Rhodium-Catalyzed Formal C-O Insertion in Carbene/Alkyne Metathesis Reactions: Synthesis of 3-Substituted 3 H-Indol-3-ols

Article abstract of DOI:10.1021/acs.orglett.9b01492

An efficient and novel rhodium-catalyzed formal C-O insertion reaction of alkyne-tethered diazo compounds for the synthesis of 3H-indol-3-ols is described. A type of donor/donor rhodium carbene generated in situ via a carbene/alkyne metathesis (CAM) proce

Full text of DOI:10.1021/acs.orglett.9b01492

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Rhodium-Catalyzed Formal C−O Insertion in Carbene/Alkyne
Metathesis Reactions: Synthesis of 3‑Substituted 3H‑Indol-3-ols
Shikun Jia, Guizhi Dong, Chaoqun Ao, Xianxing Jiang, and Wenhao Hu*
Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University,
Guangzhou 510006, China
*
S Supporting Information
ABSTRACT: An efficient and novel rhodium-catalyzed formal C−O
insertion reaction of alkyne-tethered diazo compounds for the synthesis of
3
H-indol-3-ols is described. A type of donor/donor rhodium carbene
generated in situ via a carbene/alkyne metathesis (CAM) process is the key
intermediate and terminates in a unique transformation different from
donor/acceptor carbenoids. In addition, 18O-labeling experiments indicate
that intramolecular oxygen-atom transfer from the amide group to the
carbon−carbon triple bond occurs during this transformation.
uring the past few decades, transition-metal catalyzed
carbene reactions have emerged as a powerful chemical
Scheme 1. Reaction of Metal Carbenes with Secondary
Amides
D
tool for the construction of carbon−carbon and carbon−
1
heteroatom bonds. Among these advances, carbene/alkyne
metathesis (CAM) cascade reactions have received enormous
attention owing to their extraordinary efficiency for complex
2
3
molecule synthesis. Since the pioneering work of Padwa and
4
Hoye on the carbene/alkyne metathesis process, this kind of
vinyl metal carbene intermediate has been widely explored for
many metal carbene cascade reactions, including cyclo-
5
6
7
8
propanation, cycloaddition, X−H insertion, cyclization,
9
10
the Buchner reaction, and others. Although donor/donor
carbenoids generated via a CAM process attenuated electro-
philicity compared to donor/acceptor carbenoids and acceptor
carbenoids, most of reported carbene cascade transformations
involving donor/donor carbenoids did not show the activity
difference in chemoselectivity. Herein, we report a unique
rhodium-catalyzed formal C−O insertion reaction of donor/
donor carbenoids and secondary amides, which proceeds in a
novel manner different from typical carbene reactions.
1
1
A survey of the literature indicated that N−H insertion
12
and O−H insertion reactions were the main transformations
of metal carbenes and secondary amides (Scheme 1a). Earlier,
N−H insertions of acceptor/acceptor carbenoids and secon-
dary amides were applied in the synthesis of N-containing
Recently, Reddy reported the O−H insertion
reactions of secondary amides and donor/acceptor carbenoids
through zwitterionic intermediates for the synthesis of 2-aryl-
1
1a,b
heterocycles.
intermediates generated via a CAM process. Surprisingly, 3H-
indol-3-ols were obtained via a formal C−O insertion reaction
rather than O−H insertion with secondary amides, which
exhibited the reactivity difference of donor/donor carbenoids
and donor/acceptor carbenoids (Scheme 1b). Notably, this
transformation offers a more attractive and atom-economical
12b
4
H-benzo[d][1,3]oxazine.
Furthermore, for the azavinyl
donor/acceptor carbenoids, Fokin found that less steric
hindrance of the N−H bond of the scecondary amides
preferred N−H insertion, whereas more steric hindrance of the
N−H bond led to O−H insertion/rearrangement. On the
basis of these reactions and our interest in developing carbene
transformations, we conceived that similar O−H insertion
reactions would occur through the intramolecular reaction
between the secondary amides and donor/donor carbenoid
14
13
method compared to the known synthetic routes to 3H-
indol-3-ols, which are pivotal building blocks for the
Received: April 29, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
construction of natural products and pharmaceutically active
Letter
15
Scheme 2. Substrate Scope ,
a b
1
6
molecules.
