Cobalt Catalyst Determines Regioselectivity in Ring Opening of Epoxides with Aryl Halides

Article abstract of DOI:10.1021/jacs.1c00659

Ring-opening of epoxides furnishing either linear or branched products belongs to the group of classic transformations in organic synthesis. However, the regioselective cross-electrophile coupling of aryl epoxides with aryl halides still represents a key challenge. Herein, we report that the vitamin B₁₂/Ni dual-catalytic system allows for the selective synthesis of linear products under blue-light irradiation, thus complementing methodologies that give access to branched alcohols. Experimental and theoretical studies corroborate the proposed mechanism involving alkylcobalamin as an intermediate in this reaction.

Full text of DOI:10.1021/jacs.1c00659

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Cobalt Catalyst Determines Regioselectivity in Ring Opening of
Epoxides with Aryl Halides
Aleksandra Potrząsaj, Mateusz Musiejuk, Wojciech Chaładaj, Maciej Giedyk,* and Dorota Gryko*
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ABSTRACT: Ring-opening of epoxides furnishing either linear or
branched products belongs to the group of classic transformations
in organic synthesis. However, the regioselective cross-electrophile
coupling of aryl epoxides with aryl halides still represents a key
challenge. Herein, we report that the vitamin B12/Ni dual-catalytic
system allows for the selective synthesis of linear products under
blue-light irradiation, thus complementing methodologies that give
access to branched alcohols. Experimental and theoretical studies
corroborate the proposed mechanism involving alkylcobalamin as
an intermediate in this reaction.
attack occurs predominantly at either the terminal or internal
carbon atom.
INTRODUCTION
■
Driven by high demand for sustainable and efficient reactions,
the discovery of selective reactivity patterns remains a key
challenge. As epoxides are crucial building blocks in the
synthesis of nonsymmetrical alcohols, their regioselective
reactions have been intensively studied.1−3 In particular,
considerable attention has been recently devoted to the
utilization of epoxides in cross-electrophile couplings leading,
in general, to regioisomeric (linear and branched) products
(Scheme 1).4−7 It has been shown that the innately
electrophilic epoxides can be transformed into radicals and,
as such, be involved in a transition-metal-catalytic cycle.7,8
Depending on reaction conditions, the initial nucleophilic
In 2014, Weix and co-workers developed a nickel-catalyzed,
regiodivergent cross-electrophile coupling of epoxides with
various halides and triflates.6 For aliphatic epoxides (Scheme 1,
upper part), the regioselectivity of the ring-opening step
depends on the cocatalyst used. Sodium iodide promotes the
formation of a linear product. The nucleophilic attack of the
iodide anion at the less substituted carbon atom affords
iodohydrin, which in turn undergoes reduction and Ni-
catalyzed coupling with an electrophile. On the other hand,
in the presence of a titanocene cocatalyst secondary alkyl
radicals are generated, facilitating the formation of branched
products.9,10 Aryl epoxides, however, react predominantly at the
benzylic position, regardless of the conditions employed. A similar
reactivity pattern has been recently reported by the Doyle
group, who used organic iodides and the Ti/Ni/photoredox
catalytic system in ring-opening reactions of three major
classes of epoxides, namely, aryl, aliphatic, and bicyclic
(Scheme 1, lower part).11 By changing a nickel complex, the
authors were able to transform aliphatic epoxides into linear
products, while aryl epoxides selectively formed branched ones.
Despite the enormous importance of these contributions, the
synthesis of linear products from aryl epoxides via cross-
electrophile coupling still represents an unsolved challenge.
