Nickel-catalyzed N-vinylation of heteroaromatic amines via C-H bond activation

Article abstract of DOI:10.1039/c7ob01791j

Here, we report a ligand- and reductant-free nickel-catalyzed N-vinylation of heteroaromatic amines using biorenewable p-cymene as a solvent. This unprecedented cross-coupling strategy has high functional group tolerance (halides, alkoxy, cyano, chiral motif, etc.) and proceeded via C-H bond activation.

Full text of DOI:10.1039/c7ob01791j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Nickel-Catalyzed N-Vinylation of Heteroaromatic amines via C-H
bond Activation†
Vinod G Landge, Jagannath Rana, Murugan Subaramanian, and Ekambaram Balaraman*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Here, we report a ligand- and reductant-free nickel-catalyzed N- the use of structurally complex ligand systems for palladium
Vinylation of heteroaromatic amines using biorenewable p- catalysis by merging of Ni(II) and photoredox catalysis is
cymene as a solvent. This unprecedented cross-coupling strategy reported by the research groups of Buchwald, and MacMillan.9
has high functional group tolerance (halides, alkoxy, cyano, chiral
R1
motif etc.) and proceeded via C-H bond activation.
N
R2
[Ni]
Ar
NHC / Phosphine ligand
Transition metal-catalyzed C-N bond forming reactions have
Stoichiometric reactant
X = halides, OTf, OMe,
OCONEt2, OSONR2 etc.,
been under great development, due to their importance in
X
R1
pharmaceuticals and biological science.1 Over the past few
decades, substantial development has been achieved for the
palladium-catalyzed Buchwald-Hartwig C-N bond coupling
reactions using a complex ligand architecture. The ligand
frameworks that have been used in the classical Pd-catalyzed
Buchwald-Hartwig cross-coupling reaction often employ a few
key design elements such as sterically encumbered framework,
hemilabile coordinating groups, electronically tuned
substituents to enact high catalytic efficiency.2-3 Indeed, a
general and complementary approach using non-precious
metals for productive C-N bond formation under ligand-free
conditions is highly desirable.4 Despite a few notable examples
of copper-catalyzed Ullmann C(sp2)-N cross-couplings,5
considerable efforts have been made in the field of C-N bond
forming strategy using earth-abundant and cost-effective
nickel catalyst; however, a need of sterically demanding
alkylphosphine and N-heterocyclic carbene ancillary ligands
are the potential concern.6-7 In addition, they often require
either air-sensitive Ni(0) sources or expensive Ni(II) precursors
with a stoichiometric amount of external reducing agents.8
Hence, it would be highly desirable to develop an efficient
catalytic protocol for C-N bond coupling reactions (N-arylation
and N-vinylation) under ligand-, and stoichiometric reductant-
free conditions catalyzed by cheap, commercially available
nickel salts. Very recently, an elegant approach alternative to
Ar
[Ni]
Ni
N
R2
Photoredox catalyst
Ar
+
Earth-abundant
Inexpensive
blue LED
X = Br
R1
HN
Ar2
R2
Our work
[Ni]
N
Ar1
Het
X = Cl or Br
∗ Simple and Efficient
∗ Ligand- & Reductant-free
Selective alkenylation
(in presence of aryl halides)
∗
∗ Broad substrate scope
Scheme 2. Nickel-catalyzed C-N bond formation.
The 2-pyrimidylaniline motif is a prominent structural unit
found in numerous bioactive and synthetic compounds with
vital medicinal value (e.g. Gleevec, anticancer drug) also used
in crop protection.10 Due to the good chelating ability of 1,3-
diazine motif, it has been successfully used in the ortho C-H
bond functionalization reactions.11-12 However, no reports
describe the C-N bond cross-coupling of this sterically
congested amine derivatives. Herein, we report the first
efficient nickel catalyzed N-vinylation of congested amines
pertaining 2-pyrimidylaniline motif under ligand- and the
reductant-free conditions. The readily available, cheap and
convenient NiCl2 was used as nickel source. The developed Ni-
catalyzed C-N bond forming approach is robust and has a
broad substrate scope. Importantly, aryl halides were
effectively retained during the catalysis, thus can be effectively
used for late-stage functionalization. Gratifyingly, the
underexploited, biorenewable p-cymene is employed as a
solvent for the present strategy. The p-cymene can be
obtained in large amounts from side product of cellulose and
citrus industry.13-14
Catalysis Division, Dr. Homi Bhabha Road, CSIR-National Chemical Laboratory
eb.raman@ncl.res.in;
(CSIR-NCL),
Pune
-
balaramane2002@yahoo.com
411008,
India.
