Nickel-Catalyzed Cross-Coupling of Umpolung Carbonyls and Alkyl Halides

Article abstract of DOI:10.1021/acs.joc.9b00649

An effective nickel-catalyzed cross-coupling of Umpolung carbonyls and alkyl halides was developed. Complementary to classical alkylation techniques, this reaction utilizes Umpolung carbonyls as the environmentally benign alkyl nucleophiles, providing an efficient and selective catalytic alternative to the traditional use of highly reactive alkyl organometallic reagents.

Full text of DOI:10.1021/acs.joc.9b00649

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Article
Nickel-Catalyzed Cross-Coupling of Umpolung Carbonyls and Alkyl Halides
Dianhu Zhu, Leiyang Lv, Zihang Qiu, and Chao-Jun Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00649 • Publication Date (Web): 19 Apr 2019
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Nickel-Catalyzed Cross-Coupling of Umpolung Carbonyls and Alkyl Halides
Dianhu Zhu,†,§ Leiyang Lv,†,§ Zihang Qiu† and Chao-Jun Li*†
†Department of Chemistry and FQRNT Centre for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke St. W.,
Montreal, Quebec H3A 0B8, Canada.
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1) N2H4H2O
O
R
+ baseHX
+ N2 + H2O
alkyl
2) alkylX
R'
R
R'
cat. NiII/L, base
 1o, 2o, 3o alkyl halides
 Carbonyls: aromatic/alkyl aldehydes and ketones
 Cheap Ni(II) catalyst and ligand
 New method of forming Csp3-Csp3 bonds
 Umpolung carbonyls as alkyl organometallic reagent surrogates
 N2H4 as a traceless reductant, producing N2 and H2O as by-products
Abstract: An effective nickel-catalyzed cross-coupling of umpolung carbonyls and alkyl halides was developed.
Complementary to classical alkylation techniques, this reaction utilizes umpolung carbonyls as the environmentally
benign alkyl nucleophiles, providing an efficient and selective catalytic alternative to the traditional use of highly
reactive alkyl organometallic reagents.
INTRODUCTION
Over the past decades, transition metal-catalyzed cross-coupling reactions have been among the most powerful
and straightforward tools for constructing carbon-carbon bonds and have widespread applications in organic
synthesis.1 While traditional processes mainly focus on the construction of Csp2-Csp2 bonds, there has been a recent
increase in developing effective and challenging cross-coupling to generate Csp3-Csp3 bonds with alkyl halides.2
Traditional processes typically involve the palladium-catalyzed couplings of alkyl halides with alkyl
organometallic reagents (such as organomagnesium or zinc reagents, etc.) or alkyl boron reagents (Scheme 1A).3 For
the alkyl halide partner, slow oxidative addition of alkyl electrophiles to the palladium and facile β-hydride
elimination from the intermediate are two likely causes for this comparatively less success.4 Fu made the systematic
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investigations and determined that Pd/PR3 (PR3 = PCy3 or P(t-Bu)2Me) can inhibit the β-hydride elimination and
serve as an efficient catalyst system for Suzuki reactions of primary alkyl halides with trialkylboranes.5 Alternatively,
a variety of alkyl-alkyl couplings catalyzed by nickel,6 copper,7 iron8 or cobalt,9 have emerged to make the oxidative
addition of alkyl electrophile to the metal center much easier via oxidative radical addition process. However for the
alkyl nucleophile partner, the alkyl organometallic reagents are generally air/moisture sensitive and requires
stoichiometric amounts of metals for its preparation. Moreover, the reactions of alkyl organometallic reagents often
result in poor chemoselectivity and low functional group compatibility due to their strong basicity and high
nucleophilicity. To avoid the use of alkyl organometallic reagents, metal-catalyzed reductive couplings of two alkyl
electrophiles under the metal or organic reductants (such as Zn, Mn, Mg or TDAE, etc.) represented a major step
forward (Scheme 1B), as reported by Weix, Gong, Liu and others.10 Nevertheless, stoichiometric amounts of metal
reductants will produce extra metal wastes, which complicate the synthetic operations and raise environmental
concerns. Moreover, the complex preparation of TDAE may also inhibit its synthetic applications. Notably,
MacMillan, Vanucci, Lei and others also developed photoredox/ electrochemical11 or transition metal-free12 methods
for the Csp3–Csp3 cross-coupling under mild conditions.
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In 2018, our group reported Ni(COD)2-catalyzed Csp2-Csp3 cross couplings with aryl halides and hydrazones.13e
Inspired by hydrazones serving as alkyl carbanion equivalents in the catalytic nucleophilic additions and cross
couplings,13 herein, we wish to report a nickel(II)-catalyzed alkyl-alkyl coupling with umpolung carbonyls with alkyl
halides (Scheme 1C). In this strategy, simple carbonyls act as alkyl carbanion equivalents instead of alkyl
organometallic reagents to couple with alkyl halides, with N2H4 serving as a formal traceless reductant.
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Scheme 1. Alkyl-Alkyl Couplings with Alkyl Halides.
RESULTS AND DISCUSSION
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We began our studies by evaluating the coupling of benzaldehyde hydrazone 1ae (generated in situ from
benzaldehyde and hydrazine) with iodocyclohexane (Table 1). The base-free or catalyst/ligand-free reaction did not
lead to any C-alkylated product (3ae, (cyclohexylmethyl)benzene), suggesting that catalyst/ligand and base are
indispensable for the alkylation of aldehydes in this system (entries 1-2). Later reaction optimizations showed that
C-alkylated product 3ae and homo-coupling product 4 were observed while N-alkylated product was not detected.
We think that alkyl halide (iodocyclohexane) may serve as the oxidant to form the oxidative coupling product 4. In
such a context, the key challenge is to control the cross-coupling over the homo-coupling to deliver the high yield of
C-alkylated products. Surprisingly, reaction in the presence of 2.0 equiv of tBuOK using a simple NiCl2(Py)414 /PPh3
catalytic system in 1,4-dioxane at 60 °C for 24 h provided the C-alkylated product 3ae in high yield (88%), along
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with a trace amount of homo-coupling product 4 (dibenzyl, 15%) (entry 9). With Ni(COD)2 (COD: 1,5-
cyclooctadiene) as catalyst, the reaction still successfully afforded 82% yield of the corresponding product (entry 8).
Other nickel (II) catalysts including NiCl2, NiCl2•glyme, NiCl2•diglyme, NiBr2•DME and NiCl2(PPh3)2 gave lower
yields of 3ae (entries 3-7). Parallel experiments showed that dinitrogen ligand (4 4'-di-tert-butyl-2 2'-bipyridine) and
many other monodentate or bidentate phosphine ligands proceeded to afford 62%-78% yields of C-alkylated product
3ae (entries 10-16), while the reaction delivered 28% yield of 3ae when NHC ligand such as IPr was used (entriy
17). The choice of base was found to be crucial to the de-nitrogenation: weak bases cannot deprotonate the
hydrazones, while relatively strong bases could deliver satisfactory yields of C-alkylated product 3ae (entries 9, 18-
20). For example, high yield of 3ae was observed with tBuOK, K3PO4 could not give any of this product. Moreover,
other solvents such as 2-methyltetrahydrofuran, cyclopentyl methyl ether or tetrahydrofuran were also effective to
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o
deliver lower yields of C-alkylated products (entries 21-23). The reaction could be performed at 45 C with a
decreased yield for the expected product (69%) (entry 24). Finally, lower loading of NiCl2(Py)4/PPh3 led to
unsatisfied yield (entry 26).
Table 1. Optimization of Reaction Conditionsa,b
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[a] General reaction conditions: hydrazones (0.40 mmol, 1.25 M generated in situ from benzaldehyde and hydrazine),
iodocyclohexane (0.20 mmol), catalyst (20 mol%), ligand (monodentate phosphine ligand 40 mol%, bidentate
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phosphine ligand 20 mol%) and base (2.0 equiv) in 1.0 mL solvent for 24 h. [b] GC yields. [c] NiCl2(Py)4 (10 mol%),
PPh3 (20 mol%) used instead.
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With the optimized conditions in hand, the scope of carbonyls for cross coupling was investigated in Table 2. In
general, carbonyls bearing both electron-withdrawing and electron-donating substituents gave good to high yields.
The reaction showed certain functional group compatibility, as trifluoromethyl, fluoro, chloro, methyl, ethyl, phenyl,
amino, methoxy and alkoxy substituents were all tolerated to give the corresponding products in high yields (3aa-
3ac, 3ae-3aw). Bromo group, which was not compatible with the traditional alkylations of alkyl organometallic
reagents, also worked well with our conditions (3ad). In addition to the good functional-group compatibility, para-,
meta-, ortho-, or multi-substituted aromatic aldehydes were all effective under standard conditions (3aa-3ay). Then
hydrazones generated from heterocyclic aldehydes were investigated in this system. Hydrazones prepared from
thiophene-2-carbaldehyde, thiophene-3-carbaldehyde, benzo[b]thiophene-3-carbaldehyde and nicotinaldehyde, were
all compatible with this system, affording the C-alkylated products in 52%-60% yields (3az-3bc). To our delight,
aliphatic aldehydes such as 2-phenylacetaldehyde and 3-phenylpropanal, which are challenging substrates in the most
cases of previous reports related to the umpolung hydrazone strategy, were also applicable in this cross-coupling
reaction (3bd-3be). Moreover, the attempt to apply ketones as highly active alkyl nucleophiles to couple with
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iodocyclohexane in this transformation also proved feasible (3bf-3bg).
