Cobalt-Catalyzed Chemoselective Transfer Hydrogenative Cyclization Cascade of Enone-Tethered Aldehydes

Article abstract of DOI:10.1021/acs.orglett.1c00992

The ligand-free Co-catalyzed chemoselective reductive cyclization cascade of enone-tethered aldehydes with i-PrOH as the environmentally benign hydrogen surrogate is developed by this study. Mechanistic studies disclosed that such a protocol is initiated

Full text of DOI:10.1021/acs.orglett.1c00992

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Letter
Cobalt-Catalyzed Chemoselective Transfer Hydrogenative
Cyclization Cascade of Enone-Tethered Aldehydes
Shuang-Shuang Ma, Biao-Ling Jiang, Zheng-Kun Yu, Suo-Jiang Zhang, and Bao-Hua Xu*
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ABSTRACT: The ligand-free Co-catalyzed chemoselective reductive cyclization cascade of enone-tethered aldehydes with i-PrOH
as the environmentally benign hydrogen surrogate is developed by this study. Mechanistic studies disclosed that such a protocol is
initiated by an ortho-enone-assisted Co(I)-catalyzed reduction of the aldehyde functionality with i-PrOH. Meanwhile, the selectivity
from the Michael−Aldol cycloreduction cascade to the oxa-Michael cascade is feasible and readily adjusted by the addition of steric
Lewis bases, such as TEMPO and DABCO, delivering substituted 1H-indenes and dihydroisobenzofurans, respectively.
Scheme 1. Cobalt-Catalyzed Intramolecular Coupling of
Aldehydes with π-Unsaturated Bonds
ascade reactions represent an efficient chemical pathway
Cto construct rather complex scaffolds and constitute a
great challenge in modern organic chemistry and drug
discovery.1 To this end, chemoselective variation toward
multifunctional substrates is generally a prerequisite to form
precursors of the sequence. For instance, the intramolecular
cyclization of enone-tethered electrophiles, such as aldehyde,
ketone, enone, and nitro functionalities, provides a good setup
for a Michael−Aldol coupling cascade reaction with
nucleophiles to construct cyclic alcohol motifs.2−4 However,
such a Michael-addition-initiated cascade may be replaced by a
nucleophilic attack on the more reactive electrophiles to alter
the reaction sequence.5,6 Despite a wealth of research on both
cascades toward intramolecular enone-tethered aldehydes,
transition-metal-catalyzed reductive cyclization remains less
developed. Experimental investigations into the approach of
chemoselective reductive cyclization and exploration of the
different reactivities between two modes with the same catalyst
would advance the potential of such strategies in depth.
The Co-catalyzed diastereoselective Michael−Aldol cyclo-
reduction with a stoichiometric amount of silanes was
pioneered by the Krische group (Scheme 1A), which
continued the catalytic cycling between Co(I) and Co(III).7
Recently, Co-catalyzed reductive π-unsaturated bonds with
inexpensive and sustainable hydrogen (H) surrogates have
been accessed.8 C/N alkylation with alkanols, proceeding
through a hydrogen-borrowing strategy, was thereafter
developed.9 Our group was contemporaneously focusing on
Co-catalyzed transfer hydrogenations. As a result, the Co(I)/
diphosphine-catalyzed chemoselective hydrogenation of CC
and CO bonds with alkanols was developed.10
Received: March 24, 2021
Published: May 7, 2021
https://doi.org/10.1021/acs.orglett.1c00992
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3873−3878
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1
We thus envisioned that such a system may enable the
conjugate reduction of enones to afford enolate nucleophile for
the intramolecular attack to aldehydes. But the competitive
ortho-vinyl-assisted Co(I)-catalyzed reduction of aldehydes,
followed by oxa-Michael cyclization, cannot be completely
excluded. In fact, the successive cross-coupling of alkanols with
olefins to offer ethers under Co(II) catalysis was feasible
following either aerobic oxidative cyclization11 or a hydrogen-
atom transfer and radical-polar crossover strategy.12 An
additional challenge is to suppress the potential intramolecular
hydroacylation of olefins documented by Yoshikai’s group
(Scheme 1B).13 In this study, we report the first example of the
low-valent Co-catalyzed reductive cyclization of enone-
tethered aldehydes with isopropanol (i-PrOH) (Scheme 1C).
