Pd(II)-catalyzed chelation-assisted cross dehydrogenative coupling between unactivated C(sp3)H bonds in aliphatic amides and benzylic CH bonds in toluene derivatives

Article abstract of DOI:10.1246/cl.150615

The chelation-assisted cross dehydrogenative coupling of C(sp³)H bonds is achieved by the Pd(II)-catalyzed reaction of aliphatic amides that contain a 5-chloro-8-aminoquinoline moiety as the directing group with toluene derivatives in the presence of heptafluoroisopropyl iodide. A variety of functional groups are tolerated.

Full text of DOI:10.1246/cl.150615

Received: June 25, 2015 | Accepted: July 9, 2015 | Web Released: July 18, 2015
CL-150615
Pd(II)-catalyzed Chelation-assisted Cross Dehydrogenative
Coupling between Unactivated C(sp3)-H Bonds in Aliphatic
Amides and Benzylic C-H Bonds in Toluene Derivatives
Teruhiko Kubo, Yoshinori Aihara, and Naoto Chatani*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871
(E-mail: chatani@chem.eng.osaka-u.ac.jp)
Table 1. Pd(II)-catalyzed cross dehydrogenative coupling of ali-
phatic amides 1 with toluenea
The chelation-assisted cross dehydrogenative coupling of
C(sp3)-H bonds is achieved by the Pd(II)-catalyzed reaction
of aliphatic amides that contain a 5-chloro-8-aminoquinoline
moiety as the directing group with toluene derivatives in the
presence of heptafluoroisopropyl iodide. A variety of functional
groups are tolerated.
cat. Pd(OAc)2 10 mol%
ligand 20 mol%
R
R
O
O
base
iC3F7I 2 equiv
2 equiv
N
N
H
H
N
N
H
toluene 1.0 mL
1a R = Cl
1b
Ph
140 °C, 24 h
2a-c
R = H
1c
R = OMe
Cross-coupling reactions, such as Suzuki-Miyaura coupling
are one of the most powerful methods for the formation of C-C
bonds.1 In contrast, the cross dehydrogenative coupling (CDC)
of C-H bonds represents an ideal transformation,2,3 in that there
is no need for the time-consuming prefunctionalization of the
two substrates. Following the pioneering examples reported by
Fagnou4 and Sanford,5 a number of CDC reactions of C-H bonds
has been developed.3 However, the majority of examples reported
thus far involves coupling between C(sp2)-H and C(sp2)-H
bonds. CDC involving the activation of C(sp3)-H bonds has been
a subject of extensive study.3c Li reported on the CDC between
C(sp2)-H and C(sp3)-H bonds in the Ru(II)-catalyzed reaction
of 2-arylpyridines with cycloalkanes.6 Some examples of intra-
molecular CDC involving C(sp3)-H bonds have also been
reported.7 Recently, various reactions which are demonstrated
as CDC of C(sp3)-H bonds have been reported. However, most of
these reactions involve aldol-type reactions in which one of two
substrates is activated in the form of an enolate or the equivalent
if they contain acidic C-H bonds and the other is activated as an
oxonium or iminium intermediate if oxygen or nitrogen atoms
are located adjacent to the C(sp3)-H bonds that react, indicating
that the transition-metal catalyst is not involved in the key step,
such as C-C bond formation.3c,8 To the best of our knowledge,
no examples of the intermolecular CDC of unactivated C(sp3)-H
bonds, in which chelation-assistance if involved, have been
reported.9 We wish to report here on the first example of such a
