Rh(III)-Catalyzed C-H Activation-Initiated Directed Cyclopropanation of Allylic Alcohols

Article abstract of DOI:10.1021/jacs.9b02156

We have developed a Rh(III)-catalyzed diastereoselective [2+1] annulation onto allylic alcohols initiated by alkenyl C-H activation of N-enoxyphthalimides to furnish substituted cyclopropyl-ketones. Notably, the traceless oxyphthalimide handle serves three functions: Directing C-H activation, oxidation of Rh(III), and, collectively with the allylic alcohol, in directing cyclopropanation to control diastereoselectivity. Allylic alcohols are shown to be highly reactive olefin coupling partners leading to a directed diastereoselective cyclopropanation reaction, providing products not accessible by other routes.

Full text of DOI:10.1021/jacs.9b02156

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Rh(III)-Catalyzed C−H Activation-Initiated Directed
Cyclopropanation of Allylic Alcohols
Erik J. T. Phipps and Tomislav Rovis*
Department of Chemistry, Columbia University, New York, New York 10027, United States
S
* Supporting Information
Scheme 1. Directed Cyclopropanations and Precedent
Involving N-Enoxyphthalimides
ABSTRACT: We have developed a Rh(III)-catalyzed
diastereoselective [2+1] annulation onto allylic alcohols
initiated by alkenyl C−H activation of N-enoxyphthali-
mides to furnish substituted cyclopropyl-ketones. Notably,
the traceless oxyphthalimide handle serves three func-
tions: directing C−H activation, oxidation of Rh(III), and,
collectively with the allylic alcohol, in directing cyclo-
propanation to control diastereoselectivity. Allylic alcohols
are shown to be highly reactive olefin coupling partners
leading to a directed diastereoselective cyclopropanation
reaction, providing products not accessible by other
routes.
iological and synthetic targets containing cyclopropane
Bunits have intrigued organic chemists for years as a result
of their unique properties and the synthetic challenges.1 A
number of powerful methods have been developed for the
stereoselective synthesis of cyclopropane motifs.2 These
methods largely share a common approach of an alkene that
undergoes a [2+1] annulation with carbenes, metal carbenes,
or metal-carbenoid species. In particular, allylic alcohols have
been exploited as coupling partners in cyclopropanation
reactions for their leverageable, pendent hydroxyl group.
Ultimately, this handle provides regio- and diastereoselective
cyclopropanations.
Two methods have emerged as preferred techniques for the
cyclopropanation of alkenes: Simmons−Smith type reactions
and catalyzed diazo decompositions (Scheme 1). The
Simmons−Smith approach features stoichiometric zinc
reagents to aid both the formation and transfer of carbenoid
species from simple methylene sources. Similarly, metal-
catalyzed diazo decomposition is a broadly powerful reactivity
manifold for the cyclopropanation of alkenes, with Rh,3 Ru,4
Pd,5 Cu,6 Co,7 and Fe8 catalysts utilized for their carbenoid
formation and transfer capabilities. Notably, both modes of
reactivity have also been rendered asymmetric when using
prochiral alkenes.9
With regards to allylic alcohols, notable shortcomings have
arisen in the two established methods outlined above. While
Simmons−Smith reactivity is regio- and diastereoselective, it is
largely limited to methylenation:10 substituted methylene
transfer remains underdeveloped. Metal-catalyzed diazo
decomposition fails with allylic alcohols as conversion to
cyclopropanes is low yielding due to competitive O−H
insertion.11
We have previously reported that N-enoxyphthalimides are a
unique one-carbon component for the cyclopropanation of
activated alkenes.12 Furthermore, tuning the cyclopentadienyl
(Cp) ligand on the RhIII catalyst delivers either cis- or trans-
disubstituted cyclopropanes stereoselectively.13,14 In a com-
plementary approach, we found that exchanging trifluoroetha-
nol (TFE) solvent for methanol (MeOH) and again tuning the
Cp ligand on the Rh catalyst, activated alkenes undergo syn-
1,2-carboamination.15 This chemodivergence is hypothesized
to originate from MeOH participating as a nucleophile to open
the phthalimide ring that allows the N-enoxyphthalimide to act
as a bidentate ligand throughout catalysis. On the basis of these
findings, we sought to expand the scope of our reported
Received: February 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b02156
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
cyclopropanation toward unactivated alkenes. Herein, we
report that allylic alcohols undergo directed diastereoselective
cyclopropanation using this approach.
