Cobalt-Catalyzed Reductive Dimethylcyclopropanation of 1,3-Dienes

Article abstract of DOI:10.1002/anie.201807542

Dimethylcyclopropanes are valuable synthetic targets that are challenging to access in high yield using Zn carbenoid reagents. Herein, we describe a cobalt-catalyzed variant of the Simmons–Smith reaction that enables the efficient dimethylcyclopropanation of 1,3-dienes using a Me₂CCl₂/Zn reagent mixture. The reactions proceed with high regioselectivity based on the substitution pattern of the 1,3-diene. The products are vinylcyclopropanes, which serve as substrates for transition-metal-catalyzed ring-opening reactions, including 1,3-rearrangement and [5+2] cycloaddition. Preliminary studies indicate that moderately activated monoalkenes are also amenable to dimethylcyclopropanation under the conditions of cobalt catalysis.

Full text of DOI:10.1002/anie.201807542

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Title: Cobalt Catalyzed Reductive Dimethylcyclopropanation of 1,3-
Dienes
Authors: Jacob Werth and Christopher Uyeda
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Cobalt Catalyzed Reductive Dimethylcyclopropanation of 1,3-
Dienes
Jacob Werth[a] and Christopher Uyeda*[a]
Abstract: Dimethylcyclopropanes are valuable synthetic targets that
are challenging to access in high yield using Zn carbenoid reagents.
Here, we describe a cobalt-catalyzed variant of the Simmons–Smith
reaction that enables the efficient dimethylcyclopropanation of 1,3-
dienes using a Me2CCl2/Zn reagent mixture. The reactions proceed
with high regioselectivity based on the substitution pattern of the 1,3-
diene. The products are vinylcyclopropanes, which serve as
substrates for transition-metal catalyzed ring-opening reactions,
including 1,3-rearrangements and [5 + 2]-cycloadditions. Preliminary
studies indicate that moderately activated monoalkenes are also
amenable to dimethylcyclopropanation under the cobalt-catalyzed
conditions.
tetrasubstituted carbon atom must be generated. The most
common routes utilize classical carbonyl chemistry and entail
either a double α-alkylation reaction or a double addition of a
methyl nucleophile to a carboxylic acid derivative.[3]
Figure
1.
Rings
containing
gem-dimethyl
groups,
including
dimethylcyclopropanes, are found in biologically active compounds of natural
and synthetic origins.
Figure 2. (a) Simmons–Smith-type dimethylcyclopropanation reactions of allylic
alcohols and Corey–Chaykovsky dimethylcyclopropanation reactions of α,β-
unsaturated carbonyl compounds. (b) Transition metal catalyzed reductive
dimethylcyclopropanation reactions of 1,3-dienes and ring-opening reactions to
generate 5- and 7-membered rings. (c) Proposed mechanism for a transition
metal catalyzed reductive dimethylcyclopropanation reaction.
Geminal dimethylation is a common substitution pattern in
polycyclic terpene natural products.[1] Medicinal chemists have
also explored the installation of dimethyl groups in biologically
active compounds as a strategy to improve their potency or to
eliminate metabolic liabilities.[2] There are now over 50 clinically
approved pharmaceutical compounds that feature these motifs.
The presence of gem-dimethylation in a target compound
introduces significant synthetic complexity in that a hindered
It is attractive to consider an alternative approach based on
the formation of dimethylcyclopropanes,[4] which are themselves
common in biologically active compounds[2, 5] but may also be
diversified into other frameworks through strain-induced ring-
opening reactions.[6] The Simmons–Smith reaction is potentially
well-suited to addressing these structures; however, it is known
that the efficiency of Zn carbenoid-based cyclopropanations
decreases significantly when using disubstituted gem-
dihaloalkanes.[7] For example, the addition of 2,2-diiodopropane
under Furukawa conditions has only been demonstrated for two
simple substrates, cyclopentene and cyclohexene, which provide
yields up to 59% after a reaction time of 5 days.[8] A notable
advance in this area was reported by Charette, who showed that
[a]
J. Werth and Prof. C. Uyeda
Department of Chemistry
Purdue University
West Lafayette, IN 47907, USA
E-mail: cuyeda@purdue.edu
Supporting information for this article is given via a link at the end of
the document.
