Organocatalytic enantioselective hydroxymethylation of oxindoles with paraformaldehyde as C1 unit

Article abstract of DOI:10.1021/jo100769n

(Figure Presented) A bifunctional thiourea-tertiary amine-catalyzed asymmetric hydroxymethylation of 3-substituted oxindoles using paraformaldehyde as the C1 unit was developed. A wide scope of oxindoles, bearing C3 sterically congested quaternary carbon centers, were smoothly obtained in good to excellent yields (up to 99%) and high enantioselectivities (up to 91% ee) under mild reaction conditions. A more significant feature of this approach employs cheap and readily available paraformaldehyde as a hydroxymethylation C1 unit, which is activated by chiral bifunctional thiourea organocatalysts.

Full text of DOI:10.1021/jo100769n

pubs.acs.org/joc
in the development of efficient methods to construct func-
Organocatalytic Enantioselective
Hydroxymethylation of Oxindoles
with Paraformaldehyde as C1 Unit
tionalized chiral 3,3-disubstituted 2-oxindole scaffolds.3,4 In
this regard, various electrophiles have been investigated for
the asymmetric reactions with prochiral 3-substituted oxi-
ndoles as donors. However, to the best of our knowledge, only a
single example, reported by Feng and co-workers, describes
a direct asymmetric aldol-type reaction of 3-substituted
oxindoles with aldehyde (phenylglyoxal derivatives) using
N,N0-dioxide-Sc(OTf)3 complex as catalyst.3k Thus, it is
evident that there remains further need for synthetic app-
roaches of oxindoles with aldehydes to access diversely struc-
tured 3,3-disubstituted 2-oxindoles.
Xiong-Li Liu,†,§ Yu-Hua Liao,†,§ Zhi-Jun Wu,‡,§
Lin-Feng Cun,† Xiao-Mei Zhang,† and Wei-Cheng Yuan*,†
†Key Laboratory for Asymmetric Synthesis &
Chirotechnology of Sichuan Province, Chengdu Institute of
Organic Chemistry, and ‡Chengdu Institute of Biological
Products, Chinese Academy of Sciences, Chengdu,
§
610041, China, and Graduate School of Chinese
Academy of Sciences, Beijing 100049, China
Enantioselective hydroxymethylation of carbonyl com-
pounds at their R-position with formaldehyde as the C1 unit
is one useful method for constructing chiral building blocks
in organic synthesis, and some progress has been obtained
yuanwc@cioc.ac.cn
Received April 20, 2010
(3) For the synthesis of 3,3-disubstituted oxindoles via transition-metal-
catalyzed asymmetric reactions, see: (a) Hamashima, Y.; Suzuki, T.; Takano,
H.; Shimura, Y.; Sodeoka, M. J. Am. Chem. Soc. 2005, 127, 10164. (b) Trost,
B. M.; Brennan, M. K. Org. Lett. 2006, 8, 2027. (c) Toullec, P. Y.; Jagt, R. B. C.;
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€
Marsden, S. P.; Kundig, E. P. Chem. Commun. 2008, 4040. (g) Tomita, D.;
Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 6946.
(h) Hanhan, N. V.; Sahin, A. H.; Chang, W.; Fettinger, J. C.; Franz, A. K.
Angew. Chem., Int. Ed. 2010, 49, 744. (i) Trost, B. M.; Zhang, Y. J. Am. Chem.
Soc. 2007, 129, 14548. (j) Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int.
Ed. 2005, 44, 308. (k)Shen,K.;Liu,X.;Zheng, K.;Li,W.;Hu, X.;Lin, L.;Feng,X.
Chem.-Eur. J. 2010, 16, 3736.
(4) For the synthesis of 3,3-disubstituted oxindoles via organocatalytic
asymmetric reactions, see: (a) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed.
2003, 42, 3921. (b) Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.;
Broxterman, Q. B.; Tomasini, C. J. Org. Chem. 2005, 70, 7418. (c) Bella,
M.; Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 3670.
(d) Shaw, S. A.; Aleman, P.; Christy, J.; Kampf, J. W.; Va, P.; Vedejs, E.
J. Am. Chem. Soc. 2006, 128, 925. (e) Ogawa, S.; Shibata, N.; Inagaki, J.;
Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2007, 46, 8666.
(f) Nakamura, S.; Hara, N.; Nakashima, H.; Kubo, K.; Shibata, N.; Toru, T.
