Nickel-catalyzed site-selective amidation of unactivated C(sp 3)-H bonds

Article abstract of DOI:10.1002/chem.201403356

Intramolecular dehydrogenative cyclization of aliphatic amides was achieved on unactivated sp³ carbon atoms by a nickel-catalyzed C-H bond functionalization process with the assistance of a bidentate directing group. The reaction favors the C-H bonds of β-methyl groups over the γ-methyl or β-methylene groups. Additionally, a predominant preference for the β-methyl C-H bonds over the aromatic sp² C-H bonds was observed. Moreover, this process also allows for the effective functionalization of benzylic secondary sp³ C-H bonds. β-Lactams from nickel catalysis: Intramolecular dehydrogenative cyclization of aliphatic amides was achieved on unactivated sp³ carbon atoms by a nickel-catalyzed C-H bond functionalization process with the assistance of a bidentate directing group (see scheme).

Full text of DOI:10.1002/chem.201403356

DOI: 10.1002/chem.201403356
Communication
&
CÀH Activation
Nickel-Catalyzed Site-Selective Amidation of Unactivated C(sp3)ÀH
Bonds
Xuesong Wu,[a] Yan Zhao,[a, b] and Haibo Ge*[a, b]
ligand-assisted direct functionalization of unactivated CÀH
Abstract: Intramolecular dehydrogenative cyclization of
bonds from the Daugulis’ group,[10] NiII-catalyzed site-selective
aliphatic amides was achieved on unactivated sp3 carbon
direct arylation and alkylation reactions of aliphatic amide de-
atoms by a nickel-catalyzed CÀH bond functionalization
rivatives were demonstrated very recently in Chatani’s and our
process with the assistance of a bidentate directing
laboratories, respectively (Scheme 1).[11] It is believed that a cat-
group. The reaction favors the CÀH bonds of b-methyl
groups over the g-methyl or b-methylene groups. Addi-
tionally, a predominant preference for the b-methyl CÀH
bonds over the aromatic sp2 CÀH bonds was observed.
Moreover, this process also allows for the effective func-
tionalization of benzylic secondary sp3 CÀH bonds.
alytic NiII/NiIII cycle is involved in the case of alkylation from ox-
idation of the cyclic NiII species by an alkyl radical.[11b] On the
basis of the above results, it is envisaged that with an external
Transition-metal-catalyzed direct CÀH bond functionalization of
unactivated sp2 and sp3 carbon atoms is of current research in-
terest.[1] Compared with the traditional cross-coupling reac-
tions, this process avoids the prefunctionalization of the unac-
tivated CÀH bonds, and thus is more efficient and favorable
from the economic point of view. Among this reaction class,
Ni0 or NiII-catalyzed cross-couplings on aromatic sp2 carbon
atoms has received considerable attention, and significant
progress has been made over the last few years.[2] For example,
Ni0-catalyzed direct functionalization on acidic CÀH bonds of
pyridine,[3] perfluorobenzene,[4] and azole derivatives[5] has
been well documented. Recently, the reaction scope was suc-
cessfully extended to benzene derivatives.[6] Meanwhile, NiII-
catalyzed direct CÀH bond functionalization of azole deriva-
tives was also established.[7] Very recently, the bidentate
ligand-assisted direct alkylation of benzamide derivatives by
a NiII-catalyzed CÀH bond functionalization process was also
demonstrated.[8] In comparison, Ni-catalyzed direct CÀH bond
functionalization of unactivated sp3 carbon atoms is underde-
veloped. In 2011, dehydrogenative [4+2] cyclization of form-
amides with alkynes was reported in Hiyama’s laboratory by
a Ni0-catalyzed in situ sp3 CÀH bond activation process.[9] In-
spired by the development of the PdII-catalyzed bidentate
Scheme 1. NiII-catalyzed sp3 CÀH functionalization. acac=acetylacetone;
dppbz=1,2-bis(diphenylphosphino)benzene.
single-electron oxidant, selective reductive elimination of the
resulting NiIII complex could potentially be achieved. Herein,
we report the first example of Ni-catalyzed intramolecular cycli-
zation on unactivated sp3 carbon atoms.[12] It is also notewor-
thy that the products, the monocyclic or spiro-b-lactam deriva-
tives, are important subunits in biologically active natural prod-
ucts and pharmaceutical compounds.[13]
Our investigation began with nickel-catalyzed dehydrogena-
tive cyclization of 2-ethyl-2-methyl-N-(quinolin-8-yl)pentanam-
ide (1a) with TEMPO as the external single-electron oxidant
(Table 1). After an initial solvent screening, butyronitrile proved
to be optimal, albeit with low yield (Table 1, entry 7). As ex-
pected, high site-selectivity was observed for this reaction, fa-
voring the b-methyl group over the b-methylene and g-methyl
groups. Next, an extensive screening of nickel source was car-
ried out. Interestingly, while the majority of catalysts failed to
yield the desired product, the reaction was significantly im-
proved by NiI2 (entry 11). Additionally, the reaction yield was
further increased with [Ni(dme)2I2] as the catalyst (entry 12).
