Cross-coupling reactions between C(sp2)-H and C(sp 3)-H bonds via sequential dehydrogenation and C-H insertion

Article abstract of DOI:10.1055/s-0030-1259040

Formal C(sp²)-H and C(sp³)-H cross-coupling reactions were carried out by iridium-catalyzed transfer dehydrogenation of primary alcohols and sequential manganese-catalyzed insertion of the formed aldehydes into a carbon-hydrogen bond of aromatic or olefinic compounds. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259040

LETTER
2883
Cross-Coupling Reactions between C(sp2)–H and C(sp3)–H Bonds via
Sequential Dehydrogenation and C–H Insertion
3
C
ross-Coupling Re
o
actions betwieen C( 2
c
sp )–Hand
h
C
(sp )–H Bo
i
nds ro Kuninobu,* Daisuke Asanoma, Kazuhiko Takai*
Division of Chemistry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University, Tsushima, Kita-ku,
Okayama 700-8530, Japan
Fax +81(86)2518094; E-mail: kuninobu@cc.okayama-u.ac.jp; E-mail: ktakai@cc.okayama-u.ac.jp
Received 8 September 2010
Abstract: Formal C(sp2)–H and C(sp3)–H cross-coupling reactions
R1
(a)
H
OH
R1
+
OH
were carried out by iridium-catalyzed transfer dehydrogenation of
primary alcohols and sequential manganese-catalyzed insertion of
the formed aldehydes into a carbon–hydrogen bond of aromatic or
olefinic compounds.
R2
H
R2
dehydrogenation
(b-1)
O
R1
Key words: manganese, iridium, C–H activation, dehydrogena-
tion, cross-coupling
(b-2)
H
H
insertion of aldehydes
into a C(sp2)–H bond
R2
Scheme 1 Strategy for C(sp2)–C(sp3) cross-coupling reactions
Cross-coupling reactions are powerful tools to synthesize
complex organic molecules.1 In these transformations, or-
ganometallic reagents and organic halides or triflates are
usually employed as substrates, and efficient and regio-
selective couplings can be achieved. Unfortunately, metal
salts are formed as undesired side products. Recently, to
improve the efficiency, cross-coupling reactions between
carbon–metal and carbon–hydrogen bonds2 or carbon–
hydrogen and carbon–halogen bonds3 have been reported.
The most ideal method, however, is dehydrogenative cou-
pling reactions between carbon–hydrogen bonds of two
substrates.4 However, it is usually difficult to control the
regioselectivity in such transformations. Although there
have been several reports on coupling reactions between
two aromatic compounds, those based on C(sp3)–H bonds
are still rare.5 Among the methods to synthesize benzylic
(or allylic) alcohols, dehydrogenative coupling between
aromatic (or olefinic) compounds and primary alcohols is
one of the most direct approaches (Scheme 1, step a).
However, the transformation is still difficult. Therefore,
we devised a new sequential strategy: (1) dehydrogena-
tion of a primary alcohol (the first C–H bond activation,
Scheme 1, step b-1), and (2) insertion of the formed alde-
hyde into the carbon–hydrogen bond of aromatic or ole-
finic compounds (the second C–H bond activation;
Scheme 1, step b-2). We report herein formal coupling
reactions between aryl–alkyl and alkenyl–alkyl groups to
give benzylic and allylic alcohols.
chose a manganese complex, which has already been em-
ployed as a catalyst to promote the insertion of aldehydes
into a carbon–hydrogen bond of aromatic or olefinic com-
pounds.7
In previous iridium-catalyzed transfer dehydrogenations
of alcohols, acetone was used as both solvent and hydro-
gen acceptor.6 However, manganese-catalyzed insertion
of an aldehyde into an aromatic or olefinic C–H bond is
inhibited by acetone and isopropanol which is generated
by the hydrogenation of acetone. As another example of
dehydrogenation of alcohols under iridium catalysis, tolu-
ene was used as a solvent without a hydrogen acceptor.