Scheme 1. Regioselective Nickel-Catalyzed Cross-
Electrophile Coupling of Epoxides with Aryl Halides
Received: January 19, 2021
Published: June 3, 2021
© 2021 The Authors. Published by
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Scheme 2. (A) Structures of Cocatalysts: Vitamin B12 and Derivatives; (B) Proposed Mechanistic Concept
Our recent work on the alkylation of strained molecules
showed that cobalt catalysis opens the path to a polarity-
reversal strategy for radical couplings.12 We questioned
whether it would be possible to adapt this methodology to
achieve selective reactions of epoxides. Herein, we disclose that
the nucleophilicity of Co(I) species along with sterically
restricted side chains allows generating C-radicals from
epoxides in a selective manner and engage them in Ni-
catalyzed cross-coupling.
zero or one imaginary frequency, respectively). Single-point
energies were computed at the BP86/6-311++G(2df,p) level
of theory with the D3 version of Grimme’s empirical
dispersion correction and solvation (acetone) with the SMD
model. Several hybrid and long-range corrected functionals
were tested for the model reaction (see Supporting
Information (SI) for details). BP86 was, however, selected
for further studies due to good performance reported for both
ground and exited state calculations of cobalamin systems.25−30
We performed calculations approximating the structure of
vitamin B12 (1) with a Co-corrin complex bearing 15 methyl
groups, reflecting the substitution pattern at the periphery of
the macrocyclic ring (Figure 1).
The calculated Gibbs free energy profile for the benchmark
reaction of styrene oxide (5a) with the Co-corrin complex is
depicted in Figure 1. Two paths, involving the nucleophilic
attack on either side of the epoxide, were considered. In line
with our assumptions, the ring opening of the epoxide with the
nucleophilic Co(I) complex should proceed at the less
hindered terminus with a 43.7 kJ/mol barrier, accessible
even under mild conditions (black path). The barrier for the
analogous reaction at the more hindered side is ∼8 kJ/mol
higher (gray path). Sterically driven differences in the reactivity
might be even more pronounced for native vitamin B12 or its
derivatives compared to the selected model, due to presence of
more sizable substituents at the corrin ring. Then, the resulting
Co(III) complex (I) is protonated, providing intermediate II.
As expected for alkyl cobalamins, the Co−C(sp3) bond in IIa
and IIb is relatively weak and quite vulnerable to homolytic
cleavage toward alkyl radical IIIa or IIIb and a Co(II) complex
(ΔG = 141.9 and 82.6 kJ/mol, respectively). In particular, IIa
could undergo Co−C photodissociation, presumably through
the mechanism proposed by Kozlowski, involving generation
of the singlet radical pair from the first electronically excited
state (S1).31−33
RESULTS AND DISCUSSION
■
Design of the Catalytic System. Vitamin B12 (1,
cobalamin) is a natural cobalt complex of remarkable stability
and high biological importance.13−15 Due to the unique ability
to form light-sensitive cobalt−carbon bonds, vitamin B12 (1)
and its hydrophobic and amphiphilic derivatives 2 and 3
(Scheme 2A)16−21 have also been adopted for synthetic
chemistry and used as redox mediators for the generation of
various radicals.22,23 We assumed that a nucleophilic Co(I)
complex that forms upon the reduction of cobalamin should
open electrophilic epoxides, generating alkyl cobalamins
(Scheme 2B). Such intermediates, upon light irradiation,
undergo the homolytic Co−C bond cleavage to give alkyl
radicals, which can be engaged in a number of both radical
reactions and transition-metal-catalyzed cross-couplings. Im-
portantly, from the viewpoint of regioselective design, a bulky
vitamin B12catalyst should attack an epoxide from the less
sterically hindered side. This kinetic factor may prevail over the
high thermodynamic preference for stabilized benzyl radicals
and thus allow the selective formation of primary radicals of
type III.
To examine our hypothesis, in the first instance, we
theoretically investigated the possible formation of alkyl
radicals via a sequence of the epoxide ring opening with
reduced vitamin B12 (Co(I) complex) followed by homolytic
cleavage of the Co−C bond in alkyl cobalamin II. DFT
calculations were performed with Gaussian 16.24 Geometry
optimizations were computed at the BP86/6-31G(d) level of
theory with the D3 version of Grimme’s empirical dispersion
correction and solvation (acetone) with the SMD model.