Chem.-Eur. J. 2008, 14, 8079. (g) Ishimaru, T.; Shibata, N.; Horikawa, T.;
Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2008,
47, 4157. (h) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org. Lett.
2008, 10, 3583. (i) Sano, D.; Nagata, K.; Itoh, T. Org. Lett. 2008, 10, 1593.
(j) Duffey, T. A.; Shaw, S. A.; Vedejs, E. J. Am. Chem. Soc. 2009, 131, 14.
(k) Jiang, K.; Peng, J.; Cui, H.-L.; Chen, Y.-C. Chem. Commun. 2009, 3955.
(l) Cheng, L.; Liu, L.; Jia, H.; Wang, D.; Chen, Y.-J. Org. Lett. 2009, 11, 3874.
(m) Qian, Z.-Q.; Zhou, F.; Du, T.-P.; Wang, B.-L.; Ding, M.; Zhao, X.-L.;
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D.; Chen, Y.-J. J. Org. Chem. 2009, 74, 4650. (o) Galzerano, P.; Bencivenni,
G.; Pesciaioli, F.; Mazzanti, A.; Giannichi, B.; Sambri, L.; Bartoli, G.;
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S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368. (u) Bui, T.;
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Candeias, N. R.; Barbas, C. F. j. Am. Chem. Soc. 2010, 132, 5574.
A bifunctional thiourea-tertiary amine-catalyzed asym-
metric hydroxymethylation of 3-substituted oxindoles using
paraformaldehyde as the C1 unit was developed. A wide
scope of oxindoles, bearing C3 sterically congested qua-
ternary carbon centers, were smoothly obtained in good
to excellent yields (up to 99%) and high enantioselecti-
vities (up to 91% ee) under mild reaction conditions. A
more significant feature of this approach employs cheap
and readily available paraformaldehyde as a hydroxy-
methylation C1 unit, which is activated by chiral bifunc-
tional thiourea organocatalysts.
Chiral 3,3-disubstituted 2-oxindole substructures are present
in many biologically active natural products and pharmaceutical
compounds.1,2 Recently, some progress has been described
(1) For selected reviews, see: (a) Hibino, S.; Choshi, T. Nat. Prod. Rep.
2001, 18, 66. (b) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42,
36. (c) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945. (d) Marti,
C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (e) Galliford, C. V.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748.
(2) For selected examples, see: (a) Wearing, X. Z.; Cook, J. M. Org. Lett.
2002, 4, 4237. (b) Albrecht, B. K.; Williams, R. M. Org. Lett. 2003, 5, 197.
(c) Huang, A.; Kodanko, J. J.; Overman, L. E. J. Am. Chem. Soc. 2004, 126,
14043. (d) Abadi, A. H.; Abou-Seri, S. M.; Abdel-Rahman, D. E.; Klein, C.;
Lozach, O.; Meijer, L. Eur. J. Med. Chem. 2006, 41, 296. (e) Reisman, S. E.;
Ready, J. M.; Weiss, M. M.; Hasuoka, A.; Hirata, M.; Tamaki, K.; Ovaska,
T. V.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc. 2008, 130, 2087. (f) Ruck,
R. T.; Huffman, M. A.; Kim, M. M.; Shevlin, M.; Kandur, W. V.; Davies,
I. W. Angew. Chem., Int. Ed. 2008, 47, 4711.
(5) For direct aldol reactions involving formaldehyde with transition-
metal catalysts, see: (a) Kuwano, R.; Miyazaki, H.; Ito, Y. Chem. Commun.
1998, 71. (b) Kuwano, R.; Miyazaki, H.; Ito, Y. J. Organomet. Chem. 2000,
603, 18. (c) Fukuchi, I.; Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal.
2007, 349, 509. (d) Mouri, S.; Chen, Z.; Matsunaga, S.; Shibasaki, M. Chem.
Commun. 2009, 5138. (e) Kobayashi, S.; Kokubo, M.; Kawasumi, K.;
Nagano, T. Chem. Asian J. 2010, 5, 490.
(6) For direct aldol reactions involving formaldehyde with organocata-
lysts, see: (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
ꢀ
ꢀ
Angew. Chem., Int. Ed. 2004, 43, 1983. (b) Casas, J.; Sunden, H.; Cordova, A.
Tetrahedron Lett. 2004, 45, 6117. (c) Fujii, M.; Sato, Y.; Aida, T.; Yoshihara,
M. Chem. Express 1992, 7, 309. (d) Boeckman, R. K., Jr.; Miller, J. R. Org.
Lett. 2009, 11, 4544.
