Primary amine-thioureas based on tert-butyl esters of natural amino acids as organocatalysts for the Michael reaction

Article abstract of DOI:10.1002/adsc.200800812

A new class of primary amine-thioureas based on tert-butyl esters of (S)-α-amino acids and (1S,2S)-diphenylethylenediamine was synthesized and their activity as catalysts in Michael additions was evaluated. Derivatives based on di-tert-butyl aspartate and

Full text of DOI:10.1002/adsc.200800812

FULL PAPERS
DOI: 10.1002/adsc.200800812
Primary Amine-Thioureas based on tert-Butyl Esters of Natural
Amino Acids as Organocatalysts for the Michael Reaction
Christoforos G. Kokotosa and George Kokotosa,*
a
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771,
Greece
Fax : (+30)-210-727-4761; phone: (+30)-210-727-4462; e-mail: gkokotos@chem.uoa.gr
Received: December 28, 2008; Published online: May 27, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800812.
Abstract: A new class of primary amine-thioureas the reaction of nitroolefins with acetophenone with
based on tert-butyl esters of (S)-a-amino acids and high enantioselectivity (92–98% ee). Thus, low-cost,
(1S,2S)-diphenylethylenediamine was synthesized commercially available tert-butyl esters of natural
and their activity as catalysts in Michael additions amino acids are very important chiral building
was evaluated. Derivatives based on di-tert-butyl as- blocks for the construction of novel chiral thioureas
partate and tert-butyl O-tert-butyl threoninate pro- able to catalyze asymmetric Michael additions with
vided the product of the reaction between trans-b-ni- high enantioselectivity.
trostyrene and acetone in quantitative yield and high
enantioselectivity (87–91% ee). All the thioureas Keywords: amino acids; Michael addition; nitroole-
based on tert-butyl esters of amino acids catalyzed fins; organocatalysis; thioureas
Introduction
1,2-diphenylethyACTHNGUTERNlUNG enediamine or 1,2-cyclohexanedia-
mine, for example, compound 3 (Figure 1), for the nu-
Over the course of the last decade, organocatalysis cleophilic addition of ketones to nitroolefins,[5] while
has emerged as one of the most modern and rapidly Jacobsen presented catalysts based on 1,2-trans-cyclo-
growing areas of organic chemistry.[1] Organocatalysts
are small organic molecules that do not require spe-
cial experimental handling conditions, and may be
used even in water, thus being considered environ-
mentally friendly catalysts. The most important
classes of organocatalysts up to now are proline and
proline-derived compounds, MacMillanꢀs imidazolidi-
nones and chiral thioureas.[2] In 1998, Jacobsen report-
ed that urea and thiourea derivatives (like 1,
Figure 1) can be effective asymmetric catalysts for the
Strecker reaction.[3] Since then, a variety of chiral
thio
formations.[2b,e,o,p,r,s] Takemoto and co-workers devel-
oped thiourea catalyst based on 1,2-trans-
cyclohexanediamine (2, Figure 1) and demonstrated
ACHTUNGTRENNUNGureas has been used for various asymmetric trans-
a
ACHTUNGTRENNUNG
the highly enantioselective Michael addition of 1,3-di-
carbonyl compounds to nitroolefins.[4] Most of the
known chiral thioureas are bifunctional catalysts con-
taining a tertiary amine group, for example, com-
pound 2. Only a few examples of chiral thioureas con-
taining a primary amino group have been reported up
to now. Tsogoeva has developed catalysts based on Figure 1. Examples of chiral thiourea catalysts.
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FULL PAPERS
hexanediamine (like 4, Figure 1) for the same reaction
as well as for the conjugate addition of a,a-disubsti-
tuted aldehydes to nitroolefins.[6] A primary amine-
thiourea based on a saccharide (5, Figure 1) has been
shown to be a highly enantioselective catalyst for the
reaction of aromatic ketones with nitroolefins.[7] The
aim of the present work was the synthesis of thioureas
based on a variety of natural amino acid tert-butyl
esters bearing a primary amino group and the evalua-
tion of these catalysts in the Michael reaction.
Scheme 1. Synthesis of catalysts 8a–c.
Results and Discussion
The rationale for the design of the catalysts of this
work is illustrated in Figure 2. For the construction of
the catalyst, apart from the hydrogen bond donor
Figure 2. Design of new catalytic thioureas.
thioACHTUNGTRENNUNGurea group, a chiral diamine unit is required to
provide the primary amino group ensuring the ability Scheme 2. Synthesis of catalysts 10a–h.
to form an enamine. The chiral environment should
be complemented by a bulky unit, or preferably by a
commercially available tert-butyl ester of a natural strates for the nitro-Michael addition, namely acetone
amino acid. We have chosen amino acids without side and acetophenone. Initially, a model reaction between
chain functionalities, acidic amino acids where the acetone and trans-b-nitrostyrene using 15% catalyst
side chain carboxyl group is protected by the tert- loading in the presence of AcOH and water was stud-
butyl ester group, and amino acids bearing a hydroxy ied and the results are summarized in Table 1. Both
functionality in the side chain protected as a tert-butyl catalysts 8a and 8b based on (1S,2S)-1,2-diphenylethy-
ether.
