Palladium-Catalyzed Synthesis of Dihydrobenzoindolones via C-H Bond Activation and Alkyne Insertion

Article abstract of DOI:10.1021/acs.orglett.8b01856

A palladium-catalyzed intramolecular carbopalladation, intramolecular C-H bond activation, and alkyne insertion sequence for the generation of dihydrobenzoindolones is described. Products are obtained in moderate to excellent yields as single regioisomers

Full text of DOI:10.1021/acs.orglett.8b01856

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Palladium-Catalyzed Synthesis of Dihydrobenzoindolones via C−H
Bond Activation and Alkyne Insertion
́
Jose F. Rodríguez, Austin D. Marchese, and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S
H6, Canada
3
*
S Supporting Information
ABSTRACT: A palladium-catalyzed intramolecular carbopallada-
tion, intramolecular C−H bond activation, and alkyne insertion
sequence for the generation of dihydrobenzoindolones is described.
Products are obtained in moderate to excellent yields as single
regioisomers. Various functional groups on both reaction partners
were tolerated, and the scalability of this method was determined.
2
ransition-metal-catalyzed C−H bond activation has
emerged as an important tool for the construction of
Scheme 1. Pd-Catalyzed C(sp )−H Bond Activation
T
Domino Processes
carbon−carbon and carbon−heteroatom bonds due to its high
1
,2
atom and step economy. This method has been employed in
the synthesis of various scaffolds and opens up alternative
1
,3
synthetic disconnections while reducing waste generation.
A
common requirement for this strategy is the presence of
appropriate preinstalled or transient directing groups, which
direct the metal center toward the desired C−H bond for
3
−6
subsequent functionalization.
This approach has been
applied in challenging regioselective activation of meta and
2
7
para C(sp )−H bonds of aromatic rings, as well as aliphatic
8
chains of carbonyl compounds. Alternatively, palladium-
catalyzed domino processes allow unique activation of remote
1
c,3a,c,9
C−H bonds.
These processes are initiated by the
formation of an organopalladium species which undergoes an
intramolecular migratory insertion on a tethered π-system,
generating a σ-alkyl-Pd(II) intermediate that places the metal
in close proximity to a formerly remote C−H bond. Following
C−H activation, the corresponding palladacycle can either
1
0b
reductively eliminate
partners prior to reductive elimination.
partners include the following: diaziridinones, benzynes,
or react with a range of coupling
11d
Such coupling
10a
11
5c,13
12
α-diazocarbonyl compounds, alkyl and aryl halides,
carbon monoxide, disilanes, and activated alkynes.
14
15
11e,16
Based on this method, we present herein a Pd-catalyzed
2
C(sp )−H activation/alkyne insertion cascade for the synthesis
of dihydrobenzoindolones.
In 2014, our group reported a Pd-catalyzed intermolecular
1
1a,b
2
s.
As a strategy to circumvent this challenge, our group
domino reaction encompassing two C(sp )−H bond function-
recently developed a Pd-catalyzed spirocyclization reaction
involving a sequential C(sp )−H bond activation of a tethered
phenyl moiety, using polarized, unsymmetrical alkynes as
reactive coupling partners (Scheme 1C). The spirooxindole
and spirodihydrobenzofuran products were generated in high
alizations, which was proposed to proceed via a five-membered
2
13a
palladacycle intermediate (Scheme 1A).
When an aryl group replaced the methyl substituent on the
16
2
alkene, C(sp )−H insertion occurred preferentially on the
tethered phenyl moiety so as to form spiro metalated
intermediates (Scheme 1B). As reported independently by
Garcıa
́
-Lop
́
ez and Lautens, benzynes react smoothly, but low
Received: June 14, 2018
regioselectivities were observed with unsymmetrical benzyne-
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01856
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yields and regioselectivities (>20:1 rr). In 2017, He and co-
significantly decreased when ligands other than P(2-CF −
3
workers reported a Pd-catalyzed synthesis of heterocycle-fused
C H ) were employed. Utilizing 10 mol % PPh was found to
6
4 3
3
2
9
,10-dihydrophenanthrenes via a related C(sp )−H activation/
be ineffective (entry 9), while using 10 mol % P(o-tol)3
furnished the product in low yield (entry 10). Similarly, low
yields were obtained when 10 mol % X-Phos or 5 mol % dppf
were used (entries 11 and 12).
With the optimized conditions in hand, we evaluated the
generality of this process by subjecting various acrylamides to
the optimal reaction conditions and employing 3-phenyl
ethylpropiolate (2a) as the coupling partner (Scheme 2). We
17
benzyne insertion sequence (Scheme 1D). Similarly to
previous reports, however, low regioselectivities were obtained
when unsymmetrical benzyne precursors were employed. We
envisioned that unsymmetrical alkynes could be suitable
2
coupling partners in a process involving the C(sp )−H bond
activation at the ortho position of the aryl halide in the absence
of a tethered phenyl group (Scheme 1E). Herein, we disclose
the successful realization of this approach in the synthesis of
dihydrobenzoindolones in good to high yields and excellent
regioselectivities.
Scheme 2. Substrate Scope
We began our investigation by reacting acrylamide 1a and 3-
ethyl phenylpropiolate (2a, 1.1 equiv) in the presence of a
Pd(0) catalyst under various reaction parameters (see
Supporting Information (SI)). The combination of
Pd (dba) (2.5 mol %), P(2-CF −C H ) (10 mol %), and
2
3
3
6
4 3
CsOPiv (1.2 equiv) in DMF (0.1 M) at 80 °C for 16 h was
found to be optimal, affording product 3aa in 91% isolated
yield (Table 1, entry 1). The structure of 3aa was
Table 1. Effect of Varying Reaction Parameters
a
entry
variation from “standard conditions”
3aa (%)
b
1
2
3
4
5
6
7
8
9
none
94 (91 )
9
81
88
88
90
87
32
PhMe instead of DMF
MeCN instead of DMF
0.05 M
0.2 M
60 °C
100 °C
Cs CO instead of CsOPiv
2
3
PPh (10 mol %)
N.R.
39
28
3
10
11
12
P(o-tol) (10 mol %)
X-Phos (10 mol %)
dppf (5 mol %)
3
N.R.
a
1
Yields were determined by H NMR spectroscopy analysis of the
crude reaction mixture using 1,3,5-trimethoxybenzene as an internal
standard. Isolated yield in parentheses. N.R. = No reaction.
b
a
Isolated yields of products. Yield determined by 1H NMR
b
spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.
unambiguously determined by spectroscopic analysis and
single crystal X-ray crystallography (CCDC 1848230; see
SI). The effect of varying different reaction parameters on the
efficiency of the reaction was evaluated (Table 1). Toluene and
acetonitrile have typically been optimal solvents in various
related Pd-catalyzed domino C−H activation method-
first sought to determine the effect of different substituents on
the nitrogen atom. Substrates possessing N-Bn (1b) and N-
PMB (1c) groups led to product formation in 86% and 87%
yields, respectively. When substrate 1d containing an N-MOM
was subjected to the reaction conditions, product 3d was
generated in 83% yield. Products containing N-methylenecy-
clopropane (1e) and N-methallyl (1f) groups were accessed in
90% and 88% yields, respectively. To study the effect of the
substitution on the α-position, acrylamides containing α-Bn
1
1a,b,16,17
s.
Replacing DMF with toluene in our case, however,
severely decreased the product yield (entry 2), while
acetonitrile provided the product in 81% yield (entry 3).
The yield was marginally decreased upon varying the reaction
concentration (entries 4 and 5). Interestingly, decreasing the
reaction temperature to 60 °C afforded the desired product in
i
n
(1g), α- Pr (1h), and α- Bu (1i) groups were reacted, affording
products 3g, 3h, and 3i, in 47%, 92%, and 95% yields,
respectively. The lower yield of product 3g is attributed to a
competitive C−H activation at the benzylic substituent,
9
0% yield (entry 6), while running the reaction at 100 °C
afforded 3aa in 87% yield (entry 7). Cesium pivalate was found
1
to be essential, as other bases, such as Cs CO , resulted in
generating a spirooxindole byproduct (detected by H NMR
2
3
attenuated reactivity (entry 8). The reaction efficiency was
analysis of the crude reaction mixture) upon reductive
B
DOI: 10.1021/acs.orglett.8b01856
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
8,19
elimination, as reported by Ruck and co-workers.
the coupling partner, generating benzoindolone 3aa in 93%
yield (Scheme 4). The ester functional group of the product
was hydrolyzed to form carboxylic acid 4 in 76% yield (Scheme
Substrates containing 4-chloro and 4-ester functional groups
were subjected to the reaction conditions, and products 3j and
k were obtained in good yields. Various other substituents in
the aryl moiety of the acrylamide substrates were tolerated, and
substrates containing 5-CF (3l), 5-Cl (3m), and 5-Me (3n)
substituents rendered products in 88%, 89%, and 87% yields,
3
4
).
a
3
Scheme 4. Scale-Up Reaction and Derivatization
respectively. Furthermore, benzofuran derivative 3o was
1
obtained in 73% H NMR yield. Unfortunately, attempts to
isolate this product were unsuccessful due to coelution of an
unknown impurity using silica-gel chromatography. Of note,
1
H NMR analysis of crude reaction mixtures indicates all
products were obtained as single regioisomers.
The scope of this transformation with respect to the
unsaturated alkyne component was also investigated (Scheme
a
Isolated yields are shown.
1
1
3
). An electron-rich aryl substituent on the alkyne was
́
Based on previous work reported by Garcia-Lop
group,
́
ez, our
11,16
17
and He, a plausible mechanism for this trans-
formation is presented in Scheme 5. Substrate 1a undergoes
Scheme 3. Alkyne Scope
Scheme 5. Proposed Mechanism
oxidative addition to form aryl-Pd(II) intermediate I. Intra-
molecular 5-exo-trig carbopalladation furnishes σ-alkyl-
palladium(II) intermediate II. The palladium center is in
2
close proximity to the C(sp )−H bond, generating palladacycle
intermediate III upon C−H bond activation. Subsequent
coordination and migratory insertion of 2a generates
intermediate IV. Final reductive elimination releases product
3
aa and regenerates the active Pd(0) catalyst.
In conclusion, we have developed a Pd-catalyzed C(sp )−H
2
bond activation/alkyne insertion cascade that affords access to
dihydrobenzoindolones in good to high yields and excellent
regioselectivities. The use of P(2-CF −C H ) as a ligand was
3
6
4 3
instrumental in obtaining high reaction efficiencies. The scope
of various acrylamides was investigated, and substrates
containing N-, α-, and aryl-substituents were participants in
this domino process. Additionally, several unsymmetrical
alkyne coupling partners were subjected to the reaction
conditions, furnishing products as single regioisomers.
a
Isolated yields of products. Yield determined by 1H NMR
spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.
b
tolerated, and product 3ab containing a para-OMe group
was obtained in 92% yield. Products containing electron-
ASSOCIATED CONTENT
Supporting Information
withdrawing para-CF (3ac), -Cl (3ad), and -CN (3ae) were
■
3
*
S
generated in 66%, 86%, and 55% yields, respectively. Alkyne 2f
bearing a meta-F substituent generated product 3af in 95%
yield. The reaction was also expanded to alkynes encompassing
heterocyclic motifs. Reaction of 1a and alkyne 2g afforded
product 3ag containing a benzoxazole motif in 60% yield, while
the product 3ch showcasing a pyridine moiety was obtained in
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01856.
Experimental procedures, optimizations, characteriza-
tions, and X-ray data (PDF)
1
20
7
7% H NMR yield. As discussed previously, all products
Accession Codes
were obtained as single regioisomers (>20:1).
To highlight the scalability of this process, a 2.0 mmol scale
reaction was performed using acrylamide 1a and alkyne 2a as
CCDC 1848230 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
C
DOI: 10.1021/acs.orglett.8b01856
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Wang, S.-G.; Oliveira, C. C.; Cramer, N. Chem. Rev. 2017, 117, 8908.
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c) Baudoin, O. Acc. Chem. Res. 2017, 50, 1114.
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(
1
(
́
́
́
AUTHOR INFORMATION
Corresponding Author
■
Lautens, M. Org. Lett. 2016, 18, 6324. (c) Perez-Gomez, M.; Navarro,
L.; Saura-Llamas, I.; Bautista, D.; Lautens, M.; García-Lopez, J.-A.
Organometallics 2017, 36, 4465. (d) Mehta, V. P.; García-Lopez, J.-A.
ChemCatChem 2017, 9, 1149. (e) Franzoni, I.; Yoon, H.; García-
Lopez, J.-A.; Poblador-Bahamonde, A. I.; Lautens, M. Chem. Sci. 2018,
, 1496.
12) (a) Per
García-Lopez, J.-A. Chem. Commun. 2017, 53, 2842. (b) Liu, J.-G.;
Chen, W.-W.; Gu, C.-X.; Xu, B.; Xu, M.-H. Org. Lett. 2018, 20, 2728.
13) (a) Sickert, M.; Weinstabl, H.; Peters, B.; Hou, X.; Lautens, M.
́
́
́
*
E-mail: mlautens@chem.utoronto.ca.
ORCID
F. Rodríguez: 0000-0002-7656-7260
́
Jose
́
́
9
Mark Lautens: 0000-0002-0179-2914
(
ez-Gomez, M.; Hernandez-Ponte, S.; Bautista, D.;
́ ́ ́
Notes
́
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
Angew. Chem., Int. Ed. 2014, 53, 5147. (b) Shao, C.; Wu, Z.; Ji, X.;
Zhou, B.; Zhang, Y. Chem. Commun. 2017, 53, 10429. (c) Luo, X.;
Xu, Y.; Xiao, G.; Liu, W.; Qian, C.; Deng, G.; Song, J.; Liang, Y.; Yang,
C. Org. Lett. 2018, 20, 2997.
■
We are grateful for financial support from the University of
Toronto (U of T), Natural Science and Engineering Research
Council (NSERC), and Alphora Research Inc. J.F.R. (U of T)
thanks the province of Ontario (OGS) for funding. Dr. Alan
Lough (U of T) is acknowledged for X-ray analysis. We also
thank Hyung Yoon (U of T) for various starting materials,
proofreading the manuscript, and for discussions. Dr. Ivan
Franzoni (U of T) is thanked for proofreading the manuscript.
(14) Xu, L.; Wang, C.; Gao, Z.; Zhao, Y.-M. J. Am. Chem. Soc. 2018,
140, 5653.
(15) (a) Lu, A.; Ji, X.; Zhou, B.; Wu, Z.; Zhang, Y. Angew. Chem., Int.
Ed. 2018, 57, 3233. (b) Xiao, G.; Chen, L.; Deng, G.; Liu, J.; Liang, Y.
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17) Yao, T.; He, D. Org. Lett. 2017, 19, 842.
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DOI: 10.1021/acs.orglett.8b01856
Org. Lett. XXXX, XXX, XXX−XXX