Modular bifunctional chiral thioureas as versatile organocatalysts for highly enantioselective aza-Henry reaction and michael addition

Article abstract of DOI:10.1002/adsc.201200144

A series of new modular bifunctional chiral thiourea organocatalysts were synthesized from natural Cinchona alkaloids and amino acids, and their performance in the aza-Henry reaction of nitroalkanes to imines, the Michael addition of acetylacetone to nitroolefins and the Michael addition of acetone to nitroolefins was investigated. Under the mild conditions, the important building blocks β-nitro amines and γ-nitro carbonyl compounds could be obtained in good yields (up to 95%) with excellent enantioselectivities (up to 99% ee) and diastereoselectivity (up to 17:1). Copyright

Full text of DOI:10.1002/adsc.201200144

FULL PAPERS
DOI: 10.1002/adsc.201200144
Modular Bifunctional Chiral Thioureas as Versatile
Organocatalysts for Highly Enantioselective Aza-Henry
Reaction and Michael Addition
Hua Li,a,c Xu Zhang,a,c Xin Shi,a Nan Ji,a Wei He,a,* Shengyong Zhang,a
and Bangle Zhangb,*
a
Department of Chemistry, School of Pharmacy, Fourth Military Medical University, Xi’an 710032, Peopleꢀs Republic of
China
Fax : (+86)-29-8477-6945; e-mail: weihechem@fmmu.edu.cn
Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi’an 710032, Peopleꢀs Republic
b
of China
Fax : (+86)-29-8477-4556; e-mail: blezhang@fmmu.edu.cn
These two authors contributed equally to this work.
c
Received: February 20, 2012; Revised: May 5, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200144.
Abstract: A series of new modular bifunctional nitro amines and g-nitro carbonyl compounds could
chiral thiourea organocatalysts were synthesized be obtained in good yields (up to 95%) with excel-
from natural Cinchona alkaloids and amino acids, lent enantioselectivities (up to 99% ee) and diaste-
and their performance in the aza-Henry reaction of reoselectivity (up to 17:1).
nitroalkanes to imines, the Michael addition of acety-
lacetone to nitroolefins and the Michael addition of Keywords: asymmetric catalysis; aza-Henry reaction;
À
acetone to nitroolefins was investigated. Under the C C bond formation; Michael addition; organic cat-
mild conditions, the important building blocks b- alysis
Introduction
ine or iminium catalysis), hydrogen-bonding interac-
tions (urea or the thiourea catalysis), pi-stacking,
With the development of a chiral pharmaceutical in- Brønsted acid-base interactions and ion pair interac-
dustry, the growing demands in high-throughput tions (phase-transfer catalysts), etc.[3] The combina-
screening for enantiomerically pure, biologically tion of some of these strategies may lead to an unex-
active compounds have stimulated the rapid develop- pected synergistic effect, and the success of bifunc-
ment of enantioselective synthetic methods providing tional organocatalysts in a wide array of asymmetric
exceptional stereocontrol. Although, during the last processes provides a good example.[4] Among the dif-
two decades, asymmetric catalysis has experienced an ferent skeletons of chiral promoters available nowa-
explosive growth, and many transformations demon- days, both Cinchona alkaloids and amino acid deriva-
strating excellent steroselectivities and enantioselec- tives, which could be easily reduced to b-amino alco-
tivities have been reported, the design and synthesis hols, are regarded as “privileged” scaffolds in asym-
of versatile catalysts which can be successfully used in metric catalysis.[5] We envisaged that the rational com-
a variety of transformations is still very challenging bination of these two “privileged” structure motifs
and in great demand.[1]
into one molecule by the linker of thioureas would
Organocatalysis has emerged as one of the most probably provide a new class of bifunctional organo-
rapidly growing and promising areas in synthetic or- catalyst, which has the potential to produce an unex-
ganic chemistry. The advantages of organocatalysis in- pected synergistic effect in many asymmetric transfor-
clude their operational simplicity, ready availability, mations.
low cost, and low toxicity, which confers a huge direct
Herein a series of new modular bifunctional orga-
benefit in the production of pharmaceutical inter- nocatalysts 1a–1h (Figure 1) was synthesized starting
mediates.[2] Currently, the strategies for organocataly- from natural Cinchona alkaloids and amino acids with
sis include: forming temporary covalent bonds (enam- simple procedures. Their catalytic performance was
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Figure 1. Bifunctional organocatalysts 1a–1h derived from Cinchona alkaloids and amino acids.
investigated in the aza-Henry reaction of nitroalkanes presence of 10 mol% of the catalyst. From Table 1, it
to imines, the Michael addition of acetylacetone to ni- can be seen that the organocatalysts derived from qui-
troolefins and the Michael addition of acetone to ni- nine are more active than the ones derived from cin-
troolefins. Under the mild conditions, a variety of im- chonine in this reaction (Table 1, entries 1, 2, 4 vs. 6,
portant building blocks such as b-nitro amines and g- 7, 8). Compound 1e derived from cinchonine and pro-
nitro carbonyl compounds could be prepared in good line, which does not have an intact thiourea moiety,
yields (up to 95%) with excellent enantioselectivities showed the lowest activity, suggesting the possibility
(up to 99% ee) and diastereoselectivities (up to 17:1). of H-bonding as a mechanism of activation. Among
1a–1h, 1h derived from quinine and phenylalanine
was selected for further optimization (entry 8).
