Ruthenium-Mediated Dual Catalytic Reactions of Isoquinoline via C?H Activation and Dearomatization for Isoquinolone

Article abstract of DOI:10.1002/adsc.201600313

We have unraveled the ruthenium-promoted prototype reaction based on C(sp²)?C(sp³) bond formation through the reigoselective C?H activation of isoquinoline and pyridine derivatives with various alkyl halides, leading to 1-substituted isoquinoline products in good yield. This C?H catalytic reaction did not rely on chelation assistance of the directing group of the substrates. The dimer [RuCl₂(p-cymene)]₂in combination with an N-heterocyclic carbene ligand, adamantanecarboxylic acid and K₂CO₃base in N-methyl-2-pyrrolidone solution at 150 °C are the best conditions. Simultaneously, we are also able to chemically tune the reaction mode to dearomatization by adding water, leading to isoquinolone products. This reaction methodology is not suitable for other nitrogen-containing heteroarenes such as pyridazines and pyrimidines. (Figure presented.).

Full text of DOI:10.1002/adsc.201600313

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DOI: 10.1002/adsc.201600313
Ruthenium-Mediated Dual Catalytic Reactions of Isoquinoline
À
via C H Activation and Dearomatization for Isoquinolone
Ting-Hsuan Wang,a,b,c Wei-Chih Lee,a,d and Tiow-Gan Onga,*
a
Institute of Chemistry, Academia Sinica, Taipei, Taiwan
Fax : (+886)-2-2783-1237; phone: (+886)-2-27898648; e-mail: tgong@gate.sinica.edu.tw
Department of Engineering and System Science, National Tsing Hua University, HshiChu, Taiwan
Nano Science and Technology Program, Taiwan International Graduate Program, Academia Sinica and National Tsing
b
c
Hua University, Taiwan
d
Department of Interface Chemistry, Division of Applied Chemistry, Material and Chemical Research Laboratories,
Industrial Technology Research Institute, Taiwan
Received: March 22, 2016; Revised: June 24, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600313.
Abstract: We have unraveled the ruthenium-pro-
problem arisen from functional intolerance with the
directing group.
2
3
À
moted prototype reaction based on C(sp ) C(sp )
À
bond formation through the reigoselective C H ac-
Isoquinoline motifs are considered as an essential
component in biologically active molecular structures
and possible drug precursors.[4] However, their indus-
trial value is also exhibited in ligands for metallic cat-
alysis[5] and organic light-emitting diodes in material
science.[6] Traditional synthetic manipulations to syn-
thesize isoquinolines based on Bischler–Napieralski,
Pomeranz–Fritsch and Pictet–Spengler reactions in-
volve intramolecular cyclization of substrates under
unfriendly reaction conditions and exhibited poor
functional group tolerance.[7] Quite recently, several
groups have skillfully overcome these problems in the
synthesis of isoquinolines by using transition metal-
tivation of isoquinoline and pyridine derivatives
with various alkyl halides, leading to 1-substituted
À
isoquinoline products in good yield. This C H cata-
lytic reaction did not rely on chelation assistance of
the directing group of the substrates. The dimer
[RuCl2(p-cymene)]2 in combination with an N-het-
erocyclic carbene ligand, adamantanecarboxylic
acid and K2CO3 base in N-methyl-2-pyrrolidone so-
lution at 1508C are the best conditions. Simultane-
ously, we are also able to chemically tune the reac-
tion mode to dearomatization by adding water,
leading to isoquinolone products. This reaction
methodology is not suitable for other nitrogen-con-
taining heteroarenes such as pyridazines and pyri-
midines.
À
mediated C H bond activation annulation of aromat-
ic imines, amines, oximes and hydrazones with unsatu-
rated substrates like alkynes.[8] Nevertheless, all these
protocols depend on appropriate directing groups. In
À
À
Keywords: C H bond activation; dearomatization;
stark contrast, a general approach for C H manipula-
isoquinolines; isoquinolones; ruthenium
tions of the parent isoquinoline structure is less devel-
oped in this respect[9] as its C H bond is less reactive
À
and positional selectivity would always pose an issue.
