Rh(III)-catalyzed C-H activation reactions forming 1: H -isoindoles containing a quaternary carbon center from aryl ketones or benzylamines

Article abstract of DOI:10.1039/c6cc05074c

Rh(iii)/Cu(OAc)₂ catalyzed, one-pot reactions of aryl ketones, acrylate esters and ammonium acetate or α-substituted benzylamines under microwave irradiation conditions produce 1H-isoindoles bearing a quarternary carbon center.

Full text of DOI:10.1039/c6cc05074c

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Rh(III)-catalyzed C-H activation reaction forming 1H-isoindoles
containing a quaternary carbon center from aryl ketones or
benzylamines
Received 00th January 20xx,
Accepted 00th January 20xx
Yeonhui Yi, Hyejeong Lee and Chul-Ho Jun*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Rh(III)/Cu(OAc)2 catalyzed, one-pot reactions of aryl ketones,
acrylate esters and ammonium acetate or -substituted
1) Our Previous Work
R3
α
R3
R4
O
+
R2
benzylamines under microwave irradiation conditions produce 1H-
N
R4
(eq 1)
[Cp*RhCl2]2
Cu(OAc)2.H2O
M.W.
R2
isoindoles bearing a quarternary carbon center.
NH4OAc
+
R1
R1
Several transition metal-catalyzed reactions that produce
isoquinolines and pyridines have been developed recently.1 In
comparison to conventional methods, these processes have
advantageous features associated with convenience and atom
economy. In a recent effort, we uncovered a novel one-pot
multi-component process promoted by a Rh(III) catalyst that
generates substituted isoquinolines (eq. 1).2 An advantage of
this protocol is that it does not require pre-preparation of
imine functionalized substrates.
2) This Work
CO2R3
CO2R3
NH4OAc
NH2
R2
2
O
CO2R3
R3O2C
2
N
R2
R2
(eq 2)
[Cp*RhCl2]2
[Cp*RhCl2]2
Cu(OAc)2 H2O
.
.
R1
R1
Cu(OAc)2 H2O
R1
M.W.
M.W.
TABLE 1. Optimization of the Rh(III) Catalyzed 1H-Isoindole Synthesis Methoda
CO2Et
Isoindoles are members of the broad N-heterocycle family that
hold special interest and importance because they serve as
precursors of alkaloids,3 antitumor agents4 and laser dyes.5 In
this group, 1H-isoindoles are particularly difficult to prepare
because of their intrinsic ability to isomerize to form aromatic
isoindoles.6 Recently Li and co-workers reported a method for
synthesis of 1H-isoindole starting with specially designed N-
sulfinyl ketoimines and alkene.7 In the study described below,
we developed a new Rh(III)-catalyzed, C-H bond activation
reaction between aryl ketone, acrylate ester, and NH4OAc or
Rh Metal (5 mol% [Rh])
Oxidant (1 equiv)
O
CO2Et
N
EtO2C
+
2
+
NH4OAc
1,2-DCE
M.W., 130 oC, 10 min
1a
2a
3
6a
Entry
Metal
[Cp*RhCl2]2 ( )
Oxidant
Temp (oC) Yield (%)b
.
5
Cu(OAc)2 H2O ( )
4
1
2
3
4
5
6
7
130
130
130
130
130
110
150
95
73
0
Cp*Rh(MeCN)3(SbF6)2
5
(Ph3P)3RhCl
5
Pd(OAc)2
AgOAc
5
4
4
4
32
0
α
-substituted benzylamine that produces 1H-isoindole (eq. 2).
62
70
The presence of quaternary carbon centers in the 1H-isoindole
produced in this manner prevents the prototropic shift process
that leads to aromatization. In this reaction, microwave
irradiation was utilized for the facile N-annulation reaction
compared with conventional heating.8
4
4
5
5
8c
130
37
aReaction conditions: 1a (0.2 mmol), 2a (2 equiv), 3 (2 equiv), Rh metal (5 mol%),
Oxidant (1 equiv), 1,2-dichloroethane (200 mg), M.W. (microwave) at 130 oC for
10 min. bGC yields. c onventional heating at 130 oC for 24 h.
C
In an initial phase of the study aimed at exploring conditions
required to promote the 1H-isoindole forming Rh(III)-catalyzed
reaction, acetophenone (1a) was chosen as a model aryl
ketone substrate (Table 1). Reaction of 1a with ethyl acrylate
(
2a) and NH4OAc
3 was carried out in the presence of
.
[Cp*RhCl2]2 ( , 5 mol%) and Cu(OAc)2 H2O (5
4
, 1 equiv) at 130 oC
for 10 min under microwave irradiation conditions. This
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process formed 1H-isoindole 6a in a 95% GC yield (entry 1). lead to a decrease in the product yield (entry 6). Even in high
While employing [Cp*Rh(MeCN)3(SbF6)2] as the catalyst did not temperature of 150 oC, only 70% yield of 6a was obtained
o
improve the yield of this reaction (entry 2), using Rh(I) (entry 7). Finally, when the reaction was carried out at 130 C
complexes like [(Ph3P)3RhCl] did not promote the reaction for 24 h using conventional heating, 6a was generated in only a
(entry 3). Likewise, the use of other oxidants such as Pd(OAc)2 37% GC yield, implying that the microwave irradiation is
and AgOAc instead of 5 did not improve the yield of 6a (entries required to promote a highly efficient reaction (entry 8).
4 and 5). Decrease in reaction temperature from 130 to 110 oC
Table 2. Rh(III)-catalyzed synthesis of 1H-isoindoles from aryl ketonesa
aReaction conditions: 1 (0.2 mmol), 2a (2 equiv), 3 (2 equiv), 4 (5 mol%), 5 (1 equiv), 1,2-dichloroethane (200 mg), M.W. (microwave) at 130 oC for 10 min. bHex = hexyl.
cCy = cyclohexyl.
The acrylate ester scope of the 1H-isoindole forming process An investigation was carried out to gain information about the
was explored. The results (Table 2) show that under the regioselectivities of N-annulation reactions of m-substituted
optimized conditions reactions of acetophenone (1a) with aryl ketones. The results show that reaction of 3-
ethyl (2a), methyl (2b) and n-butyl acrylate (2c) produce the methoxyacetophenone (1k) with 2a produces a mixture of 6m
respective 1H-isoindoles 6a-6c in good yields (entries 1-3).
and 6n in respective 45% and 31% yields (entry 13). In an
The scope of the process was further probed in studies of the analogous manner, 1l bearing meta-hydroxyl group reacts to
reactions of ethyl acrylate 2a with acetophenone analogs form a mixture of 6o and 6p in respective 48% and 25% yields
possessing
a
phenyl
(benzophenone,
1b),
alkyl (entry 14). In contrast reaction of m-acetamidoacetophenone
1m) formed a mixture of the respective 1H-isoindole 6q and
(heptanophenone, 1c
)
and cyclohexyl (cyclohexyl phenyl
(
ketone, 1d) groups. These processes generate the respective 6r in 3% and 67% yields, suggesting that the acetamido group
1H-isoindoles in moderate to high yields (entries 4-6). In has a pronounced steric effect on the regiochemistry of the
addition, reaction of the cyclic arylketone
α
-tetralone (1e
)
process (entry 15). A similar strong directing effect is at work
formed 1H-isoindole 6g in 81% yield (entry 7). In addition, the in governing the high degree of regioselctivity that attends
electron-withdrawing group-substituted acetophenones 1f-h reaction of the m-methylacetophenone (1n), which produced
react with 2a to produce 1H-isoindole 6h-j in 64%, 88% and 1H-isoindole 6s exclusively (56%, entry 16).
91% yield, respectively (entries 8-10). The reactions of the
electron-donating methoxy group-substituted analog 1i and 1j
produced 6k (85%) and 6l (95%) (entries 11 and 12).
2 | J. Name., 2012, 00, 1-3
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Furthermore, we found that N-annulation reaction of aryl-
acrylate 8a with acrylic ester to form 1H-isoindole 6a did not
require transition metal catalyst (eq. 4). Specifically, reactions
of esters 8a and 8c, prepared by using known methods,11 with
acrylate ester 2a and 2b and ammonium acetate (
3
) took place
in the absence of transition metal catalysts 4 and
5 to form the
corresponding 1H-isoindoles 6a, 6t and 6u in 68-78% isolated
yields.
Table 3. Rh(III)-catalyzed synthesis of 1H-isoindoles from α
-substituted benzylaminesa
SCHEME 1. Proposed mechanism for the synthesis of 1H-isoindole.
A plausible mechanism for the 1H-isoindole 6a forming Rh(III)-
catalyzed reaction of aromatic ketones 1a and acrylate esters
2a is given in Scheme 1. The overall process takes place in two
stages involving ortho-vinylation of 1a and followed by N-
annulation. Condensation of acetophenone 1a with ammonia
acetate (3) occurs first to generate imine 7a, which reacts with
Cp*Rh(OAc)2 to give the five-membered rhodacycle complex
7b.9 Carbometallation of ethyl acrylate 2a with 7b then occurs
to form the seven-membered rhodacycle 7c, which undergoes
β
-hydride elimination to give the imino-Rh complex 7d.
Reductive elimination of 7d produces imine 7e and a Rh(I)
species, which is oxidized by Cu(OAc)2 to regenerate the active
Cp*Rh(OAc)2 catalyst. Ortho-vinylated ketone 8a then forms by
hydrolysis of 7e with H2O generated in the initial condensation
aReaction conditions: 1 (0.2 mmol), 2a (3.2 equiv), 4 (5 mol%), 5 (2 equiv), 1,2-
dichloroethane (200 mg), M.W. (microwave) at 120 oC for 10 min. bHex = hexyl.
step. Next, 1,2-addition of NH3 to ketone 8a occurs to form
hydroxyl amine 7f
addition and dehydration to generate 7h
α-
,
which undergoes intramolecular 1,4- cCy = cyclohexyl.
Finally,
.
The proposal that the mechanism for this process proceeds via
intramolecular 1,4-addition of the benzylamine moiety in 7f to
the ortho-acrylic ester group stimulated thoughts about
another approach for 1H-isoindole synthesis. Specifically, we
envisaged that benzylamines might participate in Rh(III)-
catalyzed reactions with acrylates to produce 1H-isoindoles. In
deprotonation of modestly acidic 7h gives anion 7i, which
participates in conjugate addition10 to the acrylate 2a to
produce 1H-isoindole 6a
.
a test of this proposal, we observed that reaction of
methylbenzylamine (9a) with acrylate 2a (3.2 equiv based on
9a) in the presence of (5 mol%) and
(2 equiv) at 120 oC for
α-
4
5
10 min under MW irradiation, lead to formation of 1H-
isoindole 6a in a 71% isolated yield (Table 3, entry 1).
Reactions of other benzylamines possessing benzylic aryl (9b
and 9e), alkyl (9c) and cyclohexyl (9d) substituents also
produced fairly good yields of the corresponding 1H-
To confirm the involvement of the aryl-acrylate intermediate
8a in this process, reaction of 1a with styrene (2d) was carried
out using identical conditions. The observation that this
process produces aryl-styrene 8b exclusively (eq 3) shows that
an ortho-vinylation step forming 8a is likely involved in the
mechanistic pathway for 1H-isoindole formation.
isoindoles, 6 (entries 2-5).
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5 formed 6d in
a 58% yield, along with a 49% GC yield12 of ethyl propionate,
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7
8
9
SCHEME 2. Proposed mechanism of synthesizing 1H-isoindole from
α-substituted
6
benzylamine.
Based on the above results, it is possible to propose that the
mechanism for formation of 1H-isoindole 6a from
α-
substituted benzylamines 9a and 2a is the one shown in
Scheme 2. In the route, amine-directed ortho-vinylation of
benzylamine with acrylic ester by Rh(III)/Cu(II) takes place to
10 (a) A. Sartori, C. Curti, L. Battistini, P. Burreddu, G. Rassu, G.
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form 7j
,
which participates in intramolecular conjugate
Dehydrogenation of 7k
addition to generate isoindoline 7k 13
.
Int. Ed., 2011, 50
, 1064-1067; (b) K. Padala and M.
promoted by 2a then produces 7h and ethyl propionate, the
former of which undergoes 1,4-addition to acrylate 2a to
Jeganmohan, Org. Lett., 2011, 13, 6144-6147.
12 GC yield of ethyl propionate was determined using
mesitylene as an internal standard.
produce 1H-isoindole 6a 14
.
13 C. Suzuki, K. Morimoto, K. Hirano, T. Satoh and M. Miura,
Adv. Synth. Catal., 2014, 356, 1521-1526.
14 When 9f [(R)-(+)-α-methylbenzylamine] is employed as a
In the study described above, we developed a novel, one-pot,
3-component, microwave assisted N-annulation reaction of
aryl ketones with acrylate esters in the presence of ammonium
acetate or benzylamine that produces 1H-isoindoles. The
process has wide ketone and acrylate substrate scopes and it
starting material in this reaction, 1H-isoindole 6a is obtained
in racemic form in a 70% isolated yield (Scheme 2). This
result supports the proposal that dehydrogenation of 7k
takes place to afford 1H-isoindole 6a through the
efficiently generates various 1H-isoindoles containing
a
intermediate 7h
.
quaternary carbon center.
This work was supported by a grant from the National
Research Foundation of Korea (NRF 2016R1A2B4009460).
Notes and references
1
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M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed.,
4 | J. Name., 2012, 00, 1-3
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