Results and Discussion
The solvent always plays an important role in vari-
ous catalytic processes. Different solvents were tested
in the model reaction of benzaldehyde with nitrome-
thane and the typical results are shown in Table 1 (en-
Aza-Henry Reaction
The aza-Henry reaction (or nitro-Mannich reaction), tries 8–13). Using the non-polar solvent toluene, both
the nucleophilic addition of nitroalkanes to imines, is the enantioselectivity and the chemical yield were in-
one of the most important reactions in organic syn- ferior to those in dichloromethane (entry 9 vs. 8).
thesis, which opens useful ways to create a carbon- With the polar protic solvents methanol, ethanol and
carbon bond with concomitant generation of two vici- isopropyl alcohol, good yields could be obtained, but
nal stereogenic centers bearing nitro and amino func- the enantioselectivity was poor (entries 10, 11, 12).
tional groups. In recent years, several organocatalysts Surprisingly, when nitromethane was used directly as
such as bisamidine-triflate salts, ammonium betaines, solvent, the yield was not improved, and the enantio-
thioureas, phase-transfer catalysts and Brønsted acids selectivity decreased (entry 13 vs. 8). In the view of
have been successfully developed for this transforma- enantioselectivity, dichloromethane was the best
tion.[6] As newly developed thiourea organocatalysts, choice for this reaction (entry 8).
the catalytic performance of 1a–1h was first investi-
gated in the catalytic aza-Henry reaction.
The effect of temperature was also examined (en-
tries 8, 14–16). When the reactions took place at
Initially, 1a–1h were screened in the model reaction room temperature and À108C, the yield increased at
between aldimine (2a) and nitromethane (3a), which the expense of enantioselectivity (entries 14, 15 vs. 8).
wass carried out in dichloromethane at À208C in the When the reaction was carried out at À408C, the
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Modular Bifunctional Chiral Thioureas as Versatile Organocatalysts
Table 1. Screening the parameters for the asymmetric aza-Henry reaction.[a]
Entry
Ligand
Solvent
Additive
Temperature [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
MeOH
EtOH
i-PrOH
CH3NO2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
r.t.
À10
À40
À20
À20
À20
À20
À20
À20
À20
À20
À20
26
29
32
63
10
42
51
72
51
75
77
80
73
96
87
41
81
86
83
77
86
83
75
79
85
57
3
34
75
18
12
10
95
88
30
23
46
89
88
91
94
65
2
36
62
38
90
95
87
97
1g
1h
1h
1h
1h
1h
1h
1h
1h
1h
1h
1h
1h
1h
1h
1h
1h
1h
1h
9
10
11
12
13[d]
14
15
16
17[e]
18[e]
19[e]
20[e]
21[e]
22[e]
23[e]
24[e]
25[f]
DABCO
DBU
DMAP
Et3N
NaOH
Na2CO3
pyridine
Na2HPO4
4ꢂ MS
[a]
All reactions were carried out with 0.125 mmol of 2a and 1.25 mmol of nitromethane in 0.5 mL of solvent in the presence
of 10 mol% catalyst for 12 h.
Isolated yield.
Determined by HPLC analysis (Chiralcel AD-H).
0.5 mL of nitromethane were used as solvent.
0.5 equiv. of base were added.
[b]
[c]
[d]
[e]
[f]
25 mg of 4 ꢂ molecular sieve were used.
yield decreased obviously (entry 16 vs 8). Thus, afford the corresponding products (4a–m) in good
yields (81–90%, Table 2). It appears that the position
À208C was selected as the optimized temperature.
Basic additives can deprotonate the nucleophiles in and the electronic property of the substituent on the
the Henry reaction, and this may affect the yield of aromatic rings have a very limited effect on the enan-
the reaction. Therefore, several different basic addi- tioselectivities. More than 96% ee values were ob-
tives were investigated in this reaction (Table 1, en- tained for the majority of these substrates, except for
tries17–25). From Table 1 we can see that all the the 2-Cl-benzaldimine derivatives (92% ee, entry 4).
bases gave good yields but the ee values were differ- Surprisingly, the aliphatic N-Boc-imine 2m, which is
ent. 4ꢂ molecular sieve was reported to act as an ef- generally difficult in aza-Henry reaction, gave the
fective proton scavenger of the protonic acid pro- product with excellent enantioselectivity (98% ee)
duced in some reactions, and to promote the reaction and good yield (81%) catalyzed by 1h.
