Chiral 2-aminobenzimidazoles as recoverable organocatalysts for the addition of 1,3-dicarbonyl compounds to nitroalkenes

Article abstract of DOI:10.1021/jo9010552

(Chemical Equation Presented) Chiral trans-cyclohexanediamine-benzimidazole organocatalysts promote the conjugate addition of a wide variety of 1,3-dicarbonyl compounds such as malonates, ketoesters, and 1,3-diketones to nitroolefins in the presence of TF

Full text of DOI:10.1021/jo9010552

pubs.acs.org/joc
Chiral 2-Aminobenzimidazoles as Recoverable Organocatalysts for the
Addition of 1,3-Dicarbonyl Compounds to Nitroalkenes†
‡
Diana Almas-i, Diego A. Alonso,* Enrique Gomez-Bengoa, and Carmen Najera*
,‡
§
,‡
ꢀ
ꢀ
‡
´
ꢀ
´
Departamento de Quımica Organica and Instituto de Sıntesis Organica, Facultad de Ciencias, Universidad
de Alicante, Apdo. 99, E-03080 Alicante, Spain, and Departamento de Quımica Organica I, Facultad de
ꢀ
§
´
ꢀ
´ ´
ꢀ
Quımica, Universidad del Paıs Vasco, Apdo. 1072, 20080 San Sebastian, Spain
diego.alonso@ua.es; cnajera@ua.es
Received May 20, 2009
Chiral trans-cyclohexanediamine-benzimidazole organocatalysts promote the conjugate addition of
a wide variety of 1,3-dicarbonyl compounds such as malonates, ketoesters, and 1,3-diketones to
nitroolefins in the presence of TFA as cocatalyst in toluene as solvent at rt or 0 °C. The Michael
adducts are obtained in high yield and enantioselectivity, using the chiral 2-aminobenzimidazole 7b
as hydrogen-bond-mediated chiral organocatalyst. This catalyst can be recovered by acid-base
extractive workup in 94% yield. The proposed bifunctional Brønsted acid-base activation role of the
catalyst and the origin of the stereoselectivity of the process is in agreement with DFT calculations.
According to these calculations, the protonated tertiary amine from the cyclohexanediamine back-
bond activates the nitroolefin, while the benzimidazole unit activates the 1,3-dicarbonyl nucleophile.
Introduction
has been the progress observed for enantioselective conjugate
addition reactions.2 The addition of 1,3-dicarbonyl com-
pounds to nitroolefins provides access to synthetically useful
enantioenriched nitroalkanes3 under mild conditions. High
yields and enantioselectivities have been obtained for the
conjugate addition of activated methylenes (such as 1,3-
diketones)4 as well as β-ketoesters and derivatives5 to nitros-
tyrenes; cinchona alkaloid derivatives represent the most
commonly used chiral scaffolds. Few organocatalysts, such
Asymmetric organocatalysis1 is a powerful and environ-
mentally friendly strategy for the stereoselective synthesis of
highly valuable chiral building blocks. The development of a
wide variety of new organocatalysts efficiently applied to
numerous asymmetric transformations has been responsible
for the impressive progress exhibited inthe fieldof asymmetric
organocatalysis during recent years. Particularly important
† Dedicated to Josep Font on occasion of his 70th birthday.
€
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1877–1894.
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4713–4716. (b) Zhou, W.-M.; Liu, H.; Du, D.-M. Org. Lett. 2008, 10, 2817–
2820. (c) Gao, P.; Wang, C.; Wu, Y.; Zhou, Z.; Tang, C. Eur. J. Org. Chem.
2008, 4563–4566. (d) Wang, C.-J.; Zhang, Z.-H.; Dong, X.-Q.; Wu, X.-J.
Chem. Commun. 2008, 1431–1433. (e) Malerich, J. P.; Hagihara, K.; Rawal,
V. H. J. Am. Chem. Soc. 2008, 130, 14416–14417. (f) Tan, B.; Zhang, X.;
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DOI: 10.1021/jo9010552
r
Published on Web 07/23/2009
J. Org. Chem. 2009, 74, 6163–6168 6163
2009 American Chemical Society

Almas-i et al.
