Highly enantioselective three-component direct mannich reactions of unfunctionalized ketones catalyzed by bifunctional organocatalysts

Article abstract of DOI:10.1021/ol303315c

A highly stereoselective three-component direct Mannich reaction between aromatic aldehydes, p-toluenesulfonamide, and unfunctionalized ketones was achieved through an enolate mechanism for the first time with a bifunctional quinidine thiourea catalyst. The corresponding N-tosylated β-aminoketones were obtained in high yields and excellent diastereo- and enantioselectivities (up to >99:1 dr and >99% ee).

Full text of DOI:10.1021/ol303315c

ORGANIC
LETTERS
2013
Vol. 15, No. 3
508–511
Highly Enantioselective
Three-Component Direct Mannich
Reactions of Unfunctionalized
Ketones Catalyzed by Bifunctional
Organocatalysts
Qunsheng Guo and John Cong-Gui Zhao*
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle,
San Antonio, Texas 78249-0698, United States
E-mail: cong.zhao@utsa.edu.
Received December 3, 2012
ABSTRACT
A highly stereoselective three-component direct Mannich reaction between aromatic aldehydes, p-toluenesulfonamide, and unfunctionalized
ketones was achieved through an enolate mechanism for the first time with a bifunctional quinidine thiourea catalyst. The corresponding
N-tosylated β-aminoketones were obtained in high yields and excellent diastereo- and enantioselectivities (up to >99:1 dr and >99% ee).
The Mannich reaction is a very powerful tool for con-
structing carbonÀcarbon bond in organic chemistry.1 The
reaction is especially useful for the synthesis of β-amino
carbonyl derivatives.1 Due to the importance of the Mannich
products in organic synthesis, various methods for conduct-
ing highly diastereoselective and/or enantioselective Mannich
reactions have been developed in the past.1
mainly those derived from proline,4 chiral Brønsted acids,5
chiral amine thioureas,6 and cinchona alkaloids7 have been
used as the catalysts in Mannich reactions, and high
diastereoselectivities and/or enantioselectivities have been
achieved in many cases.1b,3 Nonetheless, among those re-
ported organocatalyzed direct Mannich reactions, catalysts
(4) For some leading examples, see: (a) List, B.; Pojarliev, P.; Biller,
ꢀ
Since List reported the first example of a proline-cata-
lyzed direct Mannich reaction in 2000,2 organocatalyzed
Mannich reactions have been undergoing vigorous devel-
opment in the past decade.1b,3 Amino acid derivatives,
W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827. (b) Cordova, A.;
Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem.
ꢀ
Soc. 2002, 124, 1842. (c) Cordova, A.; Watanabe, S. I.; Tanaka, F.; Notz,
W.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1866. (d) Carlone,
A.; Cabrera, S.; Marigo, M.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2007, 46, 1101. (e) Frisch, K.; Landa, A.; Saaby, S.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 6058. (f) Ibrahem, I.; Casas, J.;
(1) For reviews on Mannich reactions, see: (a) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069. (b) Kobayashi, S.; Mori, Y.;
Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626. (c) Arend, M.;
Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044. (d)
Hart, D. J.; Ha, D.-C. Chem. Rev. 1989, 89, 1447.
ꢀ
Cordova, A. Angew. Chem., Int. Ed. 2004, 43, 6528. (g) Sunden, H.;
ꢀ
Ibrahem, I.; Eriksson, L.; Cordova, A. Angew. Chem., Int. Ed. 2005, 44,
4877. (h) Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji,
M.; Sakai, K. Angew. Chem., Int. Ed. 2003, 42, 3677. (i) Hayashi, Y.;
Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc. 2003, 125, 11208. (j)
Yang, J. W.; Stadler, M.; List, B. Angew. Chem., Int. Ed. 2007, 46, 609.
(5) For some leading examples, see: (a) Uraguchi, M.; Terada, M.
J. Am. Chem. Soc. 2004, 126, 5356. (b) Terada, M.; Machioka, K.;
Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 10336. (c) Matsubara, M.;
Kawai, N.; Kobayashi, S. Angew. Chem., Int. Ed. 2006, 45, 3814.
(d) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128,
1086. (e) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am.
