Synthesis of isoquinolones: Via Rh-catalyzed C-H activation of substituted benzamides using air as the sole oxidant in water

Article abstract of DOI:10.1039/c7gc01221g

Most of the metal-catalyzed C-H activation/annulation reactions were carried out in organic solvents using expensive oxidants such as Cu(ii) and Ag(i) salts. Here, we reported a new approach for a highly regioselective synthesis of isoquinolones from N-alkyl benzamides and alkynes using an Rh(iii) catalyst and inexpensive oxygen as the sole oxidant in an aqueous medium. In the reaction, water gave the highest product yield among the solvents used. In addition, at the end of the reaction, the isoquinolone product directly precipitated out from the aqueous solution. The methodology can be applied to a gram scale synthesis. This Rh(iii)-catalyzed reaction shows interesting meta selectivity with the meta substituted benzamide and shows various regioselectivities with different substituted alkynes. Moreover, the methodology can be applied to the preparation of biologically active compounds having the isoquinolone core.

Full text of DOI:10.1039/c7gc01221g

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Synthesis of Isoquinolones via Rh-Catalyzed C−H Activation of
Substituted Benzamides Using Air as the Sole Oxidant in Water.
Received 00th January 20xx,
Nitinkumar Satyadev Upadhyay, Vijaykumar H. Thorat, Ryota Sato, Annamalai Pratheepkumar;
Chuang, Shih-Ching*and Chien–Hong Cheng*.
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/−
Most of the metal-catalyzed C−H activation/annulation reaction were synthesis of isoquinolone derivatives from N-alkyl benzamides and
carried out in organic solvent using expensive oxidant such as Cu(II) and alkynes in water using dioxygen (or air) as the oxidant. The rhodium
Ag(I) salts. Here, we reported a new approach for highly regioselective and rhuthinium-catalyzed annulations of benzamide and alkynes to
synthesis of isoquinolones from N-alkyl benzamides and alkynes using give the corresponding isoquinolones in t-amyl alcohol as the
Rh(III) catalyst and inexpensive oxygen as the sole oxidant in aqueous solvent using Cu(OAC)2.H2O as the oxidant have been reported by
medium. In the reaction, water gave the highest product yield among the of Rovis‘,8 Ackermann’s9 groups, respectively. Isoquinolone is an
solvents used. In addition, at the end of reaction the isoquinolone product important structural unit which is present in various natural
directly precipitated out from the aqueous solution. The methodology can products, biologically active molecules and pharamaceuticals.10 The
be applied to a gram scale synthesis. This Rh(III)-catalyzed reaction shows structures of some of the alkaloids and biologically active
interesting meta selectivity with the meta substituted benzamide and compounds are shown in Scheme 1. The present methodology
shows various regioselectivity with different substituted alkynes. using water as the solvent and oxygen (or air) as the oxidant is
Moreover, the methodology can be applied to the preparation of compatible with a wide-range of substituent on the benzamide and
biologically active compounds having the isoquinolone core.
alkyne substrates. Excellent regioselcetivity is obtained with
unsymmetrical alkynes. In addition, we also demostrated the utility
Transition metal-catalyzed oxidative C
−
H bond activation and of this new less expensive green methodology in the one pot
of an anti-cardiac arrhythmias agent, 3-
annulation has attracted considerable attention because the synthesis
catalytic reaction does not require pre-functionalization of the ((dimethylamino)methyl)-6-methoxy-2-methyl-4-phenylisoquinolin-
substrate and is highly regioselective. In the past several years, Rh- 1(2H)-one.11
O
catalyzed oxidative annulation reactions were mostly carried out in
the presence of an organic solvent and an expensive metal based
oxidant.1,2,3 For the catalytic reaction to be practical, expensive
organic solvent and metal-based oxidant are better avoided. Water
is the most abundant compound on the earth surface which is a
non-flammable, nontoxic green solvent. Oxygen is the third-most
abundant element in the universe and has good solubility in water,
and is the cheapest and renewable source of oxidant. Reactions
carried out in water via aerobic oxidation are generally more
ecology and environment-friendly and have fascinated many
O
N
MeO
N
N
MeO
OMe
O
2
1
O
O
Me
Me
O
N
N
O
O
O
O
O
synthetic chemists.