Frequency analysis was performed at the same level to provide
correction to thermodynamic functions and confirm the nature
of optimized structures (minima and transition states featured
The lowest singlet (IIa-S1) vertically excited states of
intermediate IIa were found at 2.20 eV (212.5 kJ/mol, TD
BP86-D3/6-311++G(2df,p)), while the relaxed S1 state lies
28.2 kJ/mol lower and features elongation of the Co−C bond
by 0.22 Å. Noticeably, due to the preference for the
nucleophilic attack at the less hindered side of the epoxide,
the above-described path (black) should provide access to a 2-
hydroxy-2-phenyl ethyl radical (IIIa), even though isomeric
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incorporating the generated alkyl radicals in the Ni catalytic
cycle. Adding electrophilic aryl halides should enable cross-
electrophile coupling and thus provide a convenient method
for the carbon−carbon bond formation.40 The plausible
mechanism for the reaction of epoxides with aryl halides in
the presence of the B12/Ni catalytic system based on literature
reports is outlined in Scheme 2B.7,41−43 The coupling requires
the cooperation of both transition metal complexes (Co and
Ni) that are activated by Zn/NH4Cl.44,45 The oxidative
addition of aryl halide to Ni(0) produces aryl nickel(II)
species IV, which undergoes subsequent alkylation with radical
III and generates intermediate V. Alternatively, the same
Ni(III) species can originate from the interception of alkyl
radical III by Ni(0), preceding the oxidative addition, as has
been recently proposed by Molander and Kozlowski.46 Both
these possible pathways are followed by irreversible reductive
elimination, leading to the regioselective formation of a linear
product. Cobalt(II) and nickel(I) complexes are regenerated to
Co(I) and Ni(0) with Zn, thereby closing the cycles.
Styrene oxide (5a), when subjected to the reaction with
p-iodotoluene (6a) in the presence of HME (3) and
NiCl2(DME), generated desired linear product 7aa as a single
regioisomer in 16% yield (Scheme 4). The replacement of
Scheme 4. Proof-of-Concept Experiments
Figure 1. Calculated Gibbs free energy profile for the reaction of
styrene oxide with the Co(I)-corrin complex.
a
Conditions: epoxide (5a, 0.2 mmol), aryl halide (6a, 1.5 equiv),
benzyl radical IIIb is thermodynamically more stable by 47.2
kJ/mol.
NiCl2(DME) (20 mol %), Zn (3 equiv), NH4Cl (3 equiv), dtbbpy
(40 mol %), dry NMP (c = 0.1 M), blue LED (single diode, 10 W),
30 min.
To support theoretical studies, the reductive photochemical
ring opening of styrene oxide (5a) in the presence of a
hydrophobic vitamin B12 derivative, HME (3), was performed
(Scheme 3). The selected Co complex 3 allows convenient
monitoring of reactive intermediates by ESI mass spectrometry
due to its tendency to undergo facile ionization.
HME (3) with native vitamin B12 increased the yield up to
41%. Noteworthy, the reaction without any cobalt complex
added not only was lower-yielding but also led to a mixture of
two regioisomers with a predominance of the branched
product. This result clearly shows the decisive influence of the
cobalt cocatalysis on the selectivity of this transformation. Control
experiments confirmed the dual-catalytic and light-induced
nature of the process, while the addition of a radical trap
(TEMPO) supported its radical character (see SI).
Scheme 3. Vitamin B12-Catalyzed Ring Opening of Epoxide
5
Noteworthy, the reaction without any cobalt complex added
not only was lower-yielding but also led to a mixture of two
regioisomers with a predominance of the branched product.
This result clearly shows the decisive influence of the cobalt
cocatalysis on the selectivity of this transformation. Control
experiments confirmed the dual-catalytic and light-induced
nature of the process, while the addition of a radical trap
(TEMPO) supported its radical character (see SI).
Optimization. Next, we turned our attention toward the
synthetic utility of the developed method. The reaction was
optimized with respect to cobalt and nickel catalysts, solvent,
ligand, and reducing system, providing the desired product 7aa
in 60% yield (Table 1, entry 1).