4872 J. Org. Chem. 2010, 75, 4872–4875
Published on Web 06/24/2010
DOI: 10.1021/jo100769n
r
2010 American Chemical Society

Liu et al.
JOCNote
SCHEME 1
TABLE 1. Optimization of Reaction Conditionsa
entry
1
2
solvent
time (h)
yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
CHCl3
toluene
EtOAc
(C2H5)2O
CH3CN
DCE
24
24
24
24
15
15
15
8
84 (4a)
84 (4a)
85 (4a)
86 (4a)
87 (4a)
91 (4a)
91 (4a)
96 (4a)
95 (4a)
93 (4a)
96 (4b)
88 (4c)
99 (4a)
99 (4a)
99 (4a)
<5 (4a)
<10 (4a)
98 (4a)
97 (4a)
<10 (4a)
99 (4a)
99 (4a)
(þ) 85
(þ) 74
(-) 72
(-) 74
(-) 86
(þ) 88
(þ) 90
(-) 33
(þ) 58
0
in this area.5-7 However, the use of formaldehyde as a useful
C1 unit in direct catalytic asymmetric aldol reactions is rela-
tively limited.5-7 Presumably, this limitation is due to the
special chemical properties of formaldehyde, such as (i) high
reactivity and (ii) the source of purely monomeric formalde-
hyde (traditionally exists as aqueous formaldehyde solution,
8
1j
16
30
30
15
15
15
15
15
15
2
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
(-) 10c
(-) 8c
(þ) 90
(þ) 86
(þ) 83
ndd
ꢀ
i.e., formalin). On the other hand, Cordova and Boeckman
independently reported the direct enantioselective hydroxy-
methylation of aldehydes utilizing organocatalysts.6b,d In
this context, we envisioned that the widely available para-
formaldehyde would serve as a C1 electrophile instead of
formaldehyde because its polymeric structure allows the
gradual release of monomeric formaldehyde under suitable
reaction conditions. This gradual release is favorable for
keeping a low concentration of formaldehyde monomer in
the reaction system so as to control its high reactivity. On the
other hand, inspired by the dramatic progress on organoca-
talysis over the past decade,8 particularly about the chiral
bifunctional urea and thiourea catalysts,9 we supposed that
these bifunctional catalysts were able to formally transform
the intermolecular reaction into an intramolecular-like reac-
tion due to their concurrently inducing and activating nucleo-
philes (3-substituted oxindoles) and electrophiles (formaldehyde)
for favorable stereoselectivity (Scheme 1). As a continuation
of our studies on organocatalysis,10 herein we describe a
ndd
(þ)87
(þ)86c
ndd,e
DCE
DCE
DCE
40
15
15
(þ) 90f
(þ) 91g
aUnless otherwise noted, reactions were carried out with 2 (0.1 mmol),
3 (3.0 equiv), and catalyst 1 (10 mol %) in 4.0 mL of solvent at rt. bDetermi-
ned by chiral-HPLC analysis. cRun at 45 °C. dNot determined. eRun at 0 °C.
f5 mol % of 1g was used. gThis reaction was carried out with 2a (0.2 mmol),
3 (3.0 equiv), and catalyst 1g (5 mol %) in 4.0 mL of DCE at rt for 15 h.
(7) For some selected examples of indirect asymmetric aldol reaction of
formaldehyde with silyl enolates, see: (a) Ozawa, N.; Wadamoto, M.;
Ishihara, K.; Yamamoto, H. Synlett 2003, 2219. (b) Ishikawa, S.; Hamada,
T.; Manabe, K.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 12236.
(c) Kobayashi, S.; Ogino, T.; Shimizu, H.; Ishikawa, S.; Hamada, T.; Manabe,
K. Org. Lett. 2005, 7, 4729. (d) Kokubo, M.; Ogawa, C.; Kobayashi, S. Angew.
Chem., Int. Ed. 2008, 47, 6909.
(8) For selected reviews on organocatalytic asymmetric reactions, see:
(a) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560.
(b) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (c) Melchiorre,
P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138.
(d) Xu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037.
(9) For selected reviews of bifunctional urea and thiourea catalysts, see:
(a) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. (b) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (c) Connon, S. J.
Chem.;Eur. J. 2006, 12, 5418. (d) Doyle, A. G.; Jacobsen, E. N. Chem. Rev.