Table 2. Scope of Carbonylsa,b
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[a] Reaction conditions: hydrazones (1.20 mmol, 1.25 M generated in situ from carbonyls and hydrazine),
iodocyclohexane (0.60 mmol), NiCl2(Py)4 (20 mol%), PPh3 (40 mol%), tBuOK (2.0 equiv) in 3.0 mL 1,4-dioxane at
60 oC for 24 h. [b] Isolated yield. [c] NiCl2(Py)4 (10 mol%), IPr·HCl (10 mol%) used instead.
To emphasize the synthetic potential of our methodology, a gram scale alkyl cross-coupling of carbonyls was
performed, giving product 3ac in 85% yields (1.06 g). Later, the transformation of natural aldehydes and their
derivatives were tested, to show the great potential of this alkyl cross-coupling reaction. Hydrazones originated from
4-hydroxyaldehyde derivative (benzyl 4-hydroxyaldehyde) gave C-alkylated products in 82% yields under the
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standard conditions (3ai). Besides, veratraldehyde (methyl vanillin) could efficiently afford the desired product (4-
(cyclohexylmethyl)-1,2-dimethoxybenzene) in 83% yield (3av).
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Subsequently, the alkyl halide substrate scope was investigated in Table 3. This method can be applied to an array
of unactivated secondary alkyl iodides or bromides, generating the desired Csp3–Csp3 bonds in moderate to high
yields. Thus, 2-iodopropane, 2-iodobutane and 2-bromododecane are all suitable substrates (3bi-3bj, 3bl). Besides,
secondary cyclic iodides or bromides such as iodocyclopentane and bromocyclohexane can be cross-coupled (3bh,
3bk). Furthermore, unactivated tertiary alkyl halides, which are significantly more hindered, such as 1-
iodoadamantane, tert-butyl iodide or bromide were also effective in this system, generating the corresponding
alkylated products (3bm-3bo). Importantly, the primary alkyl bromides and iodides, which are challenging substrate
in alkyl-alkyl coupling, are also compatible in current cross-coupling using a NiBr2•DME/PMe3 system. As
illustrated in Table 3, 1-bromohexane, 1-iodohexane, 1-bromododecane, 11-bromoundec-1-ene and (5-
bromopentyl)benzene can successfully couple with umpolung benzaldehyde (3bp-3bt).
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Table 3. Scope of Alkyl Halidesa,b
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[a] Reaction conditions: hydrazones (1.20 mmol, 1.25 M generated in situ from aldehydes and hydrazine), alkyl
halides (0.60 mmol), NiCl2(Py)4 (20 mol%), PPh3 (40 mol%), tBuOK (2.0 equiv) in 3.0 mL 1,4-dioxane at 60 oC for
24 h. [b] Isolated yield. [c] hydrazones (1.20 mmol), alkyl halides (0.60 mmol), NiBr2•DME (10 mol%), PMe3
(40 mol%), tBuOLi (3.5 equiv) in 3.0 mL 2-Me THF at 60 oC for 24 h.
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To gain preliminary insights into the cross-coupling of umpolung carbonyls and alkyl halides, several control
experiments were subsequently carried out (Scheme 2). First, the reaction of cyclohexene and benzaldehyde did not
afford the desired product, (cyclohexylmethyl)benzene, which excluded the Heck reaction intermediate. Then, the
radical inhibiting experiments were performed. It was found that the reaction was completely or nearly suppressed
by the addition of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) or 2, 6-ditertbutyl-4-methylphenol (BHT). The
radical cyclization experiment employing N-methyl-N-phenylmethacrylamide as a substrate produced cyclized
product in 13% yield. The radical additions of styrene or 1,1-diphenylethlene successfully delivered addition products
in 30% and 48% yields, respectively. These results suggest that the reaction might involve a free radical process.
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Scheme 2. Preliminary Mechanism Investigations
Although the exact mechanism of the reaction remains elusive at this moment, on the basis of preliminary
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mechanism investigations and the reported literatures,
a tentative mechanism of the nickel-catalyzed cross-
coupling of umpolung carbonyls and alkyl halides is proposed in Scheme 3. The catalytic cycle commences with the
formation of NiI species A, which is generated from the Ni(II) precatalyst. Electron transfer between the catalytically
active nickel species A and alkyl halides affords NiII species and alkyl radical B, which then form the alkyl nickel
species B (NiIII). Later B undergoes transmetalation with carbon nucleophile derived from deprotonation of
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hydrazone 1 to form the intermediate C. Then subsequent reductive elimination delivers the C-alkyl product 3 by de-
nitrogenation assisted with the base and renders NiI species A for the next cycle.
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Scheme 3. A Tentative Mechanism.
CONCLUSION
In summary, we have developed an efficient cross-coupling of umpolung carbonyls and alkyl halides enabled by
nickel(II) catalyst. Highlighted features of this methodology are: (a) effective not only for secondary and tertiary
alkyl iodides or bromides, but also for primary alkyl iodides and bromides, (b) umpolung of naturally rich carbonyls
as environmentally benign alkyl nucleophiles, (c) N2H4 as a traceless reductant, generating N2 and H2O as the
innocuous side products, (d) using cheap nickel(II) and PPh3 as the catalyst/ligand and the requirement of only a
catalytic amounts of both metal and ligand, (e) moderate to high yields and ease to scale up, (f) tolerating certain
functional groups. With all those characteristics, this umpolung reaction is expected to complement the present cross-
coupling and reductive coupling of Csp3-Csp3 bonds and provide with a novel catalytic alternative to the traditional
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use of highly reactive alkyl organometallic reagents. During the preparation for submitting our manuscript, Zhang
and co-workers just reported a Ni(COD)2-catalyzed alkyl-alkyl couplings of aldehydes and secondary alkyl
bromides.16 Detailed studies of the mechanism and applications of this reaction are underway and more strategies
using carbonyls as alkyl carbanion equivalents for cross coupling are likely to emerge in the future.
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Experimental Section
General Information. 1H NMR spectra were recorded on 500 MHz spectrometer and the chemical shifts were
reported in parts per million (δ) relative to internal solvent signal (7.28 ppm in CDCl3). The peak patterns are indicated
as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q, quartet; m, multiplet. The coupling constants, J,
are reported in Hertz (Hz). 13C NMR spectra were obtained at 125 MHz and referenced to the internal solvent signal
(central peak is 77.0 ppm in CDCl3). 19F NMR spectra were obtained at 470 MHz. CDCl3 was used as the NMR
solvent. Flash column chromatography was performed over silica gel 200-300. All reagents were purchased from
commercial source and used without further purification. The NiCl2(Py)4 and hydrazone solutions (in situ) were
synthesized according to the reported literatures. 13i, 14 The HRMS measurements were recorded on a TOF analyzer
using an ESI or APCI source in the positive mode.
General procedure and characterization data for products 3.
Method I (using NiCl2(Py)4/PPh3 as the catalyst/ligand): 25 mL Schlenk tube was charged with NiCl2(Py)4 (54.0
mg, 20 mol%), PPh3 (63.6 mg, 40 mol%) and 3 mL 1,4-dioxane under argon and stirred at room temperature for 1 h.
Then secondary or tertiary alkyl halides (0.6 mmol) were added to the mixture before hydrazone solution (0.96 mL,
t
2.0 equiv, 1.25 M generated in situ from aldehydes and hydrazine) and BuOK (136.8 mg, 2.0 equiv) were added.
The resulting mixture was stirred in oil bath at 60 oC for 24 h. After the completion of the reaction, the solution was
filtered in a short celite pad and washed with dichloromethane (20 mL×3). The solvent was removed under vacuum
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and the residue was purified by flash column chromatography to give the desired product.
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Method II (using NiBr2•DME/PMe3 as the catalyst/ligand): 25 mL Schlenk tube was charged with NiBr2•DME
(18.6 mg, 10 mol%), and then transferred into the glovebox before PMe3 (21 μL, 40 mol%) was added. The reaction
tube was then moved out of the glovebox, charged with 3 mL 2-methyltetrahydrofuran under argon and stirred at
room temperature for 1 h. Then primary alkyl halide (0.6 mmol) was added to the mixture before hydrazone solution
(0.96 mL, 2.0 equiv, 1.25 M generated in situ from aldehydes and hydrazine) and tBuOLi (168 mg, 3.5 equiv) were
added. The resulting mixture was stirred in oil bath at 60 oC for 24 h. After the completion of the reaction, the solution
was filtered in a short celite pad and washed with dichloromethane (20 mL×3). The solvent was removed under
vacuum and the residue was purified by flash column chromatography to give the desired product.
