List-Barbas-Mannich reaction catalyzed by modularly designed organocatalysts

Article abstract of DOI:10.1021/jo4019304

The List-Barbas-Mannich reaction of ethyl (p-methoxyphenylimino)acetate (p-methoxyphenyl = PMP) with unmodified aldehydes or ketones catalyzed by modularly designed organocatalysts (MDOs) that are self-assembled from proline and cinchona alkaloid thiourea

Full text of DOI:10.1021/jo4019304

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Article
List-Barbas-Mannich Reaction Catalyzed
by Modularly Designed Organocatalysts
Sandun Perera, Debarshi Sinha, Nirmal K Rana, Van Trieu-Do, and John Cong-Gui Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4019304 • Publication Date (Web): 09 Oct 2013
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List-Barbas-Mannich Reaction Catalyzed by Modularly Designed
Organocatalysts
Sandun Perera, Debarshi Sinha, Nirmal K. Rana, Van Trieu-Do, and John Cong-Gui Zhao*
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Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio,
Texas 78249ꢀ0698
Email: cong.zhao@utsa.edu
Abstract: The ListꢀBarbasꢀMannich reaction of ethyl (pꢀmethoxyphenylimino)acetate (pꢀ
methoxyphenyl = PMP) with unmodified aldehydes or ketones catalyzed by modularly designed
organocatalysts (MDOs) that are selfꢀassembled from proline and cinchona alkaloid thioureas
(such as a quinidineꢀderived thiourea) produces the corresponding γꢀoxoꢀαꢀamino acid
derivatives in high yields and excellent stereoselectivities. No solvent is necessary for this
reaction. Aldehydes are especially good substrates for this reaction: The reaction takes only a
few minutes to yield the corresponding ListꢀBarbasꢀMannich products in excellent dr (up to >
99:1) and ee values (up to > 99% ee).
Keywords: Modularly designed organocatalysts, ListꢀBarbasꢀMannich reaction, aldehyde,
ketone, imine, and amino acid derivatives
INTRODUCTION
The Mannich reaction is a highly efficient method for the synthesis of βꢀamino carbonyl
1
compounds. It is also one of the most important carbonꢀcarbon bond formation reactions in
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organic chemistry. Since the seminal work reported by List and Barbas on a prolineꢀcatalyzed
2
direct Mannich reaction, organocatalyzed ListꢀBarbasꢀMannich reactions have been undergoing
3
vigorous development in the past decade. Amino acid derivatives, mainly those derived from
0
1
2
3
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9
0
1
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3
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0
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proline, have been used as the catalysts in ListꢀBarbasꢀMannich reactions, and high
3
,4
diastereoselectivities and/or enantioselectivities have been achieved in many cases.
Organocatalysts selfꢀassembled in situ from precatalysts through hydrogen bonding or
5
,6
ionic interactions have received a lot of attention in recent years, As compared to traditional
organocatalysts, these macromolecular catalysts are very amenable to structure modification.
Moreover, a library of catalysts can be readily obtained for a high throughput screening by
5
,6
simply combining the precatalysts.
Nonetheless, despite the great progresses made on
1
,3
organocatalyzed ListꢀBarbasꢀMannich reactions, reports on conducting asymmetric Listꢀ
7
BarbasꢀMannich reactions using selfꢀassembled organocatalysts are still rare.
A few years ago we reported the modularly designed organocatalysts (MDOs) selfꢀ
8
a
assembled between amino acids and cinchona alkaloid derivatives. We have shown that these
8aꢀc
8d
8e
MDOs are highly efficient catalysts for Michael,
heteroꢀDielsꢀAlder, and aldol reactions.
Since the Mannich reaction and the aldol reaction are very similar in terms of the reaction
mechanism, we reasoned that MDOs should be also good catalysts for the ListꢀBarbasꢀMannich
reaction. Herein, we wish to disclose that MDOs selfꢀassembled from proline and cinchona
alkaloid thioureas are indeed highly efficient catalysts for the ListꢀBarbasꢀMannich reaction
between ethyl (pꢀmethoxyphenylimino)acetate and aldehydes or ketones. Aldehydes are
especially good substrates for this reaction, with which the reaction can be carried out under neat
conditions for just a few minutes to give the desired αꢀamino acid derivatives in high yields and
excellent diastereoselectivities and ee values.
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RESULTS AND DISCUSSION
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Using dodecanal (3a) and ethyl (pꢀmethoxyphenylimino)acetate (4) as the model
substrates, we initially screened MDOs formed in situ in the reaction medium from the
precatalyst modules (Figure 1) to identify the best MDO for the ListꢀBarbasꢀMannich reaction.
