Nickel complex catalyzed efficient activation of sp3and sp 2c-h bonds for alkylation and arylation of oxygen containing heterocyclic molecules

Article abstract of DOI:10.1007/s10562-013-1170-8

A nickel(II) complex (1) of N,N'-bis(2,6-diisopropylphenyl)-2,6- pyridinedicarboxamido (L) ligand was examined for catalytic coupling of Grignard reagents with the C-H bond of oxygen containing heterocyclic compounds such as tetrahydrofuran and furan. The nickel( II) complex showed excellent activity in catalyzing C-H activation and further coupling with various Grignard reagents. The effective activation of the C-H bond proceeded under ambient reaction conditions with a short reaction time (1-2 h). The catalyst (1) displays high turnover frequency of 4,130 h^-1with catalyst loading as low as 0.01 mol%. This catalytic route could prove to be an efficient mode of activation of sp³and sp²C-H bonds in various heterocycles for the preparation of synthetically and pharmaceutically relevant molecules. Springer Science+Business Media New York 2013.

Full text of DOI:10.1007/s10562-013-1170-8

Catal Lett (2014) 144:507–515
DOI 10.1007/s10562-013-1170-8
Nickel Complex Catalyzed Efficient Activation of sp3 and sp2 C–H
Bonds for Alkylation and Arylation of Oxygen Containing
Heterocyclic Molecules
•
Yashraj Gartia Punnamchandar Ramidi
•
•
Darin E. Jones Sharon Pulla Anindya Ghosh
•
Received: 12 October 2013 / Accepted: 17 November 2013 / Published online: 17 December 2013
Ó Springer Science+Business Media New York 2013
Abstract A nickel(II) complex (1) of N,N0-bis(2,6-
diisopropylphenyl)-2,6-pyridinedicarboxamido (L) ligand
was examined for catalytic coupling of Grignard reagents
with the C–H bond of oxygen containing heterocyclic
compounds such as tetrahydrofuran and furan. The nick-
el(II) complex showed excellent activity in catalyzing C–H
activation and further coupling with various Grignard
reagents. The effective activation of the C–H bond pro-
ceeded under ambient reaction conditions with a short
reaction time (1–2 h). The catalyst (1) displays high turn-
over frequency of 4,130 h-1 with catalyst loading as low as
0.01 mol%. This catalytic route could prove to be an effi-
cient mode of activation of sp3 and sp2 C–H bonds in
various heterocycles for the preparation of synthetically
and pharmaceutically relevant molecules.
research has been done on transition metal catalyzed C–H
bond activation [2–8] and cross coupling reactions by
various research groups [11, 12] for the synthesis of dif-
ferent molecules including natural products [9, 10]. A great
deal of research on C–H bond activation since the 1980s
involved thermodynamic and kinetic investigations, along
with intermediate isolation has resulted in a greater
understanding of the mechanism [3–26].
Based on the use of different coupling partners, multiple
methods have been developed using various organic
nucleophiles and electrophiles [27, 28]. As a mode of
formation of new C–C bonds, cross coupling reactions
generally employ compounds with functionalities such as
C–X (X = Halogen) bonds or C–H bonds which require
costly and wasteful pre-activation for further functionali-
zation. However, the direct and selective activation of C–H
bonds, which is the most abundant functionalizable bond in
organic molecules, is still challenging and a major area of
interest in the recent decades. Especially activation of sp2
and sp3 C–H bonds in heterocyclic molecules has generated
much interest in recent years, owing to their wide range of
applications in the pharmaceutical industry [9, 10]. Direct
activation of C–H bonds using transition metals catalysts
[2–8] can serve as a more efficient way to facilitate organic
transformations, limiting the dependence on organic
nucleophiles [29, 30] and at the same time expanding the
scope of various organic compounds [31].
Keywords Nickel(II) complex ꢀ Oxygen containing
heterocyclics ꢀ Grignard reagents ꢀ sp3 and sp2 C–H bond
activation
1 Introduction
Cross coupling reactions resulting in the formation of new
C–C bonds have been an important part of synthetic
chemistry. Since the first discovery of C–H bond activation
by transition metal in the 1960s [1], a significant amount of
The selective and effective C–H bond activation using
transition metals for direct catalysis of alkylation has been
generally dependent on the use of directing groups con-
tained in the compound [32]. The alkylation resulting from
these activations is generally an ortho-alkylated product.
Many of the previously reported C–H activations and direct
alkylation methods employ a sp2 C–H bond using various
transition metals [33–35]. The activation of sp3 C–H bond
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-013-1170-8) contains supplementary
material, which is available to authorized users.
