DOI: 10.1002/ejoc.

201900087 Full Paper

Mechanistic Studies
Mechanisms and Stereoselectivities of NHC-Catalyzed
[3 + 4] Cycloaddition Reaction between Isatin-Derived Enal and
N-(ortho-Chloromethyl)aryl Amide
Yan Li*[a] and Zhiqiang Zhang[a]

Abstract: Possible mechanisms and origins of stereoselectivity N-(ortho-chloromethyl)aryl amide generating the acyl azolium
of N-heterocyclic carbene (NHC) promoted spirobenzazepinone intermediate (step III). Then the reaction proceeds through suc-
formation from the annulation of an isatin-derived enal and N- cessive intramolecular cycloaddition (step IV), H2O-mediated
(ortho-chloromethyl)aryl amide have been investigated compu- 1,3-proton transfer (step V) and catalyst elimination (step VI) af-
tationally. DFT results (M06–2X) suggest that the preferred fording the [3+4] cycloaddition product. Step V plays a pivotal
mechanism consists of six steps: The nucleophilic coupling of role in determining the stereoselectivity of the reaction and
the NHC catalyst and isatin-derived enal was considered as the leads to the experimentally observed S-configuration product.
first reaction step (step I), followed by generation of the Breslow The DFT results account for the experimental observations.
intermediate through a HCO3– assisted proton transfer event Global reactivity index analysis has also been conducted to
(step II). The next step is the addition of Breslow intermediate to identify the role of NHC catalyst.

1. Introduction components), as shown in Scheme 1 could be effectively cata-

lyzed by using the triazolium-based NHC and Cs2CO3 as the
Nitrogen-containing heterocycles are ubiquitous substructures
base. The reaction proceeded smoothly at room temperature
in a large number of organosynthesis intermediates, pharma-
and offered the desired product with high enantioselectivities.
ceuticals, and natural products.[1] As a result, the search for effi-
cient methods to construct such compounds has been a hot
topic of chemical synthesis for a long time. On the other hand,
organocatalysis has emerged as an important and powerful tool
for the construction of heterocycles from relatively simple mate-
rials in recently years.[2] As effective organocatalysts, N-hetero-
cyclic carbenes (NHCs) have a large potential for use in many
synthetic strategies.[3] In fact, NHC catalyzed carbon–carbon
and carbon–heteroatom bond formation reactions have already
been reported.[4] In particular, a range of cycloaddition reac-
tions promoted by NHC catalysts affording carbo- and hetero-
cycles have also been reported, such as [2 + 2],[5] [2 + 2 + 2],[6]
Scheme 1. [3 + 4] cycloaddition reaction of isatin-derived enal with N-(ortho-
[2 + 4],[7] [3 + n] (n = 2, 3, 4),[8] [4 + n] (n = 2, 3)[9] cycloadditions. chloromethyl)aryl amide promoted by NHC.
In contrast, synthetic methods on NHC-catalyzed [3 + 4] annula-
tions towards quaternary carbon-containing spirocyclic struc- Accompanied by the significant progress made in experi-
tures are limited due to the difficulty in creating all-carbon ments, computational studies on annulations by using the NHC
spiro-stereocenter. catalysts have also been reported.[11] This would certainly give
Recently, the Enders's group[10] reported a novel NHC-cata- people a deeper understanding of the mechanistic details of
lyzed [3 + 4] cycloaddition reaction furnishing desired spiro- the NHC-participated reactions, and thus provide new insights
benzazepinones. The reaction between an isatin-derived enal for searching and designing new efficient catalysts for highly
(3C components) and N-(ortho-chloromethyl)aryl amide (4C selective reactions.
Unfortunately, the [3 + 4] cycloaddition reaction between an
[a] School of Chemical Engineering, University of Science and Technology isatin-derived enal and N-(ortho-chloromethyl)aryl amide cata-
Liaoning, lyzed by NHC (Scheme 1) has not been reported until now.
Anshan 114051, P. R. China Therefore, we will investigate the mechanisms and origins of
E-mail: [email protected]
http://www.ustl.edu.cn/yjs/xxcx/sdxx/51038.htm
stereoselectivity of the NHC-catalyzed [3 + 4] annulation reac-
Supporting information and ORCID(s) from the author(s) for this article are tion (Scheme 1) by density functional theory (DFT) calculations.
available on the WWW under https://doi.org/10.1002/ejoc.201900087. In particular, we wish to disclose the energetics related to the

