Nickel-catalyzed direct alkylation of C-H bonds in benzamides and acrylamides with functionalized alkyl halides via bidentate-chelation assistance

Article abstract of DOI:10.1021/ja401344e

The alkylation of the ortho C-H bonds in benzamides and acrylamides containing an 8-aminoquinoline moiety as a bidentate directing group with unactivated alkyl halides using nickel complexes as catalysts is described. The reaction shows high functional group compatibility. In reactions of meta-substituted aromatic amides, the reaction proceeds in a highly selective manner at the less hindered C-H bond.

Full text of DOI:10.1021/ja401344e

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Communication
The Nickel-Catalyzed Direct Alkylation of C-H Bonds
in Benzamides and Acrylamides with Functionalized
Alkyl Hal-ides via Bidentate-Chelation Assistance
Yoshinori Aihara, and Naoto Chatani
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja401344e • Publication Date (Web): 15 Mar 2013
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The Nickel-Catalyzed Direct Alkylation of C-H Bonds in
Benzamides and Acrylamides with Functionalized Alkyl Hal-
ides via Bidentate-Chelation Assistance
Yoshinori Aihara and Naoto Chatani*
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Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Supporting Information Placeholder
No other bidentate directing systems of other transition metal-
ABSTRACT: The alkylation of the ortho C‐H bonds in ben‐
zamides and acrylamides containing an 8‐aminoquinoline
moiety as a bidentate directing group with unactivated alkyl
halides using nickel complexes as the catalyst is described.
catalyzed transformations of C-H bonds had been reported when
this project was initiated.11 It is known that palladium complexes
can be used to catalyze many different types of transformation of
C-H bonds. However, if other transition metals could be used in
this system, it would open new possibilities for exploring new
The reaction shows a high functional group compatibility. In
catalytic reactions of C-H bonds.6c,12,13 In a previous study, we
reported that the Ru(0)-catalyzed C-H bond carbonylation of aro-
matic amides with a 2-pyridinylmethylamine moiety as the N,N-
bidentate directing group results in the formation of phthalimide
derivatives.12a This new directing group was also applicable to the
Ru-catalyzed carbonylation of aliphatic amides, which involves
the activation of unactivated C(sp3)-H bonds.12c,d The system was
also found to be applicable to the Ni(0)-catalyzed oxidative annu-
lation of aromatic amides with alkynes leading to the formation of
isoquinolones.6c Quite recently, we reported on the Ru(II)-
catalyzed ortho-arylation of aromatic amides with 2-
pyridinylmethylamine or 8-quinolinylamine as bidentate directing
groups.13 We wish to report herein that the use of Ni(II) complex-
es in conjunction with the N,N-bidentate system can be applied to
C-H bond alkylation with unactivated alkyl halides. The direct
alkylation of C-H bonds in a benzene ring with unactivated alkyl
halides is limited to several examples,14,15 compared with the
extensively studied C-H bond arylation. This is because the oxida-
tive addition of alkyl halides is unfavorable and the resulting al-
kyl-metal complexes tend to favor ß-hydride elimination.
reactions of meta‐substituted aromatic amides, the reaction
proceeds in a highly selective manner at the less hindered C‐
H bonds.