Y. Gartia ꢀ P. Ramidi ꢀ D. E. Jones ꢀ S. Pulla ꢀ A. Ghosh (&)
Department of Chemistry, University of Arkansas at Little Rock,
2801 South University Avenue, Little Rock, AR 72204, USA
e-mail: axghosh@ualr.edu
123

508
Y. Gartia et al.
is very complex, hence reports are limited [36–39]. This
complexity may be a result of sp3 C–H bond’s lack of p
orbitals to interact with the metal center, resulting in a
kinetic advantage for the sp2 C–H bonds. This makes sp3
C–H bond more difficult to activate over sp2 and sp C–H
bonds. However, sp3 C–H bonds adjacent to the heteroatom
are weaker than the simple sp3 C–H bonds of an alkane.
Taking advantage of this, Murai et al. activated the C–H
bond in pyrrolidine and piperidine using a Ru3(CO)12
complex for coupling with unactivated alkenes [40]. Since
then the presence of an a–heteroatom for sp3 C–H acti-
vation has become an essential configuration for such
reactions.
with various aryl and alkyl Grignard reagents using nick-
el(II) complex (1) (Fig. 1). The present study uses a pincer
ligand based on a diamidopyridine ligand (L, N2, N6-
bis(2, 6-diisopropylphenyl)pyridine-2,6-dicarboxamide). The
synthesis and characterizations of the nickel and ruthenium
complexes using the deprotonated form of the ligand (1)
was reported by Wasilke et al. [54], which were used for
ring closing metathesis reaction. Recently, we employed
the complex 1 for the efficient catalytic reaction of poly-
chlorinated molecules with various Grignard reagents
under ambient reaction conditions [55]. Apart from this,
the nickel complexes of the ligand (L), and analogous
ligands have been reported for the effective reaction with
carbon dioxide and other small molecules or ligands [56,
57].
Various nucleophiles such as alkyl halides [41–45],
olefins [46, 47] and organometallic reagents such as alkyl
[48] or aryl [48–50] boronic acid, organotin, Grignard
reagents [33] etc. have been employed for cross coupling
reactions. Though Grignard reagents have been used for
C–C coupling reactions, their use as nucleophiles for
coupling with a C–H bond has not been applied to a large
extent. The use of iron(III) acetylacetonate, along with zinc
chloride (ZnCl2) and tetramethylethylenediamine (TME-
DA) for C–H bond transformation of benzoquinoline and
phenylpyridine derivatives with Grignard reagents leading
to the formation of a C(sp2)–C(sp3) bond, is one such
example [51]. Use of cobalt(III) acetylacetonate with
TMEDA for similar transformation [33], using Grignard
reagent as coupling partner, further widened the scope of
1st row transition metals for such reactions. Use of a nickel
catalyst for the alkylation of a sp2 C–H bond of N-aromatic
heterocycles using Grignard reagents was also developed
[52]. More recently, Lei and co-workers reported oxidative
coupling of sp3 C–H bonds of oxygen and nitrogen con-
taining heterocycles with arylboronic acids for C(sp3)–
C(sp2) bond formation using Ni(II) acetylacetonate along
with triphenylphosphine as catalyst [53]. This motivated
the development of nickel complexes for such C–H acti-
vation and functionalization reactions with Grignard
reagents.
The uniqueness of the present research work is that to
the best of our knowledge this is the first example of a
nickel based catalyst, which is capable of catalyzing C–C
cross-coupling reactions involving various aryl or alkyl
Grignard reagents and a sp3 C–H bond in oxygen con-
taining heterocyclic molecules. In this work we present
cross coupling reaction for the formation of different type
of C–C bonds, namely C(sp3)–C(sp3), C(sp2)–C(sp3) and
C(sp2)–C(sp2). These reactions were carried out under
ambient reaction conditions within short period of time.
The C–H bond activation and subsequent coupling with
Grignard reagents were selective towards the second
position (C atom adjacent to the hetero atom) of the het-
erocyclic molecule. Similar activation of a sp3 C–H bond
of cyclic aliphatic ethers using iron catalyst for direct
arylation/alkylation at a-position has been reported
recently [58]. Catalyst 1 showed high efficiency with TOF,
as high as 4,130 h-1 at a considerably low catalyst loading
of 0.01 mol%. Such high catalytic activity is the highest for
such cross-coupling reactions. Beside THF, dioxane and
2-methyltehrahydrofuran were also used to the alkylation
process. Interestingly, 1 was also used to activate sp2 C–H
bond in heterocyclic ethers (e.g. furan) and was success-
fully coupled with Grignard reagents. The catalytic system
described here could potentially be applied to the efficient
activation of both sp3 and sp2 C–H bonds for the synthesis
Here, we report in detail, the catalytic activation of a sp3
C–H bond of a heterocyclic molecule THF and its coupling
_
O
O
i-Pr
N
i-Pr
1
N
N
Ni
Li+
+
RMgX
25 oC , Ar , 1 h
Dibromoethane
R
Cl
O
O
i-Pr
i-Pr
1
Fig. 1 Use of Grignard reagents for the synthesis of 2-substituted tetrahydrofurans using a nickel(II) pincer catalyst (1)
123

C–H Bond Activation of Oxygen Containing Heterocycles by a Nickel Complex
509
of various 2-substituted oxygen containing heterocyclic
molecules which have synthetic and pharmaceutical
importance.