Unfortunately, in the case of dehydrogenation of primary
alcohols, the yields of the formed aldehydes were low.8
Therefore, we investigated several unsaturated molecules
to find a suitable hydrogen acceptor, that is, one that will
receive hydrogen well without inhibiting the subsequent
manganese-catalyzed transformation in toluene. As a re-
sult, (E)-3-methyl-3-penten-2-one (2) was found to be the
most effective hydrogen acceptor.9,10 The reaction of ben-
zyl alcohol (1a) and 2 with catalytic amounts of an iridium
complex, [Cp*IrCl2]2, and K2CO3 in toluene, followed by
treatment with 1-methyl-2-phenyl-1H-imidazole (3a),
HSiEt3, and a catalytic amount of a manganese complex,
MnBr(CO)5, afforded benzyl ether 4a in 78% yield
(Scheme 2).11 In this reaction sequence, a new carbon–
carbon bond was constructed between the sp3-carbon of
alcohol 1a and the sp2-carbon of aromatic compound 3a.
In the first step of our strategy (Scheme 1, step b-1), irid-
ium-catalyzed transfer dehydrogenation of alcohols was
selected to prepare aldehydes.6 To achieve the insertion of
the formed aldehydes into the carbon–hydrogen bond of
aromatic or olefinic compounds (Scheme 1, step b-2), we
Next, we investigated the scope and limitations of alco-
hols 1 and aromatic or olefinic compounds 3 (Table 1).
Benzylic alcohols with an electron-donating or -with-
drawing group at the para-position, 1b–e, gave benzylic
ethers 4b–e in good to excellent yields (entries 1–4). The
corresponding benzylic ester 4f was produced in 71%
yield without losing the bromine atom (entry 5). A methyl
SYNLETT 2010, No. 19, pp 2883–2886
x
x
.x
x
.2
0
1
0
Advanced online publication: 10.11.2010
DOI: 10.1055/s-0030-1259040; Art ID: U08110ST
© Georg Thieme Verlag Stuttgart · New York

2884
Y. Kuninobu et al.
LETTER
Me
N
O
N
2 (3.0 equiv)
3a (1.0 equiv)
Me
N
[Cp*IrCl2]2 (1.0 mol%)
K2CO3 (10 mol%)
HSiEt3 (2.0 equiv)
MnBr(CO)5 (5.0 mol%)
OH
N
toluene, 150 °C, 18 h
toluene, 115 °C, 24 h
OTES
Ph
1a
Ph
(2.0 equiv)
4a 78%
Scheme 2
group at the ortho-position of benzylic alcohol 1g inhibit- When an aromatic ketimine was employed instead of 1-
ed the reaction slightly, and benzylic ether 4g was formed methyl-2-phenyl-1H-imidazole (3a), successive intramo-
in 56% yield (entry 6). (1-Naphthalenyl)methanol (1h) lecular cyclization took place, and an isobenzofuran de-
and (2-furanyl)methanol (1i) provided the corresponding rivative was obtained (Scheme 4). Thus, treatment of
benzylic ethers 4h and 4i in moderate yields, respectively benzyl alcohol (1a) with aromatic ketimine 5 in the pres-
(entries 7 and 8). Benzylic ether 4j was generated with al-
iphatic alcohol 1j (entry 9). The reaction also proceeded
Table 1 Cross-Coupling Reactions between Alcohols 1 with Aro-
using an olefinic substrate 3b, and the corresponding al-
lylic ether 4k was afforded in 38% yield (entry 10). In the
above reactions, unreacted aromatic and olefinic com-
pounds 3a and 3b were recovered. The total percentages
of the recovery of 3a and the yields of products 4 were
nearly 100%; however, ca. 20% of olefinic compound 3b
was decomposed. On the other hand, aldehydes were con-
sumed mainly by hydrosilylation of the aldehydes with
hydrosilane 2. The yields of 4 were not improved by in-
creasing the amounts of 1 and/or 2.