Chem. Soc. 2007, 129, 6756. (f) Sickert, M.; Schneider, C. Angew. Chem.,
Int. Ed. 2008, 47, 3631.
(2) List, B. J. Am. Chem. Soc. 2000, 122, 9336.
(3) For reviews, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2004, 43, 5138. (b) Marques, M. M. B. Angew. Chem., Int. Ed. 2006,
45, 348. (c) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P.;
Rutjes, F. Chem. Soc. Rev. 2008, 37, 29. (d) Xu, L-. W.; Lu, Y. Org.
Biomol. Chem. 2008, 6, 2047. (e) Bhadury, P. S.; Song, B.-A. Curr. Org.
Chem. 2010, 14, 1989. (f) Benohoud, M.; Hayashi, Y. In Science of
Synthesis, Asymmetric Organocatalysis; List, B., Maruoka, K., Eds.; Georg
Thieme Verlag: Stuttgart, 2012; Vol. 1, pp 73À134. (g) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
r
10.1021/ol303315c
Published on Web 01/23/2013
2013 American Chemical Society

that can perform the three-component direct Mannich
reactions of unfunctionalized ketones or aldehydes are
still very limited because many of the reported catalysts
and/or reaction conditions are not compatible with the in
situ generation of the imines.8,9 To our knowledge, with
the exception of a chiral phosphoric acid reported by
Gong and co-workers,9a all of the other catalysts are
mainly amine derivatives4,9b that catalyze the reaction
through the enamine mechanism.9
direct Mannich reactions of active methylene compounds are
known,6,7 such a three-component direct Mannich reaction
of unfunctionalized ketones has not been reported.9,11
Using benzaldehyde (1a), p-toluenesulfonamide, and
1,2-diphenylethanone (3a) as the model substrates, we
initially screened several chiral Brønsted bases (5À12,
Figure 1) for their ability to effect the desired enolate-
mediated three-component Mannich reactions. The results
are summarized in Table 1.
Recently, we demonstrated that Brønsted base catalysts
are capable of inducing aldol reactions of unfunctionalized
ketones.10a The reaction works through the enolate mech-
anism11 and is complementary to the amine-catalyzed
aldol reactions in terms of the substrate scope.10 Because
the reaction mechanisms of the Mannich and aldol reac-
tions are very similar, we envisioned that Brønsted bases
should be also good catalysts for the Mannich reaction of
unfunctionalized ketones via the enolate mechanism. With
this in mind, we recently realized a TMG-catalyzed high
diastereoselective three-component direct Mannich reac-
tion of unfunctionalized ketones.12 Herein we report a bi-
functional Brønsted base-catalyzed highly enantioselective
and diastereoselective three-component direct Mannich reac-
tion of unfunctionalized ketones. To our knowledge,
although enolate-mediated organocatalyzed enantioselective
(6) For some leading examples, see: (a) Uraguchi, M.; Terada, M.
J. Am. Chem. Soc. 2004, 126, 5356. (b) Terada, M.; Machioka, K.;
Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 10336. (c) Matsubara, M.;
Kawai, N.; Kobayashi, S. Angew. Chem., Int. Ed. 2006, 45, 3814.
(d) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128,
1086. (e) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am.
Chem. Soc. 2007, 129, 6756. (f) Sickert, M.; Schneider, C. Angew. Chem.,
Int. Ed. 2008, 47, 3631.
(7) For some leading examples, see: (a) Robak, M. T.; Trincado, M.;
Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 15110. (b) Wang, C.-J.; Dong,
X.-Q.; Zhang, Z.-H.; Xue, Z.-Y.; Teng, H.-L. J. Am. Chem. Soc. 2008,
130, 8606. (c) Liu, T.-Y.; Cui, H.-L.; Long, J.; Li, B. J.; Wu, Y.; Ding,
L.-S.; Chen, Y.-C. J. Am. Chem. Soc. 2007, 129, 1878. (d) Song, J.;
Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048. (e) McCooey,
S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367. (f) Zhang, H.;
Chuan, Y.-M.; Li, Z.-Y.; Peng, Y.-G. Adv. Synth. Catal. 2009, 351, 2288.
(g) Han, X.; Kwiatkowski, J.; Xue, F.; Huang, K.-W.; Lu, Y. Angew.
