Nickel-mediated synthesis of isoindolinones at room temperature

Article abstract of DOI:10.1055/s-0034-1378555

This communication describes a method for the Ni(cod)₂-mediated intramolecular arylation of alkyl C-H bonds adjacent to the nitrogen atom in benzamide substrates. The transformation proceeds at room temperature and exhibits selectivity for func

Full text of DOI:10.1055/s-0034-1378555

PAPER
▌3033
paper
Nickel-Mediated Synthesis of Isoindolinones at Room Temperature
Nickel-Mediated Synthesis of Isoindolinones
William C. Wertjes, Peter J. Waller, Kyle E. Shelton, Dipannita Kalyani*
St. Olaf College, Department of Chemistry, 1520 St. Olaf Ave., Northfield, MN 55057, USA
E-mail: kalyani@stolaf.edu
Received: 15.05.2014; Accepted after revision: 09.07.2014
This article was invited by Erick M. Carreira.
Recently, we published an example of nickel-mediated
synthesis of isoindolinones through intramolecular cou-
pling of an aryl halide with a C(sp3)−H bond (Scheme 2,
a).7,8 Despite the efficiency of these arylations mediated
Abstract: This communication describes
a method for the
Ni(cod)2-mediated intramolecular arylation of alkyl C−H bonds ad-
jacent to the nitrogen atom in benzamide substrates. The transfor-
mation proceeds at room temperature and exhibits selectivity for
functionalization of more substituted C−H bonds. The yields of the by bis(1,5-cyclooctadiene)nickel(0) [Ni(cod)2], their syn-
desired isoindolinone products are higher with benzamide sub-
strates containing tertiary alkyl groups on the nitrogen atom than
with those bearing primary or secondary alkyls. The results de-
made efforts to address this drawback and have identified
scribed herein suggest a mechanism involving radical intermediates
for these reactions.
thetic applicability is limited by the requirement for high
temperatures (145 °C). Since our initial report, we have
conditions that allow the analogous nickel-mediated syn-
thesis of isoindolinones to take place at room temperature.
Herein, we detail the scope and limitations of these trans-
Key words: amides, arylation, intramolecular, nickel, halides
formations (Scheme 2, b). To our knowledge, these reac-
tions represent the first example of nickel-mediated
Palladium-catalyzed direct arylation of both sp2 and sp3
C−H bonds has emerged as a powerful strategy for the
construction of C−C bonds.1,2 Recently, however, there
has been an increasing demand to replace precious-metal
catalysts with earth-abundant metals.3 The development
of nickel-catalyzed C−H arylations, analogous to known
Pd-catalyzed transformations, has the potential to signifi-
cantly enhance the economic viability and synthetic appli-
cability of C−H arylation protocols. In light of this
advantage, a number of research groups have described
the nickel-catalyzed arylation of C(sp2)-H bonds.3,4 In
contrast, examples of nickel-catalyzed arylation of alkyl
C−H bonds are rare: Liu et al. achieved the nickel-cata-
lyzed oxidative arylation of alkyl C−H bonds by using ar-
ylboronic acids (Scheme 1, a)5 and the groups of Chatani
and You have reported the intermolecular ligand-directed
arylation of sp3 C−H bonds using aryl halides (halide = I,
Br) (Scheme 1, b).6
arylation of sp3 C−H bonds using aryl halides at ambient
temperatures.
(a)
Br
O
Me
O
Me
Me
Ni(cod)2 (0.1 equiv)
NaOt-Bu, dioxane
N
Me
Me
N
145 °C
[ref. 7]
Me
1-Br
O
Me
Me
Me
Me
1a, 76%
Br
O
Me
Me
(b)
N
N
[Ni]
room temperature
[this work]
Me
Me
Me
Me
Scheme 2 Our previous results and proposed work
Our investigations toward establishing more moderate
conditions for nickel-mediated isoindolinone synthesis
began with a detailed screen of solvents, bases, and nickel
sources for the reaction of benzamide 1-Br at room tem-
perature (Table 1). As shown in Table 1, the use of
Ni(cod)2 in conjunction with sodium tert-butoxide afford-
ed 1a in a number of solvents at room temperature, albeit
in low yields (entries 1–5). Interestingly, however, simple
replacement of sodium tert-butoxide with potassium tert-
butoxide enabled excellent yields of 1a to be obtained af-
ter the same period of time (entry 6). Similar cation effects
have been observed for C(aryl)−H coupling with aryl ha-
lides.9 Dioxane and tetrahydrofuran performed equally
well as solvents for the arylation using potassium tert-bu-
toxide as the base (entries 6 and 7). Importantly, no reac-
tion was observed in the absence of a nickel source.
However, a number of nickel(II) salts also induced forma-
tion of 1a, albeit in low yields (entries 9–12). The addition
of triphenylphosphine as a potential reductant for nick-
(a)
ArB(OH)2
O
O
Ni catalysis
[ref. 5]
(b)
H
Ar
O
Ar-I
Ni catalysis
O
Ph
Ph
Ph
Ph
N
N
H
H
[ref. 6]
N
N
Ar
H
Scheme 1 Previous reports of nickel-catalyzed sp3 C−H bond aryla-
tion
SYNTHESIS 2014, 46, 3033–3040
Advanced online publication: 21.08.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0034-1378555; Art ID: ss-2014-c0299-op
© Georg Thieme Verlag Stuttgart · New York

3034
W. C. Wertjes et al.
PAPER
Table 1 Optimization of Room-Temperature Arylationsa
Table 3 depicts the site-selectivities observed for the intra-
molecular arylation reaction using substrates that can lead
to isomeric products. The site-selectivity for the reaction
of 6-Br, 6-I, and 7-Br exemplifies the preference for ary-
lation of more substituted sp3 C−H bonds. The reaction is
more efficient with substrates containing tertiary alkyls on
the N atom than those bearing primary or secondary alkyls
(entries 1–3 versus 4–7). Interestingly, this selectivity is
orthogonal to that documented for palladium-catalyzed
arylations.10 For example, whereas the nickel-mediated
reaction of 6-Br affords 6a as the major product, isomer
6b is the observed product under palladium catalysis. Fur-
thermore, benzamides containing two different tertiary N-
alkyl groups (8-Br and 9-Br) afforded an approximately
1:1 mixture of isomeric isoindolinones (entries 4 and 5).
Finally, use of meta-substituted amide substrates 10-Cl
and 11-Br led to a ca. 1:1.5 mixture of isomeric products
(entries 6 and 7).
