Nickel-catalyzed intramolecular addition of vinyl or aryl bromides to ketoamides

Article abstract of DOI:10.1016/j.tetlet.2014.03.069

A nickel-catalyzed intramolecular addition of vinyl or aryl bromides to ketoamides has been developed. The reactions proceeded efficiently with Ni(bpy)Br₂ as a catalyst and zinc powder as reducing agent, affording 3-hydroxypyrrolidinones, 3-hyd

Full text of DOI:10.1016/j.tetlet.2014.03.069

Tetrahedron Letters 55 (2014) 2805–2808
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Nickel-catalyzed intramolecular addition of vinyl or aryl bromides
to ketoamides
⇑
Jun-Qing He, Cheng Chen, Wu-Bin Yu, Ren-Rong Liu, Meng Xu, Yu-Jin Li, Jian-Rong Gao, Yi-Xia Jia
College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A nickel-catalyzed intramolecular addition of vinyl or aryl bromides to ketoamides has been developed.
The reactions proceeded efficiently with Ni(bpy)Br2 as catalyst and zinc powder as reducing
agent, affording 3-hydroxypyrrolidinones, 3-hydroxyoxindoles, and dihydroquinolinones as important
heterocyclic compounds in good to excellent yields.
Received 11 January 2014
Revised 6 March 2014
Accepted 9 March 2014
Available online 20 March 2014
a
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Nickel
Addition
Ketoamide
Oxindole
Bromide
The addition of aryl or vinyl fragments to carbonyl compounds
is an important synthetic access to benzylic or allylic alcohols. Con-
ventional methods rely on the nucleophilic addition of active orga-
nometallic reagents to C@O bonds, whereas the nucleophilic
organometallic reagents are normally prepared from aryl or vinyl
halides and are incompatible with sensitive functional groups in
most cases.1 Undoubtedly, elegant method would be the direct
addition of aryl or vinyl halides to C@O bonds. In this context,
OMe
Cl
CF3
OH
Me
Me
OH
O
HO
HO
O
OH
OH
H2N
N
OMe
O
O
N
Me
N
H
O
NEt2 HCl
Rigidiusculamide A
SM-130686
Penigequinolone A
Figure 1. Selected molecules containing 3-hydroxypyrrolidinone, 3-hydroxyoxindole, and dihydroquinolinone structural motifs.
HO
HO R3
R3
Br
R1
R2
O
O
10 mol% Ni(bpy)Br2
Zn, Solvent
O
or
N
R
R3
n
N
R1 R2
n = 0, 1
N
O
R
Scheme 1. Nickel-catalyzed addition of vinyl or aryl bromides to ketoamide.
⇑
Corresponding author. Tel.: +86 571 8832 0890; fax: +86 571 8832 0544.
E-mail address: yxjia@zjut.edu.cn (Y.-X. Jia).
http://dx.doi.org/10.1016/j.tetlet.2014.03.069
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

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J.-Q. He et al. / Tetrahedron Letters 55 (2014) 2805–2808
the Nozaki–Hiyama–Kishi (NHK) reaction, addition of organoha-
lides to aldehydes via generation of nucleophilic organochromium
species in situ, offers an attractive strategy to alcohols, while the
substrate was limited to aldehydes.2 Recently, the Pd-catalyzed
addition of aryl halides to a range of carbon-heteroatom multi-
bonds has been intensely developed by using the rare nucleophilic
property of organopalladium species.3–5 Nickel complexes also
showed unique catalytic activities in these transformations, thus,
the reactions of aryl halides to aldehydes,6 isocyanates,7 and
N,N-dimethylformamide8 were efficiently catalyzed by nickel com-
plex. Nevertheless, the utilization of ketone as substrate in this
field remains less exploited. And, the reaction of vinyl halides
and carbon-heteroatom multibonds was fairly rare in spite that
the additions of in situ generated vinylpalladium or vinylnickel
species to carbon-heteroatom multibonds have been extensively
involved in the annulations of ortho-halo aryl aldehydes,9
ketones,10 or nitriles11 with alkynes.