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Method III (using NiCl2(Py)4/IPr as the catalyst/ligand): 25 mL Schlenk tube was charged with NiCl2(Py)4 (27.0
t
mg, 10 mol%), IPr•HCl (25.5 mg, 10 mol%), BuOK (15.0 mg, 22 mol%) and 3 mL 1,4-dioxane under argon and
stirred at room temperature for 1 h. Then alkyl halide (0.6 mmol) was added to the mixture before hydrazone solution
(0.96 mL, 2.0 equiv, 1.25 M generated in situ from ketones and hydrazine) and tBuOK (136.8 mg, 2.0 equiv) were
added. The resulting mixture was stirred in oil bath at 60 oC for 24 h. After the completion of the reaction, the solution
was filtered in a short celite pad and washed with dichloromethane (20 mL×3). The solvent was removed under
vacuum and the residue was purified by flash column chromatography to give the desired product.
General procedure for gram scale synthesis of 3ac:
100 mL Schlenk tube was charged with NiCl2(Py)4 (540 mg, 20 mol%), PPh3 (636 mg, 40 mol%) and 30 mL 1,4-
dioxane under argon and stirred at room temperature for 1 h. Then iodocyclohexane (6 mmol) was added to the
mixture before hydrazone solution (9.6 mL, 2.0 equiv, 1.25 M generated in situ from 4-chlorobenzaldehyde and
hydrazine) and tBuOK (1.36 g, 2.0 equiv) were added. The resulting mixture was stirred in oil bath at 60 oC for 24 h.
After the completion of the reaction, the solution was filtered in a short celite pad and washed with dichloromethane
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(200 mL×3). The solvent was removed under vacuum and the residue was purified by flash column chromatography
to give 1-chloro-4-(cyclohexylmethyl)benzene 3ac (1.06 g, 85%).
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1-(Cyclohexylmethyl)-4-(trifluoromethyl)benzene (3aa). Colorless liquid (87.2 mg, 60% (method I)). Eluent:
petroleum ether (Rf = 0.8, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.54 (d, J = 10.0 Hz, 2 H), 7.26 (d, J =
5.0 Hz, 2 H), 2.56 (d, J = 10.0 Hz, 2 H), 1.66-1.74 (m, 5 H), 1.53-1.59 (m, 1 H), 1.18-1.24 (m, 3 H), 0.96-1.01 (m, 2
H); 19F NMR (470 MHz, CDCl3) δ -62.3 (s, 3 F); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 145.5, 129.4,
127.9 (q, J = 31.3 Hz), 124.9 (q, J = 3.75 Hz), 124.4 (q, J = 270.0 Hz), 43.9, 39.6, 33.1, 26.5, 26.2 ppm. HRMS
(APCI) for C14H17F2 (M-HF+H+): Calcd: 223.1298; Found: 223.1297.
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1-(Cyclohexylmethyl)-4-fluorobenzene (3ab). Colorless liquid (102.6 mg, 89% (method I) 17. Eluent: petroleum
ether (Rf = 0.8, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.10 (td, J = 10.0, 5.0 Hz, 2 H), 6.97 (tt, J = 10.0,
5.0 Hz, 2 H), 2.47 (d, J = 5.0 Hz, 2 H), 1.65-1.74 (m, 5 H), 1.46-1.54 (m, 1 H), 1.18-1.24 (m, 3 H), 0.91-0.98 (m, 2
H); 19F NMR (470 MHz, CDCl3) δ -118.3 (m, 1 F); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 161.2 (d, J =
241.3 Hz), 136.9 (d, J = 2.5 Hz), 130.4 (d, J = 3.75 Hz), 114.7 (d, J = 21.25 Hz), 43.3, 39.9, 33.1, 26.6, 26.3 ppm.
MS (EI) m/z (M+) calcd for C13H17F: 192.1, found: 192.1.
1-Chloro-4-(cyclohexylmethyl)benzene (3ac). Colorless liquid (110.0 mg, 88% (method I)) 18. Eluent: n-pentane
(Rf = 0.75, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.26 (dd, J = 10.0, 5.0 Hz, 2 H), 7.09 (dd, J = 5.0, 2.0
Hz, 2 H), 2.48 (d, J = 10.0 Hz, 2 H), 1.66-1.74 (m, 5 H), 1.48-1.57 (m, 1 H), 1.17-1.24 (m, 3 H), 0.90-0.99 (m, 2 H);
13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 139.8, 131.3, 130.5, 128.1, 43.4, 39.8, 33.1, 26.5, 26.3 ppm. MS
(EI) m/z (M+) calcd for C13H17Cl: 208.1, found: 208.2.
1-Bromo-4-(cyclohexylmethyl)benzene (3ad). Colorless liquid (120.9 mg, 80% (method I)) 18. Eluent: hexanes (Rf
= 0.7, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.40 (tt, J = 10.0, 5.0 Hz, 2 H), 7.03 (tt, J = 10.0, 5.0 Hz, 2
H), 2.46 (d, J = 10.0 Hz, 2 H), 1.66-1.73 (m, 5 H), 1.46-1.55 (m, 1 H), 1.18-1.24 (m, 3 H), 0.90-0.99 (m, 2 H);
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13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 140.3, 131.1, 130.9, 119.3, 43.5, 39.7, 33.1, 26.5, 26.3 ppm. MS
(EI) m/z (M+) calcd for C13H17Br: 252.1, found: 252.2.
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(Cyclohexylmethyl)benzene (3ae). Colorless liquid (87.8 mg, 84% (method I))19. Eluent: petroleum ether (Rf = 0.75,
UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.32 (td, J = 10.0, 5.0 Hz, 2 H), 7.23 (td, J = 10.0, 5.0 Hz, 1 H),
7.19 (dd, J = 10.0, 5.0 Hz, 2 H), 2.53 (d, J = 5.0 Hz, 2 H), 1.67-1.76 (m, 5 H), 1.53-1.61 (m, 1 H), 1.19-1.26 (m, 3
H), 0.96-1.04 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 141.4, 129.2, 128.0, 125.6, 44.2, 39.8,
33.2, 26.6, 26.4 ppm. MS (EI) m/z (M+) calcd for C13H18: 174.1, found: 174.3.
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1-(Cyclohexylmethyl)-4-methylbenzene (3af). Colorless liquid (93.7 mg, 83% (method I)) 18. Eluent: petroleum
ether (Rf = 0.75, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.13 (d, J = 5.0 Hz, 2 H), 7.08 (d, J = 5.0 Hz, 2
H), 2.50 (d, J = 10.0 Hz, 2 H), 2.37 (s, 3 H), 1.67-1.76 (m, 5 H), 1.51-1.59 (m, 1 H), 1.18-1.29 (m, 3 H), 0.92-1.03
(m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 138.3, 134.9, 129.1, 128.8, 43.7, 39.9, 33.2, 26.6, 26.4,
21.0 ppm. MS (EI) m/z (M+) calcd for C14H20: 188.1, found: 188.1.
1-(Cyclohexylmethyl)-4-ethylbenzene (3ag). Colorless liquid (99.5 mg, 82% (method I)). Eluent: hexanes (Rf =
0.7, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.16 (dd, J = 10.0, 5.0 Hz, 2 H), 7.10 (dd, J = 10.0, 5.0 Hz, 2
H), 2.68 (q, J = 10.0 Hz, 2 H), 2.50 (d, J = 5.0 Hz, 2 H), 1.69-1.76 (m, 5 H), 1.51-1.59 (m, 1 H), 1.28 (t, J = 10.0 Hz,
3 H), 1.18-1.24 (m, 3 H), 0.97-1.03 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 141.4, 138.5, 129.1,
127.5, 43.8, 39.9, 33.2, 28.5, 26.6, 26.4, 15.7 ppm. HRMS (APCI) for C15H22 (M+): Calcd: 202.1722; Found:
202.1719.
4-(Cyclohexylmethyl)-1,1'-biphenyl (3ah). Colorless liquid (120.0 mg, 80% (method I)) 20. Eluent:
dichloromethane/hexanes (1:3, Rf = 0.8, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.64 (dd, J = 10.0, 5.0
Hz, 2 H), 7.56 (dd, J = 5.0, 2.0 Hz, 2 H), 7.47 (td, J = 5.0, 5.0 Hz, 2 H), 7.37 (tt, J = 10.0, 5.0 Hz, 1 H), 7.26 (dd, J
= 10.0, 5.0 Hz, 2 H), 2.58 (d, J = 5.0 Hz, 2 H), 1.69-1.79 (m, 5 H), 1.56-1.65 (m, 1 H), 1.21-1.31 (m, 3 H), 0.98-1.06
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(m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 141.2, 140.6, 138.5, 129.6, 128.7, 127.0, 126.9, 126.8,
43.8, 39.8, 33.2, 26.6, 26.4 ppm. MS (EI) m/z (M+) calcd for C19H22: 250.2, found: 250.3.
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1-(Benzyloxy)-4-(cyclohexylmethyl)benzene (3ai). Colorless liquid (137.8 mg, 82% (method I)). Eluent:
dichloromethane/hexanes (1:2, Rf = 0.75, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.47 (td, J = 10.0, 5.0
Hz, 2 H), 7.41 (tt, J = 10.0, 5.0 Hz, 2 H), 7.35 (tt, J = 10.0, 5.0 Hz, 1 H), 7.08 (dd, J = 5.0, 1.5 Hz, 2 H), 6.92 (dd, J
= 5.0, 1.5 Hz, 2 H), 5.07 (s, 2 H), 2.45 (d, J = 5.0 Hz, 2 H), 1.65-1.73 (m, 5 H), 1.47-1.53 (m, 1 H), 1.18-1.24 (m, 3
H), 0.91-0.99 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 156.9, 137.3, 133.8, 130.0, 128.6, 127.9,
127.5, 114.4, 70.1, 43.2, 39.9, 33.1, 26.6, 26.4 ppm. HRMS (APCI) for C20H25O (M+H+): Calcd: 281.1905; Found:
281.1894.