Indeed, the formation of intermediate alkyl-cobalt(III)
complex II was observed by HR-MS (m/z = 1157.5149 [M
+ H]+, see the SI, Section 6.2), which is in good agreement
with previous reports by Scheffold34−38 and Rusling,39 who
used vitamin B12 (1) for isomerization of symmetrical epoxides
to allyl alcohols. Satisfyingly, alcohol 9a with a −OH group at
the benzylic position formed just after 30 min. These results
corroborate the proposed mechanistic concept in which
vitamin B12 opens the aromatic epoxide from the less hindered
side at the thermodynamic expense of forming the less stable
radical III in the subsequent light-induced cleavage step.
Knowing that B12 catalysis can be merged with metal-
catalyzed reactions,12 we next evaluated the feasibility of
We found that the addition of water (1.1 equiv) improved
the yield of the reaction, while kinetic studies allowed us to
determine the optimal reaction time (30 min, for details, see
SI). The use of hydrophobic HME (3) instead of the parent
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Monosubstituted aryl epoxides 5a-f, bearing both electron-
withdrawing and electron-donating substituents, are, in
general, well-tolerated and give corresponding products 7aa−
fa in 50−58% yields. However, 2-(4-methoxyphenyl)oxirane
(5e) does not afford the desired product, as it decomposes
rapidly under the present conditions. For disubstituted
epoxides, the substitution pattern determines their reactivity.
1,1-Disubsituted epoxide 5f leads to product 7fa in 44% yield,
while 1,2-disubstituted epoxide 5g remains unreactive. As far as
aryl halides are concerned, under standard conditions, both
electron-donating and electron-withdrawing substituents are
well tolerated, giving desired products 7ab−ao in good to
moderate yield (28−63%). Substitution at the 3- or 4-position
of an aryl halide does not affect the reaction. In contrast, the
more hindered halide, 2-iodotoluene (6c), undergoes coupling
with styrene oxide (5a) in reduced reaction yield (compare
7aa, 7ab, and 7ac). Although vitamin B12 exhibits exquisite
reactivity in dehalogenation reactions,11 which often precludes
the use of halogenated substrates, in our conditions product
7ad forms in 44% yield. Importantly from the standpoint of
possible further functionalizations, other functional groups
(hydroxyl, carbonyl, protected amine) remain unaffected.
Moreover, the representative heteroaryl halide, 5-iodo-(4-
methylphenylsulfonyl)indole (6l), proves to be a viable
substrate in the studied reaction without any further
optimization needed. The developed method is also suitable
for epoxides with aliphatic substituents (Scheme 5). The chain
length does not impact the transformation’s outcome; the
reaction with 1,2-epoxyhexane (5h) and 1,2-epoxydodecane
(5i) gives products in 74% and 77% yield, respectively. We also
found that aliphatic epoxide 5j, possessing a protected primary
hydroxyl group, could be converted into secondary alcohol 7ja
in 60% yield. The reaction with 4-(phenylsulfonyl)-1,2-
epoxybutane (5k) gives corresponding product 7ka in 73%
yield. The potential use of aziridines as substrates was also
investigated under the developed conditions, but only low
yields of the respective products were obtained (see SI).
Further studies on extending our methodology to other classes
of heterocycles are currently ongoing in our laboratory.
Subsequently, the scope of aryl halides for the reaction with
1,2-epoxyhexane (5h) was explored. Substrates with both types
of substituentselectron-rich and electron-deficienton the
aromatic ring afford the corresponding products 7hd−ol in
satisfactory yields. The N-Boc-protected amine, alkoxy, and
carbonyl functionalities are well tolerated. The reaction with 1-
chloro-4-iodobenzene (6d) leads to anticipated alcohol 7hd in
51% yield. Similar to the reaction with aryl epoxides, indole-
derived halide 6l proved also a competent substrate, affording
1-(1-tosyl-1H-indol-5-yl)hexan-2-ol (7hl).