Eur. J. Org. Chem. 2019, 2989–2997 2989 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Full Paper

most preferred pathway and the insights on the enantioselec- nism on the basis of our computational results is provided in
tivity. Moreover, we would like to clarify the role of the NHC Scheme 2. With the aid of CO32–, which was derived from the
catalyst. Cs2CO3 base, the precatalyst was deprotonated to produce the
bicarbonate anion (HCO3–) and Cat which was thought to be
the actual catalyst.[22] In our calculations, we used aza-o-quin-
2. Computational Details one methide as the starting reactant because it can be gener-
ated when N-(ortho-chloromethyl)aryl amide reacts with
All density functional theory (DFT) calculations were carried out
Cs2CO3. Scheme 2 shows that the catalytic cycle involves six
by using the Gaussian 09 program package.[12] For all the
steps, i.e. reaction of the NHC catalyst Cat with isatin-derived
minima and transition states, geometry optimization was per-
enal R1, affording intermediate 1 (Step I), formation of the
formed at the M06–2X/6-31G(d) level of theory in the gas
Breslow intermediate 2 through a proton migration in interme-
phase.[13] This functional (M06–2X) is chosen based on the ex-
diate 1 (Step II), addition to aza-o-quinone methide R2 results
perience of others and ourselves.[14] All the optimized struc-
in the formation of intermediate 3 (Step III), intramolecular
tures (minima or transition states) were confirmed by the vibra-
cycloaddition (Step IV) followed by the 1,3-proton transfer to
tional frequency calculations, i.e. an energy minimum has all
form intermediate 5 (Step V), and catalyst liberation provides
real frequencies while a transition state has one and only one
access to the final cycloaddition product (Step IV). Figure 1
imaginary frequency. For transition states, intrinsic reaction co-
shows the free energy profiles calculated for the reaction mech-
ordinate (IRC) calculations were also performed to verify the
anism shown in Scheme 2.
connection with their relevant minima.[15] Considering that the
ethyl acetate (EtOAc) was used as solvent, the SMD solvation Step I. Addition of NHC Catalyst to Isatin-Derived Enal R1
model[16] was employed to compute the single-point energies
The C1 atom of the NHC catalyst Cat attacks on the C2 atom of
at the SMD(EtOAc)M06–2X/6-311++G(d,p) level for all the opti-
R1 was considered as the first step of the reaction and yielding
mized structures.
intermediate Re-/Si-1. Formation of Re-1 and Si-1 are ender-
In order to inspect the effect of the functionals and basis
gonic processes with reaction energies of 15.2 (Re-1) and 10.2
sets on the studied reaction, for the carbon–carbon bond for-
(Si-1) kcal/mol. The activation free energies calculated for Re-
mation step, other functionals (B3LYP-D3, w97XD and M06–2X-
TS1 and Si-TS1 are 17.0 kcal/mol and 16.3 kcal/mol, respec-
D3) and basis set (6-311++G(2df, 2pd)) were used to compute
tively (see Figure 1 for details). As illustrated in Figure 2, for the
single-point energies. Table S1 in the supporting information
transformation of Cat + R1 → TS1 → 1, the C1–C2 bond length
shows the calculated results at different levels. It is clear that
is shortened. The C1–C2 bond length is 1.853/1.901 Å in
the dependence of functionals and basis sets was not signifi-
Re-/Si-TS1, compared with that of 1.577/1.558 Å in Re-/Si-1.
cant, because the activation free energies calculated at different
The structural results demonstrate that the carbon–carbon
levels are similar.
bond has been formed in intermediate 1. In addition, the C2–
To examine charge distribution, natural bond orbital (NBO)
O3 bond has been activated considering that the C2–O3 bond
analyses at the M06–2X/6-311++G(d,p) level were carried
length is 1.262/1.255 Å in Re-/Si-TS1 compared with that of
out.[17] Furthermore, in the present work, global reactivity index
1.316/1.318 Å in Re-/Si-1.
(GRI) analysis was also performed to investigate the role of
The results of NBO analysis (as depicted in Scheme 3) shows
the NHC catalyst. The electrophilicity index ω, written as ω =
that the positive charge increase has seen in the reaction of
(μ2/2η) (eV) reflects the molecular global electrophilicity charac-
Cat with R1 (the positive charge on the carbon atom (C1) is
ter.[18] In the above definition, μ and η represent the electronic
increased from 0.176 e (Cat) to 0.541/0.577 e (Re-/Si-1)), while
chemical and the chemical hardness, respectively and their
that on the C2 atom is decreased (0.405 e (R1) vs. 0.103/0.133
value can be obtained through the following expression
e (Re-/Si-1)). Scheme 3 also shows that the negative charge on
μ ≈ (εH -εL)/2 and η ≈ (εL – εH),[19] where εH and εL are the
the nitrogen atom is decreased (–0.486 e (Cat) vs. –0.420/–0.446
one-electron energies of the highest occupied molecular orbital
e (Re-/Si-1)), whereas that on the carbonyl oxygen atom is in-
(HOMO) and the lowest unoccupied molecular orbital (LUMO),
creased (–0.537 e in (R1) vs. –0.875/–0.855 e (Re-/Si-1)). The
respectively. Based on the HOMO energies (obtained with the
above results demonstrate that the electron of Cat is trans-
Kohn–Sham scheme ),[20] an empirical (relative) nucleophilicity
ferred to R1.
index N,[21] with the definition of N = εH (Nu) – εH (TCE) was intro-
duced by Domingo et al. where the nucleophilicity of tetra- Step II. 1,2-Proton Transfer
cyanoethylene (TCE) is taken as the reference point. From the intermediate 1, a 1,2-proton transfer takes place to
form the Breslow intermediate 2. In this work, besides the direct
proton transfer, mediators including bicarbonate anion and wa-
3. Results and Discussion ter-promoted proton transfer have also been explored.
3.1 Mechanism of NHC-Catalyzed [3+4] Cycloaddition (a) Direct Proton Transfer
Reaction
The direct proton transfer of intermediate Re-/Si-1 forms inter-
We first present and discuss the mechanism of the cycloaddi- mediates Re-/Si-2 (see Figure S1). A three-membered ring is
tion reaction of isatin-derived enal and N-(ortho-chloro- found in the corresponding transition states Re-/Si-TS2d, results
methyl)aryl amide (Scheme 1). The possible reaction mecha- in very high energy barriers for the direct proton transfer

