Divergent Synthesis of Tunable Cyclopentadienyl Ligands and Their Application in Rh-Catalyzed Enantioselective Synthesis of Isoindolinone

Article abstract of DOI:10.1021/jacs.0c02813

A series of rhodium complexes bearing sterically and electronically tunable cyclopentadienyl ligands, prepared by utilizing Co2(CO)8-mediated [2+2+1] cyclization as a key step, were synthesized. In the presence of 2.5 mol% of CpmRh4, unprecedented enantioselective [4+1] annulation reaction of benzamides and alkenes was achieved with a broad substrate scope under mild reaction conditions, providing a variety of isoindolinones with excellent regio-and enantioselectivity (up to 94% yield, 97:3 er). Preliminary mechanistic studies suggest that the reaction involves an oxidative Heck reaction and an intramolecular enantioselective alkene hydroamination reaction.

Full text of DOI:10.1021/jacs.0c02813

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Communication
Divergent Synthesis of Tunable Cyclopentadienyl Ligands and Their
Application in Rh-catalyzed Enantioselective Synthesis of Isoindolinone
Wen-Jun Cui, Zhi-Jie Wu, Qing Gu, and Shu-Li You
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c02813 • Publication Date (Web): 07 Apr 2020
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Divergent Synthesis of Tunable Cyclopentadienyl Ligands and Their
Application in Rh-catalyzed Enantioselective Synthesis of Isoindo-
linone
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Wen-Jun Cui,a,‡ Zhi-Jie Wu,a,b,‡ Qing Gu,a Shu-Li Youa,*
a State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai,
200032, China.
b School of Physical Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China
Supporting Information Placeholder
ABSTRACT: A series of rhodium complexes bearing sterically
and electronically tunable cyclopentadienyl ligands, prepared by
utilizing Co2(CO)8 mediated [2+2+1] cyclization as a key step,
were synthesized. In the presence of 2.5 mol % of CpmRh4, un-
precedented enantioselective [4+1] annulation reaction of ben-
zamides and alkenes was achieved with a broad substrate scope
under mild reaction conditions, providing a variety of isoindo-
linones with excellent regio- and enantioselectivity (up to 94%
yield, 97:3 er). Preliminary mechanistic studies suggest that the
reaction involves an oxidative Heck reaction and an intramolecu-
lar enantioselective alkene hydroamination reaction.
Remarkable progresses on cyclopentadienyl (Cp) rhodium com-
plexes catalyzed C-H bond functionalization reactions have been
made over the past decade.1 However, enantioselective RhIII-
catalyzed C-H bond functionalization reactions are rather chal-
lenging due to the inherent difficulties on the synthesis of chiral
Cp ligands. The breakthroughs were achieved via biochemical and
chemical modifications of the Cp ligand independently by Ward
and Rovis, as well as the group of Cramer in 2012, leading to a
rapid development in this field.2 Soon afterwards, the Cramer
group and our group respectively developed a series of cyclopen-
tadienyl ligands with C2 symmetry and various RhIII-catalyzed
asymmetric C-H bond functionalization reactions.3 More recently,
Antonchick, Waldmann, and Perekalin elegantly introduced piper-
idine-fused and planar chiral cyclopentadienyl ligands (IV, V),
respectively, which could be applied successfully in asymmetric
[4+2] annulation reactions (Figure 1).4 For the most studied
BINOL-derived Cp ligands (II), the chiral environment at the
metal center usually origins from both the rigid backwall and the
3,3’-substituents. There are only very few reports to investigate
the effect of substituents of the Cp ring on enantio-, regio- and
chemoselectivity systematically (II, R = tBu, iPr, etc.).5 Consider-
ing the fact that the multi-substitutent groups on the Cp ring ex-
hibited distinct regio- and chemoselectivity and reactivity in cata-
lytic reactions disclosed by Rovis6, Tanaka7, Cramer8, Chang9 and
others10, the development of efficient approach to access tunable
multi-substituted chiral cyclopentadienyl ligands is of great signif-
icance.