Chem., Int. Ed. 2011, 50, 2664.
(8) For examples of Lewis acid catalyzed three-component direct
Mannich reactions of unmodified ketones and aldehydes, see: (a) Xu,
L.-W.; Xia, C.-G.; Li, L. J. Org. Chem. 2004, 69, 8482. (b) Salter, M. M.;
Kobayashi, J.; Shimizu, Y.; Kobayashi, S. Org. Lett. 2006, 8, 3533. (c) Das,
B.; Majhi, A.; Reddy, K. R; Suneel, K. J. Mol. Catal. A: Chem. 2007, 274,
83. (d) Phukan, P.; Kataki, D.; Chakraborty, P. Tetrahedron Lett. 2006, 47,
5523. (e) Rafiee, E.; Eavani, S.; Nejad, F. K.; Joshaghani, M. Tetrahedron
2010, 66, 6858. (f) Kureshy, R. I.; Agrawal, S.; Saravanan, S.; Khan, N. H.;
Shah, A. K.; Abdi, S. H. R.; Bajaj, H. C.; Suresh, E. Tetrahedron Lett. 2010,
51, 489.
(9) For examples of enol-mediated Mannich reactions of unmodified
ketones, see: (a) Guo, Q.-X.; Liu, H.; Guo, C.; Luo, S.-W.; Gu, Y.;
Gong, L.-Z. J. Am. Chem. Soc. 2007, 129, 3790. (b) Yalalov, D. A.;
Tsogoeva, S. B.; Shubina, T. E.; Martynova, I. M.; Clark, T. Angew.
Chem., Int. Ed. 2008, 47, 6624.
Figure 1. Catalysts screened for the Mannich reaction (Ar =
3,5-(CF3)2C6H3À; 1-Nap = 1-naphthyl).
With toluene as the solvent, the reaction catalyzed by
quinidine (5) gave a poor yield (10%) and a low ee value
(45%) of the desired 4a (Table 1, entry 1). Similarly, poor
results were obtained when cupreine (6) was used (Table 1,
entry 2). In contrast, quinidine- and quinine-derived thiour-
eas 7 and 8 led to much improved yields and moderate ee
values (Table 1, entries 3 and 4). To our pleasure, when
quinine- or quinidine-derived thioureas 9, 10, 11, and 12
were applied,13 good yields and high diastereoselectivities as
well as excellent enantioselectivities were obtained (Table 1,
entries 5À8). Catalyst 9 was adopted for further optimiza-
tions (Table 1, entries 9À14) since it yields the highest
product yield and ee value. Toluene (entry 5) was identified
as the best solvent for this reaction since the other tested
solvents all led to less satisfactory results. However, it was
found that the ee value of 4a may be improved to 96% when
the reaction was carried out at 0 °C (entry 14).
(10) (a) Guo, Q.; Bhanushali, M.; Zhao, C.-G. Angew. Chem., Int.
Ed. 2010, 49, 9460. (b) Guang, J.; Guo, Q.; Zhao, J. C.-G. Org. Lett.
2012, 14, 3174.
(11) For examples of enolate-mediated Mannich reactions of thio-
esters, see: (a) Kohler, M. C.; Yost, J. M.; Garnsey, M. R.; Coltart,
D. M. Org. Lett. 2010, 12, 3376. (b) Utsumi, N.; Kitagaki, S.; Barbas,
C. F., III. Org. Lett. 2008, 10, 3405. For examples of enolate-mediated
Mannich reactions of sulfonylimidates, see: (c) Van Nguyen, H.;
Matsubara, R.; Kobayashi, S. Angew. Chem., Int. Ed. 2009, 48, 5927.
(d) Matsubara, R.; Berthiol, F.; Kobayashi, S. J. Am. Chem. Soc. 2008,
130, 1804.
Once the reaction conditions were optimized, the scope
of this reaction was evaluated, and the results are collected
in Table 2.
(13) Catalysts 9À12 were prepared according to the procedures
reported in: (a) Marcelli, T.; van der Haas, R.; van Maarseveen, J. H.;
Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 929. (b) Liu, Y.; Sun, B.;
Wang, B.; Wakem, M.; Deng, L. J. Am. Chem. Soc. 2009, 131, 418.