2007, 107, 5713. (e) Miyabe, H.; Takemoto, Y. Bull. Chem. Soc. Jpn. 2008, 81,
785. (f) Connon, S. J. Synlett 2009, 354.
FIGURE 1. Chiral organocatalysts evaluated in this study.
(10) (a) Zheng, H.-J.; Chen, W.-B.; Wu, Z.-J.; Deng, J.-G.; Lin, W.-Q.;
Yuan, W.-C.; Zhang, X.-M. Chem.;Eur. J. 2008, 14, 9864. (b) Liao, Y.-H.;
Zhang, H.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron:
Asymmetry 2009, 20, 2397. (c) Xue, Z.-Y.; Jiang, Y.; Yuan, W.-C.; Zhang,
X.-M. Eur. J. Org. Chem. 2010, 616. (d) Chen, W.-B.; Du, X.-L.; Cun, L.-F.;
Zhang, X.-M.; Yuan, W.-C. Tetrahedron 2010, 66, 1441. (e) Liao, Y.-H.;
Chen, W.-B.; Wu, Z.-J.; Du, X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C.
Adv. Synth. Catal. 2010, 352, 827. (f) Zhang, H.; Cun, L.-F.; Zhang, X.-M.;
Yuan, W.-C. Lett. Org. Chem. 2010, 7, 219. (g) Liao, Y.-H.; Liu, X.-L.; Wu,
Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2010, 12, 2896.
bifunctional thiourea-catalyzed direct asymmetric aldol reac-
tion of 3-substituted oxindoles and paraformaldehyde for the
synthesis of diversely structured 3,3-disubstituted 2-oxindoles in
high yields (up to 99%) and high ee (up to 91%).
To demonstrate the working hypothesis, our initial studies
focused on the reaction of N-Boc-oxindole 2a and parafor-
maldehyde (3) in dichloromethane (DCM). As shown in Table 1,
J. Org. Chem. Vol. 75, No. 14, 2010 4873

Liu et al.
JOCNote
we were pleased to discover that all of the diversely struc-
tured thiourea-tertiary amine catalysts11 1a-g (Figure 1)
could catalyze the direct aldol reaction, providing 4a with
a quaternary stereocenter through the hydroxymethylation
of prochiral 3-substituted oxindole (Table 1, entries 1-7). In
particular, catalyst 1g was superior to other catalysts 1a-f in
reactivity, yield, and ee value (Table 1, entries 7 vs 1-6). On
the other hand, the catalytic performance of quinidine (1h)
and quinine (1i) was also surveyed in the model reaction, and
the desired product was obtained in high yield but with poor
enantioselectivity (Table 1, entries 8 and 9). Furthermore, in
sharp contrast, catalyst 1j, derived from quinine with C-9
alcohol-protected by a benzyl group, provided racemic pro-
duct in high yield (Table 1, entry 10). Therefore, these results
indicate that the bifunctionality of chiral thiourea-tertiary
amines is crucial for high levels of stereocontrol. Subsequently,
we explored the effects of the N-protection group of oxindole
with 1g as catalyst. It revealed that N-protection with the
Boc group in oxindoles is crucial for the enantioselectivity
(Table 1, entries 7 vs 11-12).
Afterward, with 1g as catalyst, screening of solvents revea-
led that excellent yields and very high ee’s were obtained
when the reaction was conducted in 1,2-dichloroethane
(DCE) (Table 1, entry 13), CHCl3 (Table 1, entry 14), toluene
(Table 1, entry 15), and CH3CN (Table 1, entry 18). How-
ever, the process proceeded sluggishly and only gave a trace
amount of the desired product in EtOAc (Table 1, entry 16)
and diethyl ether (Table 1, entry 17). As a result, among the
solvents surveyed, the best result was obtained in DCE
(Table 1, entry 13). A further survey of reaction temperature
revealed that the reaction proceeded quickly (2 h) and gave
the product 4a in 97% yield and with 86% ee at 45 °C (Table 1,
entry 19). On the contrary, lowering the reaction tempera-
ture to 0 °C showed a severe adverse effect on the reaction
outcome, as only trace amount of product was observed even
with prolonged reaction times from 15 to 40 h (Table 1, entry 20),
presumably due to the lower temperature, which inhibited
the gradual release of monomeric formaldehyde. As to cata-
lyst loading, to our delight, 5 mol % of 1g made the reac-
tion proceed cleanly after 15 h with 99% yield and a high
enantioselectivity of 90% ee (Table 1, entry 21). Finally,
when we performed the reaction with a slightly higher
concentration of substrate 2a (0.05 M), almost the same
results were obtained as with a lower concentration (Table 1,
entry 22 vs 21).
