Ru(II)-Catalyzed C-H Activation and Annulation Reaction via Carbon-Carbon Triple Bond Cleavage

Article abstract of DOI:10.1021/acs.orglett.8b00643

An unprecedented Ru(II)-catalyzed C-H activation and annulation reaction, which proceeds via C-C triple bond cleavage, is reported. This reaction of 2-phenyldihydrophthalazinediones with alkynes, which works most efficiently in the presence of bidented ligand 1,3-bis(diphenylphosphino)propane, affords good yields of substituted quinazolines.

Full text of DOI:10.1021/acs.orglett.8b00643

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ru(II)-Catalyzed C−H Activation and Annulation Reaction via
Carbon−Carbon Triple Bond Cleavage
Rashmi Prakash, Bidisha R. Bora, Romesh C. Boruah, and Sanjib Gogoi*
Applied Organic Chemistry, Chemical Sciences & Technology Division, CSIR-North East Institute of Science and Technology,
AcSIR, Jorhat 785006, India
S
* Supporting Information
ABSTRACT: An unprecedented Ru(II)-catalyzed C−H activation and
annulation reaction, which proceeds via C−C triple bond cleavage, is
reported. This reaction of 2-phenyldihydrophthalazinediones with
alkynes, which works most efficiently in the presence of bidented
ligand 1,3-bis(diphenylphosphino)propane, affords good yields of
substituted quinazolines.
Scheme 1. Transition-Metal-Catalyzed Cleavage of Alkyne in
Intermolecular Annulation Reactions
n recent years, transition-metal-catalyzed cleavage of C−C
Isingle bonds and double bonds has emerged as one of the
most challenging areas in organic reactions because of its utility
in organic synthesis.1 In contrast, metal-catalyzed C−C triple
bond cleavage reactions are not well-studied, owing to the large
bond dissociation energy of C−C triple bonds, and still remains
one of the most challenging matters in organic chemistry.
Traditionally, stoichiometric organometallic reactions and
alkyne metathesis reactions are used for the C−C triple bond
cleavage.2 In the last two decades, only a few catalytic methods
have been developed for the C−C triple bond cleavage using
transition metal catalysts such as Pd,3 Au,4 Ru,5 and Rh.6
Concurrently, the transition-metal-catalyzed C−C triple bond
reactions have also been used to perform a few annulation
cleavage reactions for the efficient construction of some
important heterocycles. For instance, Wan and co-workers
reported a Rh(III)-catalyzed annulation reaction of nitrones with
symmetrical diaryl alkynes for the synthesis of indoles, which
proceeds via C−C triple bond cleavage (Scheme 1, eq 1).6b
Similarly, Yamamoto and co-workers reported a Ru(0)-catalyzed
simultaneous cleavage of C−C single and triple bonds of diynes
to perform an annulation reaction with o-aminophenols (Scheme
1, eq 2).5b Recently, Pan and co-workers reported a Pd(II)-
catalyzed annulation reaction of o-aminophenols with disub-
stituted alkynes which proceeds via C−C triple bond cleavage for
the synthesis of benzoxazoles (Scheme 1, eq 3).3c
In the last two decades, transition-metal-catalyzed C−H
activation and functionalization reactions have provided a new
direction for the efficient syntheses of important heterocycles.7
In particular, transition-metal-catalyzed C−H bond activation
followed by annulation of alkynes has been frequently used for
the efficient construction of a wide range of heterocycles.7a In
continuation of our work on metal-catalyzed reactions,8 here, we
disclose an unprecedented Ru(II)-catalyzed C−H activation and
annulation reaction, where the annulation occurs by cleavage of
the triple bond of the alkyne. Notably, unlike the reported alkyne
cleavage reactions, in the present reaction, both the fragments of
the alkyne remain in the same product. This new annulation
reaction provides an efficient method for the synthesis of
quinazolines. Quinazolines are the main building block of a wide
range of natural products, pharmaceutically active compounds,
and pesticides (Figure 1).9 The recent approval of a number of
quinazoline-based drugs has made it essential to develop novel
Received: February 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00643
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of 2-Phenyl-2,3-dihydrophthalazine-1,4-
a
diones 1a−m
Figure 1. Examples of quinazoline drugs and bioactive compounds.
synthetic routes which can accommodate various substituents on
the quinazoline ring. Initially, the Ru(II)-catalyzed annulation
reaction was tested with 2-phenyldihydrophthalazinedione 1a
with alkyne 2a for the synthesis of quinazoline 3aa (Table 1 and
a
Table 1. Optimization of the Reaction Conditions for 3aa
3aa
b
entry
catalyst
additive
ligand
(%)
1
2
3
4
5
6
7
8
9
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
Cu(OAc)2·H2O
CsOAc
37
32
15
28
16
43
69
78
52
CuBr2
AgOAc
KOAc
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
PPh3
c
dppe
d
dppp
Johnphos
a
a
Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), catalyst (5.0
mol %), additive (0.25 mmol), ligand (10 mol %), and AmOH (4.0
mL) at 90 °C under air for 8 h, unless otherwise mentioned.
Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), catalyst (5.0
t
t
mol %), additive (0.25 mmol), ligand (10 mol %), and AmOH (4.0
mL) at 90 °C under air for 8 h, unless otherwise mentioned. Isolated
yields. 1,2-Bis(diphenylphosphino)ethane. 1,3-Bis-
(diphenylphosphino)propane.
b
c
d
donating and electron-withdrawing substituents, such as Me,
OMe, and F on the phenyl rings of alkynes 2b−d, afforded good
yields of quinazolines 3ab−ad with 1a. The reactions of
unsymmetrical diaryl-substituted alkynes 2e−i with 1a were
found to be highly regioselective to afford compounds 3ae−
ai,3af′. Interestingly, the reaction of 2h with 1a under the
standard reaction conditions, and in the absence of the ligand
DPPP, was highly regioselective to provide the opposite isomer
3ah′. However, the reaction of unsymmetrical alkynes 2g, 2i, and
2m with 1a, both in the presence of the ligand and in the absence
of the ligand, afforded the same regioisomers. The sensitive Br-
containing unsymmetrical alkyne 2j and the aryl heteroaryl-
substituted unsymmetrical alkyne 2l were also found to be good
substrates, affording 3aj and 3al regioselectively. The alkyne
possessing biphenyl and phenyl substituent 2k was tested, which
provided highly regioselective product 3ak. The alkylaryl-
substituted alkynes 2m,n were also found to be suitable starting
materials for this annulation reaction to provide compounds
3am−an regioselectively, albeit with poor yields. Nevertheless,
the disubstituted alkyne 2o, substituted with one phenyl and one
ester group, turned out to be a very good substrate to perform
this reaction, and it provided good yield of 3ao. However, the
dialkyl-substituted alkynes, terminal alkynes, silyl- and bromo-
group-substituted alkynes were not found to be good substrates
for this reaction. Previous studies on alkyne annulation reactions,
Table SI-1). Among the additives tested for the reactions,
Cu(OAc)2·H2O provided the best yield of 3aa in the presence of
K2CO3 in tAmOH (entries 1−5). Screening of monodentate and
bidentate phosphine ligands revealed DPPP [1,3-bis-
(diphenylphosphino)propane] to be the best ligand to perform
this annulation reaction (entries 6−9 and Table SI-1). These
optimized reaction conditions were then tested for the
annulation reaction of various 2-phenyldihydrophthalazine-
diones 1a−m with alkyne 2a (Scheme 2). The 2-phenyldihydro-
phthalazinediones substituted with electron-donating and
i
electron-withdrawing substituents, such as Me, Pr, OMe, CF3,
F, and Cl at the para-position of the 2-phenyl ring (1b−g),
afforded good yields of quinazolines 3ba−ga. Similarly, the
reactions of 2-phenyldihydrophthalazinediones substituted with
electron-donating and electron-withdrawing substituents, such
as Me, F, and Cl at the meta-position of the 2-phenyl ring 1h−j,
were found to be highly regioselective to provide products 3ha−
ja. The dihydrophthalazinediones substituted with two sub-
stituents on the 2-phenyl ring 1k−m also turned out to be good
substrates for this reaction to provide good yields of 3ka−ma.
Next, the scope of the alkynes 2b−o was tested for this
annulation reaction with 1a (Scheme 3). All the tested diaryl-
substituted symmetrical alkynes, substituted with electron-
B
DOI: 10.1021/acs.orglett.8b00643
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
yield (Scheme 4, eq 1). This result indicates a similar role of the
leaving moieties in the starting materials 1a and 1p. In another
Scheme 3. Scope of Alkynes
Scheme 4. Controlled Experiments
experiment of diketo compound 4 with alkyne 2a, performed
under standard conditions, we observed the elimination of
carbon monoxide gas from the reaction mixture (Scheme 4, eq
1). However, we could not isolate any product from the reaction
mixture other than isolating the starting alkyne 2a. Interestingly,
in the absence of the alkyne 2a, the diketo compound 4 could not
react under standard conditions to produce carbon monoxide,
and 4 was recovered after 8 h. The dihydrophthalazinediones 1q
and 1r, which have fused electron-rich and electron-poor aryl
rings, did not show significant difference in their reactivity with
alkyne 2a under standard conditions (Scheme 4, eq 2). The
parallel or intermolecular competition experiments conducted
between electron-rich and electron-poor alkynes 2b and 2d with
1a revealed preferential conversion of 2d to 3ad (Scheme SI-2).
Again, in another competition experiment of dihydro-
phthalazinediones 1b and 1f possessing electron-rich and
electron-poor 2-phenyl substituents with 2a revealed preferential
conversion of 1b to 3ba (Scheme SI-3). The reaction of 1a alone
or in the presence of alkyne 2a, under the standard condition in
CD3OD, could not afford the deuterium exchanged product 1a-
D, indicating the irreversible initial C−Ru bond formation
(Scheme SI-4). The competitive intermolecular experiment
between 1a and 1a-D5 with 2c provided kH/kD = 1.2 (Scheme SI-
6), whereas the competitive parallel experiments between 1a and
1a-D5 with 2c provided kH/kD = 1.1 (Scheme SI-7). Thus, the
Ru−C bond formation step might not be the rate-determining
step of this annulation reaction.
Based on our results and the literature reports, a possible
mechanism is proposed in Scheme 5 for the formation of
quinazoline derivative 3aa.7a,11 First, the active Ru(II) catalyst A,
generated from [RuCl2(p-cymene)2] and Cu(OAc)2, irreversibly
reacts with 1a to generate Ru complex B via activation of the C−
H bond. Insertion of alkyne into the C−Ru bond produces
seven-membered Ru(II) complex C, which on further oxidation
by cleavage of the N−N bond generates Ru(IV) complex D.11
Subsequently, reductive elimination of the Ru metal generates
indole derivative E. Activation at C-2 of the indole moiety of E
leads to the formation of Ru complex F, which on subsequent
reductive elimination, in the presence of Cu(OAc)2, affords a
seven-membered amide G, and it regenerates the active catalyst
A. Next, intramolecular cyclization of G might generate
diazacyclopropane azulene H, which on intramolecular rear-
rangement and elimination reaction produces the quinazoline
derivative 3aa and diketo compound I. However, our attempt to
isolate I from the reaction mixture failed. Nevertheless, the
a
Reaction conditions: 1a (0.25 mmol), 2 (0.25 mmol), Ru catalyst
(5.0 mol %), Cu(OAc)2·H2O (0.25 mmol), DPPP (10 mol %), and
K2CO3 (0.25 mmol) in tAmOH (4.0 mL) was heated at 90 °C for 8 h
b
c
under air. Major isomer is depicted. DPPP was not used.
catalyzed by transition metal catalysts, demonstrated that the
insertion of alkyne was controlled by electronic effect rather than
the steric effect.10 In the present reaction, the annulation pattern
of diaryl-, arylalkyl-, and arylester-substituted unsymmetrical
alkynes is similar to the previously reported transition-metal-
catalyzed annulation reactions.10 In these annulation reactions of
unsymmetrical alkynes, the insertion of the alkynes occurs in
such a way that the electron-rich center of the alkyne binds with
the metal, thus providing regioselectivity into the final annulated
products. The structures of the products were determined by
spectroscopic studies and the spectral data compared to that of
the reported compounds.9
The reaction of alkyne 2a with phenyldihydropyridazinedione
1p under the standard reaction conditions provided 3aa in 65%
C
DOI: 10.1021/acs.orglett.8b00643
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Proposed Mechanism
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00643.
Experimental procedures, spectroscopic data and copies of
1H NMR, 13C NMR and HRMS spectrum of synthesized
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: skgogoi1@gmail.com or sanjibgogoi@neist.res.in.
ORCID
Sanjib Gogoi: 0000-0002-2821-3628
Notes
(12) Verma, A.; Kumar, S. Org. Lett. 2016, 18, 4388−4391.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank SERB, New Delhi, for financial support with
the GPP-0303 (YSS/2014/001018) project. R.P. thanks CSIR
for the senior research fellowship, and B.R.B. thanks DST for the
INSPIRE fellowship. R.C.B. thanks CSIR, New Delhi, for the
award of Emeritus Scientist, CSIR. We are grateful to the
Director, CSIR-NEIST, for his keen interests.
D
DOI: 10.1021/acs.orglett.8b00643
Org. Lett. XXXX, XXX, XXX−XXX