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directing group effects can be leveraged to achieve a high-
using
transition
metal
catalysis
to
address
the
yielding
dimethylcyclopropanation
of
Corey–Chaykovsky-type
α,β-unsaturated carbonyl
allylic
alcohols.[9]
dimethylcyclopropanation reaction. Here, we report a cobalt-
catalyzed dimethylcyclopropanation of 1,3-dienes using
Me2CCl2/Zn as a source of isopropylidene equivalents.
Additionally,
the
dimethylcyclopropanation
of
compounds has been developed.[10]
The [2,6-i-PrPDI]CoBr2 complex was previously shown to be an
effective catalyst for cyclopropanation reactions using
CH2Br2/Zn;[13] however, it afforded negligible yields in the
analogous reactions using Me2CCl2/Zn (Table 1, entry 7). We
reasoned that the more hindered dimethylcarbene fragment may
require the steric profile of the PDI ligand to be correspondingly
adjusted. Accordingly, a series of ligands was prepared by varying
the size of the flanking aryl substituents (L1–L4). The 2-t-BuPh
derived catalyst was identified as being optimal (entry 4), and the
dimethylcyclopropanation of a model 1,3-diene (1) provided 2 in
93% yield as a single regioisomer. Zn is not capable of directly
activating Me2CCl2, and in the absence of the Co catalyst, there
is no conversion (entry 1). Despite the fact that ZnCl2 is generated
as a stoichiometric byproduct, the presence of ZnBr2 at the start
of the reaction provided a modest beneficial effect on yield (entry
14). ZnBr2 accelerates the initial reduction of the yellow Co(II)
complex to a violet Co(I) species, which is then capable of
activating Me2CCl2. Finally, other classes of bidentate and
tridentate ligands containing combinations of pyridine and imine
donors were ineffective relative to PDI (entries 10–13). As a point
of comparison, the non-catalytic dimethylcyclopropanation of 1
Table 1. Catalyst Optimization Studies[a]
Entry
Metal Source
Ligand
Yield 2 [%]
under
Furukawa-type
Simmons–Smith
conditions
1
–
–
< 1
< 1
< 1
93
77
8
(I2CMe2/Et2Zn)[9] provided 2 in a moderate yield of 45% along with
several inseparable side products (see Supporting Information for
experimental details).
2
–
2-t-BuPDI (L1)
3
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
NiBr2
FeBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
–
2-t-BuPDI (L1)
2,4,6-MePDI (L2)
3,5-t-BuPDI (L3)
2,6-i-PrPDI (L4)
2-t-BuPDI (L1)
2-t-BuPDI (L1)
2,6-i-PrIP (L5)
2,6-i-PrDAD (L6)
bpy (L7)
With optimized conditions in hand, we next evaluated the
substrate scope of the dimethylcyclopropanation reaction (Figure
4
5
3).
A variety of 1-substituted, 1,2-disubstituted, and 1,3-
6
disubstituted dienes are viable substrates. In all cases,
cyclopropanation occurs at the terminal double bond with high
regioselectivity (rr = >19:1). Notably, there is no detectable
secondary cyclopropanation of the product alkene despite the
presence of excess Me2CCl2 and Zn in the reaction mixture.
Common functional handles for further synthetic elaboration are
tolerated, including a protected amine (8), BPin group (9), ester
(13), and free alcohol (18). The activation of Me2CCl2 by the Co
catalyst is relatively facile such that aryl chlorides (4) present in
the substrate are tolerated. The TBS-protected variant of
7
2
8
5
9
4
10
11
12
13
14[b]
15[c]
16[d]
2
<1
4
terpy (L8)
1
2-t-BuPDI (L1)
2-t-BuPDI (L1)
2-t-BuPDI (L1)
87
78
79
Danishefsky’s diene afforded
a
protected cyclopropanol
derivative in high yield (14).