Figure 1. Previously and newly designed chiral cyclopentadienyl
ligands
Chiral isoindolinone fragments are widely found in biologically
active compounds and natural products as depicted in Figure 2.11-
14 Therefore, extensive efforts have been devoted to their efficient
synthesis.15 Among which, the [4+1] annulation reaction of ben-
zamide derivatives with electron-deficient alkenes through oxida-
tive olefination reaction/aza-Michael addition, was undoubtedly a
highly attractive access to these structurally diverse 3-substituted
isoindolinone scaffolds, albeit without enantioselective studies.16
We envisioned that enantioenriched 3-substituted isoindolinone
might be constructed by asymmetric [4+1] annulation reaction
enabled by chiral Rh complexes. In this regard, chemoselectivity
is notably challenging as [4+2] annulation reactions usually pro-
2a-b, 4, 5d-e
ceed in the presence of Rh/Cp complexes (Scheme 1a).
Interestingly, Cramer and coworkers reported that 4-substituted
dihydroisoquinolones were obtained by utilizing sterically bulky
Cp derived Rh catalyst due to reverse of regioselectivity.8 How-
ever, the structure of this product was demonstrated by Ellman
and coworkers to be incorrect although the correct one remained
to be disclosed.17 During our recent efforts towards the synthesis
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Scheme 2. Synthesis of multi-Substituted Cpm Ligands and
Their RhIII Complexes
of tunable Cp ligands and their applications, we examined the
reactivity of these Cp ligands in Rh-catalyzed reaction between O-
Boc hydroxamate and styrene. The reaction was found to undergo
[4+1] annulation to afford 3-substituted isoindolinone. Herein, we
report the details of this study (Scheme 1b).
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Figure 2. Selected biologically active compounds and natural
products containing chiral isoindolinone fragment
Scheme 1. Enantioselective Synthesis of Isoquinolones and
Isoindolinones
(a) Co2(CO)8, PhCH3, 120 °C, 61−73% yields. (b) MeMgI,
i
Et2O, r.t., 89−98% yields for R2 = Me; PrMgCl•LiCl, THF, -78
ºC, 61% yield for R2 = iPr; PhLi, Et2O, -78 ºC−r.t., 96% yield for
R2 = Ph. (c) LiAlH4/AlCl3, Et2O, 50 ºC; TBAF, THF/HOAc, r.t.,
89−90% yields. (d) I2, NaHCO3 (aq.), MeCN/CH2Cl2, r.t., 79−95%
yields. (e) Me4Sn, CsF, Pd(PPh3)4, CuI, DMF, 80 ºC, 80−84%
yields. (f) LiAlH4/AlCl3, Et2O, 50 ºC, 80−92% yields. (g)
RhCl3•H2O, EtOH, 80 ºC or MW 140 ºC, 73-84% yields.
To explore the utility of these newly synthesized Rh complexes,
the reaction between O-Boc hydroxamate (7a) and styrene (8a)
was performed in the presence of 2.5 mol % of CpmRh1 complex
and 30 mol % of AgOBz in trifluoroethanol (TFE) at 25 ºC. To
our delight, the reaction did occur and afford isoindolinone (9aa)
16h
as a major product in 53% yield with 85:15 er, along with di-
hydroisoquinolone 9aa’ and olefination product 9aa’’ (Table 1,
entry 1). It was found that the substituents (R2) such as iPr and Ph
groups at the Cp ring exhibited less influence on the reaction out-
come (Table 1, entry 2-3). Pleasingly, 9aa was obtained in 70%
yield and 91.5:8.5 er when trimethyl substituted CpmRh4 was
employed (Table 1, entry 4). Investigation of the effect of R1 on
the BINOL skeleton revealed that the employment of CpmRh5-6
led to the isolation of 9aa’’ as the main product (Table 1, entries
5-6). The solvent and temperature effects were also investigated,
and the reaction in TFE at 25 °C gave the best results (for details,
see Tables S1 and S2 in the Supporting Information). The yield of
9aa could be further increased when the combination of AdCO2H
and Ag2CO3 was used (Table 1, entry 7, 79% yield, 92.5:7.5 er).
