Ruthenium-catalyzed regioselective C-H alkenylation directed by a free amino group

Article abstract of DOI:10.1021/ol401779h

The ruthenium-catalyzed alkenylation reactions of 2-aminobiphenyls and cumylamine proceed smoothly to produce the corresponding regioselectively alkenylated products. These reactions involve a C-H bond cleavage directed by their free amino groups.

Full text of DOI:10.1021/ol401779h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ruthenium-Catalyzed Regioselective
CꢀH Alkenylation Directed by a Free
Amino Group
Chiharu Suzuki,† Koji Hirano,† Tetsuya Satoh,*,†,‡ and Masahiro Miura*,†
Department of Applied Chemistry, Faculty of Engineering, Osaka University,
Suita, Osaka 565-0871, Japan, and JST, ACT-C, 4-1-8 Honcho, Kawaguchi,
Saitama 332-0012, Japan
satoh@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
Received June 24, 2013
ABSTRACT
The ruthenium-catalyzed alkenylation reactions of 2-aminobiphenyls and cumylamine proceed smoothly to produce the corresponding
regioselectively alkenylated products. These reactions involve a CꢀH bond cleavage directed by their free amino groups.
Transition-metal-mediated or -catalyzed CꢀH func-
tionalization has recently gained significant attention be-
cause of their utility as atom- and step-economical tools in
organic synthesis.1 Especially, a chelation-assisted version
with the aid of directing groups is of importance, since
they lead to a regioselective CꢀH bond cleavage through
ortho-metalation. In most precedent examples, carbonyl
(ketones, aldehydes, esters, and amides), hydroxy, carboxy,
imino, and pyridyl, and azolyl groups have been employed
as directing groups. Meanwhile, amino groups, which
are more simple and ubiquitously available in a wide range
of organic molecules, have also been utilized for stoichio-
metric ortho-functionalization.2 However, interaction be-
tween transition metals and amino groups, especially
N-unsubstituted ones, has been regarded to be too strong
to be involved in catalytic processes.3,4
† Osaka University.
‡ JST.
(1) Selected recent reviews for CꢀH functionalization: (a) Colby,
D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012,
45, 814. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem.
Res. 2012, 45, 788. (c) Mitchell, E. A.; Peschiulli, A.; Lefevre, N.;
Meerpoel, L.; Maes, B. U. W. Chem.;Eur. J. 2012, 18, 10092. (d)
Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40,
5068. (e) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc.
Rev. 2011, 40, 4740. (f) Kuninobu, Y.; Takai, K. Chem. Rev. 2011, 111,
1938. (g) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780.
(h) Ackermann, L. Chem. Rev. 2011, 111, 1315. (i) Lapointe, D.;
Fagnou, K. Chem. Lett. 2010, 39, 1118. (j) Lyons, T. W.; Sanford,
M. S. Chem. Rev. 2010, 110, 1147. (k) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624. (l) Sun, C.-L.; Li, B.-J.; Shi,
Z.-J. Chem. Commun. 2010, 46, 677. (m) Satoh, T.; Miura, M. Chem.;
Eur. J. 2010, 16, 11212. (n) Ackermann, L.; Vicente, R.; Kapdi, A. R.
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D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (p) Daugulis, O.;
Do, H.-Q.;Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (q)McGlacken,
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On the other hand, we have reported that benzamides
and phenylazoles undergo ortho-alkenylation with internal
(2) (a) Ikariya, T.; Kuwata, S.; Kayaki, Y. Pure Appl. Chem. 2010, 82,
1471. (b) Arita, S.; Koike, T.; Kayaki, Y.; Ikariya, T. Chem.;Asian J.
2008, 3, 1479. (c) Sortais, J.-B.; Pannetier, N.; Holuigue, A.; Barloy, L.;
Sirlin, C.; Pfeffer, M.; Kyritsakas, N. Organometallics 2007, 26, 1856.