Further optimization showed that this reaction was improved
by the addition of a catalytic amount of TBAI (entry 17). It was
then noticed that a high reaction yield could be obtained by
using the solvent mixture of butyronitrile and benzonitrile in
a 3:2 ratio (entry 18).
[a] Dr. X. Wu, Y. Zhao, Prof. Dr. H. Ge
Department of Chemistry and Chemical Biology
Indiana University Purdue University Indianapolis
Indianapolis, Indiana 46202 (USA)
Fax: (+1)317-2744701
E-mail: geh@iupui.edu
[b] Y. Zhao, Prof. Dr. H. Ge
Institute of Chemistry and BioMedical Sciences and
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing 210093 (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403356.
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that a tertiary a-carbon atom is
required for this process since
amides 3–5 failed in this reac-
tion.[14] Furthermore, CÀH bond
functionalization on the g-sp3
carbon atom of 3,3-dimethyl-N-
Table 1. Optimization of reaction conditions.[a]
(quinolin-8-yl)butanamide
(6)
Entry
Ni source
[mol%]
Base
(2.0 equiv)
Additive
(0.1 equiv)
Solvent (v/v)
Yield
[%][b]
was also not effective, which in-
dicated that the formation of
the six-membered ring inter-
mediate is not feasible in the cy-
clonickelation step under the
current catalytic system.
1
2
3
4
5
6
7
8
Ni(OAc)2 (10)
Ni(OAc)2 (10)
Ni(OAc)2 (10)
Ni(OAc)2 (10)
Ni(OAc)2 (10)
Ni(OAc)2 (10)
Ni(OAc)2 (10)
Ni(OAc)2 (10)
[Ni(acac)2] (10)
NiBr2 (10)
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
Na2HPO4
PhCO2Na
Li2CO3
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
KI
toluene
DMSO
DMF
NMP
EtCN
PhCN
nPrCN
nPrCN
nPrCN
nPrCN
nPrCN
nPrCN
nPrCN
nPrCN
nPrCN
nPrCN
nPrCN
0
<5
<5
7
9
11
14
<5
9
<5
49
66
On the basis of the above ob-
servations and previous re-
ports,[8,15]
mechanism
a
plausible reaction
is proposed
9
10
11
12
13
14
15
16
17
18
19
20
21[d]
NiI2 (10)
(Scheme 2). It is believed that
this process is initiated by coor-
dination of amide 1 to a NiII spe-
cies followed by a ligand ex-
change process under basic con-
ditions to produce the nickel
complex A. Cyclonickelation of
this intermediate generated the
NiII complex B, which is oxidized
to the NiIII species C by the
[Ni(dme)2I2] (10)
[Ni(dme)2I2] (10)
[Ni(dme)2I2] (10)
[Ni(dme)2I2] (10)
[Ni(dme)2I2] (10)
[Ni(dme)2I2] (10)
[Ni(dme)2I2] (10)
[Ni(dme)2I2] (5)
–
41
32
59
45
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
TBAI
TBAI
TBAI
TBAI
TBAI
75
nPrCN/PhCN (3:2)
nPrCN/PhCN (3:2)
nPrCN/PhCN (3:2)
nPrCN/PhCN (3:2)
88 (85)[c]
61
0
23
[Ni(dme)2I2] (10)
[a] Reaction conditions: 1a (0.3 mmol), Ni source, TEMPO (3 equiv), base (2 equiv), additive (0.1 equiv), 1.5 mL
of solvent, 1508C, 24 h. [b] Yields and conversions are based on 1a, determined by 1H NMR spectroscopy by
using dibromomethane as the internal standard. [c] Isolated yields. [d] At 1408C. dme=1,2-dimethoxyethane;
TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy; TBAI=tetrabutylammonium iodide.
