Nickel-catalyzed, ring-forming aromatic C–H alkylations with unactivated alkyl halides

Article abstract of DOI:10.1016/j.tet.2019.05.047

The development of a nickel-catalyzed C–H alkylation of aromatic substrates with unactivated alkyl halides is described. This carbocyclization facilitates the synthesis of diverse fused ring systems from simple aromatic substrates and is an attractive alt

Full text of DOI:10.1016/j.tet.2019.05.047

Accepted Manuscript
Nickel-catalyzed, ring-forming aromatic C–H alkylations with unactivated alkyl halides
Quentin D. Tercenio, Erik J. Alexanian
PII:
S0040-4020(19)30599-X
https://doi.org/10.1016/j.tet.2019.05.047
TET 30368
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 March 2019
Revised Date: 21 May 2019
Accepted Date: 22 May 2019
Please cite this article as: Tercenio QD, Alexanian EJ, Nickel-catalyzed, ring-forming aromatic
C–H alkylations with unactivated alkyl halides, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.05.047.
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Nickel-catalyzed, ring-forming aromatic C–
H alkylations with unactivated alkyl halides
Leave this area blank for abstract info.
Quentin D. Tercenio, Erik J. Alexanian
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United
States
Me
10 mol % Ni(cod)2
Br
Me
10 mol % xantphos
N
N
3 equiv Mn
3 equiv PMP
sulfolane, 130 °C
71% isolated yield
diverse carbocycles
and heterocycles
unactivated alkyl halides

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Nickel-catalyzed, ring-forming aromatic C−H alkylations with unactivated alkyl
halides
Quentin D. Tercenio, Erik J. Alexanian
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The development of a nickel-catalyzed C−H alkylation of aromatic substrates with unactivated
alkyl halides is described. This carbocyclization facilitates the synthesis of diverse fused ring
systems from simple aromatic substrates and is an attractive alternative to traditional polar or
radical-mediated ring formations. The present system uses unactivated primary and secondary
alkyl bromides and chlorides, while avoiding the use of precious palladium catalysts and more
reactive alkyl halides commonly used in related C–H alkylations.
Available online
Keywords:
2019 Elsevier Ltd. All rights reserved
.
Nickel catalysis
C−H alkylation
Unactivated halides
carbocyclization
1. Introduction
general approach to nickel-catalyzed Mizoroki-Heck-type
carbocyclizations proceeding via a hybrid organometallic-radical
pathway [9h]. We hypothesized that this reactivity in nickel
catalysis could unlock a general, intramolecular ring-forming
aromatic C–H alkylation using more attractive alkyl bromides
and chlorides as substrates. Herein, we report the development of
such a nickel-catalyzed C−H alkylation, applicable to a diverse
range of aromatic substrates using primary and secondary
unactivated alkyl bromides and chlorides as coupling partners
(Fig. 1).
Carbocyclizations of arenes and heteroarenes with alkyl
halides are fundamental transformations for the syntheses of
polycyclic aromatic compounds [1]. Synthetic methods achieving
this goal include the classical Friedel-Crafts reaction [2] and
radical-mediated homolytic aromatic substitutions (HAS) [3];
however, their applications are largely limited to either electron-
rich or electron-poor aromatic substrates, respectively. Undesired
reductive dehalogenation is also frequently observed in HAS
reactions, and while the use of alkyl xanthates (dithiocarbonates)
can mitigate this problem, these reactions require additional
synthetic effort [4].
Metal-catalyzed aromatic C−H alkylations constitute mild,
attractive alternatives to these processes; however, existing
methods use either activated alkyl halides (e.g., α-halocarbonyls)
[5,6], substrate directing groups [7], or require the use of
precious palladium catalysts [8]. For example, we have
previously reported a palladium-catalyzed, ring-forming C−H
alkylation of aromatic substrates using unactivated alkyl iodides
and bromides [8a]. While this work offered an attractive
approach to catalytic C–H alkylation, the required use of
palladium catalysts and relatively unstable alkyl iodides is a
drawback to the system.
Fig 1. Nickel-catalyzed C–H alkylations of aromatic substrates.
2. Results and discussion
Our studies commenced with the carbocyclization of
secondary alkyl bromide 1 (Table 1). We determined that a
catalytic system comprised of 5 mol % Ni(cod)2 and 5 mol %
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(xantphos)
Recent studies have demonstrated the broad utility of nickel
catalysts in activating alkyl halides for diverse C−C bond
was capable of catalyzing the C–H alkylation of substrate 1,
producing indoline 2 in good yield (61%). Our previously
reported protocol using 10 mol % Pd(PPh3)4 was slightly less
constructions [9]. For instance, we have recently reported a
———
Corresponding author.
E-mail address: eja@email.unc.edu.

2
Tetrahedron
ACCEPTED MANUSCRIPT
9
10
12
effective in this case (entry 2, 55%) [8a]. Substituting
Me
NiBr2·glyme as the nickel precatalyst also led to decreased yield
(entry 3) [10]. The use of xantphos as ligand was critical to the
reaction; substituting either 10 mol % PPh3 as ligand (entry 4) or
5 mol % BINAP (entry 5) led to poor reactivity. Decreasing the
reaction temperature from 130 °C to 80 °C significantly lowered
efficiency (entry 6). Substituting the inorganic base Cs2CO3 for
PMP, or Zn for Mn as reductant also significantly decreased
yield (entries 7 and 8). The use of PhtBu as solvent–as with the
palladium-catalyzed system–led to a decreased yield (entry 9)
[8a], as did omitting Mn from the reaction (entry 10). No reaction
occurred in the absence of Ni(cod)2 (entry 11).
Ms
N
X
6
7
11: X = Br
13: X = Cl
50
58
Me
Br
N
N
8
56
Me
15
14
N
Br
R
9
10
16: R = H
17: R = H
19: R = Me
47
71
18: R = Me
Table 1
X
R
R
Catalyst system development for nickel-catalyzed ring-
forming C−H alkylations.
