Base-catalyzed three-component direct Mannich reaction of enolizable ketones with high syn-selectivities

Article abstract of DOI:10.1016/j.tetlet.2012.06.140

The three-component direct Mannich reaction between aldehydes, p-toluenesulfonamide, and enolizable ketones was achieved for the first time with organic bases as the catalysts. The corresponding N-tosylated β-aminoketones were obtained in high yields and

Full text of DOI:10.1016/j.tetlet.2012.06.140

Tetrahedron Letters 53 (2012) 4866–4869
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Base-catalyzed three-component direct Mannich reaction of enolizable
ketones with high syn-selectivities
⇑
Qunsheng Guo, John Cong-Gui Zhao , Hadi Arman
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-0698, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The three-component direct Mannich reaction between aldehydes, p-toluenesulfonamide, and enolizable
ketones was achieved for the first time with organic bases as the catalysts. The corresponding N-tosylated
b-aminoketones were obtained in high yields and good to excellent diastereoselectivities using TMG as
the catalyst. Through reduction of the ketone group, the reaction product may be converted into b-aminol
with excellent diastereoselectivity.
Received 2 June 2012
Revised 26 June 2012
Accepted 28 June 2012
Available online 6 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Mannich reaction
Diastereoselective
Catalysis
b-Aminoketone
Ketones
1,1,3,3-Tetramethylguanidine
Mannich reaction is one of the most useful methods for the con-
struction of carbon–carbon bonds in organic chemistry.1 The reac-
tion is especially useful for the synthesis of b-amino carbonyl
derivatives.1 Due to the importance of the Mannich products in or-
ganic synthesis, various methods for conducting highly diastereo-
selective and/or enantioselective Mannich reactions have been
developed in the past.1 According to the ways that the reactions
are conducted, Mannich reactions may be generally divided into
direct Mannich reactions and indirect Mannich reactions.1 Because
direct Mannich reaction do not require the use of preformed eno-
lates or their equivalents as the substrates, it has many advantages
over the indirect Mannich reaction, such as better atom economy
and operational simplicity.1
can perform the three-component direct Mannich reactions of
enolizable ketones or aldehydes are relatively limited because
many of the reported catalysts and/or reaction conditions are not
compatible with the in situ generation of the imines. To our knowl-
edge, with the exception of a chiral phosphoric acid reported by
Gong and coworker,9a all the other catalysts are mainly the amine
derivatives4,9b that catalyze the reaction through the enamine
mechanism.9
Although enolate-mediated organocatalyzed direct Mannich
reactions of activated methylene compounds are well-known,6,7
to our knowledge, such an enolate-mediated Mannich reaction of
enolizable ketones or aldehydes has not been reported.9,10 This is
most probably due to the low acidity of the a-proton of these ke-
Since List reported the first example of a proline-catalyzed di-
rect Mannich reaction in 2000,2 organocatalyzed Mannich reac-
tions have been undergoing vigorous developments in the past
decade.1b,3 Amino acid derivatives, mainly those derived from pro-
line,4 chiral Brønsted acids,5 chiral amine thioureas,6 and cinchona
alkaloids7 have been used as the catalysts in the reported Mannich
reactions, and high diastereoselectivities and/or enantioselectivi-
ties have been achieved in many cases.1b,3 Three-component direct
Mannich reactions are arguably the most convenient methods for
conducting Mannich reactions since the imine substrates are also
in situ generated in these reactions. 8 Nonetheless, among those re-
ported organocatalyzed direct Mannich reactions, catalysts that
tone compounds, which is difficult to be deprotonated by organic
bases to become a suitable enolate nucleophile. Most recently,
we have demonstrated that cinchona alkaloid bases are capable
of catalyzing enolate-mediated aldol reactions of ketones.11 The
reaction works through the enolate intermediate in a complete
noncovalent catalysis and is complementary to the amine-cata-
lyzed aldol reactions in terms of the substrate scope.11 Because
the reaction mechanisms of the aldol and Mannich reactions are
very similar, we envisioned that organic Brønsted bases should
be also able to catalyze the Mannich reaction of enolizable ketones
via the enolate intermediate. Herein we wish to report the first
example of a Brønsted base-catalyzed highly syn-selective three-
component direct Mannich reaction of enolizable ketones.
Using benzaldehyde (1a), p-toluenesulfonamide, and 3,4-
dihydronaphthalen-1(2H)-one (2a) as the substrates, we initially
screened several Brønsted bases for their ability to effect the desired
⇑
Corresponding author. Tel.: +1 210 458 5432; fax: +1 210 458 7428.
E-mail address: cong.zhao@utsa.edu (J.C.-G. Zhao).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.140

