Cobalt Catalyzed Reductive Spirocyclopropanation Reactions

Article abstract of DOI:10.1002/adsc.201901293

Cobalt pyridine?diimine (PDI) complexes catalyze the reductive spirocyclopropanation of terminal 1,3-dienes. gem-Dichlorocycloalkanes serve as carbene precursors and Zn is used as a terminal electron source. The reaction is effective for a range of gem-di

Full text of DOI:10.1002/adsc.201901293

Title: Cobalt Catalyzed Reductive Spirocyclopropanation Reactions
Authors: Jacob Werth, Kristen Berger, and Christopher Uyeda
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COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Cobalt Catalyzed Reductive Spirocyclopropanation Reactions
a
a
a
Jacob Werth, Kristen Berger, and Christopher Uyeda *
Dedicated to Prof. Eric Jacobsen on the occasion of his 60th birthday.
a
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States
*E-mail: cuyeda@purdue.edu
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Cobalt pyridine–diimine (PDI) complexes
catalyze the reductive spirocyclopropanation of terminal
diazocycloalkanes in flow reactors and their
[7]
uncatalyzed addition to α,β-unsaturated esters.
1
,3-dienes. gem-Dichlorocycloalkanes serve as carbene
A
conceptually straightforward route to
precursors and Zn is used as a terminal electron source.
The reaction is effective for a range of gem-dichloro
partners including those containing sulfur and nitrogen
heterocycles. An example of an intramolecular Rh-
spirocyclopropanes would be through a Simmons–
Smith-like process using a metal carbenoid reagent
derived from
a
1,1-dihalocycloalkane. One
impediment to realizing such a reaction is that there
are no general methods available to prepare 1,1-
catalyzed [5
+
2]-cycloaddition of
a
vinyl
spirocyclopropane is demonstrated, providing rapid
access to a complex tricyclic framework. Overall, this
catalyst system is capable of suppressing the kinetically
facile 1,2-hydride shift, which has hampered the
development of Simmons–Smith reactions using Zn
carbenoids possessing β-hydrogen atoms.
[8]
diiodocycloalkanes. 1,1-Dichloro analogs are more
accessible but do not react directly with Zn or Et Zn to
2
form metal carbenoids. Secondly, Zn carbenoids are
susceptible to kinetically facile 1,2-hydride shifts,
[9]
leading to the formation of alkene side products.
Therefore, substituted Zn carbenoids containing β-
hydrogen atoms are 10g]enerally ineffective as
Keywords: cyclopropanes; spiro compounds; cobalt;
carbenes; carbenoids
[
cyclopropanating agents.
3
Polycyclic C(sp )-rich frameworks have recently
[1]
attracted significant interest in medicinal chemistry.
Pd-catalyzed cross-coupling reactions have provided a
means to access large libraries of biologically active
compounds. However, there is evidence to suggest that
reliance on cross-coupling as a strategy for fragment-
based drug discovery may be leading to higher rates of
failure in clinical development due to the poor physical
properties of flat aromatic systems (e.g., low solubility
[2]
and high melting point). One approach to addressing
this problem is to prioritize lead compounds that
3
contain higher fractions of sp -hybridized carbons. In
[3]
this vein, spirocyclopropanes combine a unique
three-dimensional architecture with conformational
rigidity, thus representing high-value targets for the
[4]
development of new synthetic methods.
Spirocyclopropanes may be prepared by the addition
of
a
carbene[
equivalent
An
to
a
5],[6]
methylenecycloalkane.
alternative
disconnection that could be considered is the addition
of a cyclic carbene to an alkene. Recently, Charette
demonstrated
the
generation
of
sensitive
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201901293
Figure 1. Spirocyclopropanes in natural products and
pharmaceutical compounds. Spirocyclopropanations of α,β
unsaturated esters using diazocycloalkanes,[7] and catalytic
optimal catalyst for the dimethylcyclopropanation
reaction, product 3 was obtained in a modest yield of
38%. We reasoned that the more hindered carbenoid
generated in the spirocyclopropanation reaction may
require a less sterically encumbered catalyst active
site. Indeed, significant improvements were observed
by replacing the 2-t-Bu (7) substituent of the catalyst
with a smaller 2-n-Pr (9) group. In our survey of PDI
ligand derivatives (Table 1), this intermediate degree
of hindrance was found to be optimal, with smaller or
reductive
spirocyclopropanations
using
1,1-
dichlorocycloalkanes.