A few Rh-catalyzed oxidative annulation
oxyavicine
oxynitidine
reactions were known to proceed in organic solvents using
inexpensive oxygen as the oxidant or in water using metal-based
Scheme 1. Natural and bioactive compounds containing isoquinolone core.
oxidant for the metal-catalyzed
C−
H
activation/annulation
reaction.4 Our continuous interest5,6,7 in the metal-catalyzed C-H
bond activation reactions prompted us to explore the possibility of
metal-catalyzed C-H bond activation and annulation in water using
dioxygen as the oxidant. In this report, we demonstrate an efficient
Rh-catalyzed environmentally friendly synthetic route for the
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Table 1. Optimization studies for the reaction of N-methylbenzamide with 2- 1a and diphenyl acetylene 2a as the substrates in the presence of
diphenylethynea
4.0 mol% of [Cp*Rh(MeCN)3][BF4]2, a base and solvent at 110 °C for
16
h.
First, the reaction of 1a and 2a in water in the presence of oxygen
but without Rh complex and base was carried out; no product 3aa
was observed. In the presence of [Cp*Rh(MeCN)3][BF4]2, but
without a base, the reaction gave 3aa in 38 % yield (entry 1). The
use of base greatly improves the product yield. Among the bases
examined (entries 2- 10), K2CO3 is most effective furnishing 3aa in
92 % yield. Other bases such as NaOAc, and NaOH are also active
affording product 3aa in 72 and 65% yields, respectively. Product
3aa was thoroughly characterized by its 1H and 13C NMR and mass
spectral analysis and the structure was further confirmed by the
result of single-crystal X-ray diffraction.13
Entry
Additive
Solvent
Yield [%]b
3aa
1
2
-
H2O
H2O
38
46
NaHCO3
NaPiv
K2CO3
K2CO3
K2CO3
NaOH
NH4OAc
KOH
3
H2O
56
The choice of solvents is also vital to the catalytic reaction. To
our surprise, of the solvent examined, water was found to be most
effective for the reaction of 1a and 2a affording 3aa in 92% yield
(Table 1, entry 4). In addition, at the end of reaction and upon
cooling of the reaction, 3aa directly precipitated out from the
aqueous solution. Other solvents such as t-amyl alcohol, methanol
also effective giving 3aa in 51 and 65 % yields, respectively. DMF,
and toluene were ineffective for the catalytic reaction (entries 13-
14). Notably, when the reaction was carried out without solvent,
product 3aa was formed in 5% yield (entry 15).
3
H2O
58c
94 (92)
94d
65
4
H2O
5
H2O
6
H2O
7
H2O
33
8
H2O
52
To evaluate the scope of the present reaction, we examined the
reaction of various N-alkyl benzamides (1a-1e) with 2a under the
optimized reaction conditions (Table 1). Thus, N-methyl (1a), N-
ethyl (2b), N-phenyl (2c), and N-benzyl (2d) benzamide and N-
phenyl p-methoxybenzamide (1e) reacted with 2a to afford the
corresponding Isoquinolones 3aa-3ea, respectively, in 75-92 %
yields.
9
Na2CO3
NaOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
H2O
47
10
11
12
13
14
15
H2O
72
t-AmOH
MeOH
DMF
toluene
-
51
65
7
0
5
a
Unless otherwise mentioned, all reactions were carried out using N-
methylbenzamide 1a (0.40 mmol), 1,2-diphenylethyne 2a (0.50 mmol),
[Cp*Rh(MeCN)3][BF4]2 (4.0 mol%), additive (0.20 mmol), oxygen balloon (1
atm, ~ 1.5 L)) and solvent (2.0 mL) at 110°C for 16 h. b Yields were measured
by 1H NMR, using mesitylene as an internal standard. The value in the
d
parenthesis is isolated yield. c 0.10 mmol of K2CO3 was used. Air was used
instead of oxygen.