Q. Guo et al. / Tetrahedron Letters 53 (2012) 4866–4869
4867
Mannich reaction and to control the diastereoselectivity of this reac-
tion. The results are summarized in Table 1. As the data in Table 1
show, when DBU was used as the catalyst in THF, the expected Man-
nich product 3a was obtained in 88% yield with a high dr value of
93:7 after reacting at rt for 15 h (entry 1). A lower yield and a poor
dr value were obtained for 3a when 1,5,7-triazabicyclo[4.4.0]dec-
5-ene (TBD) was used under similar conditions (entry 2). Moreover,
poor conversions were observed when less basic DABCO or quinucli-
dine was used (entries 3 and 4). Similarly, an inorganic base K2CO3
also led to low conversion of the substrate, but the dr value of the ob-
tained product was high (entry 5). In contrast, when 1,1,3,3-tetra-
methylguanidine (TMG) was used, a high yield of 95% and an
excellent dr value of 97:3 were obtained for 3a (entry 6). Thus,
TMG was identified as the best Brønsted base for this reaction. Next
we evaluated the solvent effects on this reaction (entries 7–12).
Among those common organic solvents, THF (entry 6) and toluene
(entry 12) were identified as the best solvents for this reaction. Since
in this reaction 1 equiv of water is formed during the formation of
the imine intermediate, we intentionally added molecular sieves
to the reaction mixture to see whether the reaction can be acceler-
ated with the water removal. As the results show, the reaction in-
deed became much faster when molecular sieves were added
(entries 13 and 14). Under these new conditions, toluene turned
out to be a better solvent than THF because a higher product yield
was obtained (entry 14). The major product obtained in this reaction
was determined to be the syn-diastereomer according to the X-ray
crystallographic analysis of the product 3a (Fig. 1).12
Figure 1. ORTEP drawing of compound 3a.
Table 2
Substrate study I: the aldehydesa
Ts
R1
O
O
HN
TMG
toluene, 4Å MS
R1 CHO+
TsNH
+
R2
2
R2
R3
R3
3
1
2
2a: R2,R3 = -CH2CH2-;
2b: R2 = Ph, R3 = H;
2c: R2 = H, R3 = H.
Once the reaction conditions were optimized, the scope of this
reaction was evaluated, and the results are collected in Tables 2
and 3.13 Firstly, the aldehyde substrates were evaluated using ke-
tones 2a–c and p-toluenesulfonamide as the substrates. As the data
in Table 2 show, when ketone 2a was used, benzaldehyde and its
derivatives that bear either an electron-withdrawing or an elec-
tron-donating group all gave the desired Mannich products 3 in
Entry
R
2
Time (h)
3
Yieldb (%)
drc
1
2
3
4
5
6
7
8
9
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
5
6
5
5
3
3
7
8
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
95
95
95
94
97
95
90
93
86
97
94
65
97:3
95:5
96:4
>99:1
95:5
95:5
93:7
93:7
88:12
95:5
88:12
—
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
2-BrC6H4
3-BrC6H4
c-C6H11
Table 1
Brønsted base-catalyzed three-component direct Mannich reaction of benzaldehyde,
p-toluenesulfonamide, and ketone 2aa
10
11
12d
5
4
72
3j
3k
3l
Ts
c-C6H11
O
O
HN
CHO
catalyst
solvent
a
TsNH
+
+
Unless otherwise indicated, all reactions were carried out at with aldehyde 1
(0.20 mmol), p-toluenesulfonamide (0.40 mmol), ketone (0.40 mmol), TMG
2
2
(0.040 mmol, 20 mol %), and 4 Å MS (50.0 mg) in toluene (0.2 mL) at rt.
1a
2a
3a
b
Yield of the isolated product after column chromatography.
c
Determined by 1H NMR analysis of the crude reaction product.
d
Ketone 2c (1.0 mmol) was used. Since only one stereogenic center was formed
in this case, there was no dr.
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
drc
high yields (P90%) and excellent dr values (P93:7, entries 1–8
and 10), except for 2-bromobenzaldehyde (entry 9), which yielded
slightly lower yield and dr, most likely due to steric effects. Ali-
phatic aldehyde may also be used in this reaction. For example,
when cyclohexanecarbaldehyde was used with 1,2-diphenyletha-
none (2b), the corresponding Mannich product 3k was obtained
in 94% yield with a dr of 88:12 (entry 11). Similarly, the reaction
of cyclohexanecarbaldehyde with acetophenone (2c) also led to
the formation of the desired product 3l in 65% yield (entry 12),
although the reaction was more sluggish as compared with the rest
of reactions. The formation of the major syn-diastereomer was
again established by an NOE experiment on compound 3i.
Next the ketone substrates were studied using benzaldehyde
and p-toluenesulfonamide as the imine precursors. As the data in
Table 3 indicate, besides ketone 2a, chroman-4-one also led to the
formation of 3k as a single syn diastereomer in 95% yield (entry
1). Similar results were also obtained for thiochroman-4-one (entry
2). Cyclohexanone is slightly less reactive, and the product was
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DBU
TBD
DABCO
Quinuclidine
K2CO3
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
THF
THF
THF
THF
THF
THF
CH3OH
DMF
CH2Cl2
Et2O
15
15
15
15
15
15
15
15
15
15
15
15
5
88
79
Trace
Trace
35
95
61
75
67
76
93
95
87
93:7
64:36
ndd
ndd
96:4
97:3
51:49
54:46
94:6
91:9
95:5
97:3
97:3
97:3
1,4-Dioxane
Toluene
THFe
Toluenee
5
95
a
Unless otherwise specified, all reactions were carried out at with benzaldehyde
(1a, 0.20 mmol), toluenesulfonamide (0.40 mmol), ketone 2a (0.40 mmol), and the
base catalyst (0.040 mmol, 20 mol %) in the indicated solvent (0.2 mL) at rt.
b
Yield of the isolated product after column chromatography.
Determined by 1H NMR analysis of the crude reaction product.
c
d
Not determined.
With 4 Å MS (50.0 mg) added.
e

