Nickel-Catalyzed Direct C (sp3)-H Arylation of Aliphatic Amides with Thiophenes

Article abstract of DOI:10.1021/acs.orglett.5b02572

Nickel-catalyzed heteroarylation of the inactive methyl C(sp³)-H bond of aliphatic amide with heteroarenes is described. The method takes advantage of chelation assistance by an 8-aminoquinolinyl moiety. The synthetic reaction has good tolerance toward functional groups, and it can be used in the construction of various kinds of alkyl-substituted heteroarenes.

Full text of DOI:10.1021/acs.orglett.5b02572

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Direct C (sp3)−H Arylation of Aliphatic Amides with
Thiophenes
Xie Wang,† Longzhi Zhu,† Sihai Chen,† Xinhua Xu,*,† Chak-Tong Au,†,‡ and Renhua Qiu*,†
†State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha, 410082, P.R. China
‡Department of Chemistry, Hong Kong Baptist University, Hong Kong, P.R. China
S
* Supporting Information
ABSTRACT: Nickel-catalyzed heteroarylation of the inactive
methyl C(sp3)−H bond of aliphatic amide with heteroarenes is
described. The method takes advantage of chelation assistance
by an 8-aminoquinolinyl moiety. The synthetic reaction has
good tolerance toward functional groups, and it can be used in
the construction of various kinds of alkyl-substituted
heteroarenes.
organometallic reagents is tedious and the generation of metal
he thiophene structure has received much attention in
Torganic synthesis because of its rigidity and distinct halide as waste is undesirable.8 As an alternative, the direct cross-
coupling strategy is more promising (Scheme 1b). The method
makes use of a prefunctionalized arene that bears a leaving group
with a C−H bond, and the most used metal catalyst is palladium.9
The method, however, is unselective and requires a directing
group or large excess of arene to activate the relatively inert
bonds.10 Nonetheless, such limitations make the research
challenging when the compatibility of the functional group is
an issue of concern in the synthetic approach. Recently, there
were the reports on the study of decarboxylative (hetero)-
arylation catalyzed by transition metal.11
For the development of new material devices such as OLEDs
(organic light-emitting diodes), alkyl-substituted heteroarenes
bearing one or multiple alkyl components were aggressively
pursued in the past decade,6 and tremendous progress has been
made to prepare these organic semiconductors (see the
Supporting Information) that have flexible side chains, such as
cross-coupling reactions,6e,f polymerization,6g and metalization6h
with functionalized alkyl-substituted heteroarenes (Figure 1).
Also, among pharmaceutical companies, there have been projects
to collect heteroaromatic molecules that are decorated with
branched alkyl chains into a medicinal compound database.12
Consequently, extensive efforts were devoted to rapid and direct
construction of C(sp2)−C(sp3) bonds.13 In practice, intermo-
lecular heteroarylation of alkanes catalyzed by a transition metal
electronic nature that allow fine-tuning of its molecular
properties.1 Compared to other phenyl-type substituents, the
thiophene structures often show higher bioactivity.2 They are
widely found in pharmaceuticals,3 agrochemicals,4 and organic
catalysts.5 Moreover, oligothiophenes make up a particularly
important class of organic materials. They are components that
are used in organic electronic devices for applications such as
solar cells, field-effect transistors, and fluorescent biosensors.6
Starting from readily available (hetero)aromatic scaffolds, the
coupling of two prefunctionalized substrates over a transition-
metal catalyst is a typical method for the synthesis of substituted
thiophenes (Scheme 1a).7 However, the method has short-
comings because the prefunctionalization of substrate with
Scheme 1. Types of Transition-Metal-Catalyzed
Heteroarylation Using Thiophenes as Aryl Source
Figure 1. Functionalized alkyl-substituted heteroarenes.
Received: September 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02572
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Letter
is a frequently used method. In the approach, the activated
C(sp3)−H bonds couple with aryl moieties to form alkyl-
substituted heteroarenes scaffolds.14 The method, however, is
limited to relatively active aryl substrates such as iodoarenes,15
hyperiodonium salts,16 arylboron reagents,17 and organozinc
reagents.12b,13,18
without an additive such as TBAI there was poor yield of 2a
(entry 1). Further investigation showed that the reaction was
improved by using benzoic acid as ligand (entries 9−12). The
screening of additives showed that a change from TBAI to the
others led to lower yields (entries 13−17). In the study, the use of
base and solvent was also optimized (see the Supporting
Information).