E-mail:
†Electronic Supplementary Information (ESI) available: [details of experimental
procedure, characterization of compounds and copy of NMR data]. See
DOI:10.1039/x0xx00000x
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substituents, regardless of their electronic properties
underwent C-N bond formation and gave the corresponding
products in good to excellent yields. Various ortho-substituted
anilines such as -OMe and -F were processed smoothly under
our optimized conditions and provided the products 3b in 60%
and 3c in 88% isolated yields. It was found that a range of
anilines bearing electron-donating, electron-withdrawing, and
halide substituent at the meta and para position of the arene
ring were effectively coupled with 2a and yielded the products
(
3d-3h) in excellent yields (up to 90%). Notably, a base
Scheme 1. Selected bioactive 2-primidyl anilines.
sensitive –CN group showed excellent functional group
tolerance. Thus, 1f reacted smoothly with 2a to afford 3f in
65% isolated yield. Both mono- and di-substituted aniline
derivatives gave the corresponding C-N bond products in good
yields (3n in 65% and 3o in 83%). It is noteworthy that the
allylic amine (1p), n-pentylamine (1q) and cyclopentyl amine
Initially, a range of nickel salt and base in the presence of N-
(m-tolyl)pyrimidin-2-amine
(
1g
)
and
(E)-(2-
bromovinyl)benzene (2a) as representative coupling partners
were investigated. Varying different nickel salts we found that
NiCl2 proved to give an optimal result (Table 1, entries 1-5).
(
1r) also proceeded efficiently and provided the corresponding
N-vinylated products in moderate to good yields (products 3p
in 69%, 3q in 63%, and 3r in 73% yields) under standard
Importantly, Ni(COD)2 also showed
a catalytic activity,
resulting in moderate yields of the C-N bonded product 3g
reaction conditions. Remarkably, a chiral amine derivative (1s
)
under standard reaction conditions (Table 1, entry 4). Under
underwent this reaction efficiently and gave the
enantiomerically pure product 3s in 75% yield. To our delight,
heterocyclic amine derivatives also underwent C-N bond
formation under optimized conditions and gave the desired
product in good isolated yields (3t in 80% and 3u in 81%).
Thus, anilines were cross-coupled with ample scope, and
the same reaction conditions (E)-2-chlorovinyl)benzene (2a′
)
gave 71% of 3g. Notably, there was no C-alkenylated product
observed under our reaction conditions. In all cases, unreacted
starting material 1g was recovered. No reaction was observed
in the absence of the nickel catalyst (Table 1, entry 7). The
efficiency of the reaction was significantly affected in the
absence of a base. An evaluation of base revealed that LiOtBu
provided a significant improvement in the yield of 3g (Table 1,
entries 8-10). However, the specific need of LiOtBu in the
present Ni-catalyzed C-N bond formation reaction is not clear
at present. The N-vinylation of anilines was not affected in the
presence of mercury, which indicates the homogeneous
functional group tolerance (-F, -Cl, -Br, -OMe, -CN).
Table 2. Scope of amines.a,b
2-pym
2-pym
NH
N
Br
2 mol% NiCl2
R
+
R
LiOtBu
p-cymene,
1
3 (up to 90%)
2a
character of a nickel catalyst (Table 1, entry 13).
Table 1. Optimization of the reaction conditions.
2-pym
2-pym
N
2-pym
N
N
R
R
R
R = H = 3a (80%)
R = OMe = 3b (60%)
R = F = 3c (88%)
R = CF3 = 3d (75%)
R = F = 3e (78%)
R = CN = 3f (65%)
R = Me = 3g (90%)
R = Cl = 3h (88%)
R = Br = 3i (80%)
R = OMe = 3j (85%)
R = Cl = 3k (90%)
2-pym
2-pym
N
2-pym
N
N
R
Me
Me
Br
Me
3n (65%)
R = H = 3l (75%)
R = Br = 3m (70%)
3o (83%)
N
N
N
2-pym
2-pym
2-pym
3p (69%)
3q (63%)
3r (73%)
Me
S
N
N
N
2-pym
2-pym
N
3u (80%)
2-pym
a Reaction conditions: 1g (0.5 mmol), 2a (X= Br) (0.75 mmol), NiCl2 (2 mol%), LiOtBu (0.6
3t (80%)
3s (75%)
b
mmol), and p-cymene (2 mL) heated at 120 oC for 12 h under argon atm. Isolated
yields. c X= Cl (2a’) was used. n.d. = not detected.
a Reaction conditions: 1 (0.5 mmol), 2a (0.75 mmol), NiCl2 (2 mol%), LiOtBu (0.6 mmol),
and p-cymene (2 mL) heated at 120 oC for 12 h under Ar atm. b Isolated yields.