(1S,2S)-1,2-Diphenylethylenediamine
lenediamine afforded the product in quantitative
and yield and good ee (entries 1 and 2, Table 1). However,
G
(6a)
(1S,2S)-cyclohexanediamine (6b) were treated with catalyst 8c led to low yield and a reduced enantiose-
commercially available exo-2-norbornyl isothiocya- lectivity (entry 3, Table 1). A comparison between the
nate (7a) and cyclohexyl isothiocyanate (7b) to afford results obtained using catalysts 8a and 8c indicate that
thioureas 8a–c (Scheme 1). A variety of commercially the (1S,2S)-1,2-diphenylethylenediamine moiety leads
available tert-butyl esters of alanine (9a), phenylala- to better results than the (1S,2S)-cyclohexanediamine
nine (9b), valine (9c), aspartic acid (9d), glutamic acid moiety. Thus, for the synthesis of catalysts based on
(9e), serine (9f), threonine (9g) and tyrosine (9h) tert-butyl esters of amino acids only diamine 6a was
were converted to the corresponding isothiocyanates used.
by treatment with thiophosgene and reacted with
(1S,2S)-1,2-diphenylethylenediamine (6a) to afford phenylalanine produced the product in ees not ex-
chiral thioureas 10a–h (Scheme 2). ceeding 80% (entries 4 and 5, Table 1). However,
The catalysts 10a and 10b based on alanine and
The asymmetric Michael addition reaction is one of using the catalyst 10c, based on valine, the product
the most important processes for the synthesis of new was isolated in 85% ee (entry 6, Table 1), indicating
À
À
C C and C X bonds and the application of organoca- that a more hindered side chain corresponding to
talysts in this reaction has been intensively studied.[8] valine, in comparison to the less hindered side chains
In the present work, the conjugate addition of ke- of alanine and phenylalanine, leads to better results.
tones to nitroolefins was explored. Our attention has Both catalysts 10d and 10e, based on aspartate and
been focused on two of the most problematic sub- glutamate, provided the product in quantitative yields
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Primary Amine-Thioureas based on tert-Butyl Esters of Natural Amino Acids
FULL PAPERS
Table 1. Michael reaction of acetone with trans-b-nitrostyr-
ene using thioureas as catalysts.
Table 2. Michael reaction of acetophenone with trans-b-ni-
trostyrene using thioureas as catalysts.
Entry
Catalyst
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8a
8b
8c
10b
10c
10d
10f
10g
10g
10h
27
53
traces
37
28
68
51
27
38
89
88
–
92
92
95
95
96
94
94
Entry
Catalyst
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
8a
8b
8c
100
100
29
88
42
84
82
77
73
79
85
91
61
75
87
81
10a
10b
10c
10d
10e
10f
10g
10h
8
77
9[c]
10
100
100
100
100
89
34
9
10
11
[a]
Isolated yield after column chromatography.
The ee was determined by HPLC on a Daicel Chiralpak
AD-H column.
[b]
[c]
[a]
The reaction was carried out under reflux.
Isolated yield after column chromatography.
The ee was determined by HPLC on a Daicel Chiralpak
[b]
AD-H column.
within 48 h and the results are summarized in Table 2.
(entries 7 and 8, Table 1). However, the aspartate Catalysts 8a and 8b gave the product in high ee, but
based catalyst 10d led to high ee (91%, entry 7, with a low to moderate yield (entries 1 and 2,
Table 1) while, in contrast, the glutamate based cata- Table 2). On the contrary, catalyst 8c failed to cata-
lyst 10e exhibited a dramatic loss in ee (61%, entry 8, lyze the reaction, indicating that the (1S,2S)-1,2-di-
Table 1). The addition of one carbon atom between phenylethylenediamine moiety is superior in compari-
the a-carbon atom and the side chain tert-butyl ester son to (1S,2S)-cyclohexanediamine.
group has a detrimental effect on the enantioselectivi-
All the catalysts based on the tert-butyl esters of
ty. Using derivatives based on serine 10f and threo- amino acids produced the product in high enantiose-
nine 10g, the product was isolated in quantitative lectivities (92–96% ee), but in variable yields. Phenyl-
yields (entries 9 and 10, Table 1), but only in the case alanine, valine, threonine and tyrosine derivatives
of threonine in high ee (87%) (entry 10, Table 1). Ob- (10b, 10c, 10g, 10h) led to low or moderate yields (en-
viously, the additional stereogenic center in the side tries 4, 5, 8 and 10, Table 2). An increase on the yield
chain of threonine positively contributes to the in- from 27% to 38% was observed, when the threonine
crease of the enantioselectivity. Finally, using the tyro- catalyst 10g was used under reflux (entries 8 and 9,
sine derivative 10h, the product was obtained in high Table 2). The ee value was slightly reduced indicating
yield and 81% ee (entry 11, Table 1). Comparing cata- that the thiourea catalysts based on tert-butyl esters of
lysts 10b and 10h, the introduction of a para-tert- amino acids may work equally well at elevated tem-
butoxy group in the phenyl ring efficiently increases perature. Among the aspartate and serine derivatives
the yield from 42% to 89%, however, it only slightly 10d and 10f (entries 6 and 7, Table 2), catalyst 10d,
influences the enantioselectivity (entries 5 and 11, exhibited the best properties affording the product in
Table 1).[9] Attempts to reduce either the loading of 68% yield and 95% ee. An attempt to reduce the
catalyst 10d, or the amount of the nucleophile ace- ratio of trans-b-nitrostyrene:acetophenone from 1:10
tone led to substantial decreases of the reaction yield to 1:5 afforded the product in comparable yield and
(data not shown).
ee, when the catalyst 10f was applied.
The application of organocatalysts in the reaction
To explore the scope of these transformations, vari-
of aromatic ketones as Michael donors with nitroole- ous nitroolefins were studied for their reactions with
fins is described as difficult and limited examples acetone and acetophenone using the aspartate-based
exist in the literature. Only thioureas 4 and 5 based thiourea 10d as a catalyst and the results are present-
on (1S,2S)-1,2-cyclohexanediamine have been shown ed in Table 3. The reaction between acetophenone
to catalyze this transformation.[6a,7] The reaction be- and various nitroolefins took place with high enantio-
tween acetophenone and trans-b-nitrostyrene was selectivity (95–98% ee) (entries 1–4, Table 3). The
studied in the presence of 15 mol% of our catalysts product was isolated in good yields (61–71%), apart
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Table 3. Michael reaction of acetone and acetophenone with various nitroolefins using thioureas as catalysts.
