Organic Letters
Letter
a
Scheme 1. Synthesis of Biisoquinolines via C−H Activation
Scheme 2. Scope of Dioximes
unsymmetrical 1,1′-biisoquinolines with high efficiency and
good selectivity.
Initially, benzil dioxime (1a) (BIDG = N−OH/N−OH)
and diphenylacetylene (2a) were selected as the model
substrates, and [RhCp*Cl2]2 (2.5 mol %) was used as a
catalyst. As shown in Table S1, a catalytic amount of NaOAc
proved innocent in the diannulation, and the monoannulated
compound 7 was generated (Table S1, entries 1−3). The
target biisoquinoline 3a was isolated in a good yield of 80%
after chromatography on silica gel when 2 equiv of NaOAc was
used (entry 4). Diannulated 3a was not formed, and only
monoannulated 7 was generated in 20% yield, when the
loading of [Cp*RhCl2]2 was reduced to 1 mol % (entry 5).
The reaction ceased in the absence of [Cp*RhCl2]2 or when
other catalysts (e.g., Ru and Ir) were used instead (entry 6).
Pleasingly, when TsOH·H2O was employed as the additive, 3a
was obtained in an excellent yield of 93% (entry 8). More
interestingly, 3a precipitated from the reaction solvent and
could be gained in a high yield of 87% just by filtration (entry
9).16 When O,O-diacetyl dioxime (1a-diOAc) was used
instead of 1a, 3a was obtained in 96% yield after filtration
With the optimal conditions in hand, the scope of dioximes
was first investigated (Scheme 2). Various symmetrical
dioximes possessing either an electron-donating or electron-
withdrawing functionality (1b−e) could diannulate with 2a
smoothly to deliver the desired 1,1′-biisoquinolines in
moderate to high yields (3b−e). It is noted that although
three regioisomers might be generated from meta-substituted
dioxime in diannulation, here only one type of regioisomer
(3f), annulated at sterically less hindered sites, was generated
in 76% yield. o-Methyl dioxime was not compatible with this
diannulation, which might be due to strong steric hindrance
between the two methyl groups. To our delight, unsymmetrical
dioximes could smoothly react with 2a to give the target
unsymmetrical biisoquinolines 3h−j in good to excellent
yields. To the best of our knowledge, this is the first example of
the synthesis of unsymmetrical 1,1′-biisoquinolines. Notably,
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), [RhCp*Cl2]2
(2.5 mol %), TsOH·H2O (25 mol %), and NaOAc (2 equiv) in
MeOH (2 mL) at 110 °C for 12 h under a N2 atmosphere. Isolated
b
yields after filtration are shown. 1a-diOAc was used instead of 1a.
c
At 120 °C.
all of the products could be obtained simply by filtration
without further processing.
Then the scope of alkynes was tested with 1a and 1a-diOAc
under conditions A and B, respectively (Scheme 3). Both 1a
and 1a-diOAc could react with various alkynes smoothly to
deliver the corresponding 1,1′-biisoquinolines 4b−m in
moderate to excellent yields, and the structure of 4g was
determined by single-crystal X-ray diffraction. Hex-3-yne
reacted with 1a to afford tetraalkyl-substituted molecule 4n
in 77% yield. Upon treatment of alkyl aryl alkynes with 1a, two
types of regioisomers were generated (4o and 4p).
With the success of symmetrical diannulation with the same
alkyne, we turned our attention to one-pot sequential
diannulation with two different alkynes, which needed two
separate steps in previous reports.14 1a was treated with 1
equiv of alkyne 2a under the conditions of [RhCp*Cl2]2 (2.5
mol %) and NaOAc (1 equiv) for 5 h (step 1), and then alkyne
2f, additional NaOAc (1 equiv), and TsOH·H2O (25 mol %)
were added and allowed to react for a further 10 h (step 2).
However, all the three isomers, cross-annulated 5af and
homoannulated 3a and 4f, were generated with poor selectivity
(Scheme 4, eq 1). Also, poor selectivity was observed in the
one-pot, two step reaction of 1a-diOAc, 2a, and 2f (Scheme 4,
eq 2). Finally, we synthesized benzil O-acetyl dioxime (1a-
OH/OAc), a “mixed BIDG” containing one N−OH and one
N−OAc. 1a-OH/OAc was treated with 2a under the
conditions of [RhCp*Cl2]2 (2.5 mol %) and NaOAc (0.3
B
Org. Lett. XXXX, XXX, XXX−XXX