The catalytic transformation of C-H bonds has recently
emerged as one of the most promising and powerful methods for
the construction of C-C bond frameworks.1 A wide variety of
transformations of C-H bonds have been developed, many of
which involve the use of various transition metal complexes as
catalysts. The use of low cost and more abundant metals, especial-
ly nickel complexes has attracted recent attention for use in the
transformation of C-H bonds.2 However, most of the Ni-catalyzed
transformations of C-H bonds reported to date involve C(sp2)-H
bonds in pyridine derivatives3 or activated C(sp2)-H bonds in
specific aromatic systems, such as perfluorobenzene4 or azole
derivatives,5 which have acidic C-H bonds. Transformations of
C(sp2)-H bonds in benzene rings using Ni complexes are still
rare,6 although a pioneering example of chelation-assisted cy-
clometallation including the activation of C(sp2)-H bonds in a
benzene ring was achieved by using a nickel complex.7
Chelation-assisted transformation has become one of common
and powerful methods for the regioselective functionalization of
ortho C-H bonds. A wide variety of functional groups has been
evaluated for use as directing groups in the transformation of C-H
bonds to date. However, in spite of the tremendous progress made
to date,1 the development of new types of directing groups contin-
ues to be important, in terms of exploring novel types of trans-
formations of C-H bonds that cannot be achieved when conven-
tional directing groups are used. Bidentate directing groups have
recently attracted the attention of researchers, because they offer
the possibility of developing new types of transformations of C-H
bonds. Sames utilized a N,O-bidentate directing system in the
vinylation and carbonylation of C(sp3)-H bonds, but the reaction
required a stoichiometric amount of a palladium catalyst.8 In 2005,
Daugulis reported on the arylation of unactivated C(sp3)-H bonds
using 8-aminoquinoline and picolinamide as N,N-bidentate direct-
ing groups in conjunction with Pd(OAc)2 as a catalyst.9 Encour-
aged by Daugulis’s promising results, a number of transfor-
mations of C-H bonds have since been developed using a similar
chelation system in conjunction with Pd(OAc)2 as the catalyst.10
The reaction of amide 1a (0.3 mmol) with butyl bromide (0.45
mmol) in the presence of Ni(OTf)2/PPh3 as a catalyst and Na2CO3
as a base in toluene at 140 °C for 24 h gave the ortho-butylation
product 2a in 79% NMR yield, along with the recovery of 15% of
unreacted 1a (eq 1). Product yield was significantly affected by
the nature of the base used; Li2CO3 3%, K2CO3 0%, NaOAc 5%,
NaHCO3 41%, 2,6-lutidine 0%. The use of 2 equivalents of butyl
bromide improved the product yield to 88% isolated yield (91%
NMR yield). The addition of phosphine ligands is also important.
No reaction occurred when the reaction was carried out in the
absence of PPh3. The use of PCy3 gave 2a in 26% NMR yield. A
variety of nickel complexes could be used as catalysts (Ni(OAc)2
70%, NiBr2(dme) 76%, NiCl2 66%, Ni(cod)2 51% NMR yields).
Curiously, Ni(0) also showed catalytic activity.16 In all cases, the
starting amide 1a was recovered when the product yield of 1a was
low.
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coordination in a N,N’-fashion by the 8-aminoquinoline moiety is
essential for the reaction to proceed. Furthermore, the use of N-
methyl amide 5 failed to result in the formation of the phenylation
product, indicating that the presence of a proton on the amide
nitrogen is required for the reaction to proceed, although NH is
not included in the product formation at the first sight. The use of
2-pyridinylmethylamine, as in 6 and 2-(methylthio)aniline moie-
ties, as in 7 as bidentate directing groups resulted in low yields of
the alkylation products. The reaction appears to be more efficient
with the 8-aminoquinoline motif.
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With the optimized reaction conditions in hand, we examined
the scope of the reaction. Table 1 shows the results for reactions
of various aromatic amides with butyl bromide under standard
reaction conditions. A variety of functional groups were tolerated
in the reaction. The reaction of meta-substituted substrates result-
ed in selective alkylation exclusively at the less hindered C-H
bonds, irrespective of the electronic nature of the substituent,
indicating that the regioselectivity of the reaction was controlled
by the steric nature of the substituent groups. In general, electron-
withdrawing groups tended to give the butylation products in
higher yields. The addition of NaI was found to result in improved
yields, as in 1b and 1c, which is discussed below.
Table 1. Butylation of C-H Bonds in Aromatic Amidesa
Table 2. Butylation of C-H Bonds in α,ß-Unsaturated Amidesa
amide
productb
O
O
N
H
N
H
N
N
Bu
15 81%
O
O
O
N
H
N
H
N
N
N
N
N
N
Bu
16 67%
O
N
H
N
H
O
O
Bu
17 72%
O
O
N
H
N
H
Bu
18 54% (E:Z = 85:15)
a
Reaction conditions: amide (0.3 mmol), BuBr (0.6 mmol),
Ni(OTf)2 (0.03 mmol), PPh3 (0.06 mmol), Na2CO3 (0.6 mmol) in
toluene (1 mL) at 140 °C for 24 h. b Isolated yields.
