Currently, the strategy of transition-metal-catalyzed direct C–H activation has become
a powerful technique for chemical transformations in the area of synthetic methodology.[1] Because of step and atom efficiency, nobility and influence on ecology, it represents
a potent approach above conventional methods of organic synthesis, opening new opportunities
in retrosynthetic directions. In the past decade, among transition metals, ruthenium
has been emerged as a capable and cost-effective catalyst for the chemical transformations
using C–H bond functionalization approach.[2]
Directing groups, by acting as Lewis base to co-ordinate the transition metals, play
vital role in selective C–H bond activation.[3] Considering the reaction pathway, in order to recycle metal catalysts in its active
form, equivalent or excessive quantity of external oxidants are often required. These
external oxidants are responsible for generation of equivalent amount of waste, causing
environmental nuisance. Thus, in order to avoid the use of external oxidants, researchers
have pioneered a concept called redox-neutral strategy, in which directing group itself
acts as an internal oxidant too.[4] Further, this strategy has additional advantages like enhanced reactivity as well
as selectivity with improved yields and the simultaneous breaking of the directing
group.
On the other hand, most of the previous reports for C–H/ N–N activation use volatile
organic solvents, convicted for serious ecological hazards. Thus, in order to reduce
the ecological pressures by conventional organic solvents, replacing it with polyethylene
glycols (PEGs) is one of the best solutions.[5] Owing to the properties like negligible vapor pressure, inexpensiveness, thermal
stability, degradable, reusable, relatively inexpensive, and less harmful, PEGs serve
as an appropriate media for safe and ecologically gentle chemical conversions. Taking
into consideration the importance of PEG as a solvent, our research group has communicated
some scientific reports.[6]
The beginning of twenty-first century has witnessed a revolutionary advancement in
the area of microwave-assisted organic synthesis.[7] Due to the capability of expeditious heating and thermal quenching, the methodology
has several advantages of improvement into rates, efficiency, and yields of chemical
transformations. Uniform and selective heating throughout the material with minimal
heat loss, low operating cost, and minimal side reactions makes it a promising and
environmentally benign technique. Moreover, many novel organic transformations could
be achieved using microwave strategy, which could not succeed by conventional heating.
Isoquinolines have emerged as an important class of heterocyclic scaffolds that is
present in various natural as well as pharmaceutical products with broad range of
biological activities[8] (Figure [1]). Moreover, isoquinoline moieties are employed for the development of ligands, photosensitizers,
alkaloids, OLEDs, and inhibitors.[9] For instance, tetrahydropalmatine, sanguinarine, and papaverine are the naturally
occurring alkaloids containing isoquinoline scaffolds, which are widely used as analgesic,
antibacterial, and vasodilator, respectively.[10]
Figure 1 Examples of isoquinoline moieties with pharmaceutical and other importance
Due to the prosperity of isoquinoline moieties, chemists have developed progressively
effective approaches toward their synthesis. In this regard, many researchers reported
synthesis of isoquinolines using multistep approaches.[11] However, these are suffered with lacunas such as lesser yields, poor regioselectivity,
and lengthier reaction times. Overcoming these issues, later, annulation reactions
with alkynes by C–H functionalization using different directing groups and catalysts
provided an efficient alternate route for their synthesis. Transition metals like
Rh[12] and Co[13] assisted with various directing groups are very well known for the synthesis of
isoquinolines by these kinds of transformations, while Ru is rarely utilized for the
isoquinoline synthesis by C–H activation reactions.[14] Likewise, N-Cbz hydrazone is rarely examined as a directing group for C–H/N–N activation reactions.
On the other hand, almost all previous approaches for the synthesis of isoquinolines
are reported in volatile organic solvents using conventional heating method for longer
reaction time involving use of additives and oxidants, having its own disadvantages.