The rhodium-catalyzed synthesis of isoquinolones via oxidative
annulation of N-alkyl benzamides with alkynes is known to depend
greatly on the reaction conditions.2,6,8,12 To understand the nature
of this reaction and to find the optimized reaction conditions, the
effect of solvent and base was examined using N-methyl-benzamide
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan.
E-mail: chcheng@mx.nthu.edu.tw; Fax: +886-3-5724698; Tel: +886-3-5721454.
† Electronic Supplementary Information (ESI) available: Experimental procedures,
Compound characterization, and copies of 1H and 13C NMR spectra. See
DOI: 10.1039/x0xx00000x
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dimethoxy-N-methylbezamide (1r) gives the expected product 3ra
in 86%, whereas N-methylbenzo[d][1,3]dioxole-5-carboxamide (1s)
reacted with 2a to give annulated product 3sa in 85 % yield in which
C−H activation also take place at the hindered side C2. Whereas
when we tested primary benzamide (PhC(O)NH2) with 2a under the
standard conditions, we observed twofold coupled alkyne product
3ta in 7%. The reaction is slow compared with N-substituted
benzamides (See more details in P. S13, Supporting Information).
Table 2. Scope of Rh-catalyzed reaction of benzamide with 2a in water.
Table 3. Scope of Rh Catalyzed reaction of alkyne in water.
a
Unless otherwise mentioned, all reactions were carried out using
After screening different benzamides, we also tested different
alkynes with 1a. Thus, symmetrical diarylalkynes including 4-methyl
(2b), 4-methoxy (2c), 4-trifluoromethyl (2d), 4-bromo (2e), and 4-
fluro (2f) substituted diarylalkynes reacted with 1a smoothly to give
products 3ab-f, respectively. The reaction of di(2-thienyl)alkyne, 2g
and 4-octyne (2h) also provided the corresponding Isoquinolones
(3ag-h) in good yields, whereas unsymmetrical alkynes 2i and 2j
gave highly regioselective products 3ai and 3aj, respectively, with
the insertion of the aryl substituted carbon attached to 3-position.
Unsymmetrical alkyne carrying an electron withdrawing group such
as ethyl 3-phenylpropiolate (2k) reacts with 1a to product 3ak, of
which the structure were further confirmed by single-crystal X-ray
diffraction.13 Unfortunately, terminal alkyne such as phenyl
acetylene does not undergo the expected annulation on reaction
with 1a.
benzamide 1a-s (0.40 mmol), 1,2-diphenylethyne 2a (0.50 mmol),
[Cp*Rh(MeCN)3][BF4]2 (4.0 mol%), K2CO3 (0.20 mmol), air (or oxygen)
balloon (1 atm, ~ 1.5 L) and water (2.0 mL) at 110°C for 16 h. b isolated yield.
c O2 was used instead of air.
It is noteworthy that we have tested some of the reactions using
dioxygen and using air and in most cases, the products yield are
close (see Table 2).
Next we tested the substituent effect of N-methyl benzamides
on the reaction with 2a. Thus, benzamide derivatives bearing 4-
methyl (1f), 4-methoxy (1g), 4-chloro (1h), 4-trifluromethyl (1i) and
4-t-butyl (1j) on the benzene ring reacted with 2a effectively under
the standard conditions to provide the corresponding products
(3fa-3ja) in 72-84 % yields. The reactions of ortho substituted N-
methyl benzamide (1k-1m) with 2a also proceeded smoothly to
afford 3ka-3ma, but in slightly lower yields compared with the
Moreover, we conducted intermolecular competition
experiment between electron rich (1f) and deficient benzamide
(1g). Interestingly, we found electron-rich benzamide is more
reactive than electron-deficient benzamide in the reaction with
alkyne 2a. In contrast to the observation, electron more deficient
alkyne 2a is more reactive than the electron rich 4-octyne (2h) in
corresponding
para-substituted
products.
Further,
2,3-
dimethoxybenzamide 1n gives the expected product 3na in 88 %.