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4-(Cyclohexylmethyl)-N,N-dimethylaniline (3aj). Colorless liquid (89.9 mg, 69% (method I)) 21. Eluent:
dichloromethane/hexanes (1:3, Rf = 0.35, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.05 (dd, J = 5.0, 1.5
Hz, 2 H), 6.73 (dd, J = 10.0, 1.5 Hz, 2 H), 2.95 (s, 6 H), 2.42 (d, J = 5.0 Hz, 2 H), 1.65-1.74 (m, 5 H), 1.45-1.52 (m,
1 H), 1.18-1.24 (m, 3 H), 0.92-0.99 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 148.9, 129.8, 113.2,
112.8, 43.1, 41.0, 40.0, 33.2, 26.7, 26.4 ppm. MS (EI) m/z (M+) calcd for C15H23N: 217.2, found: 217.2.
1-(Cyclohexylmethyl)-3-(trifluoromethyl)benzene (3ak). Colorless liquid (116.0 mg, 80% (method I)). Eluent:
petroleum ether (Rf = 0.8, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.47 (d, J = 10.0 Hz, 1 H), 7.40 (dd, J
= 15.0, 5.0 Hz, 2 H), 7.34 (d, J = 5.0 Hz, 1 H), 2.57 (d, J = 5.0 Hz, 2 H), 1.66-1.76 (m, 5 H), 1.53-1.60 (m, 1 H),
1.15-1.28 (m, 3 H), 0.95-1.03 (m, 2 H); 19F NMR (470 MHz, CDCl3) δ -62.5 (s, 3 F); 13C{1H} NMR (125 MHz,
CDCl3, 296 K, TMS) δ 142.2, 132.5, 130.4 (q, J = 32.5 Hz), 128.4, 125.7 (q, J = 3.75 Hz), 124.4 (q, J = 270.0 Hz),
122.5 (q, J = 3.75 Hz), 43.9, 39.7, 33.0, 26.5, 26.2 ppm. HRMS (APCI) for C14H17F2 (M-HF+H+): Calcd: 223.1298;
Found: 223.1298.
1-(Cyclohexylmethyl)-3-fluorobenzene (3al). Colorless liquid (95.6 mg, 83% (method I)). Eluent: petroleum ether
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(Rf = 0.70, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.22-7.27 (m, 1 H), 6.94 (td, J = 10.0, 5.0 Hz, 1 H),
6.86-6.90 (m, 2 H), 2.51 (d, J = 10.0 Hz, 2 H), 1.65-1.75 (m, 5 H), 1.52-1.58 (m, 1 H), 1.17-1.25 (m, 3 H), 0.91-1.02
(m, 2 H); 19F NMR (470 MHz, CDCl3) δ -114.4 (m, 1 F); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 162.8
(d, J = 243.7 Hz), 144.9 (d, J = 7.5 Hz), 129.3 (d, J = 7.5 Hz), 124.8 (d, J = 2.5 Hz), 115.8 (d, J = 21.25 Hz), 112.4
(d, J = 21.25 Hz), 43.8 (d, J = 1.25 Hz), 39.6, 33.1, 26.5, 26.3 ppm. MS (EI) m/z (M+) calcd for C13H17F: 192.1,
found: 192.3. HRMS (APCI) for C13H18F (M+H+): Calcd: 193.1393; Found: 193.1394.
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1-Chloro-3-(cyclohexylmethyl)benzene (3am). Colorless liquid (106.1 mg, 85% (method I)) 18. Eluent: petroleum
ether (Rf = 0.8, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.06-7.22 (m, 3 H), 7.05 (tt, J = 10.0, 5.0 Hz, 1
H), 2.49 (d, J = 10.0 Hz, 2 H), 1.66-1.75 (m, 5 H), 1.50-1.58 (m, 1 H), 1.17-1.25 (m, 3 H), 0.95-1.00 (m, 2 H);
13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 143.4, 133.8, 129.3, 129.2, 127.4, 125.8, 43.8, 39.6, 33.1, 26.5,
26.3 ppm. MS (EI) m/z (M+) calcd for C13H17Cl: 208.1, found: 208.1.
1-(Cyclohexylmethyl)-3-methylbenzene (3an). Colorless liquid (91.4 mg, 81% (method I)) 18. Eluent: petroleum
ether (Rf = 0.75, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.21 (t, J = 10.0 Hz, 1 H), 7.04 (d, J = 5.0 Hz, 1
H), 7.00 (t, J = 5.0 Hz, 2 H), 2.50 (d, J = 10.0 Hz, 2 H), 2.38 (s, 3 H), 1.67-1.78 (m, 5 H), 1.53-1.60 (m, 1 H), 1.19-
1.29 (m, 3 H), 0.98-1.03 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 141.3, 137.5, 130.0, 127.9,
126.3, 126.2, 44.1, 39.8, 33.3, 26.6, 26.4, 21.5 ppm. MS (EI) m/z (M+) calcd for C14H20: 188.2, found: 188.2.
1-(Cyclohexylmethyl)-2-fluorobenzene (3ao). Colorless liquid (92.2 mg, 80% (method I)). Eluent: petroleum ether
(Rf = 0.8, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.15-7.21 (m, 2 H), 7.01-7.09 (m, 2 H), 2.56 (dd, J =
10.0, 5.0 Hz, 2 H), 1.66-1.75 (m, 5 H), 1.55-1.62 (m, 1 H), 1.19-1.25 (m, 3 H), 0.97-1.05 (m, 2 H); 19F NMR (470
MHz, CDCl3) δ -118.0 (m, 1 F); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 161.3 (d, J = 243.7 Hz), 131.5 (d,
J = 5.0 Hz), 128.1 (d, J = 16.25 Hz), 127.3 (d, J = 8.75 Hz), 123.6 (d, J = 2.5 Hz), 115.1 (d, J = 22.5 Hz), 38.8, 36.8,
33.1, 26.5, 26.3 ppm. HRMS (APCI) for C13H18F (M+H+): Calcd: 193.1393; Found: 193.1396.
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1-Chloro-2-(cyclohexylmethyl)benzene (3ap). Colorless liquid (93.6 mg, 75% (method I)) 18. Eluent: hexanes (Rf
= 0.8, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.37 (d, J = 10.0 Hz, 1 H), 7.19 (d, J = 5.0 Hz, 2 H), 7.13-
7.17 (m, 1 H), 2.65 (d, J = 5.0 Hz, 2 H), 1.68-1.75 (m, 5 H), 1.64-1.68 (m, 1 H), 1.18-1.26 (m, 3 H), 1.01-1.08 (m, 2
H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 139.0, 134.3, 131.4, 129.4, 127.1,126.3, 41.4, 38.2, 33.2, 26.6,
26.3 ppm. MS (EI) m/z (M+) calcd for C13H17Cl: 208.1, found: 208.2.
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1-(Cyclohexylmethyl)-2-methylbenzene (3aq). Colorless liquid (84.6 mg, 75% (method I)) 22. Eluent: hexanes (Rf
= 0.7, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.18 (dd, J = 10.0, 5.0 Hz, 1 H), 7.11-7.16 (m, 3 H), 2.53
(d, J = 5.0 Hz, 2 H), 2.35 (s, 3 H), 1.68-1.77 (m, 5 H), 1.52-1.59 (m, 1 H), 1.20-1.26 (m, 3 H), 1.00-1.07 (m, 2 H);
13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 139.6, 136.2, 130.1, 130.0, 125.7, 125.4, 41.3, 38.8, 33.5, 26.6,
26.4, 19.6 ppm. MS (EI) m/z (M+) calcd for C14H20: 188.2, found: 188.2.
1,2-Dichloro-4-(cyclohexylmethyl)benzene (3ar). Colorless liquid (90.1 mg, 62% (method I))23. Eluent: petroleum
ether (Rf = 0.7, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.34 (d, J = 10.0 Hz, 1 H), 7.25 (d, J = 2.0 Hz, 1
H), 6.99 (dd, J = 10.0, 5.0 Hz, 1 H), 2.45 (d, J = 5.0 Hz, 2 H), 1.65-1.73 (m, 5 H), 1.47-1.55 (m, 1 H), 1.17-1.24 (m,
3 H), 0.89-0.99 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 141.6, 131.9, 131.0, 129.9, 129.5, 128.6,
43.2, 39.6, 33.0, 26.4, 26.2 ppm. MS (EI) m/z (M+) calcd for C13H16Cl2: 242.0, found: 242.0.