The results are summarized in Table 1. When Lꢀproline (1a) and a quinidineꢀderived thiourea 2a
(10 mol % each) were used as the precursors of the MDO in toluene at rt, the desired Mannich
product 5a was obtained in 95% yield with a dr of 95:5 for the major syn product as an
essentially pure enantiomer (ee > 99%, entry 1). Unlike those reported organocatalysts, which
normally take hours to complete this reaction, a high product yield was achieved in just 20 min.
without the need to use a large excess of the aldehyde. In contrast, under identical conditions, the
reactions using these two individual modules as the catalyst did not yield the desired product at
all (entries 2 and 4). Although by prolonging the reaction time, product 5a could be obtained in
poor yields using these two modules individually, the obtained dr and ee values were much
worse (entries 3 and 5). These data unequivocally show that the MDO formed from 1a and 2a is
indeed responsible for the observed catalysis. Similarly, the MDO of Dꢀproline (1b) and 2a
generated the opposite enantiomer of 5a in an equally high dr and ee value, although the reaction
was a little slower (entry 6). We next screened some additional amino acids using 2a as the
8
a
stereocontrolling module. Proline derivatives, such as Lꢀ4ꢀthioproline (1c, entry 7), transꢀ4ꢀ
hydroxyꢀLꢀproline (1d, entry 8), Lꢀprolinamide (1e, entry 9), and (2S,3aS,7aS)ꢀoctahydroꢀ1Hꢀ
indoleꢀ2ꢀcarboxylic acid (1f, entry 10), proved to be bad reactionꢀcenter modules as they
generated low product yields, drs, and ee values. Similarly, Lꢀpipecolic acid (1g, entry 11) and
primary amino acids (S)ꢀβꢀphenylalanine (1h, entry 12) and Lꢀ2ꢀchlorophenylglycine (1i, entry
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3) are also poor reactionꢀcenter modules. Thus, this screen identified proline 1a and 1b as the
best reactionꢀcenter modules.
HO
CO H
H
0
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2
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0
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S
CO H
2
CO H
CO H
CO H
CONH2
2
2
2
2
N
H
N
N
H
N
H
N
H
N
H
H
H
1a
1b
1c
1d
1e
1f
NH2
Cl
NH2
N
NH2
CO H
H
N
N
H
CO H
CO H
2
2
2
Ph
1g
1h
1i
MeO
1
j
S
O
S
Ph
N
S
Ar
Ph
Ar
N
H
NH
N
NH
OH
H
N
NH
Ph
N
NH
H
H
H
N
N
N
N
N
N
H
N
H
N
N
H
H
OMe
OMe
OMe
2a
2b
2c
2d
2e
S
S
Ar
N
O
Ar
N
HN
N
H
HN
N
S
H
N
N
Ph
N
N
N
N
H
H
H
H
S
H
N
Ar
N
H
N
H
MeO
2
f
2g
2h
2i
CF3
iPr
iPr
S
S
S
O
S
NH
NH
CF3
ArHN
NHAr PhHN
NHPh
H N
2
NH2
HN
N
H
iPr
iPr
Ph
CO H
2
2j
2k
2l
2m
2n
Figure 1: Precatalyst modules tested in the ListꢀBarbasꢀMannich reaction [Ar = 3,5ꢀ
(CF ) C H ꢀ]
3
2
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Table 1: Catalyst screening and reaction condition optimization for the ListꢀBarbasꢀMannich
a
reaction
PMP
O
PMP
H
O
HN
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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50
51
52
53
54
55
56
57
58
59
60
N
1/2
+
H
toluene, rt H
CO Et
2
EtO C
2
C H -n
1
0
21
C H -n
10 21
3a
4
5a
c
entry
modules
time
(min)
20
20
480
20
yield
(%)
95
0
24
0
22
92
<5
0
<5
<5
44
40
38
93
90
94
51
92
84
51
91
90
64
83
76
35
0
dr
ee
(%)
b
d
1
2
2a
ꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1a
1a
1a
ꢀ
95:5
ꢀ
47:53
ꢀ
35:65
95:5
53:47
>99
ꢀ
e
ꢀ
nd
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
ꢀ
0
>99
nd
ꢀ
1200
30
f
1b
1c
1d
1e
1f
1g
1h
1i
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1j
180
120
240
240
120
180
180
30
150
45
240
30
15
240
50
20
240
30
50:50
50:50
59:41
29:71
41:59
92:8
91:9
93:7
88:12
91:9
97:3
nd
nd
81
0
0
1
2
g
13
14
0
93
96
95
77
>99
96
85
96
95
90
92
92
0
15
16
17
18
19
2g
2h
2i
2j
2j
2
2
2
2
24
25
0
1
2
3
96:4
94:6
h
80:20
55:45
78:22
75:25
38:62
ꢀ
h
h
2k
2l
2m
2n
50
240
30
2
2
6
7
ꢀ
a
Unless noted otherwise, all reactions were carried out with 3a (0.24 mmol, 1.2 equiv.), 4 (0.20 mmol) and the
specified catalyst modules (0.020 mmol, 10 mol % each) in toluene (1.0 mL) at room temperature (ca. 25 °C).
b
c
1
Yield of isolated product after column chromatography. Determined by H NMR analysis of the crude reaction
d
e
f
mixture. Determined by HPLC analysis of the purified product on a ChiralPak IC column. Not determined. The
opposite enantiomer was obtained as the major product. The anti diastereomer was obtained in 69% ee. Et N
g
h
3
(
0.020 mmol, 10 mol %) was also added.