Br
O
Me
Me
O
Me
Me
[Ni] (0.1 equiv)
base, solvent
N
Me
N
room temperature
Me
Me
Me
1-Br
1a
Entry [Ni]
Base
Solvent
Yield of 1a
(%)b
1
2
Ni(cod)2
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
dioxane
THF
20
5
Ni(cod)2
3
Ni(cod)2
xylene
DMF
NMP
dioxane
THF
8
4
Ni(cod)2
27
33
99c
100
0
5
Ni(cod)2
6
Ni(cod)2
7
Ni(cod)2
Table 2 Scope of Intramolecular Arylations
8
none
THF
Entry Substrate
Product
Yielda,b
9
Ni(OAc)2
NiCl2(PCy3)2
Ni(acac)2
NiBr2·DMEd
Ni(OAc)2
NiBr2·DMEd
THF
24
22
25
24
27c
29c
X
O
10
11
12
13e
14e
THF
O
i-Pr
N
i-Pr
Me
THF
X = Br, 96%
X = Cl, 94%
X = I, 96%
N
i-Pr
1
THF
Me
1-Br X = Br
1-Cl X = Cl
1-I X = I
THF
1a
THF
X
O
O
a Reaction conditions: Ni(cod)2 (0.1 equiv), base (1.5 equiv), solvent,
r.t., 21 h.
i-Pr
i-Pr
N
N
X = Br, 92%
X = Cl, 83%
b 1H NMR yields against 1,4-dinitrobenzene as the internal standard
unless otherwise noted.
2
3
4
5
i-Pr
Me
MeO
Me
MeO
c Calibrated GC yields against hexadecane as the internal standard.
d DME = 1,2-Dimethoxyethane
2-Br X = Br
2-Cl X = Cl
2a
e General conditions, but with Ph3P (0.2 equiv).
O
Br
O
i-Pr
N
i-Pr
N
el(II) did not significantly affect the observed yield of 1a
under these conditions (cf. entries 9, 12 with 13 and 14).
As such, conditions employing Ni(cod)2 in conjunction
with potassium tert-butoxide in tetrahydrofuran were
identified as optimal for the formation of the desired iso-
indolinone.
99%
Me
Me
i-Pr
Me
Me
3-Br
3a
X
O
O
i-Pr
i-Pr
Me
N
N
X = Br, 51%
X = Cl, 74%
We next investigated the generality of this reaction with
respect to electronically varied benzamide substrates. As
shown in Table 2, the chloride (1-Cl) and iodide (1-I) an-
alogues of 1-Br could also be used to form 1a in excellent
yields (entry 1). Additionally, aryl rings bearing electron-
donating (entry 2) or electron-withdrawing substituents
(entry 4) underwent the desired transformation to provide
isoindolinone products in modest to excellent yields. The
moderate yield of product 4a is partly attributed to a com-
peting SNAr reaction to yield products (detected by
GC/MS analysis of the crude reaction mixtures) in which
F is substituted by the tert-butoxide anion.
i-Pr
F
Me
F
4-Br X = Br
4-Cl X = Cl
4a
O
Br
O
Cy
N
Cy
N
96%
Cy
5-Br
5a
a Reaction conditions: Ni(cod)2 (0.1 equiv), t-BuOK (1.5 equiv), THF,
r.t.
b Isolated yield.
Synthesis 2014, 46, 3033–3040
© Georg Thieme Verlag Stuttgart · New York

PAPER
Nickel-Mediated Synthesis of Isoindolinones
3035
The yield and site-selectivities of the room-temperature nism consistent with the observed reactivity and selectiv-
arylation shown in Tables 2 and 3 are comparable to those ity of this system is depicted in Scheme 3. It involves: (i)
that we previously reported using the Ni(cod)2/sodium single electron transfer from a Ni(0) complex to the sub-
tert-butoxide conditions at 145 °C.7 A plausible mecha- strate A to generate the radical anion B,11 (ii) loss of Br–
Table 3 Site-Selectivity of Intramolecular Arylation Reactionsa
Entry
Substrate
Product
Yield (%)b
45 (1:0)c
O
O
Br
O
Me
N
N
N
Me
Cy
1d
N
N
Cy
6-Br
6a
6b
O
O
I
O
O
Me
Cy
Me
2d
3d
4
52 (1:0)c
60e (4:1)f
84 (1.1:1)c
N
N
Cy
6-I
6a
7a
6b
7b
O
O
Br
Et
i-Pr
i-Pr
N
Me
N
Me
Et
Me
7-Br
O
O
Br
O
i-Pr
N
Cy
N
i-Pr
N
Me
Me
Cy
8-Br
8a
8b
O
O
Br
O
i-Pr
Cy
N
N
i-Pr
5
6
91 (1.2:1)c
N
Me
Me
Cy
F
F
F
9-Br
9a
9b
O
Cl
O
O
i-Pr
i-Pr
N
N
i-Pr
N
92 (1:1.6)c
Me
i-Pr
Me
Me
Me
Me
Me
Me
10-Cl
10a
10b
11b
O
Br
O
O
i-Pr
i-Pr
N
N
i-Pr
N
7d
53 (1:1.5)c
i-Pr
F3C
Me
Me
Me
Me
CF3
CF3
11-Br
11a
a Reaction conditions: Ni(cod)2 (0.1 equiv), t-BuOK (1.5 equiv), THF, r.t.
b Isolated yield.
c Selectivity determined by 1H NMR spectroscopic analysis of the crude reaction mixture.
d General conditions but with Ni(cod)2 (0.2 equiv).
e Reported yield of the major isomer only.
f Selectivity determined by GC/MS analysis of the crude reaction mixture.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3033–3040

3036
W. C. Wertjes et al.
PAPER
O
Br
O
Br
R
O
(i)
i-Pr
+ LnNi0
i-Pr
i-Pr
(ii)
N
N
N
H
Me
H
Me
H
Me
– Br–
– LnNiI
Me
Me
Me
A
B
C
R
R
(iii)
O
O
O
i-Pr
Me
i-Pr
N
N
(v)
R
R
O
+ t-BuO–
+ A
Me
Me
i-Pr
H
O
(iv)
Me
N
G
E
F
+
+
– t-BuOH
– B
Me
Me
i-Pr
Me
i-Pr
Me
N
N
R
D
H
Me
Me
H
R
R
Scheme 3 Proposed mechanism
to afford aryl radical C, (iii) intramolecular H-atom ab- The comparable selectivities of these room-temperature
straction to give D, (iv) radical addition to the arene to af- arylations to those obtained in the previously reported
ford isomeric intermediates E and F, and, finally (v) Ni(cod)2/sodium tert-butoxide system at 145 °C suggest
rearomatization to release the product and regenerate B. similar mechanistic pathways for the two transformations.
Importantly, this mechanism is similar to those proposed
for potassium tert-butoxide mediated coupling of aromat-
NMR spectra were obtained with a Bruker 400 (399.96 MHz for 1H;
100.57 MHz for 13C) spectrometer. 1H NMR chemical shifts are re-
ported in parts per million (ppm) relative to TMS, with the residual
solvent peak used as internal reference. Multiplicities are reported
as: singlet (s), doublet (d), doublet of doublets (dd), triplet of dou-
blets (td), triplet (t), multiplet (m), or septet (sept). IR spectra were
obtained with a Thermo scientific Nicolet iS5 iD5 ATR spectropho-
tometer. Melting points were obtained with a Thomas Hoover melt-
ing point apparatus.
ic C−H bonds with aryl halides.12–15
The pathway depicted in Scheme 3 is consistent with a
number of observations. First, the diminished yield of the
desired products in the presence of a radical scavenger
(Scheme 4) implicates the possible involvement of radical
intermediates. Second, the preferential functionalization
of more substituted tertiary C−H bonds is in agreement
with the proposed intermediacy of alkyl radical species
such as D (Scheme 3). Finally, the negligible site-selectiv-
ity observed with meta-substituted benzamide substrates
is consistent with a fast, unselective radical reaction as de-
picted in step (iv).
