Rhodium(iii)-catalyzed asymmetric [4+1] spiroannulations of: O -pivaloyl oximes with α-diazo compounds

Article abstract of DOI:10.1039/d1cc02888j

Chiral RhIII catalysts can catalyze the asymmetric [4+1] spiroannulation of O-pivaloyl oximes with α-diazo homophthalimides under redox-neutral and acid/base-neutral conditions, leading to formation of chiral spirocyclic imines as a result of C-H activation and N-O cleavage. The reaction proceeded with high efficiency and features broad substrate scope, mild reaction conditions, and high to excellent enantioselectivities. This journal is

Full text of DOI:10.1039/d1cc02888j

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Rhodium(III)-catalyzed asymmetric [4+1]
spiroannulations of O-pivaloyl oximes with a-
diazo compounds†
Cite this: Chem. Commun., 2021,
57, 8268
Received 1st June 2021,
Accepted 20th July 2021
a
c
Lincong Sun,a Bingxian Liu,
Yanlian Zhao,b Junbiao Chang,a Lingheng Kong,
b
abc
Fen Wang,c Wei-Qiao Deng
and Xingwei Li
*
DOI: 10.1039/d1cc02888j
rsc.li/chemcomm
Chiral RhIII catalysts can catalyze the asymmetric [4+1] spiroannula- (hetero)cyclic molecules, including spirocyclic scaffolds.4 Of
tion of O-pivaloyl oximes with a-diazo homophthalimides under note, rhodium(III) cyclopentadienyl complexes have been estab-
redox-neutral and acid/base-neutral conditions, leading to formation lished as one of most efficient catalysts for synthesis of spir-
of chiral spirocyclic imines as a result of C–H activation and N–O ocyclic compounds via a C–H activation pathway.5 By following
cleavage. The reaction proceeded with high efficiency and features this strategy, arenes bearing a heteroatom directing group have
broad substrate scope, mild reaction conditions, and high to excellent been successfully employed for the synthesis of various spir-
enantioselectivities.
ocyclic skeletons via coupling with unsaturated reagents such
as alkynes, alkenes, and a-diazocarbonyl compounds.6 Mean-
Spirocycles are commonly encountered structural motifs that have while, the discovery of chiral rhodium catalysts has opened a
found wild applications in synthetic chemistry. Their unique 3D new avenue to access chiral polycyclic scaffolds.7–11 In
structures may impart diversified biological, chemical, and photo- 2015, You and coworkers developed the first enantioselective
chemical properties in various natural and synthetic compounds. dearomatization reaction of 2-naphthols for the synthesis of spiro-
Thus, they have also been used as key intermediates during cyclic enones in excellent enantioselectivities (Scheme 1a).6b By
synthesis and development of drug molecules.1 Chiral spirocycles using enol as a coordinating group, the Lam group realized Rh(III)-
have also attracted much attention as prevalent scaffolds of chiral catalyzed enantioselective synthesis of spirocyclic indenes
ligands.2 A number of synthetic strategies have been documented (Scheme 1a).12 In 2019, the Waldmann group disclosed a related
to access spirocycles.3 They can be prepared through alkylation, enantioselective [3+2] spiroannulation via formal C(sp3)–H bond
metal-catalyzed reactions, and cycloaddition reactions. Despite activation (Scheme 1a).6c Very recently, we realized oxidative [4+1]
these synthetic routes, many of them suffer from employment of spiroannulation of nitrone and quinone diazides, which occurred
highly functionalized reagents and lengthy procedures with gen- via initial C–H arylation followed by axial-to-central chirality trans-
eration of waste. Therefore, atom- and step-economic catalytic fer (Scheme 1b).13 Thus, these spirocyclic products were mostly
synthesis of spirocycles with a quaternary carbon center in a regio- constructed under oxidative conditions. On the other hand, in 2014
and stereocontrolled fashion remains an ongoing theme.