Table 1
Optimization of the reaction of 1aa
HO
Br
Ph
O
O
10 mol% [Ni]
Ph
N
Ph
Zn, solvent, 75 oC
N
Ph
O
1a
2a
Entry
[Ni]
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Ni(dppe)Br2
Ni(dppe)Br2
Ni(dppe)Br2
Ni(dppe)Br2
Ni(dppe)Br2
Ni(dppe)Br2
Ni(dppe)Br2
Ni(dppe)Br2
Ni(dppp)Br2
Ni(PCy3)2Br2
Ni(bpy)Br2
THF
1,4-Dioxane
DMF
Toluene
CH3CN
THF/CH3CN (3/1)
THF/CH3CN (7/1)
THF/CH3CN (19/1)
THF/CH3CN (7/1)
THF/CH3CN (7/1)
THF/CH3CN (7/1)
72
72
72
36
36
36
36
72
36
36
20
88
34
66
Trace
Trace
70
89
88
We have previously documented a Ni(COD)2/PCy3 catalyzed
intramolecular addition of aryl chlorides or bromides to a-ketoam-
ides, furnishing oxindoles in excellent yields with Me2Zn as reduc-
ing agent.12 However, the reaction of vinyl halides was not
successful due to the undesired Negishi-coupling reaction between
vinyl halides and Me2Zn, which resulted in modest yields of the
products. We disclosed herein a NiBr2/bipyridine complex cata-
lyzed intramolecular reaction of vinyl or aryl bromides and keto-
amides, affording 3-hydroxypyrrolidinones, 3-hydroxyoxindoles,
and dihydroquinolinones, important substructural motifs existed
in natural products and biologically active molecules (Fig. 1),13 in
good to excellent yields in the presence of zinc powder as reducing
90
59
92
10
11
a
Reactions conditions: 0.2 mmol 1a, 10 mol % catalyst, and 2.5 equiv Zn in 4.0 mL
solvent at 75 °C. dppe = 1,2-bis(diphenylphosphino)ethane; PCy3 = tricyclohexyl-
phosphine; dppp = 1,3-bis(diphenylphosphino)propane; bpy = 2,20-bipyridine.
b
Isolated yield.
Table 2
Substrate scope for the reaction of vinyl bromides 1a
HO
R'
Br
O
10 mol% Ni(bpy)Br2
2.5 eq. Zn
R'
O
N
R
N
R
O
THF/CH3CN (7/1)
75 oC, 20 h
1
2
MeO
Cl
F3C
Ph
OH
OH
OH
OH
OH
O
O
O
O
O
N
N
N
N
N
Ph
Ph
2b, 89%
Ph
2c
, 96%
Ph
2d, 85%
Ph
2e, 92%
2a
, 92%
OHC
Ph
OH
O
O
S
N
OH
OH
OH
OH
OH
O
O
N
O
O
O
N
N
N
N
Ph
Ph
Ph
Ph
Ph
OMe
2g
2h
2f, 93%
, 92%
, 90%
2i, 82%
2j, 80%
2k
, 86%
Ph
Ph
OH
Ph
OH
OH
O
O
O
Ph
OH
Ph
N
OH
OH
N
N
O
O
O
N
H
N
Ph
N
Bn
Cl
, 92%
2q, NRb
CN
, 85%
O
2o
2p, 95%
, 77%
2l
2m
2n
, 94%
a
Reactions conditions: 0.2 mmol of the substrate 1, 10 mol % Ni(bpy)Br2, 2.5 equiv Zn in 4.0 mL THF/CH3CN (7/1) at 75 °C for 20 h; Isolated yield.
No reaction.
b

J.-Q. He et al. / Tetrahedron Letters 55 (2014) 2805–2808
2807
agent (Scheme 1). The reaction showed broad substrate scope and
good functional group tolerance.
tron-donating groups on the phenyl rings. 2-Naphthyl product 2h
and heteroaryl substituted products 2i–j were also obtained in
good yields, which showed the improved activity of the present
catalyst.14 Substituent effect of the phenyl ring linked to nitrogen
atom was then tested, thus the reactions of substrates bearing
AOMe, ACN, ACl, and acetyl groups at the para-position proceeded
smoothly to furnish the products 2k–n in good to excellent yields.