(d) Sortais, J.-B.; Ritleng, V.; Voelklin, A.; Holuigue, A.; Smail, H.;
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A. H. M.; de Vries, J. G.; Pfeffer, M. Org. Lett. 2005, 7, 1247.
(3) A few catalytic reactions involving a CꢀH bond cleavage directed
by a dimethylamino group have been reported: (a) Kakiuchi, F.; Igi, K.;
Matsumoto, M.; Hayamizu, T.; Chatani, N.; Murai, S. Chem. Lett.
2002, 396. (b) Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z. J. Am. Chem. Soc.
2007, 129, 7666.
r
10.1021/ol401779h
XXXX American Chemical Society

alkynes in the presence of a ruthenium/silver catalyst
system and acetic acid.5,6 Under such weakly acidic con-
ditions, the coordination ability of amino groups to a
ruthenium center seems to be weakened. Indeed, under
similar conditions using acetic acid, the alkenylation
of 2-aminobiphenyls was found to take place smoothly
via a CꢀH bond cleavage at the 20-position with the aid
of their free-amino group to produce the corresponding
2-amino-20-alkenylbiphenyls selectively. It should be
noted that 2-aminobiphenyl frameworks are included in
a wide range of functional molecules such as bioactive
reagents,7 fluorescent probes for bioimaging,8 conductive
polymers,9 inclusion compounds,10 porous materials,11
and ligands.12 Therefore, various methods for their precise
synthesis and modification are desired in such broad
fields. By using a similar reaction system, the amino-
directed ortho alkenylation of cumylamine could also be
conducted efficiently. R,R-Dialkylbenzylamine derivatives
including cumylamines are also of interest because of their
biological activities.13 These new findings are described
herein.
presence of [Ru(p-cymene)Cl2]2 (0.0125 mmol, 5 mol %),
AgSbF6 (0.05 mmol), and AcOH (1 mmol) in dioxane
at 100 °C for 3 h under N2. As a result, the alkenylation
product, (E)-20-(1,2-diphenylethenyl)-[1,10-biphenyl]-2-
amine (3a), was formed stereoselectively in 52% yield
(entry 1 in Table 1).14 Increasing the amount of 2a to
0.5 mmol significantly enhanced the product yield to 70%
(entry 2). Even with excess 2a, no overreaction was ob-
served. It was confirmed that the reaction did not proceed
at all in the absence of AcOH (entry 3). Other silver salts
such as AgBF4 and AgOTf could also be used as cocata-
lysts in place of AgSbF6 (entries 4 and 5). Without any
silver salt, 3a could not be obtained at all (entry 6). The
use of [Ru(benzene)Cl2]2 in place of [Ru(p-cymene)Cl2]2
slightly improved the yield of 3a (entry 7). A comparable
result was obtained in the case using 1-AdCO2H (Ad =
adamantyl) in place of AcOH (entry 8). Finally, the best
result was obtained at 80 °C: under such mild conditions,
3a was produced in 85% yield (entry 9). Decreasing the
reaction temperature further reduced the yield of 3a
(entries 10 and 11).
In an initial attempt, 2-aminobiphenyl (1a) (0.25 mmol)
was treated with diphenylacetylene (2a) (0.25 mmol) in the
Table 1. Reaction of 2-Aminobiphenyl (1a) with
Diphenylacetylene (2a)a
(4) Recently, free-amino-directed CꢀH alkenylation, allylation, ar-
ylation, azidation, and borylation have been reported: (a) Liang, Z.; Ju,
L.; Xie, Y.; Huang, L.; Zhang, Y. Chem.;Eur. J. 2012, 18, 15816. (b)
He, H.; Liu, W.-B.; Dai, L.-X.; You, S.-L. J. Am. Chem. Soc. 2009, 131,
8346. (c) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211. (d) Tang,
C.; Jiao, N. J. Am. Chem. Soc. 2012, 134, 18924. (e) Jiang, Q.; Duan-Mu,
D.; Zhong, W.; Chen, H.; Yan, H. Chem.;Eur. J. 2013, 19, 1903.