matic or Olefinic Compounds 3a
Me
N
3 (1.0 equiv)
MnBr(CO)5 (5.0 mol%)
HSiEt3 (2.0 equiv)
[Cp*IrCl2]2 (1.0 mol%)
2 (3.0 equiv)
N
OH
K2CO3 (10 mol%)
toluene, 150 °C, 18 h
OTES
toluene, 115 °C, 24 h
R
1
4
R
Entry
1c
R
Alco-
hols
3
Products Yield
(%)b
Me
N
The proposed mechanism is as follows (Scheme 3): (1)
iridium-catalyzed dehydrogenation of an alcohol;6,12 (2)
manganese-catalyzed carbon–hydrogen bond activation
at the ortho position of an aromatic or alkenyl imidazole;7
(3) insertion of the formed aldehyde into the manganese–
carbon bond; (4) transmetalation with hydrosilane via de-
hydrogenation.
N
4-MeOC6H4 1b
4-MeC6H4 1c
4b
63 (73)
3a
3a
2
4c14
4d
4e
4f
77 (86)
78 (84)
87 (90)
71 (73)
56 (59)
62 (64)
45 (46)
43 (46)
3
4-PhC6H4
4-F3CC6H4 1e
4-BrC6H4 1f
1d
3a
3a
3a
3a
3a
3a
3a
4d
5
Me
Me
N
N
N
6c
7c
8e
9
2-MeC6H4 1g
1-naphthyl 1h
4g
4h
4i
N
OTES
R
2-furyl
1i
1j
Mn
H2
(4)
(2)
N
n-C8H17
4j
HSiEt3
Me
Me
Me
N
N
10f
Ph
1a
4k
38 (50)
(3)
N
N
O
N
Mn
Mn H
H
O
O
3b
H
R
R
a 1 (2.0 equiv).
O
b Isolated yield. Yield determined by 1H NMR is reported in parenthe-
ses.
cat. Ir
(1)
OH
c HSiEt3 (3.0 equiv).
R
d Step 1: 2 h; step 2: HSiEt3 (4.0 equiv).
e Step 1: 2 h; step 2: HSiEt3 (3.0 equiv).
f Step 2: [ReBr(CO)3(thf)]2 (2.5 mol%) and 4 Å MS were used instead
of MnBr(CO)5.
Scheme 3 Proposed mechanism for formal cross-coupling reactions
between sp3- and sp2-carbons
Synlett 2010, No. 19, 2883–2886 © Thieme Stuttgart · New York

LETTER
Cross-Coupling Reactions between C(sp2)–H and C(sp3)–H Bonds
2885
(2) For recent examples of carbon–metal and carbon–hydrogen
bond coupling, see: (a) Giri, R.; Maugel, N.; Li, J.-J.; Wang,
D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am.
Chem. Soc. 2007, 129, 3510. For reviews, see: (b) Li, B.-J.;
Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949. (c) Chen, X.;
Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem. Int. Ed.
2009, 48, 5094.
(3) For recent examples of carbon–hydrogen and carbon–
halogen bond coupling, see: (a) Wang, X.; Lane, B. S.;
Sames, D. J. Am. Chem. Soc. 2005, 127, 4996. (b) Oi, S.;
Sakai, K.; Inoue, Y. Org. Lett. 2005, 7, 4009.
ence of catalytic amounts of an iridium complex,
[Cp*IrCl2]2, a rhenium complex, [ReBr(CO)3(thf)]2, and 4
Å molecular sieves in toluene at 115 °C for 24 hours, gave
1,3-diphenylisobenzofuran (6) in 91% yield (Scheme 4).
Both iridium-catalyzed dehydrogenation of 1a and man-
ganese-catalyzed C–H bond activation followed by the in-
sertion of an aldehyde proceeded in toluene. Therefore,
this reaction could be performed in one operation.
[Cp*IrCl2]2 (1.0 mol%)
Ph
(c) Kobayashi, K.; Sugie, A.; Takahashi, M.; Masui, K.;
Mori, A. Org. Lett. 2005, 7, 5083. (d) Ackermann, L.;
Althammer, A.; Born, R. Angew. Chem. Int. Ed. 2006, 45,
2619. (e) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K.