Extension of this reaction to thiophene-2-carboxamide 1o was also
successful giving 3oa in 76 % yield.
To know the regioselectivity of meta-substituted N-methyl
benzamides, we investigated the reactions of 1p and 1q with 2a. To the reaction with benzamide 1a to give the corresponding
isoquinolones.
our surprise, N-methyl 3-flurobenzamide (1p) reacted with 2a
efficiently to afford 3pa with the C−H bond activation and
annulation occurring majorly at the 2-position of the benzene ring.
In contrast, for N-methyl 3-methylbenzamide (1q), the C−H bond
activation occurred at the 6-position. This selectivity is caused by
effective steric shielding of such group, in a similar fashion, 3,4-
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that the ortho C-H bond cleavage is involved but is likely not the
rate limiting step.14
On the basis of the metal-catalyzed cyclization reaction and
synthesis of heterocyclic compounds,
a possible reaction
mechanism is proposed in Scheme 4 to account for the present
catalytic reaction.7,8 By using 1a and 2a as the substrates, the
catalytic reaction starts with the coordination of 1a to the rhodium
center to form intermediate I. NH deprotonation and CH activation
provides a five membered rhodacycle II. Further coordination of
alkyne 2a, followed by insertion (IV) and reductive elimination
affords the final product 3aa and a Rh(I) species (V). The latter is
protonated (VI) and then oxidized by dioxygen to regenerate the
catalytically active Rh(III) species.
To find further support this proposed mechanism, we carried
out the catalytic reaction of 1a with 2a under the standard reaction
conditions except that D2O is the solvent and the rhodium catalyst
[Cp*Rh(MeCN)3][BF4]2 is increased to 10 mol% to ensure the
detection of the rhodium species. The 1H NMR measurements of
the catalytic reaction show that only Cp*Rh(S)3]2+is present in the
catalytic solution, where S are solvent and MeCN. The results
indicate that Rh(III) species Cp*Rh(S)3]2+ are the resting state of
rhodium catalyst during the catalytic reaction. Therefore, further
reaction of this rhodium species with 1a likely determines the
turnover rate of this catalytic reaction.14 A possible rate-limiting step
is the coordination of 1a via the NHMe group to
Cp*Rh(S)3]2+replacing one of the solvent molecule to give
intermediate I. With the weak basicity of the electron lone pair on
the nitrogen atom of 1a, the coordination is likely weak and
dissociation should occur readily in a reversible manner. This
reversible coordination of 1a likely keeps the concentration of
intermediate I relative to Cp*Rh(S)3]2+ at low ratio.
Scheme 2 Intermolecular Competition Experiment.
To understand the mechanism of the catalytic reaction, we studied
ortho H/D exchange of 1a-d5 with H2O by heating the substrate in
H2O at 110°C in the absence of 2a (Scheme 3, eq 1).14 The H NMR
1
spectrum of 1a-d5 after reaction revealed extensive D/H exchange
showing D : H = 7 : 93 at both ortho positions of the phenyl ring
indicative of reversible C-H activation in the absence of alkyne.
Scheme 3. Mechanistic studies.
In contrast, when the reaction of 1a-d5 with 2a was performed in
H2O, no hydrogen was incorporated into the ortho benzo group of
the product (Scheme 3, eq.2). The results suggest that alkyne
insertion is much faster than the reverse C–H activation step. In
addition we carried out intermolecular competition and parallel
experiments for the reaction of equimolar amount of 1a-d5 and 1a
with 2a for 30 min (eq.3). The experiment gave an intermolecular
kinetic isotope effect (kH/kD) of 2.5 and 1.3 for competition and
parallel experiments, respectively, measured by 1H NMR
Integration. We also carried out the intramolecular competition of
the reaction of 1a-d1 with 2a. A kH/kD of 3.7 (eq 4) was observed.
The small kinetic isotope effects of parallel experiment suggests
Scheme 4. Proposed catalytic cycle.