Anhydrous t-BuONa, t-BuOK, 2-chlorobenzoyl chloride, anhy-
drous diisopropylamine, dicyclohexylamine, diisopropylethyl
amine, N-ethyl-N-isopropyl amine, galvinoxyl free radical, thionyl
chloride (SOCl2), and anhydrous Et3N were obtained from Aldrich
and used as received. Ni(cod)2 was obtained from Strem chemicals
and used as received. 2-Bromo-4-fluorobenzoyl chloride and 2-bro-
mo-5-trifluoromethylbenzoic acid were obtained from Matrix Sci-
entific and used as received. 2-Bromobenzoyl chloride was
obtained from TCI America and used as received. Substrates 1-Br,7
1-Cl,7 1-I,14 2-Br,7 2-Cl,7 3-Br,7 4-Br,7 4-Cl,7 5-Br,7 6-Br,7 6-I,16 and
10-Cl,7 were prepared by following reported procedures. Anhy-
drous xylene and anhydrous dioxane was obtained from Aldrich and
used as received. Anhydrous CH2Cl2, anhydrous THF, and anhy-
drous Et2O were purified by using a Glass Contour solvent purifica-
tion system column composed of neutral alumina. Toluene was
purified by using a Glass Contour solvent purification system col-
umn composed of neutral alumina and a copper catalyst. DMF was
purified with a Glass Contour solvent purification system by pass-
ing through a column packed with molecular sieves. Other solvents
were obtained from Fisher Chemical or VWR Chemical and used
without further purification. Flash chromatography was performed
on EM Science silica gel 60 (0.040–0.063 mm particle size, 230–
400 mesh) and thin-layer chromatography was performed with An-
Br
O
Me
O
Me
Me
Ni(cod)2 (0.1 equiv)
additive
N
Me
N
KOt-Bu, THF
Me
Me
Me
Me
r.t.
1-Br
1a
additive
GC yield of 1a
galvinoxyl (0.5 equiv) 10%
galvinoxyl (1.0 equiv) 0%
Scheme 4 Effect of radical scavengers
This communication describes a method for the nickel-
mediated room-temperature intramolecular arylation of
sp3 C−H bonds adjacent to amide nitrogen atoms by using
aryl halides (halide = Cl, Br, I). These arylation reactions
afford electronically and sterically diverse isoindolinone
products in good to excellent yields. In general, the yields
of the desired arylated products are higher with substrates
bearing electron-rich and electron-neutral aryl rings, and
the reactions display selectivity for the functionalization
of tertiary over primary and secondary alkyl C−H bonds.
altech TLC plates pre-coated with silica gel 60 F254
.
2-Bromo-N-ethyl-N-isopropylbenzamide (7-Br)
To a 100 mL Schlenk flask containing a solution of N-ethyl-N-iso-
propylamine (0.597 g, 6.85 mmol, 1.50 equiv), in anhydrous Et2O
(22 mL) was added diisopropylethylamine (DIPEA; 0.89 g, 6.85
mmol, 1.50 equiv) under a N2 atmosphere. The reaction mixture
was cooled to 0 °C using an ice bath and 2-bromobenzoyl chloride
Synthesis 2014, 46, 3033–3040
© Georg Thieme Verlag Stuttgart · New York

PAPER
Nickel-Mediated Synthesis of Isoindolinones
3037
(1.00 g, 4.56 mmol, 1.00 equiv) was added dropwise. The resulting
mixture was stirred at r.t. for 1 h, then transferred to a separatory
funnel using EtOAc (20 mL) and washed with sat. aq NaCl (3 × 30
mL). The organic layer was dried over MgSO4, concentrated, and
purified by chromatography on a silica gel column (hexanes–
EtOAc, 70:30) to afford product 7-Br.
1H NMR (400 MHz, CDCl3): δ = 7.30 (dd, J = 8.3, 2.3 Hz, 0.5 H),
7.29 (dd, J = 8.3, 2.3 Hz, 0.5 H), 7.143 (dd, J = 8.8, 5.8 Hz, 0.5 H),
7.136 (dd, J = 8.5, 5.5 Hz, 0.5 H), 7.03 (td, J = 8.3, 2.5 Hz, 1 H),
3.62–3.49 (m, 1 H), 3.08–2.97 (m, 1 H), 2.70–2.59 (m, 1 H), 1.98–
0.91 (m, 15 H).
13C NMR (100 MHz, CDCl3): δ = 167.6, 167.5, 161.7 (JC–F
=
Yield: 595 mg (48% yield); white solid; mp 96–97 °C; Rf = 0.40
(hexanes–EtOAc, 70:30).
250 Hz), 136.6, 136.5, 127.6 (JC–F = 8.6 Hz), 120.14 (JC–F = 23 Hz),
119.3 (JC–F = 9.5 Hz), 114.9 (JC–F = 21 Hz), 114.8 (JC–F = 21 Hz),
60.1, 55.0, 51.3, 47.2, 31.2, 31.0, 29.9, 29.4, 26.6, 26.5, 25.63,
25.58, 25.2, 25.1, 20.8, 20.6, 20.5, 20.1.
HRMS: m/z [M + Na]+ calcd for C16H21BrNO: 364.0683; found:
364.0680.
IR (neat film): 2972, 1622, 1587, 1444, 1420, 1341, 1316, 1216,
1103, 1023, 775, 753, 615 cm–1.
1H NMR (400 MHz, CDCl3): δ (mixture of rotamers) = 7.55 (t, J =
7.0 Hz, 1 H), 7.35–7.31 (m, 1 H), 7.27–7.19 (m, 2 H), 4.77 (sept,
J = 6.8 Hz, 0.3 H), 3.69–3.53 (m, 1.4 H), 3.35–3.27 (m, 0.7 H),
3.18–3.02 (m, 0.6 H), 1.32 (t, J = 7.1 Hz, 2 H), 1.30 (d, J = 6.9 Hz,
2 H), 1.24 (d, J = 6.7 Hz, 2 H), 1.06 (d, J = 6.7 Hz, 2 H), 1.00 (t, J =
7.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ (mixture of rotamers) = 168.9,
168.2, 139.3, 139.2, 132.8, 132.7, 129.7, 127.7, 127.5, 127.4, 119.1,
50.3, 46.0, 39.0, 35.3, 21.2, 21.1, 20.6, 20.1, 16.2, 14.4.
2-Bromo-N,N-diisopropyl-5-(trifluoromethyl)benzamide (11-
Br)
To a 20 mL scintillation vial containing a magnetic stirbar and a
solution of 2-bromo-5-trifluoromethyl benzoic acid (613 mg, 2.28
mmol, 1.00 equiv) in anhydrous toluene (8.0 mL) were added anhy-
drous DMF (2 drops) and SOCl2 (0.33 g, 2.77 mmol, 1.22 equiv).