JOCArticle
FIGURE 1. Hydrogen bond donor catalysts.
as 1-6 (Figure 1),6-11 have been shown to efficiently promote
the addition of malonate esters to nitroolefins with high
enantioselectivity at typical catalyst loadings between 2 and
10 mol %. Essential to the overwhelming success of these
catalysts istheirability to activatereactantsthrough hydrogen
bond interactions12 producing well-defined orientation re-
quired for the transition state of the process.
Benzimidazole is a ubiquitous element in a wide variety of
biologically relevant natural products13 whose derivatives
display a key role in pharmaceutical chemistry and in many
biological processes.14 In addition, benzimidazole deriva-
tives are widely utilized in synthetic organic chemistry as the
basis for ionic liquids15 and as precursors for N-heterocyclic
carbenes.16 The basic character of benzimidazole derivatives
[pKa (BzImH2þ)=5.4],17 their ability to act as recognition
elements through hydrogen bond interactions,13 and their
high degree of stability and facile synthesis13a,b make these
compounds an attractive alternative to thioureas and gua-
nidines as organocatalysts. However, enantioselective orga-
nocatalysis using chiral benzimidazoles has enjoyed limited
success so far.18 Here, as part of our research program on the
organocatalytic asymmetric conjugate addition to nitroalk-
enes,19 we describe a new family of hydrogen bonding
catalysts for the conjugate addition of 1,3-dicarbonyl com-
pounds to nitroolefins based on the benzimidazole moiety,
which features the introduction of a rigid chiral trans-cyclo-
hexanediamine scaffold 7 (Figure 1).
Results and Discussion
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(8) Li, H.; Zhang, S.; Yu, C.; Song, X.; Wang, W. Chem. Commun. 2009,
2136–2138.
(9) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367–
6370.
The synthesis of catalyst 7 started with a solvent-free
aromatic nucleophilic substitution of (1R,2R)-1,2-diamino-
cyclohexane to 2-chlorobenzimidazole or 2-chloro-6-(tri-
fluoromethyl)-1H-benzo[d]imidazole (obtained from 4-tri-
fluoromethyl-1,2-phenylenediamine by urea formation with
1,10-carbonyldiimidazole and further chlorination with
POCl3),20 in the presence of triethylamine as base, yielding
primary amine derivatives 7a and 7e, in 65% and 56% yields,
respectively (Scheme 1). Reductive amination of formalde-
hyde in formic acid at 120 °C with 7a and 7e afforded
organocatalysts 7b and 7d in 30% and 42% yield, respec-
tively, after purification by flash chromatography and re-
crystallization (Scheme 1). Catalyst 7c was prepared from 7a
(10) Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128,
1454–1455.
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(11) Andres, J. M.; Manzano, R.; Pedrosa, R. Chem.;Eur. J. 2008, 14,
5116–5119.
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1520–1543. (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–
5743. (c) Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516–532.
(13) (a) Wright, J. B. Chem. Rev. 1951, 48, 397–541. (b) Preston, P. N.
Chem. Rev. 1974, 74, 279–314. (c) Sundberg, R. J.; Martin, R. B. Chem. Rev.
1974, 74, 471–517. (d) Grimmet, M. R. In Comprehensive Heterocyclic
Chemistry II; Shinkai, I., Ed.; Pergamon: Oxford, 1996; Vol. 3, p 77.
(14) (a) Rastogi, R.; Sharma, S. Synthesis 1983, 861–882. (b) Horton,
(18) For benzimidazole-pyrrolidine organocatalysts in the asymmetric
aldol reaction, see: (a) Zheng, J.-F.; Li, Y.-X.; Zhang, S.-Q.; Yang, S.-T.;
Wang, X.-M.; Wang, Y.-Z.; Bai, J.; Liu, F.-A. Tetrahedron Lett. 2006, 47,
7793–7796. (b) Lacoste, E.; Vaique, E.; Berlande, M.; Pianet, I.; Vincent,
J.-M.; Landais, Y. Eur. J. Org. Chem. 2007, 167–177. (c) Reddy, K. R.;
Krishna, G. G.; Rajasekhar, C. V. Synth. Commun. 2007, 4289–4299.
D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893–930.
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(c) Boiani, M.; Gonzalez, M. Mini-Rev. Med. Chem. 2005, 5, 409–424.