The significance of this Rh-catalyzed annulation reaction is
demonstrated by its application to the one-pot synthesis of 3-
dimethylaminomethyl-6-methoxy-2-methyl-4-phenyl-isoquinolin-
1(2H)-one (ISQ-1),11 an anti-cardiac arrhythmias used for treatment
of cardiac atrial fibrillation. Thus the reaction of 4-methoxy N-
methyl benzamide with N,N-dimethyl-3-phenyl prop-2-yn-1-amine,
2l, under standard conditions provided the isoquinolone derivative
3fl in 82 % yield in a highly regioselective manner; no other isomer
4 | J. Name., 2012, 00, 1-3
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Ellman, Chem. Rev., 2010, 110, 624; e) J. Wencel-Delord, T.
Droge, F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740; f)
C.-J. Li, Chem. Rev., 2005, 105, 3095.
was detected in this catalytic reaction. The regiochemistry of
product 3fl was confirmed by NOE experiments and the structure
was further confirmed by the results of single crystal X-ray
diffraction. It is noteworthy that the regiochemistry of the insertion
of alkyne 2l is in contrast to that of alkynes 2i and 2j (see Table 3)
and we speculate that the nitrogen of substrate 2l is coordinated to
rhodium in intermediate (III) prior to insertion leading to opposite
regioselectivity for insertion and product 3fl. The unusual
regiocontrol by a directing group built in the alkyne substrate was
known before.15
2. Selected reviews see: (a) R. Jazzar, J. Hitce, A. Renaudat, J.
Sofack-Kreutzer and O. Baudoin, Chem. Eur. J., 2010, 16, 2654;
b) M. C. Willis, Chem. Rev., 2010, 110, 725. c) G.-F. Zha, H.-L.
Qin, E. Kantchev and A. B. Assen, RSC Adv., 2016, 6, 30875
3. Selected reviews on first-row transition metals; (a) A. A.
Kulkarni and O. Daugulis, Synthesis, 2009, 4087; (b) N. Yoshikai,
Synlett, 2011, 1047.
4. (a) B. Li and P. H. Dixneuf, Chem. Soc. Rev., 2013, 42, 5744; (b)
C. Fischmeister and H. Doucet, Green Chem., 2011, 13, 741; (c)
J. Zhang, H. Qian, Z. Liu, C. Xiong, Y. Zhang, Eur. J. Org. Chem.
2014, 36, 8110; (d) G. Zhang, H. Yu, G. Qin, H. Huang, Chem.
Commun., 2014, 50, 4331; (e) Y.H. Xu, T. He, Q.C. Zhang, T.P.
Loh, Chem. Commun., 2014, 50, 2784. (f) N.S.Upadhyay, J.
Jayakumar, C.-H Cheng, Adv. Synth.Catal. 2016, 358, 3381. (g)
N. S.Upadhyay, J. Jayakumar, C.-H Cheng, Chem.Commun.
2017, 53, 2491. (h) H. Gong, H. Zeng, F. Zhou and C.-J. Li
Angew. Chem. Int. Ed., 2015, 54, 5718.
Scheme 5. Synthesis of 3-dimethylaminomethyl-6-methoxy-2-methyl-4-
phenyl-2H isoquinolin-1-one.
I
mportantly, the methodology can be carried out on a gram
5. (a) K. Muralirajan, R. Haridharan, S. Prakash and C.-H. Cheng,
Adv. Synth. Catal. 2015, 357, 761; (b) K. Parthasarathy and C.
Bolm, Chem. Eur. J., 2014, 20, 4896.
scale reaction, and 3aa was isolated in 86 % yield. We have
evaluated the green chemistry metrics16 for the synthesis of
isoquinolones (3aa) on preparative scale with E factor of 10.5,
99.4% atom economy, 85.5% atom efficiency, 100% carbon
efficiency, and 85.8% reaction mass efficiency, which are better
than existing methods8a (see more details in P. S10, Supporting
Information).
6. a) C.-C. Liu, K. Parthasarathy and C.-H. Cheng, Org. Lett., 2010,
12, 3518; b) S. Maity, S. Agasti, A. M. Earsad, A. Hazra and D.