The vial was sealed with a Teflon-lined cap and the reaction mixture
was stirred at 80 °C for 2.5 h and then cooled to r.t. to afford a solu-
tion of the intermediate 2-bromo-5-trifluoromethylbenzoyl chlo-
ride. Two such reactions were conducted and the solution of the 2-
bromo-5-trifluoromethylbenzoyl chloride obtained from each reac-
tion was combined for the next step.
HRMS: m/z [M + Na]+ calcd for C12H16BrNO: 292.0307; found:
292.0302.
2-Bromo-N-cyclohexyl-N-isopropylbenzamide (8-Br)
To a 100 mL Schlenk flask containing a solution of N-cyclohexyl-
N-isopropylamine (0.97 g, 6.85 mmol, 1.50 equiv), in anhydrous
Et2O (22 mL) was added DIPEA (0.885 g, 6.85 mmol, 1.50 equiv)
under a N2 atmosphere. The reaction mixture was cooled to 0 °C us-
ing an ice bath and 2-bromobenzoyl chloride (1.00 g, 4.56 mmol,
1.00 equiv) was added dropwise. The resulting mixture was stirred
at r.t. for 1 h, then transferred to a separatory funnel using EtOAc
(20 mL) and washed with sat. aq NaCl solution (3 × 30 mL). The or-
ganic layer was dried over MgSO4, concentrated, and purified by
chromatography on a silica gel column (hexanes–EtOAc, 80:20) to
afford 8-Br.
To a 100 mL Schlenk flask containing a solution of N,N-diisopro-
pylamine (693 mg, 6.85 mmol, 1.50 equiv), in anhydrous CH2Cl2
(23 mL) was added Et3N (1.39 g, 13.7 mmol, 3.00 equiv) under a N2
atmosphere. The reaction mixture was cooled to 0 °C using an ice
bath and the solution of the 2-bromo-5-trifluoromethylbenzoyl
chloride obtained in the first step was added dropwise. The resulting
mixture was stirred at r.t. for 16 h, then transferred to a separatory
funnel and extracted with H2O (3 × 30 mL). The organic layer was
dried over MgSO4, concentrated, and purified by chromatography
on a silica gel column (hexanes–EtOAc, 80:20) to afford product
11-Br.
Yield: 1.44 g (97%); white solid; mp 74–76 °C; Rf = 0.34 (hexanes–
EtOAc, 80:20).
Yield: 582 mg (36%); white solid; mp 114–116 °C; Rf = 0.58
(hexanes–EtOAc, 80:20).
IR (neat): 2924, 1624, 1589, 1451, 1436, 1370, 1346, 1325, 992,
764, 749, 737, 693, 647 cm–1.
1H NMR (400 MHz, CDCl3): δ (mixture of rotamers) = 7.55 (d, J =
8.0 Hz, 1 H), 7.33–7.29 (m, 1 H), 7.21–7.14 (m, 2 H), 3.65–3.50
(m, 1 H), 3.11–2.99 (m, 1 H), 2.76–2.62 (m, 1 H), 2.01–0.90 (m,
15 H).
13C NMR (100 MHz, CDCl3): δ (mixture of rotamers) = 168.4,
168.2, 140.3, 140.1, 132.82, 132.76, 129.4, 129.3, 127.5, 127.4,
126.50, 126.46, 118.9, 60.0, 54.9, 51.2, 47.2, 31.2, 31.0, 29.9, 29.4,
26.7, 26.5, 25.7, 25.6, 25.3, 25.1, 20.8, 20.6, 20.1.
IR (neat): 2977, 1631, 1372, 1344, 1313, 1257, 1172, 1126, 1107,
1076, 1043, 1025, 904, 845, 795, 612 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 8.3 Hz, 1 H), 7.45 (dd,
J = 8.5, 2.2 Hz, 1 H), 7.42 (d, J = 2.2, Hz, 1 H), 3.55 (sept, J =
6.9 Hz, 1 H), 3.53 (sept, J = 6.7 Hz, 1 H), 1.58 (d, J = 6.8 Hz, 3 H),
1.57 (d, J = 6.8 Hz, 3 H), 1.25 (d, J = 6.6 Hz, 3 H), 1.09 (d, J =
6.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.7, 140.8, 133.6, 130.2 (JC–F
33 Hz), 126.2 (JC–F = 3.6 Hz), 123.45 (JC–F = 271 Hz), 123.5 (JC–F
3.6 Hz), 123.0, 51.4, 46.2, 20.7, 20.64, 20.56, 20.0.
=
=
HRMS: m/z [M + Na]+ calcd for C16H22BrNO: 346.0777; found:
346.0787.
HRMS: m/z [M + H]+ calcd for C14H17BrF3NO: 352.0518; found:
352.0523.
2-Bromo-N-cyclohexyl-4-fluoro-N-isopropylbenzamide (9-Br)
To a 100 mL Schlenk flask containing a solution of N-cyclohexyl-
N-isopropylamine (0.44 g, 3.12 mmol, 1.49 equiv), in anhydrous
Et2O (11 mL) was added DIPEA (0.41 g, 3.17 mmol, 1.51 equiv)
under a N2 atmosphere. The reaction mixture was cooled to 0 °C us-
ing an ice bath and 2-bromo-4-fluorobenzoyl chloride (0.5 g, 2.10
mmol, 1.0 equiv) was added dropwise. The resulting mixture was
stirred at r.t. for 1 h, then transferred to a separatory funnel using
EtOAc (20 mL) and extracted with sat. aq NaCl solution (3 × 30
mL). The organic layer was dried over MgSO4, concentrated, and
purified by chromatography on a silica gel column (hexanes–
EtOAc, 80:20) to afford product 9-Br.
C−H Arylation; General Procedure
To an oven-dried 20 mL scintillation vial containing a magnetic stir
bar and substrate, was added Ni(cod)2, t-BuOK, and anhydrous
THF in a glove box. The vial was sealed with a Teflon-lined cap,
taken out of the glove box, and the reaction mixture was stirred at
r.t. for the indicated time. The reaction mixture was filtered through
a 3.8 cm plug of silica gel, eluting with EtOAc (100 mL). The fil-
trate was concentrated and purified by chromatography on a silica
gel column to afford the product.
2-Isopropyl-3,3-dimethylisoindolin-1-one (1a)
From 1-Br: Following the general procedure, 1-Br (142 mg, 0.500
mmol, 1.00 equiv), Ni(cod)2 (13.8 mg, 0.05 mmol, 0.10 equiv),
t-BuOK (84.2 mg, 0.750 mmol, 1.50 equiv), and anhydrous THF
(2.00 mL) were combined in a 20 mL scintillation vial. The reaction
Yield: 562 mg (78%); light-yellow solid; mp 90–91 °C; Rf = 0.43
(hexanes–EtOAc, 80:20)
IR (neat): 2915, 1622, 1595, 1441, 1371, 1355, 1345, 1326, 1260,
1193, 1127, 892, 879, 869, 815, 584 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3033–3040

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W. C. Wertjes et al.
