Rhodium-Catalyzed Regioselective Synthesis of Isoindolium Salts from 2-Arylpyridines and Alkenes in Aqueous Medium under Oxygen

Article abstract of DOI:10.1002/adsc.201600452

A highly regioselective synthesis of pyrido[2,1-a]isoindolium salts from 2-arylpyridines and two equivalents of electron-deficient alkenes catalyzed by rhodium is demonstrated. The reaction was carried out in aqueous medium at 110 °C using inexpensive oxygen as oxidant. Reverse aza-Michael addition of the isoindolium salt occurs when the salt was treated with base to give a β-disubstituted alkene product. A reaction mechanism involving an ortho C–H olefination of 2-arylpyridine by alkene, intramolecular aza-Michael addition, deprotonation at the β-carbon of the alkene fragment followed by another Michael addition to give the final product is proposed. (Figure presented.).

Full text of DOI:10.1002/adsc.201600452

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DOI: 10.1002/adsc.201600452
Rhodium-Catalyzed Regioselective Synthesis of Isoindolium Salts
from 2-Arylpyridines and Alkenes in Aqueous Medium under
Oxygen
Nitinkumar Satyadev Upadhyay,+a Jayachandran Jayakumar,+a
and Chien-Hong Chenga,*
a
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
Fax : (+886)-3-572-4698; phone: (+886)-3-572-1454; e-mail: chcheng@mx.nthu.edu.tw
+
These two authors contributed equally to this work.
Received: April 28, 2016; Revised: August 31, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600452.
Abstract:
A
highly regioselective synthesis of
using cheap oxidants and environmentally benign
green solvents is still greatly sought after. Transition
metal-catalyzed C–H bond functionalization using
oxygen as the oxidant is known.[3,5,9,11] Furthermore,
there are a few C–H functionalization reactions
known to be carried out in aqueous medium.[7] How-
ever, to the best of our knowledge, there are no re-
ports on the C–H functionalization catalyzed by tran-
sition metal complexes using both oxygen or air as
the oxidant and water as the solvent.
Two traditional approaches were reported for the
synthesis of isoindolium salts, by cycloaddition and
photocyclization reactions requiring ortho-ester aryl-
pyridines and N-(2-halobenzyl)pyridinium bromide,
respectively.[8] Very recently, Sanford and co-workers
developed a Pd-catalyzed synthesis of cyclic pyridini-
um salts via the pyridine-directed olefination of the
C(sp3)–H bond followed by intramolecular Michael
addition.[9] Very recently, Li and co-workers reported
a Rh-catalyzed synthesis of 1H-isoindole via N-sulfi-
nylketoimines directed C–H coupling with di-alkenes
pyrido[2,1-a]isoindolium salts from 2-arylpyridines
and two equivalents of electron-deficient alkenes
catalyzed by rhodium is demonstrated. The reaction
was carried out in aqueous medium at 1108C using
inexpensive oxygen as oxidant. Reverse aza-Mi-
chael addition of the isoindolium salt occurs when
the salt was treated with base to give a b-disubsti-
tuted alkene product. A reaction mechanism involv-
ing an ortho C–H olefination of 2-arylpyridine by
alkene, intramolecular aza-Michael addition, depro-
tonation at the b-carbon of the alkene fragment fol-
lowed by another Michael addition to give the final
product is proposed.
Keywords: alkenes; C–H activation; isoindolium
salts; Michael addition; rhodium catalysis
Transition metal-catalyzed C–H functionalization has under redox neutral conditions [Scheme 1, Eq. (1)].[10]
been extensively investigated and become a powerful Inspired by these previous works and our experience
tool for organic synthesis.[1] The transformations do in metal-catalyzed synthesis of various isoquinolinium
not require pre-functionalization and can provide and pyridinium, salts via C–H activation [Eq. (2)],[11]
atom- and step-economical methods for the synthesis we herein report a Rh-catalyzed regioselective syn-
of highly substituted products.[2] However, in many thesis of pyridoisoindolium salts from arylpyridines
cases, the C–H functionalization required a stoichio- and alkenes via C–H olefination/cyclization in aque-
metric amount of expensive oxidant such as copper ous medium under 1 atm of O2 gas [Eq. (3)]. Isoindo-
and silver salts and toxic organic solvents. A typical lium salts and the derivatives belong to a new type of
example is the directing group (DG) assisted ortho azafluorenes that have attracted significant attention
olefination of arenes. Several metals such as palladi- due to their bioactivities.[12]
um,[3] rhodium,[4] ruthenium[5] cobalt and nickel are
To find the optimized conditions for the reaction of
known to catalyze the reactions in the presence of 2-phenylpyridine 1a with ethyl acrylate 2a to give pyr-
a stoichiometric amount of oxidant.[6] Thus the devel- idoisoindolium salt 3aa, we examined the effect of ox-
opment of ortho olefination and related reactions idant, and solvent used (see Table 1) on the yield of
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Table 1. Optimization studies for the reaction of 2-phenyl-
pyridine with ethyl acrylate.[a]
Entry Solvent
Oxidant
Yield [%][b] of 3aa
1
2
3
4
5
6
7
8
t-amyl alcohol
tert-butyl alcohol O2
O2
76
72
22
55
41
92
60
toluene
DMF
methanol
H2O
H2O
H2O
H2O
H2O
H2O
H2O
–
O2
O2
O2
O2
air
Scheme 1. Ketoimine and pyridine directed ortho-C–H acti-
vation/cyclization by Rh catalyst.
Cu(OAc)2 66
9
CuO
CuCl2
BQ
K2S2O8
O2
82
trace
0
10
11
12
13
14
3aa. We began with the reaction conditions consisting
of 1a (0.4 mmol), 2a (1.00 mmol), and NaBF4
(0.45 mmol) in the presence of [Cp*Rh(MeCN)3]
[BF4]2 (4 mol%) in t-amyl alcohol (2.5 mL) under O2
(1 atm). The reaction solution was heated at 1108C
for 16 h to provide salt product 3aa in 76% yield
(Table 1, entry 1). The structure of 3aa, containing an
isoindolium cation and a tetrafluoroborate anion, was
0
5
H2O
O2
65[c]
[a]
Unless otherwise mentioned, all reactions were carried
out using 2-phenylpyridine 1a (0.4 mmol), ethyl acrylate
2a (1.0 mmol), [Cp*Rh(MeCN)3][BF4]2 (4.0 mol%),
NaBF4 (0.45 mmol), oxidant·(0.8 mmol) or O2 (1 atm, ca
1.5 L) and solvent (2.5 mL) at 1108C for 16 h.
Yields were measured by H NMR, using mesitylene as
an internal standard.
In the absence of NaBF4.
1
confirmed by its H, 13C, 19F, and 11B NMR spectra
[b]
[c]
1
and MS data. The other solvents including t-butyl al-
cohol, toluene, DMF, and methanol were also tested
to give product 3aa but in lower 72–22% yields (en-
tries 2–5). Unexpectedly, water was found to be the
most effective solvent for the reaction affording 3aa studies for the reaction of 1a with 2a are presented in
in 92% yield (Table 1, entry 6). In this pyridoisoindo- the Supporting Information. Notably, we did not ob-
lium salt formation reaction, an oxidant is required. serve any ortho divinylated products (4aa) under
To find a suitable oxidant for the reaction, we investi- these reaction conditions.
gated the oxidation activities of O2, air, Cu(OAc)2,
To evaluate the scope of the present reaction, we
CuO, CuCl2, BQ and K2S2O8 (entries 7–12). Again, to examined the reactions of various acrylates (2a–2d)
our surprise, O2 gave the highest product yield, while with 1a under the optimized reaction conditions
Cu(OAc)2 and CuO are also active affording 3aa in (entry 6, Table 1). Thus, 1a reacted with methyl acry-
66 and 82% yields, respectively. In contrast, CuCl2, late 2b, cyclohexyl acrylate 2c and benzyl acrylate 2d
BQ and K2S2O8 gave only a trace or no 3aa (en- to afford the corresponding isoindolium salts 3ab–3ad
tries 10–12). Notably, when the reaction was carried in 85, 82 and 90% yields, respectively (Table 2). The
out without a solvent, product 3aa was formed in 5% structure of 3ab was further confirmed by the results
yield (entry 13). In the absence of NaBF4, the reaction of a single-crystal X-ray diffraction study.[13] Next, we
1
also gave salt 3aa in 65% yield based on the H NMR tested the effect of substituents of the arylpyridines
measurement. In this case, the counter anion is ex- on the reaction with 2a. Substrates 1 bearing as sub-
pected to be OHÀ (entry 14). Under the reaction con- stituents 5-methyl (1b), 5-methoxy (1c) and 3-me-
ditions, we believe that water acts both as the proton thoxy (1d) on the pyridine ring reacted with 2a effec-
and hydroxide sources. More detailed optimization tively under the standard conditions to provide salts
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Table 2. Results of Rh-catalyzed reaction of arylpyridines and alkenes.[a,b]
[a]
Unless otherwise mentioned, all reactions were carried out using arylpyridines 1 (0.4 mmol), alkenes 2 (1.0 mmol),
[RhCp*(CH3CN)3](BF4)2 (4.0 mol%), NaBF4 (0.45 mmol), O2 (1 atm, ca 1.5 L) and water (2.5 mL) at 1108C for 16 h.
Isolated yields.
[b]
(3ba–3da) in 74–80% yields. (3-Methylphenyl)-5- 2a efficiently to afford 3la and 3ma in 82 and 85%
methylpyridine 1e also reacted smoothly with 2a to yields, respectively. The C–H bond activation and an-
give product 3ea in 86% yield. Similarly, substrates nulation reaction occurred only at the 3-position of
1 with various substituents on the phenyl ring (1f–j) the naphthyl and m-tolyl groups. In contrast, the reac-
also reacted smoothly with 2a to afford the corre- tion of 2-(benzo[d][1,3]dioxol-5-yl)pyridine (1n) with
sponding products (3fa–3ja) in 76–90% yields. The re- 2a proceeded at the C-2 position to afford the re-
sults show that products 3 were formed in good to ex- gioisomers 3na and 3na’ in a 90:10 ratio in 78% com-
cellent yields with either electron-rich or electron- bined yield.[4m,11f] The regioselectivity of this product
poor substituents on the phenyl ring of 1. The reac- is opposite to that of most of the m-substituted phe-
tion of 2-(2,5-dimethoxyphenyl)pyridine 1k with 2a nylpyridines. In addition to acrylate, ethyl vinyl
also proceeded nicely affording the expected product ketone (2e), and phenyl vinyl ketone (2f) also under-
3ka in 70% yield. To understand the regioselectivity went reaction with 1a to afford the corresponding iso-
of this reaction, m,p-disubstituted and m-substituted indolium salts 3ae and 3af in 78–82% yields.
phenylpyridines were investigated. Thus, 2-napthyl-2-
To understand the present catalytic reaction mecha-
pyridine 1l and 2-(m-tolyl)pyridine 1m reacted with nism, several experiments were performed as shown
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in Scheme 2. To see whether ortho H/D exchange of
1a occurs, we heated the substrate in D2O at 1108C in
1
the absence of 2a [Scheme 2, Eq. (4)]. The H NMR
spectrum of 1a after reaction revealed 86% deutera-
tion at both ortho positions of the phenyl ring of 1a,
indicative of reversible C–H activation in the absence
of acrylate. In contrast, when the reaction of 1a with
2a was performed in D2O, no deuterium was incorpo-
rated into the benzene ring [Eq. (5)]. The results sug-
gest that alkene insertion is much faster than the re-
verse step of C–H activation. Additionally, H/D ex-
change was observed at both a-methylene positions
of product 3aa [Eq. (5)]. We carried out a competition
experiment between equimolar amounts of deuterio-
1a-d5 and 1a with 2a for 3 h. The experiment gave an
intermolecular kinetic isotope effect (kH/kD) of 2.0
1
measured by H NMR integration [Eq. (6)]. Similarly,
the intramolecular H/D competition gave an intramo-
lecular kinetic isotope effect (kH/kD) of 2.6 [Eq. (6)].
This result suggests that the C–H bond cleavage is
likely involved in the rate-limiting step.[14] The catalyt-
ic reaction of 1a with 2a in the absence of NaBF4 still
proceeded to give salt 3aa in 60% yield (see Table 1,
entry 14).
In contrast, the reaction of 2-(furan-2-yl)-5-methyl-
pyridine with 2a provided only the alkenylated prod-
uct 4n, the expected salt 3na was not formed probably
owing to the ring strain of this compound which
would contain two fused 5-membered rings [Eq. (7)].
We then focused on the reaction of electron richer
olefins like styrene 2h with 1a under similar reaction
conditions; the reaction gave divinylated product 4ah
in 85% isolated yield [Eq. (8)].[4b] Further treatment
of 4ah with 2h under acidic conditions to afford the
corresponding salt 3ah albeit in only 10% yield [Eq.
(9)]. This observation indicates that ortho-olefinated
2-phenylpyridine is an intermediate for the final salts.
Then, we studied the reversibility of the present isoin-
dolium salts under basic and acid conditions. Treat-
ment of 3aa with DBU in CH2Cl2 led to the C–N
cleavage to afford a mixture of b-substituted alkene 7
in 90% yield [Eq. (10)].[9] However, under acidic con-
ditions, 7 cyclized and reversed back to 3aa (see the
Supporting Information). In addition, a competitive
reaction was performed using an equimolar amount
of ethyl acrylate 2a, methyl acrylate 2b, and 2-phenyl
pyridine 1a under the standard reaction conditions
(see the Supporting Information). The reaction gave
a mixture of isoindolium salt products as expected
from the mechanism proposed in Scheme 3.
Based on the earlier transition metal-catalyzed di-
recting group-assisted C–H bond olefination/annula-
tion reactions,[1–7,9–11] a reasonable mechanism for the
present reaction is proposed and illustrated in
(Scheme 3). The catalytic cycle is likely initiated by
the coordination of pyridine to rhodium species fol-
lowed by an ortho C–H olefination to form a five-
Scheme 2. Mechanistic studies.
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Scheme 3. A proposed catalytic cycle.
membered rhodacycle I and the release of H+. Coor- indolium cation are unusually connected to each
dinative insertion of alkene 2a to the Rh–C bond of other via a tail to tail manner. The facile formation of
intermediate II gives the seven-membered rhodacycle nitrogen ylide (6a) during the catalytic reaction likely
III which undergoes b-hydride elimination to afford accounts for the formation the carbon-carbon bond in
the ortho-alkenylated intermediate 4a and a Rh–H the present isoindolium salt. A mechanistic study
species IV, which is readily oxidized by molecular strongly shows that the isoindolium salts are in equi-
oxygen to regenerate the active Rh(III) species for librium with b-substituted alkene 7 under acid or base
the next cycle. Intermediate 4a undergoes reversible conditions. The present method is suitable for the syn-
intramolecular Michael addition to the olefin group thesis of a library of functionalized azafluorenes.
providing an azafluorene salt 5a in which the hydro-
gen attached to the center carbon C-9 is acidic and
can be easily deprotonated to form a nitrogen ylide
(6a).[8d] Then, Michael addition to ethyl acrylate
occurs to afford the final product 3aa. It is noteworthy
that the steps from 4a to the final product in
Experimental Section
Scheme 3 seem not to require further Rh-assisted C–
General Procedure for the Synthesis of Isoindolium
H activation (see the observation shown in Eq. (9),
Salts 3
Scheme 2 and a very recent related report.[15] Howev-
er, we cannot completely rule out that the second ole-
fination may also be catalyzed by the rhodium com-
plex similar to the mechanism proposed by Li and his
co-workers,[10] because we were unable to isolate any
mono-olefinated 2-arylpyridine, such as 4a, to test the
current catalytic mechanism.
In summary, we have successfully developed a new,
mild but efficient Rh(III)/O2/H2O system for the one-
pot synthesis of isoindolium salts from substituted 2-
phenylpyridines and electron-withdrawing alkenes in
A
sealed tube (20 mL) containing 2-phenylpyrine
1 (0.40 mmol), acrylate 2 (1.00 mmol), [Cp*Rh(MeCN)3]
[BF4]2 (4.0 mol%), and NaBF4 (0.45 mmol) was evacuated
and filled with oxygen (O2, 1 atm, ca 1.5 L).[16] Then H2O
(2.5 mL) was added to the system via syringe and the reac-
tion mixture was allowed to stir at 1108C for 16 h. Then, the
mixture was cooled to room temperature and diluted with
CH2Cl2 (10 mL), filtered through an MgSO4/Celite pad and
the pad was further washed with dichloromethane. The com-
bined filtrate was concentrated under vacuum and the resi-
due was purified on a silica gel column using DCM/MeOH
aqueous medium. The two alkene moieties in the iso- (95:5) as eluent to afford the desired pure product 3.
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Acknowledgements
We thank the Ministry of Science and Technology of the Re-
public of China (MOST 104-2633-M-007-001) for support of
this research.
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bottom flask (25 mL) instead of a sealed tube at lower
temperature (1008C) and at ambient pressure under
standard reaction conditions, isoindolium salt 3aa was
obtained in 88% yield with a reaction time of 24 h.
Adv. Synth. Catal. 0000, 000, 0 – 0
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Rhodium-Catalyzed Regioselective Synthesis of Isoindolium
Salts from 2-Arylpyridines and Alkenes in Aqueous
Medium under Oxygen
7
Adv. Synth. Catal. 2016, 358, 1 – 7
Nitinkumar Satyadev Upadhyay, Jayachandran Jayakumar,
Chien-Hong Cheng*
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!