1,2-Dichloro-3-(cyclohexylmethyl)benzene (3as). Colorless liquid (89.0 mg, 61% (method I)). Eluent: hexanes (Rf
= 0.75, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.32 (dd, J = 10.0, 5.0 Hz, 1 H), 7.12 (t, J = 10.0 Hz, 1 H),
7.08 (dd, J = 10.0, 5.0 Hz, 1 H), 2.67 (d, J = 5.0 Hz, 2 H), 1.67-1.75 (m, 5 H), 1.62-1.67 (m, 1 H), 1.17-1.24 (m, 3
H), 0.98-1.06 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 141.4, 133.1, 132.4, 129.5, 128.0, 126.6,
42.4, 37.9, 33.1, 26.5, 26.2 ppm. HRMS (APCI) for C13H16Cl2 (M+): Calcd: 242.0629; Found: 242.0629.
1-(Cyclohexylmethyl)-2,4-dimethylbenzene (3at). Colorless liquid (85.0 mg, 70% (method I)). Eluent: hexanes (Rf
= 0.8, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.01 (d, J = 10.0 Hz, 2 H), 6.96 (dd, J = 10.0, 5.0 Hz, 1 H),
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2.48 (d, J = 5.0 Hz, 2 H), 2.33 (s, 3 H), 2.30 (s, 3 H), 1.68-1.76 (m, 5 H), 1.48-1.55 (m, 1 H), 1.18-1.24 (m, 3 H),
0.97-1.05 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 136.5, 136.0, 135.1, 130.9, 130.0, 126.1, 40.9,
38.8, 33.5, 26.7, 26.4, 20.9, 19.5 ppm. HRMS (APCI) for C15H23 (M+H+): Calcd: 203.1800; Found: 203.1800.
5-(Cyclohexylmethyl)-2,3-dihydro-1H-indene (3au). Colorless liquid (95.0 mg, 74% (method I)) 24. Eluent:
hexanes (Rf = 0.7, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.17 (d, J = 10.0 Hz, 1 H), 7.06 (s, 1 H), 6.96
(dd, J = 10.0, 5.0 Hz, 1 H), 2.91-2.95 (m, 4 H), 2.49 (d, J = 5.0 Hz, 2 H), 2.08-2.14 (m, 2 H), 1.67-1.76 (m, 5 H),
1.51-1.58 (m, 1 H), 1.18-1.29 (m, 3 H), 0.95-1.03 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 144.1,
141.3, 139.2, 127.0, 125.2, 123.8, 44.0, 40.0, 33.3, 32.9, 32.5, 26.7, 26.4, 25.6 ppm. MS (EI) m/z (M+) calcd for
C16H22: 204.1, found: 204.1.
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4-(Cyclohexylmethyl)-1,2-dimethoxybenzene (3av). Colorless liquid (116.6 mg, 83% (method I)) 25. Eluent: ethyl
acetate/hexanes (1:10, Rf = 0.4, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 6.79 (dd, J = 10.0, 5.0 Hz, 1 H),
6.69 (dd, J = 5.0, 1.5 Hz, 2 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 2.44 (d, J = 5.0 Hz, 2 H), 1.63-1.74 (m, 5 H), 1.46-1.54
(m, 1 H), 1.17-1.24 (m, 3 H), 0.91-0.99 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 148.6, 147.0,
134.0, 121.0, 112.4, 110.9, 55.9, 55.8, 43.8, 39.9, 33.2, 26.6, 26.3 ppm. MS (EI) m/z (M+) calcd for C15H22O2: 234.2,
found: 234.2.
1-Bromo-5-(cyclohexylmethyl)-2,4-dimethoxybenzene (3aw). Colorless liquid (110.0 mg, 59% (method I)).
Eluent: ethyl acetate/hexanes (1 :10, Rf = 0.5, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.22 (s, 1 H), 6.48
(s, 1 H), 3.91 (s, 3 H), 3.84 (s, 3 H), 2.41 (d, J = 10.0 Hz, 2 H), 1.64-1.71 (m, 5 H), 1.46-1.54 (m, 1 H), 1.15-1.22 (m,
3 H), 0.91-0.98 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 157.8, 154.6, 134.3, 123.7, 101.2, 96.7,
56.4, 55.7, 38.4, 37.0, 33.2, 26.6, 26.4 ppm. HRMS (ESI) for C15H21O2BrNa (M+Na+): Calcd: 335.0623; Found:
335.0619.
1-(Cyclohexylmethyl)naphthalene (3ax). Colorless liquid (100.8 mg, 75% (method I)) 26. Eluent: petroleum ether
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(Rf = 0.65, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 8.08 (d, J = 10.0 Hz, 1 H), 7.89 (dd, J = 5.0, 1.5 Hz, 1
H), 7.75 (d, J = 5.0 Hz, 1 H), 7.49-7.56 (m, 2 H), 7.43 (dd, J = 10.0, 10.0 Hz, 1 H), 7.32 (d, J = 5.0 Hz, 1 H), 2.98 (d,
J = 5.0 Hz, 2 H), 1.72-1.80 (m, 5 H), 1.67-1.70 (m, 1 H), 1.18-1.26 (m, 3 H), 1.08-1.14 (m, 2 H); 13C{1H} NMR (125
MHz, CDCl3, 296 K, TMS) δ 137.4, 134.0, 132.3, 128.7, 127.2, 126.5, 125.5, 125.3, 125.2, 124.3, 41.3, 39.0, 33.7,
26.6, 26.4 ppm. MS (EI) m/z (M+) calcd for C17H20: 224.1, found: 224.1.
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2-(Cyclohexylmethyl)naphthalene (3ay). Colorless liquid (87.4 mg, 65% (method I)) 27. Eluent: hexanes (Rf = 0.5,
UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.77-7.84 (m, 3 H), 7.60 (s, 1 H), 7.42-7.49 (m, 2 H), 7.33 (dd, J
= 10.0, 1.5 Hz, 1 H), 2.67 (d, J = 5.0 Hz, 2 H), 1.69-1.76 (m, 5 H), 1.62-1.69 (m, 1 H), 1.18-1.25 (m, 3 H), 0.98-1.06
(m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 138.9, 133.5, 131.9, 128.1, 127.6, 127.5, 127.4, 127.2,
125.8, 125.0, 44.3, 39.8, 33.2, 26.6, 26.3 ppm. MS (EI) m/z (M+) calcd for C17H20: 224.1, found: 224.1.
2-(Cyclohexylmethyl)thiophene (3az). Colorless liquid (59.4 mg, 55% (method I)). Eluent: hexanes (Rf = 0.8,
UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.13 (dd, J = 5.0, 1.5 Hz, 1 H), 6.94 (dd, J = 5.0, 5.0 Hz, 1 H),
6.77 (dd, J = 5.0, 1.5 Hz, 1 H), 2.72 (d, J = 10.0 Hz, 2 H), 1.65-1.79 (m, 5 H), 1.53-1.60 (m, 1 H), 1.15-1.31 (m, 3
H), 0.93-1.01 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 144.1, 126.6, 124.9, 122.9, 40.2, 37.8,
33.0, 26.5, 26.2 ppm. HRMS (APCI) for C11H17S (M+H+): Calcd: 181.1051; Found: 181.1049.
3-(Cyclohexylmethyl)thiophene (3ba). Colorless liquid (57.2 mg, 53% (method I)). Eluent: hexanes (Rf = 0.8,
UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.25 (dd, J = 5.0, 5.0 Hz, 1 H), 6.93 (dd, J = 5.0, 1.5 Hz, 1 H),
6.91 (dd, J = 5.0, 1.5 Hz, 1 H), 2.53 (d, J = 10.0 Hz, 2 H), 1.64-1.74 (m, 5 H), 1.52-1.58 (m, 1 H), 1.16-1.28 (m, 3
H), 0.91-0.99 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 141.7, 128.8, 124.8, 120.6, 39.2, 38.2,
33.2, 26.6, 26.3 ppm. HRMS (APCI) for C11H17S (M+H+): Calcd: 181.1051; Found: 181.1049.
3-(Cyclohexylmethyl)benzo[b]thiophene (3bb). Colorless liquid (82.8 mg, 60% (method I)). Eluent: petroleum
ether (Rf = 0.4, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.88 (dd, J = 5.0, 1.5 Hz, 1 H), 7.77 (dd, J = 5.0,
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1.5 Hz, 1 H), 7.35-7.43 (m, 2 H), 7.08 (s, 1 H), 2.76 (d, J = 5.0 Hz, 2 H), 1.70-1.81 (m, 5 H), 1.67-1.70 (m, 1 H),
1.18-1.25 (m, 3 H), 1.00-1.08 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 140.5, 139.4, 135.7, 123.9,
123.7, 122.9, 122.0, 121.8, 38.0, 36.6, 33.6, 26.5, 26.3 ppm. HRMS (APCI) for C15H19S (M+H+): Calcd: 231.1207;
Found: 231.1207.
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3-(Cyclohexylmethyl)pyridine (3bc). Colorless liquid (54.6 mg, 52% (method I)). Eluent: ethyl acetate/hexanes
(1:3, Rf = 0.25, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 8.46 (d, J = 10.0 Hz, 2 H), 7.53 (d, J = 10.0 Hz, 1
H), 7.28 (s, 1 H), 2.52 (d, J = 5.0 Hz, 2 H), 1.66-1.74 (m, 5 H), 1.50-1.58 (m, 1 H), 1.17-1.24 (m, 3 H), 0.93-1.01 (m,
2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 149.7, 146.4, 137.2, 136.9, 123.4, 41.0, 39.5, 32.9, 26.4, 26.2
ppm. HRMS (ESI) for C12H18N (M+H+): Calcd: 176.1439; Found: 176.1436.