PAPER
mixture was stirred at r.t. for 13 h. Chromatography on a silica gel
Yield: 56.6 mg (51%); white solid.
column (hexanes–EtOAc, 70:30) gave 1a.
1H NMR (400 MHz, CDCl3): δ = 7.72 (dd, J = 8.3, 5.1 Hz, 1 H),
7.07 (td, J = 8.4, 2.1 Hz, 1 H), 7.00 (dd, J = 8.2, 2.2 Hz, 1 H), 3.61
(sept, J = 6.9 Hz, 1 H), 1.53 (d, J = 6.8 Hz, 6 H), 1.46 (s, 6 H). The
spectroscopic data is consistent with the literature.7
Yield: 97.8 mg (96%); white solid.
1H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 7.5 Hz, 1 H), 7.45 (td,
J = 7.5, 1.2 Hz, 1 H), 7.34 (td, J = 7.5, 1.0 Hz, 1 H), 7.29 (d, J =
7.6 Hz, 1 H), 3.60 (sept, J = 6.8 Hz, 1 H), 1.51 (d, J = 6.8 Hz, 6 H),
1.42 (s, 6 H). The spectroscopic data is consistent with the litera-
ture.7
From 4-Cl: Following the general procedure, 4-Cl (129 mg, 0.500
mmol, 1.00 equiv), Ni(cod)2 (13.8 mg, 0.05 mmol, 0.10 equiv), t-
BuOK (84.2 mg, 0.750 mmol, 1.50 equiv), and anhydrous THF
(2.00 mL) were combined in a 20 mL scintillation vial. The reaction
mixture was stirred at r.t. for 15 h. Chromatography on a silica gel
column (hexanes–EtOAc, 80:20) gave 4a (82.4 mg, 74%) as a white
solid. The spectroscopic data was identical to the product isolated
from the reaction of 4-Br.
From 1-Cl: Following the general procedure, 1-Cl (120 mg, 0.500
mmol, 1.00 equiv), Ni(cod)2 (13.8 mg, 0.05 mmol, 0.10 equiv), t-
BuOK (84.2 mg, 0.750 mmol, 1.50 equiv) and anhydrous THF
(2.00 mL) were combined in a 20 mL scintillation vial. The reaction
mixture was stirred at r.t. for 21 h. Chromatography on a silica gel
column (hexanes–EtOAc, 70:30) gave 1a (95.5 mg, 94%) as a white
solid. The spectroscopic data was identical to the product isolated
from the reaction of 1-Br.
2′-Cyclohexylspiro(cyclohexane-1,1′-isoindolin)-3′-one (5a)
Following the general procedure, 5-Br (182 mg, 0.500 mmol, 1.00
equiv), Ni(cod)2 (13.8 mg, 0.05 mmol, 0.10 equiv), t-BuOK (84.2
mg, 0.750 mmol, 1.50 equiv), and anhydrous THF (2.00 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
stirred at r.t. for 20 h. Chromatography on a silica gel column (hex-
anes–EtOAc, 80:20) gave 5a.
From 1-I: Following the general procedure, 1-I (166 mg, 0.500
mmol, 1.00 equiv), Ni(cod)2 (13.8 mg, 0.05 mmol, 0.10 equiv), t-
BuOK (84.2 mg, 0.750 mmol, 1.50 equiv), and anhydrous THF
(2.00 mL) were combined in a 20 mL scintillation vial. The reaction
mixture was stirred at r.t. for 21 h. Chromatography on a silica gel
column (hexanes–EtOAc, 80:20) gave 1a (98.0 mg, 96%) as a white
solid. The spectroscopic data was identical to the product isolated
from the reaction of 1-Br.
Yield: 136.4 mg (96%); white solid.
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 7.0 Hz, 1 H), 7.71 (d,
J = 7.1 Hz, 1 H), 7.43–7.34 (m, 2 H), 3.12–3.04 (m, 1 H), 2.64–2.51
(m, 2 H), 1.94–1.21 (m, 18 H). The spectroscopic data is consistent
with the literature.7
2-Isopropyl-5-methoxy-3,3-dimethylisoindolin-1-one (2a)
From 2-Br: Following the general procedure, 2-Br (157 mg, 0.500
mmol, 1.00 equiv), Ni(cod)2 (13.8 mg, 0.05 mmol, 0.10 equiv), t-
BuOK (84.2 mg, 0.750 mmol, 1.50 equiv), and anhydrous THF
(2.00 mL) were combined in a 20 mL scintillation vial. The reaction
mixture was stirred at r.t. for 18.5 h. Chromatography on a silica gel
column (hexanes–EtOAc, 75:25) gave 2a.
2′-Methylspiro[cyclohexane-1,1′-isoindolin]-3′-one (6a)
From 6-Br: Following the general procedure, 6-Br (148 mg, 0.500
mmol, 1.00 equiv), Ni(cod)2 (27.5 mg, 0.10 mmol, 0.20 equiv), t-
BuOK (84.2 mg, 0.750 mmol, 1.50 equiv), and anhydrous THF
(2.00 mL) were combined in a 20 mL scintillation vial. The reaction
mixture was stirred at r.t. for 21 h. Chromatography on a silica gel
column (hexanes–EtOAc, 70:30) gave 6a.
Yield: 106.9 mg (92%); white solid.
1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 8.3 Hz, 1 H), 6.92 (dd,
J = 8.3, 2.2 Hz, 1 H), 6.80 (d, J = 2.2 Hz, 1 H), 3.87 (s, 3 H), 3.62
(sept, J = 6.8 Hz, 1 H), 1.54 (d, J = 6.8 Hz, 6 H), 1.45 (s, 6 H). The
spectroscopic data is consistent with the literature.7
Yield: 48.2 mg (45%); white solid.
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 7.0 Hz, 1 H), 7.76 (d,
J = 7.4 Hz, 1 H), 7.47 (td, J = 7.4, 1.5 Hz, 1 H), 7.42 (td, J = 7.4,
1.2 Hz, 1 H), 3.01 (s, 3 H), 2.01–1.82 (m, 7 H), 1.45–1.30 (m, 3 H).
The spectroscopic data is consistent with the literature.7
From 2-Cl: Following the general procedure, 2-Cl (135 mg, 0.500
mmol, 1.00 equiv), Ni(cod)2 (13.8 mg, 0.05 mmol, 0.10 equiv), t-
BuOK (84.2 mg, 0.750 mmol, 1.50 equiv), and anhydrous THF
(2.00 mL) were combined in a 20 mL scintillation vial. The reaction
mixture was stirred at r.t. for 12 h. Chromatography on a silica gel
column (hexanes–EtOAc, 80:20 to 70:30) gave 2a (97.4 mg, 83%)
as a white solid. The spectroscopic data was identical to the product
isolated from the reaction of 2-Br.
From 6-I: Following the general procedure, 6-I (172 mg, 0.500
mmol, 1.00 equiv), Ni(cod)2 (27.5 mg, 0.10 mmol, 0.20 equiv), t-
BuOK (84.2 mg, 0.750 mmol, 1.50 equiv), and anhydrous THF
(2.00 mL) were combined in a 20 mL scintillation vial. The reaction
mixture was stirred at r.t. for 21 h. Chromatography on a silica gel
column (hexanes–EtOAc, 70:30) gave 6a (56.1 mg, 52%) as a white
solid. The spectroscopic data was identical to the product isolated
from the reaction of 6-Br.