additional THF. Dibromoethane (90 lL, 1.04 lmol) was
added to the reaction mixture. Samples were collected for
analysis after 1 h. At the end of the reaction, excess
Grignard reagent was destroyed using methanol (1 mL)
and the reaction products were analyzed by GC–MS using
either by comparing with commercially available com-
pounds or an internal standard (2-methyltetrahydrofuran) to
quantify product formation. Product yields were reported in
turnover number (TON; moles of product formed per mole
of catalyst used) and turnover frequency (TOF; moles of
product formed per mole of catalyst in unit time).
2 Experimental
2.1 Materials and Methods
All the chemicals and solvents were obtained from Aldrich
Chemical Co., USA and Fisher Scientific Company, USA.
Chemicals were used as obtained without further purifica-
tion unless otherwise stated. Tetrahydrofuran (THF), furan
and dibromoethane were purified according to the literature
procedure [59]. Electrospray ionization mass spectra (ESI–
MS) were obtained using an Agilent 100 series MSD VL
spectrometer. Gas chromatography mass spectra (GC–MS)
were obtained using an Agilent technologies 6890N net-
work GC system equipped with an Agilent Technologies
5975 inert XL mass selective detector. Ultraviolet visible
spectra (UV–Vis) were recorded using a Varian Cary 5000
UV–Vis–NIR spectrophotometer.
2.4 Cross Coupling of Other Oxygen Containing
Heterocyclics with Grignard Reagents
Cross coupling reactions of Grignard reagents with other
heterocyclics such as furan and methyl-tetrahydrofuran
were performed according to the following general method.
Catalyst 1 (0.1 mg, 0.174 lmol) in 0.1 mL ether was
added using a gas-tight syringe to a 5 mL round bottom
flask purged with Ar. To this solution, phenylmagnesium
chloride in diethyl ether (0.92 mmol) was added. Total
volume of the solution was made up to 3.5 mL by adding
additional THF. Dibromoethane (90 lL, 1.04 lmol) was
added to the reaction mixture. Samples were collected for
analysis after 1 h. At the end of the reaction excess Grig-
nard reagent was destroyed using excess methanol (1 mL),
and the reaction products were analyzed by GC–MS using
an internal standard to quantify product formation. Simi-
larly product yields were reported in TON and TOF.
2.2 Synthesis of Nickel(II) Complex (1)
The nickel(II) complex (1) was synthesized following the
previously reported literature method [55]. Ligand N2,N6-
bis(2,6-diisopropylphenyl)pyridine-2,6-dicarboxamide
(L) was deprotonated using n-butyllithium in cool (0 °C),
dry THF under a nitrogen atmosphere followed by the
addition of solid anhydrous dimethoxyethane adduct of
nickel(II) chloride, yielding the deep red nickel(II) com-
1
plex (1) (Fig. 1). 1 was characterized by H NMR, ESI–
3 Results and Discussions
MS, FT–IR, UV–Vis, and elemental analysis. Detailed
synthesis and characterization methods are described in our
previous work employing 1 [55]. The complex (1) is an
ionic compound with lithium (Li?) as the counter cation.
Initial studies to optimize the reaction conditions were
carried out using varying amounts of catalyst 1 required for
catalyzing the reaction of phenylmagnesium chloride
(0.5 mL, 0.92 mmol) with THF. As seen in entry 1,
Table 1, in the absence of 1, only trace/no amount of
phenyl substituted tetrahydrofuran was observed. However
with the addition of just 0.05 mg (0.087 lmol, 0.01 mol%)
of 1, 39 % of the phenylmagnesium chloride coupled up
with THF giving a TOF of 4,130 h-1. A maximum yield of
66 % with a TOF of 3,490 h-1 was obtained when 0.1 mg
(0.174 lmol, 0.02 mol%) of nickel(II) complex was used.
As seen in the entry 3–5 in Table 1, the yield of phenyl
tetrahydrofuran decreased as the amount of catalyst was
increased. This resulted in a dramatic decrease in the TOF
of the reaction. Increasing the amount of 1 resulted in an
increase of side reactions (such as homocoupling) rather
than the desired coupling reaction. It was also observed
that a small amount of additive dibromoethane was nec-
essary for the reaction to proceed. As shown in entry 6,
2.3 Cross Coupling of Tetrahydrofuran with Grignard
Reagents
Owing to the small amount of catalyst needed (0.1–1.0 mg),
a stock solution of 1 mg mL-1 of 1 in THF was prepared and
used accordingly. Phenylmagnesium chloride in THF (25 %)
was used for all initial optimization reactions unless other-
wise specified. Cross coupling reactions of Grignard reagents
with tetrahydrofuran were performed according to the fol-
lowing general method.
