Enantioselective Michael addition of α,α-disubstituted aldehydes to maleimides organocatalyzed by chiral primary amine-guanidines

Article abstract of DOI:10.1016/j.tetasy.2012.11.002

New primary amine-guanidines derived from the monoguanylation of (1S,2S)- and (1R,2R)-cyclohexane-1,2-diamine have been prepared and used as chiral organocatalysts for the enantioselective conjugate addition of α,α-disubstituted aldehydes to maleimides. T

Full text of DOI:10.1016/j.tetasy.2012.11.002

Tetrahedron: Asymmetry 23 (2012) 1625–1627
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Tetrahedron: Asymmetry
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Enantioselective Michael addition of
a,a-disubstituted aldehydes to maleimides
organocatalyzed by chiral primary amine-guanidines
⇑
⇑
Angel Avila, Rafael Chinchilla , Carmen Nájera
Departamento de Química Orgánica, Facultad de Ciencias, and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 October 2012
Accepted 8 November 2012
New primary amine-guanidines derived from the monoguanylation of (1S,2S)- and (1R,2R)-
cyclohexane-1,2-diamine have been prepared and used as chiral organocatalysts for the enantioselective
conjugate addition of
a,a-disubstituted aldehydes to maleimides. The corresponding Michael adducts
bearing a new stereocenter were generally obtained in high or quantitative yields and with good enanti-
oselectivities (up to 93% ee).
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
thiourea organocatalysts have been developed and applied to the
enantioselective Michael addition of
a,a-disubstituted aldehydes
The synthesis of enantiomerically enriched substituted succini-
mides is currently an interesting topic, as these compounds have
important biological activities1 and are precursors of interesting
substances.2 For instance, succinimides can be easily transformed
to maleimides, giving excellent results.8 However, a drawback of
the use of these organocatalysts, particularly on a large scale, is
that their best performance is achieved employing chlorinated
solvents.
into
c
-lactams, a subunit widely distributed among biologically
Chiral guanidines have been shown to be interesting systems
for achieving asymmetric transformations when used as organo-
catalysts.9 However, their use in the enantioselective Michael addi-
tion reaction of carbon nucleophiles to maleimides is limited to the
reaction of malonates or 1,3-dicarbonyl compounds,10 as well as
dithiomalonates,10a 3-benzyl-substituted oxoindoles,11 or anthro-
nes12 as nucleophile precursors, due to their easy deprotonation
by the basic guanidine. No examples exist on the use of chiral gua-
nidine derivatives for performing this conjugate reaction to malei-
mides with aldehydes.
interesting natural products.3
Probably the most direct way of preparing enantiomerically en-
riched substituted succinimides is performing the enantioselective
Michael addition reaction of a carbon-centered nucleophilic spe-
cies onto a maleimide, a process which can be carried out organo-
catalytically.4 In general, the organocatalysts employed have a
basic character, therefore being able to deprotonate species bear-
ing acidic hydrogens, and thus generating the nucleophile. This
deprotonation is much more difficult in the case of substrates bear-
ing low-acidity hydrogens, such as simple ketones or aldehydes. In
this case, the reaction can be performed using chiral amines as
organocatalysts, which are amenable to generate a transient chiral
enamine responsible for asymmetric outcome of the process. Ami-
no acid derivatives has been used for this process,5 as well as chiral
diamine monosulfamides.6 Particularly good yields and enantiose-
lectivities in the conjugate addition of aldehydes to maleimides
Herein we report the synthesis of new chiral primary amine-
guanidines and their use as organocatalysts for the direct enantio-
selective reaction of particularly difficult
aldehydes to maleimides.
a,a-disubstituted
2. Results and discussion
have been obtained using
organocatalyst,7 although the enantioselection achieved using
-dialkylated aldehydes such as isobutyraldehyde was only
moderate.
This limitation prompted the search for new chiral amine
-bearing organocatalysts amenable to carry out the Michael addi-
tion reaction of disubstituted aldehydes to maleimides with a high
enantioselection. Thus, several bifunctional primary amine
a protected diarylprolinol as the
Chiral primary amine-guanidines 1a and 1b were prepared in
50% yield by the reaction of (1S,2S)-cyclohexane-1,2-diamine
(5 equiv) with diisopropylcarbodiimide and dicyclohexylcarbodi-
imide, respectively, in THF at room temperature for 48 h (Scheme 1).
These primary amine-guanidines 1 were then used as organo-
catalysts in the model Michael conjugate addition of isobutyralde-
hyde to N-phenylmaleimide under different reaction conditions
(Table 1). Thus we tested diisopropyl-containing amine guanidine
1a as the organocatalyst (20 mol %) in this model transformation,
using toluene as the solvent at room temperature. The addition ad-
duct (R)-4aa was obtained in 51% conversion (300 MHz 1H NMR)
a,a
⇑
Corresponding authors. Tel.: +34 96 5903728; fax: +34 96 5903549.
E-mail addresses: chinchilla@ua.es (R. Chinchilla), cnajera@ua.es (C. Nájera).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.002