2-Isopropyl-3,3,5-trimethylisoindolin-1-one (3a)
Following the general procedure, 3-Br (149 mg, 0.500 mmol, 1.00
equiv), Ni(cod)2 (13.8 mg, 0.05 mmol, 0.10 equiv), t-BuOK (84.2
mg, 0.750 mmol, 1.50 equiv), and anhydrous THF (2.00 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
stirred at r.t. for 16 h. Chromatography on a silica gel column (hex-
anes–EtOAc, 75:25) gave 3a.
2-Ethyl-3,3-dimethylisoindolin-1-one (7a)
Following the general procedure, 7-Br (135 mg, 0.500 mmol, 1.00
equiv), Ni(cod)2 (27.5 mg, 0.10 mmol, 0.20 equiv), t-BuOK (84.2
mg, 0.750 mmol, 1.50 equiv), and anhydrous THF (2.00 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
stirred at r.t. for 21 h. Chromatography on a silica gel column (hex-
anes–acetone–CH2Cl2, 80:5:15) gave 7a.
Yield: 107.7 mg (99%); white solid.
1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 7.6 Hz, 1 H), 7.16 (d,
J = 7.7 Hz, 1 H), 7.10 (s, 1 H), 3.59 (sept, J = 6.9 Hz, 1 H), 2.40 (s,
3 H), 1.51 (d, J = 6.9 Hz, 6 H), 1.42 (s, 6 H). The spectroscopic data
is consistent with the literature.7
Yield: 57.1 mg (60%); white solid; mp 90–91 °C; Rf = 0.13 (hex-
anes–acetone–CH2Cl2, 80:5:15).
IR (neat): 2972, 1671, 1397, 1371, 1351, 1320, 767, 699, 689,
565 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.5 Hz, 1 H), 7.49 (td,
J = 7.4, 0.7 Hz, 1 H), 7.40–7.34 (m, 2 H), 3.49 (q, J = 7.2 Hz, 2 H),
1.46 (s, 6 H), 1.28 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.2, 151.5, 131.3, 131.0, 127.8,
123.3, 120.5, 62.6, 33.9, 25.9, 14.6.
5-Fluoro-2-isopropyl-3,3-dimethylisoindolin-1-one (4a)
From 4-Br: Following the general procedure, 4-Br (151 mg, 0.500
mmol, 1.00 equiv), Ni(cod)2 (13.8 mg, 0.05 mmol, 0.10 equiv), t-
BuOK (84.2 mg, 0.750 mmol, 1.50 equiv), and anhydrous THF
(2.00 mL) were combined in a 20 mL scintillation vial. The reaction
mixture was stirred at r.t. for 16 h. Chromatography on a silica gel
column (hexanes–EtOAc, 80:20) gave 4a.
Synthesis 2014, 46, 3033–3040
© Georg Thieme Verlag Stuttgart · New York

PAPER
Nickel-Mediated Synthesis of Isoindolinones
3039
HRMS: m/z [M + Na]+ calcd for C12H15NO: 212.1046; found:
212.1047.
13C NMR (100 MHz, CDCl3): δ = 166.3, 164.1 (JC–F = 248 Hz),
152.1 (JC–F = 9.0 Hz), 128.6, 125.0 (JC–F = 9.7 Hz), 115.1 (JC–F
23 Hz), 110.9 (JC–F = 25 Hz), 65.5, 44.5, 32.9, 24.5, 22.4, 20.4.
=
2′-Isopropylspiro(cyclohexane-1,1′-isoindolin)-3′-one and
2-Cyclohexyl-3,3-dimethylisoindolin-1-one (8a and 8b)
Following the general procedure, 8-Br (162 mg, 0.500 mmol, 1.00
equiv), Ni(cod)2 (13.8 mg, 0.05 mmol, 0.10 equiv), t-BuOK (84.2
mg, 0.750 mmol, 1.50 equiv), and anhydrous THF (2.00 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
stirred at r.t. for 21 h. Chromatography on a silica gel column (hex-
anes–acetone–CH2Cl2, 85:5:10) gave a mixture of products 8a and
8b (102.1 mg, 84%) as a white solid. Note: Although the total yield
is reported for the mixture of 8a and 8b, small amounts of pure 8a
and 8b were isolated to obtain the following spectroscopic and
HRMS data.
HRMS: m/z [M + Na]+ calcd for C16H20FNO: 284.1421; found:
284.1425.
Isomer 9b
Rf = 0.40 (hexanes–acetone–CH2Cl2, 80:5:15); mp 167–168 °C.
IR (neat): 2926, 1674, 1624, 1485, 1410, 1362, 1325, 1214, 1179,
901, 890, 829, 778, 704, 693, 610 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.73 (dd, J = 8.3, 5.0 Hz, 1 H),
7.08 (td, J = 8.8, 2.3 Hz, 1 H), 7.00 (dd, J = 8.3, 2.2 Hz, 1 H), 3.17–
3.09 (m, 1 H), 2.57–2.47 (m, 2 H), 1.90–1.82 (m, 2 H), 1.66–1.60
(m, 3 H), 1.46 (s, 6 H), 1.31–1.25 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.1, 165.0 (JC–F = 249 Hz),
Isomer 8a
Rf = 0.14 (hexanes–acetone–CH2Cl2, 85:5:10); mp 119–120 °C.
153.5 (JC–F = 8.9 Hz), 127.9, 125.3 (JC–F = 9.8 Hz), 115.5 (JC–F
=
23 Hz), 108.0 (JC–F = 24 Hz), 63.0, 53.2, 30.1, 26.5, 25.4, 25.1.
HRMS: m/z [M + Na]+ calcd for C16H20FNO: 284.1421; found:
IR (neat): 2926, 1676, 1468, 1411, 1377, 1331, 1326, 765, 700,
561 cm–1.
284.1423.
1H NMR (400 MHz, CDCl3): δ = 7.82–7.80 (m, 1 H), 7.75 (d, J =
6.8 Hz, 1 H), 7.47–7.40 (m, 2 H), 3.64 (sept, J = 6.8 Hz, 1 H), 1.97–
1.84 (m, 7 H), 1.55 (d, J = 6.8 Hz, 6 H), 1.49–1.45 (m, 2 H), 1.40–
1.24 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 167.2, 150.1, 132.6, 130.3, 127.6,
123.2, 123.1, 65.8, 44.4, 33.0, 24.6, 22.5, 20.4.
2-Isopropyl-3,3,6-trimethylisoindolin-1-one and 2-Isopropyl-
3,3,4-trimethylisoindolin-1-one (10a and 10b)
Following the general procedure, 10-Cl (127 mg, 0.500 mmol, 1.00
equiv), Ni(cod)2 (13.8 mg, 0.05 mmol, 0.10 equiv), t-BuOK (84.2
mg, 0.750 mmol, 1.50 equiv), and anhydrous THF (2.00 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
stirred at r.t. for 21 h. Chromatography on a silica gel column (hex-
anes–EtOAc–CH2Cl2, 80:10:10) gave a mixture of products 10a
and 10b (10a/10b = 1.1:1).