Catalyst 1 (0.1 mg, 0.174 lmol) in 0.1 mL THF was
added using a gas-tight syringe to a 5 mL round bottom
flask purged with Ar. To this solution, phenylmagnesium
chloride in THF (0.5 mL, 0.92 mmol) was added. Total
volume of the solution was made up to 3.5 mL by adding
123

510
Y. Gartia et al.
only 14 % product was obtained in the absence of dibro-
moethane in the reaction. As 0.1 mg of catalyst
(0.02 mol% of 1) gave significant yield as well as TOF,
further reactions were carried out using 0.02 mol% of 1 in
order to check the effect of the other parameters on the
catalysis.
decreased the yield slightly to 66 %. Further increasing the
amount of Grignard reagent lead to subsequent decrease in the
yield of desired product. This may be due to the increased
Grignard reagents concentration resulting in side reactions
such as homocoupling reactions.
Reactions were additionally carried out to check for the
effect of temperature on the yield and the selectivity of the
coupling reaction towards the product. Reactions were set
up using 1 (0.1 mg, 0.174 lmol) and phenylmagnesium
chloride in THF (0.5 mL, 0.92 mmol) and dibromoethane
(45 lL, 0.52 lmol) and (90 lL, 1.04 lmol) at various
reaction temperatures ranging from -15 to 70 °C. The
increase in temperature, as expected, resulted in a faster
reaction with higher yields of phenyltetrahydrofuran
obtained within 5 min of the reaction time. The reaction
yield and turnover number (TON) in 5 min increased from
a mere 5 % and 265 at -15 °C to about 37 % yield and
1960 at 70 °C using 3 eq. of dibromoethane. Similar trends
were also observed in reactions employing 6 eq. of dibro-
moethane, with a maximum yield of 43 % at 70 °C. Dif-
ferent reaction temperatures showed little or no selectivity
of the substituted THF over the undesirable homocoupled
product (Fig. 4).
As it was observed that the coupling reaction of the
Grignard reagent with THF required dibromoethane in
addition to 1, similar reactions were performed using other
additives that have been reported in literature for C–H
activation reactions [60]. However additives such as
dichloroethane did not yield a significant amount of prod-
uct (see Supporting information, Table S1). Further opti-
mization of the amount of dibromoethane was performed
by using varying equivalents (0–48 eq.; 0–720 lL) of
dibromoethane with respect to 1. Figure 2 shows the
increase in yield of phenyltetrahydrofuran, as the ratio of
dibromoethane to nickel complex 1 was increased from 0
to 48. As seen in Fig. 2, reaction yield increased from
about 54–66 % as the amount of dibromoethane to 1
increased from 3 to 6 equivalents. The addition of 12
equivalents of dibromoethane further increased the yield to
69 %. Further increasing the amount of dibromoethane did
not significantly increase the yield of product. Hence
45–90 lL of dibromoethane (which is 3–6 times the
amount of 1) was found to be ideal for the reaction, hence
further studies were carried out using these amounts.
The effectofvarying amounts ofGrignard reagent was also
evaluated while maintaining the other parameters constant.
The reactions were set up using 1 (0.1 mg, 0.174 lmol) and
90 lL (6 eq. with respect to 1) of dibromoethane at room
temperature for 1 h. Varying amounts of phenylmagnesium
chloride in THF 0.1–2 mL (0.184–3.68 mmol) were added to
the reaction. As seen in the Fig. 3, the percent (%) yield
increased form 59 to 70 % when the amount of Grignard
reagent was increased from 0.184 to 0.46 mmol (from about
1,000 to 2,500 eq. with respect to the catalyst 1). Increase in
the Grignard reagent to 0.5 mL (0.92 mmol, 5,000 eq. to 1)
To assess the generality of the reaction, this protocol of
direct C–H alkylation was extended to a range of aryl
Grignard reagents. As seen in entry 1 and 2 in Table 2, the
Fig. 2 Effect of ratio of dibromoethane to catalyst 1 on the coupling
reaction. 1 (0.1 mg, 0.174 lmol), phenylmagnesium chloride in THF
(0.5 mL, 0.92 mmol), 25 °C, 1 h
Table 1 TOF of the reactions with different substrate to catalyst ratio
Entry
Catalyst 1
(mol%)
Dibromoethane
(lL)
Yield (%)
TOF (h-1
)
1
2
3
4
5
6
0.0
90
90
90
90
90
0
Trace
39
–
0.01
0.02
0.1
4,130
3,490
520
230
740
66
49
0.2
44
0.01
14
25 % Phenylmagnesium chloride in THF (0.5 mL, 0.92 mmol),
dibromoethane (90 lL, 1.04 lmol) at room temperature. Reaction
time 1 h. Yield (%) is the percent of phenylmagnesium chloride
coupled with THF
Fig. 3 Effect of amount of Grignard reagent (phenylmagnesium
chloride) on the coupling reaction. 1 (0.1 mg, 0.174 lmol), dibro-
moethane (90 lL, 1.04 lmol), phenylmagnesium chloride in THF
(0.1–2 mL), 25 °C, 1 h
123

C–H Bond Activation of Oxygen Containing Heterocycles by a Nickel Complex
511
use of phenylmagnesium bromide showed slight improve-
ment over its chloride counterpart. However it is worth-
while to note that both of them accounted for very high
yield, showing the high reactivity and selectivity of phenyl
Grignard reagents for such coupling reactions. Use of
phenylmagnesium iodide yielded a similarly high yield of
79 % with a TOF of about 4,180 h-1. Further use of var-
ious aryl Grignard reagents with various substituents yiel-
ded significantly high yields of the corresponding products.