Cramer reported the [4+1] annulation of N-OPiv benzamides
In the past decade, metal-catalyzed and chelation-assisted and diazo compounds for enantioselective synthesis of lactams.14
C–H bond functionalization has been developed as an increas- Later, the arene substrate was extended to indoles by Song and
ingly important strategy for the construction of complex coworkers.11a Our objective was to construct aza-spirocycles on
different platforms via C–H activation assisted by other readily
available oxidizing directing groups. As integration of eco-friendly
synthesis of spirocycles and asymmetric C–H bond activation, we
now report Rh(III)-catalyzed enantioselective [4+1] spirocyclization
between O-pivaloyl oximes and a-diazo homophthalimides
a Henan Key Laboratory of Organic Functional Molecule and Drug Innovation,
Key Laboratory of Green Chemical Media and Reactions, Ministry of Education,
School of Chemistry and Chemical Engineering, Henan Normal University,
Xinxiang 453007, China. E-mail: lixw@snnu.edu.cn
b Institute of Molecular Science and Engineering, Institute of Frontier and
Interdisciplinary Sciences, Shandong University, Qingdao, China
c School of Chemistry and Chemical Engineering, Shaanxi Normal University,
Xi’an 710062, China
(Scheme 1c).
We initiated our studies using O-pivaloyl oxime 1a as a
model substrate, and its [4+1] spiroannulation with a-diazo
homophthalimides was explored using the Cramer-type
CpXRh(III) catalysts (Table 1).7c,d The desired product (R)-3 was
obtained with generally good enantioselectivity and efficiency
when (R)-Rh2 was used in various solvents (entries 1–5), and
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data of all compounds. CCDC 2069779 (44), 2073889 (52)
and 2073891 (53). For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/d1cc02888j
8268 | Chem. Commun., 2021, 57, 8268–8271
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With the establishment of the optimal reaction conditions,
we next investigated the scope of the O-pivaloyl oximes
(Scheme 2). It was observed that introduction of various
electron-donating, -withdrawing, and halogen groups at the
para position of the phenyl ring gave consistently good yields
and excellent enantioselectivities (3–13, 87–91% ee). Of note, a
1.0 mmol scale synthesis of product 3 also proved to be
successful, with no deterioration of the yield or enantioselec-
tivity. We also found that oxime esters bearing a meta methyl,
methoxy, and halogen group also reacted efficiently (14–17)
in comparably excellent enantioselectivity (70–90% yields,
90–94% ee). In contrast, ortho-fluorine substituted O-pivaloyl
oxime (1s) underwent the C–H annulation with low regioselec-
tivity and slightly lower enantioselectivity (18 and 180). The
presence of methyl and halogen group at the ortho position was
also tolerated (19–22). No deterioration of the enantioselectivity
was observed with different alkyl substitutions (23–26). Our
studies further revealed that symmetrical benzophenone-
derived O-pivaloyl oximes were tolerated giving moderate to
good yields and excellent enantioselectivities (27–31, 94–97%
ee). In addition, cyclic O-pivaloyl oximes also reacted smoothly
with 2a, affording products 32 and 33 with 88% and 92% ee,
respectively. When 2-naphthyl-substituted O-pivaloyl oxime was
employed, the corresponding spirocyclic product 34 was also
obtained (97% yield, 89% ee). Furthermore, heteroatomic
Scheme 1 Rhodium(III)-catalyzed C–H bond functionalization–spiroannu-
lation.
DCE seemed to outperform other solvents. The reaction tem-
perature and additives were also screened (entries 5–8 and
9–14), and the enantioselectivity only slightly varied. To our
delight, both high enantioselectivity and yield were maintained
when the catalyst loading was lowered to 4 mol% even in the
absence of any acid/base additive (entry 15). In contrast, repla-
cing the catalyst with (R)-Rh1 and (R)-Rh3 gave lower enantios-
electivities (see the ESI†).
Table 1 Optimization studiesa
Entry
Additive
Solvent
T (1C)
Yieldb (%)
eec (%)
1
2
3
4
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
LiOAc
K2CO3
Cs2CO3
HOAc
PivOH
—
PhCl
TFE
40
40
40
40
40
25
10
0
10
10
10
10
10
10
10
72
65
81
80
83
83
84
75
72
50
NR
80
81
83
85
89
75
87
80
90
90
91
92
88
90
—
84
89
91
91
Et2O
EtOAc
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
5
6c
7c
8c
9c
10c
11c
12c
13c
14c
15cd
—
a
Reaction Conditions: 1a (0.06 mmol), 2a (0.05 mmol), (R)-Rh2
Scheme 2 Scope of O-pivaloyl oximes in spiro compounds synthesis.
Reaction conditions: 1 (0.12 mmol), 2 (0.10 mmol), (R)-Rh2 (4 mol%), and
AgSbF6 (16 mol%) in DCE (2 mL) under Ar for 48 h, isolated yield.