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M. L.; Nielsen, E. ø.; Peters, D.; Teuber, L. J. Med. Chem. 2008, 51, 7625–
7634.
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(15) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis, 2nd ed.;
Wiley-VCH: Weinheim, 2007.
(16) (a) Lin, I. J. B.; Vasam, C. S. Coord. Chem. Rev. 2007, 251, 642.
(b) Nolan, S. P. N-Heterocyclic Carbenes in Synthesis; Wiley-VCH: Weinheim,
2006.
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2006, 17, 2064–2068. (b) Almas-i, D.; Alonso, D. A.; Gomez-Bengoa, E.;
Nagel, Y.; Najera, C. Eur. J. Org. Chem. 2007, 2328–2343.
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(20) Ognyanov, V. I.; Balan, C.; Bannon, A. W.; Bo, Y.; Dominguez, C.;
Fotsch, C.; Gore, V. K.; Klionsky, L.; Ma, V. V.; Qian, Y.-X.; Tamir, R.;
Wang, X.; Xi, N.; Xu, S.; Zhu, D.; Gavva, N. R.; Treanor, J. J. S.; Norman,
M. H. J. Med. Chem. 2006, 49, 3719–3742.
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1987, 24, 165–169.
6164 J. Org. Chem. Vol. 74, No. 16, 2009

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SCHEME 1. Synthesis of Organocatalysts 7
the presence of other acid additives; this afforded lower
yields and/or enantioselectivities (see Supporting Infor-
mation). In the presence of TFA as cocatalyst and reduced
temperature (0 °C), the enantioselectivity decreased to 74%
ee with no noticeable effect on conversion (Table 1, entry 17).
Using 5 mol % of catalyst, high enantioselectively (93% ee)
was still achieved albeit in a modest 40% yield after 36 h
(Table 1, entry 18). At this point, the activity of catalyst
7d was again tested under the optimal conditions (rt, TFA
(10 mol %)) affording 8a in lower conversion and similar
enantioselectivity to 7b (Table 1, compare entries 16 and 19).
We also studied the recyclability of benzimidazole-derived
organocatalyst 7b and were pleased to demonstrate that 7b
could be easily recovered (94%) from the reaction mixture
after extractive acid/base workup with no loss of optical
activity.
Under the optimized reaction conditions, the scope of this
2-aminobenzimidazole-catalyzed conjugate addition was ex-
amined next (Table 2). The size of the ester group of the
malonate had a marginal effect on the selectivity of the
Michael adducts (Table 2, entries 1-3) with the exception
of the largest tert-butyl ester, which did not react (Table 2,
entry 4). Different nitroolefins were allowed to react with
diethyl malonate giving products 8e-8j in high yield and
good enantioselectivities (Table 2, entries 5-10). The reac-
tions proceeded smoothly at rt whether neutral (Table 2,
entry 1), electron-withdrawing (Table 2, entries 5-7), or
electron-donating (Table 2, entries 8 and 9) groups were
present in the aromatic rings, giving the desired adducts 8 in
excellent yields and good enantioselectivities (88-94%). The
reaction of 2-thienyl-substituted nitroolefin gave 8j in ex-
cellent yield and good enantioselectivity (Table 2, entry 10).
The efficiency of 7b was further evaluated with different
types of 1,3-dicarbonyl compounds and nitroalkenes
(Table 3). Acetylacetone proved to be a superior nucleophile:
after conjugate addition to β-nitrostyrene, product 8k was
obtained in excellent 96% ee after only 7 h employing
only 1 equiv of nucleophile and 5 mol % of 7b/TFA (Table 3,
entry 1). This result is similar in terms of yield and enantios-
electivity to that obtained with the most efficient organoca-
talysts reported so far.4a,c-e,10 Catalyst 7b/TFA also showed
high catalytic efficiency for the reaction of acetylacetone with
challenging aliphatic nitroalkenes such as 1-nitro-4-phenyl-
but-2-ene affording compound 8l in a 93% yield and 86% ee
(Table 3, entry 2). The reaction between the acyclic, nonsym-
metrical 1-phenyl-1,3-butanedione and β-nitrostyrene pro-
ceeded with low diastereoselectivity, as usually encountered
for the most selective reported organocatalysts,4e,6,7,10 to
afford ca. a 1/1 diastereomeric mixture of compound 8m with
a 92% ee (Table 3, entry 3). In this case, the diastereomeric
mixture could be separated by recrystallization in ether, which
allowed us to assign, via X-ray analysis (see Supporting
Information),23 the absolute configuration for the stereo-
center of the nucleophile in the major diastereomer to be S.