CDC of C(sp3)-H bonds by taking advantage of N,N-bidentate
chelation assistance.10
We recently reported the Ni(II)-catalyzed CDC between ortho
C-H bonds in aromatic amides and benzylic C-H bonds in
toluene derivatives.11 Ni(II) was not effective in the CDC of
C(sp3)-H bonds in the aliphatic amide 1a. However, we were
pleased to find that the reaction of amide 1a (0.3 mmol) with
heptafluoroisopropyl iodide (0.6 mmol) in the presence of
Pd(OAc)2 (0.03 mmol) as the catalyst, K2CO3 (0.6 mmol) as the
base in toluene (1 mL) at 140 °C for 24 h gave the benzylation
product 2a in 38% NMR yield, along with recovery of 1a in 33%
NMR yield (Entry 1 in Table 1). The addition of a carboxylic acid
as an additive improved the product yield (Entries 2-7). Among
the acid additives examined, 1-adamantanecarboxylic acid (1-
AdCOOH) was determined to be the acid of choice (Entry 7). The
Entry
Amide
Ligand
Base
Yield/%(2/1)b
1a
1a
1a
none
1
2
3
K2CO3
K2CO3
K2CO3
38/33
56/26
56/14
MesCOOH
(BnO)2POOH
1a
1a
1a
1a
1a
4
5
6
7
8
PivOH
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
66/11
AcOH
54/36
N-Boc-gylcine
1-AdCOOH
1-AdCOOH
31/64
75(70)/(20)
56/34
1a
1a
9
1-AdCOOH
1-AdCOOH
KOAc
13/83
0/98
10
Na2CO3
1a
11
1-AdCOOH
Li2CO3
0/87
1a
1a
1a
12
1-AdCOOH
1-AdCOOH
1-AdCOOH
Ag2CO3
K2CO3
K2CO3
51/39
44/24
8/78
13c
14d
15e
1a
1-AdCOOH
K2CO3
84(77)/8
16e
17e
1-AdCOOH
1-AdCOOH
K2CO3
K2CO3
1b
1c
(63)/(33)
(50)/(47)
aReaction conditions: amide 1a (0.3 mmol), Pd(OAc)2 (0.03 mmol),
ligand (0.06 mmol), base (0.6 mmol) and C3F7I in toluene (1.0 mL) at
140 °C for 24 h. NMR yields. The numbers in parenthesis denote the
isolated yield. c nC6F13I was used instead of iC3F7I. dCF3CH2I was used
i
b
i
e
instead of C3F7I. K2CO3 (0.9 mmol) was used and running for 48 h.
reaction was also significantly affected by the nature of the base
used (Entries 7-12). The use of 3 equivalents (0.9 mmol) of
K2CO3 improved the yield to 77% isolated yield (Entry 15). Other
perfluoroalkyl iodides were not effective (Entries 13 and 14).
Finally, Entry 15 was chosen as the standard reaction conditions.
Table 2 shows representative results for some reactions of
aliphatic amides. Benzylation took place only at the β-position.
Various functional groups are tolerated under the reaction
conditions. In the reaction of the propanoic amide derivative
3h, a mixture of the mono-benzylation product 4h and the di-
benzylation product was produced, in favor of 4h. The reaction
of 3i gave the benzylation product 4i as a single stereoisomer.
The reaction of 3j gave trans-4j.
We next examined the use of functionalized toluene
derivatives as the reagent in an unreactive solvent. Finally,
Chem. Lett. 2015, 44, 1365–1367 | doi:10.1246/cl.150615
© 2015 The Chemical Society of Japan | 1365

Table 2. Pd(II)-catalyzed cross dehydrogenative coupling of ali-
phatic amides 3a-3j in toluenea
Table 3. Pd(II)-catalyzed cross dehydrogenative coupling of ali-
phatic amide 1a with toluene derivativesa,b
cat. Pd(OAc)2 10 mol%
cat. Pd(OAc)2 10 mol%
Cl
Cl
1-AdCOOH
20 mol%
1-AdCOOH
20 mol%
O
O
O
O
H
K2CO3 3 equiv
iC3F7I 2 equiv
K2CO3 3 equiv
iC3F7I 2 equiv
Q'
Q'
R'
R'
N
N
H
N
H
N
H
H
Ar