As seen in entry 4, use of 4-bromoanisol yielded 72 % of
the coupled product. Using 2-bromoanisol slightly
increased the yield to about 78 %. 2-bromo biphenyl also
underwent a cross-coupling reaction to the corresponding
2-biphenyltetrahydrofuran product, however the yield was
comparatively less which may be due to its bulkier nature.
The cross coupling of the C–H of THF with various
alkyl Grignard reagents were also performed for the suc-
cessful synthesis of new C–C sp3–sp3 bonds. As seen in
Table 3, the reaction of THF with alkylmagnesium chlo-
ride was found to be less effective comparatively than the
aryl Grignard reagents such as phenylmagnesium chloride
(entry 2, Table 2). Use of ethylmagnesium chloride (entry
1, Table 3) gave a yield of 47 % in 2 h with a TON of
Fig. 4 Effect of temperature (-15 to 70 °C) on the coupling
reaction. 1 (0.1 mg, 0.174 lmol), phenylmagnesium chloride in
THF (0.5 mL, 0.92 mmol), dibromoethane (3 eq., 45 lL, 0.52 lmol)
and (6 eq., 90 lL, 1.04 lmol), reaction time 5 min
Table 2 Cross coupling reaction of tetrahydrofuran with various substituted phenyl Grignard reagents
MgX
1 (0.02 mol%)
F
+
F
25 oC, Ar, 1 h
O
O
6eq.Dibromoethane
X = Cl,Br,I
F = Functional group
Grignard reagent
Product
Time (h) Yield (%) TON
r
MgB
1
1
82
4340
O
M
l
gC
2
1
66
3490
O
O
MgI
3
4
1
1
79
72
4180
3810
MgBr
O
O
O
MgBr
5
6
1
1
78
80
4130
4240
O
O
O
MgI
O
r
MgB
7
1
54
2862
O
Grignard reagent in THF (0.92 mmol), dibromoethane (90 lL, 1.04 lmol) at 25 °C, 1 h. Yield (%) is percent of Grignard reagent coupled with
THF
123

512
Y. Gartia et al.
2,490. Further, the gradual increase in the carbon chain
length of the Grignard reagent resulted in a steady decrease
in the yield of desired product. As seen in entry 4, use of
octylmagnesium chloride yielded a mere 27 % product
with a TON of 1,430. Even lower C–H activated product
was observed when allylmagnesium chloride was used,
with only 12 % of 2-substituted product (entry 6, Table 3).
Use of Grignard reagents with a phenyl aromatic ring
resulted in better yields with benzylmagnesium chloride
and phenyethylmagnesium chloride yielding 51 and 44 %
(entries 9 and 10, Table 3) respectively.
is explained in detail in our previous work employing 1
with Grignard reagents [55]. Further confirmation by UV–
Vis spectrum indicates a disappearance of the characteristic
404 nm peak of the nickel(II) catalyst (1) and the appear-
ance of a new peak at around 450–500 nm (depending
upon the Grignard reagent used) (Supporting information,
Fig. S12a). The formation of such a non-transient inter-
mediate was also detected using ESI–MS. The butyl
intermediate of the nickel(II) complex was detected by the
ESI–MS with m/z 598.1 (Supporting information, Fig.
S12b). The stability of these intermediates was also studied
using UV–Vis spectroscopy. The phenyl intermediate for
example, formed, through the interaction of 1 with phen-
ylmagnesium chloride showed a persistent peak at 460 nm
with minimal decrease in the absorbance over 20 min.
However with the addition of dibromoethane to the phenyl
intermediate, the catalytic cycle is promoted which is
observed by the marked decrease in the peak absorbance
(Supporting information, Fig. S13) with respect to time.