(2-Cyclohexylethyl)benzene (3bd). Colorless liquid (67.7 mg, 60% (method I))18. Eluent: hexanes (Rf = 0.8, UV/I2).
1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.30 (t, J = 10.0 Hz, 2 H), 7.17-7.21 (m, 3 H), 2.63-2.66 (m, 2 H), 1.70-
1.82 (m, 5 H), 1.66-1.70 (m, 1 H), 1.51-1.56 (m, 2 H), 1.20-1.29 (m, 3 H), 0.92-1.00 (m, 2 H); 13C{1H} NMR (125
MHz, CDCl3, 296 K, TMS) δ 143.3, 128.4, 128.2, 125.5, 39.4, 37.3, 33.3, 33.2, 26.7, 26.4 ppm. MS (EI) m/z (M+)
calcd for C14H20: 188.2, found: 188.2.
(3-Cyclohexylpropyl)benzene (3be). Colorless liquid (65.5 mg, 54% (method I)) 18. Eluent: hexanes (Rf = 0.8,
UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.28-7.32 (m, 2 H), 7.19-7.22 (m, 3 H), 2.61 (t, J = 10.0 Hz, 2 H),
1.67-1.76 (m, 5 H), 1.62-1.67 (m, 1 H), 1.23-1.31 (m, 4 H), 1.14-1.23 (m, 3 H), 0.86-0.94 (m, 2 H); 13C{1H} NMR
(125 MHz, CDCl3, 296 K, TMS) δ 143.0, 128.4, 128.2, 125.5, 37.6, 37.2, 36.3, 33.4, 28.8, 26.8, 26.5 ppm. MS (EI)
m/z (M+) calcd for C15H22: 202.1, found: 202.1.
(1-Cyclohexylethyl)benzene (3bf). Colorless liquid (44.0 mg, 39% (method III), from iodocyclohexane) 28. Eluent:
petroleum ether (Rf = 0.7, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.30 (td, J = 10.0, 5.0 Hz, 2 H), 7.20
(tt, J = 10.0, 5.0 Hz, 1 H), 7.17 (dd, J = 10.0, 5.0 Hz, 2 H), 2.44-2.50 (m, 1 H), 1.87-1.93 (m, 1 H), 1.74-1.80 (m, 1
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H), 1.61-1.67 (m, 2 H), 1.39-1.48 (m, 2 H), 1.25 (d, J = 5.0 Hz, 3 H), 1.18-1.25 (m, 1 H), 1.08-1.17 (m, 2 H), 0.92-
1.00 (m, 1 H), 0.80-0.88 (m, 1 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 147.1, 128.0, 127.7, 125.6,
46.0, 44.2, 31.5, 30.6, 26.6, 18.8 ppm. MS (EI) m/z (M+) calcd for C14H20: 188.1, found: 188.1.
1-Cyclohexyl-2,3-dihydro-1H-indene (3bg). Colorless liquid (40.8 mg, 34% (method III), from iodocyclohexane).
Eluent: petroleum ether (Rf = 0.75, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.21-7.23 (m, 2 H), 7.15-7.17
(m, 2 H), 3.07-3.11 (m, 1 H), 2.89-2.96 (m, 2 H), 2.80-2.86 (m, 1 H), 2.08-2.13 (m, 1 H), 1.90-1.96 (m, 1 H), 1.67-
1.81 (m, 6 H), 1.25-1.32 (m, 1 H), 1.13-1.22 (m, 2 H), 0.99-1.07 (m, 1 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K,
TMS) δ 146.2, 144.6, 126.1, 125.7, 124.5, 124.3, 50.7, 41.5, 31.8, 28.5, 27.6, 26.9, 26.7 ppm. HRMS (APCI) for
C15H21 (M+H+): Calcd: 201.1643; Found: 201.1643.
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(Cyclopentylmethyl)benzene (3bh). Colorless liquid (86.5 mg, 90% (method I)) 29. Eluent: petroleum ether (Rf =
0.75, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.28-7.32 (m, 2 H), 7.19-7.22 (m, 3 H), 2.64 (d, J = 5.0 Hz,
2 H), 2.08-2.15 (m, 1 H), 1.72-1.77 (m, 2 H), 1.65-1.70 (m, 2 H), 1.30-1.35 (m, 2 H), 1.21-1.29 (m, 2 H); 13C{1H}
NMR (125 MHz, CDCl3, 296 K, TMS) δ 142.4, 128.8, 128.1, 125.5, 42.1, 42.0, 32.5, 31.6, 24.9, 22.7 ppm. MS (EI)
m/z (M+) calcd for C12H16: 160.1, found: 160.2.
1-Bromo-4-isobutylbenzene (3bi). Colorless liquid (80.0 mg, 63% (method I), from 2-iodopropane) 30. Eluent:
hexanes (Rf = 0.75, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.41 (dd, J = 5.0, 1.5 Hz, 2 H), 7.04 (dd, J =
5.0, 1.5 Hz, 2 H), 2.45 (d, J = 5.0 Hz, 2 H), 1.82-1.90 (m, 1 H), 0.93 (s, 3 H), 0.92 (s, 3 H); 13C{1H} NMR (125 MHz,
CDCl3, 296 K, TMS) δ 140.6, 131.1, 130.9, 119.4, 44.8, 30.2, 22.3 ppm. MS (EI) m/z (M+) calcd for C10H13Br: 212.0,
found: 212.0.
1-Bromo-4-(2-methylbutyl)benzene (3bj). Colorless liquid (80.2 mg, 59% (method I), from 2-iodobutane). Eluent:
hexanes (Rf = 0.80, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.41 (dd, J = 10.0, 5.0 Hz, 2 H), 7.04 (dd, J =
5.0, 1.5 Hz, 2 H), 2.61 (dd, J = 10.0, 5.0 Hz, 1 H), 2.34 (dd, J = 10.0, 5.0 Hz, 1 H), 1.60-1.67 (m, 1 H), 1.36-1.44 (m,
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1 H), 1.16-1.24 (m, 1 H), 0.93 (t, J = 10.0 Hz, 3 H), 0.86 (d, J = 5.0 Hz, 3 H); 13C{1H} NMR (125 MHz, CDCl3, 296
K, TMS) δ 140.6, 131.1, 130.9, 119.3, 42.7, 36.6, 29.1, 18.9, 11.5 ppm. HRMS (APCI) for C11H14Br (M-H+): Calcd:
225.0279; Found: 225.0279.
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(Cyclohexylmethyl)benzene (3bk). Colorless liquid (80.5 mg, 77% (method I), from bromocyclohexane)19. Eluent:
petroleum ether (Rf = 0.75, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.32 (td, J = 10.0, 5.0 Hz, 2 H), 7.23
(td, J = 10.0, 5.0 Hz, 1 H), 7.19 (dd, J = 10.0, 5.0 Hz, 2 H), 2.53 (d, J = 5.0 Hz, 2 H), 1.67-1.76 (m, 5 H), 1.53-1.61
(m, 1 H), 1.19-1.26 (m, 3 H), 0.96-1.04 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 141.4, 129.2,
128.0, 125.6, 44.2, 39.8, 33.2, 26.6, 26.4 ppm. MS (EI) m/z (M+) calcd for C13H18: 174.1, found: 174.3.
(2-Methyltridecyl)benzene (3bl). Colorless liquid (118.5 mg, 72% (method I), from 2-bromotridecane). Eluent:
hexanes (Rf = 0.80, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.31 (td, J = 10.0, 5.0 Hz, 2 H), 7.21 (tt, J =
10.0, 5.0 Hz, 1 H), 7.18 (dd, J = 10.0, 5.0 Hz, 2 H), 2.68 (dd, J = 10.0, 5.0 Hz, 1 H), 2.38 (dd, J = 10.0, 5.0 Hz, 1 H),
1.37-1.44 (m, 1 H), 1.27-1.37 (m, 20 H), 0.93 (t, J = 5.0 Hz, 3 H), 0.88 (d, J = 5.0 Hz, 3 H); 13C{1H} NMR (125
MHz, CDCl3, 296 K, TMS) δ 141.7, 129.2, 128.1, 125.6, 43.8, 36.8, 35.0, 32.0, 29.9, 29.8, 29.7, 29.6, 29.5, 29.4,
27.2, 22.7, 19.4, 14.2 ppm. HRMS (APCI) for C20H35 (M+H+): Calcd: 275.2739; Found: 275.2739.
1-Benzyladamantane (3bm). Colorless liquid (110 mg, 81% (method I), from 1-iodoadamantane) 31. Eluent:
hexanes (Rf = 0.7, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.30 (tt, J = 10.0, 5.0 Hz, 2 H), 7.24 (tt, J =
10.0, 5.0 Hz, 1 H), 7.13 (dt, J = 10.0, 5.0 Hz, 2 H), 2.43 (s, 2 H), 1.98 (s, 3 H), 1.71 (d, J = 10.0 Hz, 3 H), 1.62 (d, J
= 10.0 Hz, 3 H), 1.53 (d, J = 5.0 Hz, 6 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 138.3, 130.6, 127.5,
125.7, 51.3, 42.4, 37.0, 33.5, 28.8 ppm. MS (EI) m/z (M+) calcd for C17H22: 226.1, found: 226.2.
