Rh(III)-catalyzed cyclopropanation initiated by C-H activation: Ligand development enables a diastereoselective [2 + 1] annulation of N-enoxyphthalimides and alkenes

Article abstract of DOI:10.1021/ja506579t

N-Enoxyphthalimides undergo a Rh(III)-catalyzed C-H activation initiated cyclopropanation of electron deficient alkenes. The reaction is proposed to proceed via a directed activation of the olefinic C-H bond followed by two migratory insertions, first across the electron-deficient alkene and then by cyclization back onto the enol moiety. A newly designed isopropylcyclopentadienyl ligand drastically improves yield and diastereoselectivity.

Full text of DOI:10.1021/ja506579t

Communication
pubs.acs.org/JACS
Open Access on 08/05/2015
Rh(III)-Catalyzed Cyclopropanation Initiated by C−H Activation:
Ligand Development Enables a Diastereoselective [2 + 1] Annulation
of N‑Enoxyphthalimides and Alkenes
Tiffany Piou and Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
Scheme 1. Reaction Discovery
ABSTRACT: N-Enoxyphthalimides undergo a Rh(III)-
catalyzed C−H activation initiated cyclopropanation of
electron deficient alkenes. The reaction is proposed to
proceed via a directed activation of the olefinic C−H bond
followed by two migratory insertions, first across the
electron-deficient alkene and then by cyclization back onto
the enol moiety. A newly designed isopropylcyclopenta-
dienyl ligand drastically improves yield and diastereose-
lectivity.
Rh(III) mediated C−H activation has proven to be a powerful
approach for the synthesis of nitrogen containing heterocycles.1
Building on a foundation of reactivity first described by Miura
and Satoh2 and Fagnou,3 we4 and others5 reported the coupling
of benzamides with alkynes to form isoquinolones via Rh(III)
C−H activation.6,7 Seminal work by Fagnou8 and Glorius9
demonstrated that an internal oxidant in the form of an N-
pivaloxy substituent leads to efficient Rh(III)-catalyzed C−H
activation giving dihydroisoquinolinones from benzamides and
alkenes (eq 1, Scheme 1). A number of other internal
oxidants10 have been advanced including oximes,11 hydra-
zines,12 and phenoxyamides (eq 2).13 With prominent
exceptions (such as eqs 3 and 4), most of these examples
functionalize arene C−H bonds. Reasoning that the discovery
of novel activation reactions must entail developing new
directing groups, we sought to develop a protocol to activate
vinyl C−H bonds and considered enoxyamides as potential
precursors. The directing group would bear the ubiquitous
amide carbonyl moiety required for activation but, similar to
phenoxyamide directing groups, would result in release of the
amide in the N−O cleavage/Rh reoxidation step. Herein, we
report the development of the first Rh(III)-catalyzed cyclo-
propanation via C−H activation (eq 5). Critical to the success
of this reaction was the design of a monosubstituted
isopropylcyclopentadienyl ligand.
We selected phenyl-N-enoxyphthalimide 1a as a model
fundamental structures in organic chemistry.15 As a result, the
development of new strategies for their synthesis is of foremost
interest, and stimulated our efforts to improve and generalize
this transformation.
Our discovery and initial development of this reaction is
summarized in Table 1. The substrate 1a and ethyl acrylate 2a
substrate, readily accessible using Anderson’s approach (eq
6).14 With a suitable Rh(III)-catalyst, activation of the vinyl C−
H bond could generate seven-membered rhodacycle I, allowing
for further functionalization with a suitable electrophile. To our
surprise, when alkene 2 was used as the coupling partner in
initial screening, intermediate I acted as a one-carbon
component in a [2 + 1] annulation giving the disubstituted
trans-cyclopropane 3. Owing to their prevalence in biologically
active natural and synthetic compounds, cyclopropane units are
Received: June 30, 2014
Published: August 5, 2014
© 2014 American Chemical Society
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Communication
a
Table 1. Cyclopentadienyl Ligands Screen
Table 2. N-Enoxyphthalimide Scope
b
c
entry
Cpx
dr (trans:cis)
yield 3aa (%)
d
1
2
3
4
5
6
7
Cp*
CpCF3
Cp1
2:1
3:1
63
56
27
40
1:1
Cp2
2:1
e
Cpt
CpE
CpiPr
1:1
22
1:1
40
d
12:1
79
a
Conditions: 1a (1.0 equiv), 2a (1.2 equiv), CsOAc (2.0 equiv), [Rh]
b
(5 mol %) in TFE (0.2 M), at 21 °C for 16 h. Determined by analysis
The reactivity of a range of alkenes was examined next
(Table 3). The reaction proceeds smoothly with acrylates 2b−e
c
d
1
1
of the crude H NMR. Determined by H NMR. Isolated yield.