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Using 1a as the reactionꢀcenter module, we next screened different stereocontrolling modules.
Besides quinidine thiourea 2a, cinchonineꢀderived thioureas 2b and 2c also generated product 5a
in high yields and excellent dr and ee values, although the reactions were slower (entries 14 and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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9
0
15). Similarly, high product yield, dr, and ee value were also obtained for a quinidineꢀderived
urea 2d (entry 16). However, a lower product ee value and dr were obtained when quinidine (2e)
was used. Moreover, the reaction was also much slower (entry 17). When the quinineꢀderived
thiourea 2f was employed, the high reactivity and stereoselectivity were restored (entry 18).
Slightly inferior yield and ee value were obtained with a cinchonidineꢀderived thiourea 2g (Table
1, entry 19), but the dr was slightly higher than that obtained with 2f. When a
cyclohexanediamineꢀderived thiourea 2h (entry 20) was applied, the reaction was very sluggish
and the ee value obtained was much lower (85% ee). Nonetheless, good results were also
obtained for a quinidineꢀderived 6′ꢀthiourea 2i (entry 21). To further elucidate the role of the
cinchona alkaloid thioureas in this reaction, the reaction was also conducted with 1a and an
achiral thiourea 2j in the presence of a tertiary amine (Et N). As the results in Table 1 show,
3
although this mixture shows good reactivity and a good product ee value (95% ee) was obtained,
the dr ratio obtained was much lower (only 80:20, entry 22). In the absence of Et N, the
3
combination of 1a and 2j was much less reactive, and a poor dr (55:45) and a lower ee value of
90% were obtained (entry 23). Similarly, the combinations of 1a and achiral thioureas 2k and 2l
gave worse results in terms of the diastereoselectivities and ee values in the presence of Et N
3
(entries 24 and 25) as compared to those of the MDO of 1a and 2a (entry 1). Additionally, the
combination of 1a and an achiral urea 2m also led to poor results (entry 26). Thus, the cinchona
thiourea module is essential for achieving the optimal stereoselectivities in this reaction. On the
other hand, poor results were also obtained with the combination of 1j and 2n, in which the
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amine and thiourea moieties were switched among the reactionꢀcenter and the stereocontrolling
modules (entry 27). Through the above screening, the combination of 1a and 2a was identified as
the best MDO in terms of both the reactivity and stereoselectivity (entry 1). The opposite
enantiomer of product 5a may be readily obtained using the MDO of 1b and 2a (entry 6).
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13
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21
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25
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a
Table 2: Effects of different solvents on the ListꢀBarbasꢀMannich reaction
PMP
O
PMP
H
O
HN
N
1a/2a
+
H
solvent, rt H
CO Et
2
EtO C
2
C H -n
1
0
21
C H -n
10 21
3a
4
5a
b
c
d
entry solvent time (min) yield (%)
dr
ee (%)
>99
97
>99
94
>99
94
94
94
>99
94
>99
>99
99
1
2
3
4
5
6
7
8
9
1
toluene
toluene
benzene
xylene
hexane
CCl4
20
50
20
20
25
20
20
15
10
50
< 5
10
25
90
150
95
93
95
94
94
94
92
92
95
90
98
92
85
50
79
95:5
94:6
92:8
e
98:2
90:10
>99:1
98:2
94:6
>99:1
95:5
>99:1
97:3
90:10
50:50
80:20
CH Cl
2
2
THF
DMSO
DMSO
neat
neat
neat
f
0
11
12
g
h
i
13
14
15
neat
dioxane
96
98
j
a
Unless noted otherwise, all reactions were carried out with 3a (0.24 mmol, 1.2 equiv.), and the imine 4 (0.20 mmol)
in the presence of Lꢀproline (1a, 0.020 mmol, 10 mol %) and quinidine thiourea (2a, 0.020 mmol, 10 mol %) in 1
mL of specified solvent at room temperature (ca. 25 °C). Yield of isolated product after column chromatography.
Determined by H NMR analysis of the crude reaction mixture. Determined by HPLC analysis of the purified
b
c
1
d
e
f
g
product on a ChiralPak IC column. The reaction was carried out at 0 °C. 10 mol % of 1a was used only. The
h
i
loading of 1a and 2a was 5 mol % each. The loading of 1a and 2a was 3 mol % each. The loading of 1a and 2a
j
was 1 mol % each. 10 mol % 1a was used in 0.20 mL of 1,4ꢀdioxane.