We recently discovered that (PDI)CoBr complexes
2
(
PDI
=
pyridine–diimine) catalyze reductive
dimethylcyclopropanation reactions of 1,3-dienes
using 2,2-dichloropropane and Zn.[11] Notably, the
catalyst is able to activate gem-dichloroalkane
reagents and does not require the use of more reactive
dibromo or diiodo precursors. Additionally,
cyclopropanation proceeds in high yield with near-
stoichiometric quantities of 2,2-dichloropropane,
suggesting that the cobalt carbenoid intermediate
generated in this reaction is resistant to undergoing
larger
groups
leading
to
decreases
in
spirocyclopropane yield. For all catalysts, the
conversion of 2 is >27%, suggesting that low
cyclopropanation yields are not exclusively due to
slow C–Cl oxidative addition, but also to deleterious
decomposition pathways of the carbenoid
intermediate.
1
,2-hydride shifts. With this precedent in hand, we
sought to develop catalytic reductive
spirocyclopropanation reaction.
Table 2. Reaction Optimization Studies and Control
Experiments.
a
Table 1. Catalyst Structure–Activity Relationship Studies.
entry variation from standard conditions
yield of 3
96%
<1%
<1%
<1%
87%
96%
42%
77%
<1%
19%
60%
68%
>99%
3%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
–
no (2-n-PrPDI)CoBr
2
no CoBr
no PDI
2
Zn (nanopowder, 40–60 nm)
Mn instead of Zn
Mg instead of Zn
Al instead of Zn
Cp
TDAE instead of Zn
no ZnBr
ZnCl instead of ZnBr
ZnI instead of ZnBr
Zn(OTf) instead of ZnBr
2
Co instead of Zn
0
1
2
3
4
2
2
2
2
2
2
2
a)
Standard conditions: 0.14 mmol of the 1,3-diene substrate,
,1-dichlorocycloalkane (1.25 equiv), Zn (2.0 equiv), ZnBr
1
2
a)
Reaction conditions: 0.14 mmol of the 1,3-diene substrate,
(0.5 equiv), catalyst 9 (10 mol%), room temperature, 24 h.
Yields of 3 were determined by H NMR integration against
1
1
,1-dichlorocycloalkane (1.25 equiv), Zn (2.0 equiv), ZnBr
2
(
0.5 equiv), catalyst (10 mol%), room temperature, 24 h.
1,3,5-trimethoxybenzene as an internal standard.
1
Yields of 3 were determined by H NMR integration against
,3,5-trimethoxybenzene as an internal standard.
1
In the absence of Zn or any component of the
(
PDI)CoBr
2
catalyst, no cyclopropanation was
1
,1-Dichlorocyclohexane (2) and 1,3-diene 1 were
observed (Table 2, entries 2–4). Alternative reductants
were examined (entries 5–10), and Mn was found to
selected as model substrates for our initial
optimization studies. 1,1-Dichlorocyclohexane (2)
was prepared in a single step from cyclohexanone
be equivalently competent. The soluble reagent Cp Co
2
provided no yield of cyclopropane (entry 9), and
using WCl
6
12]
according to previously described
TDAE provided 3 in 19% yield (entry 10).
procedures.[ Using (
2-t-Bu
PDI)CoBr
complex 7, the
2
Interestingly, ZnBr
2
and ZnI
2
afforded a significant
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201901293
beneficial effect on the yield of 3 despite the fact that
reduction of the (PDI)CoBr
by a faster appearance of the violet color associated
with the (PDI)CoBr oxidation state.
2
precatalyst as evidenced
ZnCl
2
is formed as a stoichiometric byproduct of the
reaction. ZnBr
2
/ZnI appears to accelerate the initial
2
Figure 2. Substrate Scope Studies. Reaction conditions: 0.14 mmol of the 1,3-diene substrate, 1,1-dichlorocycloalkane (1.25
equiv), Zn (2.0 equiv), ZnBr (0.5 equiv), catalyst 9 (10 mol%), room temperature, 24 h. Isolated yields were determined
2
following purification by column chromatography.
The substrate scope of the 1,3-diene
spirocyclopropanation is summarized in Figure 2. The
reaction is effective for a variety of terminal
spirocyclopropanation conditions (Figure 3a).
However, moderately activated alkenes such as
cyclooctene and indene proved to be viable substrates.
Furthermore, (vinyl)Bpin reacted to form spirocyclic
organoboron reagents (products 32–33) that could
potentially serve as nucleophilic partners in cross-
monosubstituted
1,3-dienes,
including
those
possessing aliphatic, aromatic, and heteroaromatic
groups. Notably, both electron-rich (products 14 and
[13]
1
5) and electron-deficient (products 20 and 21) dienes
coupling reactions. The relatively high reactivity of
1,3-dienes compared to monoalkenes can be leveraged
to carry out a selective monocyclopropanation of a
triene substrate (product 35, 71% yield). The resulting
product was then subjected to Rh-catalyzed [5 + 2]-
cycloaddition conditions to arrive at tricyclic product
react with similar efficiency. This insensitivity to
electronic effects stands in contrast with Zn carbenoid
additions, which strongly favor electron-rich alkenes.
