Pd(II)-Catalyzed Synthesis of Alkylidene Phthalides via a Decarbonylative Annulation Reaction

Article abstract of DOI:10.1021/acs.orglett.9b00726

An unprecedented Pd(II)-catalyzed decarbonylative C-H/C-C activation and annulation reaction, which proceeds via intramolecular cyclization, is reported. This reaction of hydroxynaphthoquinones with disubstituted alkynes provides good yields of substituted alkylidene phthalides, which are the key intermediates for the synthesis of bioactive natural products.

Full text of DOI:10.1021/acs.orglett.9b00726

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd(II)-Catalyzed Synthesis of Alkylidene Phthalides via a
Decarbonylative Annulation Reaction
Somadrita Borthakur,† Swagata Baruah,† Bipul Sarma,‡ and Sanjib Gogoi*,†
†Applied Organic Chemistry, Chemical Science & Technology Division, CSIR-North East Institute of Science and Technology,
Jorhat 785006, AcSIR, India
‡Department of Chemical Sciences, Tezpur University, Tezpur 784028, India
S
* Supporting Information
ABSTRACT: An unprecedented Pd(II)-catalyzed decarbonylative
C−H/C−C activation and annulation reaction, which proceeds via
intramolecular cyclization, is reported. This reaction of hydroxynaph-
thoquinones with disubstituted alkynes provides good yields of
substituted alkylidene phthalides, which are the key intermediates for
the synthesis of bioactive natural products.
lkylidene butyrolactones are the key scaffold of various
membered 3-hydroxy-2-phenyl-chromones with alkynes for the
synthesis of spiro benzofuranones (Scheme 2, eq 1).6 Herein,
A
biologically active natural products and synthetic
compounds.1 They are the key intermediates for the synthesis
of many important heterocyclic, carbocyclic, and alicyclic
compounds.2 For example, alkylidene phthalide A (Scheme 1)3
Scheme 2. Decarbonylative Annulation Reactions
Scheme 1. Synthesis of the Spirocyclic Scaffold of
Fredericamycin A
as a continuation of our work on metal-catalyzed novel organic
reactions,7 we describe an unprecedented decarbonylative C−
H/C−C activation and annulation reaction, which proceeds
via one additional intramolecular cyclization reaction step, for
the synthesis of alkylidene phthalides (Scheme 2, eq 2). These
alkylidene phthalides are typically synthesized by the acylation
reaction of an indene anion with dimethyl phthalate, followed
by cyclization of the resulting ester to lactone under acidic
conditions.3 Furthermore, Balme and co-workers reported a
four-step palladium-catalyzed bis-cyclization reaction for the
synthesis of alkylidene phthalide.8
is the key intermediate for the synthesis of antitumor antibiotic
Fredericamycin A (Scheme 1), which was isolated from
Streptomyces griseus.4 This ylidene lactone A could be easily
transformed to the key spirocyclic scaffold B of Fredericamycin
A via reduction and oxidation reactions (Scheme 1).3
In recent years, the transition metal-catalyzed decarbon-
ylative activation of inert C−H/C−C bonds and alkyne
annulation reactions have provided a new direction for the
efficient construction of various heterocyclic compounds.
These metal-catalyzed decarbonylative annulation reactions
are mainly limited to four- and five-membered ring systems.5
Very recently, we reported a Ru(II)-catalyzed decarbonylative
annulation reaction, through C−H/C−C activation of six-
Initially, the decarbonylative annulation reaction of 1a was
studied with alkyne 2a in the presence of various transition
Received: February 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00726
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
metal catalysts (Table 1). Among the catalysts screened for this
reaction (entries 1−4), Pd(OAc)2 provided the highest yield of
Scheme 3. Scope of Hydroxynaphthoquinones 1a−h
a
Table 1. Optimization of the Reaction Conditions for 3aa
b
entry
catalyst
RuCl3·xH2O
[{RuCl2(p-cymene)}2]
[RhCp*Cl2]2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
additive
solvent
3aa (%)
1
2
3
4
5
6
7
8
9
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
CsOAc
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
H2O
0
19
16
70
54
41
51
42
88
56
AgOAc
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Pd(OAc)2
tAmOH
c
10
Pd(OAc)2
MeOH
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), catalyst (5.0
mol %), additive (0.2 mmol), and solvent (5.0 mL) at 85 °C under air
b
c
for 12 h, unless otherwise mentioned. Isolated yields. Reaction
performed at 64 °C.
3aa in the presence of additive Cu(OAc)2·H2O (entry 4).
Screening of some other commonly used additives such as
CsOAc and AgOAc could not improve the yield of annulated
product 3aa. However, screening of some other aprotic and
t
protic solvents (entries 7−10) revealed AmOH as the best
a
Reaction conditions: 1 (0.2 mmol), 2a (0.2 mmol), Pd catalyst (5.0
mol %), and Cu(OAc)2·H2O (1.0 equiv) in tAmOH (5.0 mL) heated
at 85 °C for 12 h under air.
solvent for performing this reaction (entry 9). These optimized
reaction conditions were first applied for the annulation
reaction of hydroxynaphthoquinones 1b−h with alkyne 2a. As
shown in Scheme 3, 2-phenyl-3-hydroxynaphthoquinones that
have different electron-donating and electron-withdrawing
substituents such as Me, OMe, F, Cl, and OCF3 on the 2-
phenyl ring of 1 afforded good yields of corresponding
products 3ba−fa and 3ha. The annulation reaction of 1c with
2a highly regioselectively afforded 3ca. Furthermore, hydrox-
ynaphthoquinone possessing a sensitive bromo functional
group (1g) tolerates the reaction conditions well to provide
3ga in good yield. However, the annulation reaction of
heterocycle-substituted hydroxynaphthoquinones such as 2-
(furan-2-yl)-3-hydroxynaphthalene-1,4-dione and 2-hydroxy-3-
(thiophen-2-yl)naphthalene-1,4-one with 2a under the opti-
mized reaction conditions could not afford the desired
products. Next, the scope of the reaction with some of the
alkynes 2b−n was studied with 1a. As shown in Scheme 4,
diaryl-substituted alkynes possessing electron-donating and
-withdrawing substituents on the phenyl ring (2b−d) turned
out to be good substrates for this reaction to afford compounds
3ab−ad. The unsymmetrical diaryl-substituted alkynes 2e−h
provided inseparable mixture of isomers 3ae−ah, respectively,
with 1a. Dialkyl-substituted alkynes 2i and 2j were also found
to be good substrates for this reaction to provide 3ai and 3aj,
respectively, with 1a in good yields. The annulation reactions
of alkynes 2k−m substituted with an aryl and an alkyl group
with 1a highly regioselectively afforded 3ak−am, respectively.
Similarly, phenylpropiolate 2n was also found to be a good
substrate for this reaction that afforded 3an, regioselectively.
Then, the scope of the reaction was tested with diynes 2o and
2p with 1a. As shown in Scheme 5, both tested alkynes 2o and
2p provided good yields of phthalides 3ao and 3ap,
respectively, and these reactions were highly regioselective.
Interestingly, the annulation reaction of silylalkynes 2q−s with
1a also afforded the same alkyne-containing phthalides 3ao−
ap and similar phthalide 3aq, albeit in low yields (Scheme 5).
However, under the standard reaction conditions, the reaction
of 1a with trimethyl(thiophen-3-ylethynyl)silane could not
afford the corresponding phthalide. The terminal alkynes were
not found to be suitable substrates for this annulation reaction.
As in the previous studies of the metal-catalyzed alkyne
annulation reactions, the regioselectivity of the unsymmetrical
diaryl-substituted alkynes is difficult to predict, which usually
provides a mixture of isomers.9 However, the annulation
reaction of unsymmetrical alkynes, substituted with an aryl and
an alkyl group, affords highly regioselective products. These
products are regioselective because of the preferential binding
of the metal with the electron rich center of the unsymmetrical
alkynes.9 The structures of the compounds were determined
with the help of spectroscopic studies and finally confirmed by
single X-ray crystallographic studies of compound 3aa.10
The competitive experiment performed between alkynes
possessing an electron-donating group (2b) and an electron-
withdrawing group (2d) with 1a showed a faster rate of
reaction of 2b [1.7:1 3ab:3ad (Scheme SI-3)]. Another
B
DOI: 10.1021/acs.orglett.9b00726
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Scope of Alkynes
Scheme 5. Scope of Alkynes
Scheme 6. Experiments with Isotopically Labeled
Compounds
a
Reaction conditions: 1 (0.2 mmol), 2a (0.2 mmol), Pd catalyst (5.0
mol %), and Cu(OAc)2·H2O (1.0 equiv) in tAmOH (5.0 mL) heated
at 85 °C for 12 h under air.
competitive experiment performed with electron rich and
electron poor hydroxynaphthoquinones 1b and 1f with 2a
revealed preferential formation of 3ba [3:1 3ba:3fa (Scheme
SI-4)]. 1a under standard conditions and in CD3OD could not
afford the deuterated product 1a-D, indicating the formation of
a nonreversible Ru−C bond (Scheme 6, eq 1). The
intermolecular competitive experiment performed with 1a
and 1a-D5 with 2a provided a kH/kD of 2.6 (Scheme 6, eq 2).
Again, the competitive parallel experiments with 1a and 1a-D5
with 2a provided a kH/kD of 2.3 (Scheme 6, eq 3). These kH/
kD values indicate the possibility of the Ru−C bond formation
step being the rate-determining step of this reaction. The
elimination of CO gas from the reaction mixture was proven by
performing the phosphomolybdic acid−PdCl2 test (Figure SI-1
and the Supporting Information).11
complex A by eliminating two molecules of acetic acid.
Insertion of the alkyne within the C−Pd bond provides
complex B, which on subsequent intramolecular cyclization
and cleavage of C−C bonds liberates one molecule of cabon
monoxide to afford Pd complex D. Finally, in the presence of
copper acetate and oxygen from air, reductive elimination of
the metal provides compound 3aa and it regenerates the
catalyst as shown in Scheme 7.
In summary, we have developed a novel Pd(II)-catalyzed
decarbonylative alkyne insertion reaction of six-membered ring
compounds. This annulation reaction of hydroxynaphthoqui-
nones and disubstituted alkynes proceeds via C−H/C−C
On the basis of our experiments and literature reports, a
possible mechanism is proposed for this reaction in Scheme 7.
Initially, 1a reacts with the catalyst Pd(OAc)2 to form Pd
C
DOI: 10.1021/acs.orglett.9b00726
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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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.or-
glett.9b00726.
Experimental procedures, spectroscopic data, and copies
of 1H NMR, 13C NMR, and HRMS spectra of
synthesized compounds (PDF)
Accession Codes
CCDC 1547365 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 Author
■
*E-mail: skgogoi1@gmail.com or sanjibgogoi@neist.res.in.
ORCID
Sanjib Gogoi: 0000-0002-2821-3628
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank SERB and CSIR New Delhi for financially
supporting us via the GPP-0303 (YSS/2014/001018) and
OLP-2011 projects. S. Borthakur thanks CSIR for the senior
research fellowship. The authors are grateful to the Director of
CSIR-NEIST for his keen interest.
REFERENCES
■
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DOI: 10.1021/acs.orglett.9b00726
Org. Lett. XXXX, XXX, XXX−XXX