CO2Et
CO2Et
CO2Et
Me Me
CO2Et
11b.d
12e
20: X = Br, R = H
22: X = Cl, R = H
23: X = Br, R = Cl
25: X = Br, R = CF3
21: R = H
80
51
67
63
58
Me
Me
Br
5 mol % Ni(cod)2
5 mol % xantphos
13b,d
14b,d
15b,d
24: R = Cl
26: R = CF3
28: R = OMe
3 equiv Mn
3 equiv PMP
sulfolane, 130 °C
O
N
N
Ms
Ms
Ph2P
PPh2
27: X = Br, R = OMe
1
2
xantphos
Br
E
entry
1
2
3
4
5
6
7
8
variation from standard conditions above
None
yield (%)a
E
E
69
4:1
30:31
61
55
51
0
24
19
0
19
50
38
0
16b,d
CO2Et
E
10 mol % Pd(PPh3)4, 2 equiv PMP, PhtBu,130 °C
5 mol % NiBr2•glyme instead of Ni(cod)2
10 mol % PPh3 instead of 5 mol % xantphos
5 mol % BINAP instead of 5 mol % xantphos
80 °C instead of 130 °C
Me
E = CO2Et
Me
CO2Et
Me
29
30
31
Reactions were performed with [substrate]0 = 0.15 M in sulfolane at 130
°C with 10 mol% Ni(cod)2, 10 mol % xantphos, 3 equiv Mn, and 3 equiv
PMP (1,2,2,6,6-pentamethylpiperidine) as base. aIsolated yields. bReactions
performed with 5 mol% Ni(cod)2 and 5 mol% xantphos. cReaction performed
at 150 °C. dReaction performed at 60 °C in DMSO with Et3N as the base.
Cs2CO3 instead of PMP
Zn instead of Mn
PhtBu instead of sulfolane
9
10
11
no Mn
no Ni(cod)2
eReaction performed in PhtBu
.
a
1
Reactions were performed with [1]0 = 0.15 M. Yields determined by H
NMR spectroscopy of crude reaction mixture using an internal standard.
With a suitable catalytic system in hand, we investigated the
carbocyclization using a diverse range of substrates (Table 2).
The synthesis of indoline product 2 was successful using either
the unactivated alkyl bromide 1 or the alkyl chloride 3, albeit in
reduced yield (entries 1 and 2). Transformation of an aromatic
We next applied the catalytic C−H alkylation to the synthesis
of indole derivatives (entries 8-10). Our system serves as an
efficient alternative to related carbocyclizations of indoles that
necessitated the use of stoichiometric metals or peroxides [3,4].
Catalytic cyclization of indole 14 successfully provided dihydro-
1H-pyrrolo[1,2-a]indole 15 in 56% yield (entry 8). Addition of a
methylene unit to the tether enables the preparation of
tetrahydropyrido[1,2-a]indoles from primary or secondary alkyl
bromides in 47% and 71% yield, respectively (entries 9 and 10).
ketone derivative
4
was also successful (entry 3).
Carbocyclization of a meta-substituted substrate 6 led to a
mixture of regioisomers (entry 4). Extension of the alkyl tether in
substrate 9 enabled access to the tetrahydroquinoline ring system
in good yield (58%, entry 5). We were also able to access the
tetrahydroisoquinoline framework in the cyclizations of alkyl
bromide substrate 11 and chloride 13, providing product 12 in
50% and 58% yield, respectively.
The C–H alkylation is also applicable to the preparation of
tetrahydronapthalenes, as demonstrated in entries 11-16. Both
electron-rich and electron-poor substrates provided the desired
products in moderate yield using both alkyl bromide and alkyl
chloride substrates. Interestingly, the reaction of ortho-substituted
aromatic substrate 29 delivered a 4:1 mixture of product 30 and
31–which was also previously observed using palladium
catalysis–consistent with an alkyl shift during the course of the
reaction [8a,11].
Table 2.
Scope of nickel-catalyzed carbocyclization of unactivated
alkyl bromides and chlorides.
yield
entry
substrate
product
(%)a
Several experiments were conducted to probe the reaction
mechanism and draw comparisons to our prior work involving
palladium catalysis (Scheme 2). The reaction of enantioenriched
substrate (R)-1 under standard conditions led to racemic indoline
2, which is consistent with a single-electron pathway involving
stereoablation. Moreover, when the reaction was stopped at
partial conversion, racemization of the recovered starting
material was observed, consistent with a reversible single-
electron activation of the alkyl halide substrate. Reactions
performed in the presence of radical inhibitors BHT and
hydroquinone proceeded with somewhat decreased yields (40%
and 41%, respectively) as compared to the standard reaction
1b
2c
3
1: X = Br, R = H
3: X = Cl, R = H
4: X = Br, R = C(O)Me
2: R = H
61
45
52
5: R = C(O)Me
Me
Me
Me
Br
52
1.9:1
7:8
Me
N
4
5
Ms
N
Me
N
Ms
Me
Ms
6
7
8
Me
N
Br
58
Ms

3
(61%). These results support the formation of caged radical
catalytic, ring-forming C–H alkylations to include the use of
attractive unactivated alkyl chlorides.
ACCEPTED MANUSCRIPT
intermediates rather than dissociated radical species [5d]. Finally,
deuterated 1-d5 was prepared and subjected to an intermolecular
competition KIE experiment. The lack of a kinetic isotope effect
(kH/kD = 1) indicates that C−H bond cleavage does not occurs
during the rate-determining step of the alkylation.
4. Experimental section
4.1 General information
Proton and carbon magnetic resonance spectra (1H NMR and
13C NMR) were obtained using a Bruker model AVANCE III 400
or 600 (1H NMR at 400 MHz or 600 MHz and 13C NMR at 100
MHz or 151 MHz) spectrometer with solvent resonance as
internal reference (1H NMR: CDCl3 at 7.28 ppm, 13C NMR:
CDCl3 at 77.00 ppm). 1H NMR data are reported as follows:
chemical shift (ppm), multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, bs = broad singlet), coupling
constants (Hz), and integration. Mass spectra were obtained using
a ThermoScientificQ Exactive HF-Xmass spectrometer with
electrospray introduction or atmospheric pressure chemical
ionization in positive mode. These samples were prepared in
methanol.