1-Bromo-4-neopentylbenzene (3bn or 3bo). Colorless liquid (3bq, 71.5 mg, 53% (method I), from 2-iodo-2-
methylpropane; 3br, 65.0 mg, 48% (method I), from 2-bromo-2-methylpropane) 32. Eluent: hexanes (Rf = 0.80,
UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.41 (td, J = 10.0, 5.0 Hz, 2 H), 7.02 (td, J = 10.0, 5.0 Hz, 2 H),
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2.47 (s, 2 H), 0.92 (s, 9 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 138.7, 132.1, 130.7, 119.7, 49.6, 31.7,
29.3 ppm. MS (EI) m/z (M+) calcd for C11H15Br: 226.0, found: 226.0.
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Heptylbenzene (3bp or 3bq). Colorless liquid (3bs, 54.9 mg, 52% (method II), from 1-iodohexane; 3bt, 65.5 mg,
62% (method II), from 1-bromohexane) 33. Eluent: hexanes (Rf = 0.80, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K,
TMS) 7.28-7.32 (m, 2 H), 7.18-7.21 (m, 3 H), 2.63 (t, J = 10.0 Hz, 2 H), 1.61-1.67 (m, 2 H), 1.28-1.37 (m, 8 H), 0.91
(t, J = 10.0 Hz, 3 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ 143.0, 128.4, 128.2, 125.5, 36.0, 31.8, 31.6,
29.3, 29.2, 22.7, 14.1 ppm. MS (EI) m/z (M+) calcd for C13H20: 176.1, found: 176.1.
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Tridecylbenzene (3br). Colorless liquid (92.2 mg, 59% (method II), from 1-bromododecane)34. Eluent: hexanes (Rf
= 0.8, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.28-7.31 (m, 2 H), 7.17-7.21 (m, 3 H), 2.62 (t, J = 10.0
Hz, 2 H), 1.60-1.65 (m, 4 H), 1.32-1.34 (m, 4 H), 1.28-1.32 (m, 14 H), 0.91 (t, J = 10.0 Hz, 3 H); 13C{1H} NMR (125
MHz, CDCl3, 296 K, TMS) δ 143.0, 128.4, 128.2, 125.5, 36.0, 34.1, 32.9, 31.9, 31.5, 29.9, 29.8, 29.7, 29.6, 29.5,
29.4, 22.7, 14.1 ppm. MS (EI) m/z (M+) calcd for C19H32: 260.2, found: 260.1.
Dodec-11-en-1-ylbenzene (3bs). Colorless liquid (65.9 mg, 45% (method I), from 11-bromoundec-1-ene)35. Eluent:
hexanes (Rf = 0.80, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.28-7.31 (m, 2 H), 7.18-7.21 (m, 3 H), 5.80-
5.88 (m, 1 H), 5.02 (qd, J = 15.0, 5.0 Hz, 1 H), 4.96 (qd, J = 10.0, 5.0 Hz, 1 H), 2.63 (t, J = 10.0 Hz, 2 H), 2.04-2.09
(m, 2 H), 1.61-1.67 (m, 2 H), 1.37-1.41 (m, 2 H), 1.28-1.36 (m, 12 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K,
TMS) δ 143.0, 139.3, 128.4, 128.2, 125.5, 114.1, 36.0, 33.8, 31.5, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 29.0 ppm. MS
(EI) m/z (M+) calcd for C18H28: 244.2, found: 244.2.
1,6-Diphenylhexane (3bt). Colorless liquid (72.8 mg, 51% (method I), from (5-bromopentyl)benzene) 36. Eluent:
hexanes (Rf = 0.50, UV/I2). 1H NMR (500 MHz, CDCl3, 296 K, TMS) 7.28-7.32 (m, 4 H), 7.19-7.23 (m, 6 H), 2.62
(t, J = 10.0 Hz, 4 H), 1.59-1.67 (m, 4 H), 1.37-1.41 (m, 4 H); 13C{1H} NMR (125 MHz, CDCl3, 296 K, TMS) δ
142.8, 128.4, 128.2, 125.6, 36.0, 31.4, 29.2 ppm. MS (EI) m/z (M+) calcd for C18H22: 238.1, found: 238.1.
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Supporting Information
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Copies of NMR spectra of all products of nickel-catalyzed cross-coupling of umpolung carbonyls and alkyl halides.
This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* cj.li@mcgill.ca
ORCID
Dianhu Zhu: 0000-0001-5415-9648
Leiyang Lv: 0000-0002-2850-8952
Chao-Jun Li: 0000-0002-3859-8824
Author Contributions
§ D.Z. and L.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors acknowledge the Canada Research Chair Foundation, the CFI, FQRNT Center for Green Chemistry and
Catalysis, NSERC, and McGill University for support of our research.
REFERENCES
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8
9
(1) For selected reviews of metal-catalyzed cross-coupling reactions, see: (a) Cross-Coupling Reactions: A Practical
Guide, (Ed: Miyaura, N.), Topics in Current Chemistry Series 219, Springer-Verlag, New York, 2002. (b) Handbook
of Organopalladium Chemistry for Organic Synthesis, (Ed.: Negishi, E. -I.), Wiley-Interscience, New York, 2002.
(c) Metal-Catalyzed Cross-Coupling Reactions, (Eds.: de Meijere, A.; Diederich, F.), Wiley-VCH, New York, 2004.
(2) For an overview of coupling reactions of Csp3-X electrophiles, see: (a) Cárdenas, D. J. Towards Efficient and
Wide‐Scope Metal‐Catalyzed Alkyl–Alkyl Cross‐Coupling Reactions. Angew. Chem. Int. Ed. 1999, 38, 3018-3020.
(b) Luh, T. -Y.; Leung, M. -K.; Wong, K. -T. Transition Metal-Catalyzed Activation of Aliphatic C−X Bonds in
Carbon−Carbon Bond Formation. Chem. Rev. 2000, 100, 3187-3204. (c) Cárdenas, D. J. Advances in
Functional‐Group‐Tolerant Metal‐Catalyzed Alkyl–Alkyl Cross‐Coupling Reactions. Angew. Chem. Int. Ed. 2003,
42, 384-387.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) (a) Frisch, A. C.; Beller, M. Catalysts for Cross‐Coupling Reactions with Non‐Activated Alkyl Halides. Angew.
Chem. Int. Ed. 2005, 44, 674-688. (b) Terao, J.; Kambe, N. Cross-Coupling Reaction of Alkyl Halides with Grignard
Reagents Catalyzed by Ni, Pd, or Cu Complexes with π-Carbon Ligand (s). Acc. Chem. Res. 2008, 41, 1545-1554.
(c) López-Pérez, A.; Adrio, J.; Carretero, J. C. Palladium-Catalyzed Cross-Coupling Reaction of Secondary
Benzylic Bromides with Grignard Reagents. Org. Lett. 2009, 11, 5514-5517. (d) Kambe, N.; Iwasaki, T.; Terao, J.
Pd-Catalyzed Cross-Coupling Reactions of Alkyl Halides. Chem. Soc. Rev. 2011, 40, 4937-4947. (e) Jana, R.; Pathak,
T. P.; Sigman, M. S. Advances in Transition Metal (Pd, Ni, Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-
Organometallics as Reaction Partners. Chem. Rev. 2011, 111, 1417–1492. (f) Zhou, W.; Cao, G.; Shen, G.; Zhu,
X.; Gui, Y.; Ye, J.; Sun, L.; Liao, L.; Li, J.; Yu, D. -G. Visible‐Light‐Driven Palladium‐Catalyzed Radical Alkylation
of C−H Bonds with Unactivated Alkyl Bromides. Angew. Chem. Int. Ed. 2017, 56, 15683-15687.
(4) (a) Henningsen, M. C.; Jeropoulos, S.; Smith, E. H. Nickel-Mediated Elimination of Hydrogen Halide from
Primary and Secondary Alkyl Bromides and Iodides. Synthetic Aspects. J. Org. Chem. 1989, 54, 3015-3018. (b)
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Netherton, M. R.; Dai, C.; Neuschütz, K.; Fu, G. C. Room-Temperature Alkyl−Alkyl Suzuki Cross-Coupling of
Alkyl Bromides that Possess β Hydrogens. J. Am. Chem. Soc. 2001, 123, 10099-10100. (c) Bissember, A. C.; Levina,
A.; Fu, G. C. A Mild, Palladium-Catalyzed Method for The Dehydrohalogenation of Alkyl Bromides: Synthetic and
Mechanistic Studies. J. Am. Chem. Soc. 2012, 134, 14232-14237. (d) Dupuy, S.; Zhang, K. -F.; Goutierre, A. -S.;
Baudoin, O. Terminal‐Selective Functionalization of Alkyl Chains by Regioconvergent Cross‐Coupling. Angew.
