Novel bifunctional chiral urea and thiourea derivatives as organocatalysts: Enantioselective nitro-Michael reaction of malonates and diketones

Article abstract of DOI:10.1002/chem.200800633

A modular synthesis of novel bifunctional urea and thiourea organocatalysts derived from cheap, easily accessible natural and non-natural amino acids was reported. The generality of the synthesis was demonstrated in the preparation of catalysts 4a-i in th

Full text of DOI:10.1002/chem.200800633

DOI: 10.1002/chem.200800633
Novel Bifunctional Chiral Urea and Thiourea Derivatives as Organocatalysts:
Enantioselective Nitro-Michael Reaction of Malonates and Diketones
JosØ M. AndrØs, RubØn Manzano, and Rafael Pedrosa*[a]
The ability of chiral hydrogen-bond donors to catalyze
useful enantioselective transformations constitutes an in-
creasing area of interest, and diverse types of structures
have been described to this end.[1] An important class of
species are urea and thiourea compounds[2] which have fre-
quently been used in several transformations, such as Henry
or aza-Henry,[3] Mannich,[4] Strecker,[5] and Friedel–Crafts[6]
reactions or Michael[7] and nitro-Michael[8] additions.
The modular design of these types of catalysts requires
the possibility to introduce different urea and thiourea moi-
eties and the modification of the structure with the chiral in-
formation. Most of the described catalysts until now are aryl
or diaryl ureas or thioureas with electron withdrawing
groups, although some relatively electron rich derivatives
have proved to catalyze a variety of enantioselective trans-
formations.[9]
The chiral information in the catalyst has been placed at
both the nitrogen terminus in the urea or thiourea or in the
central chiral core. In this respect, a few structures are used
in the preparation of the catalysts, namely chiral diamines,[10]
both enantiomers of trans cyclohexane-1,2-diamine,[10,11] bi-
naphthylamines,[12] diamines derived from cinchona alka-
loids,[13] amino alcohols,[14] and very recently, sugars.[15]
In our opinion, the development of novel chiral scaffolds
to be incorporated into urea and thiourea derivatives, capa-
ble to act as bifunctional organocatalyts, is necessary. Be-
cause, in general, 1,2-diamines are the structures that lead to
the best results, we planned to prepare these compounds
taking into account three facts: i) The starting material
would have be commercially available and cheap; ii) both
enantiomers of the amine must be accessible; and iii) the
synthesis should be able to provide the ability to fine-tune
the substituents at the nitrogen atoms.
We envisioned that natural a-amino acids would be the
starting material of choice and we describe here the synthe-
sis of chiral diamines derived from them and their use as or-
ganocatalysts in nitro-Michael additions of stabilized carban-
ions. The generality of the synthesis was demonstrated in
the preparation of catalysts 4a–i in three steps from com-
mercially available N-Boc protected a-amino acids. The
nature of the substituent at the stereocenter is dictated by
the election of the starting amino acid, the substituents at
the nitrogen atom can be varied in the formation of the a-
amino amide, and the structure of the urea–thiourea compo-
nent is selected depending on the isocyanate–isothiocyanate
used in the last step.
In this way, N-Boc protected l-valine, l-isoleucine, l-phe-
nylalanine, and l-tert-leucine were converted into 1a–h by
reaction with the corresponding amines,[16] which were trans-
formed into 2a–h by deprotection with TFA in methylene
chloride. Lithium aluminum hydride reduction to 3a–g and
condensation with the corresponding isocyanate or isothio-
cyanate yielded the final urea or thiourea derivatives 4a–h
in good yields.[17] The same protocol allowed the preparation
of ent-4a starting from d-valine, and 4i, regioisomer of 4a,
was obtained from l-valinamide hydrochloride by dimethy-
lation, lithium aluminum hydride reduction and reaction
with
3,5-bis(trifluoromethyl)phenyl
isothiocyanate
(Scheme 1).