Small internal substituents, such as Me, are also
tolerated
(product
19). (Z)-1,3-Dienes
are
[14]
cyclopropanated without isomerization of the internal
double bond (product 13). Finally, this method enables
the synthesis of spirocyclopropanes containing
saturated nitrogen (products 25 and 28) and sulfur
heterocycles (product 26).
Simple monoalkenes such as 1-octene, styrene, and
cyclohexene were unreactive under the standard
36 in 47% yield.
Mechanistic
possibilities
for
the
spirocyclopropanation are summarized in Figure 4a.
Previous studies have indicated that Zn is capable of
reducing
(PDI)CoCl
2
complexes
to
their
[
15]
corresponding (PDI)CoCl states.
Two-electron
oxidative addition of the 1,1-dichlorocycloalkane
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201901293
reagent would then form a putative Co(CR
2
Cl)Cl
2
species. However, because PDI ligands are not known
to stabilize Co in the +3 oxidation state, we reasoned
that if such a species were generated, it would be
susceptible to rapid reduction by Zn to form a Co(II)
carbenoid. Alternatively, a bimolecular oxidative
addition may directly afford a Co(II) carbenoid along
with an equivalent of (PDI)CoCl
2
. From here, a
Simmons–Smith-like CR transfer through a butterfly
2
transition state would generate the cyclopropane
product.[ Alternatively, Cl migration from C to Co
16]
could generate a Co=CR
2
intermediate prior to carbene
transfer.[
17]
Figure 4. (a) Mechanistic possibilities for the cobalt-
catalyzed spirocyclopropanation reaction. (b) Optimized
geometries for isomeric Co(C H )Cl and Co(C H Cl)Cl
5 8 2 5 8
complexes (S = 1/2, BP86/6-311G(d,p)/SMD(THF)//BP86-
D3BJ/6-311G(d,p) level of DFT). Calculated relative
energies are shown in kcal/mol.
Figure 3. (a) Spirocyclopropanation reactions of activated
alkenes, including (vinyl)Bpin. (b) Selective
monocyclopropanation of a triene and Rh-catalyzed [5 + 2]-
cycloaddition.
Experimental Section
In order to examine these two limiting structures for
the carbenoid intermediate in more detail, DFT
modelling studies were performed (BP86/6-
General
Procedure
for
the
Catalytic
Spirocyclopropanation of 1,3-Dienes
2-
3
11G(d,p)/SMD(THF)//BP86-D3BJ/6-311G(d,p)
2
In an N -filled glovebox, a 2-dram vial was charged with (
n-Pr
PDI)CoBr
2
9(8.6 mg, 0.014 mmol, 0.10 equiv), the 1,3-
level of theory). The (PDI)Co(CR Cl)Cl complex was
2
diene substrate (0.14 mmol, 1.0 equiv), Zn powder (18 mg,
calculated to possess an S = 1/2 ground state and
0
2
.28 mmol, 2.0 equiv), ZnBr (15 mg, 0.07 mmol, 0.50
adopts a pseudo-square planar geometry with the
equiv), THF (1.0 mL), and a magnetic stir bar. The reaction
mixture was stirred at room temperature for approximately
2
CR Cl ligand oriented axially. The (PDI)Co(CR
2
)Cl
2
1
5 min, during which time a deep violet color developed.
complex is lower in energy by 6.2 kcal/mol, and the
carbene ligand prefers to be coplanar with the PDI
ligand. The small energy difference between these two
isomers does not allow either structure to be
definitively ruled out as a potential catalytic
intermediate.
The 1,1-dichlorocycloalkane (0.175 mmol, 1.25 equiv) was
added, and stirring was continued. After 24 h, the reaction
mixture was concentrated under reduced pressure, and the
crude residue was loaded onto a SiO
purification.
2
column for
In summary, cobalt catalysis enables the
spirocyclopropanation of 1,3-dienes and activated
alkenes using a 1,1-dichlorocycloalkane/Zn reagent
combination. The carbenoid intermediate generated in
this reaction is resistant to undergoing a 1,2-hydride
shift, supressing the formation of olefin byproducts.
Ongoing studies are aimed at examining the nature of
the cobalt carbenoid intermediate generated in this
reaction.
Acknowledgements
This research was supported by the NIH (R35 GM124791). C.U.
is a Camille Dreyfus Teacher–Scholar.
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Advanced Synthesis & Catalysis
10.1002/adsc.201901293
COMMUNICATION
Cobalt Catalyzed Reductive Spirocyclopropanation
Reactions
Adv. Synth. Catal. Year, Volume, Page – Page
Jacob Werth, Kristen Berger, and Christopher
Uyeda*
6
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