1626
A. Avila et al. / Tetrahedron: Asymmetry 23 (2012) 1625–1627
Table 1
NH2
NH2
NR
Screening and optimization of the reaction conditions for the enantioselective
Michael addition
THF, rt
(50%)
RN
C
NR
+
N
H
NHR
O
O
NH2
O
H
(5 eq)
O
cat.
N
Ph
1a, R = iPr
1b, R = Cy
+
N
Ph
solvent, T
H
*
O
O
Scheme 1. Preparation of primary amine guanidines 1.
3a
4aa
2a
Entry
Cat. (mol %)
Solvent
T (°C)
t (d)
Yielda (%)
eeb (%)
and 76% ee (chiral HPLC) (Table 1, entry 1). Its (R) absolute config-
uration was determined by comparison of the elution order of the
corresponding enantiomers in chiral HPLC with those in the litera-
ture.8b However, when dicyclohexyl-containing primary amine
guanidine 1b was used as the organocatalyst under the same reac-
tion conditions, only 48% ee for adduct (R)-4aa was detected,
although in a much higher yield (Table 1, entry 2). Therefore, we
continued the search for the optimum reaction conditions using
organocatalyst 1a.
Other solvents were then assayed. Nitromethane and methanol
were also used as solvents at room temperature, although a lower
enantioselection was observed in both cases, as well as lower
yields (Table 1, entries 3 and 4). When DMF was employed as
the solvent, the enantioselection of the process increased up to
82% for adduct (R)-4aa, although in 55% yield after 2 d (Table 1, en-
try 5). However, the yield for this model reaction rose up to 70%
after 1 d reaction time when using water as the solvent at room
temperature, with compound (R)-4aa being obtained in 80% ee
(Table 1, entry 6). Therefore, the combination of DMF/H2O was
explored as the solvent mixture at room temperature, employing
different DMF/H2O ratios. Thus, a DMF/H2O 1/1 v/v gave rise to a
quantitative yield after 2 d reaction time, with (R)-4aa being ob-
tained with 85% ee (Table 1, entry 7). The use of a mixture of
DMF/H2O 2/1 v/v as solvent increased the enantioselectivity up
to 88% ee while keeping quantitative yield (Table 1, entry 8). Fur-
ther lowering the amount of water in the mixture was not benefi-
cial, as the use of a DMF/H2O 4/1 v/v mixture afforded a lower
enantioselection (84% ee) (Table 1, entry 9). Moreover, the addition
of an additive such as benzoic acid (20 mol %) to the reaction
mixture did not improve the yield or enantioselectivity of the
process.
1
2
3
4
5
6
7
8
9
1a (20)
1b (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (10)
ent-1a (20)
PhMe
PhMe
MeNO2
MeOH
DMF
H2O
25
25
25
25
25
25
25
25
25
15
25
25
2
2
2
2
2
1
2
2
2
3
3
2
51
90
30
15
55
70
99
99
99
88
99
99
76 (R)
48 (R)
46 (R)
68 (R)
82 (R)
80 (R)
85 (R)
88 (R)
84 (R)
87 (R)
83 (R)
87 (S)
DMF/H2Oc
DMF/H2Od
DMF/H2Oe
DMF/H2Od
DMF/H2Od
DMF/H2Od
10
11
12
Isolated yield (1H NMR, 300 MHz).
a
Enantioselectivities determined by chiral HPLC.14 Absolute stereochemistry
b
determined by the reported order of elution of the enantiomers in chiral HPLC.8b
c
1/1, v/v.
2/1, v/v.
4/1, v/v.
d
e
The influence of the reaction temperature was then determined.
Thus, when the temperature was lowered to 15 °C using the mix-
ture of DMF/H2O 2/1 v/v as the solvent, the enantioselection for
(R)-4aa remained essentially the same (87%) when working at
25 °C, while the reaction rate decreased considerably (Table 1, en-
try 10). In addition, we also explored the influence of lowering the
loading of the organocatalyst 1a. Thus, when the model reaction
was performed using 1a as the organocatalyst in 10 mol % loading,
the yield of the process was quantitative after a longer reaction
time (3 d), while the enantioselectivity of (R)-4aa decreased to
83% ee (Table 1, entry 11).
Expecting to achieve an opposite enantioselection, we prepared
the primary amine guanidine ent-1a in 50% yield in a similar man-
Table 2
Enantioselective Michael addition of a,a-disubstituted aldehydes to maleimides organocatalyzed by primary amine-guanidine 1a
O
O
O
O
1a (20 mol%)
R1
N
R2
+
N
R2
H
DMF/H2O 2/1
25 ºC
H
R1
R1 R1
O
O
2
4
3
Entry
Aldehyde
Maleimide
t (d)
Adduct No.
Yielda (%)
eeb,c (%)
R1
No.
R2
No.
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Et
2a
2a
2a
2a
2a
2a
2b
2c
2d
Ph
4-BrC6H4
4-AcOC6H4
Bn
Me
H
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3a
3a
3a
2
2
1.5
2
1.5
1.5
4
(R)-4aa
(R)-4ab
(R)-4ac
(R)-4ad
(R)-4ae
(R)-4af
(R)-4ba
(R)-4ca
(R)-4da
99
94
92
99
84
94
99
99
99
88
93
79
76
75
83
74
86
84
–(CH2)4–
–(CH2)5–
4
4
a
b
c
Isolated yield after flash chromatography.
Enantioselectivities determined by chiral HPLC.14
Absolute configuration determined by the reported order of elution of the enantiomers in chiral HPLC.15

A. Avila et al. / Tetrahedron: Asymmetry 23 (2012) 1625–1627
1627
ner to its enantiomer 1a, although starting from (1R,2R)-cyclohex-
Acknowledgments
ane-1,2-diamine. This compound was used as the organocatalyst in
a former model Michael reaction using a combination DMF/H2O 2/
1 v/v as solvent at 25 °C, to quantitatively afford the enantiomer
(S)-4aa in essentially the same enantioselectivity (87% ee) that
when using the enantiomeric guanidine 1a (Table 1, entry 12).
We thank for the financial support from the Spanish Ministerio
de Economía y Competitividad (projects CTQ2010-20387 and Con-
solider Ingenio 2010, CSD2007-00006), FEDER, the Generalitat Val-
enciana (Prometeo/2009/039), and the University of Alicante.
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to other
a,a
-disubstituted aldehydes and maleimides (Table 2).13
Thus, when isobutyraldehyde reacted with the N-phenylmaleimide
bearing a bromo at the 4-position of the aromatic ring 3b, the
enantioselectivity of the adduct (R)-4ab increased to 93% (Table 2,
entry 2). When a 4-acyloxy group was present 3c, adduct (R)-4ac
was isolated with a lower enantioselection (79%) (Table 2, entry
3). In addition, the influence of the other non-aromatic N-substitu-
ents in the maleimide system was also explored. Thus, the use of
N-benzylated maleimide 3d and isobutyraldehyde gave rise to ad-
duct (R)-4ad in 76% ee, a similar value when using N-methylmalei-
mide 3e, which afforded (R)-4ae in 75% ee (Table 2, entry 5). The
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yield and 74% ee (Table 2, entry 7), whereas the use of cyclopen-
tane- and cyclohexanecarbaldehyde quantitatively afforded ad-
ducts (R)-4ca and (R)-4da in 86% and 84% ee, respectively
(Table 2, entries 8 and 9).
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13. Typical experimental procedure for the enantioselective Michael addition
reaction: To a solution of 1 or ent-1a (0.04 mmol) and 3 (0.2 mmol) in DMF/
H2O (2/1, v/v) (0.5 mL) was added aldehyde 2 (0.4 mmol) and the reaction was
stirred at rt until completion (TLC). Water (10 mL) was then added and the
mixture was extracted with AcOEt (3 Â 10 mL). The organic phase was washed
with water (2 Â 10 mL), dried (MgSO4), filtered and evaporated (15 torr). The
resulting crude was purified by flash chromatography (hexane/AcOEt)
affording adducts 4.
The observed (R)-sense of enantioinduction in all of the former
adducts, achieved when employing catalyst 1a which derives from
(1S,2S)-cyclohexane-1,2-diamine was unexpected, as the (R)-enan-
tiomers have also been obtained when using amino-thioureas as a
catalyst obtained from (1R,2R)-cyclohexane-1,2-diamine.8b,d This
indicates that a different transition state operates when these
amine-guanidines are used compared to the reaction promoted
by primary amine-thioureas.
3. Conclusion
It can be concluded that the simple monoguanylation of enanti-
omerically pure trans-cyclohexane-1,2-diamines gives chiral guan-
idines which contain a primary amino group. These new systems
behave as organocatalysts in the enantioselective conjugate addi-
14. Enantioselectivities were determined by HPLC using n-hexane/2-propanol
mixtures as eluant and the following chiral columns: Chiralcel OD-H (4aa, 4ab,
4ca, 4da), Chiralpak AS-H (4ac, 4ae, 4ba), and Chiralpak AD-H (4ad, 4af).
Reference racemic samples of adducts 4 were obtained by performing the
reaction using 4-methylbenzylamine (20 mol %) as organocatalyst in toluene
as the solvent at 25 °C.
tion of
aqueous solvent, with high yields and good enantioselectivities.
This is the first reported -substitution of aldehydes employing
a,a-disubstituted aldehydes to different maleimides in an
15. The absolute configuration for the known adducts 4aa,8b 4ab,8e 4ad,8b 4ae,8b
4ba,8a 4ca,8c and 4da8c was determined according to the described order of
elution of their enantiomers in chiral HPLC. The absolute configuration of the
new adducts 4ac and 4af was assigned by analogy.
a
amine-guanidines as organocatalysts. Further studies devoted to
determine the origin and sense of the enantioselectivity when
using these guanidines, as well as expanding their catalytic ability
to other substrates are currently underway.