Reaction of Enantioenriched Bromide Stopped at Partial Conversion:
Me
Me
Br
5 mol % Ni(cod)2
5 mol % xantphos
Me
N
Br
+
3 equiv Mn
3 equiv PMP
sulfolane, 130 °C, 2h
N
N
Ms
Ms
Ms
2
1
(R)-1
35%, racemic
43%, racemic
Reactions with Radical Inhibitors:
Me
additive
none
% yield
61
Me
Br
5 mol % Ni(cod)2
5 mol % xantphos
1 equiv BHT
40
3 equiv Mn
3 equiv PMP
sulfolane, 130 °C
N
N
20 mol % hydroquinone 41
Ms
Ms
2
1
Intermolecular Competition KIE:
5 mol % Ni(cod)2
5 mol % xantphos
Me
N
Br
Me
Br
2 + 2-d4
HPLC analysis was performed on a Shimadzu SPD-M20A
photodiode array (PDA) system equipped with Daicel Chiralpak
IE, IF, IG, and OJ-H columns using a flow rate of 1 mL per
minute. The solvent system used for HPLC resolution of
d5
+
3 equiv Mn
3 equiv PMP
sulfolane, 130 °C, 2h
50 : 50
N
Ms
Ms
1-d5
kH/kD = 1
1
enantiomers
was
hexanes
and
isopropanol.
Flash
Scheme 1. Mechanistic studies of the C–H alkylation.
Chromatography was performed using SiliaFlash P60 silica gel
(40-63ꢀm) purchased from Silicycle. Visualization was achieved
using a short wave UV light (254 nm), or aqueous basic
potassium permanganate solution, or aqueous acidic ceric
ammonium molybdate solution followed by heating.
Tetrahydrofuran (THF), diethyl ether (Et2O), dichloromethane
(DCM), toluene, acetonitrile (MeCN), and dimethylformamide
(DMF) were dried by passage through a column of neutral
alumina under nitrogen prior to use. tert-Butylbenzene and
dimethylsulfoxide (DMSO) was dried over 3 Å molecular sieves
and degassed with argon prior to use. All other reagents were
obtained from commercial sources and used without further
purification unless otherwise noted.
A plausible mechanism consistent with our current studies is
depicted in Scheme 2. The nickel catalyst promotes reversible
atom abstraction of the alkyl halide substrate to generate carbon-
centered radical 32. The subsequent carbon-centered radical
cyclizes on to the aromatic ring to form the cyclohexadienyl
radical 33. Rearomatization then delivers the product, which we
hypothesize proceeds via single-electron oxidation to
a
cyclohexadienyl cation and deprotonation. This mechanism is
therefore analogous to that of our previously reported palladium-
based system [8a]. The current system is clearly more effective in
atom abstraction however, as evidenced by the successful
reactions of alkyl chlorides–which are not possible using
palladium catalysis.
4.2 Substrate preparation
Me
General procedure A: Bromination of secondary alcohols.
Me
Br
Br
H
base
To a solution of secondary alcohol (1 equiv) in Et2O (0.5 M)
was added phosphorus tribromide (0.5 equiv) dropwise. The
reaction mixture was stirred at room temperature for 1 hour and
was then quenched with H2O. The aqueous layer was back
extracted three times with Et2O and the combined organic layers
were washed with saturated NaHCO3, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography.
[Ni]0
N
N
Ms
Ms
2
1
base
Me
Me
[Ni]I
[Ni]I
Br
Br
N
N
Ms
32
Ms
33
General procedure B: Appel bromination of secondary alcohols.
To a solution of secondary alcohol (1 equiv) and 2,6-lutidine
(0.25 equiv) in THF (0.3 M) were added triphenylphosphine (1.2
equiv) and tetrabromomethane (1.2 equiv). The reaction mixture
was stirred for 16 hours at room temperature. The reaction
mixture was then diluted with hexane (50 mL) and filtered. The
filter cake was washed with hexane/ether (1:1) (50 mL). The
filtrate was concentrated under reduced pressure and purified by
flash chromatography.
Scheme 2. Plausible catalytic cycle for the nickel-catalyzed
ring-forming C−H alkylation.
3. Conclusions
In conclusion, we have developed a ring-forming C−H
alkylation of aromatic compounds using unactivated alkyl halides
and an inexpensive, first-row metal catalyst system. These
reactions provide access to an array of valuable polycyclic
carbocycles and heterocycles, without the requirements of
electronic activation common to alternative polar or radical-
mediated C–H alkylations. This work also extends the scope of
General procedure C: Tosylation of secondary alcohols.
To a solution of 4-methylbenzenesulfonyl chloride (1.5 equiv)
and trimethylamine hydrochloride (0.1 equiv) in DCM (0.3 M) at
0 °C was added triethylamine (2.5 equiv) dropwise. The alcohol
(1 equiv) was then added in DCM, and the reaction mixture was
stirred at room temperature for 16 hours. To the reaction mixture

4
Tetrahedron
ACCEPTED MANUSCRIPT
was added N,N-dimethylpropane-1,3-diamine (2 equiv) and
3.78 (m, 1H), 2.97 (s, 3H), 1.56 – 1.50 (m, 3H). 13C NMR (151
stirred for 15 minutes before being quenched with H2O. The
aqueous layer was extracted three times with DCM and the
combined organic layers were washed sequentially with 1 M HCl
solution, saturated NaHCO3, and brine. The combined organic
layers were then dried over MgSO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography.
MHz, CDCl3) δ 139.16, 129.80, 128.80, 128.64, 77.30, 77.09,
76.87, 58.38, 54.83, 37.96, 22.13. HRMS (APCI) Exact mass
calculated for C10H15ClNO2S [M+H]+, 248.0512. Found
248.0507.
N-(2-hydroxypropyl)-N-(4-(2-methyl-1,3-dioxolan-2-
yl)phenyl)methanesulfonamide (SI-4) was prepared according
to a literature procedure, and spectral data were in accordance
with the literature values [8a].
General procedure D: Chlorination of secondary tosylate.