As coupling partners in cross-coupling reactions, aryl bromides
are more useful than aryl iodides or organometallic reagents
because they are less expensive, nontoxic, and easy to handle.
Despite reports on the arylation of the C(sp3)−H bond with
aromatic halide, such as the palladium-catalyzed intermolecular
arylation with aryl bromides reported by Zeng,19a the use of aryl
bromides to convert inactive C(sp3)−H bonds to C(sp3)−
heteroaryl bonds via intermolecular coupling still remains to be
explored.19 Recently, the methods using removable directing
groups for the formation of C(sp2)−C(sp3) bonds have made a
significant impact on the field of organic chemistry.15,20
Significant progress was first achieved via the chelation-assistance
approach developed by Daugulis.15c A nickel-catalyzed system
was also reported by Chatani15a in which phenyl bromide was
used but there was no arylation product. Herein, we report the
site-selective coupling of heteroaryl bromides with C(sp3)−H
bonds to achieve intermolecular heteroarylation. The reaction is
conducted over a nickel-based catalyst and is assisted by a
removable bidentate directing group. In general, the use of less
reactive aryl bromides could enhance the practicality and hence
broaden the applicability of the method.
With the optimized conditions in hand, we studied the scope
of thiophenes. As expected, thiophene bromides show great
compatibility under the reaction conditions, and the reaction
tolerates a variety of functional groups with both steric and
electronic variations, such as the halides, methyl, acyl, aldehyde,
ester, bithiophene, and benzothiophene. As shown in Scheme 2,
a
Scheme 2. Screening the Scope of Thiophenes
We began our investigation by using aliphatic amides 1a and
2,5-dibromothiophene as substrates for the optimization of
reaction conditions (Table 1). After initial screening of catalysts,
the heteroarylated product 2a was obtained in 74% yield by using
catalytic amounts of NiBr2 and MesCOOH using excess Na2CO3
in DMF under an atmosphere of N2 (entry 2). It was noticed that
a
Reaction conditions: amide (0.2 mmol), thiophene (0.6 mmol),
NiBr2 (0.02 mmol), MesCOOH (0.04 mmol), Na2CO3 (0.4 mmol),
TBAI (0.4 mmol) in DMF (0.5 mL) at 160 °C for 24 h in 10 mL
screw-capped vials. Isolated yields of major products. The number in
parentheses is the isolated yield when 6 equiv of 2,5-dibromothio-
b
c
a
Table 1. Optimization of Reaction Conditions
d
phene was used. Three equivalents of 3-bromothiophene was used.
e
The isolated product was 2b when (5-bromothiophene-2-yl)boronic
acid was used.
b
electron-deficient substrates are well tolerated, and the reaction
shows a predominant preference for the generation of
monoheteroarylated products (2a,d−i) with good yields (41−
74%). The electron-rich thiophene substrate shows higher
reactivity, giving higher yields of mono- and diheteroarylated
products (2b,c). It is noted that steric hindrance only has a slight
influence on the transformation (2h−j). In addition, an effort
using (5-bromothiophene-2-yl)boronic acid as substrate only
results in the heteroarylated product 2b.
We then examined the scope of aliphatic amides under the
optimized conditions. As shown in Scheme 3, the use of
substituted propanamides bearing linear and cyclic chains results
in a good yield of heteroarylated products (2m,o). Surprisingly,
with a 2,2-diphenyl-substituted substrate, product 2p is obtained
in excellent yield (89%). Notably, there is difference in the mono-
to-di (m:d) ratio between aliphatic amide 2m (m:d = 2:1) and
phenyl-substituted amide 2n (m:d = 1:2). The observation
suggests that the phenyl could benefit from activation of the inert
C(sp3)−H bond. The reactions show great regioselectivity that
the methyl groups are preferred over the methylene and benzene
groups, a phenomenon like that reported in our previous work.21
To further elucidate the viability of this C(sp3)−H
heteroarylation method, we studied the N-heteroaryl substrates
entry
catalyst
NiBr2
ligand
additive
yield (%)
1
MesCOOH
MesCOOH
MesCOOH
MesCOOH
MesCOOH
MesCOOH
MesCOOH
MesCOOH
PPh3
24
74
64
66
62
67
69
52
54
51
65
58
49
51
30
37
56
2
NiBr2
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAB
AgO
3
Ni(COD)2
Ni(OTf)2
NiCl2
4
5
6
NiF2
7
Ni(acac)2
Ni(OAc)2
NiBr2
8
9
10
11
12
13
14
15
16
17
NiBr2
PCy3
NiBr2
p-HOC6H4COOH
PhCOOH
NiBr2
NiBr2
MesCOOH
MesCOOH
MesCOOH
MesCOOH
MesCOOH
NiBr2
NiBr2
CuI
NiBr2
CuBr
AgNO3
NiBr2
a
Reaction conditions: amide (0.2 mmol), thiophene (0.6 mmol),
catalyst (0.02 mmol), ligand (0.04 mmol), base (0.4 mmol), additive
(0.4 mmol) in solvent (0.5 mL) at 160 °C for 24 h in 10 mL screw-
b
capped vials. Isolated yield.