e
Low conversion.
Table 3. Alkene Scope
were submitted to various Rh(III) catalysis conditions. The
initial discovery utilized a mixture of 5 mol % of [Cp*RhCl2]2
and 2 equiv of CsOAc in trifluoroethanol (TFE) at room
temperature to provide trans-1,2-disubstituted cyclopropane
3aa in 63% isolated yield and 2:1 dr (entry 1). Attempts to
optimize the reaction conditions using different bases, solvents,
and Cp*Rh(III) complexes had only a marginal effect on the
diastereoselectivity (data not shown). On the basis of previous
reports by our group and others, we speculated that steric and
electronic tuning of the cyclopentadienyl ligand could
potentially increase selectivity and reactivity. Disappointingly,
the known sterically hindered di-tert-butylcyclopentadienyl
(Cpt)16,6d and electron deficient tetramethyl(trifluoromethyl)-
1 1 e , f
( C p C F 3
)
o r e t h o x y c a r b o n y l - ( C p E ) 1 7
cyclopentadienylrhodium(III) complexes provide no significant
improvement in the level of diastereocontrol (entries 2, 5, and
6). We then focused on the design of new cyclopentadienyl
ligands. Using isopropyl-tetramethyl-(Cp1) and tetramethyl-
(Cp2) cyclopentadienylrhodium(III) complexes failed to
improve the overall efficiency of the reaction (entries 3 and
4). To our delight, we found the isopropylcyclopentadienyl
ligand (CpiPr) affords a high degree of selectivity and reactivity,
furnishing the desired trans-disubstituted cyclopropane 3aa in
79% yield and 12:1 dr (entry 7).
With optimized reaction conditions in hand, the scope of the
cyclopropanation reaction was investigated. Structural varia-
tions on the aryl unit of the N-enoxyphthalimide were
examined (Table 2). Substituents at the para or meta positions,
regardless of their electronic nature (methyl, tert-butyl, fluoro,
and methoxy) exerted no substantial effect on the outcome of
the reaction, providing the corresponding trans-cyclopropanes
(3ba−da and 3fa−ga) in high yields and diastereoselectivities.
The ortho-fluoro substrate was compatible with the reaction
conditions and afforded 3ha in 41% yield and 11.4:1 dr.
Because of their low solubility in the reaction medium,
substrates 1e, 1i, and 1j required longer reaction times. In
contrast with 1j, substrates 1e and 1i were not fully converted
even after 48 h, giving the corresponding products 3ea and 3ia
in 41 and 32% yields, respectively.
and acrylamides 2j−k, all forming the expected trans-
disubstituted cyclopropanes 3ab−ae, 3aj, and 3ak in good to
excellent yields (64−89%) and high diastereoselectivities.
Enones 2f−i are competent coupling partners in the reaction
providing the desired trans-cyclopropanes 3af−ai as the major
isomers in good yields, although with slightly decreased dr.