To a solution of lithium chloride (3 equiv) in DMF (0.5 M) was
added the alkyl tosylate (1 equiv). The reaction mixture was
heated to 90°C and stirred for 20 hours. The reaction mixture was
cooled to room temperature and diluted with Et2O and washed
with 1 M HCl solution (2x). The organic layer was then dried
over MgSO4, filtered, and concentrated under reduced pressure.
The crude product was purified by flash chromatography.
N-(2-bromopropyl)-N-(4-(2-methyl-1,3-dioxolan-2-
yl)phenyl)methanesulfonamide (SI-5). Secondary alcohol SI-4
(0.833 g, 1 equiv, 2.80 mmol) was brominated with 2,6-lutidine
(82.0 µL, 0.25 equiv, 0.7 mmol), triphenylphosphine (0.918 g,
1.2 equiv, 3.50 mmol), and tetrabromomethane (1.11 g, 1.2
equiv, 3.36 mmol) in THF (10 mL, 0.3 M) following General
procedure B. The crude product was purified by flash
chromatography using 20% ethyl acetate in hexanes to provide
secondary bromide SI-5 as a white solid (212 mg, 20% yield). 1H
NMR (600 MHz, CDCl3) δ 7.58 – 7.53 (m, 2H), 7.37 (d, J = 8.4
Hz, 2H), 4.11 – 4.04 (m, 3H), 4.01 (dt, J = 13.4, 6.7 Hz, 1H),
3.89 (dd, J = 13.4, 6.9 Hz, 1H), 3.85 – 3.77 (m, 2H), 2.97 (s, 3H),
1.73 (d, J = 6.5 Hz, 3H), 1.67 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 144.07, 138.55, 128.46, 126.83, 108.45, 77.26, 77.05,
76.83, 64.64, 64.63, 58.72, 46.03, 37.83, 27.62, 22.92. HRMS
(APCI) Exact mass calculated for C14H21BrNO4S [M+H]+,
378.0374. Found 378.0365.
N-(2-bromopropyl)-N-phenylmethanesulfonamide (1) was
prepared according to a literature procedure, and spectral data
were in accordance with the literature values [8a].
N-(2-hydroxypropyl)-N-(phenyl-d5)methanesulfonamide
(SI-1) was prepared according to a literature procedure, and
spectral data were in accordance with the literature values [8a].
N-(2-bromopropyl)-N-(phenyl-d5)methanesulfonamide (1-
d5). Secondary alcohol SI-1 (1.5 g, 1 equiv, 6.4 mmol) was
brominated with phosphorus tribromide (0.30 mL, 0.5 equiv, 3.2
mmol) in DCM (18.7 mL, 1 M) following General procedure A.
The crude product was purified by flash chromatography using
20% ethyl acetate in hexanes to provide secondary bromide 1-d5
as a white solid (571 mg, 30% yield). 1H NMR (400 MHz,
CDCl3) δ 4.11 – 4.05 (m, 1H), 4.01 (dt, J = 13.4, 6.6 Hz, 1H),
3.90 (dd, J = 13.4, 7.0 Hz, 1H), 2.96 (s, 3H), 1.73 (d, J = 6.5 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 77.34, 77.02, 76.70, 58.72,
46.07, 37.79, 22.95. HRMS (APCI) Exact mass calculated for
C10H10D5BrNO2S [M+H]+, 297.0321. Found 297.0313.
N-(4-acetylphenyl)-N-(2-bromopropyl)
methane
sulfonamide (4). To a solution of acetal SI-5 (0.210 g, 1 equiv,
0.555 mmol) in acetonitrile (11 mL, 0.05 M) was added copper
(II) chloride dihydrate (0.189 g, 2 equiv, 1.11 mmol). The
reaction solution was stirred for 3 hours at room temperature
before being quenched with water. The aqueous layer was
extracted three times with Et2O, and the combined aqueous layer
was washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by flash chromatography using 40% ethyl acetate in
hexanes to provide secondary bromide 4 as a white solid (148
N-(2-hydroxypropyl)-N-phenylmethanesulfonamide (SI-2)
was prepared according to a literature procedure, and spectral
data were in accordance with the literature values [8a].
1
mg, 80% yield). H NMR (400 MHz, CDCl3) δ 8.09 – 8.00 (m,
2H), 7.56 – 7.50 (m, 2H), 4.10 (dd, J = 12.9, 6.5 Hz, 1H), 4.07 –
4.00 (m, 1H), 3.96 (dd, J = 12.8, 6.1 Hz, 1H), 2.98 (s, 3H), 2.64
(s, 3H), 1.72 (d, J = 6.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ
196.88, 143.41, 136.56, 129.84, 128.23, 77.26, 77.05, 76.84,
58.39, 45.96, 38.12, 26.74, 22.99. HRMS (APCI) Exact mass
calculated for C12H17BrNO3S [M+H]+, 334.0113. Found
334.0104.
1-(N-phenylmethylsulfonamido)propan-2-yl
4-
methylbenzenesulfonate (SI-3). Secondary alcohol SI-2 (2.0 g,
1 equiv, 9.0 mmol) was tosylated with 4-methylbenzenesulfonyl
chloride (2.57 g, 1.5 equiv, 13.5 mmol), trimethylamine
hydrochloride (86 mg, 0.1 equiv, 0.9 mmol), and triethylamine
(3.1 mL, 2.5 equiv, 22.5 mmol) in DCM (20 mL, 0.3 M)
following General procedure C. The crude product was purified
by flash chromatography using 30% ethyl acetate in hexanes to
provide secondary tosylate SI-3 as a colorless oil (2.5 g, 73%
N-(2-hydroxypropyl)-N-(m-tolyl)methanesulfonamide (SI-
6) was prepared according to a literature procedure, and spectral
data were in accordance with the literature values [8a].
1
yield). H NMR (600 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz, 2H),
N-(2-bromopropyl)-N-(m-tolyl)methanesulfonamide
(6).