system.[7] In accord with our expectations, 4 ꢂ molec-
ular sieve was able to improve both the yield and the reactions that use nitroethane to form two stereocen-
ee value (Table 1, entry 25) in this catalytic system. ters simultaneously still remain challenging and less
Highly diastereo- and enantioselective aza-Henry
With the optimized condition in hand, we then ex- explored compared to the reactions of nitrome-
amined the scope and limitations of enantioselective thane.[8] The good results obtained with nitromethane
aza-Henry reaction with various N-Boc-imines. A va- above prompted us to further evaluate the ligand 1h
riety of imines reacted smoothly with nitromethane to in the aza-Henry reaction with nitroethane. The pre-
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Table 2. Enantioselective aza-Henry reaction catalyzed by
Table 3. Diastereo- and enantioselective aza-Henry reaction
catalyzed by 1h.[a]
1h.[a]
Entry
R
Yield [%][b]
ee [%][c]
Entry
R
dr[b] [anti: Yield [%][c] ee [%][d]
syn]
1
2
3
4
5
6
7
8
Ph (2a)
85
86
82
87
83
84
88
88
85
89
90
85
81
97
97
98
92
99
98
99
96
99
99
96
96
98
4-Cl-C6H4 (2b)
3-Cl-C6H4 (2c)
2-Cl-C6H4 (2d)
4-Br-C6H4 (2e)
3-Br-C6H4 (2f)
2-Br-C6H4 (2g)
4-F-C6H4 (2h)
4-CF3-C6H4 (2i)
4-MeO-C6H4 (2j)
2-MeO-C6H4 (2k)
1-naphthyl (2l)
cyclohexyl (2m)
1
2
3
4
5
6
7
8
Ph (2a)
9:1
83
81
77
82
83
80
79
81
85
85
91
94
90
97
89
95
96
90
85
99
4-Cl-C6H4 (2b) 16:1
3-Cl-C6H4 (2c) 11:1
2-Cl-C6H4 (2d) 4:1
4-Br-C6H4 (2e) 6:1
3-Br-C6H4 (2f) 10:1
2-Br-C6H4 (2g) 3:1
4-F-C6H4 (2h)
1-naphthyl (2j) 8:1
4-Me-C6H4 (2l) 10:1
9
17:1
10
11
12
13
9
10
[a]
All reactions were carried out with 0.125 mmol of imines
2 and 1.25 mmol of nitroethane in 0.5 mL of dichlorome-
thane in the presence of 10 mol% catalyst for 12 h,at
À208C.
[a]
All reactions were carried out with 0.125 mmol of imines
2 and 1.25 mmol of nitromethane in 0.5 mL of dichloro-
methane in the presence of 10 mol% catalyst for 12 h at
À208C.
[b]
Assigned by HPLC data in combination with 1H NMR
data and comparison with literature reports.
Isolated yield of the mixture.
[b]
[c]
Isolated yield.
[c]
[d]
Determined by chiral HPLC analysis using Chiralcel
AD-H.
The ees were determined by chiral HPLC analysis using
Chiralcel AD-H, and here we report the ee value of anti
configurations.
liminary results are summarized in Table 3. Under the
mild conditions, all imines tested, bearing electron-
rich, or electron-deficient groups, gave the products in ment of chiral catalysts for this process has attracted
good yields (77–85%) with high enantioselectivities many research groups. In 2003, Takemoto[10] devel-
(up to 99% ee) and diastereoselectivities (up to 17:1). oped a landmark chiral bifunctional organocatalyst
The experiment results give hints that the rational for Michael additions of 1,3-dicarbonyl compounds to
combination of the Cinchona alkaloid with the amino nitroalkenes, which involves an electron-withdrawing
alcohol moiety indeed produces a perfect synergistic aryl substituent and a chiral tertiary amine group in
effect of stereocontrol. Mild conditions, easy availabil- a thiourea. Following this strategy, several thiourea-
ity of the catalysts and high steroselectivities make bifunctional organocatalysts were developed, and
this new catalytic system attractive, providing a new whatꢀs essential to their success is the ability to acti-
practical access to a wide range of chiral b-nitro vate reactants through hydrogen bond interactions
amines, which can be easily further transferred to vici- producing a well-defined orientation for the transition
nal diamines or a-amino carbonyl compounds as the state of the process.[11]
intermediates for many biologically active com-
To further extend the application of our new orga-
nocatalyst, 1a–1h were screened in asymmetric Mi-
chael addition of acetylacetone to nitroolefins
(Table 4, entries 1–8). Other parameters, such as sol-
vent (Table 4, entries 6, 9–13), temperature (Table 4,
entries 11, 14, 15) were also examined. From Table 4
pounds.[9]
Michael Addition of Acetylacetone to Nitroolefins
The asymmetric Michael addition reactions of differ- we can see that 1f derived from quinine and d-valine
ent carbon-centered nucleophiles to electron-deficient proved to be a good organocatalyst for this transfor-
nitroolefins represent a direct and most appealing ap- mation. Under the optimized conditions, using 10%
proach to synthetically valuable chiral nitroalkanes, in 1f as catalyst, 4ꢂ MS as additive, acetonitrile as sol-
which the nitro functionality can be easily trans- vent at À408C, a good yield and high enantioselectivi-
formed into a nitrile oxide, ketone, amine, or carbox- ty could be obtained (Table 4, entry 15).
ylic acid, and so on, providing a wide range of syn-
Table 5 shows the generality and scope of this cata-
thetically interesting compounds. Thus the develop- lyst system. Indeed, all tested nitroalkanes have
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Modular Bifunctional Chiral Thioureas as Versatile Organocatalysts
Table 4. Asymmetric Michael addition of acetylacetone and
a-nitrostyrene 6a under different conditions.[a]
Table 5. Asymmetric Michael addition of acetylacetone to
nitroolefins catalyzed by organocatalyst 1f.[a]
Entry
R
Yield [%][b]
ee [%][c]
Entry Catalyst Solvent Temperature
Yield
[%][b]
ee
[8C]
[%][c]
1
2
3
4
5
6
7
8
Ph (6a)
87
89
81
89
92
82
90
95
89
85
93
90
90
91
90
97
95
88
90
94
90
91
4-Me-C6H4 (6b)
4-MeO-C6H4 (6c)
4-NO2-C6H4 (6d)
4-CF3-C6H4 (6e)
4-Br-C6H4 (6f)
4-Cl-C6H4 (6g)
2-Cl-C6H4 (6h)
4-F-C6H4 (6i)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1f
1f
1f
1f
1f
1f
1f
CH2Cl2 À20
CH2Cl2 À20
CH2Cl2 À20
CH2Cl2 À20
CH2Cl2 À20
CH2Cl2 À20
CH2Cl2 À20
CH2Cl2 À20
90
83
75
76
30
95
85
88
68
95
92
93
30
89
87
36
24
30
32
8
37
3
9
10
11
25
29
56
81
41
17
85
90
3-Cl-C6H4 (6j)
1-naphthyl (6k)
9
THF
À20
10
11
12
13
14
15
CHCl3 À20
MeCN À20
[a]
All reactions were performed on a 0.1-mmol scale with
10 mol% of catalyst at a 0.1M concentration using
1 equiv. of 6 and 2 equiv. of acetylacetone in 24 h.