The peak disappeared within 10 min. Immediate inspection
of the reaction mixture using GC–MS reveals the formation
of phenyltetrahydrofuran, refuting the assumption that the
Our preliminary observations on the mechanism of the
cross-coupling reaction in relation to the formation of the
2-substituted product, suggest that an intermediate alkyl or
aryl complex of 1 may be responsible for enabling and/or
governing the substrate interactions and the catalytic cycle.
Formation or presence of such intermediates in the cata-
lytic cycles have been detected and postulated in various
other coupling reactions involving Grignard reagents [61–
63]. The presence of this non-transient intermediate was
evident in a rapid solution color change upon the addition
of various Grignard reagents to a solution of 1 in THF, and
Table 3 Synthesis of substituted tetrahydrofurans using various Grignard reagents
1 (0.02 mol%)
+
RMgX
25 oC , Ar, 2 h
R
O
O
6 eq. Dibromoethane
Grignard reagent Product
Time (h) Yield (%) TON
M
gC
l
1
2
47
2490
O
O
M
3
l
gC
2
3
2
2
41
30
2170
1590
3
M
5
l
gC
5
O
O
O
M
7
l
gC
4
5
6
2
2
2
27
29
12
1430
1530
630
7
M
l
gC
M
l
gC
l
O
M
gC
7
8
2
2
34
51
1800
2700
O
M
gC
l
O
MgCl
9
2
44
2330
O
Grignard reagent in diethylether (0.92 mmol), dibromoethane (90 lL, 1.04 lmol) at 25 °C. Reaction time 1–2 h. Yield (%) is percent of
Grignard reagent coupled to THF
123

C–H Bond Activation of Oxygen Containing Heterocycles by a Nickel Complex
513
intermediate degraded by itself or was used up in the for-
mation of other side products.
presence of an excess amount of free radical trap TEMPO.
No significant reduction in the yield was observed, negat-
ing the possibility of radical pathway in the mechanism.
Based of these information a possible mechanism of the
reaction is proposed in Scheme 1. However, more work is
necessary in this context.
Nevertheless, the interaction of the nickel(II) complex (1)
with THF cannot be denied. The interactions of heterocycles
with the metal complexes to form an alkylated intermediate
resulting in the formation of coupling product are not new,
and have been reported earlier. Similar interaction of thio-
phenes and furans to produce the iron-heteroaryl complexes
is one such example [64]. These interactions lead to the
activation of a C–H bonds to the heteroatom resulting in
2-substituted products. Thus we presume that the nickel
metal center of 1 interacts with Grignard reagent and THF,
which upon reductive elimination, results in the substituted
THF. a C–H bond in THF is relatively weak (*80 kcal -
mol-1) and therefore can easily be activated. It is also not
unlikelythat Grignard reagent may reduce the metal center to
lower valency which may facilitates the C–H bond activa-
tion. The role of dibromoethane in this reaction is unclear,
but it is believed to be required for regeneration of the Ni
metal center to its active form (possibly by destroying
hydride ligand) to maintain the catalytic cycle. Using such
molecules for regeneration the metal center is not new and is
in accordance with some previously reported C–H activation
work [52]. Presence of bromine in intermediates/side pro-
ducts (e.g. bromobenzene) (Fig. S14, Supporting informa-
tion) shows that the nickel center does interact with the
dibromoethane (only source of bromine in the reaction
mixture), which is the only route possible for the incorpo-
ration of bromine into the phenyl structure.
The feasibility of using other oxygen containing het-
erocyclic molecules was also checked for their function-
alization using Grignard reagents. Reactions were carried
out using similar five and six member ring heterocyclic
molecules. 2-methyltetrahydrofuran is one such example
where one of the 2 positions is already occupied by a
methyl group. Successful C–H activation of the C–H group
(5th position) was observed in 2-methyltetrahydrofuran
with about 41 % yield (entry 1, Table 4). However the
activation was observed in both the a C–H bonds (2 and 5)
resulting two products, as observed in the GC–MS (Sup-
porting information, Fig. S16). Use of an unsaturated five
member heterocyclic molecule, furan, resulted in 48 %
yield of the 2 phenyl-substituted product. The catalyst 1
was successful in catalyzing the coupling of furan with
various other alkyl Grignard reagents as seen in Table 4,
with the formation of new sp2(C)–sp3(C) bonds. The use
of butylmagnesium chloride with furan yielded 37 % of
butylfuran as product (Supporting information, Fig. S17).
Additionally, the catalyst 1 was also successful in the C–H
activation in six member heterocyclic molecule 1,4 diox-
ane. About 61 % yield of the 2 phenyl-substituted product
was observed in the GC (Supporting information, Fig.