Chem. Int. Ed. 2016, 55, 14793-14797. (e) Chen, F.; Chen, K.; Zhang, Y.; He, Y.; Wang, Y.; Zhu, S. Remote
Migratory Cross-Electrophile Coupling and Olefin Hydroarylation Reactions Enabled by In Situ Generation of NiH.
J. Am. Chem. Soc. 2017, 139, 13929-13935. (f) Peng, L.; Li, Y.; Li, Y.; Wang, W.; Pang, H.; Yin, G. Ligand-
Controlled Nickel-Catalyzed Reductive Relay Cross-Coupling of Alkyl Bromides and Aryl Bromides. ACS Catal.
2018, 8, 310-313.
10
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45
46
47
48
49
50
51
52
53
54
55
56
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58
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(5) (a) Kirchhoff, J. H.; Dai, C.; Fu, G. C. A Method for Palladium‐Catalyzed Cross‐Couplings of Simple Alkyl
Chlorides: Suzuki Reactions Catalyzed by [Pd2(dba)3]/PCy3. Angew. Chem. Int. Ed. 2002, 41, 1945-1947. (b)
Netherton, M. R.; Fu, G. C. Suzuki Cross‐Couplings of Alkyl Tosylates That Possess β Hydrogen Atoms: Synthetic
and Mechanistic Studies. Angew. Chem. Int. Ed. 2002, 41, 3910-3912. (c) Zhou, J.; Fu, G. C. Palladium-Catalyzed
Negishi Cross-Coupling Reactions of Unactivated Alkyl Iodides, Bromides, Chlorides, and Tosylates. J. Am. Chem.
Soc. 2003, 125, 12527-12530.
(6) For selected nickel-catalyzed cross-coupling reactions of unactivated alkyl halides/sulfonates, see: (a) Terao, J.;
Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. Nickel-Catalyzed Cross-Coupling Reaction of Grignard Reagents
with Alkyl Halides and Tosylates: Remarkable Effect of 1, 3-Butadienes. J. Am. Chem. Soc. 2002, 124, 4222-4223.
(b) Netherton, M. R.; Fu, G. C. Nickel‐Catalyzed Cross‐Couplings of Unactivated Alkyl Halides and Pseudohalides
with Organometallic Compounds. Adv. Synth. Catal. 2004, 346, 1525–1532. (c) Breitenfeld, J.; Ruiz, J.; Wodrich,
M. D.; Hu, X. Bimetallic Oxidative Addition Involving Radical Intermediates in Nickel-Catalyzed Alkyl–Alkyl
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Page 28 of 33
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Kumada Coupling Reactions. J. Am. Chem. Soc. 2013, 135, 12004−12012. and references cited therein.
5
6
7
8
9
(7) For selected copper-catalyzed processes, see: (a) Tamura, M.; Kochi, J. K. Coupling of Grignard Reagents with
Organic Halides. Synthesis, 1971, 303-305. (b) Tamura, M.; Kochi, J. K. Copper-Catalyzed Coupling of Grignard
Reagents and Akyl Halides in Tetrahydrofuran Solutions. J. Organomet Chem. 1972, 42, 205-228. (c) Lipshutz, B.
H.; Sengupta, S. Organocopper Reagents: Substitution, Conjugate Addition, Carbo/Metallocupration, and Other
Reactions. Org. React. 1992, 41, 135. (d) Cahiez, G.; Chaboche, C.; Jézéquel, M. Cu-Catalyzed Alkylation of
Grignard Reagents: A New Efficient Procedure. Tetrahedron, 2000, 56, 2733-2737. (e) Sai, M.; Someya, H.;
Yorimitsu, H.; Oshima, K. Copper-Catalyzed Reaction of Alkyl Halides with Cyclopentadienylmagnesium Reagent.
Org. Lett. 2008, 10, 2545-2547. (f) Shen, R.; Iwasaki, T.; Terao, J.; Kambe, N. Copper-Catalyzed Coupling
Reaction of Unactivated Secondary Alkyl Iodides with Alkyl Grignard Reagents in The Presence of 1,3-Butadiene as
An Effective Additive. Chem. Commun. 2012, 48, 9313-9315.
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57
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60
(8) For selected iron-catalyzed processes, see: (a) Brinker, U. H.; König, L. Carben‐Umlagerungen, X.
2‐Vinylcyclobutyliden. Chem. Ber. 1983, 116, 882-893. (b) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. Iron-
Catalyzed Cross-Coupling of Primary and Secondary Alkyl Halides with Aryl Grignard Reagents. J. Am. Chem. Soc.
2004, 126, 3686-3687. (c) Nagano, T.; Hayashi, T. Iron-Catalyzed Grignard Cross-Coupling with Alkyl Halides
Possessing β-Hydrogens. Org Lett. 2004, 6, 1297-1299. (d) Martin, R.; Fürstner, A. Cross-Coupling of Alkyl Halides
with Aryl Grignard Reagents Catalyzed by A Low-Valent Iron Complex. Angew. Chem. Int. Ed. 2004, 43, 3955-
3957. (e) Dongol, K. G.; Koh, H.; Sau, M.; Chaia, C. L. L. Iron‐Catalysed sp3–sp3 Cross‐Coupling Reactions of
Unactivated Alkyl Halides with Alkyl Grignard Reagents. Adv. Synth. Catal. 2007, 349, 1015-1018. (f) Hatakeyama,
T.; Hashimoto, T.; Kathriarachchi, K. K. A. D. S.; Zenmyo, T.; Seike, H.; Nakamura, M. Iron‐Catalyzed Alkyl–Alkyl
Suzuki–Miyaura Coupling. Angew. Chem. Int. Ed. 2012, 51, 8834–8837.
(9) For selected cobalt-catalyzed process, see: (a) Tsuji, T.; Yorimitsu, H.; Oshima, K. Cobalt‐Catalyzed Coupling
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The Journal of Organic Chemistry
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4
5
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7
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Reaction of Alkyl Halides with Allylic Grignard Reagents. Angew. Chem. Int. Ed. 2002, 41, 4137-4139. (b) Ohmiya,
H.; Tsuji, T.; Yorimitsu, H.; Oshima, K. Cobalt‐Catalyzed Cross‐Coupling Reactions of Alkyl Halides with Allylic
and Benzylic Grignard Reagents and Their Application to Tandem Radical Cyclization/Cross‐Coupling Reactions.
Chem. Eur. J. 2004, 10, 5640-5648. (c) Cahiez, G.; Chaboche, C.; Duplais, C.; Giulliani, A.; Moyeux, A.
Cobalt‐Catalyzed Cross‐Coupling Reaction between Functionalized Primary and Secondary Alkyl Halides and
Aliphatic Grignard Reagents. Adv. Synth. Catal. 2008, 350, 1484-1488.
10
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17
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21
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(10) For selected reductive alkyl-alkyl coupling of alkyl halides, see: (a) Prinsell, M. R.; Everson, D. A.; Weix, D. J.
Nickel-Catalyzed, Sodium Iodide-Promoted Reductive Dimerization of Alkyl Halides, Alkyl Pseudohalides, and
Allylic Acetates. Chem. Commun. 2010, 46, 5743–5745. (b) Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Nickel-
Catalyzed Reductive Cross-Coupling of Unactivated Alkyl Halides. Org. Lett. 2011, 13, 2138-2141. (c) Liu, J.; Yang,
C.; Lu, X.; Zhang, Z.; Xu, L.; Cui, M.; Lu, X.; Xiao, B.; Fu, Y.; Liu, L. Copper‐Catalyzed Reductive Cross‐Coupling
of Nonactivated Alkyl Tosylates and Mesylates with Alkyl and Aryl Bromides. Chem. Eur. J. 2014, 20, 15334-
15338. For selected reports using TDAE as the reductant, see: (d) Anka-Lufford, L.; Huihui, K. M. M.; Gower, N.
J.; Ackerman, L. K. G.; Weix, D. J. Nickel‐Catalyzed Cross‐Electrophile Coupling with Organic Reductants in
Non‐Amide Solvents. Chem. -Eur. J. 2016, 22, 11564-11567. and references cited therein.
(11) For selected photoredox/electrochemical methods of alkyl-alkyl coupling, see: (a) Johnston, C. P.; Smith, R. T.;
Allmendinger, S.; MacMillan, D. W. C. Metallaphotoredox-Catalysed sp3–sp3 Cross-Coupling of Carboxylic Acids
with Alkyl Halides. Nature 2016, 536, 322–325. (b) Le, C.; Liang, Y.; Evans, R. W.; Li, X.; MacMillan, D. W. C.
Selective sp3 C–H Alkylation via Polarity-Match-Based Cross-Coupling. Nature 2017, 547, 79-83. (c) Lévêque, C.;
Corcé, V.; Chenneberg, L.; Ollivier, C.; Fensterbank, L. Photoredox/Nickel Dual Catalysis for The C(sp3)–C(sp3)
Cross‐Coupling of Alkylsilicates with Alkyl Halides. Eur. J. Org. Chem. 2017, 2118–2121. (d) Paul, A.; Smith, M.
D.; Vannucci, A. K. Photoredox-Assisted Reductive Cross-Coupling: Mechanistic Insight into Catalytic Aryl–Alkyl
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