Also, after recrystallization the ee of the (S,R)-diastereomer
was improved to 99% (Table 3, entry 3).
in 20% yield by reductive amination of acetaldehyde in the
presence of NaHB(OAc)3 (Scheme 1).
Examination of crystallographic21 and computational
data (see Supporting Information) on catalyst 7b showed
that the two H atoms of the aminobenzimidazole moiety are
positioned 2.41 and 2.61 A apart, respectively (Figure 2). The
observed distance is in between the reported distances for the
highly active thiourea-6 and the recently described squara-
mide-derived organocatalysts4e (Figure 2), which should
render benzimidazole-derived catalysts 7 efficient dual hy-
drogen-bonding activating systems. Therefore, the conju-
gate addition of 1,3-dicarbonyl compounds to nitroolefins
seemed to be an ideal test for the potential activity and
selectivity of novel benzimidazole-derived catalysts 7.
2-Aminobenzimidazoles 7 (10 mol %) were screened as
catalysts in the diethyl malonate addition (2 equiv) to (E)-β-
nitrostyrene in toluene at rt (Table 1). All benzimidazole-
derived compounds 7 showed high catalytic efficiency,
and complete conjugate addition was observed after 24 h
(Table 1, entries 1-4). With respect to selectivity, organoca-
talysts 7b and 7d exhibited superior enantioselectivity and
gave complete conversion of (E)-β-nitrostyrene into ni-
troalkane 8a with 78% and 79% ee, respectively (Table 1,
entries 1 and 4). Further solvent studies with other apolar,
polar aprotic, and polar protic solvents were performed with
the more accessible catalyst 7b, indicating toluene to be the
optimal solvent for the reaction (Table 1, entries 5-15). The
effect of different acids as additives in the process was also
investigated.22 It was found that 2-aminobenzimidazole 7b
(10 mol %) in combination with TFA (10 mol %) exhibited
high catalytic activity for the asymmetric conjugate addition
in toluene at rt, affording 8a in 74% yield with a promising
92% ee after 36 h (Table 1, entry 16). No further improve-
ment could be achieved when the reaction was carried out in
In the case of the conjugate addition of acyclic β-ketoesters
such as ethyl 3-oxobutenoate to β-nitrostyrene catalyzed by
7b, the ester moiety seemed to have little influence on
(21) Crystallographic data (excluding structure factors) have been depos-
ited in the Cambridge Crystallographic Data Centre (CCDC 680867).
(22) For a review about protonated chiral organocatalysts, see: Bolm, C.;
Rantanen, T.; Schiffers, I.; Zani, L. Angew. Chem., Int. Ed. 2005, 44, 1758–
1763.
(23) Crystallographic data (excluding structure factors) have been depos-
ited in the Cambridge Crystallographic Data Centre (CCDC 723644).
J. Org. Chem. Vol. 74, No. 16, 2009 6165

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FIGURE 2. Hydrogen bond distances in hydrogen donor catalysts.
TABLE 1. Screening of Reaction Conditions for the Conjugate Addition
TABLE 2. Conjugate Addition of Dialkyl Malonates with Nitroalkenes
Catalyzed by 7ba
of Diethyl Malonate to β-Nitrostyrene Catalyzed by 7a
cocatalyst
(mol %)
yield
(%)b
ee
(%)c
entry
R
Ar
no.
