Palladium-Catalyzed Regioselective and Stereospecific Ring-Opening Suzuki-Miyaura Arylative Cross-Coupling of 2-Arylazetidines with Arylboronic Acids

Article abstract of DOI:10.1002/adsc.202100195

We have developed a palladium-catalyzed regioselective and enantiospecific ring-opening Suzuki–Miyaura arylative cross-coupling of N-tosyl-2-arylazetidines to give enantioenriched 3,3-diarylpropylamines. This reaction represents an example of transition-metal-catalyzed ring-opening cross-coupling using azetidines as a non-classical alkyl electrophile. Density functional theory rationalized the mechanism of the full catalytic cycle, which consists of the selectivity-determining ring opening of the azetidine, reaction with water, rate-determining transmetalation, and reductive elimination. Transition states of the selectivity-determining ring-opening step were systematically determined by the multi-component artificial force induced reaction (MC-AFIR) method to explain the regioselectivity of the reaction. (Figure presented.).

Full text of DOI:10.1002/adsc.202100195

FULL PAPER
DOI: 10.1002/adsc.202100195
Palladium-Catalyzed Regioselective and Stereospecific Ring-
Opening Suzuki-Miyaura Arylative Cross-Coupling of 2-
Arylazetidines with Arylboronic Acids
Youhei Takeda,a,* Kazuya Toyoda,a W. M. C. Sameera,b,* Norimitsu Tohnai,a and
Satoshi Minakataa,*
a
Department of Applied Chemistry,
Graduate School of Engineering,
Osaka University, Yamadaoka 2-1, Suita, Osaka 5650871, Japan
E-mail: takeda@chem.eng.osaka-u.ac.jp; minakata@chem.eng.osaka-u.ac.jp
Institute of Low Temperature Science,
b
Hokkaido University,
North 19, Kita-ku, Sapporo, Hokkaido 0600819, Japan
E-mail: wmcsameera@lowtem.hokudai.ac.jp
Manuscript received: February 11, 2021; Revised manuscript received: March 25, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100195
Abstract: We have developed a palladium-catalyzed regioselective and enantiospecific ring-opening Suzuki–
Miyaura arylative cross-coupling of N-tosyl-2-arylazetidines to give enantioenriched 3,3-diarylpropylamines.
This reaction represents an example of transition-metal-catalyzed ring-opening cross-coupling using azetidines
as a non-classical alkyl electrophile. Density functional theory rationalized the mechanism of the full catalytic
cycle, which consists of the selectivity-determining ring opening of the azetidine, reaction with water, rate-
determining transmetalation, and reductive elimination. Transition states of the selectivity-determining ring-
opening step were systematically determined by the multi-component artificial force induced reaction (MC-
AFIR) method to explain the regioselectivity of the reaction.
Keywords: Azetidine; Cross-Coupling; Palladium; Ring Opening; Computational Chemistry
Introduction
ROH, RSH, and RNH2),[5] formal [4+2] cycloaddition
with nitriles[6] or aldehydes,[7] the Friedel-Crafts-type
Azetidines, a family of four-membered saturated N- arylation,[8] the Hosomi-Sakurai-type allylation,[9] and
heterocycles, are found in natural products, and they ring-opening
nucleophilic
substitution
with
serve as unique pharmacophores[1] and as useful organotrifluoroborates[10] have been reported. However,
building blocks in organic synthesis.[2] Azetidines these reactions exclusively require the activation of the
accommodates
a large ring strain energy (ca. azetidines by Lewis acids (LAs) and/or Brønsted acids
25 kcalmolÀ 1), which is slightly smaller than that of (BAs) to cleavage the C–N bond. Moreover, the
the one-carbon-less N-heterocyclic analogues (i.e., stereochemistry of azetidines is lost through these
aziridines) (ca. 27 kcalmolÀ 1).[3] Using an analogy reactions, due to SN1-like mechanisms exerted under
from the high reactivities of aziridines toward nucleo- acidic conditions.