J. Am. Chem. Soc. 2006, 128, 11748. (f) Berman, A. M.;
Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2008, 130, 14926. (g) Do, H.-Q.; Daugulis, O. J. Am.
Chem. Soc. 2007, 129, 12404. For reviews, see: (h) Bellina,
F.; Rossi, R. Tetrahedron 2009, 65, 10269. (i) Daugulis, O.
Top. Curr. Chem. 2010, 292, 57. (j) Beck, E. M.; Gaunt, M.
J. Top. Curr. Chem. 2010, 292, 85. (k) Bouffard, J.; Itami,
K. Top. Curr. Chem. 2010, 292, 231.
2 (2.0 equiv)
[ReBr(CO)3(thf)]2 (2.5 mol%)
4 Å MS
Ph
O
Ph
OH
N
+
toluene, 115 °C, 24 h
Ph
5
1a (2.0 equiv)
Ph
6 91%
Scheme 4
Using an alcohol with an olefin moiety, 1k, oxidation of
1k, insertion of the formed aldehyde into a C–H bond of
aromatic ketimine 5, intramolecular nucleophilic cycliza-
tion, elimination of aniline (formation of isobenzofuran
derivative), and intramolecular cyclization by Diels–Al-
der reaction occurred. After dehydration under acidic con-
ditions, naphthalene derivative 7 was obtained in 45%
yield (Scheme 5).
(4) For recent examples of carbon–hydrogen and carbon–
hydrogen bond coupling, see: (a) Stuart, D. R.; Fagnou, K.
Science 2007, 316, 1172. (b) Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2007, 129, 11904. (c) Zhao, X.; Yeung,
C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 5837.
(5) For representative examples, see: (a) Sezen, B.; Sames, D.
J. Am. Chem. Soc. 2005, 127, 5284. (b) Li, Z.; Li, C.-J.
J. Am. Chem. Soc. 2005, 127, 6968. (c) Wang, D.-H.; Wasa,
M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190.
(d) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (e) Wasa, M.;
Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3680.
(f) Qian, B.; Guo, S.; Shao, J.; Zhu, Q.; Yang, L.; Xia, C.;
Huang, H. J. Am. Chem. Soc. 2010, 132, 3650.
In summary, we have succeeded in cross-coupling reac-
tions between sp2- and sp3-carbon bonds by iridium-cata-
lyzed dehydrogenation of primary alcohols and sequential
manganese-catalyzed insertion of the formed aldehydes
into a C–H bond of aromatic or olefinic compounds.13 We
hope that this sequential methodology will provide useful
insight to realize cross-coupling reactions between sub-
strates of difficulty.
(g) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010,
132, 3965.
(6) Fujita, K.-i.; Furukawa, S.; Yamaguchi, R. J. Organomet.
Chem. 2002, 649, 289.
(7) (a) Kuninobu, Y.; Nishina, Y.; Takeuchi, T.; Takai, K.
Angew. Chem. Int. Ed. 2007, 46, 6518. In addition, we have
also reported on rhenium-catalyzed insertion of aldehydes
into a C–H bond of aromatic and olefinic compounds. See
also: (b) Kuninobu, Y.; Nishina, Y.; Nakagawa, C.; Takai,
K. J. Am. Chem. Soc. 2006, 128, 12376. (c) Kuninobu, Y.;
Nishina, Y.; Takai, K. Tetrahedron 2007, 63, 8463.
(d) Kuninobu, Y.; Fujii, Y.; Matsuki, T.; Nishina, Y.; Takai,
K. Org. Lett. 2009, 11, 2711.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was partially supported by the Ministry of Education,
Culture, Sports, Science, and Technology of Japan.
(8) Fujita, K.-i.; Tanino, N.; Yamaguchi, R. Org. Lett. 2007, 9,
109.
References and Notes
(9) When (E)-3-methyl-3-penten-2-one (2) was used as a
hydrogen acceptor, 3-methylpentan-2-one was formed. This
result shows that the olefinic moiety of 2 was reduced.