The reaction conditions were further optimized for the MDO of 1a/2a and the results are
summarized in Table 2. Common organic solvents only show some modest influence on the
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reactivity and stereoselectivity of this MDOꢀcatalyzed ListꢀBarbasꢀMannich reaction (entries 1ꢀ
9). Among these screened solvents, the best results were obtained in DMSO, since only the syn
product was formed as a single enantiomer (entry 9). While proline itself has been reported to be
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
a good catalyst for the ListꢀBarbasꢀMannich reaction of aldehydes in DMSO, we found that,
under identical conditions, the reaction catalyzed by Lꢀproline alone was slower and led to a
slightly lower dr and ee value of 5a. Most gratifyingly, we found that the presence of a solvent
was not necessary for this reaction: Under neat conditions, the reaction finishes almost
instantaneously, and the product was obtained almost quantitatively as a single syn diastereomer
(dr > 99:1) with >99% ee (entry 11). When the catalyst loading was reduced to 5 mol %, the
reaction took 10 min to finish, yielding product 5a in very similar stereoselectivities (entry 12).
However, further lowering the catalyst loading led to poorer results (entries 13 and 14). In order
to make sure that the increased reactivity and stereoselectivity achieved by the MDO of 1a/2a
were not simply due to the increased solubility of proline in the organic solvents (through the
formation of a salt), a control reaction was also conducted using a high concentration of Lꢀ
proline in 1,4ꢀdioxane, in which Lꢀproline has good solubility. As the data in Table 2 show, the
reaction was much slower, and the diastereoselectivity and ee value obtained were also lower
(entry 15). Thus, there are some synergistic effects by forming the MDO.
Once the reaction conditions were optimized, the reaction scope was then established by
varying the donor substrates. Since 5 mol % and 10 mol % catalyst loadings generated slightly
different results for our model substrate 3a, both loadings were used for each of these substrates.
The results are summarized in Table 3. As is evident from the data in Table 3, straightꢀchain
aliphatic aldehydes, such as, dodecanal (3a, entries 1 and 2), nonanal (3b, entries 3 and 4),
heptanal (3c, entries 5 and 6), pentanal (3d, entries7 and 8), and propanal (3e, entries 9 and 10),
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all generate the synꢀdiastereomers as a pure enantiomer (ee >99%) with excellent
diastereoselectivities. Similarly, the Mannich product of dihydrocinnamaldehyde (3f) was
obtained in high dr and ee values (entries 11 and 12). Excellent results were also obtained with
the branched 3ꢀmethylbutanal (3g, entries 13 and 14). For these aldehyde substrates, it was
found that these two loadings did not show any difference in the product ee values, although the
reactions were faster with the 10 mol % loading and sometimes the dr were also slightly higher.
Ketones may also be applied in this reaction, although a higher loading of 10 equivalents is
necessary because the reactions with ketones are slower. Cyclohexanone (3h) leads to the desired
Mannich product 5h in 98% ee with a 91:9 dr in 60 min. with a loading of 5 mol % catalyst
10
11
12
13
14
15
16
17
18
19
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23
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47
48
49
50
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53
54
55
56
57
58
59
60
(entry 15) or 40 min. with a loading of 10 mol % (entry 16). In contrast, a much lower dr (around
3:1) and ee value (70%) were obtained when 4ꢀoxacyclohexanone (3i) was applied (entries 17
and 18). When acetone (3j) was employed as the donor substrate, the expected Mannich product
5j was obtained in 84% ee (entries 19 and 20). The reaction with a 10 mol % catalyst loading
(entry 20) was much faster than that of 5 mol % loading (entry 19).
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1
1
1
1
1
1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
Table 3: Substrate Scope of the ListꢀBarbasꢀMannich reaction
PMP
O
PMP
H
O
HN
N
1a/2a
R1
+
R1
CO Et
rt
2
R2
EtO C
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R2
5
3
4
1
2
c
entry
1
R
R
3/5
time yield
min) (%)
dr
ee
(%)
b
d
(
10
<5
10
<5
10
<5
10
<5
10
<5
10
<5
10
<5
60
40
60
30
120
60
92
98
88
94
89
98
92
93
88
95
92
96
85
95
89
92
70
85
77
80
97:3
>99
>99
>99
>99
>99
>99
>99
e
H
CH (CH ) ꢀ
3
2 9
a
b
c
d
e
f
2
>99:1
95:5
97:3
92:8
97:3
98:2
98:2
95:5
95:5
96:4
96:4
96:4
98:2
91:9
91:9
76:24
75:25
3
4
e
H
H
H
H
H
H
CH (CH ) ꢀ
3 2 6
5
6
e
CH (CH ) ꢀ
3 2 4
7
8
e
CH (CH ) ꢀ
3 2 2
>99f
9
1
1
12
13
>99
e
CH3ꢀ
f
0
1
>99
f
94f
e
PhCH2ꢀ
94
>99
>99
98
e
(CH ) CHꢀ
3
2
g
h
i
14
15
16
17
g
e, g
g
ꢀ(CH ) ꢀ
2 4
98
70
70
84
e, g
g
ꢀ(CH ) OCH ꢀ
2 2 2
18
1
2
9
0
e, g
Me
H
j
84
a
Unless otherwise specified, the reactions were carried out with compound 3 (0.24 mmol, 1.2 equiv) and the imine 4
0.20 mmol) in presence of Lꢀproline (1a, 0.010 mmol, 5.0 mol %) and quinidine thiourea (2a, 0.010 mmol, 5.0 mol
) under neat condition at room temperature (ca. 25 °C). Yield of isolated product 5 after column chromatography.