Entry
R1
R2
Product
Conditions
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Me
Me
Me
Me
p-MeOC6H4
p-NO2C6H4
p-FC6H4
13a
13b
13c
13d
13e
13f
13g
13h
A[c]
A[c]
A[c]
A[c]
B[d]
B[d]
B[d]
B[d]
43
61
71
70
69
94
99
94
97
96
95
98
91
88
88
92
2-furyl
p-MeOC6H4
p-NO2C6H4
p-FC6H4
2-furyl
[a]
Isolated yield after column chromatography.
The ee was determined by HPLC on a Daicel Chiralpak AD-H column.
A: CH2Cl2.
[b]
[c]
[d]
B: toluene, AcOH (15 mol%), H2O (2 equiv).
from the case of an electron-rich nitroolefin (43%, results are by far inferior to those obtained by thiour-
entry 1, Table 3). High enantioselectivity was ob- eas. In addition, to our knowledge proline or proline-
served when p-OMe-substituted nitroolefin reacted derivatives have not been reported to catalyze the re-
with acetone (entry 5, Table 3), but the yield of the action between acetophenone and trans-b-nitrostyr-
reaction was 69%. When nitroolefins substituted by ene. Thus, primary amine-thioureas based on tert-
electron-withdrawing groups were used, the products butyl esters of a-amino acids represent a new class of
obtained in high to quantitative yields (94–99%) and thiourea catalysts, which efficiently catalyze “diffi-
high enantioselectivity (88% ee) (entries 6 and 7, cult” Michael additions. Comparing the various amino
Table 3). In addition, the product of the reaction be- acid side chains, it is obvious that the existence of a
tween acetone and 2-(2-nitrovinyl)furan was isolated second tert-butyl ester group or a tert-butyl ether
in both high yield and enantioselectivity (entry 8, group at the b-carbon atom of the amino acid has a
Table 3).
profound effect on enantioselectivity. Barbas and co-
The thiourea catalysts of the present study, combin- workers have recently shown that O-tert-butyl-l-
ing the (1S,2S)-diphenylethylenediamine unit and a threonine is an efficient organocatalyst of anti-Man-
tert-butyl ester of (S)-amino acid catalyze the reaction nich and syn-aldol reactions.[13] After the experimen-
of either acetone or acetophenone with trans-nitroole- tal part of this work had been finished, it was report-
fins producing the (R)-enantiomer. In particular, the ed that self-assemblies from a-amino acids and alka-
products of the reactions with trans-b-nitrostyrene loid derivatives may efficiently catalyze direct nitro-
were obtained in 100% yield and 91% ee and 68% Michael reactions.[14] In addition, a new class of dehy-
yield and 95% ee, respectively, when the catalyst 10d droabietic amine-substituted primary amine-thiourea
based on aspartate was used. As reported in the liter- catalysts was shown to catalyze the conjugated addi-
ature, the (S)-enantiomer of the addition products be- tion of various heterocycles-bearing ketones to nitro-
tween either acetone or acetophenone with trans-b-ni- alkenes with excellent enantioselectivity.[15]
trostyrene were produced, when catalyst 4 was
A bifunctional mechanism involving hydrogen
used.[6a] Using the saccharide thiourea 5, the (S)-enan- bonding and enamine formation has been proposed to
tiomer product of the reaction between acetophenone explain the enantioselectivity observed in Michael ad-
and trans-b-nitrostyrene was obtained in 60% yield ditions catalyzed by thioureas 3, 4 and 5.[5a,6a,7] A joint
and 97% ee.[7] On the contrary, application of catalyst experimental-theoretical study showed that only one
3 in the reaction of acetone with trans-b-nitrostyrene oxygen atom of the nitro group was bound to the
produced the (R)-enantiomer in 98% yield and 91% thioACTHNUTRGNEUNG
urea moiety.[5b] A similar model may be proposed
ee.[5a] It should be noticed that proline produces the for the catalysts of the present study (Figure 3). The
product of the reaction between acetone and trans-b- thiourea functionality interacts through hydrogen
nitrostyrene in very low ee (7%).[10] We and others bonding with the nitro group enhancing the electro-
have demonstrated that homoprolyltetrazole[11] or ho- philicity of nitroolefin, while the primary amine acti-
moprolylsulfonamides[12] may substantially increase vates the ketone through the formation of an enamine
the ee to 42% and 48%, respectively. However, these intermediate.
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General Procedure for the Synthesis of Compounds
8a–c
To a stirring solution of (1,S,2S)-diphenylethylenediamine
(0.15 g, 0.71 mmol) in dichloromethane (7 mL), a solution of
the appropriate isothiocyanate (0.71 mmol) in dichlorome-
thane (15 mL) was added over a period of 15 min at room
temperature and the reaction mixture was left stirring for
18 h. The solvent was evaporated and the crude product was
purified using flash column chromatography eluting with
various mixtures of CH2Cl2:MeOH.
1-[(1S,2S)-2-Amino-1,2-diphenylethyl]-3-(bicyclo
ACHTUNGTRENN[UNG 2.2.1]-
AHCTUNGTREGhNNNU ept-2-yl)thiourea (8a): White solid; yield: 73%; mp 82–
Figure 3. Proposed transition state model for the reaction of
ketones with trans-b-nitrostyrene.