Acrylonitrile 2l gives the desired cyclopropane 3al in 54% yield
and 10.4:1 dr. We were pleased to find (E)-1,2-disubstituted
alkenes 4 were tolerated under the reaction conditions when
using [Cp*Rh(CH3CN)3](PF6)2 as the precatalyst.18 Methyl
fumarate 4a and (E)-dibenzoylbutene 4b provide the
corresponding 1,2,3-trisubstituted cyclopropanes 5aa and 5ab
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Journal of the American Chemical Society
Communication
as a single diastereoisomer in 81 and 38% yields respectively
(Scheme 2).
preserving the anti relationship of the deuterium atom and ester
(eq 10). Of mechanistic relevance, the reaction of 1a-d7 under
standard reaction conditions gives the trans-cycloadduct with
an important loss of deuterium on the cyclopropane moiety (eq
11). Control experiments performed demonstrate epimeriza-
tion does not take place after the formation of the cycloadduct
3aa in the reaction medium (see Supporting Information).
Thus, we reasoned the deuterium extrusion must occur before
the formation of the final product. Interestingly, the same
reaction with [Cp*RhCl2]2 exhibits a significant loss of
deuterium for both trans and cis-cyclopropanes, suggesting
both diastereomers are formed via similar mechanisms.
Scheme 2. Reaction with (E)-1,2-Disubstituted Alkenes
After exploring the scope of the reaction, we then sought to
study the mechanism of this transformation (Scheme 3).
On the basis of these observations, we propose the following
mechanism (Scheme 4). After formation of the active Rh(III)
Scheme 3. Mechanistic Experiments
Scheme 4. Proposed Mechanism
catalyst I, irreversible C−H activation at the β-position of the
double bond and ligand exchange leads to rhodacycle II.
Subsequent migratory insertion of the alkene 2a generates σ-
alkylrhodium(III) complex III. The latter can then undergo an
intramolecular carborhodation through a 3-exo-trig cyclization
mode to form the intermediate IV. According to the deuterium
labeling experiments (eq 11, Scheme 3), after C−C bond
rotation, β-hydride elimination could give the Rh−hydride
complex V. Then, two distinct pathways can be envisioned.
First, the Rh(III)−hydride V could collapse to form a Rh(I)
complex VI. Oxidative addition of the N−O bond into Rh(I)
following by protonation/tautomerization could liberate the
cycloadduct 3aa and regenerate the active catalyst. Alter-
natively, the Rh(III)−hydride V could reversibly reinsert into
the double bond and undergo a β-elimination with N−O bond
cleavage to close the catalytic cycle.20
To summarize, we have discovered a Rh(III)-catalyzed
cyclopropanation reaction using N-enoxyphthalimides and
alkenes. This reaction is a rare example of Rh(III)-catalyzed
carbocycle synthesis. Through ligand development, we found a
new monosubstituted isopropylcyclopentadienyl ligand enables
a high degree of diastereocontrol in the reaction. The process
allows the synthesis of a wide range of trans 1,2-disubstituted
cyclopropanes. Mechanistic studies revealed an unconventional
reactivity for Rh(III)-catalysis and allows for insight into the
diastereodetermining step of the reaction.
Conducting the reaction in TFE-d1 without 2a led to no
deuterium incorporation on the alkene, suggesting the C−H
functionalization is irreversible (eq 7, Scheme 3). In another
experiment, treatment of 1a and 2a in TFE-d1 gives the
cyclopropane 3aa′ with no deuteration observed on the phenyl
ring, suggesting the C−H functionalization event is chemo-
selective for the double bond at the expense of the neighboring
phenyl ring (eq 8). Since N-enoxyphthalimides (1) are only
partially soluble in the reaction mixture, any attempts to probe
the mechanism of the C−H functionalization step were
rendered inconclusive. However, when experiments were run
without base or with triethylamine in place of cesium acetate,
cyclopropane 3aa is not formed (eq 9), suggesting a concerted-
metalation deprotonation (CMD)19 mechanism is operative.
We believed the insertion of the alkene occurs with complete
retention of stereochemistry since only one diastereomer is
formed when (E)-1,2-disubstituted alkenes (4) are used
(Scheme 2). In agreement with our hypothesis, (E)-d1-ethyl
acrylate (E)-2a-d1 gives cyclopropane 3aa″ as the sole product,
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, compound characterization, and
additional experiments. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
rovis@lamar.colostate.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank NIGMS (GM80442) for generous support and
Johnson Matthey for a generous loan of Rh salts.
■
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