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 Full Paper

Scheme 2. The calculated reaction mechanism.

process. The corresponding transition states Re-/Si-TS2d locate coupled with the H′ transfers from O2′ to O3 via the transition
52.1/46.4 kcal/mol above the energy reference (R1 + Cat), thus states Re-/Si-TS2. The bond lengths of C2–H1, H1–O1′, O3–H′
indicating this mechanism is kinetically unfeasible. and O2′–H′ in Re-/Si-TS2 are 1.269/1.211, 1.419/1.548, 1.775/
1.691 and 0.997/0.995 Å, respectively. The structural results
(b) HCO3– Promoted Proton Transfer demonstrate that in the participation of HCO3–, the proton
Figure 1 shows the HCO3– assisted proton transfer occurs to transfer takes place in a concerted manner but not synchro-
generate the Breslow intermediates Re-/Si-2 via the seven- nous. The activation free energies calculated for the Re-/Si-TS2
membered ring transition states Re-/Si-TS2. The H1 atom of are 9.5/12.3 kcal/mol (24.7/22.5 kcal/mol relative to reactants),
intermediate 2 migrates from the C2 atom to the O1′ atom, demonstrating the proton transfer could occur more easily in

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 Full Paper

Figure 1. Free energy profile (in kcal/mol) obtained at SMD(EtOAc)/M06–2X/6-311++G(d,p) level for the [3+4] cycloaddition reaction of isatin-derived enal
with N-(ortho-chloromethyl)aryl amide.

Figure 2. Optimized structures for steps I–II. Selected bond lengths are given in Å.

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 Full Paper

Step III. Addition of 2 to R2

The third step is the formation of the carbon–carbon bond
wherein the addition of Re-/Si-2 on R2 takes place leading to
intermediates 3(R&S). It should be noted that R2 can approach
2 in either endo or exo manner. Moreover, R2 can attack inter-
mediate 2 either from its Re or from its Si face. Four attack
modes, shown in Scheme 4 were thus located for this step. As
can be seen from Scheme 4, one chiral carbon atom (C5) in
intermediates endo-3(R&S) and exo-3(R&S) is generated.

Scheme 3. The NBO results of selected atoms in Cat, R1 and Re-1 and Si-1
((in parentheses) (units of e).

the presence of HCO3– than that in its absence under the exper-
imental conditions.

(c) Water Promoted Proton Transfer

Previous studies have shown that water could promote the pro-
ton transfer process.[23] Inspired by these studies, in this paper,
we have also examined the possibility of water as a mediator
for the 1,2-proton transfer process. Figure S1 shows the free
energy profiles calculated for the proton transfer process, medi-
ated either by one molecule of water or by two water mol-
ecules. For simplicity of presentation, H2O- and 2H2O-assisted
mechanism are used to denote the proton transfer promoted
by one and two water molecule(s), respectively. The corre-
sponding reaction pathways are also collected and compared Scheme 4. The four attack modes of 2 to R2.
in Figure S1 in order to make a direct comparison between the
unassisted and mediators-assisted proton transfer results. From Figure 1, we can see that reaction complexes Re-/Si-2–
In the H2O-assisted proton transfer mechanism, the H1w 1 are generated before the transition states endo-TS3(R&S) and
atom of the H2O molecule is transferred to O3 atom, at the exo-TS3(R&S), the activation free energies for endo addition are
same time the H1 atom connected to C2 is transferred to O1w 6.7 (endo-TS3(R)) and 0.5 (endo-TS3(S)) kcal/mol with respect
atom. The C2–H1, H1–O1w, O1w–H1w and H1w–O3 bond lengths to Si-2–1. In contrast, the activation free energies for exo addi-
in Re-/Si-TS2w are 1.252/1.238, 1.469/1.467, 1.499/1.475 and tion are 2.3 (exo-TS3(R)) and 18.5 (exo-TS3(S)) kcal/mol with
1.055/1.065 Å, respectively. The structural results illustrate the respect to Re-2–1. It is clear that the endo addition via endo-
H2O-assisted proton transfer is also a concerted but asynchro- TS3(S) and the exo addition via exo-TS3(R) are energetically
nous process. The activation free energies of the Re-TS2w and more favorable compared to the other addition modes. There-
Si-TS2w, are respectively 33.1 and 33.5 kcal/mol. fore, we concentrate our attention on the pathways starting
As for 2H2O-assisted proton transfer mechanism, the 1,2-pro- from endo-3(S) and exo-3(R) in the following discussion. The
ton transfer proceeds via the seven-membered ring transition C5–C6 bond length shortens from 2.523 Å in endo-TS3(S) and
states Re-/Si-TS22w with activation free energies of 26.6/ 2.539 Å in exo-TS3(R) to 1.564 Å in endo-3(S) and 1.575 Å in
29.8 kcal/mol, indicating the 2H2O-assisted proton transfer is exo-3(R), indicating the C5–C6 bond is formed in endo-3(S)
more favored over the H2O-assisted and direct proton transfer and exo-3(R).
processes but less favorable than the HCO3– mediated proton On the other hand, we have also examined an alternative
transfer. In Re-/Si-TS22w, the bond lengths of C2–H1, H1–O2w′, pathway in which a 1,3-proton transfer of intermediate 2 (from
O1w′–H1w′ and H1w′–O3 are 1.229/1.241, 1.466/1.448, 1.640/ O3 to C4) takes place prior to the addition to R2. In the present
1.594 and 1.000/1.011 Å, respectively. The structural results work, both HCO3– and water-promoted proton transfer have
demonstrate that the 2H2O-assisted 1,2-proton transfer is a con- been examined. As presented in the Supporting Information
certed but asynchronous process, which is further confirmed by (Figure S3), the relative free energy of transition state (Re-/Si-
IRC calculations for Re-/Si-TS22w (see Figure S2 for details). TS3) for the HCO3– assisted proton transfer is 28.1/26.2 kcal/
To sum up, for the 1,2 proton transfer process, three possibili- mol higher than exo-TS3(R)/endo-TS3(S), thus excluding the
ties (including direct, HCO3– and water-mediated) have been possibility. As for the water-mediated proton transfer process,
suggested and examined in the present work. The HCO3–-as- the relative free energy of the transition state (Re-/Si-TS3w) is
sisted mechanism is the most energy feasible. calculated to be even higher (ΔG≠ = 48.6/43.0 kcal/mol for