Isolated yields.
Enantiomeric excess (ee) was determined by chiral
HPLC analysis (Chiralcel AD-H).
Et2O
DMF
À20
À20
MeCN À30
[b]
[c]
MeCN À40
[a]
All reactions were performed on a 0.1-mmol scale with
10 mol% of catalyst at a 0.1M concentration using
1 equiv. of a-nitrostyrene 6a and 2 equiv. of acetylacetone
for 24 h.
[b]
[c]
still one of the most problematic substrates for the
nitro-Michael addition due to its inactivity and small-
er steric hindrance, which leads to difficulty to obtain
good stereocontrol.[14] During the submission of this
work, Kokotos developed a nice catalytic system
Isolated yield.
Enantiomeric excess was determined by chiral HPLC
analysis using a Chiralcel AD-H column.
proven to be excellent substrates with respect to using an amine-thiourea based on (1R,2R)-1,2-diphe-
enantioselectivity and reactivity. The desired adducts nylethylenediamine and (S)-di-tert-butyl aspartate for
were obtained in good yields (up to 93%) and syn- this transformation, and they also attributte the excel-
thetically useful levels of enantioselectivity (up to lent results to a synergistic effect of enamine activa-
97% ee), with substrates bearing both electron-donat- tion and the hydrogen bonding interaction.[15]
ing (Table 5, entries 2 and 3) and electron-withdraw-
The organocatalysts 1a–1h derived from Cinchona
ing substituents (Table 5, entries 4–10). It is also alkaloids and amino acids were examined in the
worth mentioning that 6f, with a trifluoromethyl model reaction between b-nitrostyrene (6a) and ace-
group on the phenyl ring, gave the best result with tone (Table 6, entries 1–8). Different reaction condi-
92% yield and 97% ee (Table 5, entry 5). The sub- tions were screened, including solvents (entries 3, 9–
strate 6k with the bulky naphthyl moiety (Table 5, 12), additives (entries 10, 13–19) and temperatures
entry 11) also gave the product in 93% yield and 91% (entries 10, 19–21). From Table 6, we can see that 1c
ee. Here, the conjugate additions with b-alkyl-substi- was the optimized catalyst and the non-polar solvent
tuted nitroolefins were not investigated.
toluene was the best choice for this reaction. Both
base additives and acid additives were investigated,
however, 4ꢂ MS gave good yield and excellent enan-
tioselectivity. In a word, the optimized conditions for
the b-nitrostyrene (6a) and acetone are as following:
Michael Addition of Acetone to Nitroolefins
Since the organocatalytic asymmetric Michael addi- using 10% 1c as catalyst, 4ꢂ MS as additive, toluene
tion of ketones to trans-b-nitrostyrene was pioneered as solvent at 58C.
by Barbas[12] and List[13] independently, great effort
Table 7 shows the generality of this methodology.
has been devoted to the development of more enan- As shown in Table 7, all the nitroalkenes reacted with
tioselective and efficient catalytic systems for this syn- acetone smoothly to afford the corresponding g-nitro
thetically useful transformation. However, acetone is carbonyl compounds in good yields. It is encouraging
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Table 6. Screening of conditions for the asymmetric Michael addition of acetone and a-nitrostyrene 6a.[a]
Entry
Catalyst
Solvent
Additive
Temperature [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
EtOH
–
–
–
–
–
–
–
–
–
–
–
–
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
21
trace
45
55
20
trace
trace
24
88
70
91
54
57
71
72
73
74
97
40
nd[d]
43
7
29
nd[d]
nd[d]
26
36
67
54
66
99
46
43
45
47
8
9
10
11
12
13[e]
14[e]
15[e]
16[e]
17[e]
18[e]
19[e]
20[e]
21[f]
toluene
acetone
Et2O
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
TFA
AcOH
PhOH
DIPEA
DMAP
benzylamine
4 ꢂ MS
4 ꢂ MS
4 ꢂ MS
79
59
83
85
99
98
5
[a]
All reactions were carried out using a-nitroolefin 6 (0.1 mmol), acetone (1 mmol, 10 equiv.) and 0.01 mmol organocatalyst
for 4 d.
[b]
[c]
[d]
[e]
[f]
Yield of the isolated product after chromatography on silica gel.
Determined by chiral HPLC analysis.
nd=not determined.
0.1 equiv. additive was added. For 4ꢂ molecular sieve, 25 mg were used.
The reaction lasts 8 d.
that excellent enantioselectivities (more than 98% ee) deprotonates an acidic proton of acetone, and gener-
were observed for various substrates bearing either ates a ternary complex. In a word, the multiple hydro-
electron-donating or electron-withdrawing substitu- gen bonding interactions and base-acid interaction be-
ents in the para, meta, or ortho position of the aro- tween the catalyst and the substrates may be synergis-
matic ring, regardless of the nature and the position tically responsible for the excellent enantioselectivi-
of the substituted group on the aromatic ring. More- ties. Nevertheless, the real catalytic mechanism still
over, the heteroaromatic furyl substrate 6p also gave needs further investigation.
good yield and excellent enantioselectivity (entry 13).