Table 1. Optimization Studies of the Cross-Electrophile
Ring Opening of Epoxides
a
a
entry
deviation from the standard conditions
yield (%) 7aa
1
2
3
4
5
6
7
8
9
10
11
12
13
none
60
57
5
7
8
11
30
36
33
39
24
13
53
HME instead of B12
Co(acac)3 instead of B12
CoCl2 instead of B12
Co(dmgH)2Cl(py) instead of B12
Co(dmgH)2 Pr(py) instead of B12
Mn instead of Zn
NiCl2 instead of NiCl2(DME)
Ni(acac)2 instead of NiCl2(DME)
Ni(OTf)2 instead of NiCl2(DME)
1,10-phenanthroline instead of dtbbpy
terpyridine instead of dtbbpy
no water added
i
b
a
Conditions: epoxide (5, 0.2 mmol), aryl halide (7, 1.5 equiv), B12 (5
mol %), NiCl2(DME) (20 mol %), Zn (1.5 equiv), NH4Cl (3 equiv),
dtbbpy (40 mol %), H2O (1.1 equiv), dry NMP (c = 0.1 M), time 30
b
min, blue LED (single diode, 10 W) (for more details see SI). Mn
(1.5 equiv), TMSCl (0.2 equiv), dmgH = dimethylglyoxime, dtbbpy =
4,4′-di-tert-butylbipyridine.
vitamin B12 had little impact on the optimized model reaction
(entry 2), while other commonly utilized cobalt complexes
(Co(acac)3, CoCl2) led to a decrease in the yield of alcohol
7aa (entries 3, 4). We have also examined cobalt
dimethylglyooximate (dmg) complexes, which have been
used by Pattenden47 and Morandi48 in regioselective cobalt-
catalyzed coupling of aliphatic epoxides with alkenes. In our
system, however, both catalysts afforded the desired product
7aa only in low yields (entries 5, 6). Evaluation of reducing
agents ruled out manganese or tetrakis(dimethylamino)-
ethylene (TDAE) as an efficient alternative to the Zn/
NH4Cl system (entry 7). It also allowed establishing the
optimal ratio of the two components at the 1.5 equiv: 3 equiv
level. The reaction outcome did not improve in the presence of
NiCl2, Ni(acac)2, or Ni(OTf)2 as well as other ligands (entries
8−12). Finally, various solvents were tested (for more details,
see SI), but NMP with the addition of water (1.1 equiv)
assured the highest yield (entry 13).
Detailed analysis of the reaction mixture revealed the
formation of byproducts aside from desired product 7aa
under the optimized conditions (Scheme 2B). Acetophenone
(8a, a side-product originating from epoxide 5a) formed in 5%
yield presumably via β-hydride elimination, while styrene
(10a) is obtained in 30% yield from intermediate alcohol 9.49
Finally, the reductive elimination in the nickel cycle may
account for the observed small amount of biphenyl 11.50−52 In
order to gain more insight into the reaction mechanism, we
carried out the reaction with enantioenriched styrene oxide
(5a) under the optimized conditions. The expected coupling
product 7aa was obtained without any erosion of the
stereocenter, which further supports the premise of the
formation of the radical at the terminal position.
Compared to monosubstituted substrates, bicyclic epoxide
5o was converted to the desired coupling product 7oa with a
significantly lower yield.5 Therefore, to gain a better under-
standing of how the reaction conditions affect the cross-
electrophile coupling of disubstituted epoxides with aryl
halides, additional experimental and theoretical studies were
performed.
The use of hydrophobic analogue 3 instead of vitamin B12
(1) does not bring any substantial improvement (Table 2,
entries 1, 2). However, with the simultaneous replacement of
NMP with acetone, a 2-fold increase in the yield of 7oa was
observed (entry 3). A similar trend was also present for bicyclic
epoxide 5n and 1-oxaspiro[2.5]octane (5m), which provide
considerably higher yields of desired alcohols 7na and 7oa in
Substrate Scope. With the optimized conditions in hand,
we explored the scope and limitations of the developed
method (Scheme 5).
