Easy Access to 1-Amino and 1-Carbon Substituted Isoquinolines via Cobalt-Catalyzed C - H/N - O Bond Activation

Article abstract of DOI:10.1002/adsc.201501056

A green atom-economical method for the synthesis of highly functionalized 1-amino and 1-carbon substituted isoquinolines from the reaction of N′-hydroxybenzimidamides and aryl ketoximes, respectively, with alkynes via pentamethylcyclopentadienylcobalt(III)-catalyzed C - H/N - O bond activation is described. The external oxidant-free annulation reaction uses the =NOH moiety in N′-hydroxybenzimidamides or N-aromatic ketone oximes as the directing group and internal oxidant. This first row transition metal-catalyzed annulation serves as an efficient alternative for the synthesis of isoquinolines, as water is the only by-product and expensive noble metals such as rhodium(III), iridium(III), palladium(II), and ruthenium(II) are not required. The reaction proceeds via C - H activation, alkyne insertion, reductive elimination, and N - O activation.

Full text of DOI:10.1002/adsc.201501056

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DOI: 10.1002/adsc.201501056
Very Important Publication
Easy Access to 1-Amino and 1-Carbon Substituted Isoquinolines
À
À
via Cobalt-Catalyzed C H/N O Bond Activation
Krishnamoorthy Muralirajan,a Ramajayam Kuppusamy,a Sekar Prakash,a
and Chien-Hong Chenga,*
a
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
Fax: (+886)-3572-4698; e-mail: chcheng@mx.nthu.edu.tw
Received: November 17, 2015; Revised: December 18, 2015; Published online: February 11, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501056.
Abstract: A green atom-economical method for the transition metal-catalyzed annulation serves as an ef-
synthesis of highly functionalized 1-amino and 1- ficient alternative for the synthesis of isoquinolines,
carbon substituted isoquinolines from the reaction of as water is the only by-product and expensive noble
N’-hydroxybenzimidamides and aryl ketoximes, re- metals such as rhodium(III), iridium(III), palladi-
spectively, with alkynes via pentamethylcyclopenta- um(II), and ruthenium(II) are not required. The re-
À
À
À
dienylcobalt(III)-catalyzed C H/N O bond activa- action proceeds via C H activation, alkyne insertion,
tion is described. The external oxidant-free annula- reductive elimination, and N O activation.
À
tion reaction uses the =NOH moiety in N’-hydroxy-
benzimidamides or N-aromatic ketone oximes as the Keywords: alkynes; annulation; C H activation;
directing group and internal oxidant. This first row cobalt; isoquinolines; oximes
À
À
Introduction
Transition metal-catalyzed, chelation-assisted C H
activation of arenes with subsequent alkyne insertion
À
À
Substituted isoquinolines are important N-heterocy- offers a regioselective and direct route for C C/C N
clic compounds, which are often used in the synthesis bond construction.[4] In particular, metal-catalyzed,
À
of various alkaloids, inhibitors, pharmaceutically redox-neutral group-directed C H bond activation
active salts, chiral ligands, and organic light-emitting and oxidative annulation reactions are known to be
diodes.[1] Their significance in pharmaceutical and het- successful routes for the synthesis of N-heterocycles
erocyclic chemistry as well as their unique structural under a variety of conditions.[5] These methods often
features have attracted the attention of numerous syn- deliver atom economical paths in the absence of ex-
thetic organic chemists. In an effort to offer less ex- ternal metal oxidants. By utilizing this strategy, oxime
À
pensive new routes towards isoquinoline frameworks, and hydrazone directed C H activation and incorpo-
various synthetic routes have been developed ration of nitrogen may serve as leads towards a proto-
(Scheme 1).[2,3] In this context, the Pd- and Ni-cata- col for the synthesis of isoquinoline derivatives.[6]
lyzed annulation of o-halobenzimines with alkynes is These reactions do not require an external oxidant;
a classical metal-catalyzed reaction that has been the N O/N N bond of the oxime/hydrazone acts as
used to synthesize functionalized isoquinoline deriva- an internal oxidant.