B
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Letter
a
Scheme 3. Screening the Scope of Aliphatic Amides
Scheme 5. Deuterium Labeling and Radical-Trapping
Experiments
a
Reaction conditions: amide (0.2 mmol), thiophene (0.6 mmol),
NiBr2 (0.02 mmol), MesCOOH (0.04 mmol), Na2CO3 (0.4 mmol),
TBAI (0.4 mmol) in DMF (0.5 mL) at 160 °C for 24 h in 10 mL
screw-capped vials. Isolated yields of major products. The number in
parentheses is the isolated yield with time extended to 48 h.
yloxy)piperidine by GC−MS. To verify whether the reaction
activity was lowered by the oxidation property of TEMPO, and
the cyclometalation process was hindered as such, we added di-
tert-butyl peroxide (DTBP) under the standard conditions and
observed that the reaction gives the product in a lower yield.
According to the results, we deduce that the reaction does not
proceed via a radical mechanism but via one that is similar to that
proposed by Chatani and Ge.15a,b,23
b
c
that are closely related to thiophenes (Figure 2). Preliminary
results indicated that the direct application of the method under
In summary, we report the development of a low-cost nickel
catalyst system that takes advantage of chelation assistance by an
8-aminoquinolinyl moiety. This method for the heteroarylation
of the sp3 C−H bond with aliphatic amides has good tolerance
toward different functional groups and represents a facile
alternative for the construction of alkyl-substituted heteroarenes.
Figure 2. N-Heteroarylated products.
the optimized condition is successful, and the desired N-
heteroarylated products are obtained in moderate yields (3a−d).
To further test the practicality of this method, the reaction was
conducted on gram scale, and the desired product 2a was
obtained in 64% yield (Scheme 4). According to our previous
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02572.
Scheme 4. Gram-Scale Synthesis and Removal of the
Directing Group
1
Experimental procedure, characterization data, and H,
13C and 19F NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
* E-mail: xhx1581@hnu.edu.cn.
* E-mail: renhuaqiu@hnu.edu.cn.
Notes
work, the corresponding carboxylic acid 4 is easy to obtain21 and
can be readily transferred to the corresponding isocyanates as
suggested by Fevig.22a Furthermore, the heteroarylated products
can be used as substrates for the Suzuki or other cross-coupling
reactions (Scheme 4). For example, the bromide thiophene
products 2a can undergo the Suzuki protocol to give the arylated
product 6 with excellent yield (91%).22b
Several competition and radical-trapping experiments were
carried out in an attempt to determine the reaction mechanism
(Scheme 5). The intermolecular kinetic isotope effect for sp3 C−
H heteroarylation is 6.4, and the result indicates that the cleavage
of C−H bond is a rate-determining step. The addition of 3 equiv
of 2,6-di-tert-butyl-4-methylphenol (BHT) as radical scavenger
does not inhibit the reaction. The addition of 3 equiv of 2,2,6,6-
tetramethyl-1-piperidinoxyl (TEMPO); however, substantially
reduces the yield but does not completely suppress the reaction,
and there is no detection of 2,2,6,6-tetramethyl-1-(thiophene-2-
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSFC (Nos. 21373003, 21273068, J1210040) and
the Fundamental Research Funds for the Central Universities for
financial support. R.Q. thanks Prof. Nobuaki Kambe (Osaka
University, Japan), Prof. Akihiro Orita (Okayama University of
Science, Japan), and Prof. Li-Biao Han (AIST, Tsukuba, Japan)
for helpful discussions. C.-T.A. thanks HNU for an adjunct
professorship.
REFERENCES
■
(1) (a) The Chemistry of Heterocyclic Compounds: Thiophene and Its
Derivatives; Weissberger, A., Taylor, E. C., Eds.; Wiley: New York, 1991;
Vol. 44, Parts 1−4. (b) Gronowitz, S.; Hornfeldt, A. B. Thiophenes;
Elsevier: Oxford, 2004.