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a
b c
,
Scheme 5. Vitamin B12-Catalyzed Ring-Opening Cross-Electrophile Coupling of (a) Aryl Epoxides and (b) Alkyl Epoxides
a
Conditions: epoxide (0.2 mmol), aryl halide (1.5 equiv), B12 (5 mol %), NiCl2(DME) (20 mol %), Zn (1.5 equiv), NH4Cl (3 equiv), dtbbpy (40
b
mol %), H2O (1.1 equiv), dry NMP (c = 0.1 M), blue LED (single diode, 10 W), 30 min (for more details see SI). Blue LED (single diode, 3 W),
16 h. HME (5 mol %), acetone (c = 0.1 M), blue LED (single diode, 3 W), 16 h. Determined by GC.
c
d
the presence of the HME/acetone system compared to vitamin
B12/NMP. The main feature by which the studied Co catalysts
differ is the presence/absence of the so-called “nucleotide
loop” (the axial ligand located at the α face of the corrin ring
with a 5′,6′-dimethylbenzimidazol (DMB) moiety) in addition
to the replacement of amide into ester groups. Halpern et al.
reported that in methyl malonyl-coenzyme A rearrangement
switching between base-on and base-off forms of (CN)Cbl (1)
changes the strength of the Co−C bond and hence the rate of
its homolytic cleavage.53 To assess if the presence of this
structural element impacts opening of bicyclic epoxides, we
used cobalester 2 as a Co complex. This catalyst bears a
nucleotide loop in its structure, but unlike parent vitamin B12,
it dissolves well in both NMP and acetone, allowing for a direct
comparison. A decisive solvent’s dependence was observed,
with acetone assuring a higher yield than NMP (entries 4, 5),
which corroborates the sole influence of the reaction medium.
Likewise, the reaction catalyzed by cobinamide 4 (amide
groups, no nucleotide loop) in NMP gives similar results to
reactions catalyzed by other B12 derivatives in this solvent
(entry 6).
Performed kinetic studies contributed to a better under-
standing of the observed differences. The rate of the bicyclic
epoxide (5o) ring opening was found to vary significantly
depending on the conditions applied (Chart 1). It takes 6 h to
fully convert epoxide 5o in both vitamin B12- and HME-
catalyzed reactions as long as NMP is used as a solvent
(compare fields A and C). On the other hand, the reaction in
acetone provides full conversion in less than 3 h, which,
presumably, translates to greater availability of alkyl radicals at
a particular time (compare fields C and D).
The reactivity of aryl iodide toward a Ni catalyst is assumed
to be at a similar level, regardless of the conditions applied.
Therefore, in NMP an insufficient concentration of alkyl
radicals derived from bicyclic epoxides may promote Ni-
catalyzed homocoupling of aryl iodide 6a, an unproductive
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with the Co(I)-corrin complex (Figure 2). In general, the
Gibbs free energy of activation for the reaction of aryl- and
Table 2. Influence of the Co Complex Structure on the
Opening of Bicyclic Epoxides
a
entry
1
solvent
NMP
catalyst
yield (%) 7oa
B12
31
CONH2
HME
CO2Me
HME12
CO2Me
cobalester17
CO2Me
cobalester
CO2Me
cobinamide54
CONH2
loop
2
3
4
5
6
NMP
26
56
55
32
35
no loop
no loop
loop
acetone
acetone
NMP
loop
NMP
no loop
a
Conditions: epoxide (5o, 0.2 mmol), aryl halide (6a, 1.5 equiv), Co
catalyst (5 mol %), NiCl2(DME) (20 mol %), Zn (1.5 equiv), NH4Cl
(3.0 equiv), dtbbpy (40 mol %), solvent (c = 0.1 M), blue LED
(single diode, 3 W), 16 h.