TABLE 2. Catalytic Asymmetric Hydroxymethylation of Various
3-Substituted Oxindoles with Paraformaldehyde by 1ga
entry
2
yield (%) eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
R2 = 4-ClPhCH2, R4 = H (2d)
R2 = 4-FPhCH2, R4 = H (2e)
R2 = 4-MePhCH2, R4 = H (2f)
R2 = 4-MeOPhCH2, R4 = H (2g)
R2 = 2-MeOPhCH2, R4 = H (2h)
R2 = 3,4-(MeO)2PhCH2, R4 = H (2i)
R2 = Bn, R4 = Br (2j)
89 (4d)
93 (4e)
90 (4f)
94 (4g)
98 (4h)
96 (4i)
85 (4j)
95 (4k)
87 (4l)
93 (4m)
92 (4n)
92 (4o)
92 (4p)
80 (4q)
95 (4r)
90 (4r)
90
90
90
90
84
89
86
90
79
89
85
90
87
85
<5
R2 = Bn, R4 = Me (2k)
R2 = 1-naphthylmethyl, R4 = H (2l)
R2 = 2-thienylmethyl, R4 = H (2m)
R2 = 2-pyridylmethyl, R4 = H (2n)
R2 = n-C4H9, R4 = H (2o)
R2 = n-C3H7, R4 = H (2p)
R2 = Me, R4 = H (2q)
R2 = Ph, R4 = H (2r)
R2 = Ph, R4 = H (2r)
c
-
aUnless otherwise noted, reactions were carried out with 2 (0.2 mmol),
3 (3.0 equiv), and catalyst 1g (5 mol %) in 4.0 mL of solvent at room tem-
perature for 15 h. bDetermined by chiral-HPLC analysis. cThe reaction was
allowed to run for 20 h in DCE with no catalyst.
entries 3-6) substituent incorporation to the benzyl group
were tolerated to the conditions. It is noteworthy that an
o-methoxy group was well tolerated (Table 2, entry 5), and
the sterically demanding product was obtained in excellent
yield (98%) with high enantioselectivity (84% ee). In addition,
the method was compatible with the modification of the benzo
moiety of oxindole core (Table 2, entries 7 and 8). Otherwise,
oxindole 2l bearing a bulky 1-naphtylmethyl group also
provided its product in good yield (87%) and enantioselec-
tivity (79% ee) (Table 2, entry 9). At the same time, oxindoles
containing a heterocycle group, 2-thienylmethyl (Table 2,
entry 10), and 2-pyridylmethyl (Table 2, entry 11), could also
be employed as substrates furnishing very high yields and
ee values. Gratifyingly, C-3 aliphatic substituents led to almost
no deleterious effects on the reactivity and enantioselectivity
(Table 2, entries 12-14). Unfortunately, in the case of 3-phenyl-
oxindole 2r as substrate, the corresponding adduct was
obtained in high to 95% yield but with lower than 5% ee
value (Table 2, entry 15). However, as for this case, when the
reaction was performed under catalyst-free conditions, after
20 h after stirring, we found that the starting material 2r had
completely disappeared by thin-layer chromatography (Table 2,
entry 16). Thus, we assume that this competing background,
nonasymmetric reaction maybe one of the reasons for the
racemic product.
Having established a set of optimal reaction conditions,
we sought to examine the scope of the reaction. Then, a num-
ber of different 3-substitiuted oxindoles were prepared2c,3a,e
and subjected to the optimal conditions. As shown in Table 2,
significant structural variation in the oxindole system could
be accommodated in this reaction. For example, electron-
poor (Table 2, entries 1 and 2) and electron-rich (Table 2,
To determine the absolute configuration of the products,
and to further illustrate the potential utility of this methodo-
logy, the chiral product 4q was readily converted to com-
pound 8 in 85% overall yield and with complete retention of
the stereochemistry over a four-step transformation (Scheme 2).
Gratifyingly, the enantiopurity of compound 8 could be easily
enhanced up to 99% ee via single crystallization (Scheme 2).
The configuration of 8 was assigned as S by comparing
the optical rotation of the synthesized compound with the
(11) For the synthesis of chiral bifunctional thiourea-tertiary amine cata-
lysts, see: (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672. (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119. (c) McCooey, S. H.; Connon, S. J. Angew. Chem., Int.
