906
X.-L. Liu et al. / Tetrahedron Letters 52 (2011) 903–906
O
R
R'
-OH
R
N
+
H
H
H
2
3
R'
O
N
R
R2
O
R2
N
R'
H
R2
H
H
iminium ion
3
O
H
N
R1
N
R1
OH
N
R1
OH
1
R
R2
OH
O
R2
N
R'
O
N
N
R1
R1
5
4
Scheme 2. Proposed reaction pathway for the aminomethylation of 3-substituted oxindoles.
N. V.; Sahin, A. H.; Chang, W.; Fettinger, J. C.; Franz, A. K. Angew. Chem., Int. Ed.
2010, 49, 744–747; (i) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548–
14549; (j) Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44, 308–
310; (k) Shen, K.; Liu, X.; Zheng, K.; Li, W.; Hu, X.; Lin, L.; Feng, X. Chem. Eur. J.
2010, 16, 3736–3742.
presumably of great priority compared to the aldol reaction in the
reaction system, therefore, the aminomethylation products were
observed as major products in most cases. In contrast, in the case
of using some bulky structure amines or primary amines as sub-
strates (Table 3, entries 5 and 6 and 10–12), maybe the preferential
reaction is aldol reaction, thus affording the hydroxymethylation
product as the major product.
In conclusion, we have developed a simple and eco-friendly ap-
proach for the aminomethylation of various 3-substituted oxin-
doles with the three-component Mannich reaction of 3-
substituted oxindoles, secondary amines, and formalin. This trans-
formation can furnish a variety of oxindoles bearing a quaternary
carbon center at the C3 position in good yields with 10% SDS as
additive in water. Particularly valuable features of this method in-
clude employing cheap and easily available formalin as useful ami-
3. For selected examples about organocatalyzed reactions, see: (a) Hills, I. D.; Fu,
G. C. Angew. Chem., Int. Ed. 2003, 42, 3921–3924; (b) Luppi, G.; Cozzi, P. G.;
Monari, M.; Kaptein, B.; Broxterman, Q. B.; Tomasini, C. J. Org. Chem. 2005, 70,
7418–7421; (c) Bella, M.; Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem. Soc.
2005, 127, 3670–3671; (d) Shaw, S. A.; Aleman, P.; Christy, J.; Kampf, J. W.; Va,
P.; Vedejs, E. J. Am. Chem. Soc. 2006, 128, 925–934; (e) Ogawa, S.; Shibata, N.;
Inagaki, J.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2007, 46,
8666–8669; (f) Nakamura, S.; Hara, N.; Nakashima, H.; Kubo, K.; Shibata, N.;
Toru, T. Chem. Eur. J. 2008, 14, 8079–8081; (g) Ishimaru, T.; Shibata, N.;
Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed.
2008, 47, 4157–4161; (h) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org.
Lett. 2008, 10, 3583–3586; (i) Sano, D.; Nagata, K.; Itoh, T. Org. Lett. 2008, 10,
1593–1595; (j) Duffey, T. A.; Shaw, S. A.; Vedejs, E. J. Am. Chem. Soc. 2009, 131,
14–15; (k) Jiang, K.; Peng, J.; Cui, H.-L.; Chen, Y.-C. Chem. Commun. 2009,
3955–3957; (l) Cheng, L.; Liu, L.; Jia, H.; Wang, D.; Chen, Y.-J. Org. Lett. 2009, 11,
3874–3877; (m) Qian, Z.-Q.; Zhou, F.; Du, T.-P.; Wang, B.-L.; Ding, M.; Zhao, X.-
L.; Zhou, J. Chem. Commun. 2009, 6753–6755; (n) Cheng, L.; Liu, L.; Jia, H.;
Wang, D.; Chen, Y.-J. J. Org. Chem. 2009, 74, 4650–4653; (o) Galzerano, P.;
Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.; Giannichi, B.; Sambri, L.; Bartoli, G.;
Melchiorre, P. Chem. Eur. J. 2009, 15, 7846–7849; (p) He, R.; Ding, C.; Maruoka,
K. Angew. Chem., Int. Ed. 2009, 48, 4559–4561; (q) Chen, X.-H.; Wei, Q.; Luo, S.-
W.; Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819–13825; (r) Li, X.; Xi,
Z.-G.; Luo, S.; Cheng, J.-P. Org. Biomol. Chem. 2010, 8, 77–82; (s) Li, X.; Zhang, B.;
Xi, Z.-G.; Luo, S. Z.; Cheng, J.-P. Adv. Synth. Catal. 2010, 352, 416–424; (t) Shaw,
S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368–13369; (u) Bui,
T.; Syed, S.; Barbas, C. F., III J. Am. Chem. Soc. 2009, 131, 8758–8759; (v)
Bui, T.; Candeias, N. R.; Barbas, C. F., III J. Am. Chem. Soc. 2010, 132, 5574–
5575.
