Ru(II)-Catalyzed and Ligand-Controlled C-H Activation and Annulation via 1,2-Phenyl Shift: Synthesis of Quaternary Carbon-Centered Pyrimidoindolones

Article abstract of DOI:10.1021/acs.orglett.8b01330

A novel Ru(II)-catalyzed C-H activation and annulation reaction of N-arylpyrazol-5-ones and diaryl/arylalkyl-substituted alkynes is developed. Unlike the reported metal-catalyzed C-H activation and annulation reactions, in the present bidentate amine-ligand controlled C-H activation and annulation reaction, the annulation occurs via a 1,2-aryl shift to afford quaternary carbon-centered pyrimidoindolones.

Full text of DOI:10.1021/acs.orglett.8b01330

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Ru(II)-Catalyzed and Ligand-Controlled C−H Activation and
Annulation via 1,2-Phenyl Shift: Synthesis of Quaternary Carbon-
Centered Pyrimidoindolones
Swagata Baruah, Pallabi Saikia, Gauri Duarah,* and Sanjib Gogoi*
Applied Organic Chemistry, Chemical Sciences & Technology Division, CSIR-North East Institute of Science and Technology,
Jorhat 785006, AcSIR, India
*
S Supporting Information
ABSTRACT: A novel Ru(II)-catalyzed C−H activation and annulation
reaction of N-arylpyrazol-5-ones and diaryl/arylalkyl-substituted alkynes
is developed. Unlike the reported metal-catalyzed C−H activation and
annulation reactions, in the present bidentate amine-ligand controlled
C−H activation and annulation reaction, the annulation occurs via a 1,2-
aryl shift to afford quaternary carbon-centered pyrimidoindolones.
5
he quaternary carbon centers are ubiquitous in a wide
(Scheme 1, eq 2), and decomposition of diazoketamines
6
T
range of biologically active natural products and
(Scheme 1, eq 3) have been used to perform the 1,2-aryl shift.
1
In recent years, transition-metal-catalyzed C−H bond
activation and annulation reactions have emerged as a powerful
tool to construct a variety of highly functionalized heterocycles
pharmaceuticals. However, the development of new catalytic
reactions to furnish a quaternary carbon center is a challenging
2
task in organic synthesis. In the past decade, significant efforts
7
and carbocycles. In particular, comparatively less expensive
have been devoted to the construction of various quaternary
2
1
Ru(II)-catalyzed, directing group assisted, C(sp )−H bond
carbon centers. The 1,2-aryl shift reactions are one of the
functionalization and annulation reactions with alkynes have
proven to be an important tool for the construction of
heterocycles, owing to the compatibility of the catalysts with
most powerful strategies to synthesize quaternary carbon-
containing compounds. Traditionally, the 1,2-aryl shift
reactions are performed by pinacol rearrangement of
8
oxidants and their stability in air and water. The Rh(III)-
catalyzed C−H activation and annulation reaction of N-
arylpyrazol-5-ones with alkynes is known to produce pyrazolo-
3
substituted 1,2-diols. In addition to this, recently, metal-
catalyzed reactions such as the skeletal rearrangement of α-aryl
4
aldehydes (Scheme 1, eq 1), the semipinacol rearrangement
7g
[
1,2-a]cinnolines. In continuation of our work on metal-
of allylic alcohols in the presence of strong electrophiles
9
catalyzed reactions, we have developed a Ru(II)-catalyzed,
ligand-directed C−H activation and annulation reaction of N-
arylpyrazol-5-ones with diaryl/arylalkyl-substituted alkynes,
which forms a cyclic ring in a unusual way via a 1,2-aryl
shift. This reaction provides an efficient route for the synthesis
of pyrimidoindolones that possess a quaternary carbon center
Scheme 1. Examples of Metal-Catalyzed 1,2-Aryl Shifts
(
Scheme 1, eq 4). Furthermore, the annulation reaction was
extended for the synthesis of quaternary carbon-centered
pyrimidoindolediones using dialkyl-substituted alkynes. The
pyrimidoindolone motif is frequently found in bioactive natural
products, pharmaceuticals, and polarity-sensitive dyes (Figure
10
1
). Therefore, an atom and step-economic method for the
synthesis of this important scaffold starting with simple starting
11
materials is highly desirable.