(5) (a) Hashimoto, Y.; Hirano, K.; Satoh, T.; Kakiuchi, F.; Miura,
M. J. Org. Chem. 2013, 78, 638. (b) Hashimoto, Y.; Hirano, K.; Satoh,
T.; Kakiuchi, F.; Miura, M. Org. Lett. 2012, 14, 2058.
(6) Selected examples for the ruthenium-catalyzed ortho-alkenylation:
(a) Hashimoto, Y.; Ortloff, T.; Hirano, K.; Satoh, T.; Bolm, C.; Miura, M.
Chem. Lett. 2012, 41, 118. (b) Chinnagolla, R. K.; Jeganmohan, M. Eur. J.
Org. Chem. 2012, 417. (c) Ackermann, L.; Wang, L.; Wolfram, R.; Lygin,
A. V. Org. Lett. 2012, 14, 728. (d) Kwon, K.-H.; Lee, D. W.; Yi, C. S.
Organometallics 2012, 31, 495. (e) Hashimoto, Y.; Ueyama, T.; Fukutani,
T.; Hirano, K.; Satoh, T.; Miura, M. Chem. Lett. 2011, 40, 1165. (f)
Arockiam, P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Green
Chem. 2011, 13, 3075. (g) Padala, K.; Jeganmohan, M. Org. Lett. 2011, 13,
6144. (h) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13, 4153. (i)
Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura,
M. Org. Lett. 2011, 13, 706. (j) Kwon, K.-H.; Lee, D. W.; Yi, C. S.
Organometallics2010, 29, 5748. (k)Kakiuchi, F.;Yamamoto,Y.;Chatani,
N.; Murai, S. Chem. Lett. 1995, 681. For a review, see: (l) Kozhushkov,
S. I.; Ackermann, L. Chem. Sci. 2013, 4, 886.
(7) (a) Liu, B.; Lee, Y.; Zou, J.; Petrassi, H. M.; Joseph, R. W.; Chao,
W.; Michelotti, E. L.; Bukhtiyarova, M.; Springman, E. B.; Dorsey,
B. D. Bioorg. Med. Chem. Lett. 2010, 20, 6592. (b) Chen, S.-C.; Kao,
C.-M.; Huang, M.-H.; Shih, M.-K.; Chen, Y.-L.; Huang, S.-P.; Liu,
T.-Z. Toxicol. Sci. 2003, 72, 283.
(8) Wang, J.-B.; Wu, Q.-Q.; Min, Y.-Z.; Liu, Y.-Z.; Song, Q.-H.
Chem. Commun. 2012, 48, 744.
temp time yield of
entry
Ru-cat.
cocat.
(°C)
(h)
3a (%)b
1c
2
3d
4
[Ru(p-cymene)Cl2]2 AgSbF6
[Ru(p-cymene)Cl2]2 AgSbF6
[Ru(p-cymene)Cl2]2 AgSbF6
[Ru(p-cymene)Cl2]2 AgBF4
[Ru(p-cymene)Cl2]2 AgOTf
100
100
100
100
100
100
100
100
80
3
3
5
5
5
5
5
5
5
7
24
52
70
0
67
71
0
5
6
[Ru(p-cymene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(benzene)Cl2]2
ꢀ
7
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
80
82
85(61)
81
3
8e
9
10
11
60
rt
a Reaction conditions: [1a]:[2a]:[Ru-cat.]:[cocat.]:[AcOH]
=
0.25:0.5:0.0125:0.05:1 (in mmol), in dioxane (3 mL) under N2. b GC
yield based on the amount of 1a used. Value in parentheses indicates yield
after purification. c [2a] = 0.25 mmol. d Without AcOH. e 1-AdCO2H
(1 mmol) was employed in place of AcOH.
(9) Badawy, W. A.; Ismail, K. M.; Khalifa, Z. M.; Medany, S. S.
J. Appl. Polym. Sci. 2012, 125, 3410.
(10) Goto, H.; Sudoh, M.; Kawamoto, K.; Sugimoto, H.; Inoue, S.