Scheme 2. Selectivity of Cyclopropanation
Initial investigations began with phenyl-N-enoxyphthalimide
1a and trans-2-hexen-1-ol 2a in the presence of various Rh(III)
catalysts in TFE at room temperature delivering cyclopropane
3aa in moderate yield but high diastereoselectivities (Table 1,
a
Table 1. Reaction Optimization
c
Entry
CpX
Cp*
Cp*CF3
Cp*t‑Bu
CpE
Cp*CF3
Cp*CF3
Cp*CF3
Cp*CF3
Base
Solvent
Yield 3aa
1
2
3
4
5
6
7
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOPiv
KOPiv
TFE
TFE
TFE
TFE
MeOH
THF
TFE
TFE
24%
50%
22%
45%
36%
29%
64%
Scheme 3. N-Enoxyphthalimide Scope
d
e
8
81%
a
Conditions: 1a (1 equiv), 2a (1.2 equiv), Base (2 equiv),
[CpXRhCl2]2 (5 mol %), in solvent (0.2M) at 21 °C for 16 h.
b
Determined by the 1H NMR of the unpurified reaction mixture
c
d
Yields determined by 1H NMR. Reactions carried out at 0 °C
e
instead of 21 °C. Isolated yield.
entries 1−4). A solvent (entries 5 and 6) and base screen
revealed that KOPiv in TFE is optimal, providing 64% yield
and >20:1 d.r. for the desired product (entry 7). Furthermore,
we discovered that reducing the reaction temperature to 0 °C
leads to the desired cyclopropane in 81% yield while preserving
excellent diastereoselectivity (entry 8).
We next examined if the diastereoselectivity of the
trisubstituted cyclopropane product was directly correlated
with initial alkene geometry (Scheme 2). Both trans- and cis-
1,2-disubstituted primary allylic alcohols provide the desired
cyclopropanes 3aa and 3ab in good yield−81% and 62%,
respectively, and >20:1 d.r., implicating a stereospecific
transformation with respect to the alkene. Similar to the
parent allylic alcohol, we found crotyl alcohol gives cyclo-
propane 3ac in excellent diastereoselectivity and 81% yield.
Methallyl alcohol gives cyclopropane 3ad in 62% yield with
7.0:1 d.r. while prenyl alcohol furnishes 3ae in 82% yield and
>20:1 d.r. To showcase the regio-preference of our cyclo-
propanation protocol, 1a was subjected to substrate 2f
(geraniol) bearing a tethered trisubstituted alkene as a
potential competitive site for cyclopropanation. Gratifyingly,
cyclopropane 3af was generated in 55% yield with good
diastereoselectivity and excellent regioselectivity.
a
Low conversion at 0 °C, isolated yield at 21 °C
N-enoxyphthalimide16 is also a competent substrate, affording
cyclopropane 3ka in 92% yield.
Next, a range of suitable allylic alcohols for the cyclo-
propanation reaction was explored (Scheme 4). Notably, chiral
allylic alcohol substrates provide additional complexity leading
to the potential of four different stereoisomers. In the event,
these reactions deliver the corresponding cyclopropanes 3ag-
3ai with varying levels of diastereoselectivity depending on the
substituent size, from vinyl (73%, 2.5:1 d.r., major to Σ minor),
to methyl (69%, 7.1:1 d.r.) and phenyl (62%, >20:1 d.r.). Using
trans-1,2-disubstituted secondary allylic alcohols, we observed
single diastereomers of cyclopropanes 3aj−3al in outstanding
yields. Finally, we sought to assess the directing ability of cyclic
allylic alcohols. When cyclohexenol 2m is subjected to the
With optimized conditions in hand, we examined the scope
of this reaction (Scheme 3). Varying para- (3ba−3ea) and
meta- (3fa−3ha) arene substitution on the enoxyphthalimide
is tolerated, with each substrate displaying >20:1 diaster-
eoselectivity. ortho-Fluorine containing enoxyphthalimide
delivers cyclopropane 3ia in 44% yield. An alkyl substituted
B
DOI: 10.1021/jacs.9b02156
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Journal of the American Chemical Society
Communication
Scheme 4. Allylic Alcohol Scope
Scheme 5. Mechanistic Experiments
reaction conditions, no cyclopropane is observed. However,
with cyclooctenol 2n, cyclopropane 3an is afforded in excellent
yield and diastereoselectivity. On the basis of previous
Simmons−Smith cyclopropanations that explore directing
effects of cyclic systems,17 we hypothesize that the larger
ring accommodates the correct C−O bond angle for the
cyclopropanation to occur, affording the same relative
stereochemistry as observed with acyclic allylic alcohols.