philes driven by the release of ring strain,[4] one would
Over the last several years, various transition-
surmise that regioselective ring-opening substitution of metal-catalyzed ring-opening cross-coupling of azir-
azetidines with a variety of nucleophiles should idines has been extensively developed to form a
constitute a useful synthetic method for γ-functional- CÀ C,[11–16] CÀ B,[17,18] and CÀ Si bond.[19,20] The signifi-
ized alkylamines. In reality, the ring-opening function- cant features of these ring-opening cross-couplings
alization of azetidines is more limited when compared include the high regioselectivity governed by the
with those using aziridines. For example, ring-opening oxidative addition event. In contrast to the flourishing
substitution with heteroatomic nucleophiles (i.e., cross-coupling chemistry of aziridines, transition met-
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al-catalyzed ring-opening cross-couplings of azetidines the C2-position of 1a to produce 3,3-diphenylpropyla-
have not yet been developed. Given that such cross- mide 3a in 65% yield (denoted as “standard con-
coupling would offer new synthetic routes to medici- ditions”, entry 1, Table 1). Cinnamyl amide 4a (22%)
nally-important γ-functionalized propylamines,[21] it is and a trace amounts of 5a (2%) and 6a (3%) were
important to develop cross-couplings using azetidines obtained as byproducts. Amide 4a would be produced
as a non-classical alkyl electrophile. As relevant through β-hydride elimination from the oxidative
reactions, Pd- and Co-catalyzed regioselective and adduct, and the generated Pd–H could serve as a
stereospecific ring-expansive reactions of azetidines hydride source for reduction of 1a to give 5a. On one
with CO[22] and heterocumulenes, by making use of a hand, 1,3-diphenylpropene (6a) could be produced
rapid migratory insertion process, have been through a cross-coupling of 4a with 2a via η3-allyl Pd
reported.[23] Herein, we disclose a Pd/N-heterocyclic intermediate generated by the CÀ N cleavage.[24] In fact,
carbene (NHC)-catalyzed enantiospecific (stereo-inver- 6a was formed by the treatment of 4a with a
tive) and regioselective ring-opening cross-coupling of stoichiometric amount of PhB(OH)2 in similar catalytic
an enantiopure 2-arylazetidine with arylboronic acids conditions (for the details, see Scheme S1 and S2 in
to give enantioenriched 3,3-diarylpropylamine deriva- the SI). Representative results to show the effect of
tives (Scheme 1).
reaction parameters on the product distribution are
listed in Table 1. The NHC ligand (entry 2), inorganic
base (entry 3), solvent (entries 4 and 5), and water
(entries 6 and 7) are indispensable for effective
progress of the coupling. As the coupling nucleophilic
partner, phenylboronic neopentyl glycol ester PhB
Results and Discussion
Reaction Optimization and Synthetic Studies
To develop cross-coupling reaction using azetidines, (neop) 2a’ was found an alternative choice for the
we selected arylboronic acids and their derivatives as cross-coupling (entry 8).
the nucleophilic partner, as they are readily accessible,
To investigate the generality of the reaction con-
bench-stable, low-toxic, and storable to easily handle ditions and the stereochemical outcome of the reaction,
in laboratory. Initially, we applied the optimal reaction cross-coupling using an enantiopure azetidine (R)-1a
conditions for the Pd/SIPr-catalyzed regioselective with a variety of arylboronic acids 2 or neopentyl
cross-coupling of N-tosyl-2-arylaziridines with arylbor- glycol esters 2’ was explored (Table 2). The cross-
onic acids to the coupling of N-tosyl-2-phenylazetidine coupling of (R)-1a with 2-naphthylboronic acid
(1a) with PhB(OH)2 (2a).[11a] However, it turned out proceeded regioselectively at 100 C in three hours
°
that only azetidine substrate 1a was recovered without (conditions A) to give enantioenriched coupled product
giving any desired cross-coupled products. This dis- 3b (86% es, which was determined by chiral high
tinct difference in reactivities between the three- and performance liquid chromatography (HPLC) analysis)
four-membered N-heterocycles under the similar cross- in a moderate yield. The X-ray crystallographic
coupling conditions prompted us to explore the analysis of the single crystal of 3b grown from a Et2O/
appropriate reaction conditions for the cross-coupling n-hexane solution revealed its absolute stereochemistry
of 1a with 2a. As the results of extensive screening of as S configuration (the inset figure in Table 2). This
reaction conditions (for the details of the screening, see result confirmed the net inversion of the stereochemis-
the SI), in the presence of PEPPSI-MeIPr catalyst try of the starting azetidine substrate through the cross-
(8 mol%) and inorganic base (K3PO4) in the MTHP/ coupling.[25] This is consistent with our previous
H2O mixed solvent heated at 100 C, the cross- reports,[11] although the slight decrease in the enantio-
°
coupling of 1a with 2a proceeded regioselectively at meric excess (ee) of the coupled product implied the
existence of minor racemization pathways. The cou-
plings of (R)-1a with arylboronic acids or their
neopentyl glycol esters having a substituent at the p-
position (i.e., Me, Ac, F, and CF3) gave the corre-
sponding cross-coupled products (3c, 3d, 3e, and 3f,
respectively) in moderate yields with high enantiospe-
cificities (Table 2). Also, the coupling with m-amide-
substituted arylboronic acid gave the coupled product
3g in a good yield with high es. It is noted that the
other enantiomer (R)-3g was synthesized by applying
the other enantiomer (S)-1a as the substrate (see, the
SI). The cross-coupling of 1a with arylboronic acids
Scheme 1. Palladium-catalyzed regioselective and enantiospe-
cific ring-opening Suzuki–Miyaura arylative cross-coupling of
N-tosyl-2-arylazetidines.