Unlike the Simmons–Smith reaction, the cobalt-catalyzed
process is relatively insensitive to the electronic properties of the
diene.[14] For example, the presence of an electron-withdrawing
group, such as a phosphonate ester (11), a ketone (12), or an
ester (13), does not significantly decrease the rate of the reaction
nor does it result in poor yields of the product. Additionally, the
cobalt catalyst does not appear to interact strongly with alcohol
[a] Reactions were run on a 0.14 mmol scale of the 1,3-diene in THF (1 mL).
Yields of 2 were determined by GC analysis against an internal standard. [b]
Modifications from standard conditions: without ZnBr2. [c] Modifications from
standard conditions: 1.1 equiv of Me2CCl2. [d] Modifications from standard
conditions: 2.0 equiv of Me2CBr2.
We recently found that [PDI]Co (PDI = pyridine–diimine)
complexes function as catalysts[11],[12] for Simmons–Smith-type
cyclopropanation reactions and generate a reactive carbene
equivalent of significantly altered selectivity properties from Zn
carbenoids.[13] Motivated by this finding, we became interested in
directing
groups.[15]
The
diene
16
is
selectively
monocyclopropanated at the terminal double bond (rr = >19:1) as
expected based solely on steric considerations. By contrast,
Furukawa-type conditions using I2CMe2/Et2Zn afford selectivity for
the internal double bond, which is proximal to the alcohol.[9]
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Figure 3. Substrate scope studies. [a] Standard reaction conditions: 0.14 mmol scale of the 1,3-diene (1.0 equiv), Me2CCl2 (2.0 equiv), Zn (2.0 equiv), ZnBr2 (1.0
equiv), [2-t-BuPDI]CoBr2 (3) (10 mol%), and THF (1 mL); 22 °C for 24 h. [b] Simmons–Smith reaction conditions: ZnEt2 (4.0 equiv), I2CMe2 (4.0 equiv), and CH2Cl2
(1.0 mL). [c] Modifications to standard conditions: DCE (1.0 mL) instead of THF, Me2CBr2 (2.0 equiv) instead of Me2CCl2.
Synthetic ethyl chrysanthemate is prepared on industrial
scales by the addition of ethyl diazoacetate to 2,5-dimethyl-2,4-
hexadiene.[16] A limitation of this process is that the cyclopropane
is formed as a mixture of cis and trans diastereomers, whereas
natural pyrethrins are found only with the trans relative
stereochemistry. Using the cobalt-catalyzed cyclopropanation,
ethyl (E)-5-methyl-2,4-hexadienoate reacts at the less hindered
internal alkene with >19:1 trans selectivity (19). This approach
was applied to the synthesis of the commercial pesticide
phenothrin (20)[17] and unnatural pyrethrin analogues that contain
other alkyl (25), cycloalkyl (21–23), or aryl (24) substituents in the
place of the terminal methyl groups.
was prepared from the corresponding 1,3-diene precursor in 98%
yield. Heating 26 at 60 °C for 12 h in the presence of a
IPr/Ni(COD)2 catalyst provided the rearranged cyclopentene
product 27 in 65% yield.[18] The position of the alkene in 27
indicates that only the less hindered C–C bond is activated by the
catalyst.
A substrate containing both a 1,3-diene and an isolated
alkene was cyclopropanated under the cobalt-catalyzed
conditions to yield a single regioisomer of the monocyclopropane
product (28). When 28 was subjected to the Rh-catalyzed [5 + 2]-
cycloaddition conditions developed by Wender,[19] the bicyclic
product 29 was formed in 77% yield. Like the 1,3-rearrangement
reaction, the ring-opening proceeds with high regioselectivity to
furnish a single isomer of the product.