C
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Letter
(2) Lamberth, C.; Jeanguenat, A.; Cederbaum, F.; De Mesmaeker, A.;
Zeller, M.; Kempf, H. J.; Zeun, R. Bioorg. Med. Chem. 2008, 16, 1531.
(3) (a) Wang, W. L.; Chai, S. C.; Huang, M.; He, H. Z.; Hurley, T. D.;
Ye, Q. Z. J. Med. Chem. 2008, 51, 6110. (b) Oberdorf, C.; Schepmann,
D.; Vela, J. M.; Diaz, J. L.; Holenz, J.; Wunsch, B. J. Med. Chem. 2008, 51,
6531. (c) Junker, A.; Yamaguchi, J.; Itami, K.; Wunsch, B. J. Org. Chem.
2013, 78, 5579.
(4) Fokialakis, N.; Cantrell, C. L.; Duke, S. O.; Skaltsounis, A. L.;
Wedge, D. E. J. Agric. Food Chem. 2006, 54, 1651.
(5) (a) Gao, J.; Martell, A. E. Org. Biomol. Chem. 2003, 1, 2801.
(b) Bandini, M.; Benaglia, M.; Quinto, T.; Tommasi, S.; Umani-Ronchi,
A. Adv. Synth. Catal. 2006, 348, 1521.
(6) (a) Henson, Z. B.; Mullen, K.; Bazan, G. C. Nat. Chem. 2012, 4,
699. (b) Saito, S.; Matsuo, K.; Yamaguchi, S. J. Am. Chem. Soc. 2012, 134,
9130. (c) Zhang, L.; Colella, N. S.; Cherniawski, B. P.; Mannsfeld, S. C.
B.; Briseno, A. L. ACS Appl. Mater. Interfaces 2014, 6, 5327. (d) Dore, K.;
Dubus, S.; Ho, H.-A.; Levesque, I.; Brunette, M.; Corbeil, G.; Boissinot,
M.; Boivin, G.; Bergeron, M. G.; Boudreau, D.; Leclerc, M. J. Am. Chem.
Soc. 2004, 126, 4240. (e) Wang, X.-Y.; Zhuang, F.-D.; Zhou, X.; Yang,
D.-C.; Wang, J.-Y.; Pei, J. J. Mater. Chem. C 2014, 2, 8152. (f) Fan, L.;
Cui, R.; Jiang, L.; Zou, Y.; Li, Y.; Qian, D. Dyes Pigm. 2015, 113, 458.
(g) Wu, S.; Sun, Y.; Huang, L.; Wang, J.; Zhou, Y.; Geng, Y.; Wang, F.
Macromolecules 2010, 43, 4438. (h) Toutov, A. A.; Liu, W.-B.; Betz, K.
N.; Fedorov, A.; Stoltz, B. M.; Grubbs, R. H. Nature 2015, 518, 80.
(i) Adachi, K.; Hirao, Y.; Matsumoto, K.; Kubo, T.; Kurata, H. Org. Lett.
2014, 16, 5870. (j) Chen, W.; Salim, T.; Fan, H.; James, L.; Lam, Y. M.;
Zhang, Q. RSC Adv. 2014, 4, 25291.
(16) (a) Gou, Q.; Zhang, Z. F.; Liu, Z. C.; Qin, J. J. Org. Chem. 2015, 80,
3176. (b) Iyanaga, M.; Aihara, Y.; Chatani, N. J. Org. Chem. 2014, 79,
11933.
(17) (a) Chan, K. S. L.; Wasa, M.; Chu, L.; Laforteza, B. N.; Miura, M.;
Yu, J. Q. Nat. Chem. 2014, 6, 146. (b) Shang, M.; Sun, S.-Z.; Dai, H.-X.;
Yu, J.-Q. Org. Lett. 2014, 16, 5666.
(18) Liang, Y.; Fu, G. C. J. Am. Chem. Soc. 2015, 137, 9523.
(19) (a) Wei, Y.; Tang, H.; Cong, X.; Rao, B.; Wu, C.; Zeng, X. Org.
Lett. 2014, 16, 2248. (b) Li, M.; Dong, J.; Huang, X.; Li, K.; Wu, Q.;
Song, F.; You, J. Chem. Commun. 2014, 50, 3944. (c) Zhang, Q.; Yin, X.-
S.; Zhao, S.; Fang, S.-L.; Shi, B.-F. Chem. Commun. 2014, 50, 8353.
(20) (a) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192.