7.44 – 7.35 (m, 3H), 7.35 – 7.29 (m, 4H), 4.73 – 4.66 (m, 1H),
3.92 (dd, J = 14.5, 6.8 Hz, 1H), 3.75 (dd, J = 14.5, 5.3 Hz, 1H),
2.94 (s, 3H), 2.47 (s, 3H), 1.25 (d, J = 6.4 Hz, 3H). 13C NMR
(151 MHz, CDCl3) δ 144.87, 139.48, 133.88, 129.87, 129.72,
128.62, 128.47, 128.35, 127.75, 77.46, 77.28, 77.06, 76.85,
55.36, 38.01, 21.70, 18.18. HRMS (APCI) Exact mass
calculated for C17H22NO5S2 [M+H]+, 384.0939. Found 384.0934.
Secondary alcohol SI-6 (1.92 g, 1 equiv, 7.89 mmol) was
brominated with phosphorus tribromide (372 µL, 0.5 equiv, 3.95
mmol) in DCM (10 mL, 1 M) following General procedure A.
The crude product was purified by flash chromatography using
20% ethyl acetate in hexanes to provide secondary bromide 6 as a
1
white solid (450 mg, 25% yield). H NMR (400 MHz, CDCl3) δ
7.33 (dd, J = 11.1, 4.8 Hz, 1H), 7.24 – 7.15 (m, 3H), 4.09 – 3.97
(m, 2H), 3.93 – 3.83 (m, 1H), 2.97 (s, 3H), 2.41 (s, 3H), 1.77 –
1.70 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 139.95, 138.92,
129.54, 129.51, 129.41, 125.45, 77.26, 77.05, 76.84, 58.74,
46.13, 37.84, 22.96, 21.39. HRMS (APCI) Exact mass
calculated for C11H17BrNO2S [M+H]+, 306.0163. Found
306.0159.
1-(N-phenylmethylsulfonamido)propan-2-yl
4-
methylbenzenesulfonate (3). Secondary tosylate SI-3 (2.21 g, 1
equiv, 5.76 mmol) was chlorinated with lithium chloride (0.733
g, 3 equiv, 17.3 mmol) in DMF (11 mL, 0.5 M). The crude
product was purified by flash chromatography in 20% ethyl
acetate in hexanes to provide secondary chloride 3 as a white
solid (856 mg, 60% yield). 1H NMR (600 MHz, CDCl3) δ 7.48 –
7.43 (m, 2H), 7.42 – 7.37 (m, 3H), 4.03 – 3.95 (m, 2H), 3.85 –

5
N-(3-hydroxybutyl)-N-phenylmethanesulfonamide (SI-7)
was prepared according to a literature procedure, and spectral
data were in accordance with the literature values [8a].
54.63, 52.27, 39.86, 22.40. HRMS (APCI) Exact mass
ACCEPTED MANUSCRIPT
calculated for C11H17ClNO2S [M+H]+, 262.0669. Found
262.0663.
N-(3-bromobutyl)-N-phenylmethanesulfonamide
(9).
1-(3-bromobutyl)-1H-indole (14). To a suspended solution of
sodium hydride (0.48 g, 60% dispersion in mineral oil, 1.2 equiv,
12 mmol) in THF (30 mL, 0.25 M), a solution of indole (1.2 g, 1
equiv, 10 mmol) in THF (10 mL) was added dropwise and stirred
for 30 minutes. To the reaction mixture was added 1,3-
dibromobutane (2.4 mL, 2 equiv, 20 mmol) was added dropwise
and stirred for 20 hours at room temperature. The reaction
mixture was quenched with saturated NH4Cl and washed three
times with Et2O, dried with MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by flash
chromatography using a gradient of 2.5-5% ethyl acetate in
hexanes to provide secondary bromide 14 as a yellow oil (1.08 g,
Secondary alcohol SI-7 (1.43 g, 1 equiv, 5.88 mmol) was
brominated with phosphorus tribromide (0.277 mL, 0.5 equiv,
2.94 mmol) in DCM (10 mL, 0.5 M) following General
procedure A. The crude product was purified by flash
chromatography using 20% ethyl acetate in hexanes to provide
1
secondary bromide 6 as a white solid (450 mg, 25% yield). H
NMR (600 MHz, CDCl3) δ 7.48 – 7.42 (m, 2H), 7.40 – 7.35 (m,
3H), 4.21 – 4.14 (m, 1H), 3.94 – 3.83 (m, 2H), 2.91 (s, 3H), 2.04
– 1.98 (m, 2H), 1.71 (d, J = 6.7 Hz, 3H). 13C NMR (151 MHz,
CDCl3) δ 139.08, 129.67, 128.33, 128.32, 77.30, 77.08, 76.87,
49.45, 47.47, 40.00, 36.80, 26.43. HRMS (APCI) Exact mass
calculated for C11H17BrNO2S [M+H]+, 306.0163. Found
306.0158.
1
43% yield). H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 7.9 Hz,
1H), 7.44 (d, J = 8.2 Hz, 1H), 7.28 (q, J = 8.1 Hz, 1H), 7.21 (d, J
= 3.1 Hz, 1H), 7.16 (dd, J = 16.9, 9.3 Hz, 1H), 6.55 (d, J = 3.0
Hz, 1H), 4.43 (ddd, J = 14.5, 6.8, 4.4 Hz, 1H), 4.38 (ddd, J =
14.7, 8.8, 6.2 Hz, 1H), 4.01 – 3.94 (m, 1H), 2.38 – 2.32 (m, 1H),
2.27 – 2.19 (m, 1H), 1.74 (d, J = 6.7 Hz, 3H). 13C NMR (151
MHz, CDCl3) δ 135.77, 128.73, 128.07, 121.65, 121.11, 119.51,
109.36, 101.46, 77.29, 77.08, 76.87, 48.36, 44.72, 41.11, 26.66.
HRMS (APCI) Exact mass calculated for C12H15BrN [M+H]+,
252.0388. Found 252.0382.
N-benzyl-N-(2-hydroxypropyl)methanesulfonamide (SI-8)
was prepared according to a literature procedure, and spectral
data were in accordance with the literature values [8a].
N-benzyl-N-(2-bromopropyl)methanesulfonamide
(11).