S20), showing the efficiency of the process in selective
activation of a sp3 and sp2 C–H in oxygen containing
The presence of any free radical mechanism/route in the
reaction was checked using a control reaction in the
Scheme 1 Proposed reaction
mechanism
N
O
N
Ni
R
N
RMgCl
Oxygen directed
C-H activation
at 2nd position
N
(OA)
N
Ni
X
N
N
1
H
N
Ni
N
i) RE
ii) Dibromoethane
R
O
OA = Oxidative addition
RE = Reductive elimination
R
O
2-substituted
tetrahydrofuran
123

514
Y. Gartia et al.
Table 4 C–H bond activation of different oxygen containing heterocyclics for the cross coupling reaction with Grignard reagents
Heterocyclic Grignard
Entry
Product
% Yield
substrate
reagent
MgCl
,
1
41
O
O
O
O
O
O
MgCl
MgCl
2
3
61
48
O
O
O
MgCl
3
4
5
6
37
40
32
3
O
O
O
O
MgCl
O
O
MgCl
5
5
Grignard reagent in diethylether (0.92 mmol), dibromoethane (90 lL, 1.04 lmol) at 25 °C. Reaction time 1 h. Yield (%) is percent of Grignard
reagent coupled to the oxygen containing heterocyclic molecules
heterocyclic molecules using complex 1. Interestingly, all
the Grignard reagents in the above-mentioned reactions
(Table 4) were prepared and used in diethyl ether. How-
ever, no cross coupled reaction product involving C–H
bond activation of diethyl ether was obtained indicating the
selectivity of the catalyst for C–H activation towards cyclic
ethers.
also utilizing the nickel catalyst for activation of C–H
bonds in many other heterocyclic molecules.
Acknowledgments AG would like to thank National Science
Foundation EPSCoR program (Grant EPS-1003970) for financial
support. AG and DEJ also would like to thank the National Science
Foundation for the (Grant CHE-1229149) major research instrument
grant which enabled them to complete this work.
4 Conclusion
References
1. Chatt J, Davidson JM (1965)
JR9650000761
2. Crabtree RH (2001) J Chem Soc Dalton Trans. doi:10.1039/
B103147N
3. Shilov AE, Shul’pin GB (1997) Chem Rev 97:2879
¨
4. Wencel-Delord J, Droge T, Liu F, Glorius F (2011) Chem Soc
Rev 40:4740
5. Li B-J, Shi Z-J (2012) Chem Soc Rev 41:5588
6. Wencel-Delord J, Glorius F (2013) Nat Chem 5(369):2013
7. Hashiguchi BG, Bischof SM, Konnick MM, Periana RA (2012)
Acc Chem Res 45:885
8. Lyons TW, Sanford MS (2010) Chem Rev 110:1147
9. Godula K, Sames D (2006) Science 312:67
10. Chen DYK, Youn SW (2012) Chem Eur J 18:9452
11. De Meijere A, Diederich F (2004) Metal-catalyzed cross-cou-
pling reactions. Wiley, Weinheim
12. Yeung CS, Dong VM (2011) Chem Rev 1111:1215
13. Janowicz AH, Bergman RG (1983) J Am Chem Soc 105:3929
14. Jones WD, Feher FJ (1984) J Am Chem Soc 106:1650
15. Periana RA, Bergman RG (1984) Organometallics 3:508
16. Wax MJ, Stryker JM, Buchanan JM, Kovac CA, Bergman RG
(1984) J Am Chem Soc 106:1121
17. Halpern J (1985) Inorg Chim Acta 100:41
18. Jones WD, Feher FJ (1985) J Am Chem Soc 107:620
19. Stoutland PO, Bergman RG (1985) J Am Chem Soc 107:4581
J Chem Soc. doi:10.1039/
A nickel(II) pincer complex (1) was used for efficient
activation of sp3 C–H bond in oxygen containing hetero-
cyclic molecules particularly in THF. The application of 1
for activation of a sp2 and sp3 C–H bonds in other oxygen
containing heterocyclic molecules were also examined
with successful catalysis. The nickel(II) complex enabled
the activation of the C–H bond for cross coupling with
various Grignard reagents at room temperature in less than
1 h. The complex (1) is the first such nickel based pincer
complex which was used in the activation of a sp3 C–H
bond in THF and C–C bond formation by cross coupling
reactions with Grignard reagents. 1 has shown excellent
reactivity and efficiency with turnover frequency (TOF) of
4,130 h-1 with catalyst loading of only 0.01 mol%. To the
