTHOR INFORMATION
Corresponding Author
■
Shaolin Zhu − State Key Laboratory of Coordination
Chemistry, Chemistry and Biomedicine Innovation Center
(ChemBIC), Jiangsu Key Laboratory of Advanced Organic
Materials, School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing 210093, People’s Republic of
China; orcid.org/0000-0003-1516-6081;
Email: shaolinzhu@nju.edu.cn
1
729. H NMR (500 MHz, CDCl3): δ 7.66 (d, J = 8.2 Hz, 2H), 7.31
(d, J = 8.2 Hz, 2H), 6.99 (d, J = 2.5 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H),
6.68 (dd, J = 9.0, 2.6 Hz, 1H), 3.86 (s, 3H), 3.73 (s, 3H), 3.70 (s,
2H), 2.73 (d, J = 7.5 Hz, 2H), 2.41 (s, 3H), 1.73−1.64 (m, 2H),
1.39−1.27 (m, 10H), 0.91 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz,
Authors
Yuli He − State Key Laboratory of Coordination Chemistry,
Chemistry and Biomedicine Innovation Center (ChemBIC),
I
https://doi.org/10.1021/acs.organomet.0c00819
Organometallics XXXX, XXX, XXX−XXX

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pubs.acs.org/Organometallics
Article
Ni(I)-Catalyzed Reductive Cyclization of 1,6-Dienes: Mechanism-
Controlled trans Selectivity. Chem. 2017, 3, 268−280.
Jiangsu Key Laboratory of Advanced Organic Materials,
School of Chemistry and Chemical Engineering, Nanjing
University, Nanjing 210093, People’s Republic of China
Bo Han − State Key Laboratory of Coordination Chemistry,
Chemistry and Biomedicine Innovation Center (ChemBIC),
Jiangsu Key Laboratory of Advanced Organic Materials,
School of Chemistry and Chemical Engineering, Nanjing
University, Nanjing 210093, People’s Republic of China
(5) For reviews on remote functionalization via chain walking, see:
(a) Larionov, E.; Li, H.; Mazet, C. Well-Defined Transition Metal
Hydrides in Catalytic Isomerizations. Chem. Commun. 2014, 50,
9816−9826. (b) Vasseur, A.; Bruffaerts, J.; Marek, I. Remote
Functionalization through Alkene Isomerization. Nat. Chem. 2016,
8, 209−219. (c) Sommer, H.; Juliá-Hernández, F.; Martin, R.; Marek,
I. Walking Metals for Remote Functionalization. ACS Cent. Sci. 2018,
4, 153−165. (d) Janssen-Muller, D.; Sahoo, B.; Sun, S.-Z.; Martin, R.
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.0c00819
Tackling Remote sp3 C−H Functionalization via Ni-Catalyzed “chain-
walking” Reactions. Isr. J. Chem. 2020, 60, 195−206.
(6) For recent Zr-catalyzed chain walking, see: (a) Masarwa, A.;
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support was provided by the NSFC (21822105, 22001118)
and the NSF of Jiangsu Province (BK20200300,
BK20201245).
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Organometallics
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(14) When a remote aryl-substituted alkene such as (E)-3-
pentenylbenzene was employed, the regioselectivity was not as good
under the current reaction conditions.
(15) For an ortho-substituted aryl iodide, although the regioselec-
tivity is excellent, the yield is low.
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https://doi.org/10.1021/acs.organomet.0c00819
Organometallics XXXX, XXX, XXX−XXX