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 Full Paper

Re-/Si-TS3w) than that of HCO3– assisted proton transfer via ined. In this work, both direct and mediator-assisted proton
Re-/Si-TS3. These results suggest that the H2O-assisted proton transfer (H2O and HCO3–) have been considered. The results
transfer is energetically very unfavorable. Moreover, it should were provided in Figure S4 in the Supporting Information. As
be noted that we could not locate the transition state for the shown in Figure S4, the relative energies of direct proton trans-
2H2O-assisted proton transfer despite lots of attempts. fer transition states H_exo-TS4d(R)and H_endo-TS4d(S) are 34.4
and 18.8 kcal/mol higher than the cyclization transition state
Step IV. Intramolecular Cyclization exo-TS4(R) and endo-TS4(S), respectively, making the 1,3-pro-
Intramolecular cyclization of endo-3(S)/exo-3(R) via the seven- ton transfer of intermediate 3 is much less favorable as com-
membered ring (C2–C4–C5–C6–C7–C8–N9) transition states pared to intramolecular cyclization. As for H2O assisted proton
endo-TS4(S)/exo-TS4(R) affording intermediates endo-4(S) and transfer, the relative energies of H_exo-TS4(R) and H_endo-
exo-4(R), respectively. This process requires activation free en- TS4(S) are 12.5 and 11.2 kcal/mol higher than the cyclization
ergies of 11.8/21.6 (endo-TS4(S)/exo-TS4(R)) kcal/mol. Figure 3 transition state exo-TS4(R) and endo-TS4(S), respectively, thus
shows that, for 3 → 4 transformation, the C2–N9 bond length excluding the possibility. We tried to locate the transition state
shorts from 3.000 Å in endo-3(S) and 2.680 Å in exo-3(R), to for the 2H2O assisted proton transfer for intermediate endo-
1.695 Å in endo-TS4(S) and 1.676 Å in exo-TS4(R), then to 3(S), but failed despite of numerous attempts. It should be
1.511 Å in endo-4(S) and 1.499 Å in exo-4(R). noted that we cannot locate the transition states for the HCO3–
Moreover, the possibility of 1,3-proton transfer (from O3 to assisted proton transfer. Based on the above analysis, for inter-
C4) of intermediates endo-3(S)/exo-3(R) has also been exam- mediate 3, the cyclization is favored over the proton transfer.

Figure 3. Optimized structures for steps III–VI. Selected bond lengths are given in Å.