À
À
tives.[2] Transition metal-catalyzed, imine directed
To date, the majority of previous works have fo-
À
arene ortho C H activations and oxidative annula- cused on synthesizing 1-carbon substituted isoquino-
tions have also served as excellent approaches for the lines using expensive metal catalysts via redox-neutral
construction of isoquinolines.[3] However, convention- approaches. However, the synthesis of 1-amino-substi-
al methods require the use of expensive metal com- tuted isoquinolines is not well developed. It is known
plexes (Rh, Ru, and Pd), pre-functionalized starting that 1-aminoisoquinolines play an important role in
materials, oxidants, and harsh reaction conditions. the initiation and propagation of thrombotic events
Furthermore, the cost and availability of second row and antithrombotic activities.[7a–d] Particularly, 1-iso-
metals and selection of starting materials are consid- quinolinylguanidines are used as the inhibitors of uro-
ered as drawbacks in industrial applications.
kinase type plasminogen activator (uPA).[7b] Due to
the biological significance of 1-aminoisoquino-
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Easy Acces to 1-Amino and 1-Carbon Substituted Isoquinolines
Scheme 1. Synthetic strategies for isoquinolines.
lines,[7a–c] Li[7d] and Ackermann[7e] independently re- for metal catalysts such as Rh, Ru, Ir, and Pd in C H
ported Rh(III)- and Ru(II)-catalyzed oxidative cou- activation reactions.
À
pling reactions of N-arylbenzamidines and N-alkyl-
benzamidines with alkynes to give the corresponding
1-aminoisoquinloines. These methods required stoi- Results and Discussion
chiometric amounts of an external Cu(II) metal oxi-
dant. Therefore, to avoid the use of external metal ox- The reaction of N-tert-butyl-N’-hydroxybenzimid-
idants, an atom-economical approach using a function- amide 1a (0.20 mmol) with alkyne 2a (0.26 mmol) in
al group that acts as a directing group as well as oxi- the presence of 10 mol% of [CoCp*(CO)I2] and
dant is required. Our interest in developing new 20 mol% of CsOAc in TFE (2,2,2-trifluoroethanol) at
[8]
À
metal-catalyzed C H activation reactions prompted 1208C under N2 for 24 h gave N-tert-butyl-3,4-diphe-
us to explore the synthesis of highly substituted 1- nylisoquinolin-1-amine 3aa in 86% isolated yield
aminoisoquinolines in a redox-neutral fashion. Until (Table 1, entry 4). The compound was carefully char-
1
now, no first row transition metal-catalyzed method acterized by H NMR, 13C NMR, and mass spectral
for the synthesis of 1-aminoisoquinolines through data. The effects of the reaction conditions are sum-
À
a redox-neutral group-assisted C H activation has marized in Table 1. In the absence of the cobalt com-
been reported. Recently, we reported the reaction of plex, product 3aa was not observed. The presence of
N’-hydroxybenzimidamides and alkynes for the syn- additive played an important role in the redox-neutral
thesis of various 1-aminoisoquinolines and poly-N- reaction. Use of CsOAc gave 3aa in 89% (86% isolat-
heteroaromatic compounds using rhodium as the cata- ed) yield. Other additives such as NaOAc, KOAc,
lyst and copper(II) acetate as the oxidant.[6m] Direct- AgOAc, Mn(OAc)2, and Cu(OAc)2 gave only moder-
À
ing group-assisted, Co-catalyzed arene C H function- ate yields. The solvent was also crucial to attain
alizations have garnered considerable attention be- a high yield. Among the solvents examined, TFE af-
cause Co is less expensive, more abundant, and less forded the highest yield, whereas DCE and CH3CN
toxic than noble metal catalysts.[9] Particularly, some were less effective. Other solvents including MeOH,
Co(III) complexes were found to show catalytic activ- EtOH, t-AmylOH, THF, and 1,4-dioxane are totally
ities similar to Rh and Ru catalysts.[10] Herein, we ineffective (Table 1, entries 8–10, 13 and 14). Similar-
report a Co-catalyzed redox-neutral group-assisted ly, we tested various cobalt complexes including
annulation of N’-hydroxybenzimidamides with al- CoI2, CoBr2, Co(OAc)2, and Co(acac)3, but only
kynes to synthesize diverse 1-aminoisoquinolines via [CoCp*(CO)I2] was active (entries 15–18).
À
C H activation as a key step. The method offers not
With suitable reaction conditions in hand, we next
only an alternative approach to 1-aminoisoquinline explored the scope of the Co(III)-catalyzed redox-
synthesis, but may also serve as a new route to syn- neutral protocol with a variety of N’-hydroxybenzim-
thesizing various N-heterocycles and as a replacement idamides 1 (Table 2). In general, all reactions pro-
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Krishnamoorthy Muralirajan et al.
Table 1. Screening the reaction conditions.[a,b]
reaction conditions. The reaction between N-cyclo-
hexyl and isopropyl substituted N’-hydroxybenzimida-
mides and 2a afforded expected products 3la and 3ma
in 71 and 68% yields, respectively. However, treat-
ment of (Z)-N-benzyl-N’-hydroxybenzimidamide (1n)
with 2a gave 3na in a lower yield (51%). Unfortunate-
ly, (Z)-N-butyl-N’-hydroxybenzimidamide (1o) afford-
ed less than 5% yield, perhaps due to the coordina-
tion of the free NH group with the cobalt complex
À
which cannot lead to C H activation. The above re-
sults clearly revealed that sterically hindered amino
groups at the 1-position were necessary for the reac-
tion to proceed efficiently.[7e] Additionally, this Co-
catalyzed redox-neutral reaction is more convenient
for industrial applications and it is strengthened by
the scale-up experiment for the synthesis of 3fa in
85% (1.45 g) isolated yield.
Next, we studied the reactions of various aryl, sym-
metrical alkyl, and unsymmetrical alkynes with 1a
under the standard reaction conditions. The results
are shown in Table 3. Electron-rich 4-Me, 4-MeO (2b
and 2c) and halo 4-F, 4-Br (2d and 2e) substituted di-
arylacetylenes reacted smoothly with 1a to give the
desired isoquinolines 3ab–ae in 79–86% yields. Simi-
larly, thiophene-substituted alkyne 2f resulted in the
expected isoquinoline, 3af, in 70% yield. We also
tested the reactivity of dialkylalkynes; treatment of
hex-3-yne (2g) and oct-4-yne (2h) with 1a proceeded
smoothly and afforded 3ag and 3ah in 61% and 73%
yields, respectively. Furthermore, a selection of un-
symmetrical alkynes, including 1-phenyl-1-propyne
Entry [Co]
Solvent
Additive
Yield [%]
1
[CoCp*(CO)I2] TFE
–
20
38
55
89 (86)
13
2
3
4
5
6
7
8
9
[CoCp*(CO)I2] TFE
NaOAc
KOAc
CsOAc
AgOAc
Mn(OAc)2 78
Cu(OAc)2 15
[CoCp*(CO)I2] TFE
[CoCp*(CO)I2] TFE
[CoCp*(CO)I2] TFE
[CoCp*(CO)I2] TFE
[CoCp*(CO)I2] TFE
[CoCp*(CO)I2] MeOH
[CoCp*(CO)I2] EtOH
CsOAc
CsOAc
–
–
–
28
25
–
–
–
10
11
12
13
14
15
16
17
18
[CoCp*(CO)I2] t-amylOH CsOAc
[CoCp*(CO)I2] DCE
[CoCp*(CO)I2] CH3CN
[CoCp*(CO)I2] THF
CsOAc
CsOAc
CsOAc
[CoCp*(CO)I2] 1,4-dioxane CsOAc
CoI2
CoBr2
Co(OAc)2
Co(acac)3
TFE
TFE
TFE
TFE
CsOAc
CsOAc
CsOAc
CsOAc
–
–
–
[a]
Unless otherwise mentioned, all reactions were carried
out using 1a (0.20 mmol), 2a (0.26 mmol), [Co] (2i), 1-phenyl-1-butyne (2j), and 1-(hex-1-ynyl)-4-me-
(10 mol%), additive (20 mol%), and solvent (3.0 mL) at
1208C for 24 h under N2.
thoxybenzene (2k) underwent oxidative annulations
effectively with moderate regioselectivity. Interesting-
ly, the reaction of trimethyl(phenylethynyl)silane (2l),
afforded a trimethylsilyl-cleaved mixture of two sepa-
rable regioisomeric products (3al’ and 3am) in 27%
[b]
Yields were determined by the 1H NMR integration
method; the value in parenthesis indicates isolated yield.
ceeded smoothly, and resulted in moderate to high and 46% yields, respectively. Notably, terminal al-
yields of the corresponding 1-aminoisoquinolines. Re- kynes such as phenylacetylene also reacted nicely
actions of substrates with electron-donating groups under the optimized conditions to give regioselective
such as 4-methyl, 4-isopropyl, and 4-methoxy (1b–d) product 3am in 61% yield.[9j,k] The latter result is intri-
with 2a furnished the corresponding products in 81, guing because for most rhodium- and ruthenium-cata-
À
75, and 71% yields (3ba–da), respectively. Similarly, lyzed C H activation reactions, terminal alkynes
halogen-containing substrates such as 4-F, 4-Cl, and 4- cannot be used as the substrates for insertion and an-
Br (1e–g) arenes reacted efficiently and gave the nulation.[6a–k]
products in 84, 93, and 91% (3ea–ga) yields, respec-
The high catalytic efficiency in the redox-neutral
À
tively. Notably, the reaction of 3-bromo-substituted assisted direct C H activation and annulation of N-
N’-hydroxybenzimidamide 1h with 2a under the stan- substituted N’-hydroxybenzimidamides with alkynes
dard reaction conditions gave regioisomeric products sparked our interest in expanding the strategy to in-
3ha (92:8) in 79% yield. With 1i, the reaction proceed clude other directing groups such as aryl ketoximes to
selectively at the least hindered position (C-6) and af- facilitate the synthesis of 1-carbon substituted isoqui-
forded a slightly lower yield (3ia). Here, electron-rich nolines. Notably, 5 mol% [CoCp*(CO)I2] with
arenes such as 1d and 1i slightly suppressed the annu- 10 mol% KOAc at 1008C for 18 h is highly suitable
lation product, but the annulation reaction with elec- for this external metal oxidant-free oxidative annula-
tron-deficient arenes such as 1j and 1k proceeded tion reaction (see the Supporting Information for de-
very effectively. Next, we tested the effects of differ- tailed optimization studies). The treatment of aceto-
ent amino protecting groups (1l–o) under the same phenone oxime (4a) with diphenylacetylene (2a)
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Easy Acces to 1-Amino and 1-Carbon Substituted Isoquinolines
Table 2. Synthesis of 1-aminoisoquinolines from various N-substituted N’-hydroxyimidamides.[a,b]
[a]
Unless otherwise mentioned, all reactions were carried out using 1a–o (0.20 mmol), 2a (0.26 mmol), [CoCp*(CO)I2]
(10 mol%), CsOAc (20 mol%), and TFE (3.0 mL) at 1208C for 24 h.
Isolated yield.
[b]
under the mentioned reaction conditions gave 1- used by Sundararaju[11c]). In addition, we did not use
methyl-3,4-diphenylisoquinoline 5aa in 90% isolated a silver salt in the solutions to promote the reactions.
yield [95% isolated yield was observed in the pres-
Then, we tested the reaction with various acetophe-
ence of 15 mol% Mn(OAc)2 as the additive]. During none oximes under the developed catalytic conditions
our preparation of this manuscript, three reports have and the results are presented in Table 4. The presence
been appeared on the synthesis of isoquinolines. The of electron-donating and halogen groups in the para
Kanai/Matsunaga[11a] and Ackermann[11b] groups inde- position in acetophenone oximes 4b–h did not affect
pendently showed the isoquinolines synthesis by using the reaction and increased the yield to 92%. Howev-
o-acylacetophenone oximes and alkynes in the pres- er, the presence of substituents in various positions in
ence of 10 mol% [CoCp*(CO)I2] as the catalyst. It is acetophenone oximes (4i–l) provided highly regiose-
À
important to mention here that, to attain high effi- lective C H functionalized isoquinoline derivatives in
ciency, these reactions required AgSbF6 (20 mol%), 75–85% yields. The reaction of 1-(2,3-dihydroben-
NaOAc or KOAc (20 mol%) and a high temperature zo[b][1,4]dioxin-6-yl)ethanone oxime (4m) gave sepa-
(1208C). Similarly, Sundararaju et al also reported the rable, regioisomeric products 5ma and 5ma’ in 33%
synthesis of isoquinolines in the presence of 10 mol% and 59% yields, respectively. In a similar manner, the
[CoCp*(CO)I2] and 20 mol% NaOAc.[11c] We had in- effect of changing the methyl group (1 position) in
dependently found the reaction conditions for the an- acetophenone oxime 1a to other substituents was also
nulation of aryl ketoximes with alkynes. The reaction evaluated. Various 1-carbon substituted alkyl and aryl
À
conditions are similar to those reported, but we used acetophenone oximes underwent C H activation ef-
a lower amount of cobalt complex (5% vs. 10% re- fectively and afforded the corresponding isoquinolines
ported) and TFE as the solvent (the same as that in 77 to 97% yields. Similarly, the reaction of hetero-
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Krishnamoorthy Muralirajan et al.
Table 3. Synthesis of 1-aminoisoquinolines from various alkynes.[a,b]
[a]
Unless otherwise mentioned, all reactions were carried out using 1a (0.20 mmol), 2b–m (0.26 mmol), [CoCp*(CO)I2]
(10 mol%), CsOAc (20 mol%), and TFE (3.0 mL) at 1208C for 24 h.
Isolated yield.
[b]
[c]
ꢀ
2l=Me3SiC CPh.
aromatic substrates such as 1-(pyridin-4-yl)ethanone tive product 5am in 65% yield. The results with un-
oxime (4t), 1-(1H-indol-3-yl)ethanone oxime (4u), symmetrical alkynes are similar to those reported pre-
and 1-(thiophen-3-yl)ethanone oxime (4v) with 2a viously involving annulation reactions.[6]
gave the expected heterocyclic ring-containing isoqui-
nolines 5ta, 5ua, and 5va in 75%, 91%, and 73% experiments using various electronically distinct
yields, respectively. arenes (Scheme 2). The reaction of phenyl(p-tolyl)-
Finally, we conducted intramolecular competition
To develop the scope of the reaction and determine methanone oxime (6a) with 2a gave fully separable
the regioselectivity, we also investigated the reaction isomers 7aa and 7aa’ in 41% and 50% yields, respec-
À
of acetophenone oxime (4a) with various aryl, sym- tively. Here, 4-Me-substituted arenes underwent C H
metrical alkyl, and unsymmetrical alkynes under the activation more quickly than unsubstituted arenes. A
optimized conditions. The results are displayed in similar result was observed when 6b was used as the
Table 5. The reaction conditions were highly compati- substrate instead of 6a. These results were supported
ble with p-Me, p-MeO, p-F, and p-Br-containing ary- by the intramolecular competition reaction using
lalkynes, and afforded the relevant isoquinolines in NO2-substituted arene 6c as the substrate. The selec-
good to excellent yields. Similarly, heteroaromatic tivity was notable, and the results strongly suggested
(2f) and dialkyl (2g and 2h) alkynes reacted smoothly that electron-rich arenes could preferentially undergo
À
to give corresponding isoquinolines in 68–79% yields. C H activation to the cobalt complex.
Unsymmetrical alkynes such as 1-phenyl-1-propyne
(2i), 1-phenyl-1-butyne (2j),
To elucidate the reaction mechanism, we conducted
1-(hex-1-ynyl)-4- several kinetic experiments using [D5]-4a, 4a, and 2a
methoxybenzene (2k), and trimethyl(phenylethynyl)- as model substrates (Scheme 3). First, we analyzed
silane (2l), underwent annulations and afforded fully the reversibility of the reaction under the standard re-
separable regioisomeric isoquinolines in good yields action conditions at different time intervals. For up to
with excellent regioselectivities. Notably, 5al contains 10 min, no D/H exchange was observed in the ortho
a trimethylsilyl group, which might be useful for fur- position. After 15 min, 3% D/H exchange was ob-
ther transformations. Interestingly, the reaction of served. Similarly, after 30 min and 1 h time intervals
phenylacetylene (2m) with 4a gave highly regioselec- 8% and 10% D/H exchange products were observed,
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Easy Acces to 1-Amino and 1-Carbon Substituted Isoquinolines
Table 4. Synthesis of isoquinolines from various acetophenone oximes.[a,b]
[a]
Unless otherwise mentioned, all reactions were carried out using 4a–v (0.25 mmol), 2a (0.30 mmol), [CoCp*(CO)I2]
(5 mol%), KOAc (10 mol%) and TFE (2.0 mL) at 1008C for 18 h. 15 mol% Mn(OAc)2 was used for 5aa and 5va.
Isolated yield.
[b]
À
respectively. Finally, 63% of D/H exchange in [D5]-4a indicate that the C H bond cleavage step is possibly
along with 9% of D/H exchange in ketone products involved in the rate-determining step (see the Sup-
were observed under standard reaction conditions. porting Information for details on the deuterium la-
These results illustrated that the cobalt intermediate belling experiments).
was stable for up to 10 min, after which it dissociated.
A surprising result in the present isotope labelling
We tried to isolate the five-membered cobaltacycle in studies is that the intermolecular KIE of kH/kD =3.5 is
a stoichiometric reaction before 10 min, but we were substantially larger than the intramolecular value of
not able to isolate any intermediate. Additionally, we kH/kD =2.5. We should note that in most transition
À
also conducted the reaction of [D5]-4a with 2a for metal-catalyzed C H activation reactions, the intra-
5 min under standard reaction conditions. The result molecular KIE of kH/kD is larger than the correspond-
shows the existence of 3% H/D exchange in product ing intermolecular value. This is likely due to the pre-
À
[D4]-5aa. This indicates that the reaction is also rever- coordination of the directing group prior to the C H
sible in the presence of alkyne [Scheme 3, Eq. (2)]. cleavage to form the metallacycle intermediate. While
Finally, we measured inter- and intramolecular kinetic the reason for the observed contrast kinetic isotope
isotopic effects (KIEs). An intermolecular KIE of effects is still not clear, one possibility is that cobalt-
kH/kD =3.5 was observed for the competitive reaction catalyzed intermediate (C, Scheme 4) in this intramo-
of [D5]-4a and 4a with 2a to give 5aa. An intramolec- lecular oxidative annulation also undergoes H/D ex-
ular competition experiment with [D1]-4a and 2a indi- change with the solvent leading to higher H content
cated that kH/kD =2.5. The observed large KIE values of substrate 4a. For example, if the protonation of co-
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Table 5. Synthesis of isoquinolines from various alkynes.[a,b]
[a]
Unless otherwise mentioned, all reactions were carried out using 4a (0.25 mmol), 2b–m (0.30 mmol), [CoCp*(CO)I2]
(5 mol%), KOAc (10 mol%), and TFE (2.0 mL) at 1008C for 24 h.
Isolated yield.
<5% 5am was observed.
[b]
[c]
baltacycle of [D1]-4a occurs to give back the inter- sured kH/kD value from the ratio of {[D1]-5aa}/{[H4]-
mediate B, the effective concentration of [D1]-4a de- 5aa} is smaller than the real kH/kD without any H/D
creases and [H5]-4a increases. In this case, the mea- exchange.
Scheme 2. Intramolecular competition reactions.
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Easy Acces to 1-Amino and 1-Carbon Substituted Isoquinolines
Scheme 3. Kinetic experiments.
the Co-catalyzed redox-neutral pathway is shown in
Scheme 4 using 4a and 2a as model substrates.
[CoCp*(OAc)]+[10] possibly initiated the reaction by
the removal and exchange of the ligand from
[CoCp*(CO)I2] by KOAc. Then, coordination of the
nitrogen atom to the Co(III) center, followed by
À
arene ortho C H bond cleavage afforded five-mem-
bered cobaltacycle C, which was reversible in nature.
Further, coordination of the alkyne p-bond to cobal-
tacycle C and subsequent insertion of the alkyne into
À
the Co C bond of intermediate D affords a seven-
membered cobaltacyclic intermediate E. The inter-
mediate E possibly undergoes reductive elimination
to give 1-methyl-3,4-diphenylisoquinoline 2-oxide (F)
and a Co(I) species.[6,11] Finally, the cleavage of the
À
N O bond of salt F by the Co(I) species releases ex-
pected isoquinoline 5aa, Co(III) species A and by-
product H2O.[3b,6e,i]
Conclusion
Scheme 4. A plausible reaction mechanism.
In summary, we have developed an efficient method
Based on our results and known metal-catalyzed for the synthesis of 1-amino- and 1-carbon-substituted
redox-neutral reactions,[6] a plausible mechanism for isoquinolines using a more abundant first row transi-
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product. Here, the N’-hydroxybenzimidamide-direct-
À
ed, cobalt-catalyzed ortho C H addition to alkynes
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and regeneration of the active catalyst by a redox-
neutral strategy were demonstrated. This Co-cata-
lyzed method is similar to that with noble metal-con-
taining catalysts, but the atom economy in this reac-
tion is an addition advantage.
Experimental Section
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General Procedure for the Synthesis of 1-Aminoiso-
quinolines
A sealed tube containing N-substituted N’-hydroxyimida-
mides 1 (0.20 mmol), alkynes 2 (0.26 mmol), [CoCp*(CO)I2]
(10 mol%) and CsOAc (20 mol%) was evacuated and
purged with nitrogen gas three times. Then, TFE (3.0 mL)
was added via syringe under a nitrogen atmosphere and the
reaction mixture was allowed to stir at 1208C for 24 h. After
24 h, the mixture was cooled and diluted with CH2Cl2
(10 mL). The mixture was filtered through a Celite pad and
the Celite pad was washed with CH2Cl2 (3”10 mL). The fil-
trate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography using
hexane/ethyl acetate as eluent to afford the desired pure
product 3.
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Acknowledgements
We thank the Ministry of Science and Technology of the Re-
public of China (MOST-103-2633M-007-001) for support of
this research.
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