Alkyl ketoamide substrate reacted well to form product 2p in
excellent yield. N-Benzyl product 2o was also obtained in good
yield, while a free N-H substrate was fully inert and resulted in
no formation of the product 2q. Notably, the formyl group (ACHO,
2g), cyano group (ACN, 2l), and acetyl group (ACOMe, 2n), nor-
mally sensitive to active organometallic reagents,15 were well tol-
erated in this transformation.
Our study began with the optimization of the intramolecular
reaction of the vinyl bromide substrate 1a and the results are out-
lined in Table 1. Initial reaction with 10 mol % Ni(dppe)Br2 as a cat-
alyst and 2.5 equiv zinc powder as reducing agent in THF at 75 °C
for 72 h led to the desired product 2a in 88% isolated yield (entry
1). Subsequent examination revealed that the reaction outcome
was significantly depended on the solvent effect (entries 2–5).
Remarkably lower yields were observed in 1,4-dioxane and DMF,
while only trace amount of the product was detected in toluene
and acetonitrile. We noted that the catalyst was suspended in
THF solvent but was completely dissolved in acetonitrile. This pro-
moted us to test the mixed solvent of THF and acetonitrile (entries
6–8). As expected, the reaction rate was improved remarkably
when the reaction proceeded in THF/acetonitrile (7/1, v/v) (entry
7 vs entry 1). Ligand effect was then screened in this mixed solvent
(entries 9–11). Ni(dppp)Br2 showed similar catalytic activity as
Ni(dppe)Br2. Ni(bpy)Br2 with 2,20-bipyridine as a ligand gave the
best result and the reaction was completed in 20 h with 92% iso-
lated yield. Noticeably, a monodentate ligand PCy3 was inefficient
in this reaction (entry 10).
Inspired by the above success, we then examined the reactions
of aryl bromide substrates (Table 3). The coupling of aryl bromides
and
a-ketoamides was first investigated. Excellent yields (over
90%) of N-Me-3-aryloxindoles 4a–d bearing different substituents,
N-Bn-oxindole 4e, and 3-methyl oxindole 4f were obtained under
the identical reaction conditions. We then moved our attention
to the reactions of b-ketoamides, which remained unreported with
the nickel-based catalyst. Thereby, N-(2-bromophenyl)-b-ketoa-
mide substrates 3g–m were synthesized and treated under the
same reaction conditions. With 10 mol % Ni(bpy)Br2 as catalyst in
THF/CH3CN (7/1) at 75 °C for 44 h, the reactions proceeded
smoothly to produce dihydroquinolinones 4g–i bearing gem-di-
methyl groups in good yields. To our delight, the substrates bearing
To test the substrate scope, the reactions of a range of vinyl bro-
mide substrates were carried out under the optimal reaction con-
ditions. As shown in Table 2, good to excellent yields of the
corresponding 3-hydroxypyrrolidinones 2a–g were observed for
the substrates bearing either electron-withdrawing groups or elec-
Table 3
Substrate scope for the reaction of aryl bromides 3a
HO R3
HO
R1
R2
Br
R3
10 mol% Ni(bpy)Br2
O
O
O
THF/CH3CN (7/1)
2.5 eq. Zn
N
R
R3
n
N
N
R
4g-m
O
R1 R2
75 oC, 20-44 h
R
3a-f, n = 0
4a-f
3g-m, n = 1
F3C
MeO
Ph
Ph
OH
OH
OH
OH
O
OH
O
O
O
O
N
N
N
N
N
4d, 92%
Bn
4c, 90%
4e, 90%
4a
, 96%
4b, 98%
MeO
Ph OH
N
OH
OH
OH
O
N
O
N
O
N
O
4g
, 73%
4h
, 74%
4f, 90%
4i
, 76%
F
Br
Cl
Ph OH
OH
OH
N
OH
N
N
O
N
O
O
O
4j
, 75%
4k
, 74%
4l
, 84%
4m
, 85%
a
Reactions conditions: 0.2 mmol of the substrate, 10 mol % Ni(bpy)Br2, 2.5 equiv Zn in 4.0 mL THF/CH3CN (7/1) at 75 °C; For 4a–f, 20 h; For 4g–m, 44 h; Isolated yield.