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Step V. 1,3-Proton Transfer formation of intermediate exo-5(R) and finally results in the R-
The fifth step is the 1,3-proton transfer of endo-4(S)/exo-4(R) configurational product P(R) requires an activation free energy
to form intermediate endo-5(S)/exo-5(R). Similar to the discus- of 26.4 kcal/mol. Consequently, our calculation results support
sion of step II, we first examined the direct process. The com- the experimental finding that the S-configurational product is
puted activation free energies via transition states endo-TS5d(S) the major product. Moreover, the 9.9 kcal/mol energy barrier
and exo-TS5d(R) are inaccessibly high (27.8/35.7 kcal/mol with difference leading to a predicted ee of 99 % which is consistent
respect to endo-3(S)/exo-3(R)) (for details see the Supporting with the experimental reported er of 99:1.[10]
Information, Figure S5).
Then, the water-mediated proton transfer was also exam-
ined. According to our calculations, the H2O-assisted proton 3.3 The Role of NHC Catalyst
transfer proceeds via transition states endo-TS5(S)/exo-TS5(R) To better understand the role of NHC catalyst in the [3+4] cyclo-
with activation free energies of 1.5/0.2 kcal/mol, leading to in- addition reaction between isatin-derived enal and N-(ortho-
termediates endo-5(S)/exo-5(R), indicating that the 1,3-proton chloromethyl)aryl amide, we calculated global reactivity indexes
transfer could occur easily when one water molecule is involved (GRIs) (Table 1). It can be seen from Table 1, the reaction of Cat
in the reaction system. This step is exergonic by 39.5 and with R1 increases its electronic chemical potential. This obser-
42.8 kcal/mol associated with endo-5(S) and exo-5(R), respec- vation is consistent with the NBO analysis that electron density
tively. In endo-TS5(S)/exo-TS5(R), the distances of O3–H1, is transferred from NHC catalyst to R1. Furthermore, in the con-
H1–Ow, C4–Hw and Hw–Ow bonds are 1.620/1.721, 1.020/1.007, version of R1 to Re-/Si-1, then to Re-/Si-2, we observe that the
1.500/1.465 and 1.155/1.184 Å, respectively. addition of Cat enhances R1′s nucleophilicity remarkably (the
Step VI. Catalyst Regeneration nucleophilicities of Re-/Si-1 and Re-/Si-2 are larger than that of
R1) while the electrophilicity of R1 was reduced instead, which
As shown in Scheme 2, conversion of intermediates endo-5(S)/
makes the subsequent nucleophilic addition to R2 easier (for
exo-5(R) into the final cycloaddition products P(S&R) demand
details see Table 1).
the elimination of the catalyst. During this process, the catalyst
Cat releases from intermediates endo-5(S)/exo-5(R) via the Table 1. Chemical hardness (η), electronic chemical potential, (μ), global elec-
endo-TS6(S)/exo-TS6(R) with activation free energies of 5.7/ trophilicity, (ω), and global nucleophilicity (N) calculated for the selected
7.6 kcal/mol, giving rise to the final products P(S) and P(R), species.
respectively. From intermediate 5 to transition state TS6, the Species η (eV) μ (eV) ω (eV) N (eV)
C1–C2 bond length elongates from 1.572/1.570 Å (endo-5(S)/
R1 5.27 –4.57 1.98 3.39
exo-5(R)) to 1.868/2.194 Å (endo-TS6(S)/exo-TS6(R)), as shown R2 5.62 –4.68 1.95 3.10
in Figure 3. Re-1 6.07 –3.71 1.13 3.85
Si-1 6.00 –3.65 1.11 3.95
Re-2 4.86 –3.28 1.11 4.88
Si-2 4.86 –3.28 1.10 4.88
3.2 Origin of Stereoselectivity

Figure 1 shows the free energy profile calculated for the whole
catalytic cycle. It should be noted that only the reaction path-
ways with the lowest energy barriers are shown. As presented
4. Conclusion
and discussed in Subsection 3.1, three possibilities have been
calculated for the transformation of 1 → 2 (step II), and the In summary, we have performed density functional theory
HCO3–-mediated process is the most preferred mechanism. (DFT) calculations to understand the mechanisms and origins
Furthermore, only the H2O-aided 1,3-proton transfer (step V) of stereoselectivity of the [3 + 4] annulation reaction between
pathways were presented in Figure 1. isatin-derived enal and N-(ortho-chloromethyl)aryl amide cata-
According to Figure 1, the chiral center (C5 atom) is gener- lyzed by N-heterocyclic carbene (NHC). The reaction mechanism
ated in the third step (addition of 2 to R2, for details, see Sub- we favor on the basis of the computational results described
section 3.1). Starting from intermediate 3, two pathways were above includes six reaction steps: the nucleophilic addition of
located for the formation of the cycloaddition product via inter- NHC catalyst to isatin-derived enal initiates the reaction giving
mediates endo-5(S)/exo-5(R). Our calculations show that the intermediate 1, which subsequently transformed to the Breslow
formation of intermediate 3 is reversible, whereas the formation intermediate through a HCO3– assisted 1,2-proton transfer
of endo-5(S)/exo-5(R) is irreversible. Therefore, transition states event. In the ensuing step, the addition of the Breslow interme-
endo-TS5(S) and exo-TS5(R) should be the stereoselectivity- diate to aza-o-quinone methide takes place, which upon intra-
controlling transition states and consequently play a leading molecular cyclization gives the seven-membered ring interme-
role in determining the stereoselectivity of the current [3+4] diate. The subsequent H2O assisted 1,3-proton transfer and cat-
cycloaddition reaction. It is clear from Figure 1, starting from alyst liberation produces the final cycloaddition product. The
intermediate 3, the pathway that associated with endo-TS5(S) pathway leading to the S-configuration product P(S) is most
has an activation free energy of 16.5 kcal/mol to form interme- energetically favorable, allowing the P(S) to dominate. Our
diate endo-5(S) and finally leads to the S-configurational prod- computational results align with previous experimental obser-
uct P(S). The pathway that associated with exo-TS5(R) for the vations.