single-electron
oxidant
TEMPO.[16] Reductive elimination
of the intermediate C generates
the desired product 2 and a NiI
With the optimized conditions in hand, we then carried out
the substrate scope studies (Table 2). As we expected, good to
excellent yields of the desired products were obtained with
2,2-disubstituted propanamides bearing both the linear and
cyclic chains (2a–m). Additionally, a predominant preference
for the sp3 CÀH bonds of the b-methyl group over the sp2 CÀH
bonds of phenyl group was observed with the 2-phenyl-substi-
tuted substrates (2n–p), which indicated that the formation of
a five-membered ring intermediate is more favored than a six-
membered ring intermediate in the cyclonickelation step. It is
also noteworthy that in the case of copper-catalyzed cycliza-
tion, sp2 CÀH amidation products were always observed along
with the sp3 CÀH amidation products.[12] Interestingly, a prefer-
ence for CÀH bond functionalization of the primary b-methyl
groups was also observed over the relatively reactive benzylic
secondary b-carbon atoms (2q and 2r). In contrast with this,
the copper-catalyzed process favored CÀH bond functionaliza-
tion of the benzylic secondary b-carbon atoms.[12] To our de-
light, CÀH bond functionalization of the benzylic secondary
carbon atoms could also be effectively achieved (2s–z). Fur-
thermore, halogens (Cl and Br) were also well tolerated under
the current catalytic system (2u and 2v). Additionally, the re-
placement of the 8-aminoquinoline with the removable 8-
amino-5-methoxyquinoline moiety had no apparent effect to-
wards the reaction (2aa), which allows for the efficient synthe-
sis of common b-lactam derivatives.[10p] It should be mentioned
species that is reoxidized to the NiII species by TEMPO.[17]
To further gain some insights into the reaction mechanism,
we carried out a series of deuterium-labeling experiments with
2-ethyl-2-methyl-N-(quinolin-8-yl)butanamide (1c) (Scheme 3).
The H/D exchange occurred for the deuterium-labelled starting
material [D3]1c in the reaction. Additionally, this phenomenon
was observed for [D3]1c in the absence of TEMPO. These re-
sults suggest that the step of intermediate A to B is a reversible
process.
To further show the synthetic utility of this methodology, 1-
(5-methoxyquinolin-8-yl)-3-methyl-3-phenylazetidin-2-one
(2aa) was subjected to the oxidative conditions, and the de-
sired NH-b-lactam product 3-methyl-3-phenylazetidin-2-one (7)
was obtained in 66% yield (Scheme 4).[10p,12]
In summary, a highly site-selective intramolecular dehydro-
genative cyclization reaction of 2,2-disubstituted propiona-
mides was developed by a nickel-catalyzed sp3 CÀH bond
functionalization process with good functional-group toler-
ance. A great preference for CÀH bonds of b-methyl groups
over the g-methyl or b-methylene CÀH bonds was observed.
Furthermore, sp3 CÀH bond functionalization of b-methyl
groups was favored over the aromatic sp2 CÀH bonds. Addi-
tionally, sp3 CÀH bond functionalization of benzylic secondary
b-carbon atoms was effectively achieved. A detailed mechanis-
tic study of this process is currently underway in our laborato-
ry.
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Communication
Table 2. CÀH amidation on primary and secondary sp3 carbon atoms.[a]
Scheme 2. Plausible reaction mechanism.
Scheme 3. Deuterium labeling experiments.
Scheme 4. Oxidative cleavage of the 5-methoxyquinolyl group.
[a] Reaction conditions:
1 (0.3 mmol), [Ni(dme)2I2] (10 mol%), TEMPO
(3 equiv), K2HPO4 (2 equiv), TBAI (0.1 equiv), nPrCN/PhCN (1.5 mL, 3:2, v/
v), 1508C, 24 h. [b] Isolated yield. Q=8-quinolinyl.
Acknowledgements
Experimental Section
General method
We gratefully acknowledge Indiana University Purdue Universi-
ty Indianapolis for financial support. We would also like to ac-
knowledge Nanjing University for financial support. The Bruker
500 MHz NMR spectrometer was purchased using funds from
an NSF-MRI award (CHE-0619254).
A 20 mL tube was charged with a,a,a-trisubstituted N-(quinolin-8-
yl)acetamides (1, 0.30 mmol), [Ni(dme)2I2] (14.8 mg, 0.030 mmol),
TEMPO (140 mg, 0.90 mmol), K2HPO4 (104 mg, 0.60 mmol), TBAI
(11.1 mg, 0.030 mmol), and of nPrCN/PhCN (1.5 mL, 3:2, v/v). Then
the vial was sealed and stirred rigorously at 1508C for 24 h. After
removal of the solvent, the residue was purified by flash chroma-
tography on silica gel (gradient eluent of 2% EtOAc in hexanes,
v/v) to give the desired product 2.
Keywords: amidation · CÀH bond functionalization · nickel ·
site selectivity · b-lactams
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Received: May 1, 2014
Published online on && &&, 0000
&
&
Chem. Eur. J. 2014, 20, 1 – 5
www.chemeurj.org
4
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
COMMUNICATION
&
CÀH Activation
X. Wu, Y. Zhao, H. Ge*
&& – &&
Nickel-Catalyzed Site-Selective
Amidation of Unactivated C(sp3)ÀH
Bonds
b-Lactams from nickel catalysis: Intra-
molecular dehydrogenative cyclization
of aliphatic amides was achieved on un-
activated sp3 carbon atoms by a nickel-
catalyzed CÀH bond functionalization
process with the assistance of a biden-
tate directing group (see scheme).
Chem. Eur. J. 2014, 20, 1 – 5
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