Ed. 2005, 44, 6367. (d) Berkessel, A.; Cleemann, F.; Mukherjee, S. Angew.
Chem., Int.Ed. 2005, 44, 7466.(e)Li, B.-J.;Jiang,L.;Liu, M.;Chen, Y.-C.;Ding,
L.-S.;Wu,Y.Synlett 2005, 603. (f)Liu, T.-Y.;Long, J.;Li, B.-J.;Jiang, L.;Li, R.;
Wu, Y.; Ding, L.-S.; Chen, Y.-C. Org. Biomol. Chem. 2006, 4, 2097. (g) Kaik,
M.; Gawronask, J. Tetrahedron: Asymmetry 2003, 14, 1559. (h) Berkessel, A.;
Mukherjee, S.; Nuller, T. N.; Cleemann, F.; Roland, K.; Brandenburg, M.;
Neudor, J. M.; Lex, J. Org. Biomol. Chem. 2006, 4, 4319.
4874 J. Org. Chem. Vol. 75, No. 14, 2010

Liu et al.
JOCNote
SCHEME 2
selectivites in the construction of sterically congested quater-
nary carbon centers through hydroxymethylation of oxindole,
and (4) use of cheap and readily available paraformaldehyde
as a useful hydroxymethylation C1 unit, which is activated
by chiral bifunctional thiourea organocatalysts.
Experimental Section
Representative Procedure for the Hydroxymethylation of
3-Substituted Oxindoles with Paraformaldehyde as C1 Unit
(Table 1, Entry 19). In an ordinary vial equipped with a magnetic
stirring bar, to the mixture of 2a (0.2 mmol) and 1g (0.01 mmol)
in 4.0 mL of freshly distilled DCE was added paraformaldehyde
solid (18.0 mg). The reaction mixture was stirred at room tem-
perature for 15 h and was directly loaded onto silica gel and
purified by flash chromatography to give the desired products
4a as a white solid (99% yield, 91% ee): [R]20D =þ25.7 (c 1.26,
CHCl3); mp 109.1-109.9 °C; the ee was determined by HPLC
analysis using a Chiralpak AD-H column (80/20 hexane/i-
PrOH; flow rate 1.0 mL/min; λ = 254 nm; tmajor = 5.53 min,
t
minor =5.02 min); 1H NMR (300 MHz, CDCl3) δ 1.57 (s, 9H),
literature data.12 As no reactions occurred at the stereogenic
center of 4q during the conversion of 4q to 8 (Scheme 2), 4q
was thus also assigned the S configuration. The configura-
tions of all other products were assigned by analogy with this
product. In addition, it is worth emphasizing that (S)-8 may
be convert to (þ)-esermethole and (þ)-physostigmine in light
of other developed methods.12,13
In conclusion, we have developed a bifunctional thiourea-
tertiary amine-catalyzed asymmetric hydroxymethylation of
3-substituted oxindoles using readily available paraformal-
dehyde as the C1 unit. The significant features of this app-
roach are as follows: (1) mild reaction conditions, (2) broad
substrate scope, (3) good to excellent yields and high enantio-
2.45 (br s, 1H), 3.13 (d, J=13.2 Hz, 1H), 3.22 (d, J=13.2 Hz,
1H), 3.88 (d, J = 11.1 Hz, 1H), 4.04 (d, J = 11.1 Hz, 1H),
6.87-6.90 (m, 2H), 7.07-7.17 (m, 5H), 7.22-7.27 (m, 1H), 7.65
(d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 28.0, 40.0,
56.0, 66.3, 84.2, 115.0, 123.5, 124.1, 126.8, 127.8, 128.6, 130.0,
134.7, 140.1, 148.6, 178.0; IR (KBr) ν 3482, 2931, 1739, 1359,
1290, 1150, 1072, 749 cm-1; HRMS (ESI) calcd for C21H23N-
NaO4 [M þ Na]þ 376.1519, found 376.1536.
Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China
(No. 20802074) and the National Basic Research Program of
China (973 Program) (2010CB833300).
(12) Akai, S.; Tsujino, T.; Akiyama, E.; Tanimoto, K.; Naka, T.; Kita, Y.
J. Org. Chem. 2004, 69, 2478.
(13) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S. P.; Overman,
L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488.
Supporting Information Available: Experimental proce-
dures and spectra data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 14, 2010 4875