(12) Guo, Q.; Zhao, J. C.-G.; Arman, H. Tetrahedron Lett.. 2012, 53,
4866.
Org. Lett., Vol. 15, No. 3, 2013
509

Table 1. Catalyst Screening and Condition Optimizations for
the Base-Catalyzed Three-Component Direct Mannich Reactiona
Table 2. Three-Component Direct Mannich Reaction Cata-
lyzed by Bifunctional Catalysts 9 or 10a
X/R1/R2
H/Ph/Ph
1/3/4 time (h) yieldb (%) eec (%)
entry
catalyst
solvent
yieldb (%)
drc
eed (%)
45
entry
1
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
o-xylene
CH2Cl2
Et2O
10
trace
44
49
96
96
78
68
96
95
95
87
60
96
>99:1
1
a/a/a
b/a/b
c/a/c
d/a/d
e/a/e
f/a/f
48
40
48
36
24
24
40
24
48
24
30
35
72
96
24
24
40
48
96
95
88
96
95
97
97
93
96
96
95
95
75
75
95
96d
96e
95g
96
96
2
6
2
4-Me/Ph/Ph
4-MeO/Ph/Ph
4-F/Ph/Ph
3
7
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
60
78e
94
90e
94
92e
92
92
86
72
50
96
3
96
4
8
4
95
5
9
5
4-Cl/Ph/Ph
94
6
10
11
12
9
6
4-Br/Ph/Ph
94
7
7
4-CN/Ph/Ph
4-NO2/Ph/Ph
2-Br/Ph/Ph
g/a/g
h/a/h
i/a/i
97
8
8
93
9
9
95
10
11
12
13
14f
9
10
11
12
13
14
15
16
17
3-Br/Ph/Ph
j/a/j
95
9
H/4-BrC6H4/Ph
H/4-ClC6H4/Ph
H/4-MeOC6H4/Ph
H/Et/Ph
a/b/k
a/c/l
98
9
96
9
THF
a/d/m
a/e/n
a/f/o
a/g/p
f/g/q
96
9
toluene
>99
96
H/PhCH2/Ph
H/Ph/OBoc
a Unless otherwise specified, all reactions were carried out at rt with
benzaldehyde (1a, 0.20 mmol), toluenesulfonamide (2, 0.40 mmol),
ketone 3a (0.40 mmol), and the Lewis base catalyst (0.020 mmol,
>99
>99
>99
4-Br/Ph/OBoc
˚
18f H/4-MeOC6H4/OBoc a/h/r
10 mol %) in the presence of 4 A MS (50.0 mg) in the indicated solvent
(2 mL) for 24 h. b Yield of the isolated product after column chromato-
graphy. c Determined by 1H NMR analysis of the crude reaction
product. d Values of ee were determined by chiral HPLC analysis on a
ChiralCel AD-H column. e The opposite enantiomer was obtained as the
major product in this case. f The reaction was conducted at 0 °C for 48 h.
a Unless otherwise indicated, all reactions were carried out at 0 °C
with aldehyde 1 (0.20 mmol), p-toluenesulfonamide (2, 0.40 mmol),
˚
ketone 3 (0.40 mmol), catalyst 9 (0.020 mmol, 10 mol %), and 4 A MS
(50. 0 mg) in toluene (2.0 mL). b Yield of the isolated product after
column chromatography. Only a single diastereomer was detected by the
1H NMR analysis of the crude reaction product in all cases (dr >99:1)
except for entries 16À18. c Determined by HPLC analysis. d The dr of
this reaction was 93:7. e The dr of this reaction was 92:8. f Catalyst 10
(10 mol %) was used, and the opposite enantiomer was obtained as the
major product. g The dr of this reaction was 90:10.