838C; [a]2D5: À59.9 (c 1, CHCl3). 1H NMR (200 MHz,
CDCl3): d=7.42–7.01 (m, 11H), 6.29–6.08 (m, 1H), 5.21 (br
s, 1H), 4.37 (br s, 1H), 3.78–3.49 (m, 1H), 2.38–2.11 (m,
2H), 1.92–1.65 (m, 4H), 1.59–1.42 (m, 2H), 1.38–0.99 (m,
4H); 13C NMR (50 MHz, CDCl3): d=180.7, 141.9, 140.1,
129.0, 128.9, 128.8, 128.0, 126.9, 126.8, 64.2, 60.4, 57.4, 42.7,
40.6, 36.0 35.7, 28.3, 26.6; HR-MS: m/z=366.2002, calcd. for
C22H27N3S (M+H+): 366.2004.
Conclusions
In conclusion, in the present work new thioureas
based on tert-butyl esters of natural amino acids bear-
ing a primary amino group were easily synthesized
and their activity as catalysts in “difficult” Michael
additions was evaluated. In particular, the derivative
based on di-tert-butyl aspartate affords the product of
the reaction of nitroolefins with either acetophenone
or acetone in high to quantitative yields and in high
enantioselectivity (88–98% ee). Thus, low-cost, com-
mercially available tert-butyl esters of natural amino
acids proved to be very important chiral building
blocks to construct novel chiral thiourea catalysts.
1-[(1S,2S)-2-Amino-1,2-diphenylethyl]-3-cyclohexylthiour-
ea[16] (8b): White solid; yield: 65%; [a]2D5: À57.0 (c 1,
1
CHCl3). H NMR (200 MHz, CDCl3): d=7.41 (d, J=5.8 Hz,
1H), 7.31–7.05 (m, 10H), 6.13 (d, J=6.2 Hz, 1H), 5.11 (br s,
1H), 4.24 (d, J=5.8 Hz, 1H), 4.01–3.72 (m, 1H), 2.08 (br s,
2H), 1.98–1.76 (m, 2H), 1.67–1.46 (m, 2H), 1.41–0.89 (m,
6H); 13C NMR (50 MHz, CDCl3): d=180.8, 141.8, 139.6,
129.1, 128.9, 128.8, 128.0, 127.0, 126.9, 64.2, 60.7, 53.3, 32.8,
25.6, 24.7, 24.6.
1-[(1S,2S)-2-Aminocyclohexyl]-3-(bicycloACTHNURTGNEU[GN 2.2.1]hept-2-
yl)thiourea (8c): Colourless oil; yield: 31%; [a]2D5: À35.2 (c 1,
CH3OH). 1H NMR (200 MHz, CD3OD): d=4.56–4.39 (m,
1H), 4.08–3.91 (m, 1H), 3.28–2.98 (m, 1H), 2.37–2.24 (m,
2H), 2.19–1.97 (m, 2H), 1.91–1.69 (m, 4H), 1.61–1.11 (m,
10H); 13C NMR (50 MHz, CD3OD): d=182.3, 57.5, 55.5,
55.3, 42.2, 39.5, 35.9 35.2, 31.6, 30.0, 28.1, 26.1, 24.5, 23.8;
HR-MS: m/z=268.1844, calcd. for C14H25N3S (M+H+):
268.1847.
Experimental Section
General Procedure for the Synthesis of Compounds
10a–h
General Remarks
Flash chromatography was performed on silica gel (Merck
Kieselgel 60 F254 230–400 mesh). TLC was performed on
aluminum backed silica plates (0.2 mm, 60 F254) which were
developed using standard visualizing agents: UV fluores-
cence (254 and 366 nm), phosphomolybdic acid/D, anisalde-
hyde/D. Melting points were determined on a Bꢂchi 530 hot-
stage apparatus and are not corrected. 1H NMR spectra
were recorded at 200 MHz on a Varian Mercury instrument.
Chemical shifts (dH) are quoted in parts per million (ppm),
referenced to the appropriate solvent peak. 13C NMR spec-
tra were recorded at 50 MHz on a Varian Mercury instru-
ment. Chemical shifts (dc) are quoted in parts per million
(ppm), referenced to the appropriate solvent peak. 19F NMR
spectra were recorded at 188 MHz on a Varian Mercury in-
strument. Chemical shifts (dF) are quoted in parts per mil-
lion (ppm), referenced to trifluoroacetic acid as an internal
standard. Chiral HPLC analyses were performed using an
Agilent 1100 Series apparatus and a Daicel Chiralpak
column (AD-H) using hexane/2-propanol as eluent. The
configuration of the Michael addition products has been as-
signed by comparison to literature data.
To a stirring solution of amino acid tert-butyl ester hydro-
chloride (1.0 mmol) in dichloromethane (5 mL), a saturated
aqueous solution of NaHCO3 (5 mL) was added at 08C and
left stirring vigorously for 10 min. The stirring was stopped
and thiophosgene (0.1 mL, 1.05 mmol) was added to the or-
ganic layer (bottom layer) via syringe. The reaction mixture
was stirred vigorously at room temperature for 1 h. The two
layers were separated and the aqueous layer was extracted
with dichloromethane (3ꢃ5 mL). The combined organic
layers were dried over Na2SO4 and the solvent was evapo-
rated to afford the isothiocyanate of sufficient purity to be
used in the subsequent step. A solution of the isothiocyanate
in dichloromethane (15 mL) was added to a stirring solution
of (1,S,2S)-diphenylethylenediamine (0.21 g, 1.0 mmol) in di-
chloromethane (10 mL) over a period of 15 min at room
temperature and the reaction mixture was left stirring until
the consumption of the isothiocyanate (2–18 h). The solvent
was evaporated and the crude product was purified using
flash column chromatography eluting with various mixtures
of CHCl3:MeOH or CH2Cl2:MeOH.
