Co-Catalyzed Asymmetric Intramolecular [3+2] Cycloaddition of Yne-Alkylidenecyclopropanes and its Reaction Mechanism

Article abstract of DOI:10.1002/chem.202100426

Developing new transition metal-catalyzed asymmetric cycloadditions for the synthesis of five-membered carbocycles (FMCs) is a research frontier in reaction development due to the ubiquitous presence of chiral FMCs in various functional molecules. Reported here is our discovery of a highly enantioselective intramolecular [3+2] cycloaddition of yne-alkylidenecyclopropanes (yne-ACPs) to bicyclo[3.3.0]octadiene and bicyclo[4.3.0]nonadiene molecules using a cheap Co catalyst and commercially available chiral ligand (S)-Xyl-BINAP. This reaction avoids the use of precious Pd and Rh catalysts, which are usually the choices for [3+2] reactions with ACPs. The enantiomeric excess in the present reaction can be up to 92 %. Cationic cobalt(I) species was suggested by experiments as the catalytic species. DFT calculations showed that this [3+2] reaction starts with oxidative cyclometallation of alkyne and ACP, followed by ring opening of the cyclopropyl (CP) group and reductive elimination to form the cycloadduct. This mechanism is different from previous [3+2] reactions of ACPs, which usually start from CP cleavage, not from oxidative cyclization.

Full text of DOI:10.1002/chem.202100426

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&
Methods and Reactions
Co-Catalyzed Asymmetric Intramolecular [3+2] Cycloaddition of
Yne-Alkylidenecyclopropanes and its Reaction Mechanism
Xiong Xiao and Zhi-Xiang Yu*[a]
Abstract: Developing new transition metal-catalyzed asym-
metric cycloadditions for the synthesis of five-membered
carbocycles (FMCs) is a research frontier in reaction develop-
ment due to the ubiquitous presence of chiral FMCs in vari-
ous functional molecules. Reported here is our discovery of
a highly enantioselective intramolecular [3+2] cycloaddition
of yne-alkylidenecyclopropanes (yne-ACPs) to bicy-
clo[3.3.0]octadiene and bicyclo[4.3.0]nonadiene molecules
using a cheap Co catalyst and commercially available chiral
ligand (S)-Xyl-BINAP. This reaction avoids the use of precious
Pd and Rh catalysts, which are usually the choices for [3+2]
reactions with ACPs. The enantiomeric excess in the present
reaction can be up to 92%. Cationic cobalt(I) species was
suggested by experiments as the catalytic species. DFT cal-
culations showed that this [3+2] reaction starts with oxida-
tive cyclometallation of alkyne and ACP, followed by ring
opening of the cyclopropyl (CP) group and reductive elimi-
nation to form the cycloadduct. This mechanism is different
from previous [3+2] reactions of ACPs, which usually start
from CP cleavage, not from oxidative cyclization.
thons (Scheme 1a).[5] Among them, to our surprise, there is
only one asymmetric reaction, the Pd-catalyzed asymmetric
[3+2] cycloaddition between an ACP and an alkene
(Scheme 1b), which was elegantly elaborated by MascareÇas
and co-workers.[3a] In this reaction, R1 and R2 can be changed
and this reaction had good scope to synthesize 5/5 bicycles
(even though the 2p component in this [3+2] reaction re-
quired the use activated alkenes, this group could be further
converted to various groups, as demonstrated by the authors).
With these encouraging results, we wondered whether the 2p
component of the asymmetric intramolecular [3+2] reactions
can be alkynes, which was not reported in literature. We
speculated that all previously developed intramolecular [3+2]
reactions of ACPs and MCPs with alkynes either had not been
tested for their asymmetric versions or that it was difficult to
achieve high enantiomeric excess (ee).[6] Based on this, we
wondered whether, if a new metal catalyzed [3+2] cycloaddi-
tion of ACPs with alkynes could be developed, in this new sce-
nario asymmetric version could be realized by choosing appro-
priate chiral ligands. Here we report our efforts to this aim that
led to the development of a Co-catalyzed asymmetric intramo-
lecular [3+2] reaction of yne-ACPs. In addition, DFT calculations
and experimental investigations of the reaction mechanism are
also described here.