First, the aldehyde substrates were evaluated using 1,2-
diphenylethanone (3a) and p-toluenesulfonamide (2) asthe
substrates. As the data in Table 2 show, benzaldehyde (1a)
and benzaldehyde derivatives that bear either an electron-
withdrawing or an electron-donating group (1bÀj) all
produce the desired Mannich products 4 in high yields
(g88%) and excellent ee values (93À97% ee) as a single
diastereomer (>99:1 dr, entries 1À10). Next the ketone
substrates were studied using benzaldehyde (1a) and
p-toluenesulfonamide (2) as the imine precursors. Again,
excellent results (>99:1 dr, 96À98% ee) were obtained for
1,2-diphenylethanone derivatives 3b, 3c, and 3d (entries
11À13). The aliphatic 1-phenylbutan-2-one (3e) is slightly
less reactive, and a lower yield (75%) of 4n was obtained,
but this product was obtained in over 99% ee (entry 14).
Excellent results were also obtained for the aliphatic 1,3-
diphenylpropan-2-one (4o, >99:1 dr, 96% ee, entry 15).
Phenacyl tert-butyl carbonate (3g) was also evaluated as
substrate in this reaction, and the corresponding Mannich
product 4p was obtained in 96% yield and >99% ee with a
dr of 93:7 (entry 16). Similarly, when 4-bromobenzalde-
hyde (1f) was used with 3g, the desired product 4q was
obtained in 96% yield and >99% ee with a dr of 92:8
(entry 17). The stereochemistry of the major enantiomer
generated with catalyst 9 was determined to be (2S,3S)
according to the X-ray crystallographic analysis of the
reaction product 4k.14
When an aldehyde was applied under these optimized
conditions, no desired Mannich reaction product was ob-
tained, probably due to the interference of the self-aldol
reaction of the aldehyde. However, when phenylacetalde-
hyde was used with the preprepared N-tosylimine, the
desired Mannich product was obtained in a high yield.
To facilitate the purification and ee value determination,
the primary Mannich product was in situ reduced to the
corresponding alcohol 13, which was obtained in excellent
yield, dr, and ee value (Scheme 1).
The N-tosyl-β-aminoketone products obtained in this
reaction are very useful in organic synthesis. For example,
when catalyst 10 was used under these optimized condi-
tions, the reaction of 1a, 2, and 3h led to the formation of
(2R,3R)-4r with an ee value of >99% and a dr of 90:10
(Table 2, entry 18). This product may be oxidized by using
m-CPBA to produce the corresponding N-tosyl-β-amino
ester 14 (Scheme 2), which may be readily benzoylated to
(15) Ke, B.; Qin, Y.; Zhao, F.; Qu, Y. Bioorg. Med. Chem. Lett. 2008,
18, 4783.
(14) For details, see the Supporting Information.
510
Org. Lett., Vol. 15, No. 3, 2013

PMP16 groups are readily removable during synthesis,
compound 16 may be regarded as a protected paclitaxel
side chain and shouldbe useful inthe synthesisof paclitaxel
(Scheme 2).
Scheme 1. Mannich Reaction between N-Tosylimine and
Phenylacetaldehyde
In summary, we have realized the first enantioselective
enolate-mediated three-component direct Mannich reac-
tion of unmodified ketones using bifunctional cinchona
alkaloid thioureas as the base catalyst. The corresponding
N-tosylated β-aminoketones were obtained in high yields,
high enantioselectivities, and excellent syn diastereoselectiv-
ities. We also demonstrated that, with a preformed imine,
aldehyde may also be used as the substrate in this reaction.
Scheme 2. Synthesis of Protected Paclitaxel Side Chain
Acknowledgment. The generous financial support of
this research from the National Science Foundation
(Grant No. CHE 0909954), the NIH-NIGMS (Grant
No. SC1GM0828718), and the Welch Foundation (Grant
No. AX-1593) is gratefully acknowledged. We also thank
Dr. Hadi Arman (UTSA) for his assistance in the X-ray
crystallographic analyses of the reaction products.
Supporting Information Available. Full experimental
procedures, compound characterization data, ORTEP
drawings, and X-ray data of compound 4k (CIF) and
copies of NMR spectra and HPLC chromatograms. This
material is available free of charge via the Internet at
http://pubs.acs.org.
give compound 15. After removal of the N-tosyl group, the
O-Boc-protected syn-β-amino ester 16 was obtained in
high yield (78% over three steps). Since the Boc15 and
(16) Watson, D. A.; Fan, X.; Buchwald, S. L. J. Org. Chem. 2008,
73, 7096.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
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