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(S)-tert-Butyl
2-{3-[(1S,2S)-2-amino-1,2-diphenylethyl]-
27.9, 27.0; HR-MS: m/z=472.2633, calcd. for C26H37N3O3S
(M+H+): 472.2634.
ACHTUNGTRENNUNG
[a]2D5: À14.8 (c 0.5, CHCl3). H NMR (200 MHz, CDCl3): d=
1
A
2-{3-[(1S,2S)-2-amino-1,2-diphenyl-
AHCTUNGTRENNUNG
7.71 (m, 1H), 7.32–7.12 (m, 11H), 6.72 (m, 1H), 4.74 [qu
(ap), J=7.0 Hz, 1H], 4.29 (d, J=6.2 Hz, 1H), 3.12 (br s,
2H), 1.39 (s, 9H), 1.23 (d, J=6.2 Hz, 3H); 13C NMR
(50 MHz, CDCl3): d=182.0, 172.8, 141.0, 139.1, 129.0, 128.9,
128.8, 128.1, 128.0, 127.2, 82.2, 63.9, 61.0, 53.9, 28.2, 18.7;
HR-MS: m/z=400.2057, calcd. for C22H29N3O2S (M+H+):
400.2059.
oil; yield: 45%; [a]2D5: +8.2 (c 1, CHCl3). 1H NMR
(200 MHz, CDCl3): d=7.47 (d, J=5.6 Hz, 1H), 7.31–7.07
(m, 11H), 6.57 (d, J=8.4 Hz, 1H), 4.78 (d, J=6.2 Hz, 1H),
4.22 (d, J=5.6 Hz, 1H), 4.10–4.00 (m, 1H), 1.86 (br s, 2H),
1.39 (s, 9H), 1.03 (s, 9H), 0.72 (br s, 3H); 13C NMR
(50 MHz, CDCl3): d=182.4, 169.9, 141.6, 138.8, 128.8, 128.4,
127.9, 127.7, 126.8, 126.7, 81.6, 73.6, 66.2, 64.1, 64.0, 60.7,
28.6, 27.9, 20.1; HR-MS: m/z=486.2788, calcd. for
C27H39N3O3S (M+H+): 486.2790.
(S)-tert-Butyl
2-{3-[(1S,2S)-2-amino-1,2-diphenylethyl]-
ACHTUNGTRENNUNGthioureido}-3-phenylpropanoate (10b): White solid; yield:
32%; mp 92–948C; [a]2D5: +21.6 (c 1, CHCl3). 1H NMR
(200 MHz, CDCl3): d=7.43 (d, J=4.8 Hz, 1H), 7.34–7.06
(m, 15H), 6.86 (br s, 1H), 6.57 (d J=6.6 Hz, 1H), 5.21–5.12
(m, 1H), 4.27 (d, J=4.8 Hz, 1H), 3.14 (dd, J=17.0 and
6.2 Hz, 1H), 3.02 (dd, J=17.0 and 6.6 Hz, 1H), 1.73 (br s,
2H), 1.39 (s, 9H); 13C NMR (50 MHz, CDCl3): d=181.3,
170.6, 141.4, 139.1, 136.1, 129.4, 128.9, 128.5, 128.1, 126.6,
126.5, 82.3, 63.9, 60.6, 58.3, 37.9, 27.9; HR-MS: m/z=
476.2371, calcd. for C28H33N3O2S (M+H+): 476.2372.
(S)-tert-Butyl
2-{3-[(1S,2S)-2-amino-1,2-diphenylethyl]-
thioureido}-3-(4-tert-butoxyphenyl)propanoate (10h): Col-
ourless oil; yield: 32%; [a]2D5: +13.2 (c 1, CHCl3). H NMR
1
(200 MHz, CDCl3): d=7.43 (d, J=6.6 Hz, 1H), 7.33–6.98
(m, 12H), 6.97–6.70 (m, 3H), 6.51 (d J=6.6 Hz, 1H), 5.18–
5.02 (m, 1H), 4.24 (d, J=4.4 Hz, 1H), 3.17–2.85 (m, 2H),
1.82 (br s, 2H), 1.29 (s, 9H), 1.27 (s, 9H); 13C NMR
(50 MHz, CDCl3): d=181.2, 170.5, 153.9, 141.4, 139.0, 131.0,
130.1, 129.8, 128.9, 128.5, 128.0, 127.7, 126.6, 123.8, 82.2,
78.2, 63.8, 60.6, 58.7, 37.3, 28.3, 27.9; HR-MS: m/z=
548.2937, calcd. for C32H41N3O3S (M+H+): 548.2947.
(S)-tert-Butyl
2-{3-[(1S,2S)-2-amino-1,2-diphenylethyl]-
thioureido}-3-methylbutanoate (10c): Colourless oil; yield:
1
33%; [a]25: À3.2 (c 1, CHCl3). H NMR (200 MHz, CDCl3):
d=7.48 (Dd, J=5.2 Hz, 1H), 7.36–7.11 (m, 10H), 6.34 (d, J=
6.6 Hz, 1H), 4.89–4.63 (m, 2H), 4.20 (d, J=5.2 Hz, 1H),
2.12–1.97 (m, 1H), 1.88 (br s, 2H), 1.40 (s, 9H), 0.62 (d, J=
7.0 Hz, 3H), 0.56 (d, J=6.6 Hz, 3H); 13C NMR (50 MHz,
CDCl3): d=181.6, 170.9, 141.5, 138.7, 128.9, 128.5, 128.1,
127.8, 126.8, 126.6, 81.9, 64.0, 62.8, 60.7, 31.3, 27.9, 17.7,
17.6; HR-MS: m/z=428.2365, calcd. for C24H33N3O2S (M+
H+): 428.2372.
