Ruthenium-catalyzed highly regioselective cyclization of ketoximes with alkynes by C-H bond activation: A practical route to synthesize substituted isoquinolines

Article abstract of DOI:10.1021/ol301091z

Aromatic and heteroaromatic ketoximes underwent cyclization with alkynes in the presence of a catalytic amount of [{RuCl₂(p-cymene)} ₂] and NaOAc to give isoquinoline derivatives in good to excellent yields in a highly regioselective

Full text of DOI:10.1021/ol301091z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ruthenium-Catalyzed Highly
Regioselective Cyclization of Ketoximes
with Alkynes by CÀH Bond Activation: A
Practical Route to Synthesize Substituted
Isoquinolines
Ravi Kiran Chinnagolla, Sandeep Pimparkar, and Masilamani Jeganmohan*
Department of Chemistry, Indian Institute of Science Education and Research,
Pune 411021, India
mjeganmohan@iiserpune.ac.in
Received April 25, 2012
ABSTRACT
Aromatic and heteroaromatic ketoximes underwent cyclization with alkynes in the presence of a catalytic amount of [{RuCl2(p-cymene)}2] and
NaOAc to give isoquinoline derivatives in good to excellent yields in a highly regioselective manner.
Isoquinoline derivatives are an important class of het-
erocyclic compounds.1 This core is present in various bio-
logically active molecules and natural products.1 In the
literature, several methods are available to synthesize
isoquinoline derivatives.2 Palladium- or nickel-catalyzed
cyclization of o-halobenzimines with carbonÀcarbon π-
components is one of the promising methods to synthesize
isoquinoline derivatives.3 However, in these reactions, a
preactivated halogen group such as I or Br was used to
activate the ortho-carbon of the aromatic imines.
Rhodium(I)-catalyzed chelation-assisted CÀH bond ac-
tivation of aromatic and alkene imines or oximes followed
by alkenylation with alkynes and subsequent intramole-
cular electrocyclization providing isoquinolines and pyr-
idines have been reported by the Jun, Cheng, and Ellman
groups.4,5 In these reactions, the ortho aromatic or alkene
CÀH bond was activated by imine or oxime directing
groups instead of using a preactivated halogen group.
Later, Fagnou et al. and Miura et al. reported a rhodium-
(III)-catalyzed cyclization of benzaldimines with alkynes
by CÀH bond activation.6a,b Subsequently, Cheng’s group
established a nice method to synthesize isoquinolinium
salts from aromatic aldehydes, amines and alkynes in the
presence of rhodium(III) catalysts by CÀH bond activation.6c
(1) (a) Heterocycles in Natural Product Synthesis; Majumdar, K. C.,
Chattopadhyay, S. K., Eds.; Wiley-VCH: New York, 2011. (b) The
Chemistry of Hetrocyclic Compounds: Isoquinolines; Coppola, G. M.,
Schuster, H. F, Eds.: John Wiley & Sons: New York, 1981; Vol. 38, Part 3.
(2) (a) Bischler, A.; Napieralski, B. Ber. Dtsch. Chem. Ges. 1893, 26,
1903. (b) Fritsch, P. Ber. Dtsch. Chem. Ges. 1893, 26, 419. (c) Pomeranz,
C. Monatsh. Chem. 1893, 14, 116. (d) Pictet, A.; Spengler, T. Chem. Ber.
1911, 44, 2030.
(3) Reviews: (a) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285.
(b) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. Selected
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(d) Huang, Q.; Hunter, J. A.; Larock, R. C. Org. Lett. 2001, 3, 2973.
(e) Roesch, K. R.; Zhang, H.; Larock, R. C. J. Org. Chem. 2001, 66, 8042.
(f) Korivi, R. P.; Cheng, C.-H. Org. Lett. 2005, 7, 5179. (g) Korivi, R. P.;
Wu, W.-J.; Cheng, C.-H. Chem.;Eur. J. 2009, 15, 10727. (h) Korivi, R. P.;
Wu, W.-J.; Cheng, C.-H. Chem.;Eur. J. 2010, 16, 282.
(4) Reviews for oxidative cyclization: (a) Thansandote, P.; Lautens,
M. Chem.;Eur. J. 2009, 15, 5874. (b) Satoh, T.; Miura, M. Chem.;Eur.
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Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624.
(5) (a) Lim, S.-G.; Lee, J. H.; Moon, C. W.; Hong, C. J.-B.; Jun, C.-H.
Org. Lett. 2003, 5, 2759. (b) Parthasarathy, K.; Jeganmohan, M.; Cheng,
C.-H. Org. Lett. 2008, 10, 325. (c) Parthasarathy, K.; Cheng, C.-H. J.
Org. Chem. 2009, 74, 9359. (d) Parthasarathy, K.; Cheng, C.-H. Synth-
esis 2009, 8, 1400. (e) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2008, 130, 3645. (f) Martin, R. M.; Bergman, R. G.; Ellman,
J. A. J. Am. Chem. Soc. 2012, 77, 2501.
r
10.1021/ol301091z
XXXX American Chemical Society

Chiba’s group reported a Rh(III)-catalyzed cyclization of
aryl ketone O-acyloximes with alkynes by CÀH bond
activation.6dÀf Very recently, Rovis et al. and Li et al.
demonstrated a rhodium-catalyzed cyclization of aromatic
ketoximes with alkynes by CÀH bond activation.6g,h
Although several reports have been known to synthesize
isoquinolines by CÀH bond activation in the literature, the
control of regioselectivity in the cyclization of ketoximes
with unsymmetrical alkynes is still a challenging task. In all
reported reactions, a mixture of regioisomeric products was
observed in most of the unsymmetrical alkynes (except
1-phenyl-1-propyne). In all these reactions, only rhodium
complexes were used as catalysts.
Scheme 1. Substituted Ketoximes Scope
Recently, a less-expensive ruthenium catalyst has been
widely used in the cyclization reaction because of its
remarkable regioselectivityand the low costofthe metal.7,8
To the best of our knowledge, there is no report discussing
the complete regioselective synthesis of isoquinolines by
cyclization of ketoximes with unsymmetrical alkynes.
Herein, we report a highly regioselective cyclization of
aromatic and heteroaromatic ketoximes with substituted
alkynes in the presence of catalytic amount of [{RuCl2-
(p-cymene)}2] and NaOAc to afford highly substituted
isoquinoline derivatives in good to excellent yields. The
present catalytic reaction was compatible with various
sensitive functional groups substituted unsymmetrical inter-
nal as well as terminal alkynes. In all cases, the correspond-
ing isoquinoline derivatives were observed in a highly
regioselective manner. It is important to note that terminal
alkynes were also compatible for the present reaction. The
proposed mechanism of the cyclization reaction was
strongly supported by isolation of a key five-membered
ruthenacycle intermediate. Experimental evidence was also
provided to support the proposed mechanism.
regioselective manner (Scheme 1). The cyclization of o-
methyl 4-bromoacetophenone oxime (1b) and o-acetyl
4-bromoacetophenone oxime (1c) with 2a under similar
reaction conditions was also examined. In case of o-methyl
oxime 1b, the corresponding cyclization product 3a was
observed in 70% yield, whereas no cyclization product 3a
was observed in case of o-acetyl oxime 1c (for optimization
studies, see the Supporting Information). The cyclization
of 4-iodoacetophenone oxime 1d, 4-chloroacetophenone
oxime 1e, and 4-methoxyacetophenone oxime 1f with
1-phenyl-1-propyne (2a) gave isoquinoline derivatives
3bÀd in excellent yields with very high regioselectivity.
The effect of changing the methyl group in acetophenone
oxime to some other groups such as ethyl, isopropyl, and
phenyl was also investigated. Thus, propiophenone oxime
1g, isobutyrophenone oxime 1h, and benzophenone oxime
1i efficiently underwent cyclization with 2a to provide
isoquinoline derivatives 3eÀg in 78%, 84%, and 82% yields,
respectively. Next, the regioselectivity of unsymmetrical
aromatic ketoximes 1jÀl with an unsymmetrical alkyne,
1-phenyl-1-propyne (2a), was examined. Thus, 3,4-dimeth-
oxyacetophenone oxime 1j reacted with 2a regioselectively to
afford 3h in 81% yield. In the substrate 1j, therearetwoortho
aromatic CÀH bonds for cyclization. Regioselectively, the
cyclization takes place at the less hindered CÀH bond of 1j
moiety exclusively. In contrast, 3,4-methylenedioxy aceto-
phenone oxime 1k reacted with 2a to produce a reverse
regioselective product 3i exclusively in 79% yield. In 1k also,
there are two ortho aromatic CÀH bonds for cyclization.
However, oxidative cyclization takes place at the sterically
hindered CÀH bond of 1k moiety predominately. As like 1j,
2-acetonaphthone oxime 1l also underwent cyclization re-
gioselectively with 2a at the less substituted CÀH bond of 1l
A variety of aromatic ketoximes 1 was compatible for
the present cyclization reaction (Scheme 1). When 4-bro-
moacetophenone oxime (1a) was treated with an unsym-
metrical alkyne, 1-phenyl-1-propyne (2a), in the presence
of [{RuCl2(p-cymene)}2](2.5mol%) andNaOAc(25mol%)
in MeOH at 100 °C for 16 h, an isoquinoline derivative
3a was observed in 81% isolated yield in a highly
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(b) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem.
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K. K.; Lee, J.-Y.; Chiba, S. Angew. Chem., Int. Ed. 2011, 50, 5927. (g)
Zhang, X.; Chen, D.; Zhao, M.; Zhao, J.; Jia, A.; Li, X. Adv. Synth.
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Org. Lett. 2011, 13, 3278. (c) Ackermann, L.; Fenner, S. Org. Lett. 2011,
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B
Org. Lett., Vol. XX, No. XX, XXXX

4-bromoacetophenone oxime 1b and o-methyl 4-iodoace-
tophenone oxime underwent cyclization reaction with
1-phenyl-1-butyne (2b), 1-phenyl-1-hexyne (2c) and ethyl
2-butynoate (2f) toprovide the corresponding isoquinoline
derivatives 3k, 3l and 3o in 63%, 65% and 54% yields,
respectively. The catalytic reaction was also tested with
symmetrical alkynes. Thus, diphenyl acetylene (2h) and
3-hexyne (2i) underwent cyclization with 4-bromoaceto-
phenone oxime 1a or benzophenone oxime 1i to afford
isoquinoline derivatives 3r and 3s in 80% and 76% yields,
respectively.
Scheme 2. Unsymmetrical Alkynes Scope
Terminal alkynes were also compatible for the present
cyclization reaction (Scheme 2). Thus, phenylacetylene (2j)
reacted efficiently with 1i to give isoquinoline derivative 3t
in 71% yield in a highly regioselective manner. Similarly,
4-methyl phenylacetylene (2k) and pent-4-yn-1-ol (2l) also
efficiently participated in the cyclization reaction with 1i to
afford the corresponding isoquinoline derivatives 3u and
3v in 70% and 73% yields, respectively, in a highly
regioselective manner. In the reaction, highly substituted
carbon of terminal alkyne was connected to the nitrogen
atom of oxime 1i and terminal carbon of alkyne was
attached to the ortho carbon of oxime 1i. The catalytic
reaction was also tested with heteroaromatic oximes 1m
and 1n (Scheme 2). Treatment of 3-acetylindole oxime 1m
with 2a under the optimized reaction conditions gave
isoquinoline derivative 3w in 78% yield in a highly regio-
selective manner. The o-methyl 3-acetylindole oxime also
underwent cyclization reaction with 2a to provide 3w in
70% yield. 2-Acetylthiophene oxime 1n reacted with 2a
regioselectively to afford the corresponding cyclization
product 3x in 76% yield.
to give 3j in excellent 92% yield. The cyclization reaction of
various substituted o-methyl oximes with 2a was also tested.
Thus, the reaction of o-methyl 4-chloroacetophenone oxime
and o-methyl 4-methoxyacetophenone oxime with 2a pro-
duced corresponding cyclization products 3c and 3d in 73%
and 69% yields, respectively. It is important to note that
cyclization of substituted o-methyl oximes with alkynes
affording isoquinoline derivatives is unprecedented in the
literature.
Scheme 3. Proposed Mechanism
For further understanding the regioselectivity of the
present reaction, cyclization of ketoximes 1 with various
unsymmetrical alkynes was examined under similar reac-
tion conditions (Scheme 2). Unsymmetrical alkynes 1-phe-
nyl-1-butyne (2b), 1-phenyl-1-hexyne (2c), and 1-phenyl-4-
penten-1-yne (2d) reacted with 4-bromoacetophenone
oxime 1a or 4-iodoacetophenone oxime 1d regioselectively
to afford 3kÀm in 72%, 74%, and 55% yields, respectively
(Scheme 2). Surprisingly, bulky benzophenone oxime 1i
reacted efficiently with methyl phenylpropiolate (2e) to
provide the corresponding isoquinoline derivative 3n in
65% yield (Scheme 2). Ethyl 2-butynoate (2f) also reacted
efficiently with 4-iodoacetophenone oxime 1d to afford
isoquinoline derivative 3o in 63% yield in a highly regio-
selective manner. Interestingly, 3-phenyl-2-propyn-1-ol
(2g) also efficiently participated in the cyclization reaction
with 4-bromoacetophenone oxime 1a and propiophenone
oxime 1g to give the corresponding isoquinoline deriva-
tives 3p and 3q in 77% and 81% yields, respectively,
in a highly regioselective manner. Also, o-methyl
On the basis of the known metal-catalyzed CÀH bond
activation,4À8 a reasonable mechanism is proposed to ac-
count for the present cyclization reaction in Scheme 3. The
dissociation of dimeric form of ruthenium complex to mono-
mer followed by ligand exchange with NaOAc gives a
ruthenium acetate species 4 to initiate the catalytic reaction.
Coordination of the nitrogen atom of oxime 1 to the
ruthenium acetate species 4 followed by acetate accelerated
ortho-metalation affords a five-membered metalacycle
Org. Lett., Vol. XX, No. XX, XXXX
C

intermediate 5.9 Coordinative regioselective insertion of
alkyne 2 into the RuÀcarbon bond of intermediate 5
provides a seven-membered intermediate 6. Subsequent
CÀN bond formation and NÀO bond cleavage of inter-
mediate 6 in the presence of MeOH or AcOH affords
product 3 and regenerates the active ruthenium species 4
for the next catalytic cycle.6g,h,7f,9,10 The exact reason for
high regioselectivity is not very clear in the reaction. The
phenyl group of alkyne 2 might coordinates intramole-
cularly with ruthenium metal in intermediate 6 and
stabilizes it. This may be the reason for the high regio-
selectivity.
6 and regenerates the active ruthenium methoxide 4 for the
next ortho-metalation.
On the basis of these studies, the cyclization reaction of
some of the substituted oximes 1 with alkynes 2 was
examined in the absence of NaOAc and only in the
presence of [{RuCl2(p-cymene)}2] (2.5 mol %) in MeOH
at 100 °C for 16 h. The observed results showed that some
reactions such as propiophenone oxime 1g and isobutyr-
ophenone oxime 1h with 1-phenyl-1-propyne (2a) gave the
corresponding isoquinoline derivatives 3e and 3f in excel-
lent 79% and 82% isolated yields, respectively, even in the
absence of NaOAc (Scheme 1). But, in other oximes such as
benzophenone oxime 1i and 2-acetonaphthone oxime 1l with
2a, isoquinoline derivatives 3g and 3j were observed only in
25% and 62% yields, respectively (Scheme 1). In the remain-
ing reactions such as benzophenone oxime 1i with methyl
phenylpropiolate (2e) or phenylacetylene (2j), cyclization
compounds 3n and 3t were observed only in very low 25%
and 10% yields, respectively (Scheme 2). In the reaction of
benzophenone oxime 1i with 3-hexyne (2i), no cyclization
compound 3s was observed (Scheme 2). Based on these
observations, we conclude that OAcÀ anion is an efficient
base to initiate the catalytic reaction when compared to ClÀ
anion, which is present in the ruthenium catalyst.
The proposed mechanism in Scheme 3 is strongly sup-
ported by the isolation of key ruthenacycle intermediate 5a
(eq 1). When o-methyl 4-bromoacetophenone oxime (1b)
was treated with stoichiometric amount of [{RuCl2(p-
cymene)}2] and NaOAc in MeOH at 100 °C for 16 h, a
five-membered ruthenacycle intermediate 5a was observed
in 69% yield (eq 1). The structure of complex 5a was
determined by single crystal X-ray diffraction (see the
Supporting Information). Subsequently, when intermedi-
ate 5a was treated with alkyne 2a in the presence of MeOH
at 100 °C for 10 h, an isoquinoline derivative 3a was
obtained in 95% yield. In the present cyclization reaction
of oximes 1 with alkynes 2, only catalytic amount of
NaOAc (25 mol %) was used. However, a stoichiometric
amount of NaOAc (1.2 equiv) is crucial for the acetate
mediated ortho-metalation.9 It is likely that during the
CÀN bond formation of intermediate 6, MeOH proto-
nates OH group of intermediate 6 and regenerates the
active ruthenium methoxide catalyst 4 for next catalytic
cycle (assuming that due to the intramolecular coordi-
nation of the nitrogen to ruthenium in intermediate 6,
the OH group at the nitrogen side in intermediate 6 could
be basic character). This assumption is strongly sup-
ported by the following experimental evidence. Treat-
ment of benzophenone oxime (1i) with 1-phenyl-1-
propyne (2a) in the presence of a catalytic amount of
complex 5a (10 mol %) in MeOH at 100 °C for 16 h gave
isoquinoline derivatives 3g in 79% and 3a in 9% yields,
respectively (Scheme 1). In the cyclization reaction,
NaOAc was not used. This result clearly reveals that in
the cyclization reaction, NaOAc provides the OAcÀ
source to the ruthenium species to initiate the ortho-
metalation of the first catalytic cycle. In the subsequent
catalytic cycles, MeOH protonates the OH of intermediate
In conclusion, we have demonstrated a ruthenium-
catalyzed regioselective cyclization of substituted aromatic
and heteroaromatic ketoximes with internal as well as
terminal alkynes in the presence of catalytic amount of
NaOAc to afford isoquinoline derivatives in good to
excellent yields. Further extension of cyclization of sub-
stituted aldoximes with other π-components and a detailed
mechanistic investigation are in progress.
Acknowledgment. We thank the BRNS (2011/20/37C/
07/BRNS), India, for support of this research. R.K.C.
thanks the CSIR for a fellowship.
Supporting Information Available. General experimen-
tal procedure, CIF information, and characterization
details. This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) Ackermann, L. Chem. Rev. 2011, 111, 1315.
(10) (a) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc.
2011, 133, 6449. (b) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am.
Chem. Soc. 2010, 132, 6908.
The authors declare no competing financial interest.
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