To understand the high enantioselectivities ob-
served in the 1c-promoted Michael addition of ace- Conclusions
tone to nitroolefins, the absolute configuration of the
organocatalyst 1c and the Michael adduct 10h were In conclusion, we have developed a new series of
identified by their crystal structures (Figure 2).[16] As modular bifunctional chiral organocatalysts for the
with other bifunctional organocatalysts, we think that highly enantioselective aza-Henry reaction of nitroal-
the thiourea functionality interacts through hydrogen kanes to imines, the Michael addition of acetylace-
bondings with the nitro group of the nitroolefin, tone to nitroolefins and the Michael addition of ace-
meanwhile the hydroxy group from the amino alcohol tone to nitroolefins. The important building blocks b-
moiety and the nitro group may form another hydro- nitro amines and g-nitro carbonyl compounds could
gen bond, which enhances the electrophilicity of the be obtained in good yields (up to 95%) with excellent
nitroolefins. On the other hand, the tertiary amine of enantioselectivities (up to 99% ee) and diastereoselec-
the azabicyclo moiety in the quinine, acting as a base, tivities (up to 17:1).
6
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Modular Bifunctional Chiral Thioureas as Versatile Organocatalysts
Table 7. Asymmetric Michael addition of acetone to nitroo-
lefins catalyzed by organocatalyst 1c.[a]
Due to the synergistic effect through combining the
Cinchona alkaloid with amino alcohol moieties, some
usually difficult substrates, especially acetone as sub-
strate in Michael addition achieve a perfect stereo-
control. Considering the easy availability of the cata-
lysts, mild conditions, without other additives except
molecular sieves and high enantioselectivities, these
methodologies demonstrate the versatility and prac-
ticability of these new organocatalysts. Further inves-
tigation into the catalytic mechanism and applications
of these transformations to bioactive molecular syn-
thesis is ongoing in our laboratory.
Entry
R
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph (6a)
83
91
79
77
75
71
75
76
73
92
91
82
80
98
99
99
99
99
99
99
99
99
99
99
99
99
4-CH3-C6H4 (6b)
4-MeO-C6H4 (6c)
4- NO2-C6H4 (6d)
4-CF3-C6H4 (6e)
4-Br-C6H4 (6f)
4-Cl-C6H4 (6g)
2-Cl-C6H4 (6h)
4-F-C6H4 (6l)
2-NO2-C6H4 (6m)
3-NO2-C6H4 (6n)
4-CN-C6H4 (6o)
2-furyl (6p)
Experimental Section
9
10
11
12
13
General Remarks
All reactions were carried out under an argon atmosphere
in oven-dried glassware with magnetic stirring. Starting ma-
terials and reagents were purchased from commercial sup-
pliers and used without further purification. Solvents were
distilled before use: THF and diethyl ether from sodium
metal/benzophenone, CH2Cl2 from calcium hydride.
1H NMR spectra were recorded on 400 MHz spectrometers.
The samples were dissolved in CDCl3, MeOD or DMSO
and data are reported in ppm. Splitting patterns were re-
ported as s, singlet; d, doublet; t, triplet; q, quartet; m, mul-
tiplet; br, broad. 13C NMR spectra were recorded using
a 100 MHz instrument with samples dissolved in DMSO,
[a]
All reactions were carried out using a-nitroolefin 6
(0.1 mmol), acetone (1 mmol, 10 equiv.) and 1c
(0.01 mmol) in the presence of 25 mg 4ꢂ MS in toluene
(1 mL) at 58C in 8 d.
Isolated yield.
Determined by chiral HPLC analysis.
[b]
[c]
Figure 2. X-ray crystal structures of 1c and 10h.
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MeOD or CDCl3 and data are reported in ppm. Mass spec-
tra were recorded using ESI or EI techniques. HPLC analy-
ses were carried out on a chromatograph equipped with
a UV detector using different chiral colums, as indicated for
the description of each product (see below).
To a solution of NaBH4 (662 mg, 17.5 mmol) and d-phe-
nylglycine 15 (1.06 g, 7 mmol) in dry THF (30 mL) at 08C
were added a solution of I2 (2.13 g , 8.4 mmol in 10 mL
THF) slowly. Then, the solution was heated at 648C for
18 h. The solution was cooled to room temperature, and
MeOH was added drop by drop until the solution getting
clear. After stirring for 30 min, the solvent was removed
under reduced pressure and the residue was added 20%
KOH (20 mL). After stirring for 4 h, the aqueous phase was
extracted with DCM (30 mLꢃ4). The solvent was removed
under reduced pressure, and the residue was the intermedi-
ate 14; yield: 900 mg (91%).
Procedure for the Synthesis of Catalysts 1a–1h with
1c as Example
A solution of the 14 in THF (0.6M) was added to a stirred
solution of the isothiocyanate 13 in THF (0.6M) at room
temperature. After 48 h, the solvent was removed under re-
duced pressure. The residue was purified by column chroma-
tography to afford the desired product 1c; yield: 73%.
The others catalysts were synthesized according to similar
procedures.