General Procedure for the Michael Reaction
Between Acetone and Nitroolefins
To a stirring solution of catalyst (0.03 mmol) in toluene
(1 mL), acetic acid (2 mL, 0.03 mmol) and H2O (8 mL,
0.40 mmol) were added. Nitroolefin (0.2 mmol) was added
following by acetone (0.15 mL, 2.0 mmol). The reaction mix-
ture was left stirring for 48 h. The solvent was evaporated
and the crude product was purified using flash column chro-
matography eluting with a mixture of petroleum ether (40–
608C)/EtOAc (70:30) to afford the product.
(S)-Di-tert-butyl 2-{3-[(1S,2S)-2-amino-1,2-diphenylethyl]-
ACHTUNGTRENNUNG
thioureido}succinate (10d): Colourless oil; yield: 44%; [a]2D5:
+18.5 (c 1, CHCl3). 1H NMR (200 MHz, CDCl3): d=7.51
(d, J=6.6 Hz, 1H), 7.38–7.11 (m, 11H), 6.91 (br s, 1H),
5.19–5.08 (m, 1H), 4.29 (d, J=4.8 Hz, 1H), 2.79 (dd, J=17.4
and 4.2 Hz, 1H), 2.69 (dd, J=17.4 and 4.4 Hz, 1H), 1.81 (br
s, 2H), 1.39 (s, 9H), 1.31 (s, 9H); 13C NMR (50 MHz,
CDCl3): d=182.1, 170.7, 170.2, 141.9, 139.7, 129.0, 128.9,
128.8, 127.9, 126.9, 126.8, 82.4, 81.4, 64.0, 60.8, 54.8, 37.7,
28.2, 28.1; HR-MS: m/z=500.2575, calcd. for C27H37N3O4S
(M+H+): 500.2583.
(R)-5-Nitro-4-phenylpentan-2-one[6a] (11): White solid;
yield: 100%; mp 120–1228C; [a]2D5: À2.2 (c 1, CHCl3).
1H NMR (200 MHz, CDCl3): d=7.38–7.14 (m, 5H), 4.69
(dd, J=12.3 and 7.0 Hz, 1H), 4.59 (dd, J=12.3 and 7.6 Hz,
1H), 4.07–3.92 (m, 1H), 2.91 (d, J=7.0 Hz, 2H), 2.11 (s,
3H); 13C NMR (50 MHz, CDCl3): d=205.4, 138.8, 129.0,
127.8, 127.3, 79.4, 46.1, 39.0, 30.3; 91% ee measured on
chiral HPLC using a Daicel Chiralpak AD-H column, elut-
ing with a mixture of hexane:2-propanol (94:6), flow rate
1 mLminÀ1, retention time: 11.92 (major) and 11.08 (minor).
(S)-Di-tert-butyl 2-{3-[(1S,2S)-2-amino-1,2-diphenylethyl]-
ACHTUNGTRENNUNGthioureido}pentanedioate (10e): Colourless oil; yield: 38%;
[a]2D5: À23.4 (c 0.5, CHCl3). H NMR (200 MHz, CDCl3): d=
7.49 (d, J=6.2 Hz, 1H), 7.33–7.12 (m, 10H), 6.53 (d, J=
7.0 Hz, 1H), 4.89–4.76 (m, 2H), 4.24 (d, J=6.2 Hz, 1H),
2.05–1.69 (m, 6H), 1.41 (s, 18H); 13C NMR (50 MHz,
CDCl3): d=181.8, 172.3, 171.5, 141.8, 139.1, 129.1, 128.9,
128.8, 128.2, 128.0, 127.0, 82.6, 80.7, 64.2, 61.0, 57.4, 30.8,
28.3, 28.2, 27.7; HR-MS: m/z=514.2729, calcd. for
C28H39N3O4S (M+H+): 514.2740.
1
(R)-4-(4-Methoxyphenyl)-5-nitropentan-2-one[6a]
ACHTUNGTRENNUNG(13e):
White solid; yield: 69%; mp 93–958C; [a]2D5: +5.2 (c 1,
1
CHCl3). H NMR (200 MHz, CDCl3): d=7.14 (d, J=8.8 Hz,
2H), 6.86 (d, J=8.8 Hz, 2H), 4.69 (dd, J=12.3 and 6.8 Hz,
1H), 4.59 (dd, J=12.3 and 7.8 Hz, 1H), 4.04–3.91 (m, 1H),
3.78 (s, 3H), 2.93 (d, J=7.0 Hz, 2H), 2.11 (s, 3H); 13C NMR
(50 MHz, CDCl3): d=205.4, 159.1, 130.6, 128.4, 114.3, 79.7,
55.5, 46.2, 38.4, 30.4; 91% ee measured on chiral HPLC
using a Daicel Chiralpak AD-H column, eluting with a mix-
ture of hexane:2-propanol (94:6), flow rate 1 mLminÀ1, re-
tention time: 20.52 (major) and 18.17 (minor).