Introduction
Five-membered carbocycles (FMCs) are ubiquitously found in
biologically active molecules including pharmaceuticals, natu-
ral products, and non-natural products. Due to this, great ef-
forts have been made to discover and develop general reac-
tions accessing FMCs in high efficiencies.[1] Among them, tran-
sition metal-catalyzed [3+2] cycloadditions of various 3C syn-
thons with 2C synthons (which are usually alkenes, alkynes or
allenes) have evolved as powerful tools for chemists to synthe-
size various FMC-embedded functional molecules.[2] The intra-
molecular [3+2] reactions are very useful for the synthesis of
5/5 and 6/5 skeletons and have attracted efforts from many
leading chemists. Unfortunately, only a limited number of
these intramolecular [3+2] cycloadditions have their asymmet-
ric versions,[3] whereas the asymmetric intermolecular [3+2] re-
actions can be widely found.[1m,2b–d,4] Therefore, there is a high
demand for discovering and developing new intramolecular
asymmetric [3+2] reactions.
We have been inspired by many leading discoveries of the
intramolecular cycloaddition reactions of alkylidenecyclopro-
panes (ACPs) or methylenecyclopropanes (MCPs) with 2C syn-
[a] Dr. X. Xiao, Prof. Dr. Z.-X. Yu
Beijing National Laboratory for Molecular Sciences (BNLMS)
Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education
College of Chemistry
Peking University
Beijing 100871 (P. R. China)
Results and Discussion
Developing the asymmetric intramolecular [3+2] cycloaddi-
tion reaction of yne-ACPs
E-mail: yuzx@pku.edu.cn
Homepage: https://www.chem.pku.edu.cn/zxyu
Recently, cobalt-catalyzed transformations have attracted a lot
of attention with the consideration of its high natural abun-
dance, low cost, limited toxicity, and unique catalytic proper-
Supporting Information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under:
https://doi.org/10.1002/chem.202100426.
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value was just 6% (entry 8). To our delight, other
BINAP ligands (L3, L4, L5) were found to give good
yields with high ee values. For example, using steri-
cally hindered bisphospine ligand (S)-Xyl-BINAP (L5)
provided the desired product 2a in 85% yield and
89% ee (entry 11). It was interesting to observe that
using axial chiral ligands (L6–L10; entries 12–16) and
other types of ligands (L11–L13; entries 17–19) can all
realize the reaction. However, poorer enantioselectivi-
ties were obtained compared to the L5 ligand. Based
on these results, we chose L5 as the chiral ligand for
further optimization of other parameters of the reac-
tion conditions. After a brief study of solvent, tem-
perature, concentration (for more detail, see the Sup-
porting Information), we found that under these opti-
mal reaction conditions (using Me2AlCl (0.5 equiv) as
the activator, Co(L5)Cl2 (0.1 equiv) as the catalyst,
DCE/n-heptane (1:1) as the solvent, substrate in
0.1m, reaction temperature at 308C), the reaction
was completed in 1.5 h and provided the desired 2a
in 96% yield and 91% ee (entry 22).
Having the optimal reaction conditions in hand,
the scope of intramolecular [3+2] cycloaddition of
various yne-ACP substrates were examined next
(Table 2). First, substrates with a variety of aryl
groups were tested, finding that electron-donating
(OMe) (1b/1e) or electron-withdrawing groups (CF3,
Br) (1c/1d/1 f) at para or more steric hindered ortho
position in the aryl rings were tolerated and all [3+2]
Scheme 1. Transition-metal catalyzed intramolecular [3+2] cycloadditions of MCPs and
ACPs with alkenes/alkynes. EWG=electron-withdrawing group.