Initially, 3-(2-benzamidophenyl)prop-2-yn-1-yl 2-(4-chloro-
phenyl)-2-diazoacetate (1a) was treated with 1.0 mol %
Rh (OAc) in 1,2-dichloroethane (DCE) at room temperature
2
4
(Table 1, entry 1). Interestingly, a formal C−O insertion
a
Table 1. Condition Optimization
yield
b
cat. (x mol %)
T (°C)
solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
(%)
1
2
3
4
5
6
7
8
9
1
Rh (OAc) (1.0 mol %)
20
20
60
60
60
20
60
60
60
60
47
20
25
22
46
60
23
52
83
76
2
4
Rh (esp) (1.0 mol %)
2
2
Rh(cod)OH (1.0 mol %)
Ir(cod)Cl (1.0 mol %)
Cu(MeCN) PF (5.0 mol %)
4
6
c
c
Cp*RhCl (5.0 mol %)
2
Cp*IrCl (5.0 mol %)
2
Rh (OAc) (1.0 mol %)
2
4
Rh (OAc) (1.0 mol %)
1,4-dioxane
1,4-dioxane
2
4
d
0
Rh (OAc) (1.0 mol %)
2 4
a
Reactions were conducted by adding 1a (0.1 mmol) in 1 mL of the
solvent to the catalyst in 1 mL of the solvent over 5 min and then
b
stirred for another 30 min. Isolated yield after column chromatog-
c
d
raphy. Running for 24 h. With 100 mg of 4 Å molecular sieves.
product 2a was generated instead of the expected cyclization
product 2a′. To improve the yield of product 2a, various
transition metal catalysts were tested, such as other rhodium-
(
II), rhodium(I), rhodium(III), copper, iridium(I), and
iridium(III) complexes (Table 1, entries 2−7). Most of the
screened catalysts could promote the conversion of 1a,
although low yields were observed in most cases. Although
Cp*RhCl led to a better improvement in the reaction and 2a
2
was obtained in 60% isolated yield, the transformation required
17
a longer time of 24 h. Therefore, further optimizations of the
reaction conditions were carried out at higher reaction
temperatures using THF and 1,4-dioxane (Table 1, entries
a
Unless otherwise indicated, the reaction was performed at a 0.3
b
c
mmol scale. Isolated yield after column chromatography. Running
at a 1.0 mmol scale starting from diazo compound precursor.
8
−9). By employing 1,4-dioxane instead of DCE, 2a was
obtained in 83% yield, finally establishing the optimal reaction
conditions (Table 1, entry 9). Notably, the addition of 4 Å
molecular sieves led to a slight decrease in yield (Table 1, entry
Substituents on the para-, meta-, and ortho- positions of the
aromatic amide group gave the desired products 2o−2s in 52−
73% yields. 2-Naphthyl and 2-thienyl substitutions were also
successfully employed for the O-transfer cyclization to afford
products 2t and 2u, respectively, in moderate yields. Next, the
potential of this approach for late-stage functionalization was
examined, with the aim to enrich the structural diversity of the
3H-indol-3-ols using diazo compounds generated from
bioactive compounds. Starting from isoxepac, alkyne-
tethered diazo compound 1v was also well tolerated under
these conditions, affording the desired product 2v in 77% yield.
Similarly, diazoacetate 1w which was derived from estrone was
also tested in this reaction and the corresponding product was
obtained in 76% yield with 1:1 dr (2w). Meanwhile, we found
that the desired products were not formed when we employed
alkyne-tethered diazo compounds substituted with an acet-
1
0).
With these optimized reaction conditions in hand, we
investigated the substrate generality of the formal C−O
insertion reaction. As shown in Scheme 2, the current strategy
showed very good substrate scope tolerating different aryl-
substituted (from electron-withdrawing to electron-donating)
diazoacetates 1 and resulting in the desired products 2 in 57−
1
8
8
3% yields (2a−2f). Meanwhile, incorporating 2-naphthyl
substitute and heterocyclic substitutions did not affect the
efficiency of reaction (2g−2i). Subsequently, we investigated
the variation of Ar . The results showed that different
3
substituents on the phenyl rings were suitable for the reaction;
products 2j−2l were obtained in good yields. An obvious
decrease in yields was observed for the diazo compounds with
methoxy substitution on the aryl ring (2m). Furthermore, the
2
19
scope of Ar with respect to the amide group was examined.
amide group or diarylurea group. In addition to other
B
DOI: 10.1021/acs.orglett.9b01492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
spectroscopic studies, the structure of the desired product was
determined by X-ray analysis of 2a (CCDC 1898648).
Scheme 5. Proposed Reaction Mechanism
20
To exhibit the potential utility of our method, a gram-scale
reaction was carried out by using 4 mmol of 1q. We found that
the reaction proceeded smoothly under standard conditions to
give the desired product 2q in 61% yield (0.93 g). Further
transformations with 2q were conducted to show the synthetic
potential of this strategy (Scheme 3). For instance, under the
Scheme 3. Derivatization of 2q
action of Sc(OTf) , 3,3-disubstituted oxoindole 3 was obtained
3
22
which indicated that C was the key intermediate). Then
zwitterionic intermediate D was obtained, followed by
dissociation of the rhodium catalyst. A conventional O−H
insertion product 2′ could be generated via 1,4-H transfer;
however, the zwitterionic intermediate D possessed higher
nucleophilicity than the similar intermediate generated from
in 87% yield from the rearrangement from 1q. On the other
hand, reduction of 2q to indoline 4 as a single isomer
proceeded with NaBH4 in 89% yield, and the relative
configuration of indoline 4 was determined by NOE analysis.
Subsequently, indoline 4 could be efficiently converted into
2
,3-disubstituted indole 5 in 98% yield under dehydration
12b
the donor/acceptor carbenoid.
Subsequently, epoxy inter-
mediate E was generated via an intramolecular trapping
conditions.
To gain some insight into the reaction mechanism, isotopic
21b
2
0
18
process,
which proceeded to afford the corresponding
labeling experiments were conducted. When O was
product 2 by ring opening and intramolecular H-transfer. The
facilitation of H transfer and stabilization of the zwitterionic
intermediate might account for the increase of yield in polar
solvent, 1,4-dioxane.
incorporated into the carbonyl group of 1a [Scheme 4, eq
Scheme 4. 18O-Labelling Experiments
In summary, we have developed an efficient method for the
construction of 3-substituted 3H-indol-3-ol derivatives in good
yields via formal C−O insertion reactions. The key reaction
intermediate donor/donor rhodium carbene was formed via a
carbene/alkyne metathesis (CAM) process. Notably, this
transformation is an additional example that can show the
reactivity difference between donor/donor carbenoids and
1
8
donor/acceptor carbenoids. Besides, O-labeling experiments
demonstrated that intramolecular OAT occurred during this
transformation, and a trapping experiment indicated the
existence of the zwitterionic intermediate. Derivatization of
the 3H-indol-3-ol to 3,3-disubstituted oxoindole and 2,3-
disubstituted indole shows the potential utility of our method.
A], 18O-labeled product was obtained under the reaction
ASSOCIATED CONTENT
Supporting Information
18
conditions. Conversely, when H2 O was introduced in this
reaction, only normal product 2a was observed [Scheme 4, eq
B]. These results verified that intramolecular oxygen-atom
transfer (OAT) from the amide group to the carbon−carbon
triple bond occurred during the reaction process.
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01492.
On the basis of the preliminary mechanistic studies and
Experimental procedure and spectroscopic data for all
compounds (PDF)
2
1
previous work, a plausible cyclization pathway is proposed in
Scheme 5. First, alkyne-tethered diazo compounds 1 formed
rhodium carbene A in the presence of Rh (OAc) , which was
Accession Codes
2
4
converted into donor/donor rhodium carbene B via a carbene/
alkyne metathesis (CAM) process. The carbonyl of the amide
group attacked the carbene to form zwitterionic intermediate
C (C could be trapped by imine in an intermolecular manner,
CCDC 1898648 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
C
DOI: 10.1021/acs.orglett.9b01492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
nated with Intramolecular Formal [3 + 2] Cycloaddition. Org. Lett.
2
015, 17, 5638−5641.
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AUTHOR INFORMATION
Corresponding Author
■
*
2
733−2736. (b) Dong, K.; Pei, C.; Zeng, Q.; Wei, H.; Doyle, M. P.;
3
E-mail: huwh9@mail.sysu.edu.cn.
ORCID
Xu, X. Selective C(sp )−H Bond Insertion in Carbene/Alkyne
Metathesis Reactions. Enantioselective Construction of Dihydroin-
doles. ACS Catal. 2018, 8, 9543−9549. (c) Jansone-Popova, S.; May,
J. A. Synthesis of Bridged Polycyclic Ring Systems via Carbene
Cascades Terminating in C−H Bond Insertion. J. Am. Chem. Soc.
Xianxing Jiang: 0000-0002-7508-2368
Wenhao Hu: 0000-0002-1461-3671
Notes
2
012, 134, 17877−17880. (d) Le, P. Q.; May, J. A. Hydrazone-
Initiated Carbene/Alkyne Cascades to Form Polycyclic Products:
Ring-Fused Cyclopropenes as Mechanistic Intermediates. J. Am.
Chem. Soc. 2015, 137, 12219−12222.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from Guangdong
Innovative and Entrepreneurial Research Team Program
2016ZT06Y337), National Science & Technology Major
Project “Key New Drug Creation and Manufacturing Program”
China (2018ZX09711002-006), and China Postdoctoral
Science Foundation (2018M633258).
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DOI: 10.1021/acs.orglett.9b01492
Org. Lett. XXXX, XXX, XXX−XXX