best of our knowledge such high catalytic activity using a
nickel complex is unknown in the literature for cross-
coupling reaction involving activation of an a sp3 C–H
bond in heterocyclic molecules. The method could prove as
a valuable route for the production of value added pro-
ducts, under mild reaction conditions. Currently, we are
123

C–H Bond Activation of Oxygen Containing Heterocycles by a Nickel Complex
515
20. Baker MV, Field LD (1986) J Am Chem Soc 108:7433
21. Desrosiers PJ, Shinomoto RS, Flood TC (1986) J Am Chem Soc
108:1346
43. Chen Q, Ilies L, Nakamura E-I (2011) J Am Chem Soc 133:428
44. Ackermann L, Hofmann N, Vicente R (2011) Org Lett 13:1875
45. Zhao Y, Chen G (2011) Org Lett 13:4850
22. Desrosiers PJ, Shinomoto RS, Flood TC (1986) J Am Chem Soc
108:7964
46. Ilies L, Chen Q, Zeng X, Nakamura E (2011) J Am Chem Soc
133:5221
23. Shinomoto RS, Desrosiers PJ, Harper TGP, Flood TC (1990) J
Am Chem Soc 112:704
24. Chen H, Schlecht S, Semple TC, Hartwig JF (2000) Science
287:1995
25. Boutadla Y, Davies DL, Macgregor SA, Poblador-Bahamonde AI
(2009) Dalton Trans 30:5820
26. Giri R, Shi B-F, Engle KM, Maugel N, Yu J-Q (2009) Chem Soc
Rev 38:3242
27. Shimizu M, Hiyama T (2011) Sci Synth Stereosel Synth 3:567
28. Jana R, Pathak TP, Sigman MS (2011) Chem Rev 111:1417
29. Sezen B, Sames D (2003) J Am Chem Soc 125:10580
30. Yang L, Huang H (2012) Catal Sci Technol 2:1099
31. Bergman RG (2007) Nature 446:391
32. Neufeldt SR, Sanford MS (2012) Acc Chem Res 5:936
33. Choi J, Wang DY, Kundu S, Choliy Y, Emge TJ, Krogh-Jes-
persen K, Goldman AS (2011) Science 332:1545
34. Chen X, Engle KM, Wang D-H, Yu J-Q (2009) Angew Chem Int
Ed 48:5094
47. Yang L, Correia CA, Li CJ (2011) Org Biomol Chem 9:7176
48. Chen X, Goodhue CE, Yu J-Q (2006) J Am Chem Soc 128:12634
49. Romero-Revilla JA, Garcia-Rubia A, Gomez-Arrayas R, Fer-
nandez-Ibanez MA, Carretero JC (2011) J Org Chem 76:9525
50. Chu JH, Chen C-C, Wu M-J (2008) Organometallics 27:5173
51. Norinder J, Matsumoto A, Yoshikai N, Nakamura E (2008) J Am
Chem Soc 130:5858
52. Xin PY, Niu H-Y, Qu G-R, Ding R-F, Guo H-M (2012) Chem
Commun 48:6717
53. Liu D, Liu C, Li H, Lei A (2013) Angew Chem Int Ed 52:4453
54. Wasilke J-C, Wu G, Bu X, Kehr G, Erker G (2005) Organome-
tallics 24:4289
55. Gartia Y, Biswas A, Stadler M, Nasini UB, Ghosh A (2012) J
Mol Catal A 363–364:322
56. Huang D, Holm RH (2010) J Am Chem Soc 132:4693
57. Huang D, Makhlynets OV, Tan LL, Lee SC, Rybak-Akimova
EV, Holm RH (2011) Inorg Chem 50:10070
58. Singh PP, Gudup S, Ambala S, Singh U, Dadhwal S, Singh B,
Sawant SD, Vishwakarma RA (2011) Chem Commun 47:5852
59. Armarego WLF, Perrin DD (1997) Purification of laboratory
chemicals. Butterworth Heinemann, Burlington
35. Dyker G (1999) Angew Chem Int Ed 38:1699
36. Jazzar R, Hitce J, Renaudat A, Sofack-Kreutzer J, Baudoin O
(2010) Chem Eur J 16:2654
37. Yoshikai N, Mieczkowski A, Matsumoto A, Ilies L, Nakamura E
(2010) J Am Chem Soc 132:5568
60. Yoshikai N, Asako S, Yamakawa T, Ilies L, Nakamura E (2011)
Chem Asian J 6:3059
38. Nakamura E, Yoshikai N (2010) J Org Chem 75:6061
39. Li H, Li B-J, Shi Z-J (2011) Catal Sci Tech 1:191
40. Chatani N, Asaumi T, Yorimitsu S, Ikeda T, Kakiuchi F, Murai S
(2001) J Am Chem Soc 123:10935
41. Zhang Y-H, Shi B-F, Yu J-Q (2009) Angew Chem Int Ed
48:6097
61. Gartia Y, Pulla S, Ramidi P, Farris CC, Nima Z, Jones DE, Biris
AS, Ghosh A (2012) Catal Lett 142:1397
62. Csok Z, Vechorkin O, Harkins SB, Scopelliti R, Hu X (2008) J
Am Chem Soc 130:8156
63. Qian X, Kozak CM (2011) Synlett 6:852
64. Ohki Y, Hatanaka T, Tatsumi K (2008) J Am Chem Soc
130:17174
42. Ackermann L, Novak P, Vicente R, Hofmann N (2009) Angew
Chem Int Ed 48:6045
123