Palladium(ii)-catalyzed vinylic geminal double C-H activation and alkyne annulation reaction: Synthesis of pentafulvenes

Article abstract of DOI:10.1039/c9cc09564k

The first transition-metal-catalyzed vinylic geminal double C(sp²)-H activation and di-substituted alkyne annulation reaction is reported. This palladium(ii)-catalyzed, amide directed reaction of vinylic compounds with di-substituted alkynes offers an efficient synthetic path to pentafulvenes, which are very important compounds because of their bioactivity and interesting optical properties. A FeCl₃-mediated transformation of pentafulvenes to fluorescent cyclopenta[b]quinolines is also developed.

Full text of DOI:10.1039/c9cc09564k

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Palladium(II)-catalyzed vinylic geminal double
C–H activation and alkyne annulation reaction:
Cite this:DOI: 10.1039/c9cc09564k
synthesis of pentafulvenes†
Received 10th December 2019,
Accepted 13th December 2019
Jyotshna Phukon and Sanjib Gogoi
*
DOI: 10.1039/c9cc09564k
rsc.li/chemcomm
The first transition-metal-catalyzed vinylic geminal double C(sp2)–H
activation and di-substituted alkyne annulation reaction is reported.
This palladium(II)-catalyzed, amide directed reaction of vinylic com-
pounds with di-substituted alkynes offers an efficient synthetic path
to pentafulvenes, which are very important compounds because of
their bioactivity and interesting optical properties. A FeCl3-mediated
transformation of pentafulvenes to fluorescent cyclopenta[b]quinolines
is also developed.
The transition-metal-catalyzed activation of C(sp2)–H bonds and
alkyne insertion reactions have been extensively used for the
construction of various heterocycles for the last two decades.1
Among these reactions, the metal-catalyzed double C(sp2)–H
Scheme 1 Alkyne annulation by double C(sp2)–H activation.
bond activation and double alkyne insertion reactions have been geminal C(sp2)–H bonds and alkyne annulation, which could
developed lately as potential approaches for the synthesis be an easy route to construct important pentafulvene deriva-
of polyaromatic and heteroaromatic compounds. For example, tives, still remains unexplored. To extend our work further for
Jiao et al. developed a Pd(II)-catalyzed double activation of two the development of new metal-catalyzed reactions,5 herein, we
aromatic C(sp2)–H bonds of biphenyl compounds followed by disclose the first transition-metal-catalyzed activation of both
an insertion of alkyne to synthesize polycyclic aromatic hydro- the vinylic geminal C(sp2)–H bonds and alkyne annulation
carbons (Scheme 1, eqn (1)).2 Miura et al. developed an Rh(III)- reactions (Scheme 1, eqn (3)). This Pd(II)-catalyzed amide
catalyzed directing group assisted method for polyarylated directed reaction of the acetyl derivative of 2-(1-phenylvinyl)-
naphthyl and anthrylazole derivatives which proceeded via the aniline and di-substituted alkyne afforded an efficient synthetic
activation of two aromatic C(sp2)–H bonds and the insertion of route for pentafulvenes.6a–e Pentafulvenes are now considered as
two molecules of alkynes (Scheme 1, eqn (2)).3 In spite of the wonder molecules because of their unique aromaticity, dipole
importance of metal-catalyzed double C(sp2)–H activation and moment, reactivity and applications.6f–i They are the key structural
alkyne insertion reactions for the synthesis of annulated carbo- element of a wide range of bioactive compounds6h,i and organome-
cycles and heterocycles, until now, these reactions are confined to tallic compounds.7 Recently, many pentafulvenes have emerged as
the double activation of aromatic C(sp2)–H bonds. Single vinylic promising candidates for electroluminescent and display device
C(sp2)–H bond activation and alkyne annulation reactions are systems (Fig. 1).8 It is noteworthy to mention that very recently,
known in the literature for the synthesis of heterocycles.4 Zeng and Li described a Pd(II)-catalyzed alkyne annulation reaction
However, the double C(sp2)–H activation of both the vinylic of the tosyl derivative of 2-(1-phenylvinyl)aniline and di-substituted
alkyne for the synthesis of cyclopenta[b]quinolines.9 Again, the
Applied Organic Chemistry, Chemical Sciences & Technology Division, CSIR-North
East Institute of Science and Technology, AcSIR, Jorhat-785006, India.
E-mail: skgogoi1@gmail.com, sanjibgogoi@neist.res.in
cyclopenta[b]quinoline scaffold is the key structure of several bio-
active natural products and pharmaceutically important compounds
which exhibit anticancer, antimalarial and Alzheimer’s disease
inhibitory activity.10 Because of the importance of this scaffold, we
developed a very efficient method to transform the pentafulvenes to
cyclopenta[b]quinolines, which is also reported herein.
† Electronic supplementary information (ESI) available: Experimental proce-
dures, spectroscopic data and copies of the 1H NMR, 13C NMR and HRMS spectra
of the synthesized compounds. CCDC 1952908 (3ca). For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c9cc09564k
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Table 2 Scope of alkynes and vinylacetamidesa
Fig. 1 Examples of potential pentafulvenes for use in electroluminescent
and display devices.8a,b
Table 1 Optimization of the reaction conditions for 3aaa
Entry Catalyst
Additive
Solvent
3aab (%)
1
2
3
4
5
6
7
8
[{RuCl2(p-cymene)}2] Cu(OAc)2ꢀH2O MeCN
0
0
[RhCp*Cl2]2
Pd(OAc)2
PdCl2
Cu(OAc)2ꢀH2O MeCN
Cu(OAc)2ꢀH2O MeCN
Cu(OAc)2ꢀH2O MeCN
48
21
36
16
39
15
77
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CsOAc
NaOAc
AgOAc
Ag2O
MeCN
MeCN
MeCN
MeCN
a
Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), catalyst (10.0 mol%),
additive (0.75 mmol) and solvent (4.0 mL) at 100 1C under air for 18 h.
One probable isomer is shown, ratio of regioisomers (r.r.) was
b
determined by 1H NMR.
9
Cu(OAc)2ꢀH2O tAmOH
10
11
12
13c
14d
Cu(OAc)2ꢀH2O 1,4-Dioxane 63
Cu(OAc)2ꢀH2O DMF
Cu(OAc)2ꢀH2O DMSO
Cu(OAc)2ꢀH2O tAmOH
Cu(OAc)2ꢀH2O tAmOH
41
0
58
61
and phenylvinylacetamide 1a, which is shown in Table 2.
Thus, the symmetrically substituted di-aryl alkynes possessing
electron-donating and electron-withdrawing substituents viz.,
methyl, methoxy, fluoro and chloro substituents at the para-
position of the phenyl ring (2b–e) smoothly provided the corres-
ponding annulated products 3ab–ae in good yields. Similarly,
di-aryl alkynes substituted at the meta-position with methyl (2f)
and fluoro (2g) were also tested which provided the pentafulvenes
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst
(10.0 mol%), additive (0.75 mmol) and solvent (4.0 mL) at 100 1C under
b
c
air for 18 h; unless otherwise mentioned. Isolated yields. Under
argon. Additive (0.5 mmol).
d
Initially, the reaction was tried with phenylvinylacetamide 1a 3af–ag. The unsymmetrical di-aryl substituted alkynes 2h–i
and diphenylacetylene (2a) for the synthesis of pentafulvene 3aa afforded a mixture of regioisomers 3ah (7:7:1) and 3ai (3:3:1)
(Table 1). The screening of various transition metal complexes with 1a in good yields. The representative arylalkyl alkyne 2j and
using acetonitrile as the solvent showed the Pd(OAc)2 catalyst to be arylester alkyne 2k also provided a mixture of regioisomers 3aj
the ideal catalyst which provided 48% yield of 3aa in the presence (3 :3:1:1) and 3ak (5:3:1) with 1a, respectively. The di-alkyl
of Cu(OAc)2 as an additive (entry 3). The commonly used additives group substituted alkynes, terminal alkynes, and diester group
in Pd-catalyzed reactions, for instance CsOAc, NaOAc, AgOAc and containing alkynes could not afford the desired annulated
Ag2O, could not raise the yield of 3aa (entries 5–8).1e Other additives products. Then, this reaction was tested with some phenylvinyl-
such as oxone, PhI(OAc)2 and K2S2O8 provided 42%, 18% and 52% acetamides 1b–l with alkyne 2a (Scheme 2). The 1-substituted
yields of 3aa, respectively. Then, to our delight, screening of some N-(2-vinylphenyl)acetamides, substituted with para-tolyl, 4-ethyl-
solvents revealed that the choice of solvent was very important to phenyl, 1,10-biphenyl, 4-fluorophenyl and 3-thiophenyl substituents
improve the yield of 3aa. These solvent studies afforded tAmOH as 1b–f were all found to be good substrates to afford the pentafulvenes
the optimal solvent for this reaction which yielded 77% of 3aa 3ba–3fa. Unfortunately, the reaction of arylalkyl substituted vinyl-
(entry 9). Under inert conditions or the use of 1.0 equivalent of phenylamide 1g with 2a could not provide the desired compound
additive, this reaction afforded an inferior yield of 3aa (entries 13 3ga. Then, some of the N-(2-(1-phenylvinyl)phenyl)acetamides
and 14). When DMSO was used as the solvent, the acetyl derivative holding substituents such as methoxy (1h), fluoro (1i), chloro (1j)
of 3-phenyl-1H-indole was the only compound formed by an and bromo (1k) at the fourth position of the phenyl ring of the
intramolecular coupling reaction. Thus, the best conditions to N-phenylacetamide moiety 1h–k were reacted with 2a to provide
synthesize 3aa were obtained by using Pd(OAc)2 (10 mol%) and 3ha–3ka. Finally, the reaction of vinylnaphthylamide 1l was
Cu(OAc)2ꢀH2O (1.5 equiv.) in tAmOH at 100 1C for 18 h.
tested with 2a, which afforded a good yield of the desired
The optimized reaction conditions (Table 1, entry 9) were compound 3la. It is observed that the yield of this reaction is
then examined first with some of the di-substituted alkynes 2a–l relatively unaffected by the electron-rich and electron-poor
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Fig. 2 Fluorescence (2.0 ꢁ 10ꢂ5 M, excitation at 320 nm) spectra of
4ab–ad, 4af and 4ba–ca in toluene using quinine sulfate as the reference.
Scheme 2 Synthesis of cyclopenta[b]quinolines.a a Reaction conditions: 3
(0.03 mmol), FeCl3 (1.5 equiv.), CH2Cl2 (2.0 mL), CH3NO2 (0.5 mL), room
temperature under N2 for 5 h.
provide any hydrogenated compound in 24 hours at room
temperature. Whereas, the bromination reaction of 3ab per-
formed by the addition of one equivalent of Br2 to a stirred
solution of 3ab in CHCl3 afforded 77% yield of 4ab at room
temperature in 8 hours. Next, on account of the recent emergence of
pentafulvenes as potential candidates in organic light-emitting
diodes, we were interested to study the preliminary optical properties
of all the synthesized compounds.12 The absorption bands of all the
synthesized compounds appeared in the region 318 to 327 nm
depending upon the substituent present in the molecule. Among all
the compounds studied, only the cyclopenta[b]quinolines 4ab–ad,
4af and 4ba–ca exhibited fluorescence in the range from 405 to
431 nm with quantum efficiency (F of 59% (4ab), 12% (4ac), 10%
(4ad), 14% (4af), 11% (4ba) and 16% (4ca)) (Fig. 2).
To understand the mechanism of the pentafulvene formation,
some control experiments were performed. Under the standard
reaction conditions and in the absence of the directing amide
group, the vinylic compound ethene-1,1-diyldibenzene could not
afford the alkyne annulated product with the alkyne 2a. The
reactivity of this reaction is also dependent on the amine protecting
group. The benzamide derivative N-(2-(1-phenylvinyl)phenyl)benz-
amide could not afford its corresponding pentafulvene with 2a
under the standard reaction conditions. Again, the vinylacetamide
1a could not provide the deuterium-hydrogen exchanged vinyl-
acetamide 1a-D2 in deuterated solvents such as D2O, CD3COOD
and CD3OD (70 1C) under the standard reaction conditions
(Scheme 3), indicating the irreversible formation of a cyclopalladium
intermediate. Based on our experiments and literature reports,1e,6e
a probable mechanism for the formation of the pentafulvene 3
and cyclopenta[b]quinoline 4 is shown in Scheme 4. Initially,
Pd(II)-catalyzed amide group directed vinylic C(sp2)–H activation
of 1 affords the 6-membered palladacycle A.6e Then, coordination
of 2 with the metal followed by carbopalladation generates a
Pd-complex B. Then, carbopalladation of another molecule of 2
and subsequent vinylic C(sp2)–H activation affords a 6-membered
palladacycle C. Finally, a reductive elimination of the metal with
the help of air and Cu(OAc)2 resulted in the formation of
pentafulvene 3 and regenerates the active Pd-catalyst. The FeCl3
mediated conversion of amide 3 to cyclopenta[b]quinoline 4 might
have occurred via a radical cation mechanism similar to the Scholl
reaction.13 Thus, the FeCl3-mediated single electron transfer (SET)
process might have generated a radical intermediate E. This inter-
mediate on another SET process resulted in the carbocation F which
substituents present on the aromatic ring of 1. The structure of
these compounds was established with the help of NMR spectra
and single X-ray crystallography studies of 3ca.11 To check the
synthetic utility of this methodology, we performed a gram-scale
experiment of 1j and 2a under the standard conditions, which
provided 3ja in 66% yield. Because of the importance of the
cyclopenta[b]quinolines, next we attempted to transform the
pentafulvene 3ab to cyclopenta[b]quinoline 4ab (Scheme 2).
We hypothesized that a Scholl type intramolecular cyclization
proceeded via deacetylation and aromatization would be a very
good method for the conversion of these pentafulvenes to
cyclopenta[b]quinolines. Initially, we tried to perform the intra-
molecular cyclization using commonly used oxidants such as
ZnCl2, AlCl3, FeCl3 and DDQ. Fortunately, in the presence of
FeCl3 (1.5 equiv.) and DDQ (1.5 equiv.), the pentafulvene 3ab
provided 90% yield and 69% yield of 4ab, respectively, at room
temperature in CH2Cl2 and CH3NO2 (Scheme 2). To check the
substrate scope of this reaction, we tested this FeCl3-mediated
cyclization reaction with some more pentafulvenes 3ac–ad, 3af,
and 3ba–ca. The pentafulvenes possessing an electron-rich and
electron-poor aryl functionality on the five membered ring of
fulvene (3ac–ad, 3af) reacted smoothly to furnish very good yields
of the corresponding products 4ac–ad and 4af, irrespective of the
substituents present on the ring. The other two pentafulvenes
containing para-tolyl and 1,10-biphenyl substituents at the sixth
position of the fulvene scaffold 3ba–ca were also examined to
afford 4ba–ca in very good yields. Our attempt to convert 1a and
2b to 4ab in one-pot provided less yield of 4ab (56%, Scheme 3).
However, this two-step procedure (both one-pot and two-pot
reactions) provided a better yield of cyclopenta[b]quinoline 4ab
(68% two-pot, 56% one-pot) as compared to the reported 23%
yield of 4ab.9 The hydrogenation reaction of 3ab at 60 psi pressure,
using Pd/C as the catalyst and MeOH as the solvent could not
Scheme 3 One pot synthesis of 4ab and the deuterium experiment.
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CSIR-NEIST for his keen interests. J. Phukon thanks DST for the
INSPIRE-JRF fellowship.
Conflicts of interest
There are no conflicts to declare.
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and alkyne annulation reaction was developed. This amide group
directed annulation reaction provided an efficient synthetic route
for the important pentafulvene derivatives. In addition to this, a
ferric chloride mediated method was developed for the conversion
of pentafulvenes to fluorescent cyclopenta[b]quinolines with a very
high yield.
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The authors thank CSIR New Delhi for financially supporting
us via the OLP 2020 project. We are grateful to the Director,
Chem. Commun.
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