(b) Zhang, S.-Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G. J. Am. Chem. Soc.
2015, 137, 531.
(21) Wang, X.; Qiu, R.; Yan, C.; Reddy, V. P.; Zhu, L.; Xu, X.; Yin, S.-F.
Org. Lett. 2015, 17, 1970.
(22) (a) Fevig, T. L.; Bowen, S. M.; Janowick, D. A.; Jones, B. K.;
Munson, H. R.; Ohlweiler, D. F.; Thomas, C. E. J. Med. Chem. 1996, 39,
4988. (b) Lee, W.; Lee, D.-W.; Lee, M.; Hong, J.-I. Chem. Commun.
2014, 50, 14851.
(23) (a) Higgs, A. T.; Zinn, P. J.; Sanford, M. S. Organometallics 2010,
29, 5446. (b) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2013, 135, 5308.
(7) (a) Handy, S. T.; Mayi, D. Tetrahedron Lett. 2007, 48, 8108.
(b) Beaumard, F.; Dauban, P.; Dodd, R. H. Org. Lett. 2009, 11, 1801.
(c) Linshoeft, J.; Heinrich, A. C. J.; Segler, S. A. W.; Gates, P. J.; Staubitz,
A. Org. Lett. 2012, 14, 5644. (d) Kadunce, N. T.; Reisman, S. E. J. Am.
Chem. Soc. 2015, 137, 10480. (e) Molander, G. A.; Traister, K. M.;
O’Neill, B. T. J. Org. Chem. 2015, 80, 2907.
(8) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004.
(9) (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2009, 48, 5094. (b) Qin, D.; Wang, J.; Qin, X.; Wang, C.; Gao,
G.; You, J. Chem. Commun. 2015, 51, 6190. (c) Zhao, S.; Yuan, J.; Li, Y.-
C.; Shi, B.-F. Chem. Commun. 2015, 51, 12823. (d) Matsumura, K.;
Yoshizaki, S.; Maitani, M. M.; Wada, Y.; Ogomi, Y.; Hayase, S.; Kaiho,
T.; Fuse, S.; Tanaka, H.; Takahashi, T. Chem. - Eur. J. 2015, 21, 9742.
(e) Ashenhurst, J. A. Chem. Soc. Rev. 2010, 39, 540. (f) Malakar, C. C.;
Schmidt, D.; Conrad, J.; Beifuss, U. Org. Lett. 2011, 13, 1378. (g) Xu, S.;
Kim, E. H.; Wei, A.; Negishi, E. i. Sci. Technol. Adv. Mater. 2014, 15,
044201.
(10) (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(b) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (c) Mercier, L. G.;
Leclerc, M. Acc. Chem. Res. 2013, 46, 1597.
(11) (a) Zhao, S.; Liu, Y.-J.; Yan, S.-Y.; Chen, F.-J.; Zhang, Z.-Z.; Shi,
B.-F. Org. Lett. 2015, 17, 3338. (b) Wang, C.; Piel, I.; Glorius, F. J. Am.
Chem. Soc. 2009, 131, 4194. (c) Lu, Q.; Yu, H.; Fu, Y. J. Am. Chem. Soc.
2014, 136, 8252. (d) Zhang, Y.; Zhao, H.; Zhang, M.; Su, W. Angew.
Chem., Int. Ed. 2015, 54, 3817.
(12) (a) Dandapani, S.; Marcaurelle, L. A. Curr. Opin. Chem. Biol. 2010,
14, 362. (b) Yang, Y.; Niedermann, K.; Han, C.; Buchwald, S. L. Org.
Lett. 2014, 16, 4638.
(13) (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111,
1417. (b) Atwater, B.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.;
Pompeo, M.; Froese, R. D. J.; Organ, M. G. Angew. Chem., Int. Ed. 2015,
54, 9502. (c) Thapa, S.; Kafle, A.; Gurung, S. K.; Montoya, A.; Riedel, P.;
Giri, R. Angew. Chem., Int. Ed. 2015, 54, 8236.
(14) (a) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082. (b) Hattori,
K.; Ziadi, A.; Itami, K.; Yamaguchi, J. Chem. Commun. 2014, 50, 4105.
(15) (a) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2014, 136, 898.
(b) Wu, X.; Zhao, Y.; Ge, H. J. Am. Chem. Soc. 2014, 136, 1789.
(c) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005,
127, 13154. (d) Wasa, M.; Engle, K. M.; Yu, J. Q. J. Am. Chem. Soc. 2009,
131, 9886.
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