This alkylation reaction was also applicable to α,ß-unsaturated
amides, as shown in Table 2. However, the reaction was limited to
tri-substituted α,ß-unsaturated amides, suggesting that the pres-
ence of a substituent at the α-carbon is an important factor in
terms of the reactivity of the substrates. Thus, 19 and 20 did not
give the corresponding butylation products.
a
Reaction conditions: amide (0.3 mmol), BuBr (0.6 mmol),
Ni(OTf)2 (0.03 mmol), PPh3 (0.06 mmol), Na2CO3 (0.6 mmol) in
b
c
toluene (1 mL) at 140 °C for 24 h. Isolated yields. NaI (0.6
d
mmol) Run at 160 °C. e BuI (0.6 mmol) was used instead of
BuBr. f BuBr (1.2 mmol) was used.
A variety of alkyl bromides were applicable to the alkylation
reaction, as shown in Table 3. Octyl iodide as well as octyl bro-
mide gave alkyation products in high yields. When octyl chloride
We next examined the effect of directing groups. No reaction
occurred when the corresponding N-2-naphthyl benzamide (3) and
ester 4 were used as the substrate in place of 1a, indicating that
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was used, 21 was not produced. However, the addition of NaI (2
amount of H/D exchange again occurred at the ortho position (the
d-content decreased from >98% to 43%) and on the nitrogen (eq
4), indicating that the cleavage of C-H bonds is reversible and
rapid. These results indicate that the cleavage of C-H bonds is not
likely the rate determining step in the reaction.
equiv) dramatically improved the product yield to 88% isolated
yield. In fact, the use of octyl iodide gave 21 in 88% yield. This
salt effect was also observed in the case of other sterically de-
manding alkyl halides or functionalized alkyl halides. Various
functional groups were tolerated in the reaction.
CD3
O
D
D
Q
N
H
Table 3. Alkylation of C-H Bonds in Aromatic Amides with
D
Ni(OTf)2
PPh3
Na2CO3
BuBr
10 mol%
20 mol%
2 equiv
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Functionalized Alkyl Halidesa,b
D
70%
CD3
O
D
d-content
Ni(OTf)2
PPh3, Na2CO3
RBr
D
D
51%
2 equiv
O
O
N
(3)
H
+
CD3
Q
toluene, 140 °C, 8 h
N
N
H
N
H
O
toluene, 140 °C, 24 h
N
D
D
D
Q
Q
1a-d7
1a
N
H
R
d-content
O
O
O
Bu
>98%
Q
Q
N
Q
D
25%
N
N
H
H
H
Ni(OTf)2
PPh3
Na2CO3
10 mol%
20 mol%
2 equiv
Oct
CD3
O
3
CD3
O
Ph
21
Oct
I
88%
92%
CN
D
D
D
D
22 74%
N
23 77%
Oct Br
Oct Cl
N
H
(4)
H
toluene, 140 °C, 8 h
88% recovery
0% (88%)
N
D
D
O
O
O
D
D
1a-d7
Q
Q
N
Q
d-content
N
N
H
d-content
H
H
43%
>98%
3
3
OMe
Ph
24 91%
25 (62%)
26 trace (61%)
TIPS
O
O
O
Q
N
Q
N
Q
N
H
H
H
3
CO2Me
27 trace (44%)
29 60% (76%)
28 47% (81%)
O
O
O
Q
N
Q
N
Q
N
We next performed competition experiments using a 1:1 mix-
H
H
H
ture of 1b and 1j with octyl bromide (eq 5). However, 1j reacted
to give 33 mainly in the competition experiments. This result
suggests that the electronic withdrawing group facilitates the reac-
tion.