ty.[7] We wondered if we could circumvent using precious
metal catalysts of Pd and Rh in the ACPs-participated cycload-
ditions, by exploiting a Co0/CoII or CoI/CoIII redox cycle to ach-
ieve [3+2] cycloadditions of ACPs with alkynes or alkenes (the
other reason for this, as mentioned in the introduction part,
was to find a new catalytic system having great potential to
be advanced to its asymmetric version). With this goal in mind,
we started our experimental study of the intramolecular [3+2]
cycloaddition reaction of yne-ACPs using 1a as the substrate
and Co(dppf)Cl2 (dppf=(1,1’-bis(diphenylphosphino)ferro-
cene)), Zn/ZnI2 as the catalyst. This catalytic system has been
widely used to promote cycloaddition reactions.[7a,8] To our de-
light, the designed cycloadduct 2a was obtained in 15% yield
along with 74% recovery of the starting material (Table 1,
entry 1). Using Et2Zn as the reductant, an increased yield (32%)
was obtained (entry 2). In some reported cobalt-catalyzed reac-
tions, compared with other reductants, alkyl aluminum re-
agents have shown their special properties and advantages.[9]
So, we systematically screened various alkyl aluminum re-
agents, different quantities of the used reductant, various sol-
vents (for more details, see the Supporting Information), find-
ing that carrying out the cycloaddition of 1a in dichloroethane
(DCE) (0.1m) at 608C in the presence of Me2AlCl (0.5 equiv)
gave cycloadduct 2a in 93% yield. Therefore, conditions in
entry 7 were chosen as the optimal conditions for the racemic
[3+2] reaction. We then spent our efforts on advancing this re-
action to an asymmetric version by screening several chiral li-
gands. Using (S)-H8-BINAP led to high yield of 2a, but the ee
cycloadditions gave good yields (77–96%) with high enantio-
selectivities (88–92% ee; 2a–f). Single-crystal X-ray diffraction
analysis confirmed the absolute configuration of 2c, which has
an S configuration.[10] To our delight, the aryl bromide atom
can be tolerated in the reaction and this success makes it pos-
sible to further functionalize the [3+2] cycloadducts of 2d and
2 f by coupling reactions. Moreover, heterocycle-substituted
substrates (1g, 1h) also underwent cycloadditions to form the
corresponding 2g (76%, 81% ee) and 2h (92%, 92% ee), re-
spectively. The different enyne-ACP substrates (1i, 1j, 1k) can
also generate the cycloadducts (2i, 2j, 2k) in excellent yields
(from 87% to 96%) with high ee values (from 81% to 91%). In
addition, substrates with substituted alkynes, which are ali-
phatic groups such as methyl (1l), cyclopropyl (1m), and func-
tionalized alkyl group bearing a OTBS substituent (1n), gener-
ated the desired products (2l, 2m, 2n) in good yields (72–
90%) and enantioselectivities (71–87% ee). It should be point-
ed out that, in some cases, more equivalents of AlMe2Cl
(1.0 equiv) and a higher reaction temperature (608C) were
needed to accelerate the transformations and ensure efficient
conversions (entries 7–18). Interestingly, the protocol we devel-
oped can not only afford the fused 5,5-bicyclic ring systems
but also generate the bicyclo[4.3.0]nonadiene derivatives 2o
(83%, 74% ee), 2p (68%, 55% ee), and 2q (95%, 59% ee). For
the substrate bearing a methyl at the internal position of the
ACP alkene (1r), low yield and no asymmetric induction was
obtained. In addition, we also tried some substrates with a
Lewis acid-sensitive functional group (1s, 1t, 1u), lower reac-
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Experimental and DFT investigation of the asymmetric
[3+2] cycloaddition mechanism
Table 1. Reaction optimization.[a]
We performed mechanistic investigation via both experiments
and DFT calculations on the [3+2] cycloaddition of yne-ACPs.
Using stoichiometric Co(dppf)Cl2 and Zn as reductant, no trans-
formation happened, indicating that neutral Co0/CoII or CoI/
CoIII may not work under the reaction conditions.[13] In some re-
ported CoII–diphosphine complexes and alkylaluminum re-
agents for CÀC bond formation reactions, the alkylaluminum
might act as a reductant as well as an anion abstractor.[9a,b,14]
Using the counter anions NaBARF (sodium tetrakis[3,5-bis(tri-
fluoromethyl)phenyl]borate) as activator,[15] 95% yield of cyclo-
adduct 2a was obtained (Scheme 2). The above experiment
suggested a unique role of a possible cationic CoI/CoIII catalytic
cycle in our reaction. In addition, Co0 species may not be ex-
cluded since using Et2Zn as the reductant, which has been pro-
posed to form a Co0 species by Dong and co-workers,[16] only
32% yield of cycloadduct 2a was obtained (entry 2, Table 1)
To gain more insights into the catalytic pathway in our reac-
tion system, we performed DFT calculations on the reaction of
a model complex INT1 formed by yne-ACP substrate and a
cationic cobalt(I) diphosphine species (Figure 1). A smaller
methanesulfonyl protecting group and 1,3-bis(dimethylphos-
phino)propane (dmpp) were used to reduce the computational
cost without sacrificing the understanding of the reaction
mechanism. The validation of simplified ligand dmpp had
been supported by both experiment and further calculations:
experimentally using Co(dppp)Cl2 (dppp=1,3-bis(diphenyl-
phosphino)propane) as catalyst, 1a can be converted to 2a in
74% yield; using dppp as ligand in calculations, similar results
for the key steps were found compared to those from dmpp
(see the Supporting Information).
Entry
Ligand[e]
Reductant [equiv]
Time [h]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L12
L13
L5
L5
L5
Zn (0.5), ZnCl2 (0.1)
Et2Zn (0.5)
Me3Al (1.0)
24
1
15
32
5
6
6
–
–
–
–
–
–
–
6
87
85
89
60
33
54
22
À39
À16
25
21
90
90
91
16
16
16
10
16
18
18
18
18
18
18
18
18
18
18
18
18
18
18
1.5
Et3Al (1.0)
Et2AlCl (1.0)
Me2AlCl (1.0)
Me2AlCl (0.5)
Me2AlCl (0.5)
Me2AlCl (0.5)
Me2AlCl (0.5)
Me2AlCl (0.5)
Me2AlCl (0.5)
Me2AlCl (0.5)
Me2AlCl (0.5)
Me2AlCl (0.5)
Me2AlCl (0.5)
Me2AlCl (0.5)
Me2AlCl (0.5)
Me2AlCl (0.5)
Me2AlCl (0.5)
Me2AlCl (0.5)
Me2AlCl (0.5)
94
93
90
94
86
85
12
82
73
17
76
85
82
83
98
99
96
9
10
11
12
13
14
15
16
17
18
19
20[b]
21[c]
22[d]
[a] General reaction conditions: DCE as solvent and 608C as temperature;
isolated yields and enantiomeric excess (ee) values were determined by
high-performance liquid chromatography (HPLC).[c] Reaction tempera-
ture: 308C. [c] Reaction temperature: 08C. [d] Solvent: DCE/n-heptane
(1:1), reaction temperature: 308C. [e] Ligands used herein:
The energy profile was drawn based on the relative Gibbs
free energies in DCE solution (DGDCE). Note that the suffixes s
and t on the structure numberings refer to the singlet and trip-
let states, respectively. The first step of the catalytic cycle is the
activation of ACPs. The majority of reported transition metal-
catalyzed cycloaddition of ACPs and unsaturated partners are
initiated by oxidative addition of the metal (typically Pd, Rh, Ni
or Ru) to either the proximal or distal CÀC bond of the cyclo-
propane.[17] However, we found that the distal CÀC cleavage of
ACPs via TS1a–s has an activation free energy of 42.8 kcal
molÀ1 and proximal CÀC cleavage of ACPs via TS1b–s has an
activation free energy of 43.7 kcalmolÀ1, indicating that these
two modes of activation are infeasible. Then a mechanism in
which the double bond of the ACPs is first activated was pro-
tion yields were obtained, partially because of the Lewis-acidic
character of the reducing agent. Similar results were also re-
ported for Co/Al-catalyzed cycloadditions.[11] It is interesting to
find that using Zn/ZnI2 as activator instead, the oxygen-teth-
ered substrate 1s and carbon-tethered substrates 1t and 1u
can participate in the [3+2] reactions, affording the desired
product 2s (90%, 87% ee), 2t (81%, 88% ee), and 2u (92%,
88% ee), respectively.[12] We also tested the substrate 1v with
an aryl group as tether, finding that the reaction took place in
high yield of 85%, but almost no ee was obtained.
Scheme 2. Experimental investigation of reaction mechanism. N.R.=no reac-
tion.
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Table 2. Scope of reaction.[a]
Entry
Substrate
Product
1[b]
2[b]
3[b]
4[b]
5[b]
6[b]
7[c]
8[c]
1a, Ar=Ph
2a, 2 h, 96%, 91% ee
2b, 3 h, 92%, 91% ee
2c, 6 h, 77%, 92% ee
2d, 3 h, 94%, 89% ee
2e, 3 h, 89%, 91% ee
2 f, 3 h, 80%, 88% ee
2g, 0.5 h, 76%, 81% ee
2h, 0.5 h, 92%, 92% ee
1b, Ar=4-MeOC6H4
1c, Ar=4-CF3C6H4
1d, Ar=4-BrC6H4
1e, Ar=2-MeOC6H4
1 f, Ar=2-BrC6H4
1g, X=O
1h, X=S
9[c]
10[c]
11[c]
1i, R1 =H, R2 =H, R3 =H
1j, R1 =H, R2 =CH3, R3 =CH3
1k, R1 =CH3, R2 =H, R3 =H
2i, 0.5 h, 96%, 83% ee
2j, 0.5 h, 92%, 81% ee
2k, 1 h, 87%, 91% ee
12[c]
13[c]
14[c]
1l, R=CH3
1m, R=cyclopropyl
1n, R=CH2OTBS
2l, 1 h, 83%, 85% ee
2m, 1 h, 90%, 87% ee
2n, 1 h, 72%, 71% ee
15[c]
16[c]
1o, R=CH3
1p, R=vinyl
2o, 2 h, 83%, 74% ee
2p, 5 h, 68%, 55% ee
17[c]
18[c]
19[d]
1q
1r
1s
2q, 0.5 h, 95%, 59% ee
2r, 4 h, 13%, 0% ee
2s, 4 h, 90%, 87% ee
20[d]
21[d]
1t, R=COOMe
1u, R=CH2OTs
2t, 12 h, 81%, 88% ee
2u, 8 h, 92%, 88% ee
22[c]
1v
2v, 1.5 h, 85%, 7% ee
[a] Isolated yields and ee were determined by high-performance liquid chromatography (HPLC); the reaction was run on 0.08 mmol scale; the reported
yield was average of two runs; the absolute configuration of all products was determined by analogy to 2c, which was confirmed by X-ray analysis.
[b] Me2AlCl (0.5 equiv) was added to the solution of 1 and Co[(S)-Xyl-BINAP]Cl2 in DCE/n-heptane (1:1) (0.1m) at 308C. [c] Me2AlCl (1.0 equiv) was added to
the solution of 1 and Co[(S)-Xyl-BINAP]Cl2 in DCE/n-heptane (1:1) (0.1m) at 608C. [d] Co[(S)-Xyl-BINAP]Cl2 (0.1 equiv), Zn (0.5 equiv), ZnI2 (0.1 equiv) was
used in DCE (0.1m) at 808C.
posed.[18] This reaction can proceed through coordination of
cationic CoI to the alkyne and alkene followed by oxidative cy-
clometallation to form cationic CoIII metallacycle INT2-s with
an energy barrier of 16.7 kcalmolÀ1 (via TS1c–s). Next, ring
opening of the cyclopropyl group via TS2-s affords the p-allyl
metallacycle intermediate INT3-s. This step is exergonic by
25.7 kcalmolÀ1 with a computed activation free energy of
21.9 kcalmolÀ1. The followed reductive elimination preferential-
ly occurs in the triplet state TS3-t with a much lower energy
barrier (23.3 kcalmolÀ1 vs. 33.0 kcalmolÀ1 in the singlet state
TS3-s with respect to INT3-s). Here, the triplet intermediate
INT3-t may be connected to the corresponding singlet inter-
mediate INT3-s by minimum energy crossing point (MECP2).
Finally, an endergonic process of catalyst transfer between
INT4 and starting material to release the cycloadduct occurs to
close the catalytic cycle. In general, the reductive elimination
process is the rate-determining step and the overall activation
Gibbs activation energy of 23.3 kcalmolÀ1 (from INT3-s to TS3-
t) is in accordance with our experimental observation that the
reaction took place smoothly under mild conditions.
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Figure 1. Computed energy surface for the [3+2] cycloaddition catalyzed by a model cobalt(I)-diphospine species at the SMD(DCE)/M06L/6–311+G(2d,p)
(SDD for Co)//B3LYP/6-31G(d) (LANL2DZ for Co) level.
formed to confirm that each stationary point was either a mini-
mum or a transition structure and to evaluate its zero-point energy
and the thermal corrections at 298 K. IRC calculations[23] were car-
Conclusions
We have developed for the first time a cobalt-catalyzed enan-
tioselective intramolecular [3+2] cycloaddition of yne-ACPs
using a commercially available ligand and reductant. This reac-
tion greatly expands the scope of cobalt catalysis in asymmet-
ric synthesis, considering that both bicyclo[3.3.0]octadienes
and bicyclo[4.3.0]nonadienes can be obtained in good-to-ex-
cellent yields with high ee. The experimental and DFT investi-
gations of the reaction mechanism revealed that the reaction
starts with oxidative cyclometallation of alkyne and alkene cat-
alyzed by cationic CoI, followed by a ring opening of the cyclo-
propyl group to afford the p-allyl metallacycle intermediate
and a subsequent rate-limiting reductive elimination step to
form the cycloadduct. We expect that the present reaction will
become a useful tool for synthetic chemists and the mecha-
nism here will be inspiring for understanding/designing of
known/new Co-catalyzed reactions.[12]
ried out to confirm that the key transition state structures connect-
ing the corresponding reactant and product. On the basis of the
gas phase optimized structures, the solvation energies (DGsolvation
)
were obtained at the SMD(DCE)/B3LYP/6-31G(d) (LANL2DZ for
Co)[24] level and the single-point energy refinements were per-
formed at M06L/6–311+G(2d,p) (SDD for Co).[25] Pruned integra-
tion grids with 99 radial shells and 590 angular points per shell
were used during single-point energy calculations. Gibbs free ener-
gies in solution were obtained from sums of the large basis set
gas-phase single-point energies, DGsolvation and the gas-phase Gibbs
free energy corrections (at 298 K). The minimum energy crossing
points (MECP) between the singlet and triplet states were located
with the sobMECP program[26] at the M06L/6–311+G(2d,p) (SDD
for Co). All the graphics of molecular structures were prepared
using CYLview software.[27]
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (91856105 and 21933003) and High-Per-
formance Computing Platform of Peking University.
Computational Methods
DFT calculations with the Gaussian 09 program[19] were used to ex-
plore the mechanism of the reaction. The B3LYP functional[20] was
used to optimize the geometries of all stationary points in the gas
phase with the LANL2DZ basis set[21] for cobalt and 6-31G(d) basis
set[22] for the other atoms. The keyword “5D” was used to specify
that five d-type orbitals were used for all elements in structure op-
timization. Frequency calculations at the same level were per-
Conflict of interest
The authors declare no conflict of interest.
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D. E. Negru, D. Shang, Angew. Chem. Int. Ed. 2015, 54, 4768–4772;
Angew. Chem. 2015, 127, 4850–4854.
[6] J. Durµn, M. Gulías, L. Castedo, J. L. MascareÇas, Org. Lett. 2005, 7,
5693–5696. In this Pd-catalyzed intramolecular [3+2] cycloaddition be-
tween alkynes and ACPs, poor asymmetric results were obtained using
chiral ligands.
Keywords: cobalt · carbocycles · alkylidenecyclopropanes ·
homogeneous catalysis · reaction mechanisms
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Manuscript received: February 3, 2021
Accepted manuscript online: February 7, 2021
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