H3C
+
N
N
R
H
R
toluene 1.0 mL
chlorobenzene 0.7 mL
10 equiv
O
3
4
Ar
Ph
1a
140 °C, 48 h
2
140 °C, 48 h
O
O
O
O
O
O
Q'
Q'
Q'
Q'
Q'
Q'
Q'
N
N
N
H
N
H
N
N
N
H
H
H
H
H
Ar
Ph
Ph
4b Ar = Ph 53% (34%b)
Ph
4a 67% (26%)
4e 55% (25%)
4c
4d
= 4-MeOC6H4 43% (48%b)
= 4-FC6H4 40% (51%b)
CF3
CO2Me
F
2f
O
O
O
2a
2d
2e
60%
59%
51%b
61%
Q'
Q'
Q'
N
N
N
O
O
O
O
H
H
H
BocHN
Q'
Q'
Q'
N
Q'
MeO2C
N
N
N
H
H
H
H
Ph
Ph
Ph
45% (42%b)
O
51% (46%)
66%c/11%b,d (8%b)
4h
4f
4g
O
Ph
N
Q'
Q'
N
H
H
Cl
Br
OAc
2g 67%b
2h 48%
2i 40%b
2j 57%b
Ph
Ph
O
O
O
O
47%f (26%b)
trans- 35%e (51%b)
4i
4j
Q'
N
Q'
Q'
Q'
N
N
H
N
H
aReactions were conducted on a 0.3 mmol scale. Isolated yields are
reported and the numbers in parentheses denote the amount of starting
amide recovered. Q¤ = 5-chloro-8-aminoquinolinyl group. bNMR
yield. cK3PO4 and (BnO)2POOH were used instead of a base and
ligand. dThe di-benzylation product was formed in 11% NMR yield.
ePd(OAc)2 (0.06 mmol) and PivOH (0.12 mmol) were used. fOne
isomer.
H
H
OMe
tBu
2k 48%b
2l 44%b
2m 68%b
2n 56%b
O
O
O
Q'
N
Q'
Q'
N
iC3F7I
equiv
ratio
N
yield
chlorobenzene was found to be the solvent of choice. Some
representative results are shown in Table 3. The reaction again
shows a high functional group compatibility. As in 2h, the bromo
group remained intact, indicating that the products may be used
for further elaboration. The reaction of 1a with 3-bromo-5-
fluorotoluene under the standard reaction conditions gave a 3:2
mixture of the benzylation product 2o and the C-H arylation
product 5, the latter of which was produced by the arylation of
C-H bonds (C-H/C-Br coupling). The ratio of the products is
H
H
H
2o
5
+
0
2
60%
ndc
0
3
1
2
F
6
76%d 10
1
F
F
Br
2p 75%b
2o
5
aReactions were conducted on a 0.3 mmol scale. Isolated yields are
reported. Q¤ = 5-chloro-8-aminoquinolinyl group. bArene (1 mL) was
c
d
used as a solvent. Not determined. NMR yield of 2o.
i
highly dependent on the amount of C3F7I used in the reaction.
i
When the reaction was carried out in the absence of C3F7I, the
(Scheme 1d). Although it is difficult to draw a final conclusion,
it appeared that the cleavage of C-H bonds is probably not the
rate-determining step.
arylation product 5 was obtained in 60% yield as the single
product. The use of 6 equivalents of iC3F7I gave 2o in 76% yield
as the major isomer.
The issue we were most interested in understanding is the
actual benzylation species in the reaction and how it is generated
under the reaction conditions employed. To determine this,
reactions with various combinations of reagents were carried out.
Based on several control experiments,13 benzyl iodide appears to
act as the benzylation reagent. In the absence of the amide 1a,
only a small amount of benzyl iodide was formed in any of the
reactions. It was found that, in the reaction of the amide 1a and
K2CO3, the formation of benzyl iodide is accelerated. The
reaction of 1a, K2CO3, and iC3F7I in toluene at 140 °C for 3 h (no
Pd(OAc)2) gave benzyl iodide in 33% yield. In the case of the
reaction for 3 h under otherwise the standard reaction conditions,
benzyl iodide was formed in 49% yield, along with the
benzylation product 2a in 33% yield.