OBn
32 83%
30 35% (70%)
31 72% (92%)
a
Reaction conditions: amide 1a (0.3 mmol), RBr (0.6 mmol),
Ni(OTf)2 (0.03 mmol), PPh3 (0.06 mmol), Na2CO3 (0.6 mmol) in
toluene (1 mL) at 140 °C for 24 h. b Isolated yields. A number in
the parenthesis is the yield using NaI (0.6 mmol).
Several studies were carried out, in an attempt to determine the
mechanism for the reaction. We anticipated that the alkylation
takes place via the addition of C-H bonds with alkenes which may
involve the generation of alkyl halides via dehydrobromination,
under the reaction conditions employed. However, when 1a was
reacted with octene, no alkylation products were produced, indi-
cating that the alkyl halide itself functions as a coupling partner
(eq 2).
Scheme 1. Proposed Mechanism
A proposed mechanism for the reaction is shown in Scheme 1.
The coordination of amide 35 to the nickel center followed by
ligand exchange with the concomitant generation of HX gives the
nickel complex 36, which undergoes reversible cyclometalation to
give the complex 37, probably via a CMD mechanism. The oxida-
tive addition of RBr followed by reductive elimination gives 39,
which undergoes protonation to afford the desired alkylation
product with the regeneration of nickel(II).17,18 As shown in equa-
The deuterated amide 1a-d7 was reacted with BuBr for 8 h un-
der otherwise standard reaction conditions (eq 3). We observed a
significant amount of H/D exchange at the ortho position (the d-
content decreased from >98% to 51%) and on the nitrogen in the
recovered amide. Even in the absence of BuBr, a significant
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(j) Vechorkin, O.; Proust, V.; Hu, X. Angew. Chem., Int. Ed. 2010, 49,
tions 3 and 4, the cleavage of C-H bonds appears to be a reversi-
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In summary, we report the development of a new catalytic sys-
tem that takes advantage of chelation assistance by an 8-
aminoquinoline moiety. This represents the first example of the
nickel-catalyzed ortho-alkylation of benzamides and acrylamide
derivatives with unactivated alkyl halides in which C-H bonds are
cleaved. The reaction proceeds in a highly selective manner at the
less hindered C-H bonds in the reaction of meta-substituted aro-
matic amides.
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ASSOCIATED CONTENT
Supporting Information
(6) (a) Shacklady-McAtee, D. M.; Dasgupta, S.; Watson, M. P. Org. Lett.
2011, 13, 3490. (b) Ogata, K.; Atsumi, Y.; Shimada, D.; Fukuzawa, S.
Angew. Chem. Int. Ed. 2011, 50, 5896. (c) Shiota, H.; Ano, Y.; Ahihara,
Y.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 14952.
Experimental procedures and spectroscopic data for all new com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
(7) Kleiman, J. P.; Dubeck, M. J. Am. Chem. Soc. 1963, 85, 1544.
(8) Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D. J. Am.
Chem. Soc. 2002, 124, 11856.
Corresponding Author
chatani@chem.eng.osaka-u.ac.jp
(9) Zaitsev, V.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127,
13154.
ACKNOWLEDGMENTS
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3391. (b) Giri, R.; Maugel, N.; Foxman, B. M.; Yu, J.-Q. Organometallics
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Z.-H.; Liang, Y.-M. Org. Lett. 2009, 11, 5726. (d) Shabashov, D.; Daugu-
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Chem. Int. Ed. 2011, 50, 5192. (f) Zhao, Y.; Chen, G. Org. Lett. 2011, 13,
4850. (g) Reddy, B. V. S.; Revathi, G.: Reddy, A. S.; Yadav, J. S. Tetra-
hedron Lett. 2011, 52, 5926. (h) Ano, Y.; Tobisu, M.; Chatani, N. J. Am.
Chem. Soc. 2011, 133, 12984. (i) He, G.; Zhao, Y.; Zhang, S.; Lu, C.;
Chen, G. J. Am. Chem. Soc. 2012, 134, 3. (j) Nadres, E. T.; Daugulis, O. J.
Am. Chem. Soc. 2012, 134, 7. (k) Ano, Y.; Tobisu, M.; Chatani, N. Org.