(R)-4-(4-Nitro-phenyl)-5-nitropentan-2-one (13f): Yellow
oil; yield: 94%; [a]2D5: À1.9 (c 1, CHCl3). 1H NMR
(200 MHz, CDCl3): d=8.20 (d, J=8.8 Hz, 2H), 7.44 (d, J=
8.8 Hz, 2H), 4.77 (dd, J=12.8 and 6.5 Hz, 1H), 4.65 (dd, J=
12.8 and 8.0 Hz, 1H), 4.21–4.07 (m, 1H), 2.94 (d, J=7.0 Hz,
(S)-tert-Butyl
2-{3-[(1S,2S)-2-amino-1,2-diphenylethyl]-
thioureido}-3-tert-butoxypropanoate (10f): Colourless oil;
1
yield: 34%; [a]25: +13.7 (c 1, CHCl3). H NMR (200 MHz,
CDCl3): d=7.5D1 (d, J=5.2 Hz, 1H), 7.31–7.16 (m, 11H),
6.61 (d, J=6.6 Hz, 1H), 5.12–4.97 (m, 1H), 4.25 (d, J=
5.2 Hz, 1H), 3.62 (dd, J=8.8 and 3.0 Hz, 1H), 3.46–3.31 (m,
1H), 1.84 (br s, 2H), 1.45 (s, 9H), 0.91 (s, 9H); 13C NMR
(50 MHz, CDCl3): d=181.5, 169.4, 141.6, 138.9, 128.8, 128.5,
127.8, 127.7, 126.7, 126.6, 81.6, 72.7, 63.7, 62.2, 60.6, 58.7,
1360
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1355 – 1362

Primary Amine-Thioureas based on tert-Butyl Esters of Natural Amino Acids
FULL PAPERS
2H), 2.16 (s, 3H); 13C NMR (50 MHz, CDCl3): d=204.4,
147.3, 146.3, 128.6, 124.2, 78.5, 45.6, 38.6, 30.3; HR-MS:
m/z=275.0638, calcd. for C11H12N2O5 (M+Na+): 275.0644.
88% ee measured on chiral HPLC using a Daicel Chiralpak
AD-H column, eluting with a mixture of hexane:2-propanol
(85:15), flow rate 1 mLminÀ1, retention time: 22.62 (major)
and 16.65 (minor). The stereochemistry has been tentatively
assigned by comparison to analogous compound 11.
(R)-4-(4-Fluorophenyl)-5-nitro-pentan-2-one (13g): White
solid; yield: 99%; [a]2D5: +2.4 (c 1, CHCl3). 1H NMR
(200 MHz, CDCl3): d=7.29–7.11 (m, 2H), 7.06–6.93 (m,
2H), 4.67 (dd, J=12.4 and 6.7 Hz, 1H), 4.55 (dd, J=12.4
and 7.9 Hz, 1H), 4.11–3.89 (m, 1H), 2.88 (d, J=7.0 Hz, 2H),
2.11 (s, 3H); 13C NMR (50 MHz, CDCl3): d=205.1, 162.1 (d,
J=246.8 Hz), 134.5 (d, J=3.3 Hz), 129.0 (d, J=8.1 Hz),
115.9 (d, J=21.5 Hz), 79.4, 46.1, 38.3, 30.4; 19F NMR
(188 MHz, CDCl3): d=À48.4 (m, 1F,); HR-MS: m/z=
248.0698, calcd. for C11H12FNO3 (M+Na+): 248.0699. 88%
ee measured on chiral HPLC using a Daicel Chiralpak AD-
H column, eluting with a mixture of hexane:2-propanol
(94:6), flow rate 1 mLminÀ1, retention time: 17.17 (major)
and 15.12 (minor). The stereochemistry has been tentatively
assigned by comparison to analogous compound 11.
12.3 and 7.9 Hz, 1H), 4.24–4.07 (m, 1H), 3.77 (s, 3H), 3.44
(dd, J=16.5 and 6.5 Hz, 1H), 3.37 (dd, J=16.5 and 6.6 Hz,
1H); 13C NMR (50 MHz, CDCl3): d=197.0, 159.0, 136.4,
133.5, 131.0, 128.7, 128.5, 128.0, 114.4, 79.8, 55.2, 41.6, 38.6.
97% ee measured on chiral HPLC using a Daicel Chiralpak
AD-H column, eluting with a mixture of hexane:2-propanol
(80:20), flow rate 1 mLminÀ1, retention time: 21.13 (major)
and 15.54 (minor).
(R)-4-Nitro-3-(4-nitrophenyl)-1-phenylbutan-1-one[17]
AHCTUNGTERNNUNG
(13b): Yellow solid; yield: 61%; mp 104–1058C; [a]2D5: +32.9
1
(c 1, CHCl3). H NMR (200 MHz, CDCl3): d=8.20 (d, J=
8.8 Hz, 2H), 7.90 (dd, J=8.3 and 1.2 Hz, 2H), 7.61–7.42 (m,
5H), 4.88 (dd, J=12.8 and 6.4 Hz, 1H), 4.73 (dd, J=12.8
and 8.2 Hz, 1H), 4.43–4.27 (m, 1H), 3.49 (d, J=7.0 Hz,
2H); 13C NMR (50 MHz, CDCl3): d=195.9, 147.5, 146.5,
135.9, 133.9, 128.9, 128.6, 128.0, 124.2, 78.8, 41.0, 38.9. 96%
ee measured on chiral HPLC using a Daicel Chiralpak AD-
H column, eluting with a mixture of hexane:2-propanol
(80:20), flow rate 1 mLminÀ1, retention time: 42.34 (major)
and 25.09 (minor). The stereochemistry has been tentatively
assigned by comparison to analogous compound 12.
(R)-3-(4-Fluorophenyl)-4-nitro-1-phenylbutan-1-one[18]
AHCTUNGTRENNUNG
(13c): Yellow oil; yield: 71%; [a]2D5: +23.7 (c 1, CHCl3).