having an electron-deficient functionality such as Ac
and CF3 group allowed for the preparation of the 3,3-
diarylpropylamines otherwise difficult to synthesize
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Table 1. Effect of reaction parameters on the cross-coupling of 1a with 2a.[a]
Entry
Alternations from the “standard conditions”
Yield (%)[b]
Recovery of 1a (%)[b]
3a
4a
5a
6a
1
2
3
None
65 (47)[c]
0
8
10
27
0
0
60
22
16
47
35
31
7
2
5
3
3
4
0
0
0
3
0
PEPPSI-SIPr[d] in place of PEPPSI-MeIPr
Na2CO3 in place of K3PO4
Toluene in place of MTHP
THF in place of MTHP
without H2O
Trace
67
36
47
34
93
73
0
5
4
3
0
0
3
4
5[e]
6
7
MeOH in place of H2O
13
37
8[e]
PhB(neop)[f] (2a’) in place of PhB(OH)2
[a] Standard conditions: (�)-1a (0.20 mmol), PhB(OH)2 (0.42 mmol), (4,5-dimethyl-1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene)(3-chloropyridyl)palladium(II) dichloride (PEPPSI-MeIPr) (16 μmol), K3PO4 (0.42 mmol), 4-methyltetrahydropyrane
°
(MTHP)/H2O (1.2 mL, 5:1 v/v), 100 C, 3 h.
1
[b] Determined by the H NMR analysis of the crude product.
[c] Isolation yield.
[d] PEPPSI-SIPr: (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride.
[e]
°
The reaction was run at 60 C for 12 h.
[f] PhB(neop): phenylboronic acid neopentyl glycol ester.
through the Friedel-Crafts ring-opening arylation of unit to Pd, as indicated in the computational studies
azetidines.[8] Arylboronic acid having a sterically- (vide infra). In the case of non-aromatic substituted
demanding substituent at the o-position was also azetidine, the absence of π-unit that can coordinate to
applicable to the reaction conditions to give enantioen- the Pd center does not allow for the oxidative addition
riched 3,3-diarylpropylamine 3h in a stereospecific step, which is the starting point of the catalytic cycle.
manner (Table 2). As for the variation of nucleophilic
partner, some other boronic acid derivatives such as n-
butylboronic acid and allylboronic acid pinacol ester
Computational Studies
were examined, but no reaction occurred.