Figure 2. Gibbs free energy barriers for the opening of epoxides with
the Co(I)-corrin complex calculated at the BP86-D3/6-311++G-
(2df,p)/SMD(acetone)//BP86-D3/6-31G(d)/SMD(acetone) level
of theory.
pathway, leading to biphenyl (11a) (fields A and C).50,52 This
side-product is observed only in the presence of the Ni
complex. The higher reactivity of monosubstituted aliphatic
epoxide 5h is reflected by its faster conversion as compared to
bicyclic epoxide 5o (compare fields A and B). In their case, the
catalyst and the solvent do not affect the reaction; yields are
almost identical (74%) in both cases.
alkyl-monosubstituted epoxides (TS1a and TS2a, 43.7 and
47.1 kJ/mol for Ph- and Me-substituted, respectively) is
smaller than for more sterically demanding 1,2-disubstituted
epoxides (TS3 and TS4, >70 kJ/mol). Nevertheless, bicyclic
substrates 5n,o provide desired products 7na and 7oa in good
yields, while epoxide 5g, for which the activation barrier is ∼3
kJ/mol higher, remains unreactive (TS3 versus TS4a)
The observed reactivity pattern corresponds well with the
calculated barriers for the nucleophilic opening of the epoxides
a b
,
Chart 1. Kinetic Profile of the Opening of Bicyclic Epoxides (6o) (A, C, D) and Aliphatic Epoxide 6h (B)
a
Conditions: epoxide (5, 0.2 mmol), aryl halide (6a, 1.5 equiv), Co catalyst (5 mol %), NiCl2(DME) (20 mol %), Zn (1.5 equiv), NH4Cl (3.0
b
equiv), dtbbpy (40 mol %), solvent (c = 0.1 M), blue LED (single diode, 3 W), 16 h, dodecane as an internal standard. Measurements at t = 0 min
refer to concentrations of compounds before mixing two solutions; see SI.
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regardless of the Z/E configuration of the epoxide (TS4a vs
TS4b, ΔG⧧ = 74.4 vs 78.9 kJ/mol). Additionally, the observed
regioselectivity is well reflected by the energetically favored
attack of the Co(I)-corrin on the less hindered side on
propylene oxide (a model used for an alkyl epoxide, TS2a vs
TS2b, ΔG⧧ = 47.1 vs 67.4 kJ/mol).
ACKNOWLEDGMENTS
■
The authors thank Prof. Pawel M. Kozlowski for helpful
discussions. Financial support for this work was provided by
the Foundation for Polish Sciences (FNP TEAM
POIR.04.04.00-00-4232/17-00). M.G. gratefully acknowledges
funding from the National Science Centre (SONATA 2018/
31/D/ST5/00306). Calculations have been carried out using
resources provided by Wroclaw Centre for Networking and
Supercomputing (http://wcss.pl), grant no. 518.
CONCLUSIONS
■
We have developed a highly regioselective, Co/Ni-catalyzed
ring-opening reaction of epoxides with aryl halides. The scope
of our method has been demonstrated in a broad range of
aliphatic and aromatic epoxides. Gratifyingly, these include
cyclic and disubstituted epoxides even though the Gibbs free
energy of activation for their reactions are higher than for alkyl-
and aryl-monosubstituted substrates. Due to the mild reaction
conditions, a wide range of functional groups is well tolerated.
Only the cooperation of vitamin B12 as a Co catalyst with Ni
catalysis assures high regioselectivity of the cross-electrophile
coupling. The crucial ring opening by the Co(I) complex
occurs from the less hindered side, leading to linear products.
This new methodology complements the existing ap-
proaches providing access to a diverse array of substituted
alcohols, which are valuable feedstock chemicals in synthetic
and medicinal chemistry. Consequently, it closes the gap in the
synthesis of linear and branched alcohols via cross-electrophile
coupling; they are now accessible from both alkyl and aryl
epoxides.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
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AUTHOR INFORMATION
■
Corresponding Authors
Maciej Giedyk − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland;
Email: maciej.giedyk@icho.edu.pl
Dorota Gryko − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland; orcid.org/
0000-0002-5197-4222; Email: dorota.gryko@icho.edu.pl
Authors
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Aleksandra Potrząsaj − Institute of Organic Chemistry, Polish
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0000-0003-0549-7792
Mateusz Musiejuk − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland
Wojciech Chaładaj − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland; orcid.org/
0000-0001-8143-3788
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00659
Notes
The authors declare no competing financial interest.
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