To our surprise, the Michael−Aldol cycloreduction cascade
proceeds smoothly without ligands and is terminated with a
dehydration step to provide 1H-indene derivatives. By
contrast, the selectivity to the oxa-Michael cascade can be
readily adjusted with the addition of Lewis bases, such as
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and 1,4-
diazabicyclo[2.2.2]octane (DABCO), delivering the substi-
tuted dihydroisobenzofurans.
the typical H NMR resonance of secondary CH at δ 3.88 for
2a and tertiary CH at δ 5.93 for 3a, a ratio of ca. 2:1 was
determined. The structural recognition of both products upon
isolation was confirmed by 2D 13C/1H HETCOR (HMQC
and HMBC) experiments. We next screened selected bidentate
phosphine ligands, which differed in their respective bite angles
and functionalities (entries 2−6), thereby tuning the
coordination mode of either enone or aldehyde with the Co
center to improve the chemoselectivity and reactivity.
Evidently, different yields of 2a and 3a were detected.
However, it is difficult to elucidate the precise pathway by
which the type of ligand influences the reaction. As shown, the
steric dtbpx significantly improved the reactivity, giving a total
yield of 91% with a moderate ratio of 2a to 3a. Surprisingly,
this result is comparable to that without ligands (entry 7).
Further studies demonstrated that the in situ generation of
low-valent Co(I) species was indispensable (entry 8). In
addition, the Lewis acidic InI3 (10 mol %) formed in situ could
not provide the desired reductive coupling (entry 9).
Subsequently, the limit and scope of this protocol were
studied (Scheme 2). We observed that electronic variation of
the phenyl group (Ar1) adjacent to the carbonyl site of the
enone affects the reactivity. Specifically, the cyclized products
substituted with electron-withdrawing groups at the para
position (2h, 2i, 2l, and 2m) were obtained in slightly higher
The Co-catalyzed transfer hydrogenative cyclization of 1a
was conducted with an in-situ-generated Co(I)-diphosphine
catalyst and i-PrOH (Table 1 and Table S1). As a result of
Table 1. Condition Optimization for the Michael−Aldol
Scheme 2. Co-Catalyzed Michael−Aldol Cycloreduction
a
a
Cycloreduction of 1a
Cascade Leading to 1H-Indenes (2)
b
entry
[Co]
ligand
additive (mol %) conv. (%)
2a/3a
1
2
3
4
5
6
7
8
9
CoI2
CoI2
CoI2
CoI2
CoI2
CoI2
CoI2
CoI2
dcpp
dppp
dppb
dcpe
xantphos
dtbpx
In (40)
In (40)
In (40)
In (40)
In (40)
In (40)
In (40)
72
64
70
37
31
91
93
0
2:1
2:1
6:1
1:1
3:4
4:1
8:1
InI3 (10)
0
a
General conditions: 1a (0.1 mmol), CoI2 (10 mol %), ligand (15
b
mol %), toluene (0.5 mL), under Ar. Conversion was determined by
1H NMR using 2-methylindole as the internal standard.
preliminary examinations, the reaction was carried out with
CoI2 (10 mol %), dcpp (15 mol %), indium powder (In) (40
mol %), and i-PrOH (10 equiv) in toluene at 80 °C for 24 h
under argon (Table 1, entry 1). Instead of the cyclic alcohol
upon a typical Michael−Aldol coupling cascade,3,4 appreciable
quantities of the indene counterpart 2a, featuring an indenyl
1H NMR signal at δ 7.49 and δ 3.88, were formed. Notably, de
Bruin reported the transformation of o-cinnamyl N-tosyl
hydrazones to substituted 1H-indenes, facilitated by the native
reactivity of a Co(III) carbene radical intermediate.14 The oxa-
Michael product 3a was also obtained, but in less yield. From
a
Reaction conditions: toluene (0.5 mL), under Ar, isolated yield.