Computational methods. All structure optimizations
Then, the scope of azetidines was examined using were performed using the density functional theory
phenylboronic acid (2a) or its neopentyl glycol ester (DFT) as implemented in the Gaussian16 programme
2a’ as the nucleophile (Table 3). Since the asymmetric (Version C.01).[26] The B3LYP[27] method, employing
synthetic methods for 2-arylazetidines have not been the D3 version of Grimme’s dispersion with Becke-
established, racemic azetidines were applied for the Johnson damping,[28] was used. The SDD[29] basis sets
reaction. The cross-coupling of 2-arylazetidines having and the associated effective core potential were applied
an electron-donating (i.e., Me, OMe) and an electron- for Pd, and the 6-31G(d)[30] basis sets were used for the
withdrawing functional group (i.e., F, CF3) at the p- other atoms. The polarizable continuum model
position with 2a or 2a’ proceeded regioselectively to (PCM)[31] was employed as the implicit solvent model
afford the corresponding 3,3-diarylpropylamines in with the dielectric constant of 7.4257 (tetrahydrofur-
low to moderate yields. Azetidines that have an an). Vibrational frequency calculations were performed
extended π-moiety as the 2-aryl substituent was also at 298.15 K and 1 atm to confirm the nature of the
cross-coupled with phenylboronic acid to provide the stationary points [i.e. no imaginary frequency for a
coupling products 3b, 3j, and 3k (Table 3). In local minimum (LM) and one imaginary frequency for
contrast, the coupling using N-tosyl-2-(o-tolyl) a transition state (TS)], and to calculate zero-point
azetidine (1b) gave the corresponding coupled product energy. Potential energy of the fully optimized LMs
3h in less than 5% (Table 3). Also, in the case of an and TSs was calculated as the single-point energy
azetidine having a non-aromatic substituent (Me) at the using the SDD basis sets for Pd and cc-pVTZ[32] basis
2-position, any reaction did not proceed at all sets for the other atoms.
(Table 3). These results would support the oxidative
The multi-component artificial force induced reac-
addition of azetidine via the pre-coordination of arene tion (MC-AFIR) method,[33] implemented in the
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Table 2. Pd-catalyzed cross-coupling of enantiopure (R)-1a
with 2 or 2’.[a,b]
Table 3. Pd-catalyzed cross-coupling of 1 with 2a or 2a’.[a]
[a] conditions A: (R)-1a (0.20 mmol), Ar1B(OH)2 2 (0.42 mmol),
[a] conditions A: (�)-1 (0.20 mmol), PhB(OH)2 2a (0.42 mmol),
PEPPSI-MeIPr (16 μmol), K3PO4 (0.42 mmol), MTHP/H2O
PEPPSI-MeIPr (16 μmol), K3PO4 (0.42 mmol), MTHP/H2O
°
(1.2 mL, 5:1 v/v), 100 C, 3 h; conditions B: (R)-1 a
°
(1.2 mL, 5:1 v/v), 100 C, 3 h; conditions B: (�)-1
(0.20 mmol), Ar1B(neop) 2’ (0.42 mmol), PEPPSI-MeIPr (16
μmol), K3PO4 (0.42 mmol), MTHP/H2O (1.2 mL, 5:1 v/v),
(0.20 mmol), PhB(neop) 2a’ (0.42 mmol), PEPPSI-MeIPr
(16 μmol), K3PO4 (0.42 mmol), MTHP/H2O (1.2 mL, 5:1 v/
°
60 C, 12 h.
°
v), 60 C, 12 h.
[b] The yields indicate isolation yields; The enantiospecificity
(es) was determined by chiral HPLC analysis.
[b] The yields indicate isolation yields;
GRRM17 programme,[34] was used for searching
reaction paths of the ring-opening step. The two-layer
ONIOM[35] method was used for calculating potential
energy and derivatives for the MC-AFIR search (Fig-
ure 1a). The B3LYPÀ D3 method and the SDD basis
sets for Pd, and 3-21G basis sets for the other atoms
were applied for the ONIOM high-layer. The PM6-
D3[36] method was used for the ONIOM low-layer. The
artificial force parameter (γ) of 1000 kJ/mol was
applied between Pd and the azetidine ring, as shown in
Figure 1b, which is suitable for determining the ring-
opening reaction paths. The resulting AFIR paths were
inspected, and approximate TSs were identified. Then,
all approximate TSs were fully optimized, and the
Boltzmann distribution of all fully optimized TSs was
used for calculating the regioselectivity of the ring-
opening step.
Figure 1. (a) Partitioning of the molecular system for two-layer
ONIOM calculations. (b) Adding of the artificial force between
the two fragments.