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Acknowledgments [7] a) Z. F. Zhang, C. L. Zhang, Z. Y. Song, Z. H. Gao, S. Ye, Chem. Eur. J. 2018,
24, 8302–8305; b) C. L. Zhang, Z. H. Gao, Z. Q. Liang, S. Ye, Adv. Synth.
This research work was supported financially by the National Catal. 2016, 358, 2862–2866; c) L. M. Fang, F. Wang, P. J. Chua, Y. B. Lv,
Natural Science Foundation of China (No. 21403024). All calcula- L. J. Zhong, G. F. Zhong, Org. Lett. 2012, 14, 2894–2897; d) X. Q. Fang,
X. K. Chen, Y. R. Chi, Org. Lett. 2011, 13, 4708–4711.
tions were performed on the supercomputers from the National
[8] a) L. Yang, Y. Lv, F. Wang, G. Zhong, Org. Biomol. Chem. 2018, 16, 4433–
Supercomputing Center in Shenzhen. 4438; b) X. Y. Chen, K. Q. Chen, D. Q. Sun, S. Ye, Chem. Sci. 2017, 8, 1936–
1941; c) L. L. Zhao, X. S. Li, L. L. Cao, R. Zhang, X. Q. Shia, J. Qi, Chem.
Commun. 2017, 53, 5985–5988; d) C. Fang, T. Lu, J. Zhu, K. Sun, D. Du,
Keywords: Reaction mechanisms · Density functional Org. Lett. 2017, 19, 3470–3473; e) S. Y. Zhu, Y. Zhang, W. Wang, X. P. Hui,
calculations · N-heterocyclic carbene · Stereoselectivity · Org. Lett. 2017, 19, 5380–5383; f) T. Shu, Q. Ni, X. Song, K. Zhao, T. Wu,
Annulation R. Puttreddy, K. Rissanenb, D. Enders, Chem. Commun. 2016, 52, 2609–
2611; g) Q. Lin, Y. Li, D. K. Das, G. Zhang, Z. Zhao, S. Yang, X. Fang, Chem.
Commun. 2016, 52, 6459–6462; h) S. R. Yetra, S. Mondal, E. Suresh, A. T.
Biju, Org. Lett. 2015, 17, 1417–1420; i) C. Guo, M. Schedler, C. G. Daniliuc,
[1] a) Akhtar, A. A. Khan, Z. Ali, R. Haider, M. S. Yar, Eur. J. Med. Chem. 2017,
F. Glorius, Angew. Chem. Int. Ed. 2014, 53, 10232–10236; Angew. Chem.
125, 143–189; b) A. Mohammad, Int. J. Bioorg. Chem. 2017, 2, 146–152;
2014, 126, 10397; j) J. D. Tessier, E. A. O'Bryan, T. B. H. Schroeder, D. T.
c) R. Dalpozzo, Chem. Soc. Rev. 2015, 44, 742–778; d) J. H. Ryan, C. Hy-
Cohen, K. A. Scheidt, Angew. Chem. Int. Ed. 2012, 124, 5047–5051; Angew.
land, A. G. Meyer, J. A. Smith, J. X. Yin, Prog. Heterocycl. Chem. 2012, 24,
Chem. 2012, 124, 5047.
493–536; e) J. J. Vaquero, A. M. Cuadro, B. Herradyn, Modern Heterocyclic
[9] a) X. Li, Y. Wang, Y. Wang, M. S. Tang, L. B. Qu, Z. J. Li, D. H. Wei, J. Org.
Chemistry, Vol. 4 (Eds.: J. Alvarez-Builla, J. J. Vaquero, J. Barluenga), Wiley-
Chem. 2018, 83, 8543–8555; b) J. L. Li, F. Lu, J. Wu, K. C. Yang, Q. Z. Li,
VCH, Weinheim, 2011; f) D. Lednicer, Strategies for Organic Drug Synthesis
X. J. Gou, C. Peng, B. Han, X. D. Shen, Chem. Commun. 2017, 53, 6875–
and Design, Wiley, New York, 1998, 12, p. 362–378.
6878; c) G. Zhang, W. Xu, J. Liu, D. K. Das, S. Yang, S. Perveen, H. Zhang,
[2] a) Y. Ota, A. Kondoh, M. Terada, Angew. Chem. Int. Ed. 2018, 57, 13917–
X. Li, X. Fang, Chem. Commun. 2017, 53, 13336–13339; d) H. Yao, Y. Zhou,
13921; Angew. Chem. 2018, 130, 14113; b) D. J. Cheng, Y. D. Shao, Adv.
X. Chen, P. Zhang, J. Xu, H. Liu, J. Org. Chem. 2016, 81, 8888–8899; e)
Synth. Catal. 2018, 360, 3614–3642; c) Y. Y. Wang, D. W. Pan, T. T. Li, Z. C.
Y. W. Xie, Y. L. Que, T. J. Li, L. Zhu, C. X. Yu, C. S. Yao, Org. Biomol. Chem.
Jin, Chem. Asian J. 2018, 13, 2149–2163; d) B. Mondal, M. Balha, S. C.
2015, 13, 1829–1835; f) J. Izquierdo, A. Orue, K. A. Scheidt, J. Am. Chem.
Pan, Asian J. Chem. 2018, 7, 1788–1792; e) S. Sopena, M. Cozzolino, C.
Soc. 2013, 135, 10634–10637.
Maquilon, E. C. Escudero-Adan, M. M. Belmonte, A. W. Kleij, Angew. Chem.
[10] L. Wang, S. Li, M. Blümel, A. R. Philipps, A. Wang, R. Puttreddy, K. Rissa-
Int. Ed. 2018, 57, 11203–11207; Angew. Chem. 2018, 130, 11170; f) C.
nen, D. Enders, Angew. Chem. Int. Ed. 2016, 55, 11110–11114; Angew.
Yue, F. Na, X. Fang, Y. Cao, J. C. Antilla, Angew. Chem. Int. Ed. 2018, 57,
Chem. 2016, 128, 11276.
11004–11008; Angew. Chem. 2018, 130, 000–000; g) B. Satpathi, A. Mon-
[11] a) Y. Wang, L. B. Qu, D. H. Wei, Chem. Asian J. 2019, 14, 293–300; b) Y.
dal, S. S. V. Ramasastry, Chem. Asian J. 2018, 13, 1642–1653.
[3] a) K. J. R. Murauski, A. A. Jaworski, K. A. Scheidt, Chem. Soc. Rev. 2018, Wang, Q. Y. Wu, T. H. Lai, K. J. Zheng, L. B. Qu, D. H. Wei, Catal. Sci.
47, 1773–1782; b) S. Mondal, S. Mukherjee, T. K. Das, R. Gonnade, A. T. Technol. 2019, 9, 465–476; c) N. Liu, Y. F. Xie, C. Wang, S. J. Li, D. H. Wei,
Biju, ACS Catal. 2017, 7, 3995–3999; c) Z. Wu, J. Wang, ACS Catal. 2017, M. Li, B. Dai, ACS Catal. 2018, 8, 9945–9957; d) Y. Wang, D. H. Wei, W. J.
7, 7647–7652; d) B. Harish, M. Subbireddya, S. Suresh, Chem. Commun. Zhang, ChemCatChem 2018, 10, 338–360; e) Y. Wang, S. R. Zhang, Y. Y.