HRMS: m/z [M + Na]+ calcd for C16H21NO: 266.1515; found:
266.1513.
Isomer 8b
Rf = 0.18 (hexanes–acetone–CH2Cl2, 85:5:10); mp 141–142 °C.
Yield: 99.5 mg (92%); clear oil.
1H NMR (400 MHz, CDCl3): δ (10a) = 7.56 (s, 1 H), 7.30 (d, J =
7.7 Hz, 1 H), 7.21 (d, J = 7.7 Hz, 1 H), 3.62 (sept, J = 6.8 Hz, 1 H),
2.41 (s, 3 H), 1.54 (d, J = 6.9 Hz, 6 H), 1.44 (s, 6 H). The spectro-
scopic data is consistent with the literature.7
1H NMR (400 MHz, CDCl3): δ (10b) = 7.62 (d, J = 7.2 Hz, 1 H),
7.31–7.24 (m, 2 H), 3.63 (sept, J = 6.8 Hz, 1 H), 2.47 (s, 3 H), 1.56
(d, J = 6.9 Hz, 6 H), 1.53 (s, 6 H). The spectroscopic data is consis-
tent with the literature.7
IR (neat): 2953, 2932, 2857, 1672, 1614, 1469, 1451, 1414, 1364,
1325, 764, 699 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 7.5 Hz, 1 H), 7.49 (td,
J = 7.4, 0.8 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.33 (d, J = 7.5 Hz,
1 H), 3.18–3.10 (m, 1 H), 2.60–2.50 (m, 2 H), 1.87–1.80 (m, 2 H),
1.70–1.60 (m, 3 H), 1.47 (s, 6 H), 1.36–1.25 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.0, 151.1, 132.0, 131.1, 127.8,
123.2, 120.5, 63.3, 53.1, 30.1, 26.5, 25.5, 25.2.
HRMS: m/z [M + Na]+ calcd for C16H21NO: 266.1515; found:
266.1512.
2-Isopropyl-3,3-dimethyl-6-(trifluoromethyl)isoindolin-1-one
and 2-Isopropyl-3,3-dimethyl-4-(trifluoromethyl)isoindolin-1-
one (11a and 11b)
6′-Fluoro-2′-isopropylspiro(cyclohexane-1,1′-isoindolin)-3′-one
and 2-Cyclohexyl-5-fluoro-3,3-dimethylisoindolin-1-one (9a
and 9b)
Following the general procedure, 11-Br (176 mg, 0.500 mmol, 1.00
equiv), Ni(cod)2 (27.5 mg, 0.10 mmol, 0.20 equiv), t-BuOK (84.2
mg, 0.750 mmol, 1.50 equiv), and anhydrous THF (2.00 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
stirred at r.t. for 21 h. Chromatography on a silica gel column (hex-
anes–EtOAc–CH2Cl2, 80:10:10) gave 11a and 11b (71.3 mg, 53%)
as a white solid. Note: Although the total yield is reported for the
mixture of 11a and 11b, small amounts of pure 11a and 11b were
isolated to obtain the following spectroscopic and HRMS data.
Following the general procedure, 9-Br (171 mg, 0.50 mmol, 1.00
equiv), Ni(cod)2 (13.8 mg, 0.05 mmol, 0.10 equiv), t-BuOK (84.2
mg, 0.75 mmol, 1.50 equiv), and anhydrous THF (2.00 mL) were
combined in a 20 mL scintillation vial. The reaction mixture was
stirred at r.t. for 21 h. Chromatography on a silica gel column (hex-
anes–acetone–CH2Cl2, 80:5:15) gave a mixture of products 9a and
9b (119 mg, 91%) as a white solid. Note: Although the total yield is
reported for the mixture of 9a and 9b, small amounts of pure 9a and
9b were isolated to obtain the following spectroscopic and HRMS
data.
Isomer 11a
Rf = 0.33 (hexanes–EtOAc, 85:15); mp 133–135 °C.
IR (neat): 2976, 1678, 1322, 1279, 1159, 1113, 1077, 1049, 907,
852, 794, 655, 631 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.04 (s, 1 H), 7.77 (d, J = 7.9 Hz,
1 H), 7.47 (d, J = 7.9 Hz, 1 H), 3.66 (sept, J = 6.8 Hz, 1 H), 1.56 (d,
J = 6.8 Hz, 6 H), 1.51 (s, 6 H).
Isomer 9a
Rf = 0.33 (hexanes–acetone–CH2Cl2, 80:5:15); mp 122–124 °C.
IR (neat): 2940, 1676, 1413, 1364, 1330, 1169, 961, 896, 884, 834,
785, 755, 695, 654 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.77 (dd, J = 8.3, 5.4 Hz, 1 H),
7.43 (dd, J = 9.3, 2.1 Hz, 1 H), 7.12 (td, J = 8.7, 2.2 Hz, 1 H), 3.62
(sept, J = 6.8 Hz, 1 H), 1.96–1.24 (m, 10 H), 1.54 (d, J = 6.8 Hz,
6 H).
13C NMR (100 MHz, CDCl3): δ = 165.7, 154.4, 132.8, 130.7 (JC–F
=
33 Hz), 128.1 (JC–F = 3.6 Hz), 123.9 (JC–F = 271 Hz), 121.3, 120.7
(JC–F = 3.9 Hz), 63.5, 44.8, 25.2, 20.4.
HRMS: m/z [M + Na]+ calcd for C14H16F3NO: 294.1076; found:
294.1073.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3033–3040

3040
W. C. Wertjes et al.
PAPER
(8) For other representative reports on sp3 C–H arylation
Isomer 11b
Rf = 0.28 (hexanes–EtOAc, 58:15); mp 55–57 °C.
adjacent to nitrogen atoms, see: (a) Dastbaravardeh, N.;
Kirchner, K.; Schnürch, M.; Mihovilovic, M. D. J. Org.
Chem. 2013, 78, 658. (b) McNally, A.; Prier, C. K.;
MacMillan, D. W. C. Science 2011, 334, 1114.
(c) Prokopkova, H.; Bergman, S. D.; Aelvoet, K.; Smout, V.;
Herrebout, W.; Van der Veken, B.; Meerpoel, L.; Maes, B.
U. W. Chem. Eur. J. 2010, 16, 13063. (d) Campos, K. R.
Chem. Soc. Rev. 2007, 36, 1069. (e) Pastine, S. J.; Gribkov,
D. V.; Sames, D. J. Am. Chem. Soc. 2006, 128, 14220.
(f) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P.
G.; Chem, C. Y. J. Am. Chem. Soc. 2006, 128, 3538.
(g) Snieckus, V.; Cuevas, J.-C.; Sloan, C. P. Liu H. T.;
Curran, D. P. J. Am. Chem. Soc. 1990, 112, 896.