Maiti, Chem. Eur. J., 2015, 21, 11320; c) M. Moselage, J. Li and
L. Ackermann, ACS Catal., 2016, 6, 498; d) G. Sivakumar, A.
Vijeta and M. Jeganmohan, Chem. Eur. J., 2016, 22, 5899.
7. Salt synthesis see (a) J. Jayakumar, K. Parthasarathy and C.-H.
Cheng, Angew. Chem., Int. Ed., 2012, 51, 197; (b) K.
Muralirajan and C.-H. Cheng, Chem. Eur. J., 2013, 19, 6198; (c)
C.-Z. Luo, P. Gandeepan, J. Jayakumar, K. Parthasarathy, Y.-W.
Chang and C.-H. Cheng, Chem. Eur. J., 2013, 19, 14181; (d) G.
Zhang, L. Yang, Y. Wang, Y. Xie and H. Huang, J. Am. Chem.
Soc., 2013, 135, 8850; (e) C.-Z. Luo, J. Jayakumar, P.
Gandeepan, Y.-C. Wu and C.-H. Cheng, Org. Lett., 2015, 17,
924; f) R. P. Korivi, Y.-C. Wu and C.-H. Cheng, Chem. Eur. J.,
2009, 15, 10727-10731.
8. Selected examples of Rh(III)-catalyzed C-H activation: a) T. K.
Hyster and T. Rovis, J. Am. Chem. Soc., 2010, 132, 10565; b) N.
Guimond, C. Gouliaras and K. Fagnou, J. Am. Chem. Soc., 2010,
132, 6908; c) N. Guimond, S. I. Gorelsky and K. Fagnou, J. Am.
Chem. Soc., 2011, 133, 6449; d) T. Satoh and M. Miura, Chem.
Eur. J., 2010, 16, 11212; e) S. Mochida, N. Umeda, K. Hirano, T.
Satoh and M. Miura, Chem. Lett. 2010, 39, 744. f) G. Song, D.
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2012, 48, 3236.
In conclusion, we have developed the first rhodium catalyzed
oxidative annulation reaction of alkynes and benzamides through C-
H bond activation in water using oxygen as the sole oxidant. It is
interesting to note that water is the most effective solvent in this
catalytic reaction giving much higher catalytic activity than organic
solvents. The catalytic reaction proceeds with high regioselectivity
and is accomplished through N−H and C−H bond cleavage, and C−C
and C−N bond formation. Moreover, the applications of this
methodology is successfully applied to the total synthesis of
bioactive compound 3-((dimethylamino)methyl)-6-methoxy-2-
methyl-4-phenylisoquinolin-1(2H)-one, 3fl with 82 % excellent yield.
Further studies towards inexpensive oxidant to catalyzed oxidative
C-H bond functionalization are underway in our laboratory by using
metal and water as a medium.
9. Selected examples of Ru(II)-catalyzed C-H activation: a) L.
Ackermann, A. V. Lygin and N. Hofmann, Angew. Chem., Int.
Ed., 2011, 50, 6379; b) R. Manikandan, P. Madasamy and M.
Jeganmohan, Chem. Eur. J., 2015, 21, 13934; c) K.
Parthasarathy, N. Senthilkumar, J. Jayakumar and C.-H. Cheng,
Org. Lett., 2012, 14, 3478; d) L. Ackermann and S. Fenner, Org.
Lett., 2011, 13, 6548; e) B. Li, H. Feng, S. Xu and B. Wang,
Chem. Eur. J., 2011, 17, 12573; f) L. Ackermann, A. V. Lygin and
N. Hofmann, Org. Lett., 2011, 13, 3278; g) R. Manoharan and
M. Jeganmohan, Chem. Commun., 2015, 51, 2929; h) P. B.
Arockiam, C. Fischmeister, C. Bruneau and P. H. Dixneuf, Green
Chem., 2011, 13, 3075.
Acknowledgement
We thank the Ministry of Science and Technology of the Republic of
China (MOST 104-2633-M-007-001) for support of this research.
Notes and references
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6 | J. Name., 2012, 00, 1-3
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