2808
Ph
J.-Q. He et al. / Tetrahedron Letters 55 (2014) 2805–2808
Ph
Acknowledgments
OH
O
OZnBr
We are grateful for the generous financial supports by the
O
N
Ph
N
Ph
National Natural Science Foundation of China (21002089,
21372202), New Century Excellent Talents in University (NCET-
12-1086), and young scholarship for the doctoral program of high-
er education (20103317120001).
E
ZnBr2
Zn
N
N
Br
Br
Ni
ZnBr2
Br
N
N
Ni
Ph
O
N
Ni
N
Supplementary data
O
N
Ph
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.03.
069.
D
Br
O
Ph
ZnBr2
N
N
-
Ph
O
ZnBr3
N
Br
References and notes
Ni
O
N
N
Ni
O
1. (a) Blomberg, C.; Hartog, F. A. Synthesis 1977, 18; (b) Luche, J. L.; Damiano, J. C. J.
Am. Chem. Soc. 1980, 102, 7926; (c) Silverman, G. S.; Rakita, P. E. Handbook of
Grignard Reagents; Marcel Dekker: New York, 1996.
2. (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett.
1983, 24, 5281; (b) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644; (c) Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 2533; (d)
Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349; (e) Grigg, R.; Putnikovic,
B.; Urch, C. J. Tetrahedron Lett. 1997, 38, 6307.
Ph
N
Ni
N
N
Ph
Ph
N
Ph
C
O
O
A
O
Ph
ZnBr2
N
Ph
B
-
O
ZnBr3
3. Addition to C@O double bonds: (a) Quan, L.-G.; Lamrani, M.; Yamamoto, Y. J.
Am. Chem. Soc. 2000, 122, 4827; (b) Sole, D.; Vallverdu, L.; Peidro, E.; Bonjoch, J.
Chem. Comm. 2001, 1888; (c) Hosoi, K.; Nozaki, K.; Hiyama, T. Org. Lett. 2002, 4,
2849; (d) Sole, D.; Vallverdu, L.; Solans, X.; Font-Bardia, M.; Bonjoch, J. J. Am.
Chem. Soc. 2003, 125, 1587; (e) Cacchi, S.; Fabrizi, G.; Gavazza, F.; Goggiamani,
A. Org. Lett. 2003, 5, 289; (f) Sole, D.; Serrano, O. Angew. Chem., Int. Ed. 2007, 46,
7270; (g) Sole, D.; Serrano, O. J. Org. Chem. 2008, 73, 9372; (h) Zhao, Y.-B.;
Mariampillai, B.; Candito, D. A.; Laleu, B.; Li, M.; Lautens, M. Angew. Chem., Int.
Ed. 2009, 48, 1849; (i) Jia, Y.-X.; Katayev, D.; Kündig, E. P. Chem. Commun. 2010,
46, 130; (j) Yin, L.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2011, 50,
7620; (k) Sawant, D. N.; Wagh, Y. S.; Bhatte, K. D.; Bhanage, B. M. J. Org. Chem.
2011, 76, 5489.
4. Addition to C@N double bonds: Ohno, H.; Aso, A.; Kadoh, Y.; Fujii, N.; Tanaka, T.
Angew. Chem., Int. Ed. 2007, 46, 6325.
5. Addition to nitriles: (a) Pletnev, A. A.; Larock, R. C. J. Org. Chem. 2002, 67, 9428;
(b) Pletnev, A. A.; Larock, R. C. Tetrahedron Lett. 2002, 43, 2133.
6. (a) Majumdar, K. K.; Cheng, C.-H. Org. Lett. 2000, 2, 2295; (b) Huang, C.-Y.;
Majumdar, K. K.; Cheng, C.-H. J. Org. Chem. 2002, 67, 1682.
Figure 2. Proposed catalytic cycle.
a single methyl group could also react well to afford the corre-
sponding products 4j–m in satisfactory yields. No desired product
was isolated for the reaction of the substrate lack of methyl substi-
tuent (Eq 1). The necessity of a methyl group may ascribe to the
compression between methyl group and carbonyl group facilitat-
ing coordination of the carbonyl group to nickel catalyst and the
subsequent nucleophilic addition reaction, which is similar to the
Thorpe–Ingold effect.16
Br
7. Hsieh, J. C.; Cheng, C.-H. Chem. Comm. 2005, 4554.
10 mol% Ni(bpy)Br2
O
O
8. (a) Ju, J.; Jeong, M.; Moon, J.; Jung, H. M.; Lee, S. Org. Lett. 2007, 9, 4615; (b) Jo,
Y.; Ju, J.; Choe, J.; Song, K. H.; Lee, S. J. Org. Chem. 2009, 74, 6358.
