Cp*Co(III) catalyzed annulation of N-Cbz hydrazones for the redox-neutral synthesis of isoquinolines via C–H/N–N bond activation

Article abstract of DOI:10.1080/00397911.2019.1655765

A new cascade oxidative cyclization reaction of N-Cbz hydrazones with internal alkynes has been explored for the preparation of isoquinoline derivatives using Cp*Co^III-catalyst through C–H and N–N bond functionalization. N-Cbz hydrazones are ra

Full text of DOI:10.1080/00397911.2019.1655765

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Cp*Co(III) catalyzed annulation of N-Cbz
hydrazones for the redox-neutral synthesis of
isoquinolines via C–H/N–N bond activation
Dnyaneshwar D. Subhedar, Dewal S. Deshmukh & Bhalchandra M. Bhanage
To cite this article: Dnyaneshwar D. Subhedar, Dewal S. Deshmukh & Bhalchandra M.
Bhanage (2019): Cp*Co(III) catalyzed annulation of N-Cbz hydrazones for the redox-neutral
synthesis of isoquinolines via C–H/N–N bond activation, Synthetic Communications, DOI:
10.1080/00397911.2019.1655765
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1655765
ꢀ
Cp Co(III) catalyzed annulation of N-Cbz hydrazones for
the redox-neutral synthesis of isoquinolines via C–H/N–N
bond activation
Dnyaneshwar D. Subhedar, Dewal S. Deshmukh, and Bhalchandra M. Bhanage
Department of Chemistry, Institute of Chemical Technology, Mumbai, India
ABSTRACT
ARTICLE HISTORY
Received 1 June 2019
A new cascade oxidative cyclization reaction of N-Cbz hydrazones
with internal alkynes has been explored for the preparation of iso-
III
ꢀ
KEYWORDS
quinoline derivatives using Cp Co -catalyst through C–H and N–N
bond functionalization. N-Cbz hydrazones are rarely explored as
directing group for redox-neutral [4 þ 2] cyclization reaction through
the cyclometallation and this catalyst system does not require any
external oxidizing agent, as well as, silver or antimony salt. The cur-
rent efficient approach has been utilized for the synthesis of different
isoquinoline derivatives with good regioselectivity and yields.
C–H/N–N bond activation;
cobalt; N-Cbz hydrazone;
silver salt-free
GRAPHICAL ABSTRACT
Introduction
Transition metal-catalyzed C–H bond functionalization reactions showed a potential
pathway for the transformation of various organic molecules.[1–5] The strategy of C–H
bond activation has been widely used for the preparation of naturally occurring com-
pounds, drug molecules, and intermediates of the biologically active compounds.[6]
Also, C–H bond activation is an important tool in synthetic organic chemistry for the
CONTACT Bhalchandra M. Bhanage
bm.bhanage@gmail.com, bm.bhanage@ictmumbai.edu.in
Department of
Chemistry, Institute of Chemical Technology, Matunga, Nathalal Parekh Marg, Mumbai 400019, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
D. D. SUBHEDAR ET AL.
development of C¼O, C–N, C–S, and C–C bonds considering the regioselective and
green chemistry perspective.[7–9] Most of the C–H bond activation reactions involve the
use of expensive metal catalysts. In the last few decades, first-row transition metals have
become a prominent replacement to the expensive transition metals for C–H functional-
ization reactions due to their less toxicity, inexpensive nature and mode of coordin-
ation.[10,11] In this background, many research groups took efforts on the improvement
[12,13]
ꢀ
of Cp Co(CO)I2 catalyzed C–H bond activation reactions.
Isoquinoline derivatives are naturally occurring compounds which represent an essential
class of heterocycles with a broad range of pharmacological activity.[14] Isoquinoline motifs
can be used as ligands in various asymmetric catalysts and photochemical reactions.[15,16]
They are also used in material sciences, dyes and paint industries.[17] Due to the importance
of isoquinoline moieties, various name reactions such as Bischler–Napieralski,[18]
Pomeranz–Fritsch,[19] and Pictet–Spengler[20] are reported for their synthesis. In the last few
decades, C–H bond activation reactions have been recognized as a prominent route for the
preparation of isoquinoline derivatives with promising yields.[21]
Transition metal-catalyzed divergent synthetic routes for the preparation of isoquino-
lines have been widely studied using various directing groups via N–O bond cleav-
age.[22–26] Also, N–N bond cleavage became a promising tool for the synthesis of
isoquinolines using diverse directing groups assisted by transition metals
(Scheme 1).[27–32] However, most of the above methods suffer from one or more draw-
backs such as the use of external oxidants, expensive transition metal catalysts, and
unavailability of starting material. Considering these limitations, cobalt, a relatively inex-
pensive catalyst has been employed for the preparation of isoquinolines through C–H/
N–N bond activations.[33–35] In light of this, Zhu group demonstrated Co-catalyzed
access to isoquinolines using bidentate directing group under air as an external oxi-
dant.[36] Next, Lade and coworkers synthesized isoquinolines by annulation of arylhy-
drazones. This protocol having some lacunas like the use of silver salt and air as an
external oxidant.[37] However, to the best of our knowledge N-Cbz hydrazone are rarely
explored for the synthesis of isoquinolines. Also, considering above drawbacks for the
synthesis of isoquinolines, there is need to develop its synthetic protocol using a rela-
tively inexpensive Co catalyst which is efficient, free from the use of silver salt, as well
as, external oxidant.
Recently our research group explored various directing groups to accelerate C–H
bond activation at ortho position for the preparation of heterocycles and other bio-
logically active scaffolds.[38–41] In view of this, herein, we decided to employ N-Cbz
hydrazone, a rarely explored directing group for the cyclization reaction with alkynes
ꢀ
using Cp Co(III) as a catalyst via C–H/N–N bond activation for the preparation of
isoquinolines. The proposed reaction methodology is elegant, relatively inexpensive
and facile which works efficiently under external oxidant as well as silver
salt-free conditions.
Results and discussion
Optimization of reaction conditions has been carried out employing 0.5 mmol of
N-Cbz hydrazone (E)-benzyl 2-(1-phenylethylidene)hydrazine carboxylate and

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SYNTHETIC COMMUNICATIONSV
3
Scheme 1. Transition metal catalyzed annulation reaction for the synthesis of isoquinoline.
diphenylacetylene as model substrates using 2 mL of trifluroethanol as a solvent
(Table 1). Initially, the reaction was performed using model substrates in presenceꢁ of
ꢀ
Cp Co(CO)I2 as a catalyst and NaOAc and AgSbF6 as additives for 16 h at 100 C,
which could produce isoquinoline 3a with a satisfactory yield of 71% (Table 1, entry 1).
With these satisfactory results, we then screened different acetate sources such as
KOAc, CsOAc, Zn(OAc)2, AgOAc and Cu(OAc)2 for the model reaction to check their
effect on the yield of isoquinoline product, however, they are found to be less effective
for the given transformation (Table 1, entries 2–6). Next, we have tested the solvent
effect on the model reaction. Using 1,2-DCE as a solvent instead of TFE for the model
reaction results in a lower product yield (Table 1, entry 7). On the other hand, MeOH
and t-AmOH as a solvent found to be less effective for the proposed conversion
(Table 1, entries 8 and 9). When the reaction was carried out in the absence of NaOAc,
sudden decrease in the yield of product was observed. This is possibly due to the
requirement of acetate ligand for the removal of hydrogen at the ortho position of the
directing group (Table 1, entry 10). Considering the environmental impact of silver and
antimony salt, we next, checked its necessity for our protocol. Surprisingly, no effect on

4
D. D. SUBHEDAR ET AL.
Table 1. Optimization of Co(III)-catalyzed cyclization of N-Cbz hydrazones.a
entry
Additive 1
Additive 2
solvent
temp (oC)
Yield (%)b
1
2
3
4
5
6
7
8
NaOAc
KOAc
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
–
–
–
–
–
–
–
TFE
TFE
TFE
TFE
TFE
100
100
100
100
100
100
100
100
100
100
100
110
120
110
110
110
110
71
52
46
35
42
48
58
14
26
15
69
87
88
87
75
45
88
CsOAc
Zn(OAc)2
AgOAc
Cu(OAc)2
NaOAc
NaOAc
NaOAc
–
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
TFE
1,2-DCE
MeOH
tAmOH
TFE
TFE
TFE
TFE
TFE
TFE
TFE
9
10
11
12
13
14c
15d
16e
17f
a
TFE
ꢀ
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Cp Co(CO)I2 (10 mol%), NaOAc (5 mol%), AgSbF6 (20 mol%) in TFE
(2 mL) for 16 h. bGC yield, reaction performed for 18 h, reaction performed for 14 h, 5 mol% [Cp Co(CO)I2] was used
and 15 mol% [Cp Co(CO)I2] catalyst was used.
c
d
e
ꢀ
f
ꢀ
the yield of the final product was observed when the reaction was carried out in the
absence of silver hexafluoroantimonate salt. (Table 1 entry 11).
Next, the effect of temperature on the model reaction was studied. When the tem-
perature of the reaction was increased to 110 ꢁC, a substantial effect on the yield of
product was observed. Further, with the increase of temperature up to 120 ꢁC, no sig-
nificant change in the yields of the titled product was observed (Table 1, entry 12 and
13). Furthermore, reaction time increased to 18 h, which does not change the yield of
the titled product (Table 1, entry 14). On the other hand, low product yield was
obtained on decreasing time to 14 h (Table 1, entry 15). Further, we also studied the
optimum catalyst loading for the model reaction which suggests that 10 mol% catalysts
are optimum for the proposed transformation (Table 1, entries 16 and 17).
Employing the above-optimized reaction conditions, we further investigated the ver-
satility of the proposed protocol for different substituted N-Cbz hydrazones (Scheme 2).
For this, we employed various N-Cbz hydrazones containing electron-donating, as well
as, electron-withdrawing groups such as methyl, methoxy, fluoro, chloro, bromo, and
nitro for annulation with internal alkynes to give respective isoquinoline products with
promising yields (87–78%). N-Cbz hydrazone with no substituent gave a prominent
yield of titled product (3a). The incorporation of methyl and methoxy group at the para
position of the phenyl ring of N-Cbz hydrazone slightly increased the yields of 3b and
3c by 88 and 90%, respectively. Next, the introduction of electron-deficient functional
groups like fluoro, chloro, bromo and nitro at the para position of N-Cbz hydrazone
affected the reaction providing 3d–g product yields in 80, 77, 72, and 63%, respectively.
When the functional group is present at different positions of the N-Cbz hydrazone, it

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5
aReaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Cp*Co(CO)I2 (10 mol %), NaOAc (5 mol
%) in TFE (2 mL) at 110 οC for 16 h.
Scheme 2. The scope of substituted N-Cbz hydrazones and Alkynes. Reaction conditions: 1a
ꢁ
ꢀ
(0.5 mmol), 2a (0.6 mmol), Cp Co(CO)I2 (10mol%), NaOAc (5 mol%) in TFE (2 mL) at 110 C for 16 h.
shows the marginal effect of the yields of the desired product. The reaction of methyl
substituent at meta position of N-Cbz hydrazone with diphenyl acetylene generated cor-
responding isoquinoline product in 71% yield (3h). Methoxy and chloro group present
at the meta position of N-Cbz hydrazone lead to a slight decrease in yields of corre-
sponding products (3i and 3j). Next, we moved to annulation of disubstituted N-Cbz

6
D. D. SUBHEDAR ET AL.
Scheme 3. Plausible reaction mechanism.
hydrazones with diphenyl acetylene to give desired product 3k in 85% yield. Pleasantly,
N-Cbz hydrazone derived from different ketones such as propiophenone (1l),
cyclopropyl phenyl ketone (1m), benzophenone (1n) and acetylnaphthalene(1o), also
produced desired isoquinoline products 3l–o with 89, 85, 82, and 81% product yields,
respectively.
Gratifyingly, N-Cbz hydrazone derived from heterocyclic ketone also reacts efficiently
with diphenyl acetylene to afford the desired product (3p) with satisfactory yield. After
the scope of N-Cbz hydrazones had been examined, we next turned our attention to
explore the scope of alkyne for the preparation of isoquinoline derivatives. Symmetrical
aliphatic alkyne i.e. 3-hexyne reacts with N-Cbz hydrazone (1a) affording good yields of
the isoquinoline product (3q). Similarly, the reaction of unsymmetrical alkyne (i.e., but-
1-yn-1-ylbenzene and prop-1-yn-1-ylbenzene) with N-Cbz hydrazone (1a) generated
corresponding products 3r and 3s with 81 and 79% yields, respectively.
The plausible reaction mechanism for the proposed transformation is shown in
III
ꢀ
Scheme 3. In the first step, Cp Co forms complex I in presence of NaOAc. Complex
I then coordinates with N-Cbz hydrazone 1a to give intermediate II. Next, intermediate
II undergoes concerted cyclometallation-deprotonation with the release of HOAc to
form five-membered cobaltocycle intermediate III. In a further step, intermediate III
coordinates with alkyne 2 to form intermediate IV followed by insertion of alkyne to
form the seven-membered intermediate V. Finally, isoquinoline 3a releases from the
catalytic cycle in presence of HOAc to regenerate active catalytic species I for the fur-
ther cycle.

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SYNTHETIC COMMUNICATIONSV
7
Conclusion
III
ꢀ
In conclusion, we develop the Cp Co -catalyzed dehydrative cyclization of N-Cbz
hydrazones with alkynes through the C–H and N–N bond activation. This protocol is
the redox neutral type and no external oxidant as well as silver salt required for the
preparation of isoquinoline derivatives. Utilizing this facile and efficient methodology
for the various substituted and disubstituted N-Cbz hydrazones (nitro, fluoro, chloro,
bromo, and methoxy groups) to form multi-substituted isoquinoline derivatives. This
pathway is useful for the reaction of different alkynes with N-Cbz hydrazones to afford
corresponding isoquinoline derivatives in good to excellent yields.
Experimental procedure
Materials and methods
All chemicals and solvents were purchased with high purities and used without further
purification. The progress of the reaction was monitored by gas chromatography (GC)
with a flame ionization detector (FID) with a capillary column (30 m ꢂ 0.25 mm ꢂ
0.25 lm) and thin layer chromatography (using silica gel 60 F-254 plates). The products
were visualized with a 254 nm UV lamp. GC-MS (Rtx-17, 30 m ꢂ 25 mm ID, film thick-
ness (df ¼ 0.25 lm) (column flow 2 mL minꢃ1, 80 to 240 ꢁC at 10 ꢁC minꢃ1 rise) was
used for the mass analysis of the products. Products were purified by column chroma-
1
tography on 100–200 mesh silica gel. The H NMR spectra were recorded on 400 and
500 MHz spectrometers using tetramethylsilane (TMS) as an internal standard. The 13C
NMR spectra were recorded at 100 and 125 MHz and chemical shifts were reported in
parts per million (d) relative to tetramethylsilane (TMS) as an internal standard.
Coupling constant (J) values were reported in hertz (Hz). The splitting patterns of the
proton are described as s (singlet), d (doublet), dd (doublet of doublet), t (triplet), and
m (multiplet) in 1H NMR spectroscopic analysis. The products were confirmed by
1
GCMS, H and 13C NMR spectroscopy analysis.
General experimental procedure for the preparation of isoquinoline derivative
A dry reaction tube with a magnetic stirrer was charged with N-Cbz hydrazone 1
ꢀ
(0.5 mmol), alkyne 2 (0.6 mmol), NaOAc (5 mol%), and [Cp Co(CO)I2] (10 mol%).
Then the tube was evacuated and nitrogen was purged three to four times in the reac-
tion tube. Next, TFE (2 mL) was added to the tube with the help of a syringe. The reac-
tion mixture was stirred at 110 ꢁC for 16 h. After the completion of the reaction, the
reaction mixture was allowed to cool at room temperature followed by extraction with
25 mL of ethyl acetate; the organic layer was washed with brine solution, dried over
anhydrous Na2SO4 and filtered. Finally, the solvent was removed under vacuum on a
rotary evaporator. The resulting mixture was purified by silica gel column chromatog-
raphy using pet ether/ethyl acetate as eluent to get the pure final product 3 in
good yield.

8
D. D. SUBHEDAR ET AL.
1-Methyl-3,4-diphenylisoquinoline (3a)
1
Pale yellow solid; mp 154–156 ꢁC; Yield 87%; H NMR (400 MHz, CDCl3) d 8.20–8.18
(m, 1H), 7.64 (d, J ¼ 4.6 Hz, 1H), 7.59–7.56 (m, 2H), 7.36–7.32 (m, 5H), 7.24–7.16 (m,
5H), 3.07 (s, 3H); 13C NMR (101 MHz, CDCl3) d 156.74, 148.45, 140.03, 136.61, 135.04,
130.43, 129.29, 128.92, 128.21, 127.20, 126.61, 126.13, 126.03, 125.94, 125.53, 125.22,
125.19, 124.54, 21.72; GCMS (EI 70 eV) m/z (% rel. inten.) 295 (Mþ, 51), 294, 252,
146, 139.
1
Supplementary data (copies of H and 13C NMR spectra of all the synthesized com-
pounds) associated with this article can be found through the “Supplementary Content”
section of this article’s webpage.
Funding
The author D.D.S. would like to thankful to the University Grant Commission (UGC), New
Delhi, Govt. of India for providing financial support under the Dr. D. S. Kothari Post Doctoral
Fellowship Scheme [No.F.4-2/2006 (BSR)/CH/16-17/0210]
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