Propargyl Alcohols as One-Carbon Synthons: Redox-Neutral Rhodium(III)-Catalyzed C-H Bond Activation for the Synthesis of Isoindolinones Bearing a Quaternary Carbon

Article abstract of DOI:10.1021/acs.orglett.7b00089

Herein, rhodium(III)-catalyzed C-H activation/subsequent [4 + 1] cyclization reactions between benzamides and propargyl alcohols are reported in which propargyl alcohols serve as unusual one-carbon units. This title transformation led to a series of isoin

Full text of DOI:10.1021/acs.orglett.7b00089

Letter
pubs.acs.org/OrgLett
Propargyl Alcohols as One-Carbon Synthons: Redox-Neutral
Rhodium(III)-Catalyzed C−H Bond Activation for the Synthesis of
Isoindolinones Bearing a Quaternary Carbon
Xiaowei Wu,†,‡ Bao Wang,†,§ Yu Zhou,† and Hong Liu*,†
†Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road,
Shanghai 201203, China
‡University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
§School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Pudong, Shanghai 201210, China
S
* Supporting Information
ABSTRACT: Herein, rhodium(III)-catalyzed C−H activation/subse-
quent [4 + 1] cyclization reactions between benzamides and propargyl
alcohols are reported in which propargyl alcohols serve as unusual one-
carbon units. This title transformation led to a series of isoindolinones
bearing a quaternary carbon with moderate to good yields without the
requirement for external metal oxidants. Due to the mild and simple
reaction conditions, this reaction is compatible with various functional
groups.
Scheme 1. Rh(III)-Catalyzed C−H Activation Assisted by
soindolinones are ubiquitous in pharmaceuticals and
1
Oxidizing Directing Groups
Icomplex natural products.
Efficient methods for their
preparation are an important topic of research because of
their varied biological activities.2,3 In the past decade, transition-
metal-catalyzed cycloaddition reactions have emerged as an
efficient method to synthesize heterocycles;4 however,
stoichiometric amounts of external oxidants are usually required
in annulations involving C−H activation steps. Therefore, an
oxidizing directing group that acts as an internal oxidant
becomes an elegant and environmentally friendly strategy for
transition-metal-catalyzed annulations.5 Accumulating studies
have demonstrated that oxidizing directing groups are effective
internal oxidants.5a For instance, Rovis et al. pioneered the
development of rhodium(III)-catalyzed C−H activation/
cyclization of benzamides and diazo compounds for iso-
indolinone synthesis (Scheme 1, eq 1).6a In this case,
benzamides with a N−O group serve as an internal oxidant
and α-diazo carbonyl compounds can serve as one-carbon units
in a [4 + 1] cyclization reaction that provides interesting
isoindolinones bearing a quaternary carbon.
internal alkynes. Thus, in the present study, we report a
Rh(III)-catalyzed [4 + 1] cyclization reaction of benzamides
with propargyl alcohols to produce isoindolinones bearing a
quaternary carbon under external oxidant-free conditions (eq
3) in which internal alkynes serve as unusual one-carbon units
rather than normal two-carbon components.
We initiated our investigations with the reaction of N-tert-
butoxybenzamide 1a-1 and propargyl alcohol 2a catalyzed by
rhodium complexes in the presence of CsOAc at 80 °C for 12
h. First, after a screen of solvents (see Table S1), we found that
no reaction took place in MeOH, CH3CN, and DMF. When we
use THF or DCE as the solvent, the reaction gave the desired
In recent years, transition-metal-catalyzed redox-neutral
annulation reactions of benzamides with internal alkynes have
been well established (eq 2). Among these reactions, internal
alkynes generally serve as two-carbon reaction partners5a,7−9
and are seldom considered as one-carbon components.10 To
the best of our knowledge, there have been few examples of
Rh(III)-catalyzed [4 + 1] cyclizations10a,11 of arenes with
internal alkynes under external oxidant-free conditions. Rh(III)-
catalyzed [4 + 1] annulation reactions of aromatic compounds
with one-carbon partners represent a powerful approach for the
synthesis of isoindolinones; therefore, we are interested in
developing Rh(III)-catalyzed [4 + 1] annulation reactions with
Received: January 10, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b00089
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product 3a in 26% yield and 40% yield, respectively. The
reaction did not take place while using Na2CO3 as the base;
when [Cp*Rh(CH3CN)3SbF6]2 was used as the catalyst, an
compatible with the standard reaction conditions, which
guaranteed further transformation. These results showed
good reactivity and regioselectivity in this reaction.
Furthermore, the scope of propargyl alcohols was explored
(Scheme 3). We found the propargyl alcohols bearing electron-
1
unsatisfactory result was obtained. The H NMR yield was
improved to 77%, and the ratio of 3a/4a was also improved to
90/10 when substrate 1a was used. In addition, it failed to give
the desired product 3a when pivaloyl instead of a methyl group
was used. When 3.0 equiv of propargyl alcohol 2a was used, the
1H NMR yield increased to 89%. Moreover, the reaction did
not take place in the absence of CsOAc or the catalyst
[Cp*RhCl2]2.
a,b
Scheme 3. Scope of Propargyl Alcohols
With the optimized reaction conditions in hand, we first
explored the substrate scope of benzamides 1 with propargyl
alcohol 2a (Scheme 2). Generally, the benzamides with various
a,b
Scheme 2. Scope of Benzhydroxamic Acids
a
Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), [Cp*RhCl2]2 (5
mol %), CsOAc (1 equiv) in anhydrous DCE (4 mL) at 80 °C for 12
b
h, Ar atmosphere. Isolated yields are reported.
poor substituents showed good reactivity and afforded the
desired products (3p−s) in good yields. A nitro group on the
phenyl moiety of the propargyl alcohols (2g) gave a decreased
yield. In addition, the structure of 3s was confirmed by X-ray
crystallographic analysis (see the Supporting Information for
details).12 Coupling with an electron-rich group propargyl
alcohol provided the desired product (3t) in excellent yield.
Furthermore, other aryl groups, including thiophene 2h,
naphthalene 2i, and pyridine 2j, also reacted with 1a to
generate the desired product in good yields. When we used a
benzyl group to replace the phenyl moiety of the propargyl
alcohol, it also gave a satisfactory result (3y). Notably, the
introduction of bulkier groups (such as propyl and cyclopropyl)
in the R1 moiety of substrates also provided the corresponding
products in moderate to good yields (3z and 3za).
Unfortunately, the reaction did not yield the desired products
3zb and 3zc when 1,3-diphenylprop-2-yn-1-ol 2n and 1-
phenylprop-2-yn-1-ol 2o were used as substrates, respectively.
In general, substrates bearing electron-withdrawing groups
(such as trifluoromethyl, nitro, and halides), electron-donating
groups, and heteroaryl groups were well tolerated under the
standard reaction conditions.
To assess the efficiency and potential for applications of this
method, we carried out a scale-up experiment and explored the
transformation of the product 3zd to construct isoindolo[2,1-
a]quinoline derivative 3zd-1 (Scheme 4).
To probe the reaction mechanism, a series of deuterium-
labeling experiments were performed. First, we carried out the
reaction without the propargyl alcohol in the presence of
methanol-d4 to determine the reversibility of the C−H
activation (Scheme 5). We found that about 30% of the
deuterium was incorporated at the ortho position of the
a
Reaction conditions: 1 (0.2 mmol), 2a (0.6 mmol), [Cp*RhCl2]2 (5
mol %), CsOAc (1 equiv) in anhydrous DCE (4 mL) at 80 °C for 12
b
h, Ar atmosphere. Isolated yields are reported.
electron-withdrawing groups, electron-donating groups, and
neutral groups all underwent smooth coupling with propargyl
alcohol 2a, and the desired products were obtained in moderate
to good yields (42−85%). We found that the electron density
of benzamides 1 played an important role in this reaction.
Introduction of electron-donating groups (−Me and −OMe)
could give good yields (1b−d,o). In contrast, substrates bearing
strong electron-withdrawing groups such as COOMe, NO2, and
CN (1g, 1h, and 1j) resulted in decreased yields of the desired
products. In addition, the desired products were obtained in
good yields when halogen groups such as chlorine (1e) and
bromine (1f) were introduced at the para position of the
benzene ring. When a bromine group (1l) was placed at the
meta position of the benzene ring, a single isomer was obtained
in 53% yield; a similar effect was also observed with
naphthylamides (1n) and substrate 1o. It is worth mentioning
that a p-vinyl group (1k) is well tolerated in this reaction.
Because of the mild conditions, various functional groups (such
as vinyl, cyano, nitro, methyl carboxylate, halides, etc.) were
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kinetic isotope effect (KIE) value (kH/kD = 5.2). Besides, two
independent reactions using 1a and 1a-d5 gave a KIE value of
1.9. These results indicated that C−H bond cleavage was likely
involved in the rate-limiting step. In addition, to determine
whether the first step comprises propargyl alcohol isomerizing
to an α,β-unsaturated ketone under Rh(III) catalysis, we
performed two control experiments (see the SI for details). The
reaction did not provide the desired product when an α,β-
unsaturated ketone was used as the substrate. The control
experiments confirmed that the first step of the reaction was
not propargyl alcohol isomerizing to an α,β-unsaturated ketone.
Based on the preliminary mechanistic experiments and
previous studies,7b,13 we proposed a plausible catalytic cycle
(Scheme 6). The first step is the formation of an active catalyst
Scheme 4. Gram-Scale Preparation of 3s and Conversion of
the Product
Scheme 6. Proposed Mechanism
Scheme 5. Preliminary Mechanism Studies
through anion exchange with cesium acetate. Next, the
coordination of benzamide 1 via the amide nitrogen to Rh(III)
and subsequent irreversible C−H bond cleavage of 1 occurs to
produce a five-membered rhodacycle I, which is coordinated
and inserted with propargyl alcohol 2a to form a seven-
membered rhodacycle intermediate II. One pathway is followed
by the reductive elimination of intermediate II to provide the
minor product 4a. The other pathway presumably follows the
abstraction of the allylic proton by the rhodium complex to
form a π-allylic rhodacycle intermediate III. Subsequently,
reductive elimination and enol−keto tautomerism of inter-
mediate III leads to intermediate IV. Finally, Rh(I) complexes
in intermediate IV could be oxidized by the intramolecular N−
O bond, providing the desired product 3, EtOH, and the active
Rh(III) catalyst to furnish the catalytic cycle.
In summary, by use of an oxidizing directing group, a mild
and efficient Rh(III)-catalyzed [4 + 1] cyclization reaction
between benzamides and propargyl alcohols was developed.
This reaction provides a straightforward method for accessing
potentially bioactive isoindolinones bearing a quaternary
carbon with moderate to good yields. The biggest characteristic
of this method is that a novel synthetic utility of propargyl
alcohols has been found in Rh(III)-catalyzed cyclizations with
benzamides, which can lead to an unusual [4 + 1]
transformation. In view of the mild reaction conditions and
good functional group tolerance, this reaction might have
potential for practical applications.
benzamides based on 1H NMR analysis (see the SI for details).
Performing the same reaction in the presence of methanol-d4
and propargyl alcohol 2a led to no deuterium being
incorporated at the ortho position of γ-lactam 3a. These results
suggested that the step of C−H activation might be irreversible
under the reaction conditions. In addition, both protons at the
α-methylene group of 3a were partially deuterated (33% D).
Compound 1a-d5 was subjected to the reaction with propargyl
alcohol 2a under the standard conditions and produced the
product [D]n-3a smoothly and less than 5% deuterium
incorporation at the α-methylene group. In addition, we carried
out the reaction using a deuterium-labeled propargyl alcohol
2a-D; about 5% deuteration was observed at the α-methylene
group. To probe the C−H activation process further, treatment
of an equimolar mixture of 1a and 1a-d5 with propargyl alcohol
2a under the standard reaction conditions gave a relatively large
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00089.
■
S
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Experimental procedure, characterization of the products,
1
and H, 19F, and 13C NMR spectra of products (PDF)
Crystallographic data of 3s (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hliu@simm.ac.cn.
ORCID
Hong Liu: 0000-0002-0863-7853
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (81620108027,
21632008, 21602234, and 81220108025) and the Major
Project of Chinese National Programs for Fundamental
Research and Development (2015CB910304).
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135, 16625. (c) Zhao, D.; Shi, Z.; Glorius, F. Angew. Chem., Int. Ed.
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