Chirality 2012, 24, 867.
(11) (a) Hinterholzinger, F. M.; Wuttke, S.; Roy, P.; Preusse, T.;
Schaate, A.; Behrens, P.; Godt, A.; Bein, T. Dalton Trans. 2012, 41, 3899.
(b) Schaate, A.; Roy, P.; Godt, A.; Lippke, J.; Waltz, F.; Wiebcke, M.;
Behrens, P. Chem.;Eur. J. 2011, 17, 6643.
Next, the alkenylation of substituted 2-aminobiphenyls
was examined under the optimized conditions (entry 8
in Table 1). 40-Methyl (1b), -methoxy (1c), -chloro (1d),
and -trifluoromethyl (1e) substituted 2-aminobiphenyls
€
(12) (a) Gao, H.; Ess, D. H.; Yousufuddin, M.; Kurti, L. J. Am.
Chem. Soc. 2013, 135, 7086. (b) Bryan, A. M.; Merrill, W. A.; Reiff,
W. M.; Fettinger, J. C.; Power, P. P. Inorg. Chem. 2012, 51, 3366.
(13) (a) Buyukbingol, E.; Sisman, A.; Akyildiz, M.; Alparslan, F. N.;
Adejare, A. Bioorg. Med. Chem. 2007, 15, 4265. (b) Hatanaka, T.;
Nabuchi, Y.; Ushio, H. J. Pharm. Pharmacol. 2002, 54, 549. (c)
Thurkauf, A.; deCosta, B.; Yamaguchi, S.-I.; Mattson, M. V.; Jacobson,
A. E.; Rice, K. C.; Rogawski, M. A. J. Med. Chem. 1990, 33, 1452.
(14) Selected reviews for CꢀH bond cleavage/alkyne insertion: (a)
de Mendoza, P.; Echavarren, A. M. Pure Appl. Chem. 2010, 82, 801. (b)
Nakao, Y. Chem. Rec. 2010, 11, 242. (c) Kitamura, T. Eur. J. Org. Chem.
2009, 1111. (d) Vasil’ev, A. V. Russ. J. Org. Chem. 2009, 45, 1. (e) Jia, C.;
Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633.
B
Org. Lett., Vol. XX, No. XX, XXXX

reacted with 2a smoothly to produce the corresponding
alkenylated products 3bꢀe in 75ꢀ82% yields (entries 1ꢀ4
in Table 2). The reactions of 30-substituted substrates 1f
and 1g with 2a took place at the sterically less hindered
position exclusively to produce 3f and 3g (entries 5 and 6).
A series of 5-substituted 2-aminobiphenyls 1hꢀk also
underwent the alkenylation to afford 3hꢀk (entries 7ꢀ10).
Table 3. Reaction of 2-Aminobiphenyl (1a) with Alkynes 2a
Table 2. Reaction of 2-Aminobiphenyls 1 with Diphenylacetylene
(2a)a
a Reaction conditions: [1a]:[2]:[{Ru(benzene)Cl2}2]:[AgSbF6]:[AcOH] =
0.25:0.5:0.0125:0.05:1 (in mmol), in dioxane (3 mL) at 80 °C under N2.
b Isolated yield based on the amount of 1a used. c [{Ru(benzene)Cl2}2] =
0.025. d Determined by 1H NMR.
cleavage at the 20-position to form a ruthenacycle inter-
mediate A. Then, alkyne insertion into the resulting arylꢀ
Ru bond to form an intermediate B and subsequent pro-
tonolysis may take place to produce 3. The last step appears
to be promoted by added AcOH.15
a Reaction conditions: [1]:[2a]:[{Ru(benzene)Cl2}2]:[AgSbF6]:[AcOH] =
0.25:0.5:0.0125:0.05:1 (in mmol), in dioxane (3 mL) at 80 °C under N2.
b Isolated yield based on the amount of 1 used.
Scheme 1
The reactions of 1a with various alkynes 2 were next
examined. para-Substituted diphenylacetylenes 2bꢀe
coupled with 1a to form 3lꢀo (entries 1ꢀ5 in Table 3).
