Rhodium(III)-catalyzed C-H activation mediated synthesis of isoquinolones from amides and cyclopropenes

Article abstract of DOI:10.1055/s-0033-1339510

We have developed a synthesis of 4-substituted isoquinolones from the rhodium(III)-catalyzed, C-H activation mediated coupling of O-pivaloyl benzhydroxamic acids and 3,3-disubstituted cyclopropenes. Experiments suggest the formation of a [4.1.0] bicyclic system, which can open under acidic conditions to generate the desired isoquinolone. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339510

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Synlett. Author manuscript; available in PMC 2014 October 23.
Published in final edited form as:
Synlett. 2013 ; 24(14): 1842–1844. doi:10.1055/s-0033-1339510.
Rhodium(III)-Catalyzed C–H Activation Mediated Synthesis of
Isoquinolones from Amides and Cyclopropenes
*
Todd K. Hyster and Tomislav Rovis
Department of Chemistry, Colorado State University, Fort Collins, CO 80526, USA
Abstract
We have developed a synthesis of 4-substituted isoquinolones from the Rh(III)-catalyzed, C–H
activation mediated, coupling of O-pivaloyl benzhydroxamic acids and 3,3-disubstituted
cyclopropenes. Experiments suggest the formation of a [4.1.0] bicyclic-system, which can open
under acidic conditions to generate the desired isoquinolone.
Keywords
C–H activation; heterocycles; isoquinolone; cyclopropene; donor-acceptor cyclopropane
1
Isoquinolones are a ubiquitous motif found in numerous medicinally interesting targets. An
approach to access this core is the Rh(III)-catalyzed coupling of amides with alkynes to
2
2c
2b,d
provide 3,4-disubstituted isoquinolones. Early reports by our group and others
found
that terminal alkynes were incompatible with the oxidative reaction conditions because of
unwanted Glaser-type couplings. In contrast, when an internal oxidant is utilized, terminal
2e
alkynes can be used to provide 3-substituted isoquinolones in excellent yield. Glorius
expanded on this work by using MIDA-boronate terminal alkynes to access 3-MIDA
2f
boronate-substituted isoquinolones. Absent from these reports is the ability to access 4-
substituted isoquinolones (Figure 1).
We imagined this substitution pattern could be accessed through formation of an
3
intermediate donor–acceptor cyclopropane. We were intrigued by some recent reports on
4
the use of nitrogen donors on activated cyclopropanes. We speculated that 3,3-
disubstituted-cyclopropenes could be coupled to benzhydroxamic acids to generate a [4.1.0]
bi-cyclic heterocycle. In the presence of either a carboxylic acid or the Lewis acidic Rh(III)
catalyst, the resultant cyclopropane could be opened to generate a 4-substituted isoquinolone
(Figure 1). In contrast to previous examples which used alkynylation to achieve
isoquinolones, our approach requires an alkenylation. This reactivity has previously been
2e
5
reported independently by Fagnou and Glorius, and further developed by Rovis and
6
7
8
Ward, Cramer, and Molander.
© Thieme Stuttgart
*rovis@lamar.colostate.edu.

Hyster and Rovis
Page 2
Equation 1
We were pleased to find that O-pivaloyl benzhydroxamic acid 1a could be coupled to
activated cyclopropene 2a in MeOH with CsOAc (200 mol %) and [RhCp*Cl ] (1 mol %)
2 2
to provide the desired 3-substituted isoquinolone 3a in excellent yield (99%) (Equation 1).
The reaction scope is illustrated in Table 1. A variety of para-substituents are tolerated
providing product in excellent yield (Table 1, 3b-3e, 3h). Substitution at the meta-position
provides variable levels of selectivity. Methyl substituted starting materials offer product in
>10:1 regioselectivity in the C–H activation, favoring activation distal to the substituent
(Table 1, 3f). In contrast, methoxy-substituents provide product, but at a 1.1:1 mixture of
regioisomers (Table 1, 3g). Highly electron rich gallic acid derivatives provide product in
excellent yield (Table 1, 3i). Finally, when di-ethyl malonate based cyclopropene is used,
the desired product is isolated in exquisite yield without transesterification.
Unfortunately, our attempts to increase the scope of the cyclopropene component to include
simple mono-activated cyclopropenes failed to provide the desired 4-substituted
isoquinolone. We were, however, able to isolate the [4.1.0] bicyclic intermediate in 60%
yield as a 1.4:1 ratio of inseparable diastereomers (Scheme 1).
Disappointed that the cyclopropane did not open under the reaction conditions, we sought an
alternative method to open the donor-acceptor cyclopropane. When cyclopropanes 4a and
4b were submitted to a 2:1 mixture of 4M HCl in 1,4 dioxane/DCM and heated to 60 °C for
2 hours, the desired isoquinolone 5 was furnished in 95% yield (Scheme 2).
Based on these experiments, we propose that a Rh(III) catalyzed olefination occurs as
described by Fagnou and Glorius to afford the [4.1.0] bi-cycle. We suggest that pivalic acid
or [RhCp*Cl ] , acting as a Lewis acid, catalyzes the opening of the donor acceptor
2 2
cyclopropane to generate an acyl-imine, which tautomerizes to form the desired
isoquinolone. In the absence of two activating groups, a stronger acid is required to achieve
opening.
In conclusion, we have discovered a method to access 4-substituted isoquinolones from
cyclopropenes and amides under Rh(III) catalysis. Isolation of a [4.1.0] bicycle supports the
mechanism occurs in two discrete steps.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Synlett. Author manuscript; available in PMC 2014 October 23.

Hyster and Rovis
Page 3
References
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9. General Proceedure for the synthesis of 3a A 1.5 dram vial was charged with a stir bar, 1a (0.2
mmol), [RhCp*Cl ] (1 mol %), CsOAc (0.4 mmol), and MeOH (1 mL). After stirring for 30
2 2
seconds, cyclopropene 2a (0.22 mmol) was added and the reaction mixture was allowed to stir for 8
hours at 23 °C. Upon completion, as determined by TLC, the reaction mixture was concentrated.
The crude residue was purified via column chromatography (2:1 Hexanes/EtOAc with 1% Et N) to
3
provide the isoquinolone 3a as a white solid (99% yield).
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Hyster and Rovis
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Figure 1.
Proposed approach to access mono-substituted isoquinolones
Synlett. Author manuscript; available in PMC 2014 October 23.

Hyster and Rovis
Page 5
Scheme 1.
mono-activated cyclopropenes
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Hyster and Rovis
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Scheme 2.
Cyclopropane Opening
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Hyster and Rovis
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Table 1
Isoquinolone Scopea
a
Reaction conditions: Amides (1 equiv), cyclopropene (1.1 equiv), [RhCp*Cl ] (1 mol %), CsOAc (200 mol %), MeOH (0.2 M), 23 °C, 8 hours.
2 2
b
Product provided as a 1.1:1 ratio of C-H activation regioisomers.
Synlett. Author manuscript; available in PMC 2014 October 23.