Metal-free meerwein carboarylation of alkenes with anilines: A straightforward approach to 3-benzyl-3-alkyloxindoles

Article abstract of DOI:10.1002/ejoc.201402010

A metal-free, straightforward carboarylation reaction of alkenes with anilines was developed that proceeds through a radical C-H cyclization. In the presence of benzoyl peroxide (5 mol-%), tert-butyl nitrite, and an array of anilines, a wide variety of N-arylacrylamides underwent a tandem Meerwein arylation/C-H cyclization to construct the pharmaceutically important 3-benzyl-3-alkyloxindole scaffold in moderate to good yields. Copyright

Full text of DOI:10.1002/ejoc.201402010

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DOI: 10.1002/ejoc.201402010
Metal-Free Meerwein Carboarylation of Alkenes with Anilines:
A Straightforward Approach to 3-Benzyl-3-alkyloxindoles
Shi Tang,*[a] Dong Zhou,[a] and Ying-Chun Wang*[a,b]
Keywords: Nitrogen heterocycles / Domino reactions / Radical reactions / Cyclization / Amines
A metal-free, straightforward carboarylation reaction of alk-
enes with anilines was developed that proceeds through a
radical C–H cyclization. In the presence of benzoyl peroxide
(5 mol-%), tert-butyl nitrite, and an array of anilines, a wide
variety of N-arylacrylamides underwent a tandem Meerwein
arylation/C–H cyclization to construct the pharmaceutically
important 3-benzyl-3-alkyloxindole scaffold in moderate to
good yields.
rial anilines, transformations that employ aryl diazonium
salts that are prepared by the in situ diazotization of anil-
ines with alkyl nitrite are undoubtedly of practical inter-
est.[7,12,8c] Herein, we demonstrate the straightforward and
metal-free carboarylation of alkenes with anilines through
a tandem Meerwein arylation/C–H cyclization process to
construct 3,3-disubstituted oxindoles.
Introduction
The mild and straightforward construction of multiple
C–X (X = carbon, heteroatom) bonds in a cascade process
is a perennial topic of interest for organic chemists.[1] In this
regard, the Meerwein arylation of alkenes with aryl diazo-
nium salts has gained increasing attention in recent years.[2]
In these transformations, alkyl radicals that are derived
from the oxidative addition of aryl radicals to alkenes can
trap various nucleophilic ions or groups to furnish C–X (X
= N,[3] O,[4] S,[5] CN,[6] CF3,[7] halogen,[8] etc.) and C–C
bonds in a single step. On the other hand, there has been
significant progress, and thus increasing importance, with
regard to direct C–C bond formation through the coupling
of an aryl radical, which is generated from an aryl diazo-
nium salt, with an aromatic Csp2–H bond.[9] Therefore, we
envisage that a double C–C bond formation through the
intermolecular coupling of an alkyl radical, which is gener-
ated by the addition of aryl radical to alkene, and an aro-
matic Csp2–H bond is possible by employing the Meerwein Figure 1. Meerwein arylation of alkenes.
arylation of alkenes (see Figure 1). However, such a proto-
col has to our best knowledge rarely been successful, with
the exception of a recently reported reaction that employs
The 3,3-disubstituted oxindole is a common structural
a Ru catalyst under light irradiation.[10] The current pro- motif of pharmaceutical agents and natural products (see
gress and merit of metal-free coupling reactions prompted Figure 2), and there has been an increasing interest in their
us to seek a metal-free method for the tandem Meerwein synthesis.[13] Remarkably, significant progress has currently
arylation/radical Csp2–H cyclization process.[11] In addition, been achieved in the construction of these scaffolds through
given the simplicity of the preparation and handling of ma- the radical difunctionalization of N-arylacrylamides.[14] The
terials as well as the ease of availability of the starting mate- reaction conditions, however, are typically not ideal (e.g.,
transition-metal catalyst, elevated temperatures, excess
[a] College of Chemistry and Chemical Engineering, Jishou
amount of oxidant). Moreover, it is worth mentioning that
University,
these previously reported approaches to the targeted 3-
benzyl-3-aryloxindole scaffold (e.g., anticancer reagent I,
see Figure 2) usually involved the transition-metal-cata-
lyzed Heck reaction of halogenated N-arylamides with or-
ganometallic reagents.[15] Therefore, the development of a
metal-free and straightforward carboarylation of N-arylac-
rylamides with anilines to furnish 3-benzyl-3-alkyloxindoles
Jishou 416000, China
E-mail: stang@jsu.edu.cn
http://chem.jsu.edu.cn/
[b] Key Laboratory for the Chemistry and Molecular Engineering
of Medicinal Resources (Ministry of Education of China),
Guangxi Normal University,
Guilin 541004, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402010.
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S. Tang, D. Zhou, Y.-C. Wang
FULL PAPER
under mild conditions is still of great interest and would Table 1. Screening of reaction conditions.[a]
provide an alternative pathway to construct the family of
3,3-disubstituted oxindoles.
Entry Initiator [mol-%]
1a/2a/tBuONO Solvent % Yield[b]
1
2
3
4
5
6
7
8
none
CuCl (5)
CuBr (5)
CuI (5)
FeSO4·7H2O (5)
Fe(NH4)2(SO4)2·6H2O (5)
Mn(OAc)2·4H2O (5)
CoCl3·6H2O (5)
BPO (5)
1:3:3
1:3:3
1:3.3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:2:2
1:4:4
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE[c]
26
56
62
75
68
71
36
37
81
61
36
37
26
79
65
80
53
56
38
41
Ͻ10
9
10
11
12
13
14
15
16
17
18
19
20[d]
21[e]
AIBN (5)
TBHP (5)
DTBP (5)
PhI(OAc)2 (5)
BPO (10)
BPO (5)
BPO (5)
BPO (5)
BPO (5)
BPO (5)
BPO (5)
Figure 2. Several bioactive compounds that contain the 3,3-disub-
stituted oxindole skeleton.
EtOAc
toluene
CH3CN
CH3CN
Results and Discussion
BPO (5)
[a] Reagents and conditions: 1a (0.3 mmol), 2a (2–4 equiv.),
tBuONO (2–4 equiv.), initiator (5–10 mol-%), and solvent (2 mL)
at 50 °C for 4 h. [b] Yield of the isolated product. [c] DCE = 1,2-
dichloroethane. [d] Reaction temperature was 30 °C. [e] iAmONO
was used instead of tBuONO.
In the course of our research that targeted the carboaryl-
ation of alkenes with anilines to construct 3,3-disubstituted
oxindoles, the reaction between N-methyl-N-phenylacryl-
amide 1a and 4-nitroaniline (2a) was employed as the model
to explore the optimal conditions (see Table 1). In the initial
experiment, the reaction was conducted without a catalyst,
With the optimal reaction conditions in hand, we set out
and we were delighted to observe the formation of the de- to investigate the scope of N-arylacrylamides 1 in the
sired cyclization product 3a in a 26% yield (see Table 1, carboarylation reaction with 4-nitroaniline (2a) as aryl dia-
Entry 1). Encouraged by this result, a number of metallic zonium source (see Scheme 1). An initial screening revealed
salts (e.g., Cu, Fe, Mn, Co) were subsequently used as an that the N-substituents of the acrylamides have an obvious
initiator to enhance the yield of the reaction (see Table 1, effect on the reaction. For example, N-arylacrylamides with
Entries 2–8).[2b] Among the metals examined, copper iodide a N-methyl or -ethyl substituent were compatible with the
was the most effective, and 3a was afforded in a yield of reaction conditions, whereas unsubstituted N-arylacrylam-
75%. Happily, further investigations revealed that the yield ide 3c (R2 = H) was less efficient in the cyclization reaction.
dramatically improved to 81% with the employment of ben- Next, we investigated the effect of a substitutent on the N-
zoyl peroxide (BPO), a efficient radical initiator for aryl dia- aryl moiety. Gratifyingly, a wide array of substituents such
zonium salts,[12a] instead of copper iodide. Other initiators/ as Me, MeO, Cl, Br, CN, and F at the 2-, 3-, or 4-position
oxidants, such as 2,2Ј-azobisisobutyronitrile (AIBN), tert- of the aromatic ring displayed good reactivity.[16] We deter-
butylhydroperoxide (TBHP, 70% aqueous solution), di-tert- mined that poor electron-withdrawing and electron-donat-
butyl peroxide, (DTBP), and PhI(OAc)2 gave lower yields ing groups were more reactive than strong electron-with-
(see Table 1, Entries 10–13). An increase in the loading of drawing groups, which is compatible with previously re-
BPO hindered the reaction to some extent (see Table 1, En- ported reactions that occur through the radical C–H cycli-
try 14). Next, we screened for the molar ratio of the sub- zation of N-arylacrylamides.[14d] Interesting, the Cl, Br, and
strates and observed that 3 equiv. of aniline 2a and F group remained intact in the C–H functionalization
tBuONO gave the best yield (see Table 1, Entry 9 vs. 15 and process, which thereby facilitated additional modifications
16). The sequential screening of solvents revealed CH3CN at the halogenated positions. The reaction of the N-aryl-
as the best choice. With regard to the effect of temperature, acrylamide with a meta-substituted methyl group afforded
a lower reaction temperature decreased the reaction yield a mixture of two regioisomeric products 3j and 3jЈ. How-
to some extent (see Table 1, Entry 20). Using isoamyl nitrite ever, only a low yield or a trace amount of the product was
(i-AmONO) instead of tBuONO resulted in an inferior obtained by using the ortho-substituted N-arylacrylamide.
yield (see Table 1, Entry 21).
These results might be attributed to the steric hindrance of
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Metal-Free Meerwein Carboarylation of Alkenes with Anilines
Scheme 1. The scope of the N-arylacrylamines. Reagents and conditions: 1 (0.3 mmol), 2a (0.9 mmol), tBuONO (0.9 mmol), initiator
(5 mol-%), and CH3CN (2 mL) at 50 °C for 5 h, yields are for the isolated product after column chromatography. [a] Reaction performed
on a 3 mmol scale.
the ortho substituent. As expected, the pyridyl ring was well that had different substituents such as Cl, F, Br, OEt, or
tolerated under the optimal conditions, and the desired OMe on the aromatic ring. In comparison to nitroaniline
oxindoles 3m were provided in a yield of 58%. Sequential 2a, the above-mentioned anilines had a reduced reactivity
investigations revealed that several groups such as Ph, in the reaction, and an increased amount of the aniline
CH2OH, and CH2OAc at the 2-position of the acrylamide (4 equiv.) and tBuONO (4 equiv.) was useful to achieve
moiety were compatible with the optimal conditions to af- good reaction efficiency. Interestingly, 4-fluoroaniline af-
ford 3n, 3o, and 3p, respectively, whereas a monosubstituted forded a higher yield when the reaction was conducted in
olefin moiety (R3 = H) was inert under the carboarylation the absence of the initiator BPO. Furthermore, we were
process.
happy to find that 3-aminopyridine was a suitable aryl dia-
We next set out to explore the scope of anilines in the zonium source, and it underwent the C–H cyclization
presence of N-methyl-N-phenylacrylamide 1, aniline 2, smoothly to introduce a pyridyl moiety into the desired ox-
BPO, and tBuONO (see Scheme 2). The carboarylation indole. To further investigate the generality of this C–H cy-
process turned out to be compatible with various anilines clization protocol, we then examined the reactivity of vari-
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S. Tang, D. Zhou, Y.-C. Wang
FULL PAPER
ous N-arylacrylamides in the reaction with sterically hin-
dered o-anisidine (2f) as the diazonium source. In this case,
a Cl and OMe group on the aromatic ring of N-aryl moiety
as well as a CH2OH group at the 2-position of the acrylam-
ide moiety were well-tolerated in the transformation.
Scheme 3. Control experiments.
radical intermediate C by aryl diazonium salt A affords the
desired 3-benzyl-3-alkyloxindole.
Scheme 4. Proposed mechanism.
Scheme 2. The scope of the anilines. Reagents and conditions: 1
(0.3 mmol), 2 (1.2 mmol), tBuONO (1.2 mmol), BPO (5 mol-%),
and CH3CN (2 mL) at 50 °C for 5 h, yields are for isolated product
after column chromatography. [a] Reaction performed in the ab-
sence of the initiator BPO.
Conclusions
In summary, we have demonstrated a metal-free and
straightforward carboarylation reaction of alkenes and anil-
ines that occurs through a radical C–H cyclization to con-
struct the 3,3-disubstituted oxindole scaffold. This protocol
proceeds through a radical process and avoids the use of a
transition-metal catalyst, an excess amount of oxidant, and
elevated temperatures. Of importance, it provides an alter-
native pathway for a single-step synthesis of the pharma-
ceutically interesting 3-benzyl-3-alkyloxindole. An investi-
gation of a detailed mechanism and application of this reac-
tion to more complex targets are currently underway in our
laboratory.
To elucidate the mechanism of this tandem Meerwein
2
arylation/Csp –H cyclization process, inter- and intramolec-
ular kinetic isotope control experiments were performed as
shown in Scheme 3. No kinetic isotope effect (kH/D = 1.0)
was observed, which suggests that the C–H functionaliza-
tion cyclization step might be compatible with either the
SEAr mechanism or a free radical mechanism.[17] Notably,
the free radical mechanism was supported by a control ex-
periment. A stoichiometric amount of 2,2,6,6-tetrameth-
ylpiperidine-1-oxyl radical (TEMPO, 4 equiv.), a well-
known radical inhibitor, was used in the reaction of N-
methyl-N-phenylmethacrylamide (1a) with 4-nitroaniline
(2a) and BPO, and the formation of the desired disubsti-
tuted oxindole was suppressed.
Experimental Section
On the basis of the above experimental results and General Methods: All reactions were carried out in flame-dried
glassware under argon. Syringes that were employed to transfer
anhydrous solvents or reagents were purged with argon prior to
use. The NMR spectroscopic data were recorded with the samples
dissolved in deuterated chloroform (CDCl3), and residual CHCl3
(δ = 7.26 ppm for 1H NMR) and CDCl3 (δ = 77.0 ppm for 13C
NMR) were used as the internal standards. Abbreviations for the
multiplicity of the signals are reported as s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), and br. (broad). Purifications
by column chromatography were performed with SiO2 (0.040–
0.063 mm, 230–400 mesh ASTM) and a mixture of n-hexane/ethyl
previous reports, a possible mechanism was proposed for
the carboarylation process of N-arylacrylamides (see
Scheme 4).[2–8,10,11,13] First, the in situ diazotization of the
arylamines with tBuONO generates aryl diazonium salt A.
This resulting diazonium alkoxide easily decomposes to
give an aryl radical,[18] which undergoes an addition to the
carbon-carbon double bond of N-methyl-N-phenylacrylam-
ide (1a) to yield alkyl radical B. The intramolecular cycliza-
tion of intermediate B with an aryl ring forms radical inter-
mediate C, and then the abstraction of an aryl hydrogen of acetate as the eluent. Unless otherwise noted, the commercially
4
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Metal-Free Meerwein Carboarylation of Alkenes with Anilines
b) T. Xiao, X. Dong, Y. Tang, L. Zhou, Adv. Synth. Catal.
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General Procedure for the Synthesis of 3,3-Disubstituted Oxindoles:
To a mixture of N-arylacrylamide 1 (0.3 mmol), aniline 2 (3–
4 equiv.), and BPO (5 mol-%) in CH3CN (2 mL) was added
tBuONO (3–4 equiv.) dropwise at 50 °C, and the resulting mixture
was then stirred at the indicated temperature for 5 h. The solvent
was evaporated under reduced pressure, and the resulting mixture
was filtered through a pad of Florisil. The filtrate was diluted with
Et2O, and the resulting solution was washed with water and then
brine. The organic layer was dried with anhydrous MgSO4 and con-
centrated in vacuo. The residue was purified by flash chromatog-
raphy on a silica gel column to afford the desired 3,3-disubstituted
oxindole.
[10]
[11]
Supporting Information (see footnote on the first page of this arti-
1
cle): Experimental details, copies of the H and 13C NMR spectra,
and HRMS of all key intermediates and final products as well as
X-ray crystal data for compound 3e.
Acknowledgments
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Job/Unit: O42010
/KAP1
Date: 24-04-14 17:30:02
Pages: 7
S. Tang, D. Zhou, Y.-C. Wang
FULL PAPER
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Received: February 4, 2014
Published Online: ᭿
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Job/Unit: O42010
/KAP1
Date: 24-04-14 17:30:02
Pages: 7
Metal-Free Meerwein Carboarylation of Alkenes with Anilines
Metal-Free Carboarylation
S. Tang,* D. Zhou, Y.-C. Wang* ...... 1–7
Metal-Free Meerwein Carboarylation of
Alkenes with Anilines: A Straightforward
Approach to 3-Benzyl-3-alkyloxindoles
A metal-free, straightforward carboaryl-
ation reaction of alkenes with anilines was
developed. In the presence of benzoyl per-
oxide, tert-butyl nitrite, and an array of
anilines, a wide variety of N-arylacryl-
amides underwent a tandem Meerwein
arylation/C–H cyclization to construct the
pharmaceutically important 3-benzyl-3-
alkyloxindole scaffold in moderate to good
yields.
Keywords: Nitrogen heterocycles / Domino
reactions / Radical reactions / Cyclization /
Amines
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