Among them, the reaction with 2c was somewhat sluggish
under the standard conditions (entry 2). Increasing the
amount of [Ru(benzene)Cl2]2 slightlyimproved the yield of
3m (entry 3). The reactions of unsymmerical alkynes 2f
and 2g gave the corresponding 20-alkenyl[1,10-biphenyl]-2-
amines as mixtures of regioisomers 3and 30 (entries 6 and 7).
The reaction of 1a with 2-methyl-4-phenylbut-3-yn-2-ol
(2h) proceeded through alkenylation and cyclization to
produce 4, albeit with low efficiency (entry 8). The structure
of 4 was determined by X-ray crystallography (see the
Supporting Information).
(15) It is possible that AcOH promotes the CꢀH bond activation
step: (a) Flegeau, E. F.; Bruneau, C.; Dixneuf, P. H.; Jutand, A. J. Am.
Chem. Soc. 2011, 133, 10161and references therein. See also: (b)
Boutadla, Y.; Davies, D. L.; Macgregor, S. A.; Poblador-Bahamonde,
A. I. Dalton Trans. 2009, 5820. (c) Davies, D. L.; Al-Duaij, O.; Fawcett,
J.; Giardiello, M.; Hilton, S. T.; Russell, D. R. Dalton Trans. 2003, 4132.
In contrast, the exact role of a silver cocatalyst is obscure at the present
stage.
A plausible mechanism for the reaction of 1a with 2 is
illustrated in Scheme 1. Coordination of the amino nitrogen
in 1a seems to be the key for the regioselective CꢀH bond
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 4. Reaction of Cumylamine (5) with Alkynes 2a
Scheme 2
In the early stage (30 min) of the reaction of a deuterated
2-aminobiphenyl 1a-d5 with 2a, considerable contamina-
tion by protons at the 60-position of 20-alkenylated product
3a-dm and at the 20- and 60-positions of recovered 1a-dn
occurred (Scheme 2). These facts indicate that the CꢀH
bond cleavage step to form A appears to be reversible. In
addition, deuterium incorporation in the alkenyl position
of the product could not be detected by 1H NMR. There-
fore, the reaction pathway involving oxidative addition of
a CꢀH bond at the 20-position, which should bring about
deuterium incorporation at the alkenyl position, can be
excluded.
a Reaction conditions: [5]:[2]:[{Ru(p-cymene)Cl2}2]:[AgSbF6]:[AcOH] =
0.25:0.25:0.0125:0.05:1 (in mmol), in dioxane (3 mL) at 100 °C under N2.
b GC yield based on the amount of 5 used. Value in parentheses indicates
yield after purification. c [2a] = 0.5. d At 80 °C.
directing group have beenlessexplored, and thisrepresents
a new, effective protocol for achieving chelation control.
Further work for developing related reactions at the
proximal positions of common and ubiquitous function
is underway.
The alkenylation procedure could be applied to the reac-
tions of cumylamine (5). Thus, treatment of 5 with 2a
under the standard conditions gave ortho-alkenylated
product 6a in 64% yield (entry 1 in Table 4). Using 1 equiv
of 2a at 100 °C, 6a was obtained in 74% yield (entry 3).
Under similar conditions, 5 reacted with 2b, 2d, and 2e to
form 6bꢀd, respectively (entries 4ꢀ6).
Acknowledgment. We thank Prof. Dr. N. Tohnai, Osaka
University, for X-ray crystal-structure analysis and helpful
discussions. This work was partly supported by Grants-in-
Aid from MEXT, JSPS, and JST, Japan.
Supporting Information Available. Standard experimen-
tal procedure and characterization data of products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
In summary, we have demonstrated that the ruthenium-
catalyzed alkenylation of 2-aminobiphenyls with alkynes
takes place efficiently via amino-group-directed CꢀH
bond cleavage. The procedure is also applicable to cumyl-
amine. Catalytic processes utilizing a free amino group as a
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX