Cobalt-Catalyzed Cyclization of Aliphatic Amides and Terminal Alkynes with Silver-Cocatalyst

Article abstract of DOI:10.1021/jacs.5b07424

A new method of cobalt-catalyzed synthesis of pyrrolidinones from aliphatic amides and terminal alkynes was discovered through a C-H bond functionalization process on unactivated sp³ carbons with the silver cocatalyst using a bidentate auxiliary. For the first time, a broad range of easily accessible alkynes are exploited as the reaction partner in C(sp³)-H bond activation to give the important 5-ethylidene-pyrrolidin-2-ones in a site-selective fashion. The reaction tolerates a wide variety of functional groups including -F, -Cl, -Br, -CF₃, ether, cyclopropane, and thiophene. Both pyridine ligand and aromatic solvent play the important role for the promotion of reactivity. This cobalt-catalyzed cyclization reaction can be successfully extended to a variety of aromatic amides to afford a variety of isoindolinones. Attractive features of this catalytic system include its low cost, easy operation, and convenient access to a wide range of pyrrolidinones and isoindolinones.

Full text of DOI:10.1021/jacs.5b07424

Subscriber access provided by CMU Libraries - http://library.cmich.edu
Article
Cobalt-Catalyzed Cyclization of Aliphatic Amides
and Terminal Alkynes with Silver-Cocatalyst
Jitan Zhang, Hui Chen, Cong Lin, Zhanxiang Liu, Chen Wang, and Yuhong Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b07424 • Publication Date (Web): 21 Sep 2015
Downloaded from http://pubs.acs.org on September 21, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 9
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Cobalt-Catalyzed Cyclization of Aliphatic Amides and Terminal
Alkynes with Silver-Cocatalyst
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
,※
※
Jitan Zhang, † Hui Chen, †, Cong Lin, † Zhanxiang Liu, † Chen Wang,§ Yuhong Zhang*,†,‡
†Department of Chemistry, Zhejiang University, Hangzhou 310027, China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China.
§Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, Shaoxing University, Shaoxing 312000,
China
ABSTRACT: A new method of cobaltꢀcatalyzed synthesis of pyrrolidinones from aliphatic amides and terminal alkynes was disꢀ
covered through a CꢀH bond functionalization process on unactivated sp3 carbons with the silver coꢀcatalyst using a bidentate auxilꢀ
iary. For the first time, a broad range of easily accessible alkynes are exploited as the reaction partner in C(sp3)ꢀH bond activation
to give the important 5ꢀethylideneꢀpyrrolidinꢀ2ꢀones in a siteꢀselective fashion. The reaction tolerates a wide variety of functional
groups including ꢀF, ꢀCl, ꢀBr, ꢀCF3, ether, cyclopropane, and thiophene. Both pyridine ligand and aromatic solvent play the imꢀ
portant role for the promotion of reactivity. This cobaltꢀcatalyzed cyclization reaction can be successfully extended to a variety of
aromatic amides to afford a variety of isoindolinones. Attractive features of this system include its low cost, its ease of operation,
and its ability to access a wide range of pyrrolidinones and isoindolinones.
INTRODUCTION
proven to be the powerful strategy for the activation of sp3 Cꢀ
H bonds.14,15
Transition metalꢀcatalyzed CꢀH bond activations, which
provide the attractive alternatives for traditional crossꢀ
coupling reactions without the need for prefunctionalization,
have long been one of the most important research objectives
in organic chemistry.1 Significant advances have been made
with catalysts based on precious metal catalysts such as Pd,
Rh, Ru, and Ir.2 However, with the increasing interest in susꢀ
tainable catalysis, considerable effort in this area has been
directed towards the new reactions by utilizing low cost and
environmentally benign firstꢀrow transition metals in the place
of noble transition metals currently. In this regard, cobalt cataꢀ
lysts in various oxidation states have attracted particular attenꢀ
tion due to their unique properties demonstrated in C(sp2)ꢀH
activation as new catalytic systems,3 and pioneering progress
has been made by Nakamura,4 Daugulis,5 and Kanai6. Followꢀ
ing these fundamental paradigms, a series of novel cobaltꢀ
catalyzed organic transformations of arenes and alkenes have
been developed by the groups of Glorious,7 Ellman,8 Yoshiꢀ
kai,9 Song,10 and Ackermann 11 recently.
In contrast to the direct functionalization of C(sp2)ꢀH bond,
the use of cobalt catalysts in the transformations of unactivatꢀ
ed sp3 CꢀH bond cleavage is extremely underdeveloped.12 Beꢀ
cause the C(sp3)ꢀH bonds lack π electrons that can readily
interact with transition metals, most transformations of C(sp2)ꢀ
H bonds are quite difficult to be achieved for a sp3 CꢀH bond.
Cenini12a,12b and Zhang12f,12h have demonstrated the cobaltꢀ
catalyzed functionalization of relatively reactive sp3 CꢀH, and
an unusual cobaltꢀcatalyzed activation of C(sp3)ꢀH bond adjaꢀ
cent to nitrogen was reported by Brookhart.12d,12g Very recentꢀ
ly, Ge and coworkers reported an elegant example of cobaltꢀ
catalyzed intraꢀ and intermolecular amination of unactivated
sp3 CꢀH bonds.13 One of the key point of this successful reacꢀ
tion is the utilizing of a bidentate chelating auxiliary, which is
The pivotal role of terminal alkynes as outstanding building
blocks has attracted considerable attention of both industrial
and academic laboratories for decades because of their promiꢀ
nent reactivity and vast number that are commercially availaꢀ
ble. A number of new transformations for applying terminal
alkynes in the C(sp2)ꢀH bond functionalizations as the reaction
partners have been reported.16,17 However, this chemistry is
limited to the fuctionalization of C(sp2)ꢀH bonds, and the use
of terminal alkynes in unactivated sp3 CꢀH bond fuctionalizaꢀ
tions is still not achieved yet.18 It has been widely considered
that the terminal alkynes interference the CꢀH activation step
potentially and the homocoupling of the terminal alkynes
along with the main reaction product decelerate the efficacy of
its crossꢀcoupling with inert CꢀH bond under oxidative reacꢀ
tion conditions. To overcome these problems, bromoalkyne
was successfully explored as a preactivated alkynes in the
palladiumꢀcatalyzed alkynylation of unactivated C(sp3)ꢀH
bonds by Chatani and Yu.19 From the viewpoint of atom and
step economy, the direct use of terminal alkynes as coupling
partner is more appealing. In the present study, we wish to
disclose a cobaltꢀcatalyzed transformation of unactivated
C(sp3)ꢀH bonds with terminal alkynes with the assistance of 8ꢀ
aminoquinolyl group to access the important pyrrolidinones,
which are prevalent motifs in drugs and natural products.20,21
Superior reactivity is demonstrated by this cobalt catalytic
system and the homocoupling of terminal alkynes is supꢀ
pressed. The reaction can be successfully extended to a variety
of aromatic amides to afford a variety of isoindolinones. This
transformation not only represents a significant step forward
for implementing alkynes as privileged counterparts in C(sp3)ꢀ
H activation endeavors, but also provides useful insight to the
catalytic C(sp3)ꢀH bond functionalization by cobalt catalysis.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 9
RESULTS AND DISSCUSION
73% yield with absolute Eꢀconfiguration (Table 1, entry 2),
1
2
3
4
5
6
7
8
and the homocoupling reaction was suppressed apparently. It
was observed that the Zꢀconfiguration product 3a' was initially
formed and gradually changed into the Eꢀconfiguration prodꢀ
uct 3a under the reaction conditions (see Supporting Inforꢀ
mation). The replacement of TBAI with tetrabutylammonium
bromide (TBAB) gave a slightly less yield (Table 1, entry 2, in
parenthesis). However, the promotional effect of tetrabuꢀ
tylammonium chloride (TBACl), tetraethylammonium broꢀ
mide (TEAB) and tetraethylammonium iodide (TEAI) deꢀ
creased drastically (see Supporting Information). These results
implicate that the main role of TBAI in this transformation
may be the phase transfer catalyst. A remarkable solvent
effect was observed. No reaction took place in the comꢀ
mon solvents, such as DMF, DMSO, TFEtOH, and DCE (see
Supporting Information). An exception was the use of toluene,
which generated pyrrolidinone 3a in 57% yield (Table 1, entry
3). The subsequent studies revealed that the use of other aroꢀ
matic solvents, such as chlorobenzene, bromobenzene, and
fluorobenzene, resulted in pyrrolidinone 3a as well (Table 1,
entries 4ꢀ6), but superior reaction outcome was obtained by
trifluoromethylbenzene which gave a 73% yield (Table 1,
entry 2). We hypothesize that the enhanced reactivity with
aromatic solvent arises in part from its coordination with coꢀ
balt catalyst, which would facilitate the formation of Co πꢀ
arene intermediate.22 A number of bases were also examined,
and the nature of bases as well as its counterion influence the
catalytic reactivity. For example, NaOAc and KOAc quitted
the reaction (Table 1, entries 7ꢀ8). K2CO3, NaHCO3 and
KHCO3 gave inferior reactivity (Table 1, entries 9ꢀ11), but
Na2CO3 showed significant effect on the reaction to give the
product in 82% yield (Table 1, entry 12). To further improve
the conversion, several ligands were screened and application
of pyridine showed an enhancement of reactivity to give a
95% yield (Table 1, entry 13), albeit low background reaction
rate in the presence of its analogous 2,2'ꢀbipyridine and 1,10ꢀ
phenanthroline was observed (Table 1, entries 15ꢀ18). Various
cobalt sources, such as CoBr2, CoCl2, CoI2 and Co(acac)2,
were examined (see supporting Information). The other metal
catalysts such as Mn(OAc)2·4H2O, Fe(acac)3, Ni(OAc)2 were
examined. It was found that Mn(OAc)2·4H2O and Fe(acac)3
failed to promote the reaction, but 20 mol % Ni(OAc)2 cataꢀ
lyzed the reaction under the reaction conditions to give the
same product in 59% yield (Table 1, entries 19ꢀ21). These
studies reconfirmed that Co(OAc)2 is the optimal cobalt cataꢀ
lyst source. No reaction was observed in the absence of the
cobalt catalyst or silver salt (see supporting Information).
Our investigation to explore the cobaltꢀcatalyzed sp3 CꢀH
activation began with the reaction of propioamide 1a and pheꢀ
nylacetylene (2a) in the presence of Co(OAc)2 and selected
additives as shown in Table 1. Initial observations revealed
Table 1. Optimization of Reaction Conditions a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
1
reaction conditions
yield (%)b
trace
73 (71)
57
Co(OAc)2, TFB
2
Co(OAc)2, TBAI (TBAB), TFB
Co(OAc)2, TBAI, toluene
3
4
Co(OAc)2, TBAI, PhCl
51
5
Co(OAc)2, TBAI, PhBr
26
6
Co(OAc)2, TBAI, PhF
70
7
Co(OAc)2, TBAI, NaOAc, TFB
Co(OAc)2, TBAI, KOAc, TFB
Co(OAc)2, TBAI,K2CO3, TFB
Co(OAc)2, TBAI, NaHCO3, TFB
Co(OAc)2, TBAI, KHCO3, TFB
Co(OAc)2, TBAI, Na2CO3, TFB
Co(OAc)2, TBAI, Na2CO3, pyridine, TFB
Co(OAc)2, TBAI, pyridine, TFB
Co(OAc)2, TBAI, Na2CO3, bipy, TFB
Co(OAc)2, TBAI, Na2CO3, oꢀphen, TFB
TBAI, Na2CO3, pyridine, TFB
Co(OAc)2, TBAI, Na2CO3, oꢀphen, TFB
N.R.
N.R.
52
8
9
10
11
12
13
14
15
16
17
18c
19
20
21
66
40
82
95
60
trace
trace
N.R.
N.R.
Mn(OAc)2, TBAI, Na2CO3, pyridine, TFB N.R.
Fe(acac)3, TBAI, Na2CO3, pyridine, TFB
Ni(OAc)2, TBAI, Na2CO3, pyridine, TFB
N.R.
59
To explore the scope and limitation of this cobaltꢀcatalyzed
cyclization reaction, a number of alkynes were applied under
the optimal reaction conditions as shown in Scheme 1. In genꢀ
eral, both electronꢀrich and electronꢀdeficient alkynes were
compatible with the reaction conditions (3aꢀ3k). For example,
1ꢀethynylꢀ4ꢀmethylbenzene reacted smoothly to give the deꢀ
sired product in 95% yield (3b). Its analogous 1ꢀethynylꢀ3ꢀ
methylbenzene and 1ꢀethynylꢀ2ꢀmethylbenzene gave the
products in good yields (3c and 3d). However, 1ꢀethynylꢀ4ꢀ
methoxylbenzene was less active to give the product in 65%
yield (3e). The electronꢀdeficient acetylenes showed similar
reactivity and afforded the corresponding pyrrolidinones in
moderate to good yields (3fꢀ3i). Notably, the strong electronꢀ
deficient 4ꢀethynylꢀ1,2ꢀdifluorobenzene and 1ꢀethynylꢀ4ꢀ
(trifluoromethyl)benzene could be tolerated in the reaction,
although the corresponding pyrrolidinones were provided in
aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol),
Co(OAc)2·4H2O (0.04 mmol), Ag2CO3 (0.6 mmol), TBAI (0.8
mmol), base (0.6 mmol), additive (0.4 mmol), TFB (0.6 mL), N2,
22 h at 150 oC. bIsolated yield of 3a by flash column
c
chromatography. 0.2 equiv bipy or oꢀphen was added. TFB =
trifluoromethylbenzene, Bipy = 2,2'ꢀbipyridine, oꢀphen = 1,10ꢀ
phenanthroline. Q = Quinolinꢀ8ꢀyl, TBAI = Tetrabutylammonium
Iodide, TBAB = Tetrabutylammonium Bromide.
that the dimmer of alkyne was the major product and only a
trace of pyrrolidinone 3a was observed (Table 1, entry 1).
Gratifyingly, the combination of cobalt catalyst with tetrabuꢀ
tylammonium iodide (TBAI) resulted in the isolation of 3a in
ACS Paragon Plus Environment

Page 3 of 9
Journal of the American Chemical Society
Scheme 1. Substrate Scope of Alkynes a,b
corresponding pyrrolidinones (3q and 3r). However, relatively
1
2
3
4
5
6
7
8
lower yields were obtained with these substrates, which might
be attributed to their lower stability comparing with the exꢀ
tended conjugation of aromatic alkynes. The regioselectivity
of the reaction is always such that CꢀN bond formation takes
place on the terminal carbon atom. In all cases the Eꢀisomers
are afforded. The structure of the pyrrolidinone 3a was conꢀ
firmed by Xꢀray crystallography (Figure 1).
Scheme 2. Substrate Scope of Aliphatic Amides a,b
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReaction conditions: 1a (0.2 mmol),
2
(0.4 mmol),
Co(OAc)2·4H2O (0.04 mmol), Ag2CO3 (0.6 mmol), Na2CO3 (0.6
mmol), pyridine (0.4 mmol), TBAI (0.8 mmol), TFB (0.6 mL),
N2, 22 h at 150 oC. bIsolated yield of 3 by flash column chromaꢀ
tography. TFB = Trifluoromethylbenzene, Q = Quinolinꢀ8ꢀyl,
TBAI = Tetrabutylammonium Iodide.
moderate yields (3j and 3k). 1ꢀEthynylnaphthalene participatꢀ
ed in the reaction smoothly to give the product in 71% yield
(3l). The employment of 2ꢀ and 3ꢀethynylthiophene as subꢀ
strates afforded the desired pyrrolidinones with the comparaꢀ
ble yields (3m and 3n), although 2ꢀethynylthiophene showed
better reactivity partially due to the more efficient conjugated
system of 2ꢀethynylthiophene. The conjugated eneynes particꢀ
ipated in the reaction to afford the pyrrrolidones containing
conjugated diene (3o and 3p), which may allow the synthesis
of more complex molecules. It should be noted that aliphatic
alkynes, which are relatively less active in many coupling
reactions, showed comparable reactivity to afford the
aReaction conditions:
1
(0.2 mmol), 2a (0.4 mmol),
Co(OAc)2·4H2O (0.04 mmol), Ag2CO3 (0.6 mmol), Na2CO3 (0.6
mmol), pyridine (0.4 mmol), TBAI (0.8 mmol), TFB (0.6 mL),
o
b
N2, 22 h at 150 C. Isolated yield of 4 by flash column chromaꢀ
tography. TFB = trifluoromethylbenzene, Q = Quinolinꢀ8ꢀyl,
TBAI = Tetrabutylammonium Iodide.
The scope of the aliphatic amides was investigated as disꢀ
played in Scheme 2. Depending on the substituent at αꢀcarbon,
a mixture of diasteroisomers was obtained, albeit the ratio of
the diastereoisomers was close. Theoretical calculations were
carried out to determine the relative stability of different conꢀ
figurations of 4a (see Supporting Information). Two racemic
pairs of enantiomers were located, and the results showed that
the configurations in which the ethyl on C3 and 8ꢀ
aminoquinolynal lie on the same side of the lactam were
slightly more stable than the configurations in which the meꢀ
thyl on C3 and pyridine lie on the same side of the lactam.
Figure 1. ORTEP Drawing of Pyrrolidinone 3a.
ACS Paragon Plus Environment

Journal of the American Chemical Society
High selectivity of the βꢀmethyl groups over the methylene
Page 4 of 9
1
groups was observed (4aꢀ4l), and the coupling of γꢀ or δꢀ
methyl group CꢀH bonds with phenylacetylene was not obꢀ
served. The substituents at the αꢀposition of the amide slightly
influenced the reactivity: the yield was decreased with the
increasing of the alkyl chain (4a-4e). A variety of functionaliꢀ
ties, including methyl, bromide, chloride, fluoride, aryloxyl,
and naphthyl, were well tolerated (4f and 4hꢀ4l). Notably, the
Sonogashira reaction of aryl bromide and aryl chloride was
suppressed thoroughly using this cobalt catalytic system and
the cyclization products were delivered smoothly (4j and 4k).
Substrate bearing sterically hindered substituents at αꢀcarbon
can be converted into the corresponding product in 71% yield
(4m). This cobaltꢀcatalyzed reaction was found to be powerful
enough to create the valuable spiroꢀγꢀlactam product (4n) with
an amide bearing the alicyclic group at αꢀposition. Interestingꢀ
ly, along with the enlargement of the ring at αꢀposition of
amides, the enhanced reactivity was obtained and the diverse
spiroꢀγꢀlactam products were obtained in higher yields (4oꢀ4q),
which is owed in part to the more suitable angle for the forꢀ
mation of metallacycle intermediate.23
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. ORTEP Drawing of Pyrrolidinone 6f.
6g). The isoindolinone 6j was obtained in 44% yield from 2ꢀ
ethynylthiophene. The structure of the isoindolinone 6f was
confirmed by Xꢀray crystallography (Figure 2).
Scheme 4. Investigation of the Possible Intermediate
Scheme 3. Reactions of Aromatic Amides and Terminal
Alkynes a,b
To gain insight into the reaction mechanism, GCꢀMS analyꢀ
sis was performed with the reaction solution for 5 h and the
trace of alkynylated product 9 was detected with the formation
of the pyrrolidinone 3a in 89% (Scheme 4, eq 1, see Supportꢀ
ing Information). This result indicates that the cyclization may
proceed in two steps: first the alkynylation of sp3 CꢀH bond,
and second the cyclization of alkynylated product 9 under the
reaction conditions. When the reaction was performed in the
absence of TBAI, the trace of alkynylated product 9 was still
detected, but the amount of pyrrolidinone 3a drastically deꢀ
creased (Scheme 4, eq 2). Using a literature method 25 we synꢀ
thesized compound 9 which was subjected to the standard
reaction conditions. Surprisingly, the cyclization took place
very rapidly and the reaction completed in ten minutes
(Scheme 4, eq 2). Further study revealed that the use of cataꢀ
lytic amount of Ag2CO3 (10 mol %) and stoichiometric TBAI
was acquired for the cyclization (Scheme 4, eq 3). The cyꢀ
clization is sluggished in the absence of TBAI (Scheme 4, eq
4).
aReaction conditions:
5
(0.2 mmol),
2 (0.4 mmol),
Co(OAc)2·4H2O (0.04 mmol), Ag2CO3 (0.8 mmol), TBAI (0.6
mmol), PhCF3 (1.0 mL), N2, 3 h at 120 oC. bIsolated yield of 6
by flash column chromatography. Q = Quinolinꢀ8ꢀyl, TBAI =
Tetrabutylammonium Iodide.
In light of the importance of isoindolinones as the biologiꢀ
cally active molecules and natural products,24 we studied the
use of aromatic amides as coupling partners (Scheme 3). After
slight modification of the reaction conditions, this cobaltꢀ
catalyzed cyclization reaction can be successfully extended to
a variety of aromatic amides as shown in Scheme 3. A variety
of aromatic amides bearing either electronꢀwithdrawing or
electronꢀdonating groups were applicable to give the diverse
isoindolinones in moderate to good yields (6bꢀ6d), albeit elecꢀ
tronꢀdeficient aromatic amides gave the lower yields (6c).
In contrast to our previous methods of nickelꢀcatalyzed thiꢀ
oetherfication26 and copperꢀmediated aryloxylation27 of unacꢀ
tivated sp3 CꢀH bonds, this cobalt catalytic system is very senꢀ
sitive to the solvent and only aromatic solvents give the comꢀ
parable yields (Table 1, entries 2ꢀ6). In accord with known
coordination properties of Co(III) with arenes,22 we
For the aryl acetylene derivatives, we found that electronꢀ
rich aryl acetylene was more reactivity and gave slightly highꢀ
er yields (6e) than electronꢀdeficient aryl acetylenes (6fꢀ
ACS Paragon Plus Environment

Page 5 of 9
Journal of the American Chemical Society
Scheme 6. Radical and Deuterium-Labeling Experiments
1
2
3
4
5
6
O
Q
N
O
standard conditions
NHQ
(1)
+
H
Ph
with TEMPO (2.0 equiv)
Ph
H
1a, 0.2 mmol 2a, 0.4 mmol
3a, 43%
O
O
standard conditions
NHQ
NHQ
CD3
(2)
CD3
(D3)-1q, 0.2 mmol, > 99% D
(D3)-1q, 95%, > 99% D
7
8
9
10
11
12
13
14
Q
O
O
N
H(D)
NHQ
CD3
(D3)-1q, 0.1 mmol, > 99% D
Ph
D
D
(D2)-4q
standard conditions
+
H
Ph
(3)
+
KIE 3.3
Q
O
O
2a, 0.4 mmol
N
H(D)
NHQ
Ph
4q
1q, 0.1 mmol
Q
N
O
O
O
H(D)
Ph
standard conditions
Figure 3. Matrixꢀassisted Laser Desorption Ionization Timeꢀofꢀ
(4)
(5)
NHQ
+
+
H
Ph
with D2O (5.0 equiv)
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
flight Mass Spectroscopy (MALDIꢀTOFꢀMS) of IM (Exact Mass:
589.1625) Obtained from the Reaction of 1a and 2a Under Standꢀ
ard Conditions for 5 h.
1q, 0.2 mmol
2a, 0.4 mmol
4q, 32%, 36% D
Q
N
O
H(D)
Ph
standard conditions
NHQ
D
Ph
hypothesize that the aromatic solvent may coordinated with
Co(III) and influence the reactivity. To support this hypothesis,
we performed a MALDIꢀTOF analysis experiment using a
mixture of the reaction solution which reacted for 5 h. Indeed,
a series of signals identified with species A are detected as
shown in Figure 3 (See Supporting Information), displaying
that both pyridine and aromatic solvent coordinated with
Co(III) center. This result suggests that pyridine and aromatic
solvent might be implicated with the formation of metallacycle
intermediate and influence the reactivity. In addition, the reacꢀ
tion is inhibited thoroughly during the course of catalysis with
6 equiv of phenylacetylene (Scheme 5, eq 1). The large excess
of phenylacetylene is supposed to diminish Ag2CO3 oxidant
by formation of silver(I) phenylacetylide17i,28 and hence stop
the oxidation of Co(II) to Co(III). To further confirm the role
of Ag2CO3, the reaction of silver(I) phenylacetylide with the
amide substrate 1a by the use of Co(II) was performed in the
presence or absence of silver carbonate (Scheme 5, eq 2ꢀ3). It
was found that the reaction failed in the absence of silver carꢀ
bonate, and in contrast, the desired reaction for the pyrroliꢀ
dinone 3a carried out smoothly in the presence of silver carꢀ
bonate. These findings demonstrate the pivotal role of Co(III)
species in the activation of the inert sp3 CꢀH bond.
1q, 0.2 mmol
D-2a, 0.4 mmol
4q, 90%, 17% D
expected C(sp2)ꢀC(sp) coupling product was observed (see the
Supporting Information for details). This result supports the
existence of the alkynyl radical during the reaction. On the
other hand, we performed the reaction with the deuteriumꢀ
labeled compound (D3)ꢀ1q in the absence of phenylacetylene
under the standard reaction conditions. In this case, the deuterꢀ
iumꢀproton exchange was not observed (Scheme 6, eq 2), inꢀ
dicating that the activation of sp3 CꢀH bond is irreversible. An
intermolecular kinetic isotope effect experiment was perꢀ
formed by the treatment of equivalent amide 1q and its deuterꢀ
ated analogues (D3)-1q under the reaction conditions (Scheme
6, eq 3). A kinetic isotope effect (KIE) of 3.3 was disclosed,
suggesting that the cleavage of CꢀH bond may be involved in
the rateꢀdetermining step. The incorporation of deuterium on
the alkenyl carbon was always observed in the presence of
deuterium sources. For example, the deuteriumꢀlabeled prodꢀ
uct on the alkenyl carbon was detected in the reaction of eq 3
to eq 5 (Scheme 6, eq 3ꢀ5). This result is reasonable because
Scheme 7. A Tentative Reaction Mechanism
O
N
Scheme 5. Investigation of the Possible Co(III) Intermedi-
ate
H
N
H
+
NaHCO3, NaX
Na2CO3
Ag0
CoIIIX3Ln
+
O
O
N
CoIII
N
N
Ag2CO3
CoIII
N
N
N
L
X
L
L = p
yridine
or Ph
CF3
CF3
A
CoIIX2Ln
IM, by MALDI-TOF
H
Ag
Ag2CO3
O
L
Ph
Ag0
Ph
Ph
N
The addition of 2,2,6,6ꢀtetramethylpiperidine (TEMPO, 2
equiv) as a radical quencher drastically decreased the yield to
43%, implying that a radical pathway may involve in the reacꢀ
tion process (Scheme 6, eq 1). In order to trap the possible
formed alkynyl radical 29 in the reaction, the electronꢀrich 1,1ꢀ
diphenylethene was subjected into the reaction and the
CoIV
N
L
B
Ph
O
O
H
N
Ph
H
cat. Ag2CO3
TBAI
N
N
N
Ph
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 9
the deuterium occurs during the final protonation of CꢀM bond
ACKNOWLEDGMENT
of the cyclization intermediate.30
1
2
3
4
5
6
7
8
Funding from Natural Science Foundation of China (No.
21272205, 21472165), National Basic Research Program of China
(No. 2011CB936003), and the Program for Zhejiang Leading
Team of S&T Innovation (2011R50007) is acknowledged.
On the basis of these experiments and previous reꢀ
ports,13,30,31 a catalytic cycle outlined in Scheme 7 is proposed.
The first step of the catalytic reaction is the oxidation of Co(II)
by Ag2CO3 to give Co(III) species, which activated the inert
sp3 CꢀH bond to form the key intermediate A. Both pyridine
ligand and trifluoromethylbenzene might be involved in the
formation of intermediate A and promote the reaction (Figure
3). The attack of alkyne radical into Co(III) gives the species
B, which undergoes the reductive elimination to give the alꢀ
kynylated product and liberate the Co(II) species. The oxidaꢀ
tion of Co(II) to Co(III) by silver salts continues the cycle. The
subsequent catalytic cyclization occurs rapidly in the presence
of 10 mol % Ag2CO3 and TBAI to give the pyrrolidinone
products. Another possible pathway is through the ion exꢀ
change of intermediate A with alkynyl anion and subsequent
reductive elimination to give the alkynylated product 7
through a Co(III)/Co(I) mechanism.10b
REFERENCES
(1) For selected reviews of C−H functionalizations: (a) Giri, R.;
Shi, B.ꢀF.; Engle, K. M.; Maugel, N.; Yu, J.ꢀQ. Chem. Soc. Rev. 2009,
38, 3242. (b) Chen, X.; Engle, K. M.; Wang, D.ꢀH.; Yu, J.ꢀQ. Angew.
Chem., Int. Ed. 2009, 48, 5094. (c) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624. (d) Wang, D.ꢀH.; Engle, K.
M.; Shi, B.ꢀF.; Yu, J.ꢀQ. Science 2010, 327, 315. (e) McMurray, L.;
O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885. (f)
Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976. (g)
Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902. (h) Hartwig, J. F. Chem.
Soc. Rev. 2011, 40, 1992. (i) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc.
Rev., 2012, 41, 3464. (j) Rouquet, G.; Chatani, N. Angew. Chem., Int.
Ed. 2013, 52, 11726. (k) Hashmi, A. S. K. Acc. Chem. Res. 2014, 47,
864.
(2) (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(b) WencelꢀDelord, J.; Dröge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev.
2011, 40, 4740. (c) Kwak, J.; Ohk, Y.; Jung,Y.; Chang, S. J. Am.
Chem. Soc. 2012, 134, 17778. (d) Li, G.; Leow, D.; Wan, L.; Yu, J.ꢀ
Q. Angew. Chem., Int. Ed. 2013, 52, 1245. (e) Liu, B.; Fan, Y.; Gao,
Y.; Sun, C.; Xu, C.; Zhu, J. J. Am. Chem. Soc. 2013, 135, 468. (f)
Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (g) Cho, S. H.;
Hartwig, J. F. Chem. Sci. 2014, 5, 694. (h) Liu, B.; Zhou, T.; Li, B.;
Xu, S.; Song, H.; Wang, B. Angew. Chem., Int. Ed. 2014, 53, 4191.
(3) (a) Hess, W.; Treutwein, J.; Hilt, G. Synthesis 2008, 3537. (b)
Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087. (c) Ackermann,
L. Chem. Commun. 2010, 46, 4866. (d) Yoshikai, N. Synlett, 2011,
1047. (e) Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem.,
Int. Ed. 2012, 51, 775. (f) Ackermann, L. J. Org. Chem. 2014, 79,
8948. (g) Fallon, B. J.; Derat, E.; Amatore, M.; Aubert, C.; Chemla,
F.; Ferreira, F.; PerezꢀLuna, A.; Petit, M. J. Am. Chem. Soc. 2015,
137, 2448.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
This protocol is readily scalable, and when the reaction was
scaled up to 5 mmol with a gram scale, the pyrrolidinone
product 3a was isolated in 75% yield (Scheme 8).
Scheme 8. Gram-Scale Reaction of 1a
CONCLUSIONS
The cobalt catalyst demonstrated promising catalytic propꢀ
erty for the cyclization of aliphatic amides with terminal alꢀ
kynes. For the fist time, terminal alkyne was exploited as the
coupling partner of sp3 CꢀH bond to give the useful pyrroliꢀ
dinones. The cobalt catalytic system can be successfully exꢀ
tended to the aromatic amides and thus diverse isoindolinones
can be accessed. This new transformation demonstrates good
functional group tolerance, excellent reactivity, and high
yields. MALDIꢀTOF analysis and related experiments eviꢀ
dence that the coordination of both ligand and solvent toward
cobalt serve as critical factors for ensuring reactivity of this
sp3 CꢀH functionalization reaction. On the basis of the insights
provided in this study, efforts are currently on the way for the
exploration of other cobaltꢀcatalyzed sp3 CꢀH bond functionalꢀ
izations.
(4) (a) Ilies, L.; Chen, Q.; Zeng, X.; Nakamura, E. J. Am. Chem.
Soc. 2011, 133, 5221. (b) Chen, Q.; Ilies, L.; Nakamura, E. J. Am.
Chem. Soc. 2011, 133, 428. (c) Chen, Q.; Ilies, L.; Yoshikai, N.;
Nakamura, E. Org. Lett. 2011, 13, 3232.
(5) (a) Grigorjeva, L.; Daugulis, O. Angew. Chem., Int. Ed. 2014,
53, 10209. (b) Grigorjeva, L.; Daugulis, O. Org. Lett. 2014, 16, 4684.
(c) Grigorjeva, L.; Daugulis, O. Org. Lett. 2014, 16, 4688. (d)
Grigorjeva, L.; Daugulis, O. Org. Lett. 2015, 17, 1204.
(6) (a) Yoshino, T.; Ikemoto, H.; Matsunaga, S.; Kanai, M. Angew.
Chem., Int. Ed. 2013, 52, 2207. (b) Yoshino, T.; Ikemoto, H.;
Matsunaga, S.; Kanai, M. Chem.-Eur. J. 2013, 19, 9142. (c) Sun, B.;
Yoshino, T.; Matsunaga, S.; Kanai, M. Adv. Synth. Catal. 2014, 356,
1491. (d) Ikemoto, H.; Yoshino, T.; Sakata, K.; Matsunaga, S.; Kanai,
M. J. Am. Chem. Soc. 2014, 136, 5424. (e) Suzuki, Y.; Sun, B.;
Yoshino, T.; Kanai, M.; Matsunaga, S. Tetrahedron 2015, 71, 4552.
(7) (a) Yu, D. G.; Gensch, T.; de Azambuja, F.; VasquezꢀCespedes,
S.; Glorius, F. J. Am. Chem. Soc. 2014, 136, 17722. (b) Zhao, D.;
Kim, J. H.; Stegemann, L.; Strassert, C. A.; Glorius, F. Angew.
Chem., Int. Ed. 2015, 54, 4508.
(8) (a) Hummel, J. R.; Ellman, J. A. J. Am. Chem. Soc. 2015, 137,
490. (b) Hummel, J. R.; Ellman, J. A. Org. Lett. 2015, 17, 2400.
(9) (a) Gao, K.; Yoshikai, N. Acc. Chem. Res. 2014, 47, 1208. (b)
Gao, K.; Lee, P.ꢀS.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2010,
132, 12249. (c) Lee, P. S.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc.
2011, 133, 17283. (d) Ding, Z.; Yoshikai, N. Org. Lett. 2010, 12,
4180. (e) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 9279.
(f) Lee, P.ꢀS.; Yoshikai, N. Org. Lett. 2015, 17, 22. (g) Yang, J.; Seto,
Y. W.; Yoshikai, N. ACS Catal. 2015, 5, 3054.
ASSOCIATED CONTENT
Supporting Information. Detailed experimental procedures and
characterization data for new compounds. This material is availaꢀ
ble free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*yhzhang@zju.edu.cn
Author Contributions
※These two authors contributed equally.
Notes
The authors declare no competing financial interest.
(10) (a) Zhang, L. B.; Hao, X. Q.; Zhang, S. K.; Liu, Z. J.; Zheng,
X. X.; Gong, J. F.; Niu, J. L.; Song, M. P. Angew. Chem., Int. Ed.
2015, 54, 272. (b) During the submission of this manuscript, a
cobalt(II)ꢀcatalyzed Csp2ꢀH alkynylation/annulation with terminal
ACS Paragon Plus Environment

Page 7 of 9
Journal of the American Chemical Society
alkynes was reported, Zhang, L.ꢀB.; Hao, X.ꢀQ.; Liu, Z.ꢀJ.; Zheng,
X.ꢀX.; Zhang, S.ꢀK.; Niu, J.ꢀL.; Song, M.ꢀP. Angew. Chem., Int. Ed.
2015, 54, 10012.
Angew. Chem., Int. Ed. 2014, 53, 2722. (n) Xu, Y.ꢀH.; Zhang, Q.ꢀC.;
He, T.; Meng, F.ꢀF.; Loh, T.ꢀP. Adv. Synth. Catal. 2014, 356, 1539.
(17) (a) Li, Z.; Li, C.ꢀJ. J. Am. Chem. Soc. 2004, 126, 11810. (b)
Cheng, K.; Yao, B.; Zhao, J.; Zhang, Y. Org. Lett. 2008, 10, 5309. (c)
de Haro, T.; Nevado, C. J. Am. Chem. Soc. 2010, 132, 1512. (d)
Yang, L.; Zhao, L.; Li, C. J. Chem. Commun. 2010, 46, 4184. (e)
Matsuyama, N.; Kitahara, M.; Hirano, K.; Satoh, T.; Miura, M. Org.
Lett. 2010, 12, 2358. (f) Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M.
J. Am. Chem. Soc. 2010, 132, 2522. (g) Kim, S. H.; Yoon, J.; Chang,
S. Org. Lett. 2011, 13, 1474. (h) Kim, S. H.; Park, S. H.; Chang, S.
Tetrahedron 2012, 68, 5162. (i) Jie, X.; Shang, Y.; Hu, P.; Su, W.
Angew. Chem., Int. Ed. 2013, 52, 3630. (j) Zhou, B.; Chen, H.; Wang,
C. J. Am. Chem. Soc. 2013, 135, 1264. (k) Shang, M.; Wang, H. L.;
Sun, S. Z.; Dai, H. X.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2014, 136, 11590.
(l) Dong, J.; Wang, F.; You, J. Org. Lett. 2014, 16, 2884. (m) Liu, Y.
J.; Liu, Y. H.; Yin, X. S.; Gu, W. J.; Shi, B. F. Chem.-Eur. J. 2015,
21, 205.
(18) For first examples of goldꢀcatalyzed alkylꢀC,Hꢀinsertions
involving alkynes, both intraꢀ and intermolecular, see: (a) Hashmi, A.
S. K.; Braun, I.; Nösel, P.; Schädlich, J.; Wieteck, M.; Rudolph, M.;
Rominger, F. Angew. Chem., Int. Ed. 2012, 51, 4456. (b) Hashmi, A.
S. K.; Wieteck, M.; Braun, I.; Rudolph, M.; Rominger, F. Angew.
Chem., Int. Ed. 2012, 51, 10633. (c) Hansmann, M. M.; Rudolph, M.;
Rominger, F.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2013, 52,
2593. (d) Hashmi, A. S. K.; Lauterbach, Tobias; Nösel, P.;
Vilhelmsen, M. H.; Rudolph, M.; Rominger, F. Chem.-Eur. J. 2013,
19, 1058. (e) Nösel, P.; Lauterbach, Tobias; Rudolph, M.; Rominger,
F.; Hashmi, A. S. K. Chem. Eur. J. 2013, 19, 8634.
1
2
3
4
5
6
7
8
(11) (a) Song, W.; Ackermann, L. Angew. Chem., Int. Ed. 2012, 51,
8251. (b) Punji, B.; Song, W.; Shevchenko, G. A.; Ackermann, L.
Chem.-Eur. J. 2013, 19, 10605. (c) Ma, W.; Ackermann, L. ACS
Catal. 2015, 5, 2822. (d) Li, J.; Ackermann, L. Angew. Chem., Int.
Ed. 2015, 54, 3635. (e) Li, J.; Ackermann, L. Chem.-Eur. J. 2015, 21,
5718. (f) Moselage, M.; Sauermann, N.; Richter, S. C.; Ackermann,
L. Angew. Chem., Int. Ed. 2015, 54, 6352.
(12) (a) Cenini, S.; Tollari, S.; Penoni, A.; Cereda, C. J. Mol.
Catal. 1999, 137, 135. (b) Ragaini, F.; Penoni, A.; Gallo, E.; Tollari,
S.; Gotti, C. L.; Lapadula, M.; Mangioni, E.; Cenini, S. Chem.-Eur. J.
2003, 9, 249. (c) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62,
2439. (d) Bolig, A. D.; Brookhart, M. J. Am. Chem. Soc. 2007, 129,
14544. (e) Boutadla, Y.; Davies, D. L.; Macgregor, S. A.; Pobladorꢀ
Bahamonde, A. I. Dalton Trans. 2009, 5820. (f) Lu, H.ꢀJ.; Zhang, X.
P. Chem. Soc. Rev. 2011, 40, 1899. (g) Lyons, T. W.; Brookhart, M.
Chem.-Eur. J. 2013, 19, 10124. (h) Lu, H.ꢀJ.; Li, C.ꢀQ.; Jiang, H.ꢀL.;
Lizardi, C. L.; Zhang, X. P. Angew. Chem., Int. Ed. 2014, 53, 7028.
(13) Wu, X.; Yang, K.; Zhao, Y.; Sun, H.; Li, G.; Ge, H. Nat.
Commun 2015, 6, 6462.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(14) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem.
Soc. 2005, 127, 13154. (b) Daugulis, O.; Do, H.ꢀQ.; Shabashov, D.
Acc. Chem. Res. 2009, 42, 1074.
(15) For recent examples of C(sp3)ꢀH bonds functionalization by
using bidentate directing groups, see: (a) Shabashov, D.; Daugulis, O.
J. Am. Chem. Soc. 2010, 132, 3965. (b) Hasegawa, N.; Charra, V. ;
Inoue, S.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2011, 133,
8070. (c) Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011,
133, 12984. (d) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012,
134, 7. (e) He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am.
Chem. Soc. 2012, 134, 3. (f) Zhang, S. Y.; He, G.; Zhao, Y.; Wright,
K.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2012, 134, 7313. (g)
Shang, R.; Ilies, L.; Matsumoto, A.; Nakamura, E. J. Am. Chem. Soc.
2013, 135, 6030. (h) Zhang, S. Y.; Li, Q.; He, G.; Nack, W. A.; Chen,
G. J. Am. Chem. Soc. 2013, 135, 12135. (i) Zhang, S. Y.; He, G.;
Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013,
135, 2124. (j) Zhang, Q.; Chen, K.; Rao, W.; Zhang, Y.; Chen, F.ꢀJ.;
Shi, B.ꢀF. Angew. Chem., Int. Ed. 2013, 52, 13588. (k) Chen, F.ꢀJ.;
Zhao, S.; Hu, F.; Chen, K.; Zhang, Q.; Zhang, S.ꢀQ.; Shi, B.ꢀF. Chem.
Sci. 2013, 4, 4187. (l) Shan, G.; Yang, X.; Zong, Y.; Rao, Y. Angew.
Chem., Int. Ed. 2013, 52, 13606. (m) Wang, C.; Chen, C.; Zhang, J.;
Han, J.; Wang, Q.; Guo, K.; Liu, P.; Guan, M.; Yao, Y.; Zhao, Y.
Angew. Chem., Int. Ed. 2014, 53, 9884. (n) Wang, Z.; Ni, J.;
Kuninobu, Y.; Kanai, M. Angew. Chem., Int. Ed. 2014, 53, 3496. (o)
Wu ,X.; Zhao, Y.; Zhang, G.; Ge, H. Angew. Chem., Int. Ed. 2014,
53, 3706. (p) Wu, X.; Zhao, Y.; Ge, H. Chem.-Eur. J. 2014, 20, 9530.
(q) Li, M.; Dong, J.; Huang, X.; Li, K.; Wu, Q.; Song, F.; You, J.
Chem. Commun. 2014, 50, 3944. (r) Gu, Q.; Al Mamari, H. H.;
Graczyk, K.; Diers, E.; Ackermann, L. Angew. Chem., Int. Ed. 2014,
53, 3868. (s) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2014, 136,
898. (t) Wu, X.; Zhao, Y.; Ge, H. J. Am. Chem. Soc. 2014, 136, 1789.
(u) Zhang, S. Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G. J. Am. Chem.
Soc. 2015, 137, 531. (v) Li, M.; Yang, Y.; Zhou, D.; Wan, D.; You, J.
Org. Lett. 2015, 17, 2546. (w) Wu, X.; Zhao, Y.; Ge, H. J. Am. Chem.
Soc. 2015, 137, 4924.
(19) (a) Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011,
133, 12984. (b) He, J.; Wasa, M.; Chan, K. S. L.; Yu, J.ꢀQ. J. Am.
Chem. Soc. 2013, 135, 3387. (c) AlꢀAmin, M.; Arisawa, M.; Shuto,
S.; Ano, Y.; Tobisu, M.; Chatani, N. Adv. Synth. Catal. 2014, 356,
1631.
(20) (a) Robson, R. H.; Prescott, L. F. Br. J. Clin. Pharmacol.
1979, 7, 81. (b) Ward, J. W.; Gilbert, D. L.; Franko, B. V.; Woodard,
G.; Mann, G. T. Toxicol. Appl. Pharmacol. 1968, 13, 242. (c)
Isolation: Rainey, D. P.; Smalley, E. B.; Crump, M. H.; Strong, F. M.
Nature 1965, 205, 203. (d) Isolation: Issa, H. H.; Tanaka, J.; Rachmat,
R.; Setiawan, A.; Trianto, A.; Higa, T. Marine Drugs 2005, 3, 78. (e)
Ye, L.ꢀW., Shu, C.; Gagosz, F. Org. Biomol. Chem. 2014, 12, 1833.
(21) (a) Snyder, H. L.; Hamlin, E. J. Am. Chem. Soc. 1950, 72,
5082. (b) Berlin, S.; Ericsson, C.; Engman, L. J. Org. Chem. 2003,
68, 8386. (c) Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151.
(d) Xu, F.; Corley, E.; Murry, J. A.; Tschaen, D. M. Org. Lett. 2007,
9, 2669. (e) Jakubec, P.; Helliwell, M.; Dixon, D. J. Org. Lett. 2008,
10, 4267. (f) He, Gang, Zhang, S.ꢀY.; Nack, W. A.; Li, Q.; Chen, G.
Angew. Chem., Int. Ed. 2013, 52, 11124.
(22) (a) P. J. Fagan, M. D. Ward and J. C. Calabrese, J. Am. Chem.
Soc. 1989, 111, 1698. (b) Schneider, J. J.; Denninger, U.; Heinemann,
O.; Krüger, C. Angew. Chem., Int. Ed. 1995, 34, 592. (c) HungꢀLow,
F.; Bradley, C. A. Organometallics 2011, 30, 2636. (d) HungꢀLow,
F.; Krogman, J. P.; Tye, J. W.; Bradley, C. A. Chem. Commun. 2012,
48, 368. (e) Yoshikai, N.; Asako, S.; Yamakawa, T.; Ilies, L.;
Nakamura E. Chem. Asian J. 2011, 6, 3059.
(23) Shang, R.; Ilies, L.; Matsumoto, A.; Nakamura, E. J. Am.
Chem. Soc. 2013, 135, 6030.
(24) (a) Kato, Y.; Ebiike, H.; Achiwa, K.; Ashizawa, N.; Kurihara,
T.; Kobayashi, F. Chem. Pharm. Bull. 1990, 38, 2060. (b) Lamblin,
M.; Couture, A.; Deniau, E.; Grandclaudon, P. Org. Bioorg. Chem.
2007, 5, 1466.
(25) Witham, C, A.; Mauleón, P.; Shapiro, N. D.; Sherry, B. D.;
Toste, F. D. J. Am. Chem. Soc. 2007, 129, 5838.
(26) Lin, C.; Yu, W.; Yao, J.; Wang, B.; Liu, Z.; Zhang, Y. Org.
Lett. 2015, 17, 1340.
(16) For CꢀH bond alkynylation, see: (a) Brand, J. P.; Waser, J.
Chem. Soc. Rev. 2012, 41, 4165. (b) Kobayashi, K.; Arisawa, M.;
Yamaguchi, M. J. Am. Chem. Soc. 2002, 124, 8528. (c) Seregin, I. V.;
Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742. (d)
Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250. (e)
Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11,
4156. (f) Besselivre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009, 48,
9553. (g) Kim, S. H.; Chang, S. Org. Lett. 2010, 12, 1868. (h) Brand,
J. P.; Waser, J. Angew. Chem., Int. Ed. 2010, 49, 7304. (i) Ano, Y.;
Tobisu, M.; Chatani, N. Org. Lett. 2012, 14, 354. (j) Ano, Y.; Tobisu,
M.; Chatani, N. Synlett 2012, 2763. (k) Li, Y.; Brand, J. P.; Waser, J.
Angew. Chem., Int. Ed. 2013, 52, 6743. (l) Xie, F.; Qi, Z.; Yu, S.; Li,
X. J. Am. Chem. Soc. 2014, 136, 4780. (m) Feng, C.; Loh, T.ꢀP.
(27) Zhang, J.; Chen, H.; Wang, B.; Liu, Z.; Zhang, Y. Org. Lett.
2015, 17, 2768.
(28) Viterisi, A.; Orsini, A.; Weibel, J.ꢀM.; Pale, P. Tetrahedron
Lett. 2006, 47, 2779.
(29) (a) Martelli, G.; Spagnolo, P.; Tiecco, M. J. Chem. SOC. (B)
1970, 1413. (b) Xie, J.; Shi, S.; Zhang, T. Mehrkens, N.; Rudolph,
M.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2015, 54, 6046.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 9
(30) (a) Fang, G.; Bi, X. Chem. Soc. Rev. 2015, DOI:
10.1039/c5cs00027k. (b) Gainer, M. J.; Bennett, N. R.; Takahashi, Y.;
Looper, R. E. Angew. Chem., Int. Ed. 2011, 50, 684.
(31) Liu, J.ꢀB.; Chen, C.; Chu, L.; Chen, Z.ꢀH.; Xu, X.ꢀH.; Qing,
F.ꢀL. Angew. Chem., Int. Ed. 2015, 54, DOI: 10.1002/anie.201506329.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 9 of 9
Journal of the American Chemical Society
1
2
3
TOC Graphic
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment