Oxidant-Free Rhodium(I)-Catalyzed Difunctionalization of Acrylamide: An Efficient Approach to Synthesize Oxindoles

Article abstract of DOI:10.1021/acs.orglett.5b00732

(Figure Presented) The first rhodium(I)-catalyzed difunctionalization of arylacrylamides to synthesize oxindoles is developed, and it does not require the assistance of an oxidant. This method provides an efficient approach to generate various useful functionalized oxindoles, some of which cannot be easily accessed by previous approaches.

Full text of DOI:10.1021/acs.orglett.5b00732

Letter
pubs.acs.org/OrgLett
Oxidant-Free Rhodium(I)-Catalyzed Difunctionalization of
Acrylamide: An Efficient Approach To Synthesize Oxindoles
Chen-Chen Li†,‡ and Shang-Dong Yang*,†,§
‡
†State Key Laboratory of Applied Organic Chemistry and Cuiying Hornors College, Lanzhou University, Lanzhou 730000, P. R.
China
§State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: The first rhodium(I)-catalyzed difunctionalization of arylacrylamides to synthesize oxindoles is developed, and it
does not require the assistance of an oxidant. This method provides an efficient approach to generate various useful
functionalized oxindoles, some of which cannot be easily accessed by previous approaches.
Scheme 1. Different Difunctionalization of Alkenes To
Synthesize Oxindoles
xindoles are an important class of heterocycles prevalent in
Onumerous biologically active compounds and natural
products, and they have also been widely used as important
intermediates in organic synthesis.1 Consequently, efficient
assembly of oxindoles from readily available precursors remains
a prominent objective of chemical research.2 Recently, research
has proven the direct difunctionalization3 of the N-phenyl-
acrylamide to be the most efficient approach to generate
oxindoles, given the abundance and accessibility of starting
materials. In general, this strategy mainly involves two different
mechanisms: one is a radical process that includes either metal4
or metal-free5 catalyzed cascade radical cyclizations, and different
kinds of functionalized oxindoles were achieved (Scheme 1a);
the second involves the transition metal-catalyzed oxidative-
elimination pathway through which only a few examples have
been performed (Scheme 1b).6 For example, Liu’s group has
recently reported a hypervalent iodine-assisted Pd(II)/Pd(IV)-
catalyzed aryltrifluoro methylation and arylalkylation.6a,b Zhou
and Fu’s groups independently disclosed a Cu(I)/Cu(III)-
catalyzed arylation- and vinylation-carbocyclization.6c,d In
particular, Li’s group has developed a unique palladium-catalyzed
oxidative difunctionalization of acrylamides with α-carbonyl alkyl
bromides toward oxindoles by a radical process in 2014.4b
Overall, these aforementioned methods require an equivalent
oxidant in order to assist in the formation of the oxindoles.4−6
Herein, we report an oxidant-free rhodium(I)-catalyzed
difunctionalization of N-phenylacrylamide in order to synthesize
oxindole derivates (Scheme 1c). This reaction successfully avoids
the use of the oxidant and provides various functionalized
oxindoles, some of which cannot be easily accessed by
established methods.
alkylation of the oxindole in the presence of the Rh(I) catalyst.
We chose this because the Rh(I) works more easily with
Initially, we chose N-methyl-N-phenylmeth acrylamide (1a)
Received: March 13, 2015
and benzyl bromide (2a) as the substrates in order to achieve
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00732
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Organic Letters
Letter
haloalkanes by the oxidative addition7 and is usually used in
activation of alkenes.8 Disappointingly, however, no desired
product was observed. However, we added 10 mol % ligand
BINAP (L1) in the reaction system and, at the same time, tested
different kinds of solvents for this reaction (Table 1 entries 2−5).
Fortunately, a significant amount of the target product 3aa was
obtained by the catalysis of [Rh(COD)Cl]2 with BINAP and
KOH in PhMe, THF, and dioxane. Next, we also examined other
low valences of transition metal catalysts such as Pd(PPh3)4 and
[Ir(COD)Cl]2 (entries 6−7). Results showed that [Rh(COD)-
Cl]2 was still the best choice. Exploration of the other ligands
revealed that BINAP (L1) and Segphos (L4) gave comparatively
better yields (entries 8−10). For economic considerations, we
chose BINAP as the ligand in this reaction. Increasing the
reaction temperature also proved beneficial for the reaction: a
better yield of 46% was obtained (entry 11). Following this part,
the influence of oxygen in this reaction was also examined, and
results indicated that an oxygen atmosphere would inhibit this
reaction (entries 12−13). A series of base screening showed that
the best yield (82%) was obtained in the presence of NaHCO3
(entries 14−19). Further study of the reaction conditions
indicated that prolonging the reaction time or reducing the
temperatures did not help to improve product yield (entries 20−
22).
With optimized conditions in hand, we turned our study to the
scope of the substrates. First we tested the effect of the N-
protecting group. We found that N-phenylacrylamide with
different nitrogen-protecting groups all gave the product in
comparatively good yields (3aa−3fa, Scheme 2). To our
surprise, even when the nitrogen protecting group was acetyl,
the reaction also proceeded well and afforded the desired product
(3da) in moderate yield, which was a breakthrough for this type
of reaction. However, when N-free acrylamide was used as a
substrate, no desired product was detected. Then, we discovered
that substrates with substituents on the para-position of the
arylacrylamide reacted well and the majority of products were
obtained with high yields (3oa−3sa), but when the substituent
group was nitro (3oa), the substrate provided the product in just
a 34% yield. Similarly, the products could be produced in
considerable yield when different substituent groups were
located at the ortho- (3fa−3ia) and meta-positions (3ma−
3na) of aromatic ring, whereas when there was a halogen
substituent, such as bromine at the ortho-position, the yield of
product (3ia) was quite low and the reaction system became very
complex. Then, substituent alkenes were tested. We found that
just a trace amount of product (3la) was observed when using a
monosubstituted olefin as a substrate. When the substituent
group (R2) was methyl (3aa) or benzyl (3ka), the reaction could
produce the product in an excellent yield and a hydroxymethyl
substituent gave a lower yield (3ja).
a
Table 1. Reaction Conditions Screening
catalyst
t
yield
b
entry
1
(mol %)
ligand
solvent
PhMe
base
KOH
(°C)
(%)
[Rh(COD)Cl]2
(2.5)
80
80
80
80
80
trace
22
0
2
3
4
5
[Rh(COD)Cl]2
(2.5)
L1
L1
L1
L1
PhMe
KOH
KOH
KOH
KOH
[Rh(COD)Cl]2
(2.5)
CH3NO2
dioxane
THF
[Rh(COD)Cl]2
(2.5)
24
25
[Rh(COD)Cl]2
(2.5)
6
7
Pd(PPh3)4 (5)
L1
L1
THF
THF
KOH
KOH
80
80
trace
10
[Ir(COD)Cl]2
(2.5)
8
[Rh(COD)Cl]2
(2.5)
L2
L3
L4
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
THF
KOH
KOH
KOH
KOH
KOH
KOH
80
0
9
[Rh(COD)Cl]2
(2.5)
THF
80
trace
22
46
45
0
10
11
[Rh(COD)Cl]2
(2.5)
THF
80
[Rh(COD)Cl]2
(2.5)
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
120
120
120
120
120
120
120
120
120
120
100
80
c
12
[Rh(COD)Cl]2
(2.5)
d
13
[Rh(COD)Cl]2
(2.5)
14
15
16
17
18
19
[Rh(COD)Cl]2
(2.5)
trace
75
73
0
[Rh(COD)Cl]2
(2.5)
K2CO3
[Rh(COD)Cl]2
(2.5)
Na2CO3
DBU
[Rh(COD)Cl]2
(2.5)
[Rh(COD)Cl]2
(2.5)
DABCO
NaHCO3
NaHCO3
NaHCO3
NaHCO3
trace
82
82
62
36
Subsequently, we investigated the reactivity of different kinds
of halogenated hydrocarbons. The results indicated that the
benzyl bromide and some of its derivatives could react well and
provide the product in a high yield. The substituted allyl bromide
(3ai−3aj) and aryl halides (3ab), however, did not work in this
reaction. The halogenated alkanes could give only trace amounts
of product (3af). Among the substituted benzyl bromide,
aromatic ring-substituted benzyl bromide (3ac−3ae) afforded
desired products in comparatively high yield, especially with
electron-withdrawing substituents (3ad). However, possibly
because of the steric problems, the reaction barely occurred if a
substituent was present at the benzyl position (3ag−3ah).
Finally, we tested the reactivity of different kinds of halogen and
results showed that benzyl chloride gave the product (3aa) in a
much lower yield than benzyl bromide.
[Rh(COD)
Cl]2 (2.5)
e
20
[Rh(COD)Cl]2
(2.5)
21
22
[Rh(COD)Cl]2
(2.5)
[Rh(COD)Cl]2
(2.5)
a
The reaction was carried out with catalyst, ligand (10 mol %), base
(1.0 equiv), 1a (0.20 mmol), and 2a (0.40 mmol) in solvent (2.5 mL)
b
c
for 24 h under argon. Yield of isolated product. The reaction was
d
Next, we focused our study on investigating the mechanism.
We tested first if this was a free radical reaction; see Scheme 3 for
proof that the addition of 0.5 equiv of TEMPO suppresses the
carried out in standard conditions with the solvent degassed. The
reaction was carried out in standard conditions under oxygen. The
e
reaction was carried out in standard conditions for 30 h.
B
DOI: 10.1021/acs.orglett.5b00732
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Scheme 2. Representative Example of Difunctionalization of
Alkenes Leading to Oxindoles
Scheme 3. Experiments to Determine the Mechanism
a b
,
indicates that the initiation of halogenated hydrocarbons is
necessary for this reaction.
Based on the analysis above and previous work, we illustrate a
possible catalytic cycle in Scheme 4.11 This reaction may be
Scheme 4. One Possible Mechanism of Rhodium(I) Catalyzed
Intermolecular Difunctionalization of Alkenes
a
The reaction was carried out with [Rh(COD)Cl]2 (2.5 mol %),
BINAP (10 mol %), NaHCO3 (1.0 equiv), 1 (0.25 mmol), and 2 (0.50
mmol) in dioxane (3.1 mL) at 120 °C for 24 h under argon.
Conditions A: X = Br. Conditions B: X = Cl. Conditions C: X = I.
b
Yield of the isolated product.
reaction (eq 1). However, with 2 equiv of BHT added, the
reaction (eq 2) still proceeded although the yield of the desired
product was a bit lower and capture of the free radical species was
detected in neither reaction systems. In addition, we did not add
any oxidant to this reaction system, which does not agree with the
mode of mechanism for this type of reaction.9 We were therefore
able to rule out the radical mechanism for this reaction,
subsequently performing an intermolecular kinetic isotope effect
experiment with 1a′ with no kinetic isotope effect (kH/kD = 0.85)
observed (eq 3). This result indicates that the process of C−H
rupture is not the rate-determining step.10 We then added 1
equiv of 1a, 1 equiv of 2d, and 1 equiv of 2e and allowed the
reaction to occur under standard conditions for 3 h (eq 4), after
which we detected 26% yield of 3ad but just 1% yield of 3ae.
These results indicate that the rate-determining step might
involve the oxidation addition, and then cyclization and reductive
elimination may therefore explain the mechanism of this
reaction. Finally, as a unique substrate, 1a reacted in the
presence of 2.5 mol % [Rh(COD)Cl]2 and 10 mol % BINAP in
dioxane at 120 °C for 24 h. However, C−H functionalization did
not occur, and the product 3a was not observed (eq 5), which
initiated by the coordination of the olefin in order to generate the
Rh(I) complex A. Then, the rhodium(I) goes on to attack the
halogenated hydrocarbons 2 in order to complete the process of
oxidative addition in order to give complex B. After that, the
electrophilic substitution reaction of the aromatic ring is carried
out to give C. Finally, after the reductive elimination and proton
leaving with the help of the base, the target product 3 is formed.
In conclusion, we have developed rhodium(I)-catalyzed
intermolecular difunctionalization of arylacrylamides to synthe-
size oxindoles. This reaction successfully avoids the use of
oxidant so that the method can be compatible with many
oxidizable substrates. Furthermore, as this reaction is not based
C
DOI: 10.1021/acs.orglett.5b00732
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Organic Letters
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Wei, W.-T.; Deng, G.-B.; Li, J.-H. Chem. Sci. 2013, 4, 2690. (b) Tao, S.;
Yuan, Y.; Jiao, N. Chem. Commun. 2014, 50, 554. (c) Li, Y.-M.; Wei, X.-
H.; Li, X.-A.; Yang, S.-D. Chem. Commun. 2013, 49, 11701. (d) Matcha,
K.; Narayan, R.; Antonchick, A. P. Angew. Chem., Int. Ed. 2013, 52, 7985.
(e) Kong, W.; Casimiro, M.; Fuentes, N.; Merino, E.; Nevado, C. Angew.
Chem., Int. Ed. 2013, 52, 13086. (f) Xu, P.; Xie, J.; Xue, Q.; Pan, C.;
Cheng, Y.; Zhu, C. Chem.Eur. J. 2013, 19, 14039. (g) Lv, J.; Zhang-
Negrerie, D.; Deng, J.; Du, Y.; Zhao, K. J. Org. Chem. 2014, 79, 1111.
(h) Wang, H.; Guo, L.-N.; Duan, X.-H. Org. Lett. 2013, 15, 5254.
(i) Zhou, Z.-Z.; Hua, H.-L.; Luo, J.-Y.; Chen, Z.-S.; Zhou, P.-X.; Liu, X.-
Y.; Liang, Y.-M. Tetrahedron 2013, 69, 10030. (j) Li, Y.-M.; Shen, Y.;
Chang, K.-J.; Yang, S.-D. Tetrahedron 2014, 70, 1991.
(6) (a) Mu, Y.; Wu, T.; Wang, H.-Y.; Guo, Y.-L.; Liu, G. J. Am. Chem.
Soc. 2012, 134, 878. (b) Wu, Y.; Mu, Y.; Liu, G. Angew. Chem., Int. Ed.
2011, 50, 12587. (c) Zhou, B.; Hou, W.; Yang, Y.; Feng, H.; Li, Y. Org.
Lett. 2014, 16, 1322. (d) Shi, L.; Wang, Y.; Yang, H.; Fu, H. Org. Biomol.
Chem. 2014, 12, 4070. (e) Jaegli, S.; Dufour, J.; Wei, H.-L.; Piou, T.;
Duan, X.-H.; Vors, J.-P.; Neuville, L.; Zhu, J. Org. Lett. 2010, 12, 4498.
(7) For selected examples, see: (a) Berman, A. M.; Bergman, R. G.;
Ellman, J. A. J. Org. Chem. 2010, 75, 7863. (b) Berman, A. M.; Lewis, J.
C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 14926.
(c) Miyamoto, M.; Harada, Y.; Tobisu, M.; Chatani, N. Org. Lett. 2008,
10, 2975. (d) Lewis, J. C.; Berman, A. M.; Bergman, R. G.; Ellman, J. A. J.
Am. Chem. Soc. 2008, 130, 2493.
(8) For selected examples of recent research about rhodium(I)
catalyzed reaction, see: (a) Xia, Y.; Liu, Z.; Liu, Z.; Ge, R.; Ye, F.;
Hossain, M.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2014, 136, 3013.
(b) Liao, W.; Yu, Z.-X. J. Org. Chem. 2014, 79, 11949. (c) Hiener, S.;
Kolb, A.; Westmeier, J.; Gebhardt, S.; Middel, S.; Harms, K.; Zezschwitz,
P. V. Org. Lett. 2014, 16, 3162. (d) Wen, B.; Hexum, J. K.; Widen, J. C.;
Harki, D. A.; Brummond, K. M. Org. Lett. 2013, 15, 2644. (e) Grugel, H.;
Albrecht, F.; Minuth, T.; Boysen, M. M. K. Org. Lett. 2012, 14, 3780.
(f) Low, D. W.; Pattison, G.; Wieczysty, M. D.; Churchill, G. H.; Lam, H.
W. Org. Lett. 2012, 14, 2548. (g) Dong, K.; Wang, Z.; Ding, K. J. Am.
Chem. Soc. 2012, 134, 12474. (h) Zhang, J.; Liu, J.-F.; Ugrinov, A.; Pillai,
A. F. X.; Sun, Z.-M.; Zhao, P. J. Am. Chem. Soc. 2013, 135, 17270.
(i) Mizuno, H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2011, 133,
1251.
on a mechanism of free radicals, it provides a possibility for
asymmetric synthesis of oxindoles, which continues to represent
a difficulty for chemists.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yangshd@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the National Natural Science Foundation of
China (Nos. 21272100 and 21472076) and Gansu Natural
Science Foundation of China (1208RJZA216) financial support.
S.F. Reichard of the University of Chicago contributed editing.
REFERENCES
■
(1) (a) Trost, B. M.; Xie, J.; Sieber, J. D. J. Am. Chem. Soc. 2011, 133,
20611. (b) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104. (c) Lin,
H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36. (d) Dalpozzo,
R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012, 47, 7247.