Therefore, a complementary method of functionaliz-
À
ing the C H bond of isoquinoline in a selective
Ruthenium-promoted synthetic methodology based manner will be desirable.
À
on C H activation has increasingly emerged as an at-
In an effort to advance the field of ruthenium catal-
tractive paradigm for the step-economical formation ysis we envisioned that alkyl cross-coupling reactions
[1]
À
of C C bonds. Despite the milestone progress in the with isoquinoline might be possible via non-directing
À
À
ruthenium catalysis, most Ru-mediated C H reactivi- C H bond cleavage to afford 1-substituted isoquino-
ty relied on chelation assistance of the directing lines, considering that C-1 substituted isoquinolines
group embedded in the targeted substrate,[2,3] where present essential molecular motifs found in numerous
À
the C H transformation is in close proximity to the biologically active products and pharmaceutical drugs
directing group. However, the widespread application as shown in Scheme 1.[4a–e] During the course of this
for synthetic utility based on the directing group investigation, we also found that the ruthenium com-
method might be limited by (i) the feasibility of re- plex could catalyze the dearomatization of isoquino-
moving directing group and (ii) the post-synthesis step lines to generate isoquinolones upon slightly altering
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the reaction conditions by the addition of water. Ob-
viously, this new chemical synthesis involving transfor-
mation of isoquinoline to isoquinolone should serve
as an attractive complementary method to annulation
processes.[10] Herein, we unravel the Ru-promoted
À
prototype reaction based on C C bond formation
through the C H activation of isoquinoline and other
À
nitrogen-based heteroarenes with alkyl halide, leading
to the 1-substituted isoquinoline products. Simultane-
ously, we are also able to chemically tune the reaction
mode towards producing isoquinolones just by adding
water.
À
To examine the viability of the C H bond function-
alization of isoquinoline (2a) (Table 1), we attempted
the reaction using benzyl chloride (1a) at 1308C in
toluene with 2.5 mol% [RuCl2(p-cymene)]2 in the
presence of K2CO3 (2 equiv.) and N-acetylglycine
(0.3 equiv.) as an additive. To our delight, the expect-
ed benzylated product (3a) was obtained in 48%
yield (entry 1). The efficacy of the reaction could be
further improved to a higher yield of 60% by chang-
ing the additive to 1-adamantanecarboxylic acid and
increasing the reaction temperature to 1508C
(entry 3). Subsequently, we looked into the possibility
Scheme 1. Biologically active C-1 substituted isoquinolines.
Table 1. Selected optimization parameters.[a]
[a]
1a 1.5 mmol, 2a 0.5 mmol.
[RuCl2(p-cymene)]2 2.5 mol%.
Isolated yield.
1,10-Phen=1,10-phenanthroline.
IMes=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene.
IPr=1,3-bis(2,6-diisopropyl-phenyl) imidazol-2-ylidene.
1.5 mL.
[b]
[c]
[d]
[e]
[f]
[g]
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of a ligand-promoted reaction. It was found that
To further expand the utility of this methodology,
strong s-donating ligands like IPr[11] (92%) and we explored the generality of the transformation with
IMes[12] (90%) with NMP solvent had beneficial ef- various isoquinolines and pyridines as well (Table 3).
fects on the yields of the reaction (entries 8 and 9). A Excellent-to-moderate yields were realized with 5-ar-
series of control experiments established that the Ru ylisoquinolines (2b–g) containing various electron-do-
complex, the acid additive and base are all essential nating and electron-withdrawing groups (entries 2–6).