(5 mol%), AgSbF6 (20 mol%), additive (1.0 equiv.), solvent (1 mL),
under Ar for 24 h. Isolated yield. Under Ar for 48 h. (R)-Rh2
(4 mol%) and AgSbF6 (16 mol%) were used.
b
c
d
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substrate such as thienyl ring, afforded the corresponding
products with lower enantioselectivity (35 and 36).
Next, we investigated the scope of the diazo compounds. As
shown in Scheme 3, introduction of various electron-donating,
-withdrawing, and halogen groups to the N-phenyl ring allowed
the coupling to gave the desired products in good to excellent
yields and high enantioselectivities (37–46, 86–96% ee), which
revealed that the reaction efficiency was slightly affected by the
electronic effect. Meanwhile, the absolute configuration of the
product 44 was assigned as (R) by X-ray crystallography (CCDC†
2069779). Moreover, variation of the N-substituent to –Bn (47)
and 2-Naph (49) group all led to high yields (82% and 85%,
respectively) and enantioselectivities (90% ee and 91% ee,
respectively). However, lower enantioselectivity (79% ee) was
obtained for the N-nBu (48) diazo compound, indicative of the
electronic effect. Examination of the 6-substituent in the diazo
compound revealed compatibility of bromo group (50, 91% ee).
To demonstrate the synthetic utility of the reaction system,
the synthetic transformations of 3 was conducted (Scheme 4).
Treatment of 3 with m-CPBA afforded the oxidation product
N-oxide 51 in 64% yield without loss of the enantiopurity. Pd/
C-catalyzed reduction of 3, surprisingly, afforded a ring-
opening and ring-expansion product 52 (CCDC† 2073889) in
88% yield (4 : 1 dr), which may occur via CQN reduction and
C–N reductive cleavage. Treatment of 3 with NaBH4 in EtOH
led to ring-opening of the imide group with incorporation of
the solvent, affording hemiaminal 53 in 55% yield, and the
structure of 53 (CCDC† 2073891) was determined by X-ray
crystallography.
Scheme 4 Synthetic transformations of compounds 3.
To shed light on the mechanism of this spirocyclization
reaction, we carried out several experimental studies
(Scheme 5). First, H/D exchange of 1a was carried out in the
presence of D2O, the reactant was recovered in 92% yield and
the 1H NMR analysis revealed slight deuteration at the ortho
positions of the phenyl ring, suggesting reversibility of the C–H
cleavage. Second, another H/D exchange in the presence of 2a
was conducted under the standard conditions, affording
compound 3-Dy (the Dy is a statistical average value of com-
pound 3-Dy), and the deuterium incorporation was observed at
Scheme 5 Preliminary mechanistic studies.
the methyl group probably due to acidity of the a-methyl
group.15 Two parallel reactions of 1a and 1a-D5 with 2a were
performed for kinetic isotope effect, and the kH/kD = 2.2 was
obtained at a low conversion under the standard conditions,
suggesting that the ortho C–H activation event might be
involved in the turnover-limiting step.
On the basis of the previous reports,11a,14 the enantioselec-
tivity for the (R)-3 formation may be explained by the following
stereochemical model (Scheme 6). Following the C–H bond
activation and formation of the carbene species, both inter-
mediates A and B can be possible. Regarding the subsequent
migratory insertion, the intermediate B is preferred likely
because of the reduced steric interaction between the OPiv
group and the carbene ligand as we have previously proposed in
the [4+1] annulation of quinone diazides,13 eventually leading
Scheme 3 Scope of diazo compounds in spiro compounds synthesis
(see Scheme 2 for reaction conditions).
Scheme 6 Plausible stereochemical model of the chiral induction.
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may also suggest a lower kinetic barrier during the migratory
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In summary, we have developed an efficient and mild
protocol for the enantioselective synthesis of spirocyclic imines
through a procedure of rhodium-catalyzed enantioselective
C–H functionalization and N–O cleavage. This asymmetric
[4+1] spiroannulation occurred under redox-neutral and acid/
base additive-free conditions via C–H bond activation of the
oxime ester with cyclic a-diazo compounds as a coupling
reagent. The reaction proceeded in high efficiency and features
broad substrate scope, mild and redox-neutral reaction condi-
tions, and high to excellent enantioselectivities. Further develop-
ment of new reaction modes of rhodium-catalyzed enantio-
selective C–H activation reactions is underway in our laboratory.
We acknowledge the financial support for this work from
NSFC (21525208 and 21801066) and the Shaanxi Normal
University.
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Conflicts of interest
The authors declare no competing financial interest.
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