However, recently, the Bolm and Huang research groups reported additive-free C–H functionalization
reactions using Ru(II) catalysts.[15]
Considering all these facts, there continues to be the need to develop a protocol
for the synthesis of isoquinolines which is rapid and free from additives as well
as external oxidants using non-volatile greener solvent. In this perspective, continuing
our endeavors to develop N-heterocycles,[14b]
[16] herein, we disclose the ruthenium-catalyzed microwave-assisted synthesis of isoquinolines
by C–H/N–N activation using rarely explored acetophenone N-Cbz hydrazone as a directing group in PEG-400 as a green solvent (Scheme [1]). Furthermore, the proposed strategy works in very short time without use of any
additives and external oxidants.
Scheme 1 Transition-metal-catalyzed synthesis of isoquinolines
Table 1 Optimization of the Reaction Conditionsa
|
|
Entry
|
Additive
|
Solvent
|
Temp (°C)
|
Time (min)
|
Yield (%)b
|
|
1
|
AgSbF6
|
PEG-400
|
100
|
10
|
62
|
|
2
|
AgSbF6
|
PEG-400
|
110
|
10
|
87
|
|
3
|
AgSbF6
|
PEG-400
|
120
|
10
|
90
|
|
4
|
AgSbF6
|
PEG-400
|
110
|
12
|
88
|
|
5
|
AgSbF6
|
PEG-400
|
110
|
8
|
76
|
|
6c
|
AgSbF6
|
PEG-400
|
110
|
10
|
78
|
|
7d
|
AgSbF6
|
PEG-400
|
110
|
10
|
86
|
|
8e
|
AgSbF6
|
PEG-400
|
110
|
10
|
55
|
|
9d
|
–
|
PEG-400
|
110
|
10
|
87
|
|
10d
|
–
|
PEG-200
|
110
|
10
|
58
|
|
11d
|
–
|
PEG-600
|
110
|
10
|
71
|
|
12d
|
–
|
ethylene glycol
|
110
|
10
|
28
|
|
13d,f
|
–
|
PEG-400
|
110
|
10
|
34
|
a Reaction conditions: N-Cbz hydrazone 1a (0.5 mmol), diphenylacetylene (2a; 0.6 mmol), [Ru(p-cymene)Cl2]2 (5 mol%), additive (10 mol%), solvent (2 mL).
b GC yield.
c [Ru(p-cymene)Cl2]2 used: 7.5 mol%.
d [Ru(p-cymene)Cl2]2 used: 2.5 mol%.
e [Ru(p-cymene)Cl2]2 used: 1.5 mol%.
f Under standard conditions without microwave irradiation (conventional oil-bath heating).
We initiated our studies by investigating the annulation reactions of acetophenone
N-Cbz hydrazone with diphenylacetylene in the presence of [Ru(p-cymene)Cl2]2 and AgSbF6 in PEG-400 at 100 °C for 10 minutes as model reaction. Monitoring the reaction at
different temperatures, we found that there was no satisfactory yield at 100 °C (Table
[1], entry 1). While, increasing the temperature to 110 °C, isoquinoline 3aa was produced in 87% yield (entry 2). Only a slight improvement in the product yield
was observed on further increase in temperature (entry 3). Next, screening the reaction
at different periods of time, increase in the reaction time from 10 minutes to 12 minutes
did not induce any noteworthy progress in the product yield (entry 4), although a
consequent decrease in time to 8 minutes reduced the product yield to 76% (entry 5).
In addition, organized optimization with respect to catalyst loading, within the 1.5–7.5
mol% range (Table [1], entries 6–8), allowed the identification of its optimal quantity (2.5 mol%), which
leads to the higher yield and the product was obtained in 86% yield. Considering the
environmental threats by the use of antimonate salt, we checked the necessity of AgSbF6 as an additive for the proposed transformation. Pleasantly, the reaction worked also
in the absence of silver salt with the same efficiency (entry 9). The catalytic reaction
was also tested with various solvents such as ethylene glycol and with some biodegradable
solvents like PEG-200, PEG-400, and PEG-600. PEG-200 and PEG-600 gave product in 58%
and 71% yield, respectively (entries 10 and 11). While in the presence of ethylene
glycol, the unsatisfactory product yield 28% was obtained (entry 12). Finally, PEG-400
proved to be a compatible solvent for the stated methodology. The reaction was also
attempted without microwave irradiation (conventional oil-bath heating) under standard
condition, however, only 34% product yield was obtained (entry 13).