(entries 10–12). Finally, benzyl bromide and iodide Our protocol was effective for pyridine (2i) and fused
were also examined and found to be less effective re- cyclopentylpyridine derivatives like 2h in good yield.
actants compared to the chloride analogues, furnish- Good reactivities are seen with bulkier pyridines like
ing only coupling product 3aa in ~40% yield.
p-phenylpyridine (2j) and o,p-dimethylpyridine (2k)
With the optimized conditions in hand (entry 1, (~60%) to effect a highly selective ortho-benzylation
Table 2), we examined the reaction scope with various with respect to the N atoms of 3aj and 3ak, respec-
benzyl chlorides 1 with isoquinoline (2a) (entries 2– tively. In spite of the success in this methodology,
14). Excellent yields were observed for methyl-substi- other nitrogen-based heteroarenes such as pyridazines
tuted benzyl chlorides 1b and 1c. Commercially avail- and pyrimidines are not viable in this reaction.
able benzyl chlorides bearing chloro functional
During the course of this investigation, we also dis-
groups at para (66%) and meta (60%) positions af- covered that the ruthenium complex could catalyze
forded the corresponding 2-benzylisoquinoline prod- a dearomatization process of isoquinolines to gener-
ucts 3da and 3fa in good yields in contrast to the ate N-benzylated isoquinolones by slightly altering
ortho chloro substituent 1e (30%). Similarly, 1g (fluo- the reaction conditions through addition of water. In
ride) was suitable in this catalytic reaction (~60%). the screening process for maximizing the ruthenium
Other electron-withdrawing entities like nitro (1h), selectivity for dearomatization of 1a with 2a, we
ester (1i) and vinyl (1j) delivered rather inferior found that the reaction conditions of 2.5 mol%
yields (entries 8–10). Encouragingly, other primary [RuCl2(p-cymene)]2 in the presence of 4 equiv. of
alkyl halides (1k–m) were possible in this reaction K2CO3 and water under air, afforded a 92% yield of
with good yields. But the secondary alkyl halide (1n) 1-benzylisoquinolinone
adduct
4aa
(Table 4,
gave a lower yield of 35% (entry 14) than its primary entry 1).[13] High yields with complete chemoselectivi-
counterparts, which could be attributed to the steric ty for isoquinolinones were observed for benzyl chlor-
factor.
ides containing methyl, chloro and fluoro groups (1b–
Table 2. Scope of reactions with various alkyl halides.[a]
[a]
Conditions:
1
(1.5 mmol),
2
(0.5 mmol), [RuCl2(p-cymene)]2 (0.0125 mmol), IPr
(0.05 mmol), 1-AdCO2H (0.15 mmol) and K2CO3 (2.0 mmol) in NMP (1.5 mL) at 1508C
for 12 h unless otherwise noted.
Isolated yield.
24 h.
[b]
[c]
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Table 3. Scope of various heteroarenes.[a]
[a]
Conditions: 1 (1.5 mmol), 2 (0.5 mmol), [RuCl2(p-cymene)]2 (0.0125 mmol), IPr (0.05 mmol), 1-
AdCO2H (0.15 mmol) and K2CO3 (2.0 mmol) in NMP (1.5 mL) at 1508C for 12 h unless other-
wise noted.
Isolated yield.
24 hours.
[b]
[c]
[d]
DCPE=1,2-bis(dicyclohexylphosphino)ethane (0.025 mmol) instead of IPr.