9. (a) Larock, R. C.; Doty, M. J.; Cacchi, S. J. Org. Chem. 1993, 58, 4579; (b)
Gevorgyan, V.; Quan, L.-G.; Yamamoto, Y. Tetrahedron Lett. 1999, 40, 4089; (c)
Chang, K.-J.; Rayabarapu, D. K.; Cheng, C.-H. J. Org. Chem. 2004, 69, 4781.
10. (a) Quan, L.-G.; Gevorgyan, V.; Yamamoto, Y. J. Am. Chem. Soc. 1999, 121, 3545;
(b) Rayabarapu, D. K.; Cheng, C.-H. Chem. Comm. 2002, 942; (c) Rayabarapu, D.
K.; Yang, C.-H.; Cheng, C.-H. J. Org. Chem. 2003, 68, 6726.
11. (a) Larock, R. C.; Tian, Q.-P.; Pletnev, A. A. J. Am. Chem. Soc. 1999, 121, 3238; (b)
Pletnev, A. A.; Tian, Q.-P.; Larock, R. C. J. Org. Chem. 2002, 67, 9276; (c) Tian, Q.-
P.; Pletnev, A. A.; Larock, R. C. J. Org. Chem. 2003, 68, 339.
12. Hu, J.-X.; Wu, H.; Li, C.-Y.; Sheng, W.-J.; Jia, Y.-X.; Gao, J.-R. Chem. Eur. J. 2011,
17, 5234.
13. (a) Li, J.; Liu, S.-C.; Niu, S.-B.; Zhuang, W.-Y.; Che, Y.-S. J. Nat. Prod. 2009, 72,
2184; (b) Tokunaga, T.; Hume, W. E.; Umezome, T.; Okazaki, K.; Ueki, Y.;
Kumagai, K.; Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R.
J. Med. Chem. 2001, 44, 4461; (c) Kimura, Y.; Kusano, M.; Koshino, H.; Uzawa, J.;
Fujioka, S.; Tani, K. Tetrahedron Lett. 1996, 37, 4961.
14. Product 2j was isolated in 60% yield with our previous catalyst system (ref. 12).
15. (a) Yamataka, H.; Kawafuji, Y.; Nagareda, K.; Miyano, N.; Hanafusa, T. J. Org.
Chem. 1989, 54, 4706; (b) Itoh, T.; Kude, K.; Hayase, S.; Kawatsura, M.
Tetrahedron Lett. 2007, 48, 7774; (c) Zong, H.; Huang, H.-Y.; Liu, J.-F.; Bian, G.-L.;
Song, L. J. Org. Chem. 2012, 77, 4645; (d) Mateos, C.; Rincón, J.; Villanueva, J.
Tetrahedron Lett. 2013, 54, 2226.
(1)
85% of SM recovered
THF/CH3CN (7/1)
2.5 eq. Zn
N
Ph
75 oC, 44 h
Considering the reaction mechanism, a catalytic cycle is pro-
posed in Figure 2.3j,6a,12 Ni(bpy)Br2 was first reduced to Ni(0) by
zinc powder, which was followed by the oxidative addition of vinyl
bromide to nickel(0) to generate intermediate A. Subsequent li-
gand exchange led to the six-membered coordination intermediate
B. Isomerization to C and the nucleophilic addition of vinyl to C@O
bond yielded intermediate D. Through transmetalation of D with
zinc bromide, the catalyst Ni(bpy)Br2 was regenerated to fulfill
the catalytic cycle and zinc alkoxide E was afforded in the mean-
time. The final product was formed from E during work up.
In summary, we have developed a nickel-catalyzed intramolec-
ular addition of vinyl or aryl bromides to ketoamides. The process
works efficiently to produce 3-hydroxypyrrolidinones, 3-hydroxy-
oxindoles, and dihydroquinolinones in good to excellent yields
under mild reaction conditions. Further extension of this method-
ology towards the synthesis of other important heterocyclic com-
pounds is under way in our laboratory.
16. Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915, 107, 1080.