1H and 13C NMR and HR-Mass Spectra Data for the
Organocatalysts 1a–1h
Calalyst 1a:
Diisopropyl azodicarboxylate (DIAD, 2.5 mL, 12.5 mmol)
was added to a solution of the cinchonine (2.94 g, 10 mmol)
and triphenylphosphine (3.28 g, 12.5 mmol) in absolute THF
(30 mL) at 08C all at once. After 5 min, a solution of HN3
(17 mL, 12.5 mmol) in dry CHCl3 was added dropwise at
08C. The mixture was warmed to room temperature. After
being stirred overnight, the solution was heated at 608C for
24 h. Then, triphenylphosphine (3.28 g, 12.5 mmol) was
added, and the heating was maintained until the gas evolu-
tion had ceased. The solution was cooled to room tempera-
ture, and water (10 mL) was added. After stirring for 24 h,
the solvents were removed, and the residue was dissolved in
DCM and 2M HCl (1:1, 70 mL). The aqueous phase was ex-
tracted with DCM (30 mLꢃ3). Then, the aqueous phase was
made alkaline with a saturated aqueous solution of Na2CO3
and extracted with DCM. Concentration of the dried ex-
tracts afforded a residue, which was purified by column
chromatography to afford 9-amino-9-deoxyepicinchonine
12; yield: 2.23 g (78%).
White solid; yield: 76%; mp 127–1298C; [a]: +19.00 (c
0.25, CH3OH); IR (KBr): n=3261, 3063, 2955, 2937, 2872,
1590, 1540, 1510, 1466, 1337, 1312, 1265, 1242, 1068, 991,
918, 849, 762, 737 cmÀ1 1H NMR (CDCl3, 400 MHz): d=
;
8.89 (d, 1H, J=4.0 Hz), 8.39 (br s, 1H),8.18 (d, 1 H, J=
8.0 Hz), 7.78 (t, 1H, J=7.4 Hz), 7.67(t, 1H, J=7.6 Hz), 7.48ACHTUNGTRENNUNG(
s, 2H), 5.87 ( t, 1H, J=3.2 Hz), 5.19 (d, 2H, J=9.6 Hz),
4.33 (br s, 1H), 3.77 (t, 1H, J=8.6 Hz), 3.58 (s, 1H), 3.51 (d,
1H, J=6.8 Hz), 3.19 (br s, 1H), 3.03 (m, 2H), 2.35 (m,
6H),1.67–1.50 (m, 3H), 1.25–1.19 (m, 1H), 0.98–0.92 (m,
1H), 0.68–0.49 (m, 6H); 13C NMR (CDCl3, 100 MHz): d=
182.8, 150.2, 148.7, 139.7, 130.8, 129.9, 127.5, 115.3, 77.4,
76.9, 76.9, 76.7, 48.8, 47.1, 39.0, 27.3, 26.2, 25.0, 24.8, 19.2,
19.0, 18.3, 15.3; HR-MS (ESI+; free base): m/z=439.2529,
calcd. for C25H34N4OS (M+H)+: 439.2532.
Calalyst 1b:
To a solution of 12 (400 mg, 1.36 mmol) in dry THF
(1.36 mL) at À108C were added CS2 (0.5 mL, 8.18 mmol)
and DCC (280.6 mg, 1.36 mmol). The reaction mixture was
warmed slowly to room temperature over a period of 3 h
and then stirred at room temperature overnight. The precip-
itate was removed by filtration, and the solvent was subse-
quently removed under vacuum. The residue was taken up
in diethyl ether. The solvent was removed under reduced
pressure, and the residue was purified by flash chromatogra-
phy to afford the product 9-deoxyepiquinidine isothiocya-
nate 13; yield: 352 mg (71%).
White solid; yield: 81%; mp 188–1908C; [a]: +9.12 (c
0.25, CH3OH); IR (KBr): n=3244, 3060, 2961, 2874, 1639,
1545, 1472, 1362, 1339, 1267, 1240, 1086, 1051, 1022, 999,
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Modular Bifunctional Chiral Thioureas as Versatile Organocatalysts
928, 851, 770, 731 cmÀ1
;
1H NMR (DMSO, 400 MHz): d=
base): m/z=487.2529, calcd. for C29H34N4OS (M+H)+:
487.2532.
Calalyst 1e:
8.85 (d, 1H), 8.49 (d, 1H), 8.01 (d, 1H), 7.73 (d, 1H), 7.60
(dd, 2H), 7.45 (dd, 1H), 5.89–5.98 (m, 1H), 5.11–5.20 (m,
2H), 4.59 (s, 1H), 4.00 (d, 1H), 3.40 (m, 6H), 3.07 (s, 1 H),
2.93ACHTUNGTRENNUNG(s, 4H), 2.27 (s, 1H), 1.46–1.52 (s, 3H), 1.12–0.7 (s, 9H);
13C NMR (100 MHz, DMSO): d=182.6, 150.1, 148.6, 147.8,
140.6, 129.5, 128.8, 127.1, 126.0, 124.5, 124.3, 119.6, 114.7,
62.2, 60.6, 60.2, 48.5, 46.6, 34.3, 33.4, 27.1, 27.0, 25.8, 24.8,
24.6; HR-MS (ESI+; free base): m/z=453.2691, calcd. for
C26H36N4OS (M+H)+ : 453.2688.
Calalyst 1c:
White solid; yield: 57%; mp 134–1368C; [a]: +4.72 (c
0.25, CH3OH); IR (KBr): n=3249, 3074, 2932, 2872, 1508,
1456, 1402, 1352, 1076, 1047, 914, 866, 851, 754, 735 cmÀ1
;
1H NMR (CDCl3, 400 MHz): d=8.84 (d, 1H), 8.85 (dd,
1H), 8.09 (d, 1H), 7.70 (s, 1H), 7.60 (dd, 1H), 7.44 (s, 1H),
5.88–5.93 (dd, 2H), 5.22 (dd, 2H), 4.71 (dd, 1H), 3.63–3.65
(m, 4H), 3.02 (s, 6 H), 2.35 (s, 1H), 2.03 (s, 3H), 1.78 (dd,
1H), 1.21–1.69 (m, 5H), 0.92 (s, 1H); 13C NMR (100 MHz,
MeOD): d=150.9, 148.8, 141.3, 130.9, 129.6, 129.2, 127.8,
126.6, 115.5, 61.8, 61.3, 40.2, 28.8, 27.0, 26.8, 26.1, 24.4; HR-
MS (ES; free base): m/z=437.2380, calcd. for C25H32N4OS
(M+H)+: 437.2370.
White solid; yield: 73%; mp 154–1568C; [a]: +10.92 (c
0.25, CH3OH); IR (KBr): n=3252, 3059, 3032, 2932, 2870,
1589, 1539, 1510, 1495, 1454, 1352, 1335, 1063, 1028, 918,
1
851, 760, 700 cmÀ1; H NMR (CDCl3, 400 MHz): d=8.77 (s,
Calalyst 1f:
1H), 8.25 (br s, 1H), 8.12 (d, 1H, J=8.4 Hz), 7.74 (t, 2H,
J=7.2 Hz), 7.57 (s, 2H), 7.43–7.16 (m, 5H), 5.87–5.85 (m,
1H), 5.30 (s, 1H), 5.12–5.17 (m, 2H), 3.80–3.89 (m, 3H),
3.51 (dd, 1H, J=6.8 Hz), 2.96 (m, 4H), 2.32 (dd, 2H, J=
7.2 Hz), 2.17 (br s, 1H), 1.64–1.47ACHTUNTRGNEUNG(m, 3H), 1.21 (dd, 1H, J=
6.8 Hz), 0.89 (m, 1H); 13C NMR (CDCl3, 100 MHz): d=
181.3, 145.0, 148.3, 139.6, 138.4, 130.2, 129.3, 128.0, 126.7,
123.8, 123.7, 115.3, 66.2, 66.7, 53.5, 48.8, 47.1, 39.0, 27.3, 26.1,
25.6, 25.0, 15.3, 12.0; HR-MS (ESI+; free base) m/z=
473.2381, calcd. for C28H32N4OS (M+H)+: 473.2370.
Calalyst 1d:
White solid; yield: 76%; mp 136–1388C; [a]: À6.40 (c
0.25, CH3OH); IR (KBr): n=3261, 3070, 2957, 2935, 2870,
1622, 1531, 1510, 1474, 1362, 1263, 1242, 1229, 1173, 1186,
1
1080, 1030, 987, 918, 852, 736; H NMR (DMSO, 400 MHz):
d=8.47 (d, 1H), 7.92 (d,1H), 7.67 (d, 2H), 7.18–7.21 (m,
2H), 5.56–5.58 (m, 2H), 4.67–4.77 (dd, 2H), 4.45 (s, 1H),
3.70 (s, 3H), 2.98–3.26 (d, 9H), 2.46 (s, 1H), 2.04 (s, 1H),
1.60 (s, 1H), 1.34 (s, 3H), 0.96 (s, 1H), 0.49–0.60 (m, 5H);
13C NMR (100 MHz, DMSO): d=182.1, 156.9, 147.5, 144.1,
141.6, 131.1, 127.9, 121.2, 114.4, 103.1, 60.5, 59.8, 55.6, 55.6,
55.0, 40.9, 28.1, 27.0, 25.3, 19.2, 18.2; HR-MS (ESI+; free
base): m/z=469.2642, calcd. for C26H36N4OS (M+H)+:
469.2632.
White solid; yield: 81%; mp 115–1188C; [a]: +8.20 (c
0.25, CH3OH); IR (KBr): n=3250, 3059, 3028, 2935, 2878,
1531, 1512, 1495, 1454, 1387, 1335, 1265, 1086, 1032, 991,
Calalyst 1g:
1
920, 851, 748, 702 cmÀ1; H NMR (CDCl3,400 MHz): d=8.88
(d, 1H, J=4.4 Hz), 8.45 (d, 1H, J=4.8 Hz), 8.14 (dd, 1H),
7.77 (dd, 1H), 7.66–7.54 (m, 2H), 7.32 (br s, 1H), 7.25–7.15
(m, 5H), 5.90–5.81 (m, 1H), 5.29–5.23 (m, 2H), 4.58 (br s,
1H), 3.65 (m, 1H), 3.54 (m, 1H), 3.42 (m, 1H), 3.21 (m,
1H), 3.12–2.87 (m, 6H), 2.78 (m, 1H), 2.43 (m, 1H), 1.73–
1.62 (m, 3H), 1.29 (m, 1H), 1.05–1.92 (m, 2H); 13C NMR
(CDCl3, 100 MHz): d=182.4, 150.5, 150.3, 148.6, 139.7,
139.4, 138.5, 137.7, 130.3, 129.6, 129.3, 128.9, 128.4, 127.2,
126. 9, 126.4, 124.1, 123.9, 120.0, 116.1, 115.6, 62.6, 61.2, 57.3,
48.9, 46.9, 38.1, 37.1, 27.0, 25.1, 24.6; HR-MS (ESI+; free
White solid; yield: 68%; mp 153–1568C; [a]: À12.88 (c
0.25, CH3OH); IR (KBr): n=3256, 3070, 2951, 2868, 1622,
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1540, 1508, 1475, 1366, 1263, 1240, 1229, 1084, 1030, 918,
General Procedure for Michael Addition Reactions
of Acetone to Nitroolefins
1
854, 737 cmÀ1; H NMR (CDCl3, 400 MHz): d=8.79 (d, 1H),
8.06 (dd, 1H), 7.70 (d, 2H), 7.43 (s, 2H), 6.46 (dd, 1H), 6.09
(dd, 1H), 5.71 (dd, 1H), 5.04 (d, 2H), 4.40 (dd, 1H), 3.87–
4.01 (m, 4 H), 3.24–3.50 (m, 4H), 2.82 (m, 3H), 2.37 (s, 1H),
1.46–1.73 (m, 4H), 0.99–0.97 (m, 9H), 0.80–0.96 (m, 4H),
0.38–0.36 (m, 5H); 13C NMR (100 MHz, DMSO): d=156.9,
156.7, 149.2, 147.5, 144.0, 143.9, 142.5, 141.9, 131.1, 127.0,
121.2, 120.9, 119.1, 114.2, 114.1, 102.9, 102.4, 70.8, 60.6, 55.8,
55.5, 55.0, 41.7, 27.4, 26.4, 24.0; HR-MS (ESI+; free base):
m/z=483.2782, calcd. for C27H38N4O2S (M+H)+: 483.2788.