To probe the reaction mechanism, we carried out a series of
experiments using the deuterium-labelled amide 1a-d7 and tol-
uene-d7 (Scheme 1). H/D exchange occurred only at the β-
position both in the recovered starting amide 1a-d7 and the
product 2 in the reaction of 1a-d7, indicating that the C-H bonds
cleavage is reversible (Scheme 1a). The result of Scheme 1b
indicates that no H/D exchange occurred at the benzylic position
even when the reaction was extended to 48 h. Based on this result,
a competition experiment between toluene and toluene-d8 was
carried out to determine the KIE (Scheme 1c). A KIE of 5.7 was
obtained by integration of the signal of the benzylic proton (1.7/
0.3 = 5.67).12 The result of a competition experiment between
1a and 1a-d7 indicated a KIE of 1.9 (1.96/1.04 = 1.88)
1366 | Chem. Lett. 2015, 44, 1365–1367 | doi:10.1246/cl.150615
© 2015 The Chemical Society of Japan

cat. Pd(OAc)2 10 mol%
1-AdCOOH 20 mol%
(a)
of complex 7 with the benzyl iodide affords the Pd(II) species 8,
from which the reductive elimination and protonation occurs to
give the final product 2a with the generation of a Pd(II) complex.
In fact, the reaction of 1a with benzyl iodide in the absence of
iC3F7I under otherwise standard reaction conditions afforded 2a in
74% NMR yield. However, a mechanism in which 7 reacts with
a benzyl radical cannot be excluded. The addition of TEMPO
completely quenched the reaction. The finding reported herein
indicates that the reaction involves the formation of a free radical.
We report here on the first example of the chelation-assisted
CDC of unactivated C(sp3)-H bonds with toluene C-H bonds.
The reaction does not require the use of a toluene derivative as the
solvent. Rather, toluene derivatives can be used as the coupling
reagent in chlorobenzene. The scope of the reaction is broad with
regard to both aliphatic amides and toluene derivatives.
O
O
O
K2CO3 3 equiv
iC3F7I 2 equiv
D
D
Q'
D
D
Q'
D
D
Q'
N
N
N
H
H
H
D
D
D
D
D
+
D3C
D3C
D3C
toluene 1 mL
0.36H
Ph
19%
140 °C, 2 h
0.23H
1a-
d7
0.0H
2
1a-d7
60%
0.0H
O
(b)
Q'
O
O
N
H
D
Q'
N
Q'
N
H
+
H
D
toluene-d8
48 h
D
D
D
0.0H
1a
1a
22%
D
2
58%
D
O
(c)
(d)
Q'
O
O
N
H
D
D
Q'
N
Q'
N
H
+
H
toluene/toluene-d8 1:1
3 h
D
D
D
D
1.7H
Supporting Information is available electronically on J-STAGE.
1a
1a
52%
2
28%
D
References and Notes
cat. Pd(OAc)2 10 mol%
1-AdCOOH 20 mol%
1
2
For recent reviews on the Suzuki-Miyaura cross-coupling, see:
a) F.-S. Han, Chem. Soc. Rev. 2013, 42, 5270. b) A. J. J. Lennox,
G. C. Lloyd-Jones, Chem. Soc. Rev. 2014, 43, 412.
O
K2CO3 3 equiv
iC3F7I 2 equiv
Q'
N
1a : 1a-
1:1
d7
H
For recent selected reviews on functionalization of C-H bonds,
see: a) D. Y.-K. Chen, S. W. Youn, Chem.®Eur. J. 2012, 18, 9452.
b) J. Yamaguchi, A. D. Yamaguchi, K. Itami, Angew. Chem., Int.
Ed. 2012, 51, 8960. c) N. Kuhl, M. N. Hopkinson, J. Wencel-
Delord, F. Glorius, Angew. Chem., Int. Ed. 2012, 51, 10236. d) B.
Li, P. H. Dixneuf, Chem. Soc. Rev. 2013, 42, 5744. e) J. Wencel-
Delord, F. Glorius, Nat. Chem. 2013, 5, 369. f) K. Gao, N.
Yoshikai, Acc. Chem. Res. 2014, 47, 1208. g) S. De Sarkar, W.
Liu, S. I. Kozhushkov, L. Ackermann, Adv. Synth. Catal. 2014,
356, 1461. h) M. Miura, T. Satoh, K. Hirano, Bull. Chem. Soc.