4868
Table 3
Q. Guo et al. / Tetrahedron Letters 53 (2012) 4866–4869
Substrate study II: the ketonesa
Ts
O
O
HN
R1
CHO
TMG
toluene, 4Å MS
TsNH
+
+
R2
2
R2
R1
1a
2
3
Entry Ketone
Time(h) Product
Yieldb (%) drc
O
Ts
O HN
1
5
5
3m 95
>99:1
>99:1
Ph
O
O
O
Ts
O HN
2
3n
3o
96
Ph
S
S
O
Ts
O HN
3
12
15
7
86
78:22
ndd
Figure 2. ORTEP drawing of compound 4.
Ph
O
Ts
ketones as well. For example, the Mannich product of
propiophenone (3p) was obtained in 92% yield with a dr of 88:12
(entry 5), and that of 1,2-diphenylethanone (3q) was obtained in
96% yield as a single diastereomer (entry 6). Acetophenone also par-
ticipates in this reaction, and the corresponding product 3r was ob-
tained in a high yield of 91% (entry 7). As expected, acetone is less
reactive, and the product 3s was obtained in 65% after 48 h of reac-
tion (entry 8).
O HN
4
Trace
92
Ph
O
Ts
O HN
5
3p
3q
88:12
>99:1
Ph
O
Ts
O HN
6
1
96
The N-tosyl-b-aminoketone products obtained in this reaction
are very useful in organic synthesis. For example, we demonstrated
that product 3a may be reduced by using LiAlH4 to produce the cor-
responding N-tosyl-b-aminol compound 4 in 95% yield as a single
diastereomer (dr > 99:1, Scheme 1).13 The newly formed hydroxy-
substituted stereogenic center was found to be anti to the existing
stereogenic centers according to the X-ray crystallographic analysis
of this compound (Fig. 2).14 The tosyl group in 4 may be further re-
moved15 in a two-step sequence to give the Boc-protected anti, syn-
b-aminol 5 in high yield (91% over two steps, Scheme 1)13
In summary, we have realized the first example of a base-cata-
lyzed three-component direct Mannich reaction of enolizable ke-
tones using TMG as the catalyst. The corresponding N-tosylated
b-aminoketones were obtained in high yields and good to excellent
syn diastereoselectivities. The development of an enantioselective
version of this reaction is currently under way and will be reported
in due course.
Ph
Ph
Ph
O
Ts
O HN
e
7
7
3r
3s
91
65
—
Ph
O
Ts
O HN
e
8
48
—
Ph
a
All reactions were carried out at with benzaldehyde (1a, 0.20 mmol), toluene-
sulfonamide (0.40 mmol), ketone 2 (0.40 mmol), TMG (0.040 mmol, 20 mol %), and
4 Å MS (50.0 mg) in toluene (0.2 mL) at rt.
b
Yield of the isolated product after column chromatography.
Determined by 1H NMR analysis of the crude reaction product.
c
d
Not determined.
e
Since only one stereogenic center was formed in this case, there was no dr.
Ts
Ts
O
HN
OH HN
a
b
Acknowledgments
This project was financially supported by the Welch Foundation
(Grant. No. AX-1593) and a partial funding from the National Sci-
ence Foundation (Grant No. CHE 0909954).
4
3a
Boc
O
Ts
Boc
N
HN
Boc
O
Boc
c
Supplementary data
5
Supplementary data (detailed experimental procedures, charac-
terization data of all new compounds, and copy of the NMR spec-
tra) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.140.
Scheme 1. Further elaborations of the reaction product 3a. Reaction conditions: a:
LiAlH4 (3.0 equiv.), THF, °C, 5 h, 95%, dr >99:1; b: Boc2O (4.0 equiv.), Et3N
(4.0 equiv.), DMAP (10 mol %), THF, rt, 24 h, 98%; c: SmI2 (12.0 equiv.), HMPA, THF,
0
Ar, reflux, 6 h, 93%.
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4869
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