Having established optimization conditions, the scope of the annulation reaction of
substituted acetophenone N-Cbz hydrazones 1a–q with diphenylacetylenes 2a–d was explored as shown in Table [2]. The annulation proceeded smoothly for a wide range of substrates in good to excellent
yields. Acetophenone N-Cbz hydrazone without any substitution led to the formation of desired isoquinoline
product 3aa in an isolated yield of 87% (Table [2], entry 1). N-Cbz Hydrazones with electron-donating groups (i.e., methyl and methoxy) at para-position led to a considerable increase in yields of products 3ba and 3ca to 90% and 92% yield, respectively (entries 2 and 3).
Notably, the presence of electron-withdrawing groups (e.g., bromo, chloro, fluoro,
and nitro) at para-position of hydrazones provided the corresponding products 3da, 3ea, 3fa, and 3ga in 82%, 84%, 79% and 80% yield, respectively (Table [2], entries 4–7). Next, the reactions of meta-substituted acetophenone N-Cbz hydrazones were investigated. It was noted that hydrazones containing Me, Cl,
and NO2 at meta-position preferentially annulated with alkynes at the less hindered position to form
the corresponding products 3ha, 3ja, and 3ka particularly in 85%, 78% and 74% yield, respectively, while N-Cbz hydrazone with OMe at the meta-position generated two regioselective products 3ia and 3ia′ in 48% and 34% yield, respectively (entries 8–11). Furthermore, the disubstituted
acetophenone N-Cbz hydrazone, gave the respective product 3la with exclusive regioselectivity in 82% isolated yield (entry 12). In the next set
of experiments, N-Cbz hydrazones derived from various ketones such as propiophenone, cyclopropyl phenyl
ketone, and benzophenone were explored as substrates, which led to the formation of
corresponding isoquinoline products 3ma, 3na, and 3oa, respectively in very good yields (entries 13–15). Fused N-Cbz hydrazone derived from 1-acetylnaphthalene could also be converted into the desired
product 3pa in 81% yield (entry 16). In addition, N-Cbz hydrazone of heterocyclic ketone also could be smoothly converted into the corresponding
product 3qa in 79% yield (entry 17).
Further, the scope of the symmetrical and unsymmetrical substituted internal alkynes
for the stated methodology was investigated. Hex-3-yne, 1-phenylbut-1-yne, and 1-phenylprop-1-yne
reacted hassle-free with acetophenone N-Cbz hydrazone to generate corresponding products 3ab, 3ac, and 3ad in 76%, 82% and 80% yield, respectively (Table [2], entries 18–20).
Table 2 Ruthenium-Catalyzed Annulation of N-Cbz Hydrazones with Alkynesa
|
|
Entry
|
1
|
2
|
Product 3
|
Yield (%)b
|
|
1
|
1a
|
2a
|
3aa
|
87
|
|
2
|
1b
|
2a
|
3ba
|
90
|
|
3
|
1c
|
2a
|
3ca
|
92
|
|
4
|
1d
|
2a
|
3da
|
82
|
|
5
|
1e
|
2a
|
3ea
|
84
|
|
6
|
1f
|
2a
|
3fa
|
79
|
|
7
|
1g
|
2a
|
3ga
|
80
|
|
8
|
1h
|
2a
|
3ha
|
85
|
|
9
|
1i
|
2a
|
3ia
|
48
|
3ia′
|
34
|
|
10
|
1j
|
2a
|
3ja
|
78
|
|
11
|
1k
|
2a
|
3ka
|
74
|
|
12
|
1l
|
2a
|
3la
|
82
|
|
13
|
1m
|
2a
|
3ma
|
89
|
|
14
|
1n
|
2a
|
3na
|
88
|
|
15
|
1o
|
2a
|
3oa
|
93
|
|
16
|
1p
|
2a
|
3pa
|
81
|
|
17
|
1q
|
2a
|
3qa
|
79
|
|
18
|
1a
|
2b
|
3ab
|
76
|
|
19
|
1a
|
2c
|
3ac
|
82
|
|
20
|
1a
|
2d
|
3ad
|
80
|
a Reaction conditions: ketazine 1 (0.5 mmol), alkyne 2 (0.6 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol%), PEG-400 (2 mL), 110 °C (microwave heating), 10 min.
b Isolated yield.
In conclusion, we have developed a microwave-assisted rapid protocol for the synthesis
of isoquinolines by annulation reaction with internal alkynes via C–H/N–N activation.
N-Cbz Hydrazones were employed as directing group for redox-neutral Ru-catalyzed transformation.
Additionally, the stated methodology works efficiently in the absence of any additives
as well as external oxidants. This protocol is applicable to a wide range of N-Cbz hydrazones possessing electron-donating and electron-withdrawing groups as well
as internal alkynes for the synthesis of isoquinolines, producing corresponding products
in good to excellent yields. Use of non-volatile and biodegradable solvent is the
additional advantage of the present system.
All chemicals and solvents were purchased with high purities and used without further
purification. PEGs were dried prior to use by the literature methods. Microwave-assisted
annulation reactions were carried out in ‘Discover’ (CEMSP 1245) CEM Corporation USA)
microwave reactor. The progress of the reaction was monitored by GC with a flame ionization
detector (FID) using a capillary column (30 m × 0.25 mm × 0.25 μm) and TLC (using
silica gel 60 F-254 plates). The products were visualized with a 254 nm UV lamp. GC-MS
[Rtx-17, 30 m × 25 mm ID, film thickness (df = 0.25 μm) (column flow 2 mL min–1, 80 to 240 °C at 10 °C min–1 rise] was used for the mass analysis of the products. Products were purified by column
chromatography on 100–200 mesh silica gel. The 1H NMR spectra were recorded on an Agilent Technologies 400 MHz spectrometer using
TMS as an internal standard. The 13C NMR spectra were recorded on 100 MHz and chemical shifts were reported in parts
per million (δ) relative to TMS as an internal standard. Coupling constant (J) values were reported in hertz (Hz). Standard abbreviations were used for describing
the splitting patterns of proton in 1H NMR spectroscopic analysis. The products were confirmed by GCMS, 1H, and 13C NMR spectroscopy analysis.
Ruthenium-Catalyzed Isoquinoline Synthesis; 1-Methyl-3,4-diphenylisoquinoline (3aa);[13d] Typical Procedure
A microwave vessel was charged with N-Cbz hydrazone 1a (134 mg, 0.5 mmol), diphenylacetylene (2a; 107 mg, 0.6 mmol), [Ru(p-cymene)Cl2]2 (8 mg, 2.5 mol%), and PEG-400 (2 mL). The closed reaction vessel was irradiated at
110 °C using microwave irradiation of 50 W power for 10 min. At the end of the reaction,
the reaction mixture was cooled, and diluted with Et2O. The upper layer of Et2O containing the product mixture was separated, the solvent evaporated, and the residue
was purified through a silica gel column using PE and EtOAc as eluents to give pure
3aa; yield: 134 mg (87%); pale yellow solid; mp 154–156 °C.
1H NMR (400 MHz, CDCl3): δ = 8.21–8.19 (m, 1 H), 7.65 (d, J = 3.1 Hz, 1 H), 7.60–7.57 (m, 2 H), 7.37–7.32 (m, 5 H), 7.24–7.17 (m, 5 H), 3.08
(s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 157.70, 149.29, 140.80, 137.49, 136.02, 131.37, 130.25, 129.97, 129.24, 128.17,
127.58, 127.03, 126.94, 126.54, 126.23, 126.13, 125.52, 22.62.
GCMS (EI 70 eV): m/z = 295 (M+), 294, 278, 253, 145.
6-Methoxy-1-methyl-3,4-diphenylisoquinoline (3ca)
[13d]
Yield: 150 mg (92%); pale yellow solid; mp 179–181 °C.
1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 9.1 Hz, 1 H), 7.35–7.29 (m, 5 H), 7.24–7.14 (m, 6 H), 6.91 (d, J = 2.2 Hz, 1 H), 3.71 (s, 3 H), 3.02 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 160.61, 156.95, 149.97, 140.97, 138.10, 137.78, 131.25, 130.20, 128.63, 128.24,
127.53, 127.46, 127.08, 126.88, 121.84, 118.71, 104.50, 55.18, 22.51.
GCMS (EI 70 eV): m/z = 325 (M+), 324, 281, 154, 146.
6-Bromo-1-methyl-3,4-diphenylisoquinoline (3da)
[13d]
Yield: 153 mg (82%); slightly yellow solid; mp 192–194 °C.
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 8.8 Hz, 1 H), 7.80 (d, J = 1.8 Hz, 1 H), 7.66–7.64 (m, 1 H), 7.34 (m, 5 H), 7.24–7.17 (m, 5 H), 3.04 (s, 3
H).
13C NMR (101 MHz, CDCl3): δ = 157.76, 150.53, 140.50, 137.40, 136.77, 131.26, 130.18, 130.03, 128.41, 128.33,
128.30, 127.63,127.45, 127.29, 127.19, 125.10, 124.57, 22.61.
GCMS (EI 70 eV): m/z = 375 (M+, 2%), 373 (M+), 374, 372, 293, 292, 252, 147, 139, 125.
1,7-Dimethyl-3,4-diphenylisoquinoline (3ha)
[13d]
Yield: 131 mg (85%); slightly yellow solid; 131–133 °C.
1H NMR (400 MHz, CDCl3): δ = 7.96 (s, 1 H), 7.56 (d, J = 8.6 Hz, 1 H), 7.43–7.32 (m, 6 H), 7.24–7.17 (m, 5 H), 3.05 (s, 3 H), 2.57 (s, 3
H).
13C NMR (101 MHz, CDCl3) δ = 156.98, 148.55, 140.97, 137.71, 136.40, 134.19, 132.08, 131.36, 130.25, 129.09,
128.13, 127.55, 127.03, 126.80, 126.32, 126.10, 124.49, 22.66, 21.86.
GCMS (EI 70 eV): m/z = 309 (M+), 308, 293, 252, 146, 139.
7-Methoxy-1-methyl-3,4-diphenylisoquinoline (3ia)
[13d]
Yield: 78 mg (48%); slightly yellow solid; mp 142–144 °C.
1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 9.2 Hz, 1 H), 7.38–7.31 (m, 6 H), 7.25–7.14 (m, 6 H), 3.98 (s, 3 H), 3.04 (s, 3
H).
13C NMR (101 MHz, CDCl3): δ = 157.90, 155.95, 147.46, 140.60, 137.5, 131.39, 131.31, 130.22, 129.26, 128.14,
128.01, 127.54, 127.31, 127.09, 126.77, 122.37, 103.52, 55.48, 22.68.
GCMS (EI 70 eV): m/z = 325 (M+), 324, 308, 293, 154, 146.
5-Methoxy-1-methyl-3,4-diphenylisoquinoline (3ia′)
[12a]
Yield: 55 mg (34%); white solid; mp 145–147 °C.