Energy decomposition analysis (EDA)[37] was per- Then, the interaction energy (INTAB) and deformation
formed for the important transition states that lead to energy (DEFAB) were calculated. The INTAB is defined
the desired or undesired products (Figure 2). For this as the interaction energy between A and B at the TS
purpose, TS structure was separated into two frag- geometry. The DEFAB is the energy of A and B at the
ments, specifically catalyst (A) and substrate (B). TS compared to the optimized structures of the isolated
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energy (ΔEsol).[38] EDA was performed using the
B3LYPÀ D3BJ method in the ADF programme (Ver-
sion 2020.101).[39] The TZ2P[40] basis sets were used
for all electrons in the system, and the relativistic
Scalar ZORA[41] approach was used for Pd. The
COSMO[42] method was used as the implicit solvent
model, where tetrahydrofuran was used as the solvent.
Catalytic cycle. For the mechanistic survey, we
have used MeIPr–Pd as the catalyst, and 1a as the
substrate. Computed free energy profile is shown in
Figure 3. When MeIPrÀ Pd encounters 1a, a π-coordi-
nated adduct (I1) is formed, which is À 14.2 kcal/mol
stable compared to the free energy sum of the isolated
MeIPrÀ Pd and 1a. Then, we have searched TSs for the
ring-opening (vide infra). In the lowest energy TS
Figure 2. Energy decomposition analysis (EDA) for two tran- (TS1), the ring opening occurs at the benzylic carbon
sition states, (AB)1 and (AB)2.
position of 1a, leading to the desired product of the
reaction. The computed free energy barrier for the
ring-opening process is 14.9 kcal/mol, which is a larger
A and B (denoted as A0 and B0). The energy difference barrier than that for the ring-opening process for N-
between the two transition states (ΔΔE) can be defined tosyl-2-phenylaziridine (7.4 kcal/mol), a three-mem-
as the sum of the interaction energy difference (ΔINT) bered ring system.[11c] Since the ring component atoms
and deformation energy difference (ΔDEF). The ΔINT of the azetidines have higher sp3-hybrized character
term was further separated into electrostatic interac- than those of aziridines, the reacting point in the ring-
tions (ΔEelstat), Pauli repulsion (ΔEPauli), orbital inter- opening process of azetidine (i.e., the C(2) atom) is
action (ΔEoi), dispersion energy (ΔEdisp), and solvation more sterically hindered, and the bond dissociation
Figure 3. Computed free energy (kcal/mol) profile for the reaction of MeIPrÀ Pd with 1a and PhB(OH)2.
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energy of the C(2)À N(1) is larger than that of
aziridines. Given these differences in the three- and
four-membered ring systems, the SN2 type oxidative
addition of the azetidine is reasonably higher than that
for aziridines.
The resulting intermediate (I2, À 8.9 kcal/mol)
interacts with water molecules in the solution to initiate
the consecutive proton and hydroxy anion transfer to
the N atom and the Pd center of the oxidative adduct,
respectively. Calculated free energy barrier for this
process is 9.4 kcal/mol. When the resulting Pd-hydroxo
intermediate (I3, À 6.6 kcal/mol) encounters PhB(OH)2
in the solution, a relatively stable intermediate (I4,
À 12.3 kcal/mol) is formed. It is important to note that
the concentration of PhB(OH)2 in the solution is large.
Thus, I4 in solution is stabilized, allowing the trans-
Figure 4. Transition state groups for the ring-opening step.
metalation with an overall free energy barrier of represents the ring-opening through the C(2)À N(1)
24.2 kcal/mol, giving rise to I5 (À 29.1 kcal/mol). After bond cleavage with stereoinversion in an SN2 fashion,
removing B(OH)3 from the metal coordination sphere giving rise to the cross-coupling product. In Group B,
of I5, a more stable intermediate I6 (À 34.5 kcal/mol) ring opening through the C(4)À N(1) bond cleavage
can be formed. Finally, the reductive elimination gives the regioisomeric cross-coupled product. The
occurs with a free energy barrier of 8.9 kcal/mol enantiomer of the product and its regioisomeric
(TS4), lending to the product (P). At the same time, coupled product can be formed through the TSs in the
the catalyst (MeIPrÀ Pd) for the next catalytic cycle is Group E and Group F, respectively, where stereo-
recovered.
chemistry is retained. Group C/G and Group D/H
Based on the computed free energy profile, we represent the ring opening through the C(3)À C(4) and
concluded that the selectivity-determining step of the C(2)À C(3) bonds, respectively.
mechanism is the ring opening of the azetidine (i.e.,
Fully optimized TSs, their relative free energies,
the oxidative addition), and the rate-determining step and existence probabilities are summarized in Table 4.
of the mechanism is the transmetalation. The overall The lowest energy transition state, TSa (=TS1) in
free energy barrier for the transmetalation is 26.1 kcal/ Group A, contributes to 58.8% of the cross-coupling
mol (i.e. free energy difference between TS3 and I1), product formation, and TSb (21.3%), TSc (18.0%),
which can be achieved under the reaction conditions. and TSd (1.0%) also give some contributions. TSe
When N-tosyl-2-arylaziridine was used as the substrate (0.7%) and TSf (0.1%) are the lowest energy transition
(i.e., a three-membered ring system), the overall free states in Group F, leading to the regioisomeric cross-
energy barrier for the rate-determining step (i.e. trans- coupling product. However, their contributions are
metalation) was relatively lower (20.9 kcal/mol).[11c] very low (0.8% in total). Thus, concentration of the
Compared to the three-membered ring system, the subsequent intermediates or the rate of the formation
four-membered ring system is sterically-demanding for of the regioisomeric cross-coupling product would be
the transmetalation step that requires for the associa- very low. The existence probabilities of the TSs in
tion of an oxidative adduct and phenylboronic acid. Group C, D, G, and H are zero. Therefore, the ring
Thus, the entropic penalty to overcome the barrier for openings through C(3)À C(4) and C(2)À C(3) are un-
the transmetalation is larger in the four-membered likely to occur. This prediction is consistent with the
system. As a result, the four-membered ring-opening experimental results. By considering all TSs, the
cross-coupling reaction rate would be lower than that computed regioselectivity (99:1) is in good agreement
of the three-membered ring-opening cross-coupling with the experimental results (100:0).
reactions. To accelerate the desired coupling reaction
Energy decomposition analysis. In order to get
of azetidines, a higher reaction temperature than some insights into the origin of the selectivity of the
aziridines is requried. This concomitantly allowed for reaction between MeIPrÀ Pd and 1a, an EDA was
side reactions that lead to byproducts such as 4a, 5a, performed (Table 5) using the lowest energy transition
and 6a through β-hydride elimination. As a result, sates that lead to the major product (TSa) and the
moderate yield of the desired cross-coupled products minor product (TSe). Geometries of the optimized TSa
was observed.
and TSe are shown in Figure 5. Computed free energy
Regioselectivity. We have searched reaction paths difference (ΔΔG) between TSa and TSe is 2.6 kcal/
for the regioselectivity-determining ring-opening step mol, while the potential energy difference (ΔΔE) is
using an MC-AFIR search. Calculated TSs were 2.3 kcal/mol. Thus, ΔΔE is the key to the origin of the
categorized into eight groups (Figure 4). Group A selectivity, and the entropy plays a minor role. For the
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Table 4. Groups, relative free energies (kcal/mol), and exis-
tence probabilities (%) of the TSs for the ring opening.
TS
TS Groups
A
ΔG
ΔΔG
%
TSa
(= TS1)
TSb
TSc
TSd
TSe
TSf
TSg
TSh
TSi
TSj
TSk
TSl
TSm
TSn
TSo
TSp
TSq
TSr
TSs
0.7
0.0
58.8
A
A
A
F
F
F
1.3
3.1
1.4
3.3
4.5
6.6
7.8
8.5
12.1
12.3
12.9
14.8
15.4
16.0
17.5
17.5
25.6
33.3
34.6
36.7
38.9
45.8
0.6
2.4
0.7
2.6
3.8
5.9
7.1
7.8
11.4
11.6
12.2
14.1
14.7
15.3
16.8
16.8
24.9
32.6
33.9
36.0
38.2
45.1
21.3
18.0
1.0
0.7
0.1
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
F
F
Figure 5. Geometries of the optimized TSa and TSe. Bond
distances are shown in Å.
H
H
H
G
H
H
B
B
B
F
regioselectivity. In the case of TSa, the benzylic
carbon of 1a approaches the Pd center (Figure 5),
while in the case of TSe, the N atom of 1a approaches
the Pd center. Among the negative components of the
ΔINT, dispersion interactions (ΔEdisp =À 14.4 kcal/mol)
of TSa is dominant, compared to electrostatic inter-
action (ΔEelstat =À 7.6 kcal/mol) or orbital interactions
(ΔEoi =À 7.6 kcal/mol). These interactions together
overcome the Pauli repulsion (ΔEPauli =11.1 kcal/mol)
and solvation energy (ΔEsol =10.2 kcal/mol).
TSt
C
C
C
B
TSu
TSv
TSw
Conclusion
Table 5. Energy decomposition analysis.
In conclusion, we have developed a Pd/NHC-catalyzed
regioselective and steroinvertive Suzuki-Miyaura ary-
lation of 2-arylazetidines to afford medicinally impor-
tant enantioenriched 3,3-diarylpropylamines. The de-
veloped reaction represents an example of transition
metal-catalyzed CÀ C cross-coupling using azetidines
as a non-classical alkyl electrophile. In contrast to
traditional Brønsted or Lewis acid-catalyzed C(2)-
selective ring-opening arylations, the developed reac-
tion allows for the preparation of biologically-impor-
tant enantio-enriched 3,3-diarylpropylamines.
Computational studies rationalize the mechanism of
the full catalytic cycle that involves the selectivity-
determining ring opening (oxidative addition), reaction
with water, rate-determining transmetalation, and
reductive elimination (Scheme 2). A systematic survey
on the TSs for the selectivity-determining step was
performed using an MC-AFIR search, and the lowest
TS DEF (DE-
FA,DEFB)
INT
(EPauli, Eelstat, Eoi, Edisp, Esol)
TSa 45.8 (4.7, 41.2)
TSe 42.9 (3.5, 39.5)
À 63.4
(131.9, À 92.9, À 57.0, À 26.2, À 19.2)
À 54.7
(139.5, À 104.0, À 49.4, À 11.5,
À 29.4)
ΔDEF
ΔINT
(ΔDEFA, ΔDEFB) (ΔEelstat, ΔEPauli, ΔEoi, ΔEdisp, ΔEsol)
TSa –
TSe 2.9
(1.2, 1.7)
–
À 8.7
(À 7.6, 11.1, À 7.6, À 14.7, 10.2)
ΔΔE=ΔDEF+ΔINT
TSa
TSe
–
À 5.8
EDA, we have used the B3LYPÀ D3(BJ)/TZ2P/ZORA/ energy TSs contributing to the selectivity of the
COSMO level of theory as implemented in the ADF reaction were identified. Computed regioselectivity
program, where the computed ΔΔE is relatively high reproduced the experimental results. EDA indicated
(5.8 kcal/mol).
that interactions between the catalyst and the substrate
According to EDA, deformation of the catalyst is the key to achieve the regioselectivity of the
(ΔDEFA =1.2 kcal/mol) and deformation of the sub- reaction. Our combined experimental and computa-
strate (ΔDEFB =1.7 kcal/mol) equally contributed to tional study would give important mechanistic insights
the ΔDEF (2.9 kcal/mol). Computed ΔINT is to develop ring-opening cross-coupling reactions of
À 8.7 kcal/mol, and it contributes mainly to the ΔΔE saturated N-heterocyclic compounds in a selective
that stabilizes TSa over TSe to achieve the complete fashion.
Adv. Synth. Catal. 2021, 363, 1–11
7
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using 1,1,1,2-tetrachloroethane as an internal standard. The
crude product was purified by flash column chromatography on
silica gel followed by GPC to give coupling product.
Acknowledgements
This work was supported by Grant-in-Aid for Scientific
Research on Innovative Areas “Precisely Designed Catalysts
with Customized Scaffolding” (KAKENHI, JP16H01023, to YT)
and “Coordination Asymmetry” (KAKENHI, JP19H04580, to
NT). W.M.C.S. thanks to the Grants-in-Aid for Scientific
Research on Innovative Areas grand, JP17H06445. Super-
computing resources at the Institute of Molecular Science in
Japan and the Academic Center for Computing at Media
Studies at Kyoto University in Japan are also acknowledged.
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1
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1
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Palladium-Catalyzed Regioselective and Stereospecific Ring-
Opening Suzuki-Miyaura Arylative Cross-Coupling of 2-Ary-
lazetidines with Arylboronic Acids
Adv. Synth. Catal. 2021, 363, 1–11
Y. Takeda*, K. Toyoda, W. M. C. Sameera*, N. Tohnai, S.
Minakata*