Secondary alcohol SI-8 (1.30 g, 1 equiv, 5.34 mmol) was
brominated with phosphorus tribromide (0.25 mL, 0.5 equiv,
2.67 mmol) in DCM (10 mL, 0.5 M) following General
procedure A. The crude product was purified by flash
chromatography using 20% ethyl acetate in hexanes to provide
1-(4-bromobutyl)-1H-indole (16) was prepared according to
a literature procedure, and spectral data were in accordance with
the literature values [12].
1
secondary bromide 11 as a white solid (408 mg, 25% yield). H
NMR (600 MHz, CDCl3) δ 7.40 (t, J = 5.7 Hz, 4H), 7.38 – 7.34
(m, 1H), 4.63 (d, J = 15.1 Hz, 1H), 4.41 (d, J = 15.1 Hz, 1H),
4.14 (h, J = 6.8 Hz, 1H), 3.52 – 3.46 (m, 2H), 2.94 (s, 3H), 1.61
(d, J = 6.7 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 135.41,
128.93, 128.65, 128.36, 77.27, 77.06, 76.85, 55.38, 52.52, 46.76,
39.76, 23.23. HRMS (APCI) Exact mass calculated for
C11H17BrNO2S [M+H]+, 306.0163. Found 306.0156.
1-(4-bromopentyl)-1H-indole (18) was prepared according to
a literature procedure, and spectral data were in accordance with
the literature values [12].
Diethyl 2-benzyl-2-(2-bromoethyl)malonate (20) was
prepared according to a literature procedure, and spectral data
were in accordance with the literature values [8a].
1-(N-benzylmethylsulfonamido)propan-2-yl
4-
Diethyl 2-benzyl-2-(2-chloroethyl)malonate (22). To
a
methylbenzenesulfonate (SI-9). Secondary alcohol SI-8 (1.74 g,
1 equiv, 7.15 mmol) was tosylated with 4-methylbenzenesulfonyl
chloride (2.04 g, 1.5 equiv, 10.7 mmol), trimethylamine
hydrochloride (68.3 mg, 0.1 equiv, 0.715 mmol), and
triethylamine (2.49 mL, 2.5 equiv, 17.9 mmol) in DCM (80 mL,
0.3 M) following General Procedure C. The crude product was
purified by flash chromatography using 30% ethyl acetate in
hexanes to provide secondary tosylate SI-9 as a colorless oil
suspended solution of sodium hydride (1.06 g, 60% dispersion in
mineral oil, 1.3 equiv, 26.5 mmol) in THF (6.8 mL, 0.3 M) was
added benzyl malonate (5.1 g, 1 equiv, 20.4 mmol). The reaction
mixture was stirred for 30 minutes at room temperature and then
1-bromo-2-chloroethane (17.0 mL, 10 equiv, 204 mmol) was
added. The reaction mixture was heated to reflux and stirred for
24 hours. The reaction was quenched with H2O and extracted
three times with Et2O. The combined organic layers were washed
with brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
chromatography using a gradient of 5-10% ethyl acetate in
1
(1.65 g, 58% yield). H NMR (600 MHz, CDCl3) δ 7.79 (d, J =
8.3 Hz, 2H), 7.41 – 7.31 (m, 7H), 4.78 – 4.70 (m, 1H), 4.58 (d, J
= 15.2 Hz, 1H), 4.33 (d, J = 15.2 Hz, 1H), 3.44 (dd, J = 15.4, 8.2
Hz, 1H), 3.22 (dd, J = 15.4, 4.3 Hz, 1H), 2.92 (s, 3H), 2.48 (s,
3H), 1.07 (d, J = 6.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ
145.12, 135.19, 133.88, 129.98, 128.88, 128.73, 128.23, 127.75,
77.28, 77.07, 76.99, 76.86, 51.54, 50.72, 40.00, 21.72, 18.04.
HRMS (ESI) Exact mass calculated for C18H23NO5S2Na
[M+Na], 420.0915. Found 420.0907.
1
hexanes to give a colorless oil (2.4 g, 38% yield). H NMR (600
MHz, CDCl3) δ 7.33 – 7.23 (m, 3H), 7.15 – 7.09 (m, 2H), 3.63 –
3.56 (m, 2H), 3.29 (s, 2H), 2.34 – 2.19 (m, 2H), 1.29 (t, J = 7.1
Hz, 6H). 13C NMR (151 MHz, CDCl3) δ 170.41, 135.37, 129.90,
128.48, 127.25, 77.27, 77.06, 76.85, 61.67, 57.89, 40.09, 39.35,
35.73, 14.02. HRMS (APCI) Exact mass calculated for
C16H22ClO4 [M+H]+, 313.1207. Found 313.1191.
N-benzyl-N-(2-chloropropyl)methanesulfonamide
(13).
Secondary tosylate SI-9 (1.64 g, 1 equiv, 4.13 mmol) was
chlorinated with lithium chloride (0.525 g, 3 equiv, 12.4 mmol)
in DMF (8 mL, 0.5 M). The crude product was purified by flash
chromatography in 20% ethyl acetate in hexanes to provide
secondary chloride 13 as a white solid (648 mg, 60% yield). 1H
NMR (600 MHz, CDCl3) δ 7.42 – 7.37 (m, 4H), 7.35 (qd, J =
7.7, 3.5 Hz, 1H), 4.63 (d, J = 15.1 Hz, 1H), 4.43 (d, J = 15.2 Hz,
1H), 4.14 (h, J = 6.7 Hz, 1H), 3.40 (d, J = 7.0 Hz, 2H), 2.95 (s,
3H), 1.43 (d, J = 6.6 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ
135.45, 128.90, 128.59, 128.29, 77.31, 77.10, 76.89, 55.31,
Diethyl 2-(2-bromoethyl)-2-(4-chlorobenzyl)malonate (23)
was prepared according to a literature procedure, and spectral
data were in accordance with the literature values [8a].
Diethyl
2-(2-bromoethyl)-2-(4-(trifluoromethyl)benzyl)
malonate (25) was prepared according to a literature procedure,
and spectral data were in accordance with the literature values
[8a].

6
Tetrahedron
ACCEPTED MANUSCRIPT
Diethyl 2-(2-bromoethyl)-2-(4-methoxybenzyl)malonate
Mixture of 3,7-dimethyl-1-(methylsulfonyl)indoline and
(27) was prepared according to a literature procedure, and
spectral data were in accordance with the literature values [8a].
3,6-dimethyl-1-(methylsulfonyl)indoline (7 and 8) was
synthesized according to C-H alkylation procedure A using
secondary bromide 6 (38.3 mg, 0.125 mmol). The crude product
was purified by flash column chromatography using 15% ethyl
acetate in hexanes to provide to provide a 1.9:1 ratio of 7 and 8 as
a colorless oil (14.6 mg, 52% yield). Physical and spectral data
were in accordance with literature data [8a].
Diethyl 2-(2-bromoethyl)-2-(2-methylbenzyl)malonate (29)
was prepared according to a literature procedure, and spectral
data were in accordance with the literature values [8a].
4.3 Nickel-catalyzed reactions
C-H alkylation procedure A:
4-methyl-1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoline
(10) was synthesized according to C-H alkylation procedure A
using secondary bromide 9 (38.3 mg, 0.125 mmol). The crude
product was purified by flash column chromatography using 10%
ethyl acetate in hexanes to provide 10 as a light orange solid
(16.3 mg, 58% yield). Physical and spectral data were in
accordance with literature data [8a].
To a one-dram vial equipped with a magnetic stir bar in a
glove box under argon atmosphere was added Ni(cod)2 (3.4 mg,
10 mol %, 0.0125 mmol), xantphos (7.2 mg, 10 mol %, 0.0125
mmol), Mn (20.6 mg, 3 equiv, 0.375 mmol), 1,2,2,6,6-
pentamethylpiperidine (67.9 µL, 3 equiv, 0.375 mmol), primary
or secondary bromide or chloride (0.125 mmol, 1 equiv) and
dissolved in sulfolane (1.046 g, 0.15 M). The reaction vial was
removed from the glove box and heated to 130 °C, stirring for 8-
24 hours. The reaction was allowed to cool to ambient
temperature, was diluted with Et2O, and was quenched with 1 M
HCl solution. The organic layer was washed twice with H2O,
dried over a MgSO4, filtered, concentrated under reduced
pressure. The crude product was purified by flash
chromatography or preparatory TLC using ethyl acetate and
hexanes as the eluent. Any modifications to procedures are noted
in Table 2.
4-methyl-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline
(12) was synthesized according to C-H alkylation procedure A
using secondary bromide 11 (38.3 mg, 0.125 mmol). The crude
product was purified by flash column chromatography using 10%
ethyl acetate in hexanes to provide 12 as a light orange solid
(14.1 mg, 50% yield). Physical and spectral data were in
accordance with literature data [8a].
4-methyl-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline
(12) was synthesized according to C-H alkylation procedure A
using secondary chloride 13 (32.7 mg, 0.125 mmol). The crude
product was purified by flash column chromatography using 10%
ethyl acetate in hexanes to provide 12 as a light orange solid
(16.3 mg, 58% yield). Physical and spectral data were in
accordance with literature data [8a].
C-H alkylation procedure B:
To a one-dram vial equipped with a magnetic stir bar in a
glove box under argon atmosphere was added Ni(cod)2 (1.7 mg, 5
mol %, 0.00625 mmol), xantphos (3.6 mg, 5 mol %, 0.00625
mmol), Mn (20.6 mg, 3 equiv, 0.375 mmol), triethylamine (52.3
µL, 3 equiv, 0.375 mmol), primary bromide (0.125 mmol, 1
equiv) and dissolved in DMSO (0.83 mL, 0.15 M). The reaction
vial was removed from the glove box and heated to 60 °C,
stirring for 8-24 hours. The reaction was allowed to cool to
ambient temperature, was diluted with Et2O, and was quenched
with 1 M HCl solution. The organic layer was washed twice with
H2O, dried over a MgSO4, filtered, concentrated under reduced
pressure. The crude product was purified by flash
chromatography or preparatory TLC using ethyl acetate and
hexanes as the eluent.
1-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole (15) was
synthesized according to C-H alkylation procedure A using
secondary bromide 14 (31.5 mg, 0.125 mmol). The crude product
was purified by preparatory TLC using 2.5% ethyl acetate in
hexanes to provide 15 as a pale-yellow oil (12.0 mg, 56% yield).
Physical and spectral data were in accordance with literature data
[13].
6,7,8,9-tetrahydropyrido[1,2-a]indole (17) was synthesized
according to C-H alkylation procedure A using primary bromide
16 (31.5 mg, 0.125 mmol). The crude product was purified by
preparatory TLC using 2.5% ethyl acetate in hexanes to provide
17 as a pale-yellow oil (10.1 mg, 47% yield). Physical and
spectral data were in accordance with literature data [14].
3-methyl-1-(methylsulfonyl)indoline (2) was synthesized
using Ni(cod)2 (1.7 mg, 5 mol %, 0.00625 mmol) and xantphos
(3.6 mg, 5 mol %, 0.00625 mmol) according to C-H alkylation
procedure A using secondary bromide 1 (36.5 mg, 0.125 mmol).
The crude product was purified by flash column chromatography
using 10% ethyl acetate in hexanes to provide 2 as a light orange
solid (16.1 mg, 61% yield). Physical and spectral data were in
accordance with literature data [8a].
9-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indole (19) was
synthesized according to C-H alkylation procedure A using
secondary bromide 18 (33.3 mg, 0.125 mmol). The crude product
was purified by preparatory TLC using 2.5% ethyl acetate in
hexanes to provide 19 as a pale-yellow oil (16.4 mg, 71% yield).
Physical and spectral data were in accordance with literature data
[13].
3-methyl-1-(methylsulfonyl)indoline (2) was synthesized
according to C-H alkylation procedure A using secondary
chloride 2 (30.9 mg, 0.125 mmol) was heated to 150 °C. The
crude product was purified by flash column chromatography
using 10% ethyl acetate in hexanes to provide 2 as a light orange
solid (11.9 mg, 45% yield). Physical and spectral data were in
accordance with literature data [8a].