Determined by analysis of H NMR of the crude reaction mixture. Determined by HPLC analysis of the purified
product using a ChiralPak IC column. The absolute configuration of the products was assigned by comparing the
(
b
%
c
1
d
e
observed spectral data and optical rotation values with the reported data. Carried out with 1a (0.020 mmol, 10.0 mol
) and 2a (0.020 mmol, 10.0 mol %). Determined by using the corresponding reduced aminol. 2.0 mmol (10.0
f
g
%
equiv.) of the ketone was used.
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S
S
Ar1
Ar1
HN
N
N
NH
O
H
H
PMPHN
NH
Ar2
Ar2
NH
H
CHO
favored
favored
O C
2
O C
CO Et
2
2
H
PMP
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
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N
N
C H -n
10 21
N
PMP
N
O
C
C
H
OEt
C H -n
H
OEt
C H -n
1
0 21
10 21
NHPMP
MDO of
OHC
MDO of
CO Et
1
a/2a
2
1a/2f
C H -n
1
0 21
5a
S
Ar1
N
NH
H
NHPMP
OHC
Ar2
NH
H
favored
ent-5a
O C
2
PMP
EtO C
2
H
O
N
N
C H -n
10 21
C
H
C H -n
10 21
EtO
F3C
MDO of
b/2a
OMe
1
2
Ar =
; Ar =
1
N
F3C
Scheme 1: Proposed Favored Transition States for the MDOꢀCatalyzed ListꢀBarbasꢀMannich
Reactions
1
The relative stereochemistry was assigned by comparing the HNMR spectra of the
aldehyde Mannich products obtained with MDO of 1a/2a with the reported data. The absolute
stereochemistry of was assigned as (2S,3S) by comparing the measured optical rotations of
compounds 5b and 5j with the reported data. Moreover, the major enantiomers obtained in our
study is the same as those out of Lꢀproline catalysis, which is known to yield (2S,3S) products in
9
such a ListꢀBarbasꢀMannich reaction. Our data also indicate that the product absolute
configuration depends only on the absolute stereochemistry of the reactionꢀcenter module,
whereas the cinchona alkaloid thioureas do not affect the stereochemical outcome (Table 1).
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
These results may be explained by the proposed transition states in Scheme 1. As shown in
Scheme 1, dodecanal (3a) reacts with the Lꢀproline moiety (1a) of the MDOs to form an (E)ꢀ
enamine, whereas ethyl (pꢀmethoxyphenylimino)acetate (4) is hydrogenꢀbonded to the thiourea
moiety of the MDOs. In both cases of the MDOs of 1a/2a and 1a/2f, the attack of the enamine
onto the Si face of imine 4 is favored. Thus, both MDOs of 1a/2a (Table 1, entry 1) and 1a/2f
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Table 1, entry 18) should produce the same enantiomers of the synꢀ5a, even though these two
MDOs are pseudo diastereomeric (Scheme 1, upper equations). On the other hand, the (E)ꢀ
enamine formed between Dꢀproline and the MDO of 1b/2a attacks the Re face of the imine in the
favored transition state (Scheme 1, lower equation), which should lead to the formation of the
enantiomer of synꢀ5a (Table 1, entry 6). Thus, although the cinchona thiourea modules are
crucial for achieving the observed high stereoselectivities, they do not cause stereochemical
switches in the ListꢀBarbasꢀMannich products.
CONCLUSION
In summary, MDOs selfꢀassembled from proline and cinchona alkaloid thioureas are high
efficient catalysts for the ListꢀBarbasꢀMannich reaction of aldehydes and ketones with ethyl (pꢀ
methoxyphenylimino)acetate. The desired ListꢀBarbasꢀMannich products may be obtained in
excellent diastereoselectivities (up to > 99:1) and ee values (up to > 99% ee) in short times under
solventꢀfree conditions.
EXPERIMENTAL SECTION
General Experimental Methods: All reactions were carried out in oven dried glassware.
Solvents were dried using standard protocols. Aldehydes and ketones were freshly distilled
before use. Ethyl (pꢀmethoxyphenylimino)acetate (4) was prepared following the known
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procedure. Precatalyst modules 1a-1i, 2e and 2k were commercially available. Precatalyst
1
1
11
11
12
13
14
15
14
14
modules 1j, 2a-2d, 2f-2g, 2h, 2i, 2j, 2l , 2m and 2n were synthesized following
1
13
the reported procedures. H NMR (300 or 500 MHz) and C NMR (75 or 125 MHz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
respectively) spectra were recorded at 25 ºC using CDCl as solvent. Known compounds were
3
1
6ꢀ19
identified by comparing their spectral and optical data with those reported in literature.
High
resolution mass spectra were recorded using electrospray ionization (ESI) technique with a TOF
analyzer.
General Procedure for the List-Barbas-Mannich reaction catalyzed by modularly designed
organocatalyst: LꢀProline (1a, 2.4 mg, 0.020 mmol, 10 mol %) and quinidineꢀderived thiourea
2a (11.9 mg, 0.020 mmol, 10 mol %) were added to dodecanal (3a, 44.2 mg, 0.24 mmol, 1.2
equiv.) while stirring at rt. (Note: Precatalysts 1a and 2a were first taken in 1.0 mL of the
corresponding solvent and the mixture was stirred for 15 min. before the addition of aldehyde, if
the reaction was conducted in a solvent). The mixture was further was stirred at room
temperature for 10 min. Then the imine (4, 41.4 mg, 0.20 mmol) was added. The reaction
finished almost instantaneously (monitored by TLC). Upon completion, the whole reaction
mixture was transferred to a column packed with silica gel and hexane and eluted with a 90:10
hexane/EtOAc mixture to yield product 5a as a colorless gummy liquid (76.7 mg, 98% yield; dr
>99:1, >99% ee).
(2S,3S)-Ethyl 3-formyl-2-[(4-methoxyphenyl)amino]tridecanoate (5a): Colorless gummy
25
1
liquid; 76.7 mg, 98% yield; dr > 99:1, >99% ee; [α]D = ꢀ36.5 (c = 1.0, CH Cl ); H NMR
2
2
(CDCl , 500 MHz): δ 9.71 (d, J = 1.9 Hz, 1H), 6.77 – 6.75 (m, 2H), 6.66 – 6.63 (m, 2H), 4.34
3
(dd, J = 9.7, 4.9 Hz, 1H), 4.23 – 4.12 (m, 2H), 3.93 (d, J = 9.9 Hz, 1H), 3.74 (s, 3H), 2.71 (dtd, J
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
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5
5
5
5
5
5
5
5
5
6
=
6.7, 4.8, 1.9 Hz, 1H), 1.86 (ddd, J = 18.7, 9.2, 4.7 Hz, 1H), 1.65 – 1.53 (m, 1H), 1.41 (dd, J =
1
3
8
2
2
.9, 4.0 Hz, 1H), 1.35 – 1.18 (m, 18H), 0.88 (t, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl ) δ
3
02.9, 172.6, 153.4, 140.6, 116.2, 114.9, 61.7, 58.5, 55.8, 53.9, 32.0, 29.71, 29.69, 29.68, 29.5,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
9.4, 27.6, 25.3, 22.8, 14.3, 14.3. νmax (neat, cm ): 2922, 2852, 1723, 1511, 1464, 1443, 1239,
+
1180, 1033, 821; HRMS (EI) calcd. m/z for C H NO [M+H] = 392.2801, found 392.2795.
2
3
38
4
1
6
(2S,3S)-Ethyl 3-formyl-2-[(4-methoxyphenyl)amino]decanoate (5b): Colorless gummy
2
5
1
liquid; 65.7 mg, 94% yield; dr = 97:3, >99% ee; [α]D = ꢀ21.5 (c = 1.0, CH Cl ); H NMR (500
2
2
MHz, CDCl ) ) δ 9.71 (d, J = 1.9 Hz, 1H), 6.77 – 6.75 (m, 2H), 6.66 – 6.64 (m, 2H), 4.34 (d, J =
3
4.9 Hz, 1H), 4.22 – 4.13 (m, 2H), 3.96 (s, 1H), 3.73 (s, 3H), 2.71 (dtd, J = 6.7, 4.8, 1.9 Hz, 1H),
1.86 (ddd, J = 18.8, 9.2, 4.7 Hz, 1H), 1.60 (ddd, J = 14.2, 10.1, 4.8 Hz, 1H), 1.47 – 1.37 (m, 1H),
1
3
1.36 – 1.21 (m, 12H), 0.88 (t, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl ) δ 202.8, 172.6,
3
153.4, 140.6, 116.2, 114.9, 61.7, 58.5, 55.8, 53.9, 31.9, 29.6, 29.1, 17.6, 15.3, 22.7, 14.3, 14.2.
9
,16
(2S,3S)-Ethyl 3-formyl-2-[(4-methoxyphenyl)amino]octanoate (5c):
Colorless gummy
2
5
1
liquid; 63.0 mg, 98% yield; dr = 97:3, >99% ee; [α]D = ꢀ28.4 (c = 1.0, CH Cl ); H NMR (500
2
2
1
MHz, CDCl ) H NMR (500 MHz, CDCl ) δ 9.72 (d, J = 1.9 Hz, 1H), 6.79 – 6.76 (m, 2H), 6.68
3
3
– 6.64 (m, 2H), 4.36 (d, J = 5.0 Hz, 1H), 4.22 – 4.15 (m, 2H), 3.75 (s, 3H), 2.73 (dtd, J = 6.7,
4.7, 1.9 Hz, 1H), 1.87 (ddd, J = 14.1, 9.4, 5.0 Hz, 1H), 1.63 – 1.56 (m, 1H), 1.45 – 1.39 (m, 1H),
13
1.36 – 1.28 (m, 5H), 1.24 (t, J = 7.1 Hz, 3H), 0.91 – 0.87 (m, 3H); C NMR (125 MHz, CDCl )
3
δ 202.9, 172.6, 154.5, 140.5, 116.3, 114.9, 61.7, 58.6, 55.8, 53.8, 31.8, 27.3, 25.2, 22.5, 14.3,
4.1.
1
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(
2S,3S)-Ethyl 3-formyl-2-[(4-methoxyphenyl)amino]hexanoate (5d):
Colorless gummy
2
5
1
liquid; 54.6 mg, 93% yield; dr = 98:2, >99% ee; [α]D = ꢀ36.4 (c = 1.0, CH Cl ); H NMR (500
2
2
MHz, CDCl ) δ 9.71 (d, J = 1.9 Hz, 1H), 6.85 – 6.70 (m, 2H), 6.70 – 6.58 (m, 2H), 4.41 – 4.29
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
43
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45
46
47
48
49
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52
53
54
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57
58
59
60
(
m, 1H), 4.23 – 4.12 (m, 2H), 3.95 (s, 1H), 3.73 (s, 3H), 2.77 – 2.68 (m, 1H), 1.92 – 1.81 (m,
1H), 1.62 – 1.53 (m, 1H), 1.46 (tdd, J = 10.1, 7.4, 5.2 Hz, 1H), 1.42 – 1.32 (m, 1H), 1.23 (t, J =
13
7
.1 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H); C NMR (125 MHz, CDCl ) δ 202.7, 172.5, 153.4, 140.6,
3
1
16.2, 114.9, 61.7, 58.5, 55.8, 53.6, 27.4, 20.9, 14.3, 14.2.
9,17,18
(2S,3S)-Ethyl 2-[(4-methoxyphenyl)amino]-3-methyl-4-oxobutanoate (5e):
Colorless
1
gummy liquid; 50.4 mg, 95% yield; dr = 95:5, >99% ee; H NMR (500 MHz, CDCl ) δ 9.73 (d,
3
J = 0.7 Hz, 1H), 6.81 – 6.71 (m, 2H), 6.71 – 6.61 (m, 2H), 4.46 (s, 1H), 4.19 (dtt, J = 10.8, 7.1,
3
.7 Hz, 2H), 3.92 (s, 1H), 3.74 (s, 3H), 2.88 (qdd, J = 7.2, 4.4, 0.7 Hz, 1H), 1.28 – 1.19 (m, 6H);
1
3
C NMR (125 MHz, CDCl ) δ 201.9, 172.5, 153.6, 140.6, 116.5, 114.9, 61.7, 58.7, 55.8, 48.4,
3
1
4.3, 9.2. Enantiomeric excess was determined for the corresponding alcohol, after reduction of
the Mannich product.
16,18
(
2S,3S)-Ethyl 3-benzyl-2-((4-methoxyphenyl)amino)-4-oxobutanoate (5f):
Colorless
1
gummy liquid; 65.5 mg, 96% yield; dr = 96:4, 94% ee; H NMR (500 MHz, CDCl ) δ 9.77 (d, J
3
=
1.1 Hz, 1H), 7.33 (dd, J = 10.4, 4.2 Hz, 2H), 7.28 – 7.20 (m, 3H), 6.78 – 6.68 (m, 2H), 6.54 –
.45 (m, 2H), 4.34 – 4.27 (m, 1H), 4.18 – 4.06 (m, 3H), 3.73 (s, 3H), 3.25 (dd, J = 14.0, 7.4 Hz,
1H), 3.13 (tdd, J = 7.3, 4.4, 1.1 Hz, 1H), 2.98 (dd, J = 14.0, 7.0 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H);
6
1
3
C NMR (125 MHz, CDCl ) δ 201.9, 201.9, 172.2, 153.3, 140.2, 138.1, 129.2, 128.4, 127.0,
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5
5
5
6
1
16.0, 114.9, 61.8, 57.5, 55.6, 31.7, 14.3. Enantiomeric excess was determined for the
corresponding alcohol, after reduction of the Mannich product.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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0
16,18,19
(2S,3S)-Ethyl
3-formyl-2-[(4-methoxyphenyl)amino]-4-methylpentanoate
(5g):
25
Colorless gummy liquid; 55.7 mg, 95% yield; dr = 98:2, >99% ee; [α]D = ꢀ43.2 (c = 1.0,
1
CH Cl ); H NMR (500 MHz, CDCl ) δ 9.79 (d, J = 3.0 Hz, 1H), 6.80 – 6.76 (m, 2H), 6.68 –
2
2
3
6.65 (m, 2H), 4.33 (dd, J = 10.2, 6.9 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 3.87 (d, J = 10.2
Hz, 1H), 3.75 (s, 3H), 2.56 (td, J = 7.1, 3.0 Hz, 1H), 2.32 (dq, J = 13.9, 6.9 Hz, 1H), 1.22 (t, J =
13
7.1 Hz, 3H), 1.17 (d, J = 6.9 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H); C NMR (125 MHz, CDCl ) δ
3
203.9, 172.8, 153.2, 140.3, 115.9, 115.0, 61.6, 59.8, 57.1, 55.8, 26.4, 21.1, 19.4, 14.3.
1
6,18
(S)-Ethyl 2-[(4-methoxyphenyl)amino]-2-[(S)-2-oxocyclohexyl]acetate (5h):
Colorless
2
5
1
gummy liquid; 56.2 mg, 92% yield; dr = 91:9, 98% ee; [α]D = ꢀ38.6 (c = 1.0, CH Cl ); H
2
2
NMR (500 MHz, CDCl ) δ 6.79 – 6.74 (m, 2H), 6.74 – 6.70 (m, 2H), 4.23 (d, J = 5.1 Hz, 1H),
3
4.18 – 4.10 (m, 2H), 3.73 (s, 3H), 2.85 – 2.77 (m, 1H), 2.49 – 2.42 (m, 1H), 2.36 – 2.26 (m, 1H),
2.20 (ddd, J = 9.1, 5.7, 2.7 Hz, 1H), 2.09 – 2.03 (m, 1H), 1.98 – 1.92 (m, 1H), 1.81 (ddd, J =
1
3
25.5, 12.6, 3.5 Hz, 1H), 1.71 – 1.64 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H); C NMR (125 MHz,
CDCl ) δ 210.2, 173.6, 153.1, 141.2, 116.2, 114.8, 61.3, 58.2, 55.9, 53.7, 42.0, 29.7, 27.0, 24.9,
3
14.3.
1
6
(S)-Ethyl 2-[(4-methoxyphenyl)amino]-2-[(R)-4-oxotetrahydro-2H-pyran-3-yl]acetate (5i):
25
Colorless gummy liquid; 52.2 mg, 85% yield; dr = 75:25; 70% ee [α]D = ꢀ51.6 (c = 1.0,
1
CH Cl ); H NMR (500 MHz, CDCl ) δ 6.80 – 6.74 (m, 2H), 6.74 – 6.68 (m, 2H), 4.25 (d, J =
2
2
3
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.7 Hz, 1H), 4.21 – 4.07 (m, 4H), 4.01 (dd, J = 11.5, 8.2 Hz, 1H), 3.91 (ddd, J = 11.3, 7.6, 5.5
1
3
Hz, 1H), 3.74 (s, 3H), 2.96 – 2.87 (m, 1H), 2.64 – 2.53 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H); C
NMR (125 MHz, CDCl ) δ 206.0, 172.7, 153.5, 140.9, 116.4, 115.0, 69.7, 68.2, 61.7, 56.8, 55.8,
3
10
11
12
13
14
15
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56
57
58
59
60
5
4.6, 42.2, 14.2.
1
6,18
(S)-Ethyl 2-[(4-methoxyphenyl)amino]-4-oxopentanoate (5j):
Colorless gummy liquid;
2
5
1
4
6
3
2.3 mg, 80% yield, 84% ee; [α]D = ꢀ22.5 (c = 1.0, CH Cl ); H NMR (500 MHz, CDCl ) δ
2
2
3
.79 – 6.75 (m, 2H), 6.68 – 6.62 (m, 2H), 4.33 (t, J = 5.6 Hz, 1H), 4.17 (qd, J = 7.1, 0.7 Hz, 2H),
13
.74 (s, 3H), 2.96 (d, J = 5.6 Hz, 2H), 2.18 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H); C NMR (125 MHz,
CDCl ) δ 206.1, 173.2, 153.2, 140.6, 115.9, 115.0, 61.6, 55.8, 54.4, 46.0, 30.5, 14.3.
3
Acknowledgment: The generous financial support from the Welch Foundation (Grant No. AXꢀ
1593) and the National Science Foundation (Grant No. CHE 0909954) is gratefully appreciated.
Supporting Information Available: Copies of NMR spectra and HPLC chromatograms. This
material is available free of charge via the Internet at http://pubs.acs.org.
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Graphic Abstract
CF3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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0
S
PMP
O
PMP
O
HN
N
F
3
C
N
NH
MDO
neat, rt, 5 min H
+
MDO =
CO H
+
H
N
2
H
N
CO Et
2
H
H
R2
EtO C
2
R2
N
H
up to > 99:1 dr and > 99% ee
OMe
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