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yields compared with those with electron-donating groups (2d
and 2e). In addition, the performance decreased in the order of
para (2d/2h/2l) > ortho (2b/2f/2j) > meta (2c/2g/2k)
regardless of the electronic property, suggesting that both the
nucleophilicity and the stabilization of the transient α-carbon
nucleophile play a crucial role in the cyclization. On the
contrary, the steric hindrance of the Ar1 has nearly no
influence. Various disubstituted phenyl ring such as p-F/m-Me
(2n), p-OMe/m-OMe (2q), p-Me/m-Me (2r), and p-Me/o-
Me (2s) were tolerated and provided the corresponding 1H-
indenes in 72−82% yields. The reductive cyclization also
proceeded smoothly when the Ar1 was replaced by either
naphthyl derivatives (2o and 2p) or heteroaromatic thiophene
(2t). Finally, the functionalities of the phenyl group (Ar2) at
the bridge with such a protocol were examined. Substituents
with not only electron-withdrawing (2u, 2v, 2y, and 2z)
functionalities but also electron-donating groups (2w and 2x)
were found to be tolerated. We also investigated the Michael−
Aldol cycloreduction of 1a on a scale of 4.24 mmol, which
provided 2a in an acceptable yield of 71% under the optimum
conditions (Scheme S3).
Ar1 and Ar2 were tolerated, wherein neither an electronic nor a
steric effect has been remarkably detected.
The potential for performing an intermolecular Michael−
Aldol reductive coupling was also evaluated under standard
conditions, taking the reaction of benzaldehyde (4) with
chalcone (5) as an example (Table 2, entry 1). Unfortunately,
Table 2. Cross Experiments on the Intermolecular
a
Michael−Aldol Reductive Coupling
b
yield (%)
entry
4 (x)
5 (y)
ligand (z)
6
7
8
1
2
3
4
5
6
7
8
9
(0.1)
(0.1)
(0.1)
(0.1)
(0.1)
(0)
(0)
(0)
(0)
(0.1)
(0.02)
(0)
(0.1)
(0.02)
(0.1)
(0.1)
(0.1)
(0.1)
(0)
(0)
(0)
44
38
6
58
8
0
0
0
0
On the basis of our previous studies10 and the present
results, this low-valent Co-catalyzed Michael−Aldol cyclo-
reduction may proceed via the famous Meerwein−Ponndorf−
Verley reduction route.15 To identify whether it follows a
concerted or stepwise fashion, the poisoning studies using
TEMPO as an inhibitor were performed (Table S3). To our
surprise, the formation of 2a was significantly suppressed with
the addition of TEMPO, whereas the yield of 3a increased. We
rationally suspected that the hydrogen transfer leading to the
Michael−Aldol cycloreduction product (2) proceeds via the
transiency Co−H species. In contrast, the oxa-Michael route to
3 occurs mainly in a concerted fashion. These two paths are in
competition. Having clarified the selectivity to each cascade
under the present protocol, we turned our attention to the
optimum conditions leading to 3 and its substrate tolerance
(Scheme 3). As a result, the best yield of 3a (82%) was
obtained with the addition of 4 equiv of TEMPO. In addition,
enone-tethered aldehydes with functionalities at both sites of
dtbpx (15)
dtbpx (15)
(0)
dtbpx (15)
dcpp (15)
dcpe (15)
0
0
0
1
14
0
0
0
0
84
98
0
a
b
Reaction conditions: toluene (0.5 mL), under Ar. Yields were
1
determined by H NMR using CH2Br2 as the internal standard.
the desired two-component cascade addition product was not
detected. Instead, only the reduction of 4 partially proceeded,
and a catalytic amount of 5 was sufficient but necessary for
such a transformation (entries 2 and 3). The addition of dtbpx
(15 mol %) did not improve the reactivity (entry 4 vs entry 1).
Meanwhile, a stoichiometric amount of 5 was required to
obtain a comparative efficiency (entry 4 vs entry 5). This is due
to the preferred coordination to Co(I) with dtbpx over 5,
whereas the latter functions as the active site for the reduction
of 4. To ascertain whether the reductive cyclization leading to
2 proceeds via the typical Michael−Aldol coupling cascade and
whether the varied reactivities under study differ from the
reactivity of the Michael reduction of enones, chalcone (5) was
subjected to the optimum conditions (entry 6). To our
surprise, 5 remained unchanged. In addition, the reduction of 5
proceeded poorly in the presence of dtbpx (entry 7), dppb,
xantphos, and dppp (Table S2) but readily occurred with dcpp
and dcpe (entries 8 and 9). Collectively, a high efficiency in the
Michael reduction of enones did not promise the formation of
1H-indene 2 over dihydroisobenzofuran 3. The aldehydes were
preferentially reduced in the presence of an enone function-
ality, most likely functioning as the ligand.
Scheme 3. Co-Catalyzed oxa-Michael cascade Leading to
a
Dihydroisobenzofurans (3)
Deuterium labeling experiments with the purpose of
obtaining insights into the route leading to such a Michael−
Aldol cycloreduction cascade were conducted (Table 3).
Consequently, the benchmark reaction was carried out with
(CD3)2CDOH (i-PrOH-d7) and (CD3)2CDOD (i-PrOH-d8),
respectively. The five-membered ring of 2a−d is significantly
deuterated, delivering a full deuteration at the methylene (Ha−
Hb) with a high percentage (>60%). In addition, the deuterium
content is almost the same with two H surrogates. This
suggests that the tertiary CH in i-PrOH, rather than the
hydroxyl group, functions as a H source in the formation of 2a.
a
Reaction conditions: toluene (0.5 mL), under Ar, isolated yield.
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a
Table 3. Deuterium Labeling Experiments
b
yield (%)
D occupation (D %)
H−H/H−D/D−D
[H]
2a-d
3a-d
Ha/Hb
Hc
Hd
He
Hg
Hh
Ha-Hb
Hd-He
Hg-Hh
i-PrOH-d8
i-PrOH-d7
60
64
15
13
80
74
50
20
65
50
40
15
40
40
40
40
10:21:69
10:30:60
25:45:30
35:65:0
20:80:0
20:80:0
a
b
Reaction conditions: toluene (0.5 mL), under Ar. Isolated yield.
Moreover, there is nearly no proton−hydride exchange during
such a process. Herein the formation of 3a is non-
enantioselective, but only one enantiomer is displayed for
clarity. We observed that the deuterium content of the
methylene group at the ring (Hg−Hh) does not vary with H
surrogates, whereas those adjacent to the carbonyl site (Hd−
He) differ remarkably. These results indicate that the oxa-
Michael addition in the formation of 3a is a fast and
nonreversible step.
addition provides F, which is thereafter terminated with a
dehydration step to deliver 2 and regenerate A by further
reaction with 1 and i-PrOH. The presence of Co-enolate E was
confirmed by subjecting the saturated ketone-tethered
aldehyde 9a to the optimum conditions (Scheme S2), which
provides 2a in only 33% yield. For cycle II, complex C
undergoes oxa-Michael addition directly, providing the Co-
enolate G. Next, the nucleophilic substitution of enolate with i-
PrOH and the coordination with another 1 regenerates A,
coincidingly offering 3.
Under the optimized conditions, the β−H elimination in C
takes place prior to the competitive oxa-Michael addition, thus
affording 1H-indene (2) as the major product. However, the
reversed hydride transfer from Co(I) to carbonyls is
accelerated with Lewis bases of proper steric and electronic
properties,16 such as TEMPO. Thus the conversion from C to
D becomes reversible, and the oxa-Michael addition leading to
3 is thereby dominant. To confirm this opinion, a variety of
Lewis basic amines were examined as the substitute for
TEMPO, wherein the steric DABCO performs comparably
(Table S4). In this regard, it is partially understandable that the
selectivity varied with different steric bidentate phosphines.
In summary, the ligand-free low-valent Co-catalyzed chemo-
selective transfer hydrogenative cyclization cascade of enone-
tethered aldehydes with i-PrOH as the environmentally benign
H surrogate was developed. The selectivity from 1H-indenes to
dihydroisobenzofurans could be readily adjusted by the
addition of Lewis bases. New perspectives could be obtained
by this study to solve some prominent problems in the field of
cobalt catalysis. For example, the challenging Co-catalyzed β−
H elimination9d,10 and the impeded hydride transfer from
Co(III)−H species to carbonyl moieties10,13,16 can be
approached by launching a proper cobalt valence and chelate
environment. Further studies toward the Co-catalyzed enone-
trigged cascade reactions are currently under way.
In the light of the literature and our present results, a
tentative reaction mechanism is proposed and outlined in
Scheme 4. It contains two catalytic cycles of I and II,
Scheme 4. Proposed Mechanism
representing the pathways to 2 and 3, respectively. Both cycles
initiate after the formation of A from the reduction of CoI2 and
the subsequent nucleophilic substitution of iodide with i-
PrOH. It is noteworthy that the low-valent Co(I) can be
coordinated by 1 in either the (η2, η6) or the (η4, η4) mode to
satisfy the electronic and geometric requirements. Herein only
one of them is demonstrated to clarify the main pathway. As
confirmed by experiments, the subsequent hydrogen transfer in
a concerted fashion to the aldehyde is preferred over the enone
functionality. Complex C is thus formed with the dissociation
of an acetone. In detail, we supposed that the intramolecular
transfer via B is unlikely because the cyclic six-membered ring
therein is highly distorted. Instead, the formation of a flat six-
membered ring at the stable 18-electron Co(I) by coordination
with another 1 in B′ renders the hydrogen transfer plausible.
Next, β−H elimination in C occurs to give D for cycle I,
followed by hydride transfer from Co to the enone site,
resulting in the cobalt-enolate E. The subsequent aldol
ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Author
■
Bao-Hua Xu − Beijing Key Laboratory of Ionic Liquids Clean
Process, Key Laboratory of Green Process and Engineering,
Institution of Process Engineering, Chinese Academy of
Sciences, Beijing 100190, China; College of Chemistry and
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divergent preparation of various heterocycles via phase-transfer
catalysis: Enantioselective synthesis of functionalized piperidines.
Adv. Synth. Catal. 2020, 362, 1167−1175.
Sciences, Beijing 100049, China; Innovation Academy for
Green Manufacture, Chinese Academy of Sciences, Beijing
100190, China; orcid.org/0000-0002-7222-4383;
Email: bhxu@ipe.ac.cn
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Authors
Shuang-Shuang Ma − Beijing Key Laboratory of Ionic Liquids
Clean Process, Key Laboratory of Green Process and
Engineering, Institution of Process Engineering, Chinese
Academy of Sciences, Beijing 100190, China; College of
Chemistry and Chemical Engineering, University of Chinese
Academy of Sciences, Beijing 100049, China
Biao-Ling Jiang − Beijing Key Laboratory of Ionic Liquids
Clean Process, Key Laboratory of Green Process and
Engineering, Institution of Process Engineering, Chinese
Academy of Sciences, Beijing 100190, China
Zheng-Kun Yu − Innovation Academy for Green Manufacture,
Chinese Academy of Sciences, Beijing 100190, China;
orcid.org/0000-0002-9908-0017
Suo-Jiang Zhang − Beijing Key Laboratory of Ionic Liquids
Clean Process, Key Laboratory of Green Process and
Engineering, Institution of Process Engineering, Chinese
Academy of Sciences, Beijing 100190, China; College of
Chemistry and Chemical Engineering, University of Chinese
Academy of Sciences, Beijing 100049, China
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Excellent Young Scientists Fund
(22022815) and the Innovation Academy for Green
Manufacture, CAS (IAGM2020C13) is gratefully acknowl-
edged.
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