Reducing the loading of additive did not have notable influence
on the reaction outcome (Table 1, entry 8, 83% yield, 93:7 er).
Large excess of 8a was not required, and the reaction with 1.5
equiv of 8a afforded 9aa in 82% yield and 95:5 er (Table 1, entry
9).
The synthesis of these tunable Cp ligands started from the known
diyne (R)-1 as illustrated in Scheme 2.18 Intramolecular [2+2+1]
cyclization reaction mediated by Co2(CO)8, described by Takanori
Shibata et al,19 was used as the key reaction to afford cyclopenta-
i
dienones (R)-2 in 61-73% yields. Me, Pr and Ph groups could be
i
introduced by the addition of MeMgI, PrMgCl•LiCl and PhLi,
respectively, to ketone, resulting in tertiary alcohols (R)-3 (89−98%
i
yields for Me; 61% yield for Pr; 96% yield for Ph). Subsequent
reduction of the hydroxyl group by LiAlH4/AlCl3 and the removal
of the TMS group by TBAF provided cyclopentadienes (R)-6a−c
(R1 = H) in 89-90% yields. (R)-4 (R2 = Me) were obtained in 79-
95% yields by iodination of (R)-3. Then Pd-catalyzed Stille cou-
pling reaction with Me4Sn at 80 ºC afforded trimethyl alcohols
(R)-5 in 80-84% yields. Fully substituted cyclopentadienes (R)-
6d-6f were obtained in 80-92% yields after reduction with
LiAlH4/AlCl3. Finally, the metalation of sterically less demanding
cyclopentadienes (R)-6a-b and 6d-e with RhCl3 in EtOH at 80 ºC
as described by Rovis et al6e afforded CpmRh1-2 and CpmRh4-5.
While for more sterically hindered cyclopentadienes (R)-6c and 6f,
microwave heating was required to furnish CpmRh3, 6 efficent-
ly.20
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conditions, [4+2] cyclization reaction proceeded to afford 4- and
Table 1. Catalyst Screening and Reaction Condition Opti-
mizationa
3-phenethyl substituted dihydroisoquinolones in 64% yield with
60:40 er and 24% yield with 58:42 er, respectively (For details,
see the Supporting Information).
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4
5
Scheme 3. Substrate Scope for Styrenesa
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yield
entry [Rh]
additive
erc
ratiod
(%)b
53
40
52
70
2
CpmRh1
1
AgOBz
AgOBz
AgOBz
AgOBz
AgOBz
AgOBz
AdCO2H
Ag2CO3
AdCO2H
Ag2CO3
AdCO2H
Ag2CO3
85:15
82:18
65/13/22
67/7/26
CpmRh2
CpmRh3
CpmRh4
CpmRh5
CpmRh6
2
3
80.5:19.5 68/13/19
4
91.5:8.5
89/4/7
3/2/95
0/0/100
5
6e
-
-
0
7f
79
83
82
92.5:7.5
93:7
92/4/4
93/4/3
93/4/3
CpmRh4
CpmRh4
CpmRh4
8g
9h
95:5
a Reaction conditions: 7a (0.20 mmol), 8a (1.20 mmol), [Rh]
(2.5 mol %) and additive in TFE (1.0 mL) at 25 °C for 24 h.
b
c
Isolated yield of 9aa. Determined by HPLC analysis on a chiral
stationary phase. Ratio of 9aa/9aa’/9aa’’ was determined by 1H
d
e
f
NMR analysis of the crude mixture. 9aa’’ in 44% yield. 30
mol % of AdCO2H and 15 mol % of Ag2CO3 were used. g 15 mol %
h
of AdCO2H and 7.5 mol % Ag2CO3 were used. 1.5 equiv of 8a,
15 mol % of AdCO2H, 7.5 mol % of Ag2CO3 were used.
Under the optimized conditions (Table 1, entry 9), the generality
of the protocol was examined firstly with respect to the styrene
coupling partners (Scheme 3). In general, substituents at the para
position were well tolerated regardless of their steric or electronic
properties. Specifically, styrenes bearing an alkyl group (methyl
or tert-butyl) provided their desired products in good yields with
excellent enantiomeric ratio (9ab: 78% yield, 94.5:5.5 er; 9ac: 68%
yield, 96.5:3.5 er). The absolute configuration of 9aa was as-
signed as S by comparing the sign of the optical rotation with that
of known compound.21 Electron-donating groups such as methox-
yl or acetyloxy could be well tolerated and their corresponding
products (9ad-ae) were obtained with comparable yields and en-
antiomeric ratio (68-77% yields, 95:5-96:4 er). With styrenes
bearing an electron-withdrawing group (nitro, ester or trifluoro-
methyl) at the para position, the reaction proceeded smoothly to
deliver isoindolinones 9af-ah in slightly higher yields with excel-
lent enantiomeric ratios (86-90% yields, 95.5:4.5-97:3 er). De-
lightedly, halogen-substituted styrenes (fluoro, chloro or bromo)
worked very well (9ai-ak: 76-87% yields, 95.4: 4.5 er), leaving
the halogen atom intact. meta-Substituted styrenes proved to be
suitable substrates, giving annulated products (9al-ao: 78-92%
yields, 94.5:5.5-96:4 er).22 Unfortunately, the annulation reaction
with ortho-substituted styrenes led to isoindolinones 9ap-ar in
89-91% yields, but with poor enantioselective control (51:49-
65.5:34.5 er). With 2,6-dichloro styrene, isoindolinone 9as was
obtained in 23% yield with 78.5:21.5 er. When alkyl substituted
alkene such as but-3-en-1-ylbenzene was subjected to the standard
a
Reaction conditions: 7a (0.20 mmol), 8 (0.30 mmol), (R)-
CpmR4 (2.5 mol %), AdCO2H (15 mol %) and Ag2CO3 (7.5
mol %) in TFE (1 mL) at 25°C for 24 h. Yields of isolated prod-
ucts are given. The er values were determined by HPLC analysis
on a chiral stationary phase.
Next, the generality of O-Boc hydroxamates was tested with sty-
rene. These results are summarized in Scheme 4. Hydroxamates
bearing electronically varied substituents (Me, Bu, OMe, OPh,
t
NO2, CF3, Ph) reacted with 8a smoothly, leading to the isolation
of corresponding products (9ba-oa) in satisfactory yields (57-94%)
and with excellent enantiomeric ratios (88.5:11.5-95:5). Notably,
halogen substituted hydroxamates (4-F, 4-Cl, 4-Br, 4-I and 3-I)
were compatible in this transformation, affording their corre-
sponding halogen-containing products 9k–o in 90–92% yields
with 90:10-94:6 er. 2-Naphthoic acid and indole-6-carboxylic acid
derived hydroxamates were also suitable substrates, affording 9pa
in 88% yield with 87:13 er and 9qa in 73% yield with 90.5:9.5 er,
respectively.
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treatment with AdCOOH and Ag2CO3. Ligand exchange with the
Scheme 4. Substrate Scope for Hydroxamate Derivativesa
substrate, followed by ortho C–H bond activation affords the 5-
membered rhodacycle I. Then coordination to the olefin and 1,2-
migratory insertion provide 7-membered rhodacycle II. Syn β-H
elimination and the subsequent second migratory insertion lead to
thermodynamically stable 6-membered rhodacycle IV with deu-
teration at the benzylic position. The steric interaction between
the substrate and ligand facilitates β-hydride elimination. Finally,
a stepwise C-N bond reductive elimination followed by N-O bond
oxidative addition liberates the isoindolinone product and regen-
erates the active catalyst.23
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a
Reaction conditions: 7 (0.20 mmol), 8a (0.30 mmol), (R)-
CpmRh4 (2.5 mol %), AdCO2H (15 mol %) and Ag2CO3 (7.5
mol %) in TFE (1 mL) at 25°C for 24 h. Yields of isolated prod-
ucts are given. The er values were determined by HPLC analysis
on a chiral stationary phase.
To demonstrate the potential utility of this asymmetric [4+1] an-
nulation reaction, 1 mmol-scale reaction was performed, and iso-
indolinone 9aa was isolated in 84% yield with 96:4 er. N-Methyl
substituted 10aa was prepared in 96% yield without notable ero-
sion of enantioselectivity upon the treatment with MeI in the pres-
ence of Cs2CO3 (Scheme 5).
Scheme 5. 1 mmol Scale Reaction and Product Transfor-
mation
Figure 3. Isotope Labelling Experiment and Proposed Catalytic
Cycle
In conclusion, we developed a series of rhodium complexes bear-
ing sterically and electronically tunable cyclopentadienyl ligands,
which were synthesized by utilizing Co2(CO)8 mediated [2+2+1]
cyclization as a key step. With one of the Rh complexes (R)-
CpmRh4 (2.5 mol %), the first enantioselective [4+1] annulation
reaction of benzamides and alkenes has been achieved. A variety
of isoindolinones with excellent regio- and enantioselectivity were
obtained under mild reaction conditions. Further applications of
these CpRh complexes are going in our laboratory.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
To shed lights on the mechanism of this cross-coupling reaction, a
preliminary mechanistic study was conducted with deuterated
styrene substrate 8o-d2 (D content: 76%), H/D scrambling oc-
curred at the benzylic position of the product (with 76% D, Figure
3a). Based on this result, a preliminary catalytic cycle for this
transformation was proposed as shown in Figure 3b. The catalytic
species Cp*Rh(OCOAd)2 is generated from Cp*RhCl2 by the
Experimental procedures and characterization of all new com-
pounds (PDF).
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Indoles
and
7-Azabenzonorbornadienes
by
C-H
Activa-
AUTHOR INFORMATION
Corresponding Author
slyou@sioc.ac.cn
ORCID
tion/Desymmetrization. Angew. Chem. Int. Ed. 2019, 58, 322. (j) Li, H.;
Yan, X.; Zhang, J.; Guo, W.; Jiang, J.; Wang, J. Enantioselective Synthe-
sis of C-N Axially Chiral N-Aryloxindoles by Asymmetric Rhodium-
Catalyzed Dual C-H Activation. Angew.Chem. Int. Ed. 2019, 58, 6732. (k)
Tian, M.; Bai, D.; Zheng, G.; Chang, J.; Li, X. Rh(III)-Catalyzed Asym-
metric Synthesis of Axially Chiral Biindolyls by Merging C-H Activation
and Nucleophilic Cyclization. J. Am. Chem. Soc. 2019, 141, 9527. (l) Mi,
R.; Zheng, G.; Qi, Z.; Li, X. Rhodium-Catalyzed Enantioselective Oxida-
tive [3+2] Annulation of Arenes and Azabicyclic Olefins through Twofold
C-H Activation. Angew. Chem. Int. Ed. 2019, 58, 17666.
(4) (a) Jia, Z.-J.; Merten, C.; Gontla, R.; Daniliuc, C. G.; Antonchick, A.
P.; Waldmann, H. General Enantioselective C-H Activation with Effi-
ciently Tunable Cyclopentadienyl Ligands. Angew. Chem. Int. Ed. 2017,
56, 2429. (b) Trifonova, E. A.; Ankudinov, N. M.; Mikhaylov, A. A.;
Chusov, D. A.; Nelyubina, Y. V.; Perekalin, D. S. A Planar-Chiral Rhodi-
um(III) Catalyst with a Sterically Demanding Cyclopentadienyl Ligand
and Its Application in the Enantioselective Synthesis of Dihydroisoquin-
olones. Angew. Chem. Int. Ed. 2018, 57, 7714.
1
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Shu-Li You: 0000-0003-4586-8359
Qing Gu: 0000-0003-4963-2271
Author Contributions
‡ W.-J. C. and Z.-J. W. contributed equally to this work.
9
Notes
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The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the National Key R&D Program of China
(2016YFA0202900), National Natural Science Foundation of
China (21821002, 91856201, 19590750400), the CAS
(XDB20000000, QYZDY-SSW-SLH012) and Science and Tech-
nology Commission of Shanghai Municipality (18JC1411302) for
generous financial support. Shu-Li You acknowledges the support
from the Tencent Foundation through the XPLORER PRIZE. This
paper is dedicated to Prof. Mingyuan He on the occasion of his
80th birthday
(5) For recent reports of chiral multi-substituted Cp ligands, see: (a)
Teng, H.-L.; Luo, Y.; Wang, B.-L.; Zhang, L.; Nishiura, M.; Hou, Z.-M.
Synthesis of Chiral Aminocyclopropanes by Rare-Earth-Metal-Catalyzed
Cyclopropene Hydroamination. Angew. Chem. Int. Ed. 2016, 55, 15406.
(b) Smits, G.; Audic, B.; Wodrich, M. D.; Corminboeuf, C.; Cramer, N. A
β-Carbon Elimination Strategy for Convenient in situ Access to Cyclopen-
tadienyl Metal Complexes. Chem. Sci. 2017, 8, 7174. (c) Sun, Y.; Cramer,
N. Tailored Trisubstituted Chiral Cpx Rh(III) Catalysts for Kinetic Resolu-
tions of Phosphinic Amides. Chem. Sci. 2018, 9, 2981. (d) Sun, Y.;
Cramer, N. Enantioselective Synthesis of Chiral-at-Sulfur 1,2-
Benzothiazines by CpXRhIII-Catalyzed C-H Functionalization of Sul-
foximines. Angew. Chem. Int. Ed. 2018, 57, 15539. (e) Brauns, M.;
Cramer, N. Efficient Kinetic Resolution of Sulfur-Stereogenic Sul-
foximines by Exploiting CpXRhIII-Catalyzed C-H Functionalization. An-
gew. Chem. Int. Ed. 2019, 58, 8902. (f) Wang, S.-G.; Liu, Y.; Cramer, N.
Asymmetric Alkenyl C-H Functionalization by CpXRhIII forms 2H-Pyrrol-
2-ones through [4+1]-Annulation of Acryl Amides and Allenes. Angew.
Chem. Int. Ed. 2019, 58, 18136. (g) Audic, B.; Wodrich, M. D.; Cramer, N.
Mild Complexation Protocol for Chiral Cpx Rh and Ir Complexes Suitable
for in situ Catalysis. Chem. Sci. 2019, 10, 781. (h) Ozols, K., Jang, Y.-S.,
Cramer, N. Chiral Cyclopentadienyl Cobalt(III) Complexes Enable Highly
Enantioselective 3d-Metal-Catalyzed C-H Functionalizations. J. Am.
Chem. Soc. 2019, 141, 5675.
(6) (a) Hyster, T. K.; Rovis, T. Pyridine Synthesis from Oximes and
Alkynes via Rhodium(III) Catalysis: Cp* and Cpt Provide Complementary
Selectivity. Chem. Commun. 2011, 47, 11846. (b) Hyster, T. K.; Rovis, T.
An Improved Catalyst Architecture for Rhodium(III) Catalyzed C–H
Activation and Its Application to Pyridone Synthesis. Chem. Sci. 2011, 2,
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Rh(III)-Catalyzed C-H Activation: An Unsymmetrical Cyclopentadienyl
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Divergent Synthesis of Tunable Cyclopentadienyl Ligands and Their Application in Rh-catalyzed Enantioselective Synthesis
of Isoindolinone
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