g) at different positions. Several electron-withdrawing catalytic reaction with the reaction efficiency ranging
benzyl chlorides such as nitro (1h, 64%), methyl ester from good to moderate yields. Next, we systematically
(1i, 75%) and nitrile (1o, 82%) afforded amide prod- examined the effects of the isoquinoline derivatives
ucts in good yields with the exception that vinyl and other heteroarenes on this reaction (entries 17–
group 1j gave no reaction, which could perhaps be at- 25, Table 4). A general observation is that electronic
tributed to the poor solubility of 1j in the aqueous or electronic perturbations invoked by different sub-
conditions. Beside benzyl chloride, a variety of pri- stituents (2b–g, entries 17–22) at the aryl ring of the
mary alkyl chlorides (1k–p) were also suitable in this 5-arylisoquinoline did not have any adverse effect on
Figure 1. Preparation of papaverine and related compounds. Standard conditions A: 1 (1.5 mmol), 2 (0.5 mmol), [RuCl2(p-
cymene)]2 (0.0125 mmol), IPr (0.05 mmol), 1-AdCO2H (0.15 mmol) and K2CO3 (2.0 mmol) in NMP (1.5 mL) at 1508C for
12 h. Standard conditions B: 1 (2.0 mmol), 2 (0.5 mmol), [RuCl2(p-cymene)]2 (0.0125 mmol) and K2CO3 (4.0 mmol) in H2O
(1.0 mL) at 1308C in air for 12 h.
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Table 4. Scope of the dearomatization process.[a]
[a]
Conditions:
1
(2.0 mmol),
2
(0.5 mmol), [RuCl2(p-cymene)]2 (0.0125 mmol) and K2CO3
(4.0 mmol) in H2O (1.0 mL) at 1308C in air for 12 h unless otherwise noted.
[b]
[c]
[d]
Isolated yield.
Addition of 0.2 mL DME.
24 h.
the reaction yield or chemoselectivity. We also tested to bioactive papaverine, which is used as a non-nar-
isoquinolines with election-withdrawing groups (2m, cotic antispasmodic agent. Figure 1 shows that the
n) at the C-5 position, and found that they readily synthesis of papaverine and its derivatives could be
provided the expected dearomatized amidation prod- achieved in one step with acceptable yields of 50–
ucts with good yields of 72–90%. Interestingly, a bioac- 60% (5aa–5ac) starting from isoquinoline. Somewhat
tive heterocyclic quinazolinone (4aj) could also be re- surprisingly, a 4-methoxy-substituted benzyl chloride
alized in a moderate yield from quinazoline (2o), il- lacking one of the methoxy groups at the meta posi-
lustrating the viability of this method for heteroarenes tions failed to give any product. Alternatively, dearo-
other than isoquinolines.
matization compounds bearing methoxy groups (5ba,
Finally, the utility of this methodology could be fur- 5bb) have also been successfully prepared with rea-
ther applied to the preparation of compounds related sonable yields.
Scheme 2. Inter-molecular competition experiment.
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To gain insights into the reaction mechanism, the
following experiments were conducted. The catalytic
reactions of isoquinoline with an equal amount of
electronic-rich (2c) and electron-deficient (2d) benzyl
chlorides were examined (Scheme 2). As revealed by
1H NMR analysis, there is no significant difference
between electron-withdrawing and electron-donating
derivatives in intermolecular competition reactions.
The result indicated that the oxidative addition of
benzyl chloride may not be the slowest step in the re-
activity profile. The kinetic isotope effect (KIE) was
investigated by an intermolecular competition be-
tween 2a and 2a-d2 (Scheme 3). The small KIE value
Scheme 3. Kinetic isotope experiment (KIE) study.
À
of 1.45 obtained in C-1 alkylation suggested that C H
bond cleavage may not be significant with respect to
[14]
the overall rate-determining step.
Based on these activation through cyclometallation–deprotonation
mechanistic studies, we propose the catalytic pathway (CMD) with 7 to afford 8. Subsequently, a facile oxi-
À
described in Scheme 4. The initial step is slow C H dative addition of benzyl chloride occurred to furnish
À
Scheme 4. Proposed mechanism for the catalytic reaction of C H benzylation.
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Ru(IV) complex 9. Finally, reductive elimination of 9
occurred to afford the coupling product 3. However,
the mechanism of isoquinolone formation triggered
by water may undergo a different operative mecha-
nism and still remains elusive at this stage, which is
the subject of our continuing study.