Jpn. 2014, 87, 751.
toluene 1 mL
Ph
140 °C, 3 h
2.0H
1.96H
Scheme 1. Deuterium-labelling experiments.
Rf-I
_
Cl
1a
O
N
I-
HX
K2CO3
1a
+
Pd
X
N
KHCO3
+ KX
H
CH3
Rf
Ar
1a
6
3
For recent reviews on the cross dehydrogenative coupling of C-H
bonds, see: a) B.-J. Li, Z.-J. Shi, Chem. Soc. Rev. 2012, 41, 5588.
b) ref 2c. c) S. A. Girard, T. Knauber, C.-J. Li, Angew. Chem., Int.
Ed. 2014, 53, 74.
Cl
CH2
O
Rf-H
LnPdXI
Ar
Rf-I
Rf
N
Pd
N
4
5
6
7
D. R. Stuart, K. Fagnou, Science 2007, 316, 1172.
7
Ar
I
K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2007, 129, 11904.
G. Deng, L. Zhao, C.-J. Li, Angew. Chem., Int. Ed. 2008, 47, 6278.
a) B. Liégault, K. Fagnou, Organometallics 2008, 27, 4841. b) X.
Guo, C.-J. Li, Org. Lett. 2011, 13, 4977. c) C. Pierre, O. Baudoin,
Tetrahedron 2013, 69, 4473.
Cl
O
2a
N
Pd
Cl
O
HX
N
I
N
8
9
J. M. Curto, M. C. Kozlowski, J. Am. Chem. Soc. 2015, 137, 18.
Sanford reported only one isolated example, where a quinolone
nitrogen acts as a directing group for the oxidative coupling of
8-methylquinoline and benzene. See ref 5.
Ar
8
N
Pd
I
HX = KHCO3, H2O, 1a ....
Ar
9
10 For reviews on the functionalization of C-H bonds utilizing N,N-
bidentate directing group, see: a) G. Rouquet, N. Chatani, Angew.
Chem., Int. Ed. 2013, 52, 11726. b) L. C. M. Castro, N. Chatani,
Chem. Lett. 2015, 44, 410. c) O. Daugulis, J. Roane, L. D. Tran,
Acc. Chem. Res. 2015, 48, 1053. d) R. K. Rit, M. R. Yadav, K.
Ghosh, A. K. Sahoo, Tetrahedron 2015, 71, 4450.
11 Y. Aihara, M. Tobisu, Y. Fukumoto, N. Chatani, J. Am. Chem. Soc.
2014, 136, 15509.
12 V. B. Luzhkov, Chem. Phys. 2005, 320, 1.
Scheme 2. A proposed mechanism for the Pd(II)-catalyzed cross
dehydrogenative coupling.
On the basis of the above experimental results and data
obtained from previous reports, a plausible reaction mechanism
for the present reaction is proposed in Scheme 2. The coordination
of amide 1a to the Pd(II) center gives the Pd(II) complex 6 with
the generation of HX, which is trapped by K2CO3. The C-H bonds
in the complex 6 then undergo reversible cleavage to give the
palladacycle 7. A base-promoted single electron transfer to Rf-I14
from the anion of 1a, which is generated by 1a and K2CO3, gives a
Rf radical which abstracts a hydrogen from toluene to generate a
benzyl radical and Rf-H.15 The benzyl radical abstracts the iodide
from Rf-I to give benzyl iodide and the Rf radical. The reaction
13 For more details, see Supporting Information.
14 a) T. Xu, C. W. Cheung, X. Hu, Angew. Chem., Int. Ed. 2014, 53,
4910. b) B. Zhang, A. Studer, Org. Lett. 2014, 16, 3990. c) J.
Zhang, W. Wu, X. Ji, S. Cao, RSC Adv. 2015, 5, 20562.
15 The formation of Rf-H was confirmed by 19F NMR spectra of the
reaction mixtures.
Chem. Lett. 2015, 44, 1365–1367 | doi:10.1246/cl.150615
© 2015 The Chemical Society of Japan | 1367