We considered the possibility that the vinyl cyclopropane
products generated by this method might serve as substrates for
transition metal-catalyzed ring-opening reactions; however, it was
unknown at the outset whether the steric hindrance imposed by a
gem-dimethyl group would be tolerated. Vinylcyclopropane 26
Finally, it was of interest to test whether the catalytic
conditions developed for the dimethylcyclopropanation of 1,3-
dienes could be applied to isolated alkenes. Simple, unactivated
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alkenes such as 1-octene or cyclohexene were unreactive (<2%
yield); however, substrates possessing a moderate degree of
strain proved to be viable. For example, cyclopentene is
cyclopropanated in 87% yield under the standard optimized
conditions (30). This result represents a significant improvement
in yield and reaction time over the only previously reported
attempt to carry out this transformation (45% yield after 5 days
using I2CMe2/Et2Zn).[8] Additionally, cyclooctene (31), indene (32),
and norbornene (33) react in high yield. In the latter case, the exo-
addition product is formed exclusively. N-Boc-2,5-dihydropyrrole
(34) is cyclopropanated in 90% yield to generate 35, which is a
protected precursor to the HCV protease inhibitor boceprevir.[20]
The process-scale route to this bicyclic amine consists of a multi-
step sequence in which the gem-dimethylcyclopropane unit is
ultimately derived from ethyl chrysanthemate.
induced
ring-opening
reactions.
Moderately
activated
monoalkenes are also cyclopropanated efficiently to generate
building blocks for medicinal chemistry. These studies collectively
highlight the unique properties of transition metal carbenoids over
their Zn counterparts as reactive species in cyclopropanation
chemistry.
Experimental Section
General procedure for the catalytic dimethylcyclopropanation. In an
N2-filled glovebox, a 2-dram vial was charged with [2-tBuPDI]CoBr2 3 (9.0
mg, 0.014 mmol, 10 mol%), the 1,3-diene or alkene (0.14 mmol, 1.0 equiv),
Zn powder (18 mg, 0.28 mmol, 2.0 equiv), ZnBr2 (31 mg, 0.14 mmol, 1.0
equiv), THF (1.0 mL), and a magnetic stir bar. The reaction was stirred at
room temperature for approximately 15 min, during which time a deep
violet color was observed corresponding to the reduced cobalt catalyst.
Me2CCl2 (31.6 mg, 0.28 mmol, 2.0 equiv) was added, and the reaction
mixture was stirred at room temperature. After 24 h, the reaction mixture
was exposed to ambient atmosphere and concentrated under reduced
pressure. The crude residue was directly loaded onto a SiO2 column for
purification.
Tricyclic antidepressants (TCAs) are a class of compounds
that commonly contain
a
dibenzazepine.[21] Parent 5H-
dibenz[b,f]azepine (36), bearing an unprotected N-H group, could
be directly dimethylcyclopropanated to provide 37 in 96% yield.
Notably, previous attempts to cyclopropanate this substrate under
Simmons–Smith conditions (CH2I2 + Zn/Cu) only yielded the
product of methylene insertion into the N–H bond.[22] One-step
derivatization of 37 using chlorosulfonyl isocyanate[23] yielded a
Acknowledgements
dimethylcyclopropane-containing
analogue
(38)
of
carbamazepine,[21b] which is used as a treatment for epilepsy and
neuropathic pain.
This work was supported by the National Institutes of Health (R35
GM124791). C.U. is an Alfred P. Sloan Foundation Research
Fellow.
Keywords: homogeneous catalysis • cobalt • carbenoids •
carbocycles • cycloaddition
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carbamazepine. Standard dimethylcyclopropanation conditions: 0.14 mmol
scale of the 1,3-diene (1.0 equiv), Me2CCl2 (2.0 equiv), Zn (2.0 equiv), ZnBr2
(1.0 equiv), [2-t-BuPDI]CoBr2 (3) (10 mol%), and THF (1 mL); 22 °C for 24 h.
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A cobalt catalyst promotes the regioselective dimethylcyclopropanation of 1,3-dienes using Me2CCl2 as an isopropylidene source and
Zn as a stoichiometric reductant. The products are gem-dimethylated vinylcyclopropanes, which may be converted into other cyclic
systems by strain-induced ring opening reactions. Moderately activated isolated alkenes are also viable substrates, providing access
to medicinally relevant building blocks.
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