(e) Ohmatsu, K.; Ando, Y.; Ooi, T. J. Am. Chem. Soc. 2013, 135, 18706.
(f) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748.
(2) (a) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem.Eur. J. 2007, 13,
961. (b) Lapierre, A. J. B.; Geib, S. J.; Curran, D. P. J. Am. Chem. Soc.
2007, 129, 494. (c) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S.
P.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488.
(d) Seashore-Ludlow, B.; Somfai, P. Org. Lett. 2012, 14, 3858.
(e) McDermott, M. C.; Stephenson, G. R.; Hughes, D. L.;
Walkington, A. J. Org. Lett. 2006, 8, 2917. (f) Piou, T.; Bunescu, A.;
Wang, Q.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2013, 52, 12385.
(3) For selected reviews and some examples about difunctionalization
of alkenes, see: (a) Kolb, H. C.; van Nieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483. (b) McDonald, R. I.; Liu, G.; Stahl, S. S.
Chem. Rev. 2011, 111, 2981. (c) Beccalli, E. M.; Broggini, G.; Martinelli,
M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318. (d) Cong, H.; Fu, G. C.
J. Am. Chem. Soc. 2014, 136, 3788.
(9) For the specific mechanism of free-radical-type intermolecular
difunctionalization of alkenes, see refs 4 and 5.
(10) (a) Tunge, J. A.; Foresee, L. N. Organometallics 2005, 24, 6440.
(b) Taylor, R. Electrophilic Aromatic Substitution; John Wiley & Sons
Inc.: New York, 1990; pp 25−57.
(11) For the references of the proposal mechanism, see ref 6.
(4) For selected examples of metal catalyzed cascade radical
cyclizations, see: (a) Zhou, M.-B.; Wang, C.-Y.; Song, R.-J.; Liu, Y.;
Wei, W.-T.; Li, J.-H. Chem. Commun. 2013, 49, 10817. (b) Fan, J.-H.;
Wei, W.-T.; Zhou, M.-B.; Song, R.-J.; Li, J.-H. Angew. Chem., Int. Ed.
2014, 53, 6650. (c) Wei, W.-T.; Zhou, M.-B.; Fan, J.-H.; Liu, W.; Song,
R.-J.; Liu, Y.; Hu, M.; Xie, P.; Li, J.-H. Angew. Chem., Int. Ed. 2013, 52,
3638. (d) Ouyang, X.-H.; Song, R.-J.; Li, J.-H. Eur. J. Org. Chem. 2014,
3395. (e) Fan, J.-H.; Zhou, M.-B.; Liu, Y.; Wei, W.-T.; Ouyang, X.-H.;
Song, R.-J.; Li, J.-H. Synlett 2014, 25, 657. (f) Yuan, Y.; Shen, T.; Wang,
K.; Jiao, N. Chem.Asian J. 2013, 8, 2932. (g) Li, Y.-M.; Sun, M.; Wang,
H.-L.; Tian, Q.-P.; Yang, S.-D. Angew. Chem., Int. Ed. 2013, 52, 3972.
(h) Wei, X.-H.; Li, Y.-M.; Zhou, A.-X.; Yang, T.-T.; Yang, S.-D. Org. Lett.
2013, 15, 4158. (i) Wang, H.; Guo, L.-N.; Duan, X.-H. Chem. Commun.
2013, 49, 10370. (j) Yang, F.; Klumphu, P.; Liang, Y.-M.; Lipshutz, B. H.
Chem. Commun. 2014, 50, 936. (k) Fu, W.; Xu, F.; Fu, Y.; Zhu, M.; Yu, J.;
Xu, C.; Zou, D. J. Org. Chem. 2013, 78, 12202. (l) Xu, X.; Tang, Y.; Li, X.;
Hong, G.; Fang, M.; Du, X. J. Org. Chem. 2014, 79, 446. (m) Feng, Y.;
Wang, X.-S. Org. Lett. 2014, 16, 1128. (n) Li, Z.; Zhang, Y.; Zhang, L.;
Liu, Z. Org. Lett. 2014, 16, 382. (o) Lu, M.-Z.; Loh, T.-P. Org. Lett. 2014,
16, 4698. (p) Xu, Z.; Yan, C.; Liu, Z.-Q. Org. Lett. 2014, 16, 5670.
(5) For selected examples of metal-free catalyzed cascade radical
cyclizations, see: (a) Zhou, M.-B.; Song, R.-J.; Ouyang, X.-H.; Liu, Y.;
D
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