Diethyl
3,4-dihydronaphthalene-2,2(1H)-dicarboxylate
(21) was synthesized according to C-H alkylation procedure B
using primary bromide 20 (44.7 mg, 0.125 mmol). The crude
product was purified by flash column chromatography using 5%
ethyl acetate in hexanes to provide 21 as a colorless oil (27.6 mg,
80% yield). Physical and spectral data were in accordance with
literature data [8a].
1-(3-methyl-1-(methylsulfonyl)indolin-5-yl)ethan-1-one (5)
was synthesized according to C-H alkylation procedure A using
secondary bromide 4 (41.8 mg, 0.125 mmol). The crude product
was purified by flash column chromatography using 10% ethyl
acetate in hexanes to provide 5 as a light orange solid (16.5 mg,
52% yield). Physical and spectral data were in accordance with
literature data [8a].
Diethyl
3,4-dihydronaphthalene-2,2(1H)-dicarboxylate
(21) was synthesized according to C-H alkylation procedure A
using primary chloride 22 (39.1 mg, 0.125 mmol) in tert-
butylbenzene (0.83 mL, 0.15 M). The crude product was purified
by flash column chromatography using 5% ethyl acetate in
hexanes to provide 18 as a colorless oil (17.6 mg, 51% yield).

7
Physical and spectral data were in accordance with literature data
[8a].
Supplementary data to this article can be found online at
ACCEPTED MANUSCRIPT
References and notes
Diethyl
6-chloro-3,4-dihydronaphthalene-2,2(1H)-
dicarboxylate (24) was synthesized according to C-H alkylation
procedure B using primary bromide 23 (49.0 mg, 0.125 mmol).
The crude product was purified by flash column chromatography
using 5% ethyl acetate in hexanes to provide 24 as a colorless oil
(26.0 mg, 67% yield). Physical and spectral data were in
accordance with literature data [8a].
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Diethyl
6-(trifluoromethyl)-3,4-dihydronaphthalene-
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alkylation procedure B using primary bromide 25 (53.2 mg,
0.125 mmol). The crude product was purified by flash column
chromatography using 5% ethyl acetate in hexanes to provide 26
as a colorless oil (27.1 mg, 63% yield). Physical and spectral data
were in accordance with literature data [8a].
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6-methoxy-3,4-dihydronaphthalene-2,2(1H)-
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procedure B using primary bromide 24 (48.4 mg, 0.125 mmol).
The crude product was purified by flash column chromatography
using 5% ethyl acetate in hexanes to provide 28 as a colorless oil
(27.6 mg, 80% yield). Physical and spectral data were in
accordance with literature data [8a].
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Mixture of diethyl 8-methyl-3,4-dihydronaphthalene-
2,2(1H)-dicarboxylate
and
diethyl
5-methyl-3,4-
dihydronaphthalene-2,2(1H)-dicarboxylate (30 and 31) was
synthesized according to C-H alkylation procedure B using
primary bromide 26 (46.4 mg, 0.125 mmol). The crude product
was purified by flash column chromatography using 5% ethyl
acetate in hexanes to provide a 4:1 ratio of 30 and 31 as a
colorless oil (25.0 mg, 69% yield). Physical and spectral data
were in accordance with literature data [8a].
[6]
[7]
4.3 Stereochemical experiments
(S)-N-(2-hydroxypropyl)-N-phenylmethanesulfonamide
((S)-SI-2) was prepared according to a literature procedure, and
spectral data were in accordance with the literature values [8a].
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(R)-N-(2-bromopropyl)-N-phenylmethanesulfonamide
((R)-1). Secondary alcohol (S)-SI-2 (1.5 g, 1 equiv, 6.5 mmol)
was brominated with 2,6-lutidine (0.18 g, 0.19 mL, 0.25 equiv,
1.6 mmol), triphenylphosphine (2.1 g, 1.2 equiv, 8.2 mmol), and
tetrabromomethane (2.6 g, 1.2 equiv, 7.9 mmol) in THF (20 mL,
0.3 M) following General Procedure B. The crude product was
purified by flash chromatography using 20% ethyl acetate in
hexanes to provide secondary bromide SI-5 as a white solid
(0.693 g, 36% yield).
[8]
(R)-N-(2-bromopropyl)-N-phenylmethanesulfonamide ((R)-1)
was subjected to Ni(cod)2 (1.7 mg, 5 mol %, 0.00625 mmol) and
xantphos (3.6 mg, 5 mol %, 0.00625 mmol) following C-H
alkylation procedure A and was stopped after 2 hours. The crude
reaction mixture was purified by flash chromatography using
10% ethyl acetates in hexanes to provide the product 2 and
unreacted starting material. The enantiomeric excess of 2 was
determined to be 0% and the recovered starting material (R)-1
was determined to have racemized by chiral HPLC analysis using
99:1 hexanes:isopropanol mobile phase and column IF [15].
[9]
Acknowledgments
Financial support was provided by Award R01 GM 107204 from
the National Institute of General Medical Sciences.
(f) Z. Ruan, S. Lackner, L. Ackermann, Angew. Chem. Int. Ed. 55
(2016) 3153–3157;
Appendix A. Supplementary data

8
Tetrahedron
ACCEPTED MANUSCRIPT
(g) O. Vechorkin, V. Proust, X. Hu, Angew. Chem. Int. Ed. 49
(2010) 3061–3064;
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[10] Reaction using NiBr2•glyme as the precatalyst and Schlenk technique
instead of a glovebox resulted in a slightly decreased yield (48%).
[11] See the Supporting Information for proposed mechanism for
formation of rearrangement product 31 via alkyl shift prior to
rearomatization.
[12] S.J. Kaldas, A. Cannillo, T. McCallum, L. Barriault, Org. Lett. 17
(2015) 2864–2866.
[13] A.P. Dobbs, K. Jones, K.T. Veal, Tetrahedron 54 (1998) 2149–2160.
[14] M. Ishikura, W. Ida, K. Yanada, Tetrahedron 62 (2006) 1015–1024
[15] See the Supporting Information for additional details on
stereochemical experiments.