IR (neat): 2977, 1686, 1422, 1380, 1370, 1352, 1307, 1234, 1159,
1121, 1081, 1066, 829, 769, 709, 615, 561 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 7.5 Hz, 1 H), 7.80 (d,
J = 7.8 Hz, 1 H), 7.55 (t, J = 7.7 Hz, 1 H), 3.66 (sept, J = 6.8 Hz,
1 H), 1.573 (s, 6 H), 1.571 (d, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 165.0, 147.4, 134.8, 129.5 (JC–F
5.7 Hz), 128.4, 127.2, 124.7 (JC–F = 33 Hz), 123.9 (JC–F = 271 Hz),
65.5, 44.6, 23.7, 20.3.
HRMS: m/z [M + Na]+ calcd for C14H16F3NO: 294.1076; found:
294.1072.
=
(9) (a) Buden, M. E.; Guastavino, J. F.; Rossi, R. A. Org. Lett.
2013, 15, 1174. (b) Cheng, Y.; Gu, X.; Li, P. Org. Lett. 2013,
15, 2664.
(10) (a) Rousseaux, S.; Gorelsky, S. I.; Chung, B. K. W.; Fagnou,
K. J. Am. Chem. Soc. 2010, 132, 10692. (b) Rousseaux, S.;
Davi, M.; Sofack-Kreutzer, J.; Pierre, C.; Kefalidis, C. E.;
Clot, E.; Fagnou, K.; Baudoin, O. J. Am. Chem. Soc. 2010,
132, 10706.
Acknowledgment
This work was supported by the NIH (R15 GM107892) and St. Olaf
College.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
(11) Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 7547.
(12) (a) Shirakawa, E.; Hayashi, T. Chem. Lett. 2012, 41, 130.
(b) Yanagisawa, S.; Itami, K. ChemCatChem 2011, 3, 827.
(c) Studer, A.; Curran, D. P. Angew. Chem. Int. Ed. 2011, 50,
5018. (d) Lei, A.; Lei, W.; Liu, C.; Chen, M. Dalton Trans.
2010, 10352.
(13) (a) Liu, W.; Tian, F.; Wang, X.; Yu, H.; Bi, Y. Chem.
Commun. 2013, 49, 2983. (b) Mehta, V. P.; Punji, B. RSC
Adv. 2013, 11957. (c) Wu, Y.; Wong, S. M.; Mao, F.; Chan,
T. L.; Kwong, F. Y. Org. Lett. 2012, 14, 5306. (d) Bhakuni,
B. S.; Kumar, A.; Balkrishna, S. J.; Sheikh, J. A.; Konar, S.;
Kumar, S. Org. Lett. 2012, 14, 2838. (e) De , S.; Ghosh, S.;
Bhunia, S.; Sheikh, J. A.; Bisai, A. Org. Lett. 2012, 14, 4466.
(f) Shirakawa, E.; Itoh, K.-I.; Higashino, T.; Hayashi, T.
J. Am. Chem. Soc. 2010, 132, 15537. (g) Liu, W.; Cao, H.;
Zhang, H.; Chung, K. H.; He, C.; Wang, H.; Kwong, F. Y.;
Lei, A. J. Am. Chem. Soc. 2010, 132, 16737. (h) Sun, C.-L.;
Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu, X.-Y.; Huang, K.;
Zheng, S.-F.; Li, B.-J.; Shi, Z.-J. Nature Chem. 2010, 2,
1044.
10.1055/s-00000084.SunpfgIpi
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References
(1) For some recent reviews on C–H functionalization, see:
(a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174. (b) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013.
(c) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev.
2009, 38, 2447. (d) Chen, X.; Engle, K. M.; Wang, D.-H.;
Yu, J.-Q. Angew. Chem. Int. Ed. 2009, 48, 5094.
(e) Ackermann, L.; Vincente, R.; Kapdi, A. R. Angew.
Chem. Int. Ed. 2009, 48, 9792. (f) Bellina, F.; Rossi, R.
Tetrahedron 2009, 65, 10269. (g) Lyons, T. W.; Sanford, M.
S. Chem. Rev. 2010, 110, 1147. (h) Daugulis, O. Top. Curr.
Chem. 2010, 292, 57. (i) Chiusoli, G. P.; Catellani, M.;
Costa, M.; Motti, E.; Della Ca’, N.; Maestri, G. Coord.
Chem. Rev. 2010, 254, 456. (j) Kuhl, N.; Hopkinson, M. N.;
Wencel-Delord, J.; Glorius, F. Angew. Chem. Int. Ed. 2012,
51, 10236. (k) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C.
Adv. Synth. Catal. 2014, 356, 17.
(2) (a) Giri, R.; Shi, B.-F.; Engle, K.-M.; Maguel, N.; Yu, J.-Q.
Chem. Soc. Rev. 2009, 38, 3242. (b) Jazzar, R.; Hitse, J.;
Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem. Eur.
J. 2010, 16, 2654. (c) Wasa, M.; Engle, K. M.; Yu, J.-Q. Isr.
J. Chem. 2010, 50, 605. (d) Bellina, F.; Rossi, R. Chem. Rev.
2010, 110, 1082. (e) Baudoin, O. Chem. Soc. Rev. 2011, 40,
4902.
(14) The mechanism in Scheme 3 is just one proposal. The
regeneration of Ni0 in step (v) cannot be excluded amongst
other possibilities.
(15) We have explored the use of phenanthroline in place of
Ni(cod)2 for the room temperature arylations described in
this paper. Specifically, the reaction of 1-Br or 1-Cl using
phenanthroline in place of Ni(cod)2 under otherwise
identical conditions showed no product in the GC/MS trace
of the crude reaction mixture. Interestingly, the arylation of
1-I using phenanthroline (0.2 equiv), t-BuOK (1.5 equiv),
and THF did proceed at room temperature to afford 1a in
80% yield, as determined by GC/MS analysis of the crude
reaction mixture against hexadecane as the internal standard.
These results suggest that Ni(cod)2 is a more effective
initiator for the arylations of bromide and chloride
substrates. However, either Ni(cod)2 or phenanthroline
could serve as initiator for the reaction of iodide substrates.
(16) Bhakuni, B. S.; Yadav, A.; Kumar, S.; Patel, S.; Sharma, S.;
Kumar, S. J. Org. Chem. 2014, 79, 2944.
(3) Yamaguchi, J.; Muto, K.; Itami, K. Eur. J. Org. Chem. 2013,
19.
(4) (a) Wang, J.; Ferguson, D. M.; Kalyani, D. Tetrahedron
2013, 69, 5780. (b) Muto, K.; Yamaguchi, J.; Itami, K.
J. Am. Chem. Soc. 2012, 134, 169.
(5) Liu, D.; Liu, C.; Li, H.; Lei, A. Angew. Chem. Int. Ed. 2013,
52, 4453.
(6) (a) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2014, 136,
898. (b) Li, M. L.; Dong, J. X.; Huang, X. L.; Li, K. Z.; Wu,
Q.; Song, F. J.; You, J. S. Chem. Commun. 2014, 50, 3944.
(7) Wertjes, W. C.; Wolfe, L. C.; Waller, P. W.; Kalyani, D.
Org. Lett. 2013, 15, 5986.
Synthesis 2014, 46, 3033–3040
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