Cationic lr(l)-catalyzed sp3 C- H bond alkenylation of amides with alkynes

Article abstract of DOI:10.1021/ol900404r

A cationic lr(l)-BINAP catalyst cleaved sp³ C-H bonds of arylamides rather than sp² C-H bonds, which was followed by alkenylation with alkynes to give allylamides. Several types of amides and alkynes were suitable as substrates, and

Full text of DOI:10.1021/ol900404r

ORGANIC
LETTERS
Cationic Ir(I)-Catalyzed sp3 C-H Bond
Alkenylation of Amides with Alkynes
2009
Vol. 11, No. 8
1821-1823
Kyoji Tsuchikama, Mitsugu Kasagawa, Kohei Endo, and Takanori Shibata*
Department of Chemistry and Biochemistry, School of AdVanced Science and
Engineering, Waseda UniVersity, Okubo, Shinjuku, Tokyo 169-8555, Japan
tshibata@waseda.jp
Received February 26, 2009
ABSTRACT
A cationic Ir(I)-BINAP catalyst cleaved sp3 C-H bonds of arylamides rather than sp2 C-H bonds, which was followed by alkenylation with
alkynes to give allylamides. Several types of amides and alkynes were suitable as substrates, and the corresponding allylamides were obtained
in moderate to good yield. We also demonstrated that carbonyl-directed sp3 C-H bond cleavage would be an initial step in the present
reaction by a deuterium-labeling experiment.
The direct functionalization of unactivated carbon-hydrogen
bonds has attracted much attention in both academic and
industrial fields over the past decade. Especially, transition metal
catalysts have been comprehensively investigated as a powerful
tool in C-H activation/carbon-carbon or carbon-heteroatom
bond-forming processes.1 However, transformation at sp3 C-H
bonds is still a challenging topic due to the lack of a π-electron
system which would facilitate the interaction between catalyst
and substrate. Recently, the coupling of sp3 C-H bonds with
several functionalities such as alkenes,2a-d aryl halides,2e-g
and boronic acids2h,i has been developed using a directing
group or R-quaternary carbon.3 To the best of our knowledge,
however, there have been only limited examples of sp3 C-H
bond functionalization in which alkynes were used as a
coupling partner.4 In this study, we found that a cationic
Ir(I)-BINAP complex showed high catalytic activity in the
sp3 C-H bond alkenylation of amides with alkynes through
carbonyl-directed C-H bond activation, which prevailed over
aromatic sp2 C-H bond activation.2d
We previously reported that a cationic Ir(I)-BINAP
complex can act as an effective catalyst in the ortho-
alkenylation of arylketones with alkynes via carbonyl-
directed sp2 C-H bond activation.5 During our investigation
of substrates, we found that the alkenylation of arylamides
(1) (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731.
(b) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. (c) Dyker,
G., Ed. Handbook of C-H transformations; Wiley-VCH: Weinheim,
Germany, 2005. (d) Godula, K.; Sames, D. Science 2006, 312, 67. (e) Dick,
A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. (f) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (g) Campos, K. R. Chem.
Soc. ReV. 2007, 36, 1069. (h) Davies, H. M. L.; Manning, J. R. Nature
2008, 451, 417.
(2) For selected examples of sp3 C-H activation, see: (a) Ishii, Y.;
Chatani, N.; Kakiuchi, F.; Murai, S. Organometallics 1997, 16, 3615. (b)
Jun, C.-H.; Hwang, D.-C.; Na, S.-J. Chem. Commun. 1998, 1405. (c)
Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai, S.
J. Am. Chem. Soc. 2001, 123, 10935. Sames and co-workers reported the
neutral Ir(I)-catalyzed intramolecular cross coupling of sp3 C-H bonds of
amides with alkenes, see: (d) DoBoef, B.; Pastine, S. J.; Sames, D. J. Am.
Chem. Soc. 2004, 126, 6556. (e) Zaitsev, V. G.; Shabashov, D.; Daugulis,
O. J. Am. Chem. Soc. 2005, 127, 13154. (f) Lafrance, M.; Gorelsky, S. I.;
Fagnou, K. J. Am. Chem. Soc. 2007, 129, 14570. (g) Chaumontet, M.;
Piccardi, R.; Audic, N.; Hitce, J.; Peglion, J.-L.; Baudoin, O. J. Am. Chem.
Soc. 2008, 130, 15157. (h) Pastine, S.; Gribkov, D. V.; Sames, D. J. Am.
Chem. Soc. 2006, 128, 14220. (i) 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.
(3) For selected examples of sp3 C-H bond activation without assisting
groups, see: (a) Murphy, J. M.; Lawrence, J. D.; Kawamura, K.; Incarvito,
C.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 13684. (b) Ishiyama, T.;
Ishida, K.; Takagi, J.; Miyaura, N. Chem. Lett. 2001, 30, 1082. (c) Shimada,
S.; Batsanov, A. S.; Howard, J. A. K.; Marder, T. B. Angew. Chem., Int.
Ed. 2001, 40, 2168. (d) Dong, C.-G.; Hu, Q.-S. Angew. Chem., Int. Ed.
2006, 45, 2289. (e) Ren, H.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45,
3462.
10.1021/ol900404r CCC: $40.75
Published on Web 03/18/2009
2009 American Chemical Society

proceeded with unexpected chemoselectivity: in the presence
of cationic Ir(I)-BINAP catalyst in chlorobenzene, the ad-
dition of N,N-dimethylbenzamide (1a) to diphenylacetylene
(2a) occurred at the sp3 C-H bond to provide allylamide
3aa as an (E)-isomer, albeit in low yield (eq 1). In contrast,
only trace amounts of adduct 3aa′ derived from alkenylation
Table 2. Intermolecular Addition of Amides to Alkynes
6
1
at the sp2 C-H bond was detected by H NMR.
We further screened several reaction conditions using
benzamide 1a and alkyne 2a as model substrates (Table 1).
Table 1. Optimization of the Reaction Conditions
entry
ligand
X
yield of 3aa (%)a yield of 3aa′ (%)a
1
2
3
rac-BINAP
rac-BINAP
rac-BINAP
rac-BINAP
rac-BINAP
BIPHEP
SbF6
PF6
OTf
OTf
OTf
OTf
31
41
6
5
80 (75)b
(78)b
91
5 (4)b
5
4c
5d
6
6
53
ND
ND
<5
11
ND
7
8
DPPBenzene OTf
PPh3 OTf
a Yield was determined by 1H NMR integration relative to 1,1,2,2-
tetrachloroethane as an internal standard. b Isolated yield. c 1a/2a ) 2:1.
d 1a/2a ) 1:5. BIPHEP, 2,2′-bis(diphenylphosphino)-1,1′-biphenyl. DPP-
Benzene, 1,2-bis(diphenylphosphino)benzene. ND, not detected.
The counteranion of the cationic iridium complex was found
to be an important factor in the product yield and the
chemoselectivity: high conversion was achieved when trif-
luoromethanesulfonate anion (OTf) was used as a counter-
anion for the iridium complex, and the adduct at the sp3 C-H
bond of benzamide 1a was formed predominantly (eq 1 and
entries 1-3 in Table 1).7 A decrease in the amount of alkyne
2a did not affect the reaction rate (entry 4). Moreover, an
excess amount of the alkyne improved the yield without the
formation of multialkenylated adducts (entry 5). Moderate
yield was achieved with BIPHEP, whereas ligands without
a biaryl scaffold were ineffective (entries 6-8).
a Dialkenylated product 4ba was also isolated in 11% yield; 160 °C.
b Dialkenylated product 4da was also isolated in 10% yield. c Amide/Alkyne
) 2:1.
found to be good substrates in the present reaction: benzy-
lamide, pivalamide, acetamide, and N-methyl-2-pyrrolidinone
(NMP) were cleanly converted to the corresponding allyla-
mides in good yields (entries 1-4). N,N-Dimethylformamide
(DMF) also participated in the reaction with alkyne 2a to
give allylamide 3fa, albeit in low yield (entry 5). In addition,
N-methylacetamide also afforded allylamide 3ga in moderate
To survey the substrate scope, several amides and alkynes
were subjected to catalytic addition by using the best catalyst
([Ir(cod)2]OTf + rac-BINAP) (Table 2). Alkylamides were
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Org. Lett., Vol. 11, No. 8, 2009

yield without the formation of enamides derived from
hydroamidation (entry 6).8 In contrast, N-ethyl-2-pyrrolidi-
none and N-benzyl-2-pyrrolidinone did not give any adducts,
which indicates that alkenylation at secondary sp3 C-H
bonds did not proceed under the present reaction conditions.
Both electron-rich and electron-deficient diarylacetylenes
were tolerable as coupling partners (entries 7-9). Dinaph-
thylacetylene also underwent the reaction despite of its
bulkiness (entry 10). Moreover, the reaction of 1-phenyl-1-
hexyne with amide 1a proceeded regioselectively to give
adduct 3af as the sole regioisomer in moderate yield (entry
11). However, dialkylacetylenes such as 4-octyne were
inactive, which illustrates that at least one aryl substituent
on the alkyne terminus should be required.
Next, several experiments were conducted to elucidate the
reaction mechanism. First, the reaction of deuterated NMP
1e-d3 with alkyne 2a was examined. As a result, the
corresponding allylamide 3ea-d3 was obtained along with
almost the complete incorporation of deuterium at the vinylic
position and partial protonation at the allylic position
(Scheme 1). Second, the reaction of N,N-dimethybenzylamine
alkyne insertion would give allylamides.9 There may be
successive C-H bond cleavage of the allylamides at the
allylic position, resulting in partial protonation by an external
proton source such as water.10
In summary, we developed a cationic Ir(I)-BINAP complex-
catalyzed alkenylation of amides with alkynes via carbonyl-
directed sp3 C-H bond activation. This transformation
allowed for a straightforward construction of highly substi-
tuted allylamides. Further studies on modification of the
catalyst and elucidation of the detailed reaction mechanism
are in progress.
Acknowledgment. This work was supported by a Waseda
University Grant for Special Research Projects. We are also
grateful to the Japan Society for the Promotion of Science
for the fellowship support to K. Tsuchikama.
Supporting Information Available: Experimental pro-
cedures and spectral data for new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900404R
(4) The Rh-catalyzed alkenylation of simple alkanes with terminal
alkynes under UV irradiation: (a) Tokunaga, Y.; Sakakura, T.; Tanaka, M.
J. Mol. Catal. 1989, 56, 305. The neutral Ir(I)-catalyzed alkenylation of
sp3 C-H bonds adjacent to imine moiety using 1-hexyne: (b) Sakaguchi,
S.; Kubo, T.; Ishii, Y. Angew. Chem., Int. Ed. 2001, 40, 2534. The Cu-
catalyzed oxidative alkynylation of sp3 C-H bonds: (c) Li, Z.; Li, C.-J.
J. Am. Chem. Soc. 2004, 126, 11810.
Scheme 1
(5) Tsuchikama, K.; Kasagawa, M.; Hashimoto, Y.; Endo, K.; Shibata,
T. J. Organomet. Chem. 2008, 693, 3939.
(6) The corresponding Rh catalyst ([Rh(cod)2]BF4 + rac-BINAP) did
not give adduct 3aa at all, but gave a trace amount of adduct 3aa′. The
cationic Rh(I)-catalyzed sp2 C-H bond alkenylation of pyrrolidine amides
with alkynes was recently reported, see: Shibata, Y.; Otake, Y.; Hirano,
M.; Tanaka, K. Org. Lett. 2009, 11, 689.
(7) A typical experimental procedure (entry 3 in Table 1): [Ir(cod)2]OTf
(5.7 mg, 10 µmol) and rac-BINAP (6.8 mg, 11 µmol) were placed in a
Schlenk tube, which was then evacuated and backfilled with argon (×3).
To the reaction vessel were added N,N-dimethylbenzamide (1a) (15.0 mg,
0.1 mmol), diphenylacetylene (2a) (36.6 mg, 0.2 mmol), and PhCl (0.2
mL). The solution was then stirred at 135 °C for 24 h. After completion of
the reaction, the solvent was evaporated. The crude products were purified
by thin-layer chromatography (hexane/AcOEt ) 1/1) to give analytically
pure 3aa (75%) and 3aa′ (4%).
(8) Togni and co-workers reported that neutral iridium-bis(diphenylphos-
phino)biaryl complexes catalyzed the hydroamidation of benzamide to
norbornene, see: Aufdenblatten, R.; Diezi, S.; Togni, A. Monatsh. Chem.
2000, 131, 1345.
(9) At present, we cannot rule out an alternative mechanism, which
includes nucleophilic addition of the vinyliridium to the iminium ion
intermediate generated from A. For a recent report on the oxidative cyanation
of sp3 C-H bonds via an iminium intermediate, see: Murahashi, S.-I.; Nakae,
T.; Terai, H.; Komiya, N. J. Am. Chem. Soc. 2008, 130, 11005.
(10) When allylamide 3ea-d3 and H2O (3 equiv) were heated in the
presence of Ir(I)-BINAP catalyst, the deuteration ratio at the allylic position
decreased to 37%-D.
was examined under the same reaction conditions; however,
no adducts were detected. On the basis of these results, we
assume that carbonyl-directed sp3 C-H bond cleavage of
amides is an initial step to afford intermediate A. Subsequent
Org. Lett., Vol. 11, No. 8, 2009
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