Initially, the reaction conditions for the oxidative annulation
reaction of commercially available N-arylpyrazol-5-one 1a with
alkyne 2a (Table 1 and Table SI-1) were optimized for the
synthesis of 3aa. Among the catalysts screened, [RuCl (p-
2
cymene) ] provided 27% yield of 3aa in the presence of
2
Received: April 27, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01330
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of Diaryl-Substituted Alkynes (2a−l) with
1
a
Figure 1. Examples of compounds containing a pyrimidoindolone
core structure.
a
Table 1. Optimization of the Reaction Conditions for 3aa
b
3
aa
entry
catalyst
oxidant
ligand
(%)
1
2
[RuCl (PPh ) ]
Cu(OAc) .H O
0
23
2
3
3
2
2
[{RuCl (p-
Cu(OAc) ·H O
2
2
2
cymene) }]
2
3
4
5
6
7
8
9
Pd(OAc)2
[(Cp*RhCl ) ]
Cu(OAc) ·H O
Cu(OAc) ·H O
2 2
CuBr2
CsOAc
AgOAc
0
0
2
2
2
2
[RuCl (p-cymene) ]
<5
11
<5
20
23
2
2
[RuCl (p-cymene) ]
2
2
[RuCl (p-cymene) ]
2
2
[RuCl (p-cymene) ]
Cu(OAc) ·H O
P(Cy)3
DCYPE
2
2
2
2
[[RuCl (p-
Cu(OAc) ·H O
2
2
2
cymene)2]
1
1
1
1
0
1
2
3
[RuCl (p-cymene) ]
Cu(OAc) ·H O
dppf
15
81
75
73
2
2
2
2
[RuCl (p-cymene) ]
Cu(OAc) ·H O
(±)-BINAM
(±)-BINOL
(±)-BINAM
2
2
2
2
a
[RuCl (p-cymene) ]
Cu(OAc) ·H O
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), Ru-catalyst (5
mol %), (±)-BINAM (20 mol %), and Cu(OAc) ·H O (0.5 mmol) in
2
2
2
2
c
[RuCl (p-cymene) ]
Cu(OAc) ·H O
2
2
2
2
2
2
t
a
AmOH (6.0 mL) was heated at 95 °C for 24 h under air.
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst (5 mol
), oxidant (0.5 mmol), ligand (20 mol %), and solvent (6.0 mL) at
%
b
9
5 °C under air for 24 h; unless otherwise mentioned. Isolated
yields. 15 mol % of ligand.
proved to be good substrates to afford the products 3ae−ai.
Similarly, unsymmetrical aryl−heteroaryl- and aryl−alkyl-
disubstituted alkynes 2j−l also participated in the annulation
reaction to afford 3aj−al (64−76%). Our attempt to obtain the
enantiomerically pure compound 3af using either the (S)-
(−)-BINAM or (R)-(+)-BINAM under the standard reaction
conditions met with failure. Then the reaction scope was
examined by varying the substitution patterns on the N-
arylpyrazol-5-ones (1b−l, Scheme 3). Thus, the annulation
reaction of N-arylpyrazol-5-one-bearing substituents such as
ethyl, n-propyl, isopropyl, and phenyl at the 3-position of
pyrazole-5-one ring 1b−e was tested with alkyne 2a to afford
3ba−ea. Next, some of the representative N-arylpyrazol-5-
ones, bearing electron-donating and electron-withdrawing
groups such as methyl, isopropyl, methoxy, fluoro, and chloro
on the phenyl ring 1f−k, were examined for this annulation
reaction with 2a. Irrespective of the position of the substituent,
these reactions afforded good yields of 3fa−ka. The reaction of
1g with 2a was highly regioselective to afford 3ga. Similarly,
representative N-arylpyrazol-5-one, substituted at the 3,4-
positions of the pyrazole-5-one ring 1l, was also tested to
afford the desired product 3la in good yield. The dialkyl-
c
Cu(OAc) ·H O as the oxidant (entry 2). The other frequently
used catalysts for the oxidative annulation reactions, such as
(Cp*RhCl ) ] and Pd(OAc) , could not provide the desired
2
2
[
2 2 2
product 3aa (entries 3 and 4). Other oxidants such as CuBr2,
CsOAc, and AgOAc and solvents surveyed for this reaction
could not further improve the yield of the reaction (entries 5−
7
and Table SI-1). Then a series of monodentate and bidentate
ligands were screened (entries 8−13 and Table S1). The
bidentate ligand (±)-1,1′-binaphthyl-2,2′-diamine (BINAM)
was found to be highly effective to provide the best yield of 3aa
(
81%, entry 11).
With the optimized reaction conditions in hand, we first
tested the scope in the oxidative annulation reaction of 1a with
symmetrically substituted diarylalkynes (2b−d, Scheme 2).
These diaryl alkynes, bearing electron-donating and electron-
withdrawing groups on the phenyl ring 2b−d, were well
tolerated to provide pyrimidoindolones 3ab−ad. The unsym-
metrical aryl alkynes substituted with different electron-
donating and electron-withdrawing groups 2e-I were also
B
DOI: 10.1021/acs.orglett.8b01330
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 3. Scope of Pyrazolones (1b−l) with 2a
Scheme 4. Scope of Dialkyl-Substituted Alkynes (2m−o)
a
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), Ru-catalyst (5
mol %), (±)-BINAM (20 mol %), and Cu(OAc) ·H O (0.5 mmol) in
2
2
t
AmOH (6.0 mL) was heated at 95 °C for 24 h under air.
Scheme 5. Deuteration Experiments
a
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), Ru-catalyst (5.0
mol %), (±)-BINAM (20 mol %), and Cu(OAc) ·H O (0.5 equiv) in
2
2
t
AmOH (6.0 mL) was heated at 95 °C for 24 h under air.
substituted alkynes could not provide the corresponding alkyl-
shifted product under the standard conditions. As the aryl−
alkyl-substituted alkynes 2k,l provided good yields of 3ak,al,
the cyclization of alkyne must be highly regioselective in the
intermediate step to allow the 1,2-phenyl shift to occur. The
structures of the products were fully characterized by
spectroscopic studies and single crystal X-ray analysis of
compound 3ca. Notably, under the standard conditions,
reaction of dialkyl-substituted alkynes 2m-o with 1a provided
quaternary carbon-centered pyrimidoindolediones 3am−ao in
very good yields (Scheme 4). The scope of the aliphatic alkyne
2
n was also tested with 3-substituted pyrazolones 1b−d and
k /k = 2.3, eqs 2 and 4, Scheme 5). Furthermore, the
competitive parallel experiments, performed using substrates
H
D
electron-rich/electron-poor aryl substituted pyrazolones 1h−j
to provide good yields of 3bn−dn,hn−jn (Scheme 4).
The competition experiments revealed preferential con-
version of electron-rich alkyne 2b and electron-rich pyrazolone
1a/1a-d with 2a and 1a/1a-d with 2n also showed significant
5
5
kinetic isotope effects (k /k = 1.8 and k /k = 2.1) (Scheme
H
D
H
D
9a
5, eqs 3 and 5). These results indicate that the C−H bond-
cleavage step might be the rate-limiting step. To understand
the mechanism of the reaction, a series of experiments were
performed. The reaction between 4,4-disubstituted pyrazole
1m with 2a under the standard conditions afforded hydro-
arylated compound 5ma (Scheme 6, eq 1). This result
suggested the crucial role of 4-methylene protons in the
annulation reaction. The reaction between 1a and 2n using the
standard conditions under argon atmosphere could not
1
f to their corresponding products 3ab and 3fa (Schemes SI 2
and SI 3). The deuterium-labeling experiment of 1a alone in
CD OD under the standard conditions provided D/H-
3
exchanged product 1a-d (Scheme 5, eq 1) which indicates a
1
reversible cycloruthenation step in this annulation reaction.
The intermolecular kinetic isotope effect experiments
performed between 1a + 1a-d with 2a and 1a + 1a-d with
5
5
2
n showed significant kinetic isotope effects (k /k = 2.7 and
H D
C
DOI: 10.1021/acs.orglett.8b01330
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 6. Control Experiments
Scheme 7. Proposed Mechanism
provide 3an, indicating the requirement of oxygen for the
reaction to proceed. Under argon atmosphere, pyrimidoindo-
lone 5an was the only product isolated from the reaction
mixture (Scheme 6, eq 2). Furthermore, the product isolated
from the reaction of 1a and 2n under the standard conditions
1
8
18
and in the presence of H O , could not provide O
2
incorporated product 3an-O18 (Scheme 6, eq 2). Again, the
reaction between 1a and 2n under standard conditions and in
the presence of 1 equiv of TEMPO provided 5an (23%)
instead of 3an. Interestingly, the pyrimidoindolones 3am−an
could be easily converted to imidazoindolone 3am′−an′ by
treatment with m-CPBA (Scheme 6, eq 3).
On the basis of our observations and the literature reports, a
possible mechanism is proposed for the formation of
7
compound 3aa in Scheme 7. First, the active Ru(II) catalyst
of N-arylpyrazol-5-ones and diaryl/arylalkyl-substituted al-
kynes which is controlled by bidentate ligand BINAM is a
new approach to access biologically important pyrimidoindo-
lones. Furthermore, using dialkyl-substituted alkynes, the same
reaction conditions have been effectively utilized for the
synthesis of quaternary carbon-centered pyrimidoindolediones.
A reversibly reacts with 1a′, the tautomer of 1a, to afford a
Ru(II) intermediate B via C−H activation. The alkyne−metal
coordination, followed by insertion of the alkyne into the Ru−
C bond, generates a seven-membered intermediate C. Further
oxidation of Ru(II) to Ru(IV) by the cyclic N−N bond
7h,i
cleavage affords six-membered intermediate D. Although we
have not studied the details of ligand effect in this Ru(II)-
catalyzed reaction, probably, the bidentate ligand increases the
electron density on the metal, which helps the metal for further
oxidative insertion in N−N bond of the pyrazolone scaffold.
Subsequent reductive elimination, followed by further
activation at the C-2 of the generated indole derivative, affords
a seven membered Ru complex F. The reductive elimination of
F could provide either amine G or G′ using diphenylalkyne 2a
and dialkylalkyne 2n, respectively. Finally, 1,2-aryl group
migration of G affords 3aa. In contrast, an alkyl substituent
present in G′ might help in elimination of a molecule of acetic
acid via dehydroelimination and subsequent oxidation of
vinylic amine in the presence of oxygen affords H′. Next,
elimination of one molecule of water from H′ affords 3am.
The oxidation of vinylic amine G′ to H′ might have followed a
free-radical mechanism since in the presence of TEMPO 5an
was the only product isolated from the reaction of 1a and 2n
under the standard conditions. Formation of 3am′ from 3am
might have proceeded through Criegee intermediate I′, which
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01330.
Experimental procedures, spectral data and spectra for
all compounds (PDF)
Accession Codes
CCDC 1428291 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-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*
*
on further rearrangement and elimination of a CO molecule
2
E-mail: skgogoi1@gmail.com, sanjibgogoi@neist.res.in.
E-mail: gauriduarah@gmail.com.
ORCID
affords 3am′.
In summary, we have developed a novel method for the
Ru(II)-catalyzed C−H activation and annulation reaction in
which the annulation proceeds via a 1,2-aryl shift. This reaction
Sanjib Gogoi: 0000-0002-2821-3628
D
DOI: 10.1021/acs.orglett.8b01330
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank SERB, New Delhi, for financially supporting us with
the GPP-0303 (YSS/2014/001018) Project. We thank CSIR,
New Delhi, for financially supporting us through the OLP-
2
002 Project. We are grateful to the Director of CSIR-NEIST
for his keen interest in our project.
REFERENCES
■
(
1) For selected examples, see: (a) Nicolaou, K. C.; Snyder, S. A.;
Huang, X. H.; Simonsen, K. B.; Koumbis, A. E.; Bigot, A. J. Am. Chem.
Soc. 2004, 126, 10162−10173. (b) Kodama, S.; Hamashima, Y.;
Nishide, K.; Node, M. Angew. Chem., Int. Ed. 2004, 43, 2659−2661.
(
c) Feng, J.; Holmes, M.; Krische, M. J. Chem. Rev. 2017, 117,
1
(
2564−12580.
2) (a) Christoffers, J.; Baro, A. Quaternary StereocentersChallenges
and Solutions for Organic Synthesis; Wiley-VCH: Weinheim, 2005.
(
(
b) Wang, B. M.; Tu, Y. Q. Acc. Chem. Res. 2011, 44, 1207−1222.
c) Chen, Z.-S.; Huang, X.-Y.; Gao, J.-M.; Ji, K. Org. Lett. 2016, 18,
5
(
876−5879.
3) For an example, see: Pettit, G. R.; Lippert, J. W.; Herald, D. L. J.
Org. Chem. 2000, 65, 7438−7444.
4) (a) Gutierrez-Bonet, A.; Flores-Gaspar, A.; Martin, R. J. Am.
(
́
́
Chem. Soc. 2013, 135, 12576−12579. (b) Alvarez-Bercedo, P.; Flores-
Gaspar, A.; Correa, A.; Martin, R. J. Am. Chem. Soc. 2010, 132, 466−
4
67.
(
5) For selected examples, see: (a) Chen, Z.-M.; Bai, W.; Wang, S.-
H.; Yang, B.-M.; Tu, Y.-Q.; Zhang, F.-M. Angew. Chem., Int. Ed. 2013,
2, 9781−9785. (b) Liu, X.; Xiong, F.; Huang, X.; Xu, L.; Li, P.; Wu,
5
X. Angew. Chem., Int. Ed. 2013, 52, 6962−6966. (c) Zhang, Q.-W.;
Fan, C.-A.; Zhang, H.-J.; Tu, Y.-Q.; Zhao, Y.-M.; Gu, P.; Chen, Z.-M.
Angew. Chem., Int. Ed. 2009, 48, 8572−8574. (d) Kleinbeck, F.; Toste,
F. D. J. Am. Chem. Soc. 2009, 131, 9178−9179.
(
(
6) Jiang, N.; Qu, Z.; Wang, J. Org. Lett. 2001, 3, 2989−2992.
7) For selected recent examples, see: (a) Zhu, R.-Y.; Farmer, M. E.;
Chen, Y.-Q.; Yu, J.-Q. Angew. Chem., Int. Ed. 2016, 55, 10578−10599.
b) Ackermann, L. Acc. Chem. Res. 2014, 47, 281−295. (c) Gulías, M.;
Mascarenas, J. L. Angew. Chem., Int. Ed. 2016, 55, 11000−11019.
d) Qiu, Y.; Tian, C.; Massignan, L.; Rogge, T.; Ackermann, L. Angew.
Chem., Int. Ed. 2018, 57, 5818−5822. (e) Wencel-Delord, J.; Glorius,
ge, T.;
(
̃
(
F. Nat. Chem. 2013, 5, 369−375. (f) Wencel-Delord, J.; Dro
̈
Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740−4761. (g) Xing, L.;
Fan, Z.; Hou, C.; Yong, G.; Zhang, A. Adv. Synth. Catal. 2014, 356,
9
2
2
72−976. (h) Zhao, D.; Shi, Z.; Glorius, F. Angew. Chem., Int. Ed.
013, 52, 12426−12429. (i) Zhang, Z.; Jiang, H.; Huang, Y. Org. Lett.
014, 16, 5976−5979. (j) Ma, W.; Graczyk, K.; Ackermann, L. Org.
Lett. 2012, 14, 6318−6321.
(
8) (a) For a recent review on hydroarylation, see: Manikandan, R.;
Jeganmohan, M. Org. Biomol. Chem. 2015, 13, 10420−10436.
b) Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem., Int.
(
Ed. 2011, 50, 6379−6382. (c) Ackermann, L.; Wang, L.; Lygin, A. V.
Chem. Sci. 2012, 3, 177−180.
(
9) (a) Kaishap, P. P.; Duarah, G.; Sarma, B.; Chetia, D.; Gogoi, S.
Angew. Chem., Int. Ed. 2018, 57, 456−460. (b) Kaishap, P. P.; Sarma,
B.; Gogoi, S. Chem. Commun. 2016, 52, 9809−9812.
(
10) (a) Kshirsagar, U. A. Org. Biomol. Chem. 2015, 13, 9336−9352.
(
b) Dell’Acqua, M.; Ronda, L.; Piano, R.; Pellegrino, S.; Clerici, F.;
Rossi, E.; Mozzarelli, A.; Gelmi, M. L.; Abbiati, G. J. Org. Chem. 2015,
8
0, 10939−10954. (c) Udemba, A.; Smith, G.; Nguyen, Q.-D.;
Kaliszczak, M.; Carroll, L.; Fortt, R.; Fuchter, M. J.; Aboagye, E. O.
Org. Biomol. Chem. 2015, 13, 5418−5423.
(
11) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259−
2
81. (b) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc.
Chem. Res. 2008, 41, 40−49.
E
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