1H NMR (400 MHz, CDCl3) : δ = 7.79 (d, J = 8.4 Hz, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 7.23–7.21 (m, 2 H), 7.16–7.08 (m, 8 H), 6.95 (d, J = 7.7 Hz, 1 H), 3.39 (s, 3 H), 3.04 (s, 3 H).
13C NMR (101 MHz, CDCl3) : δ = 157.04, 156.86, 150.91, 141.38, 141.34, 130.35, 130.21, 127.91, 127.48, 127.45,
127.26, 127.16, 126.48, 125.61, 118.04, 110.18, 55.53, 23.24.
GCMS (EI 70 eV): m/z = 325 (M+), 324, 281, 162, 139.
1-Cyclopropyl-3,4-diphenylisoquinoline (3na)
[12c]
Yield: 141 mg (88%); white solid; mp 149–151 °C.
1H NMR (400 MHz, CDCl3): δ = 8.50–8.48 (m, 1 H), 7.65–63 (m, 1 H), 7.59–7.56 (m, 2 H), 7.36–7.33 (m, 5 H),
7.27–7.21 (m, 2 H), 7.16 (d, J = 2.8 Hz, 3 H), 2.83–2.81 (m, 1 H), 1.40–1.25 (m, 2 H), 1.16–1.13 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 160.55, 148.50, 141.42, 138.33, 136.21, 131.40, 130.42, 129.73, 128.30, 128.23,
127.32, 127.07, 126.87, 126.40, 126.26, 126.24, 124.90, 13.60, 9.39.
GCMS (EI 70 eV): m/z = 321 (M+), 320, 243, 152, 146.
1-Methyl-3,4-diphenylbenzo[h]isoquinoline (3pa)
[13d]
Yield: 140 mg (81%); slightly yellow solid; mp 142–144 °C.
1H NMR (400 MHz, CDCl3): δ = 8.90 (d, J = 8.3 Hz, 1 H), 7.91 (d, J = 7.4 Hz, 1 H), 7.79–7.71 (m, 2 H), 7.65 (t, J = 7.1 Hz, 1 H), 7.55 (d, J = 9.1 Hz, 1 H), 7.42 (d, J = 5.9 Hz, 2 H), 7.35 (d, J = 6.5 Hz, 3 H), 7.25–7.19 (m, 5 H), 3.44 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 155.39, 150.80, 140.43, 137.95, 137.27, 132.96, 131.64, 131.22, 130.21, 129.73,
128.74, 128.26, 127.64, 127.58, 127.27, 127.19, 126.88, 126.64, 124.19, 123.95, 30.43.
GCMS (EI 70 eV): m/z = 345 (M+), 344, 343, 342, 307, 265, 154, 146.
7-Methyl-4,5-diphenylthieno[2,3-c]pyridine (3qa)
[13d]
Yield: 113 mg (79%); white solid; mp 145–147 °C.
1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 5.4 Hz, 1 H), 7.35–7.29 (m, 5 H), 7.24–7.18 (m, 6 H), 2.91 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 151.33, 150.78, 145.76, 140.14, 138.16, 134.24, 131.08, 130.51, 130.30, 128.27,
128.23, 127.69, 127.15, 127.10, 124.25, 23.52.
GCMS (EI 70 eV): m/z = 301 (M+), 300, 258, 150, 149.
4-Ethyl-1-methyl-3-phenylisoquinoline (3ac)
[13d]
Yield: 101 mg (82%); white solid; mp 121–123 °C.
1H NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 8.0 Hz, 1 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.73 (t, J = 7.6 Hz, 1 H), 7.59 (t, J = 7.6 Hz, 1 H), 7.51–7.37 (m, 5 H), 3.01–2.97 (m, 5 H), 1.25 (t, J = 7.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 155.82, 150.56, 141.66, 135.16, 129.89, 129.19, 128.62, 128.14, 127.41, 126.68,
126.38, 126.20, 124.13, 22.38, 21.64, 15.66.
GCMS (EI 70 eV): m/z = 247 (M+), 246, 232, 231, 230, 115.