(R)-4-Furan-5-nitropentan-2-one[6a]
(13h): White solid;
1H NMR (200 MHz, CDCl3): d=7.93 (d, J=7.0 and 1.6 Hz,
2H), 7.62–7.41 (m, 3H), 7.32–7.21 (m, 2H), 7.07–6.92 (m,
2H), 4.82 (dd, J=12.5 and 6.6 Hz, 1H), 4.65 (dd, J=12.5
and 8.0 Hz, 1H), 4.40–4.15 (m, 1H), 3.47 (dd, J=18.0 and
6.8 Hz, 1H), 3.38 (dd, J=18.0 and 7.3 Hz, 1H); 13C NMR
(50 MHz, CDCl3): d=196.6, 162.2 (d, J=246.8 Hz), 136.3,
134.8 (d, J=3.4 Hz), 133.6, 129.1 (d, J=8.2 Hz), 128.8, 128.0,
116.0 (d, J=21.5 Hz), 79.6, 41.5, 38.6; 19F NMR (188 MHz,
CDCl3): d=À47.8 (1F, m). 95% ee measured on chiral
HPLC using a Daicel Chiralpak AD-H column, eluting with
yield: 94%; mp 53–558C; [a]2D5: À7.2 (c 1, CHCl3). H NMR
(200 MHz, CDCl3): d=7.34 (dd, J=1.8 and 0.7 Hz, 1H),
6.30 (dd, J=3.2 and 1.8 Hz, 1H), 6.14 (d, J=3.2 Hz, 1H),
4.71 (dd, J=12.6 and 6.6 Hz, 1H), 4.65 (dd, J=12.6 and
6.6 Hz, 1H), 4.22–4.04 (m, 1H), 3.00 (dd, J=16.7 and
5.2 Hz, 1H), 2.88 (dd, J=16.7 and 6.0 Hz, 1H), 2.18 (s, 3H);
13C NMR (50 MHz, CDCl3): d=205.1, 151.6, 142.3, 110.4,
107.0, 77.0, 43.4, 32.8, 30.2; 92% ee measured on chiral
HPLC using a Daicel Chiralpak AD-H column, eluting with
1
a
mixture of hexane:2-propanol (94:6), flow rate
a
mixture of hexane:2-propanol (90:10), flow rate
1 mLminÀ1, retention time: 26.03 (major) and 18.55 (minor).
(R)-3-Furan-2-yl-4-nitro-1-phenylbutan-1-one[7]
(13d):
1 mLminÀ1, retention time: 14.04 (major) and 12.09 (minor).
ACHTUNGTRENNUNG
Colourless oil; yield: 70%; [a]2D5: +11.6 (c 1, CHCl3).
1H NMR (200 MHz, CDCl3): d=7.99–7.91 (m, 2H), 7.65–
7.41 (m, 3H), 7.35–7.31 (m, 1H), 6.32–6.26 (m, 1H), 6.18 (d,
J=3.3 Hz, 1H), 4.81 (dd, J=11.6 and 5.4 Hz, 1H), 4.73 (dd,
J=11.6 and 6.0 Hz, 1H), 4.41–4.26 (m, 1H), 3.53 (dd, J=
17.7 and 6.1 Hz, 1H), 3.41 (dd, J=17.7 and 7.3 Hz, 1H);
13C NMR (50 MHz, CDCl3): d=196.8, 152.2, 142.6, 136.5,
133.9, 129.0, 128.4, 110.7, 107.4, 77.6, 39.2, 33.4. 98% ee mea-
sured on chiral HPLC using a Daicel Chiralpak AD-H
General Procedure for the Michael Reaction between
Acetophenone and Nitroolefins
To a stirring solution of catalyst (0.03 mmol) in dichlorome-
thane (1 mL), nitroolefin (0.2 mmol) was added following by
acetophenone (0.23 mL, 2.0 mmol). The reaction mixture
was left stirring for 48 h. The solvent was evaporated and
the crude product was purified using flash column chroma-
tography eluting with a mixture of petroleum ether (40–
608C)/EtOAc (80:20) to afford the product.
column, eluting with
a mixture of hexane:2-propanol
(90:10), flow rate 1 mLminÀ1, retention time: 17.28 (major)
and 14.21 (minor).
(R)-4-Nitro-1,3-diphenylbutan-1-one[7] (12): White solid;
1
yield: 68%; mp 91–938C; [a]2D5: +23.1 (c 1, CHCl3). H NMR
(200 MHz, CDCl3): d=7.98–7.85 (m, 2H), 7.62–7.21 (m, 8H),
4.84 (dd, J=12.5 and 6.7 Hz, 1H), 4.68 (dd, J=12.5 and
7.8 Hz, 1H), 4.31–4.04 (m, 1H), 3.50 (dd, J=17.7 and 6.4 Hz,
1H), 3.40 (dd, J=17.7 and 7.5 Hz, 1H); 13C NMR (50 MHz,
CDCl3): d=196.8, 139.1, 136.4, 133.5, 129.1, 128.7, 128.0,
127.9, 127.4, 79.5, 41.5, 39.3. 96% ee measured on chiral
HPLC using a Daicel Chiralpak AD-H column, eluting with
Acknowledgements
The project is co-funded by the European Social Fund and
National Resources (EPEAEK II). The authors would like
to thank Prof. A. Giannis (University of Leipzig) for HR-MS
analysis.
a
mixture of hexane:2-propanol (90:10), flow rate
1 mLminÀ1, retention time: 21.07 (major) and 15.45 (minor).
(R)-3-(4-Methoxyphenyl)-4-nitro-1-phenylbutan-1-one[6a,7]
G
0.5, CHCl3). H NMR (200 MHz, CDCl3): d=7.98–7.85 (m,
2H), 7.61–7.48 (m, 3H), 7.19 (d, J=8.7 Hz, 2H), 6.85 (d, J=
8.7 Hz, 2H), 4.80 (dd, J=12.3 and 6.7 Hz, 1H), 4.63 (dd, J=
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asc.wiley-vch.de
1361

Christoforos G. Kokotos and George Kokotos
FULL PAPERS
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