Lett. 2012, 14, 354. (l) Xie, Y.; Yang, Y.; Huang, L.; Zhang, X.; Zhang, Y.
Org. Lett. 2012, 14, 1238. (m) Tran, L. D.; Daugulis, O. Angew. Chem.,
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This work was supported, in part, by a Grant-in-Aid for Scientific
Research on Innovative Areas "Molecular Activation Directed
toward Straightforward Synthesis" from Monbusho (The Ministry
of Education, Culture, Sports, Science and Technology).
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Soc. 2008, 130, 16170. (b) Kanyiva, K. S; Kashihara, N.; Nakao, Y.;
Hiyama, T.; Ohashi, M.; Ogoshi, S. Dalton Trans., 2010, 39, 10483. (c)
Doster, M. E.; Hatnean, J. A.; Jeftic, T.; Modi, S.; Johonson, S. A. J. Am.
Chem. Soc. 2010, 132, 11923. (d) Hatnean, J. A.; Beck, R.; Borrelli, J. D.;
Johnson, S. A. Organometallics 2010, 29, 6077. (e) Guihaumé, J.; Halbert,
S.; Eisenstein, O.; Perutz, R. N. Organometallics 2012, 31, 1300. For
transformation of C-H bonds in pyridines, see: Nakao, Y.; Idei, H.;
Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2009, 131, 15996. Tamura,
R.; Yamada, Y.; Nakao, Y.; Hiyama, T. Angew. Chem. Int. Ed, 2012, 51 ,
5679.
(15) Recent examples of C-H bond alkylation with alkyl halides, see: (a)
Chen, Q.; Llies, L.; Nakamura, E. J. Am. Chem. Soc. 2011, 133, 428. (b)
Ackermann, L.; Hofmann, N.; Vicente, R. Org. Lett. 2011, 13, 1875. (c)
Zhao, Y.; Chen, G. Org. Lett. 2011, 13, 4850. (d) Xiao, B.; Liu, Z.-J.; Liu,
L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 616. See also refs 10f, 10j, and
10p.
(16) It is known that Ni complex reacts with RX to give a coupling prod-
uct with the generation of Ni(II) complex. Semmelhack, M. F.; Helquist, P.
M.; Jones, L. D. J. Am. Chem. Soc. 1971, 93, 5908.
(5) (a) Clement, N. D.; Cavell, K. J. Angew. Chem. Int. Ed. 2004, 43, 3845.
(b) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Heterocycles 2007, 72, 677. (c)
Canivet, J.; Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett. 2009, 11, 1733. (d)
Hachiya,H.; Hirano, K.; Satoh, T.;Miura, M. Org. Lett. 2009, 11, 1737.
(e)Mukai,T.; Hirano, K.; Satoh, T.;Miura, M. J. Org. Chem. 2009, 74,
6410. (f) Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009,
11, 4156. (g) Kanyiva, K. S.; Löbermann, F.; Nakao, Y.; Hiyama, T. Tet-
rahedron Lett. 2009, 50, 3463. (h) Hachiya, H.; Hirano, K.; Satoh, T.;
Miura, M. Angew. Chem., Int. Ed. 2010, 49, 2202. (i) Matsuyama, N.;
Kitahara, M.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 2358.
(17) Kambe proposed a Ni(II)/Ni(IV) catalytic cycle in the Ni-catalyzed
Grignard cross-coupling. Terao, J.; Kambe, N. Acc. Chem. Res. 2008, 41,
1545. Recently, Sanford suggested the intermediacy of Ni(IV) species in
halogenation of cyclometallated nickel complex(II). Higgs, A. T.; Zinn, P.
J.; Sanford, M. S. Organometallics 2010, 29, 5446.
(18) We have no direct evidence to support a Ni(II)/Ni(IV) catalytic cycle.
However, an alternative mechanism, a Ni(0)/Ni(II) cycle cannot be ex-
cluded, based on the data presented. Stoichiometric reactions are now
being conducted in order to isolate or detect key catalytic species.
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