2017, 53, 3338–3341; e) A. Bhaumik, R. S. Verma, B. Tiwari, Org. Lett. Wang, L. B. Qu, D. H. Wei, Org. Chem. Front. 2018, 5, 2065–2072; f) Y. Li,
2017, 19, 444–447; f) H. Yuan, L. Zhang, Z. Liu, Y. Liu, J. Wang, W. Li, Org. Z. Q. Zhang, C. H. Liang, Org. Biomol. Chem. 2018, 16, 951–9258; g) R.
Biomol. Chem. 2017, 15, 4286–4290; g) Z. Huang, X. Huang, B. Li, C. Mou, Maji, S. E. Wheeler, J. Am. Chem. Soc. 2017, 139, 12441–12449; h) Y. Niu,
S. Yang, B. A. Song, Y. R. Chi, J. Am. Chem. Soc. 2016, 138, 7524–7527; N. Wang, A. Muñoz, J. Xu, H. Zeng, T. Rovis, J. K. Lee, J. Am. Chem. Soc.
h) T. Kato, S. Matsuoka, M. Suzuki, Chem. Commun. 2016, 52, 8569–8572; 2017, 139, 14917–14930; i) Y. Wang, D. Wei, M. Tang, J. Org. Chem. 2017,
i) A. Axelsson, E. Hammarvid, L. Ta, H. Sundén, Chem. Commun. 2016, 82, 13043–13050; j) Y. Li, T. T. Liu, C. H. Liang, Mol. Catal. 2017, 441, 199–
52, 11571–11574; j) D. M. Flanigan, F. R. Michailidis, N. A. White, T. Rovis, 208; k) Y. Y. Wang, D. H. Wei, Y. Wang, W. J. Zhang, M. S. Tang, ACS Catal.
Chem. Rev. 2015, 115, 9307–9387; k) M. Fèvre, J. Pinaud, Y. Gnanou, J. 2016, 6, 279–289.
Vignolle, D. Taton, Chem. Soc. Rev. 2013, 42, 2142–2172. [12] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
[4] a) J. Kim, S. H. Hong, Chem. Sci. 2017, 8, 2401–2406; b) S. Premaletha, A. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Na-
Ghosh, S. Joseph, S. R. Yetra, A. T. Biju, Chem. Commun. 2017, 53, 1478– katsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G.
1481; c) V. Kumar, S. J. Connon, Chem. Commun. 2017, 53, 10212–10215; Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hase-
d) J. L. Liu, Y. T. Zhang, H. F. Liu, L. Zhou, J. Chen, Org. Lett. 2017, 19, gawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A.
5272–5275; e) H. Lu, J. L. Zhang, J. Y. Liu, H. Y. Li, P. F. Xu, ACS Catal. 2017, Montgomery Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Broth-
7, 7797–7802; f) D. J. Müller, M. Fleige, D. Schlüns, M. Wollenburg, C. G. ers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghava-
Daniliuc, J. Neugebauer, F. Glorius, ACS Catal. 2016, 6, 5735–5739; g) P. chari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega,
Haghshenas, J. Wilson Quail, M. Gravel, J. Org. Chem. 2016, 81, 12075– J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J.
12083; h) A. Lee, K. A. Scheidt, Chem. Commun. 2015, 51, 3407–3410; Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi,
i) H. Lu, J. Y. Liu, C. G. Li, J. B. Lin, Y. M. Liang, P. F. Xu, Chem. Commun. C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski,
2015, 51, 4473–4476; j) J. Xu, C. Mou, T. Zhu, B. A. Song, Y. R. Chi, Org. G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö.
Lett. 2014, 16, 3272–3275; k) M. Wang, Z. J. Huang, J. F. Xu, Y. R. Chi, J. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09,
Am. Chem. Soc. 2014, 136, 1214–1217; l) L. H. Sun, Z. Q. Liang, W. Q. Jia, Revision D.01, Gaussian, Inc., Wallingford CT, 2013.
S. Ye, Angew. Chem. Int. Ed. 2013, 52, 5803–5806; Angew. Chem. 2013, [13] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215–241.
125, 5915; m) D. E. A. Raup, B. C. David, D. Holte, K. A. Scheidt, Nat. Chem. [14] a) H. Xue, D. Jiang, H. Jiang, C. W. Kee, H. Hirao, T. Nishimura, M. W.
2010, 2, 766–771. Wong, C. H. Tan, J. Org. Chem. 2015, 80, 5745–5752; b) M. W. Wong,
[5] a) A. T. Davies, A. M. Z. Slawin, A. D. Smith, Chem. Eur. J. 2015, 21, 18944– A. M. E. Ng, Aust. J. Chem. 2014, 67, 1100–1109; c) H. Yang, M. W. Wong,
18948; b) H. M. Zhang, Z. H. Gao, S. Ye, Org. Lett. 2014, 16, 3079–3081; J. Am. Chem. Soc. 2013, 135, 5808–5818; d) E. H. Krenske, E. C. Davison,
c) J. Douglas, J. E. Taylor, G. Churchill, A. M. X. Slawin, A. D. Smith, J. Org. I. T. Forbes, J. A. Warner, A. L. Smith, A. B. Holmes, K. N. Houk, J. Am.
Chem. 2013, 78, 3925–3938; d) X. N. Wang, L. T. Shen, S. Ye, Org. Lett. Chem. Soc. 2012, 134, 2434–2441; e) H. Yang, M. W. Wong, J. Org. Chem.
2011, 13, 6382–6385; e) T. Wang, X. L. Huang, S. Ye, Org. Biomol. Chem. 2011, 76, 7399–7405; f) Y. Zhao, D. G. Truhlar, Acc. Chem. Res. 2008, 41,
2010, 8, 5007–5011. 157–167.
[6] a) A. T. Davies, A. M. Z. Slawin, A. D. Smith, Chem. Eur. J. 2016, 21, 18944– [15] C. Gonzalez, H. B. Gonzalez, J. Phys. Chem. 1990, 94, 5523–5527.
18948; b) X. N. Wang, L. T. Shen, S. Ye, Chem. Commun. 2011, 47, 8388– [16] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009, 113,
8390. 6378–6396.