The catalytic activity of 4a–i was first evaluated in the re-
action of trans b-nitrostyrene 5a with diethyl malonate 6a in
the presence of 10 mol% of catalyst at room temperature,
and the results are collected in Table 1. A set of five differ-
ent solvents was tested as reaction media (entries 1–5 in
Table 1) showing that the reactions occurred in good yields
and moderate to good ee. Only in the case of methanol
(entry 1) the enantioselectivity decreased to 40% ee, proba-
bly because the competitive establishment of hydrogen acti-
vation of the solvent with the catalyst,[8a] and the enantiose-
lectivity increased when less polar solvents were used (com-
pare entries 1–5), or if the reaction was carried out without
[a] Dr. J. M. AndrØs, R. Manzano, Prof. Dr. R. Pedrosa
Centro de Innovación en Química y Materiales Avanzados
(CINQUIMA) and Departamento de Química Orgµnica
Facultad de Ciencias, Universidad de Valladolid
Dr. Mergelina s/n, 47011 Valladolid (Spain)
Fax : (+34)983423211
pedrosa@qo.uva.es
Supporting information for this article is available on the WWW
under http://www.chemistry.org or from the author.
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COMMUNICATION
Table 1. Nitro-Michael reaction of trans-nitrostyrene with 6a catalyzed
by 4a–i.
Entry Catalyst Solvent
t [h] Yield [%][b] ee [%][c] (Config.)[d]
1
2
3
4
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
CH3OH 28
73
82
64
77
83
81
85
55
87
93
83
93
–
44
90
88
67
94
91
97
65
90
40 (S)
79 (S)
85 (S)
86 (S)
88 (S)
84 (S)
88 (S)
89 (S)
87 (S)
85 (S)
87 (S)
87 (S)
–
14 (S)
95 (S)
93 (S)
89 (S)
92 (S)
92 (S)
94 (S)
85 (S)
93 (R)
CH3CN
THF
30
31
32
25
23
48
48
29
30
22
22
48
46
44
46
46
43
19
48
96
48
CH2Cl2
toluene
neat
5
6
7e
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
8f
9
10
11
12
13
14
15[g]
16[g]
17[g]
18[g]
19[g]
20[g]
21[g]
22[g]
4d
4e
4 f
4i
4a
4b
4c
4d
4e
4g
4h
ent-4a
Scheme 1. Synthesis of urea and thioureas 4a–i.
[a] Unless otherwise specified, the reaction was carried out with 1 equiv
of 5a and 2 equiv of 6a in the presence of 10 mol% of catalyst at room
temperature. [b] Isolated yield. [c] Enantiomeric excess was determined
by HPLC analysis of 7a using a chiral column. [d] Absolute configuration
was determined by comparing the optical rotation of 7a with that of the
literature data. [e] 5 mol% of the catalyst was used. [f] 2 mol% of the
catalyst was used. [g] The reaction was carried out at À188C.
solvent (entry 6). Further optimization of this process shown
that the reaction could be performed with 5 mol% (entry 7)
or 2 mol% (entry 8) of catalyst loading without decreasing
the enantioselectivity, although in the last case the yield de-
creased for the same reaction time.
The effect of the modification of the core chiral structure
of ureas and thioureas on the enantioselectivity was sudied
by using 4b–i as catalysts in toluene as solvent. In general,
the modification of the alkyl substituent has little influence
on the reaction enantioselectivity (85–88% ee, entries 5, 9–
11), with valine-derived catalyst providing the best results.
Interestingly, the use of urea 4e as catalyst gave excellent
yield and very good ee (entry 12).
On the contrary, the substituents at the amine nitrogen
atom or the stereogenic nature of the carbon atom where
the thiourea environment is attached were observed to exert
a very significant effect on both the yield and the enantiose-
lectivity of the reaction. In this way, N,N-dibenzyl derivative
4 f was unable to promote the reaction after 48 h at RT
(entry 13). Catalyst 4i, regiosisomer of 4a where the thiour-
ea substituent is attached to a non-stereogenic carbon atom,
led to the addition product in low yield and very low enan-
tioselectivity (entry 14).
The reaction temperature also plays an important effect
on the enantioselectivity. The reactions carried out in tolu-
ene with 10 mol% of the catalyst at À188C (entries 15–22)
demonstrated that at low temperature the enantioselectivity
increased to 95% ee without decreasing the yield, although
in same cases the reaction time must be increased to 48 h.
In these conditions, the N-methyl-N-isopropyl derivative 4g
lead to the addition product in excellent yield (97%) and ee
(94%), and the phenylthiourea 4h which has a greater pKa
than the 3,5-bis(trifluoromethyl) derivatives, and conse-
quently with decreased H-bond donating ability,[17] also pro-
motes the reaction with moderate yield (65%) and good ee
(85%) although for a long period of time (entry 21). Cata-
lysts 4a–i, derived from l-amino acids gave addition prod-
ucts with S configuration at the created stereocenter, and as
expected thiourea ent-4a, derived from d-valine yielded the
addition product with R configuration with excellent yield
and ee (entry 22).
We next studied the effect of the variations of the nucleo-
philic structure on the addition reaction. To this end, trans
b-nitrostyrene was treated with different malonates or acety-
lacetone (6a–h) in toluene at À188C and 10 mol% of cata-
lyst 4a, and the results are summarized in Table 2. It is note-
worthy that the ease of the reaction is dependent upon the
size of the alcoxy group of the unsubstituted malonates (en-
tries 1-4 in Table 2). The reaction with dimethyl malonate
6b was completed after 24 h, and the addition product was
obtained in excellent 95% yield and 93% ee (entry 2), and
the reaction time increased, and the yield diminished with
the bulk of the alcoxy substituent. The bulkiest di-tert-butyl
malonate did not react in the described conditions after
120 h of stirring.
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R. Pedrosa et al.
Table 2. Enantioselective nitro-Michael reaction of 5a with malonates
6a–h in the presence of 4a.
Table 3. Enantioselective Michael reaction of nitroolefins 5a–f with di-
ethyl malonate 6a in the presence of 4a–e.
Entry Cat.
R
t [h] Yield [%][b] Product (ee [%])[c]
(Config.)[d]
Entry R1
R2
t [h] Yield [%][b] Product (ee [%])[c]
(Config.)[d]
AHCTREUNG
AHCTREUNG
1
2
3
4
5
6
7
8
9
4a
4a
4b
4d
4e
4a
4a
4a
4a
C6H5 (5a)
44
47
48
27
24
90
96
94
98
94
8a (95) (S)
8b (93) (S)
8b (92) (S)
8b (93) (S)
8b (91) (S)
8c (94) (+)[e]
8d (87) (+)[e]
8e (95) (À)[e]
8 f (81) (À)[e]
1
2
3
4
5
6
7
8
OEt (6a)
H
H
H
H
H
Me
Cl
44
24
96
120
4
90
95
64
n.r.
99
57
86
53
7a (95) (S)
7b (93) (S)
7c (91) (S)
–
7e (93) (S)
7 f (96) (À)[e]
7g (99) (+)[e]
7h (79) (À)[e]
4-Cl-C6H4 (5b)
4-Cl-C6H4 (5b)
4-Cl-C6H4 (5b)
4-Cl-C6H4 (5b)
4-MeO-C6H4 (5c) 72
2-NO2-C6H4 (5d) 48
OMe (6b)
OiPr (6c)
OtBu (6d)
Me (6e)
OMe (6 f)
OMe (6g)
OEt (6h)
94
72
1
>99
94
2-furyl (5e)
C6H5CH2CH2 (5 f) 144
46
NHBoc 72
69
[a] The reactions were carried out with 1 equiv of 5a and 2 equiv of 6 in
the presence of 10 mol% of catalyst at À188C. [b] Isolated yield. [c] En-
antiomeric excess was determined by HPLC analysis of 7 using a chiral
column. [d] Absolute configuration was determined by comparing the op-
tical rotation of 7 with that of the literature data. [e] Not determined.
[a] The reaction was carried out with 1 equiv of 5 and 2 equiv of 6a in
the presence of 10 mol% of catalyst at À188C. [b] Isolated yield. [c] En-
antiomeric excess was determined by HPLC analysis of 8 using a chiral
column. [d] Absolute configuration was determined by comparing the op-
tical rotation of 8 with that of the literature data. [e] Not determined.
Acetylacetone 6e easily reacted with nitrostyrene yielding
the addition product 7e in 99% yield and 93% ee within 4 h
(entry 5). More interesting are the additions of substituted
malonates because of the formation of a quaternary carbon
center in the final products. In this way, 2-methyl dimethyl
malonate yielded the addition product 7 f in moderate yield
(57%) but excellent 96% ee after 72 h of reaction (entry 6),
whereas the protected 2-amino diethyl malonate also react-
ed in moderate yield and ee (entry 8). In contrast, the reac-
tion of 2-chlorodimethyl malonate was completed after only
1 h leading to 7g in excellent 86% yield and complete enan-
tioselectivity (entry 7).
non-natural amino acids. The method allowed the prepara-
tion of both enantiomers of the catalysts starting from l- or
d-amino acid series. Taking the Michael addition of malo-
nates or dicarbonyl compounds to nitroolefins as a model
we have tested the ability of these structures as enantiose-
lective organocatalysts, proving the generality of their use.
Among the tested catalysts, 4a and ent-4a, thioureas derived
from l- or d-valine respectively, are the most promising in
terms of cost, yield and enantioselectivity. The enantioselec-
tive additions in presence of these catalysts occurred with
excellent yield and ee, and they are compatible with a varie-
ty of nitroolefins and donors. In this way, they can be effi-
ciently used to create tertiary and quaternary carbon center.
Finally, we screened a series of reactions of diethyl malo-
nate with nitroolefins 5a–f bearing different b-substituents
promoted by catalysts 4a–e in toluene at À188C. As illus-
trated in Table 3, p-chloronitrostyrene 5b underwent conju-
gate addition of diethyl malonate in the presence of cata-
lysts 4a–e in excellent yields and ee values; the results are
almost independent of the nature of the catalyst. The reac-
tion promoted by urea 4e was faster than those carried out
with thiourea catalysts, although the ee was slightly lower
(entry 5). The addition of diethyl malonate to p-methoxyni-
trostyrene 5c in the presence of 4a proceeded with high
yield and enantioselectivity, but the rate of the reaction was
somewhat decreased, probably due to the electron-rich char-
acteristics of the substituent, whereas the o-nitro substituted
nitrostyrene and the nitroolefin with a 2-furyl substituent
behaves in a similar way as b-phenylnitrostyrene do (en-
tries 7, 8 in Table 3). In contrast to this general behavior, the
nitroolefin with a saturated substituent at b-position (5 f)
slowly reacted with diethyl malonate, yielding the addition
product 8 f in moderate yield (69%) and ee (81%) after
144 h of stirring in toluene at À188C (entry 9).
Acknowledgements
We acknowledge financial support by the Spanish DGICYT (project
CTQ2005-01191/BQU) and Junta de Castilla
VA025A06). R.M. also thanks the Ministerio de Educación y Ciencia for
a predoctoral fellowship (FPU).
y
León (project
Keywords: asymmetric catalysis · asymmetric synthesis ·
Michael addition · organocatalysis · thioureas
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In summary, we have successfully developed a modular
synthesis of novel bifunctional urea and thiourea organoca-
talysts derived from cheap, easily accessible natural and
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Organocatalysts
COMMUNICATION
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Received: April 3, 2008
Published online: April 22, 2008
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