To investigate the mechanism of this cyclopropanation
reaction (Scheme 5), we subjected 1a to the reaction
conditions in the absence of alkene with TFE-d1 solvent and
observed no deuteration of the alkenyl protons suggesting that
the C−H activation is irreversible. Homoallylic alcohol 4a
gives cyclopropane 5aa in only 12% yield indicating the chain
length from the oxygen atom to the olefin is of great
importance. Similarly, bis-homoallylic alcohol 6a gives cyclo-
propane 7aa in only 17% yield. Allylic ether 8a is a poor
substrate with only trace 9aa observed indicating the presence
of an unhindered hydroxyl-group is necessary for the reaction
to take place. Allylic carboxylic acid 8b gives cyclopropane 9ab
in trace yield. Interestingly, protected allylic amine 8c gives
cyclopropane 9ac in 77% yield and 9.5:1 d.r. indicating the
importance of the strength of the pendent nucleophile. In
another experiment, we set out to detect potential reactivity
between 1a and 2c in the absence of Rh catalyst and were
surprised to observe the formation of dioxazoline 10ac in 38%
yield with 1 equiv of KOPiv in THF at room temperature. We
speculate this occurs via opening of the phthalimide ring and
acylation of the allylic alcohol (eq 8). Subjecting dioxazoline
10ac to the cyclopropanation reaction conditions did not
afford cyclopropane, suggesting that dioxazoline 10ac is an off-
cycle product.
On the basis of these experiments, we propose the following
mechanism (Scheme 6). First, 2 undergoes acylation with 1
that gives intermediate I. Maintaining the reaction temperature
at 0 °C inhibits cyclization of 10ac, which is instead
intercepted by the active Rh(III) catalyst II. Intermediate I
undergoes irreversible C−H activation via concerted metal-
ation-deprotonation that gives rhodacycle III. At this stage, we
hypothesize the formation of intermediate IV by cleavage of
the N−O bond and formation of a Rh-carbene. Due to the
prior acylation of the allylic alcohol, intermediate V is formed
via the [2+1] annulation where the Rh-carbene is delivered
across the alkene and on the same face as the pendent oxygen
atom in stereoselective fashion. Protodemetalation and
subsequent phthalimide ring closure releases the product and
turns the catalyst over.
In summary, we have developed a directed diastereoselective
cyclopropanation protocol for the [2+1] annulation of N-
enoxyphthalimides and allylic alcohols. The diastereoselectivity
C
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Journal of the American Chemical Society
Communication
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Scheme 6. Proposed Catalytic Cycle
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b02156.
■
S
Experimental descriptions, analytical data, and NMR
spectra (PDF)
Data for C17H16O2 (CIF)
AUTHOR INFORMATION
Corresponding Author
*tr2504@columbia.edu
ORCID
Tomislav Rovis: 0000-0001-6287-8669
Notes
The authors declare no competing financial interest.
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■
ACKNOWLEDGMENTS
■
We thank NIGMS (GM80442) for support. We thank Daniel
Paley (Columbia) for solving the structure of 3ai. Single crystal
X-ray diffraction was performed at the Shared Materials
Characterization Laboratory at Columbia University. Use of
the SMCL was made possible by funding from Columbia
University.
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