nomethylation C1 unit, using water as
a reaction medium.
Meanwhile, we also observed hydroxymethylation product as a
major product in some examples, while using bulky structure sec-
ondary amines or primary amines as substrates. Further studies to-
ward the development of more efficient protocol for the
preparation of structurally diverse oxindoles are ongoing in our
laboratory.
Acknowledgment
We are grateful for the financial support from the National Nat-
ural Science Foundation of China (No. 20802074).
4. Our recent research about using oxindoles as nucleophiles, (a) Liao, Y.-H.; Liu,
X.-L.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2010, 12, 2896–
2899; (b) Liu, X.-L.; Liao, Y.-H.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. J.
Org. Chem. 2010, 75, 4872–4875, to our delight, this article has been selected by
the Editorial Board of SYNFACTS for its important insights, see: Synfacts 2010, 9,
1065.
Supplementary data
5. The first stereoselective Mannich reaction of 3-substituted oxindoles with
imines was reported by Chen et al., see Ref. 3h.
6. For selected review, see Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int.
Ed. 1998, 37, 1044–1070.
Supplementary data associated with this article can be found, in
7. (a) Head-Gordon, T. Chem. Rev. 2002, 102, 2651–2670; (b) Li, C.-J. Chem. Rev.
2005, 105, 3095–3166; (c)Organic Reaction in Water: Principles, Strategies and
Applications; Lindstrom, U. M., Ed.; Blackwell Publishing: Oxford, UK, 2007.
8. (a) Chen, W.-B.; Du, X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron
2010, 66, 1441–1446; (b) Chen, W.-B.; Wu, Z.-J.; Pei, Q.-L.; Cun, L.-F.; Zhang, X.-
M.; Yuan, W.-C. Org. Lett. 2010, 12, 3132–3135; (c) Chen, W.-B.; Liao, Y.-H.; Du,
X.-L.; Zhang, X.-M.; Yuan, W.-C. Green Chem. 2009, 11, 1465–1476.
9. Formalin we used in this work, is an aqueous solution of formaldehyde and
contains 37% formaldehyde by volume.
References and notes
1. (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945–2964; (b) Lin, H.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36–51; (c) Galliford, C. V.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748–8758.
2. For selected examples about transition metal-catalyzed reactions, see: (a)
Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M. J. Am. Chem.
Soc. 2005, 127, 10164–10165; (b) Trost, B. M.; Brennan, M. K. Org. Lett. 2006, 8,
2027–2030; (c) Toullec, P. Y.; Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.;
Minnaard, A. J. Org. Lett. 2006, 8, 2715–2718; (d) Shintani, R.; Inoue, M.;
Hayashi, T. Angew. Chem., Int. Ed. 2006, 45, 3353–3356; (e) Ishimaru, T.;
Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. J. Am. Chem. Soc.
2006, 128, 16488–16489; (f) Jia, Y.-X.; Hillgren, J. M.; Watson, E. L.; Marsden, S.
P.; Kündig, E. P. Chem. Commun. 2008, 4040–4042; (g) Tomita, D.; Yamatsugu,
K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 6946–6948; (h) Hanhan,
10. The amount of formalin used in the reaction is based on the pure
formaldehyde.
11. The compound 4d was confirmed by 1H NMR spectroscopy of the crude
reaction mixture and TLC analysis.
12. The trace amount of aminomethylation products (<10% yield) were monitored
by TLC.