Eur. J. Org. Chem. 2019, 2989–2997 www.eurjoc.org 2996 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Full Paper
[17] a) E. D. Glendening, A. E. Reed, J. E. Carpenter, F. Weinhold, NBO Version [22] a) Q. Zhang, H. Z. Yu, Y. Fu, Org. Chem. Front. 2014, 1, 614–624; b) J.
3.1, Theoretical Chemistry Institute, University of Wisconsin, Madison, WI, Mahatthananchai, J. W. Bode, Acc. Chem. Res. 2014, 47, 696–707.
1996; b) A. E. Reed, L. A. Curtiss, F. Weinhold, Chem. Rev. 1988, 88, 899– [23] a) Y. Wang, P. J. Cai, Z. X. Yu, J. Org. Chem. 2017, 82, 4604–4612; b) Y.
926; c) J. P. Foster, F. Weinhold, J. Am. Chem. Soc. 1980, 102, 7211–7218. Wang, Z. X. Yu, Org. Biomol. Chem. 2017, 15, 7439–7446; c) Y. Wang, L. J.
[18] R. G. Parr, L. V. Szentpály, S. Liu, J. Am. Chem. Soc. 1999, 121, 1922–1924. Zheng, D. H. Wei, M. S. Tang, Org. Chem. Front. 2015, 2, 874–884; d) Y. Z.
[19] a) R. G. Parr, W. Yang, Density Functional Theory of Atoms and Molecules, Xia, Y. Liang, Y. Y. Chen, M. Wang, L. Jiao, F. Huang, S. Liu, Y. H. Li, Z. X.
Oxford University Press, New York, 1989; b) R. G. Parr, R. G. Pearson, J. Yu, J. Am. Chem. Soc. 2007, 129, 3470–3471.
Am. Chem. Soc. 1983, 105, 7512–7516.
[20] W. S. Kohn, L. J. Sham, Phys. Rev. 1965, 140, 1133–1138.
[21] L. R. Domingo, E. Chamorro, P. Pérez, J. Org. Chem. 2008, 73, 4615–4624. Received: January 17, 2019

Eur. J. Org. Chem. 2019, 2989–2997 www.eurjoc.org 2997 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim