Synthesis of isoquinolines via rhodium(III)-catalyzed dehydrative C-C and C-N coupling between oximines and alkynes

Article abstract of DOI:10.1002/adsc.201000887

Isoquinolines have been synthesized from the redox-neutral dehydrative C-N and C-C cross-coupling between oximines and alkynes using a catalytic amount of (pentamethylcyclopentadiene)rhodium dichloride dimer {[RhCp*Cl ₂]₂} and cesium

Full text of DOI:10.1002/adsc.201000887

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DOI: 10.1002/adsc.201000887
Synthesis of Isoquinolines via Rhodium(III)-Catalyzed
G
À
À
Dehydrative C C and C N Coupling between Oximines and
Alkynes
Xingping Zhang,a,b Dan Chen,b,c Miao Zhao,b Jing Zhao,a,* Aiqun Jia,c,*
and Xingwei Lib,*
a
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093,
Peopleꢀs Republic of China
Fax : (+86)-25-8359-2672; e-mail: jingzhao@nju.edu.cn
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Peopleꢀs Republic of China
b
Fax : (+86)-411-8437-9089; e-mail: xwli@dicp.ac.cn
School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing 210014,
c
Peopleꢀs Republic of China
Fax : (+86)-25-8431-5512; e-mail: jiaaiqun@gmail.com
Received: November 24, 2010; Published online: March 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000887.
Abstract: Isoquinolines have been synthesized from
isoquinolines starting from o-haloaldimines and alk-
ACHTUNGTRENNUNG
ynes.[4] However, in this process, the formation of a
À
À
the redox-neutral dehydrative C N and C C cross-
coupling between oximines and alkynes using a cat-
alytic amount of (pentamethylcyclopentadiene)rho-
dium dichloride dimer {[RhCp*Cl2]2} and cesium
stoichiometric amount of salt can pose a problem.
Our interest in developing synthetic methods using
minimally functionalized substrates led us to investi-
À
À
acetate (CsOAc), a process that involves ortho C
gate an efficient synthesis of isoquinolines via C H
H activation of oximines and subsequent functional-
ization with alkynes. This redox-neutral catalytic
isoquinoline synthesis operates under mild condi-
tions, and is insensitive to moisture or air. A broad
scope of coupling partners has been established,
and a likely mechanism has been suggested.
activation pathway under mild conditions with mini-
mal waste production. It has been realized that rhodi-
À
um catalysts stand out in the area of C C coupling
that proceeds via a C H activation pathway owing to
À
their high functional group tolerance and a wide
range of synthetic utility.[1a,5] In fact, Rh(I) and
RhACTHNUGRTENUNG(III) catalysts have been used for the synthesis of
Keywords: alkynes; arenes; isoquinolines; oxi-
mines; rhodium catalysis
isoquolines in two categories, namely, oxidative and
redox-neutral C C coupling between arenes and al-
À
kynes (Scheme 1). Importantly, interactions between
RhCp* and IrCp* complexes and arenes leading to
À
ortho C H activation have been well studied recently
in both stoichiometric[6] and catalytic reactions. Inde-
Transition metal-catalyzed direct functionalization of pendent work by Fagnou and Miura revealed that
À
the C H bonds of arenes represents a powerful strat- Rh
egy in organic chemistry because it enables rapid and pling between aldimines and alkynes using a Cu(II)
(III)Cp* complexes can catalyze the oxidative cou-
efficient assembly of complex structures.[1] Of these oxidant.[7] Alternatively, Bergman and Ellman,[8]
processes, activation of C H bonds of arenes followed Jun,[9] and Cheng[10] have developed rhodium(I)-cata-
À
by coupling with alkynes has been recognized as an lyzed approaches under redox-neutral conditions
increasingly important tool to construct condensed ar- starting from imines or oximines. However, either a
omatics.[2] Arguably, isoquinolines represent one of two-step process, a relatively high catalyst loading (3–
the most important classes of heterocycles that dis- 5 mol% Rh), or a rather high reaction temperature
play important biological activity.[3] Consequently, var- (130–1508C) is necessary. We now report a rhod
ACHTUNGTRENNUNG
ious metal-catalyzed synthetic methods have been de-
ACHTUNGTRENNUNG
veloped over the years. For example, Larock and co- conditions, where no exclusion of water or air is nec-
workers developed a palladium-catalyzed synthesis of essary.
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Xingping Zhang et al.
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hydroxy substituent can be tolerated (entry 7). In con-
trast, Rovis and co-workers reported that protection
of the hydroxy groups in alkynes is necessary under
RhACTHNUTRGNEUNG
(III)-catalyzed oxidative coupling conditions.[12]
The reaction scope with respect to oximines was
further defined. No coupling reaction occurred be-
ꢀ
tween benzaldehyde oximine and PhC CPh under
ꢀ
the standard conditions. In contrast, PrC CPr reacted
although sluggishly to give 3bb in 39% isolated yield
(entry 8), and most of the unreacted starting materials
were recovered. A broad scope of acetophenone oxi-
mines was investigated in the coupling with
ꢀ
PhC CPh. Simple acetophenone oximine reacted to
give 3ca in 79% isolated yield. Introduction of an
ortho methyl group has a dramatic steric effect and
product 3da was isolated in only 35% yield. It is
likely that the spatial proximity of the two methyl
groups rendered the formation of the metallacyclic in-
termediate high in energy barrier. When a meta-
À
Scheme 1. Rh-catalyzed synthesis of isoquinolines.
We initiated our studies with the cross-coupling be- methyl group is present, the C H functionalization
ꢀ
tween Ph2C=NOH and PhC CPh. A reaction success- occurred selectively at the less hindered position para
fully occurred under mild conditions (608C, MeOH) to the methyl group (entry 11). In addition, the oxi-
with high regioselectivity when [RhCp*Cl2]2 was used mine can be extended to that of 1-acetonaphthanone
as a catalyst in rather low loading (1 mol%) in the (1f), and the product was obtained in high yield. In
presence of a catalytic amount of CSOAC. Thus prod- an attempt to examine the electronic effect of the aryl
uct 3aa was isolated in 92% yield. We noted that cat- group on this coupling reaction, substrate 1i was sub-
À
alytic,
chelation-assisted
C H
activation
of jected to the standard conditions (entry 15). NMR
PhC(O)NHACHTUNGTRENNUNG(OMe) followed by insertion of alkyne analysis of the reaction mixture revealed that two re-
has been reported under this set of reaction condi- gioisomers were obtained in equimolar ratio and each
tions.[11] Here the scope of isoquinoline formation was was isolated in 39% yield. Solid conclusions on the
À
demonstrated using a variety of oximines and internal electronic effect of para substituents on the C H acti-
À
alkynes. As given in Table 1, oximine 1a readily react- vation, however, cannot be drawn because C H acti-
ed with symmetrically substituted alkyl- or arylalk- vation can be complicated by the prior E-Z isomeriza-
ACHTUNGTRENNUNGynes in high isolated yield (entries 1–4). Unsymmetri- tion of 1i.
cally substituted alkynes are also applicable. The in-
sertion of PhC CMe is high in regioselectivity, and probe the electronic effects of the two coupling part-
Two competition reactions were carried out to
ꢀ
3ae was obtained as the only isomeric product in 91% ners on the efficiency of this catalysis. Competition
ꢀ
ꢀ
isolated yield. In contrast, when PhC CPr-n was used, between 1g and 1h for the coupling with PhC CPh
two regioisomeric products can be separately isolated under the optimized conditions could provide infor-
in analytically pure form in 20% and 55% yield mation on the electronic effects of the para substitu-
(entry 6), with the phenyl being disposed adjacent to ent, and NMR analysis of the crude product revealed
the N atom in the major product. The difference in that 3ga and 3ha were obtained in a 3:1 ratio [Eq.
product distribution with respect to the alkyl groups (1)], indicating that a donating group facilitates this
is likely ascribed to the steric effect of the alkyl sub- coupling. Similarly, the competition between alkynes
stituent, and this observed regioselectivity is consis- also revealed that a donating group in the alkyne
tent with that observed in other RhCp*-catalyzed favors this reaction (see Supporting Information).
coupling reactions of internal alkynes.[7,10] It is note- These results are in sharp contrast to Rh
worthy that under these mild reaction conditions the lyzed oxidative coupling of amides with alkynes,
ACHTUNGTRENUN(NG III)-cata-
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Synthesis of Isoquinolines via RhodiumACTHNUTRGNEU(GN III)-Catalyzed Dehydrative C C and C N Coupling
Table 1. Coupling between oximines and alkynes.[a]
[a]
Reaction conditions: acetophenone oximes 1 (1.0 mmol), alkynes 2 (1.3 mmol), [RhCp*Cl2]2
(1 mmol%), CsOAc (30 mmol%), methanol (4 mL), 608C, 16 h.
Isolated yield.
[b]
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Xingping Zhang et al.
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Scheme 2. Possible pathways for the formation of isoquinolines.
where we[13] and Rovis[12] have observed that electron- dergo protonation by an acid (likely the HX generat-
withdrawing groups in both coupling partners facili- ed from the cyclometallation step), leading to water
tated the coupling.
loss and the formation of a Rh(V) species. Subse-
À
Three reaction pathways with a common intermedi- quent C N reductive elimination affords the coupled
ate can be envisioned as given in Scheme 2. Pathway product and regenerates the RhX3 catalyst.
(a) involes all Rh
hydroarylation intermediate, while pathways (b) and nism of this coupling reaction. A possible intermedi-
(c) involve Rh(III)-Rh(I) and Rh(III)-Rh(V) cycles, ate 4 was synthesized and was subjected to the stan-
A
Experiments were carried out to probe the mecha-
A
ACHTUNGTRENNUNG
1
À
respectively. We propose that ortho C H activation of dard conditions. H NMR analysis revealed that es-
an oximine affords a rhodacycle, which undergoes sentially no isoquinoline product was detected and
alkyne insertion to give a seven-membered rhodacy- the starting material was fully recovered [Eq. (2)].
clic intermediate. In pathway (a), subsequent proto- This observation indicated that pathway (a) is unlike-
À
nolysis of the Rh C bond is proposed to afford a hy- ly, and the alkyne hydroarylation product is not in-
droarylation product. Cheng and co-workers have re- volved in the catalytic cycle. This is in contrast to
ported that the isolated olefin intermediate can un- Chengꢀs Rh(I)-catalyzed synthesis of isoquinolines. To
dergo electrocyclization and dehydration to yield the test the likelihood of pathway (b), a mixture of iso-
final product, albeit at a rather high temperature quinoline N-oxide, acetophenone oximine, and
(1508C).[2e,7c,10] In pathway (b), reductive elimination PhC CPh in a 1:1:1.2 ratio was allowed to react
ꢀ
of this common seven-membered rhodacyclic inter- under the standard conditions [Eq. (3)]. As expected,
mediate is proposed to yield a Rh(I) intermediate and the coupled product was obtained in high yield (93%
a hydroxyisoquinolinium species, which can be in NMR yield). However, essentially no isoquinoline
equilibrium with the corresponding isoquinoline N- was detected by GC. The absence of isoquinoline sug-
oxide when a base is present. Either this N-oxide or gested that oxidation of a Rh(I) intermediate, if any,
the isoquinolinium might eventually oxidize the Rh(I) by an N-oxide species seems unlikely.[11] Therefore,
intermediate to regenerate the Rh
furnish the coupled product. In pathway (c), this
common rhodacycle intermediate is proposed to un- pling between oximines and alkynes using a low load-
ACHTUNGTRENNUNG
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Synthesis of Isoquinolines via RhodiumACTHNUTRGNEU(GN III)-Catalyzed Dehydrative C C and C N Coupling
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as the only by-product, and it is not sensitive to mois-
ture or air. A broad scope of coupling partners has
been established. This synthetic method should find
broad applications in the synthesis of related complex
molecules. Further computational studies are under-
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À
way to understand the nature of the C N bond for-
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Experimental Section
Synthesis of 3aa
A Schlenk tube containing CsOAc (29 mg, 0.151 mmol,
30 mol%) and [RhCp*Cl2]2 (3.2 mg, 0.005 mmol, 1 mol%)
was evacuated and was purged with nitrogen. Methanol
(4 mL), ketoxime 1a (100 mg, 0.508 mmol, 1 equiv.), and di-
phenylacetylene (117.7 mg, 0.660 mmol, 1.3 equiv.) were se-
quentially added, and the resulting mixture was stirred at
608C for 16 h, followed by removal of the solvent under re-
duced pressure. Purification was performed by flash column
chromatography on silica gel using EtOAc in hexane to give
isoquinoline 3aa; yield: 166.8 mg (92%). 1H NMR
(500 MHz, CD2Cl2): d=8.06 (d, J=8.0 Hz, 1H), 7.59–7.70
(m, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.42–7.52 (m, 5H), 7.28–
7.34 (m, 5H), 7.20–7.22 (m, 2H), 7.08–7.11 (m, 3H);
13C NMR (125 MHz, CD2Cl2): d=160.2, 150.2, 141.7, 140.4,
138.2, 137.6, 131.9, 131.0, 130.7, 130.6, 130.4, 129.1, 128.9,
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Acknowledgements
We thank the Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, for generous financial support. This
work is supported by the National Basic Research Program
of China (2010CB923303), the National Science Foundation
of China (NSFC) (Grants no. 20902045 and 21072188), and
Program of New Century Excellent Talents in University.
X.L. conceived and designed the experiments. We thank a ref-
eree for suggestions on the revision of our proposed path-
ways.
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