(10) Investigation of hydrogen acceptors in dehydrogenation of
alcohol 1a {hydrogen acceptor: 1.5 equiv; [Cp*IrCl2]2: 0.50
mol%; K2CO3: 5.0 mol%; toluene, 150 °C; 18 h}: (E)-3-
(1) Metal-Catalyzed Cross Coupling Reactions, 2nd ed., Vol. 1
and 2; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004.
[Cp*IrCl2]2 (1.0 mol%)
Ph
Ph
2 (2.0 equiv)
[ReBr(CO)3(thf)]2 (2.5 mol%)
4 Å MS
Ph
H2SO4
AcOH
N
+
OH
toluene, 115 °C, 24 h
1k (2.0 equiv)
5
45%
7
Scheme 5
Synlett 2010, No. 19, 2883–2886 © Thieme Stuttgart · New York

2886
Y. Kuninobu et al.
LETTER
(3, 0.250 mmol), HSiEt3 (58.1 mg, 0.500 mmol), and
MnBr(CO)5 (3.4 mg, 0.013 mmol) were added, and the
mixture was stirred at 115 °C for 24 h. The product was
isolated by column chromatography on silica gel [hexane–
EtOAc = 5:1. Before column chromatography, the silica
gel was treated with Et3N {5% solution in hexane–EtOAc
(5/1)}.] to give 4.
methyl-3-penten-2-one >99%; (1E,4E)-1,5-diphenyl-1,4-
pentadien-3-one >99%; 3-methyl-2-cyclohexenone 92%;
(E)-4-phenyl-3-buten-2-one 92%; 1-penten-3-one 82%;
p-benzoquinone 78%; 2-cyclohexenone 57%; 2-cyclo-
pentenone 52%; 3-ethoxy-2-cyclohexenone 8%.
(11) First, we conducted the reactions between benzyl alcohol
(1a), (E)-3-methyl-3-penten-2-one (2), 1-methyl-2-phenyl-
1H-imidazole (3a), and HSiEt3 in the presence of catalytic
amounts of an iridium complex, [Cp*IrCl2]2, K2CO3, and a
manganese complex, MnBr(CO)5, in toluene. However, the
desired reaction did not proceed at all. Therefore, we carried
out the coupling reactions in two steps.
(12) 3-Methyl-2-pentanone, which is formed by hydrogenation
of (E)-3-methyl-3-penten-2-one (2), was observed by 1H
NMR and GCMS.
(13) General Procedure of Formal Cross-Coupling Reaction
A mixture of alcohol (1, 0.500 mmol), (E)-3-methyl-3-
penten-2-one (2, 73.6 mg 0.750 mmol), [Cp*IrCl2]2 (2.0 mg,
0.0025 mmol), K2CO3 (3.5 mg, 0.025 mmol), and toluene
(1.0 mL) was heated at 150 °C for 18 h. Then, imidazole
(14) 1-Methyl-2-[2-(p-tolyltriethylsilanyloxymethyl)phenyl]-
1H-imidazole (4c)
1H NMR (400 MHz, CDCl3): d = 0.54 (q, J = 8.0 Hz, 6 H),
0.86 (t, J = 8.0 Hz, 9 H), 2.23 (s, 3 H), 2.69 (s, 3 H), 6.15 (s,
1 H), 6.74 (d, J = 8.8 Hz, 2 H), 6.81 (s, 1 H), 6.93 (d, J = 6.8
Hz, 2 H), 7.11 (d, J = 7.2 Hz, 1 H), 7.18 (s, 1 H), 7.28 (t,
J = 7.2 Hz, 1 H), 7.50 (t, J = 7.2 Hz, 1 H), 8.03 (d, J = 7.6
Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 4.7, 6.7, 32.4,
72.5, 120.2, 125.7, 126.1, 126.8, 127.8, 128.1, 128.3, 129.3,
129.8, 136.2, 141.7, 146.4, 146.6; IR (nujol): n = 1178 (m),
1117 (m), 1072 (m), 1011 (m), 851 (m) cm–1. HRMS (EI+):
m/z calcd for C23H34N2OSi [M+]: 392.2284; found:
392.2291.
Synlett 2010, No. 19, 2883–2886 © Thieme Stuttgart · New York