Calalyst 1h:
A mixture of a-nitroolefin 6 (0.1 mmol), 1c (0.01 mmol),
acetone (1 mmol, 10 equiv.) and 25 mg of 4ꢂ MS in 0.5 mL
toluene was stirred at 58C, the reaction was monitored by
thin layer chromatography. After evaporation of the solvent,
the residue was purified by flash chromatography on a silica
gel column (hexane/EtOAc=4:1) to afford the product 10.
Enantiomeric excesses were determined by HPLC with
a Chiralcel AD-H column.
Acknowledgements
The financial support of National Natural Science Founda-
tion of China (21072228 and 20702063) and the Young Schol-
ar Foundation of the Fourth Military Medical University is
gratefully acknowledged. We also would like to express our
great thanks to Professor Weiping Chen for valuable discus-
sion and kind help.
White solid; yield: 77%; mp 133–1368C; [a]: À10.72 (c
0.25, CH3OH); IR (KBr): n=3252, 3061, 3028, 2932, 2864,
1622, 1531, 1510, 1474, 1454, 1346, 1263, 1229, 918, 852, 737,
References
702 cmÀ1
;
1H NMR (CDCl3, 400 MHz):d=8.70 (d, J=
4.4 Hz, 1H), 8.01 (d, J=9.6 Hz, 1H),7.86 (s, 1H),7.67 (s,
1H),7.42 (m,1H), 7.40 (q, J=4.4 Hz, 1H), 7.20 (m, 3H),
7.09 (s, 2H), 5.68 (br s, 1H), 4.98 (m, 2H), 3.99 (s, 3H), 3.
67–3.65 (m, 2H), 3.54 (s, 2H), 3.33 (s, 2H), 3.20 (m, 2H),
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2.76 (m, 3H), 2.65 (s, 1H), 2.35 (s, 1H), 1.70 (s, 3H), 1.41ACTHNUTRGNEUNG(s,
1H), 0.87 (m, 1H); 13C NMR (100 MHz, CDCl3): d=182.0,
158.1, 147.5, 144.7, 140.2, 131.6, 129.1, 128.5, 126.6, 126.8,
122.3, 115.3, 102.2, 77.4, 77.0, 76.7, 57.7, 56.0, 55.1, 41.4, 38.8,
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General Procedure for Aza-Henry Reaction of
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Nitroalkanes to N-Boc-imines
A
mixture of N-Boc-imine
2
(0.125 mmol), 1h
(0.0125 mmol), and 25 mg of 4ꢂ MS in 0.5 mL of dichloro-
methane was cooled to À208C and stirred. Then the nitroal-
kane (1.25 mmol) was added. The reaction was monitored
by thin layer chromatography. After evaporation of the sol-
vent, the residue was purified by flash chromatography on
a silica gel column (hexane/EtOAc=10:1) to afford the
product 4 or 5. Enantiomeric excesses were determined by
HPLC with a Chiralcel AD-H column.
General Procedure for Michael Addition Reactions
of Acetylacetone to Nitroolefins
A mixture of a-nitroolefin 6 (0.1 mmol), 1f (0.01 mmol) and
25 mg of 4ꢂ MS in 1 mL acetonitrile was cooled to À408C.
Then acetylacetone (0.2 mmol) was added and the mixture
stirred overnight. The reaction was monitored by thin layer
chromatography. After evaporation of the solvent, the resi-
due was purified by flash chromatography on a silica gel
column (hexane/EtOAc=3:1) to afford the product 8.
Enantiomeric excesses were determined by HPLC with
a Chiralcel AD-H column.
10
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Modular Bifunctional Chiral Thioureas as Versatile Organocatalysts
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FULL PAPERS
12 Modular Bifunctional Chiral Thioureas as Versatile
Organocatalysts for Highly Enantioselective Aza-Henry
Reaction and Michael Addition
Adv. Synth. Catal. 2012, 354, 1 – 12
Hua Li, Xu Zhang, Xin Shi, Nan Ji, Wei He,*
Shengyong Zhang, Bangle Zhang*
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