With the optimal conditions in hand, we began to study the
scope of the process with respect to the aniline derivatives
(Table 2). Thus, 2-pyrimidyl anilines bearing different
Next, the scope of β-bromostyrene coupling partner was
investigated with 1a as the benchmark substrate in the Ni-
2 | J. Name., 2012, 00, 1-3
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catalyzed C−N cross-coupling reaction. The β-bromostyrenes coupling reactions with 2a, highlighting the unique features of
2a 2f bearing substituents such as a fluoro, chloro, alkyl, the pyrimidyl aniline motif for this transformation.
phenyl, naphthyl and di-substituted 2g afforded the
-
(
)
corresponding products in 60-83% yield under the standard
reaction conditions. However, cis-β-bromostyrene, and α-
bromostyrene and simple vinyl bromide didn’t give the desired
N-vinylated product.
Table 3. Scope of vinylbromides.a,b
a Reaction conditions: 1g (0.5 mmol), 2 (0.75 mmol), NiCl2 (2 mol%), LiOtBu (0.6 mmol),
and p-cymene (2 mL) heated at 120 oC for 12 h under argon atm. b Isolated yields.
Importantly, aryl halides were effectively retained during the
C-N bond formation. Thus, the present NiCl2-catalyzed N-
vinylation strategy can be used for late-stage functionalization
(Scheme 3). As an indication of the possible practical potential
of this nickel-catalyzed N-vinylation strategy, a gram-scale
reaction was conducted, and notably, no significant erosion of
yield of 3g (1.4 g) was observed.
Scheme 4. Mechanistic studies.
Deuterium labeling experiments were performed with an
isotopically labeled substrate ([D1]-1c) in the absence as well
as in the presence of 2a. These experimental results indicated
that there were decreased in D%, and signifies that N-
vinylation can occur via the C-H bond activation by mono-
dentate chelation assistance of the pyrimidyl aniline
motif.11b,15 However, the formation of products 3p
, 3q, 3r, and
3s didn't support the ortho-C-H bond activation pathway. The
radical trapping experiment was carried out using (2,2,6,6-
tetramethylpiperidin-1-yl)oxidanyl (TEMPO) and prop-1-en-2-
ylbenzene under standard reaction condition, and it was
observed that the reaction was inhibited, which implies that
the single-electron transfer (SET) mechanism could not be
Scheme 3. Applications in the late-stage functionalization.
ruled out.
A competition experiment with a different
electronic substituent on anilines revealed that the reaction
favors the electron-withdrawing group. To know the nature of
catalytically active species, a model reaction was carried out
separately using Ni(II), and Ni(0) salts under identical
To define the possible intermediates and pathway, several
control experiments were carried out as shown in Scheme 4. It
is noteworthy that diphenylamine, N-phenylpyridin-2-amine,
and N-phenylpyrazin-2-amine failed to undergo C-N cross-
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conditions. The self-coupled product
7
was observed in case
Conclusions
the of Ni(COD)2, which illustrates that Ni(0) converted into
Ni(II) during the catalysis and the in situ generated Ni(II)
catalyzed the C-N bond formation. This experimental results
confirmed that Ni(II) might be the catalytically active species. A
time-dependent experiment on the direct formation of 3a was
conducted to study the reaction kinetics (Fig. 1). The kinetic
studies on the formation of 3a indicate that there is an
induction period in the present nickel catalysis.
In summary, we have reported on the first nickel catalyzed N-
vinylation sterically congested anilines under ligand- and
reductant-free conditions. Deuterium labeling studies provided
evidence for a C-H metalated intermediate by mono-dentate
chelation assistance of the pyrimidyl aniline motif.
A
biorenewable p-cymene (a side product of cellulose and citrus
industry) has been employed as a solvent for the present
strategy.
Acknowledgements
This research is supported by the SERB (SB/FT/CS-065/2013).
VGL and JR thank the CSIR-SRF for the research fellowship.
Notes and references
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Figure 1. Kinetic studies on the formation of 3a.
In another experiment, the mixture of NiCl2, aniline 1j and
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HRMS analysis of the reaction mixture (Scheme 5) showed the
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15 See the ESI.†
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