In summary, we have unraveled the Ru-promoted
2
3
À
prototype reaction based on C(sp ) C(sp ) bond for-
À
mation through the C H activation of isoquinoline
and pyridine derivatives with alkyl halides, leading to
the 1-substituted isoquinoline products. Simultaneous-
ly, we are able to chemically tune the reaction mode
by adding water towards dearomatization, leading to
isoquinolones. Ongoing work seeks to gain a detailed
mechanistic understanding of the dual reaction modes
of isoquinoline mediated by ruthenium.
À
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Experimental Section
Typical Procedure for the Synthesis of 3aa
Benzyl chloride 1a (190 mg, 1.5 mmol) and isoquinoline 2a
(65 mg, 0.5 mmol) were added to a mixture of [RuCl2(p-
cymene)]2 (7 mg, 0.00125 mmol), IPr (20 mg, 0.05 mmol), 1-
AdCOOH (27 mg, 0.15 mmol) and K2CO3 (138 mg, 1 mmol)
in NMP (1.5 mL) under N2. After heating at 1508C for 12 h,
the resulting mixture was filtered through Celite, the residue
washed with ethyl acetate. After concentration, the crude
product was purified by flash chromatography (ethyl ace-
tate/n-hexane 1:8).
Typical Procedure for the Synthesis of 4aa
Benzyl chloride 1a (253 mg, 2 mmol) and isoquinoline 2a
(65 mg, 0.5 mmol) were added to a mixture of [RuCl2(p-
cymene)]2 (7 mg, 0.00125 mmol) and K2CO3 (276 mg,
2 mmol) in H2O (1 mL). The reaction mixture was heated at
1308C for 12 h. After extraction with ethyl acetate (3ꢁ
5 mL) and filtration over Celite, the collected organic layers
were dried over MgSO4. After concentration, the crude
product was purified by flash chromatography (ethyl ace-
tate/n-hexane 1:8).
Acknowledgements
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This work is financially supported by the Ministry of Science
& Technology of Taiwan (MOST-104–2628M-001-005-MY4
grant) and Academia Sinica Career Development Award
(104-CDA-M08). Finally, this lab is grateful to Dr. Mei-Chun
Tseng for mass spectrometry.
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9, 773–782; b) T. Ishikawa, K. Shimooka, T. Narioka, S.
Noguchi, T. Saito, A. Ishikawa, E. Yamazaki, T. Har-
ayama, H. Seki, K. Yamaguchi, J. Org. Chem. 2000, 65,
9143–9151; c) A. Bischler, B. Napieralski, Ber. Dtsch.
Chem. Ges. 1893, 26, 1903–1908. For Pomeranz–Fritsch
examples, see: d) E. V. Brown, J. Org. Chem. 1977, 42,
3208–3209; e) W. Herz, S. Tocker, J. Am. Chem. Soc.
1955, 77, 6353–6355; f) P. Fritsch, Ber. Dtsch. Chem.
Ges. 1893, 26, 419–422; g) C. Pomeranz, Monatsh.
[10] a) L. Shi, K. Yu, B. Wang, Chem. Commun. 2015, 51,
17277–17280; b) Y. Wu, P. Sun, K. Zhang, T. Yang, H.
Yao, A. Lin, J. Org. Chem. 2016, 81, 2166–2173.
[11] 1,3-Bis(2,4,6-trimethylphenyl)imidazol-2-ylidene.
[12] 1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
[13] For further details of the optimization, see the Support-
ing Information.
[14] The KIE value is based on the rate constant derived
from a plot of the first order reaction of 2a and 2a-d.
See the Supporting Information for details.
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These are not the final page numbers!

COMMUNICATIONS
Ruthenium-Mediated Dual Catalytic Reactions of
9
À
Isoquinoline via C H Activation and Dearomatization for
Isoquinolone
Adv. Synth. Catal. 2016, 358, 1 – 9
Ting-Hsuan Wang, Wei-Chih Lee, Tiow-Gan Ong*
Adv. Synth. Catal. 0000, 000, 0 – 0
9
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!