yield (%)b
ee (%)c
entry 7 (mol %) solvent
t (h)
1
2
3
4
5
6
7
8
9
10
Et
Ph
Ph
Ph
Ph
8a
8b
8c
8d
8e
8f
8g
8h
8i
97
95
42
<5
95
97
96
98
98
98
92
89
89
nd
88
90
94
88
88
87
1
2
3
4
5
6
7
8
7a (10)
7b (10)
7c (10)
7d (10)
7b (10)
7b (10)
7b (10)
7b (10)
7b (10)
7b (10)
7b (10)
7b (10)
7b (10)
7b (10)
7b (10)
7b (10)
7b (10)d
7b (5)
toluene
toluene
toluene
toluene
benzene
xylenes
pentane
Et2O
THF
CH2Cl2
NMP
DMSO
MeOH
H2O
24
24
24
24
24
24
24
24
24
24
24
24
24
24
36
36
36
36
36
99
99
99
99
99
99
99
99
99
99
99
99
99
99
74
74
99
40
67
60
78
66
79
72
72
67
64
30
70
28
2
36
56
52
92
74
93
91
Me
i-Pr
t-Bu
Et
Et
Et
Et
Et
Et
4-ClC6H4
2-CF3C6H4
2,4-(Cl)2C6H3
4-MeC6H4
4-MeOC6H4
2-thienyl
9
8j
10
11
12
13
14
15
16
17
18
19
aThe reaction was performed with the nitroolefin (1.16 mmol), dialkyl
malonate (2.32 mmol), catalyst 7b (0.116 mmol), and TFA (0.116 mmol)
b
at rt in toluene (2.3 mL) for 2 d. Isolated yield after flash chromato-
graphy. cDetermined by chiral HPLC analysis on the crude reaction
mixture (see Supporting Information).
neat
toluene
toluene
toluene
toluene
TFA (10)
TFA (10)
TFA (5)
7d (10)
TFA (10)
85% ee being observed for the major one (Table 3, entry 5).
Again, the enantiomeric excess could be improved by recrys-
tallization in ether to 98%. The low yield obtained in
this particular reaction was due to the formation of
compound 9 from conjugate addition of the enol form of the
1,3-diketone nucleophile to the β-nitrostyrene.
aThe reaction was performed with β-nitrostyrene (1.16 mmol), diethyl
malonate (2.32 mmol), catalyst 7 (0.116 mmol), and TFA (0.116 mmol)
at rt in the corresponding solvent (2.3 mL) at the time indicated. bYield
of the crude product determined by 1HNMR. cDetermined by chiral
HPLC analysis (Chiralpack AD, hexane/i-PrOH 90/10) of the crude
reaction mixture. dThe reaction was performed at 0 °C.
the selectivity of the process since very low diastereoselec-
tivity was observed again, with good enantioselectivities for
both isomers of 8n (90% and 88% ee, Table 3, entry 4).
Acyclic β-ketoesters seem to be challenging substrates
since only catalysts 16 and 510 (Figure 1) have so far been
reported to efficiently promote the conjugate addition of
this type of activated methylenes to nitrostyrenes. Moreover,
these processes have been found to be non-diastereoselective.
Conversely, R-substituted dicarbonyl compounds affor-
ded, in general, good yields and enantioselectivities at the
β-position to the nitro group for the quaternary stereocenter-
containing derivatives 8o-q (Table 3, entries 5-7).24 The
observed diastereoselectivities were usually higher than
those observed for the acyclic nucleophiles (compare entries
3 and 4 with 5-7). Thus, compound 8o was isolated after 24 h
at rt in a 42% yield as a 84/16 mixture of diastereomers with
Cyclic β-ketoesters were also suitable partners for con-
jugate addition to β-nitrostyrene, affording nitro derivatives
8p and 8q in 95% and 92% isolated yields, respectively, at
0 °C and in short reaction times (3-6.5 h). The addition
product 8p (Table 3, entry 6), derived from ethyl 2-oxocy-
clopentanecarboxylate, was obtained in high diastereoselec-
tivity (dr = 91/9) with the enantioselectivity being higher
for the minor enantiomer (eemajor = 70%, eeminor = 93%).
Lower diastereoselectivity (dr = 62/38) was seen for com-
pound 8q, obtained with only 1 equiv of methyl 1-oxo-2,3-
dihydro-1H-indene-2-carboxylate, with a high ee (90%) for
the major diastereomer (Table 3, entry 7). The level of
selectivity for compound 8q is similar to the best results
(24) For a recent review about organocatalytic formation of quaternary
stereocenters, see: Bella, M.; Gasperi, T. Synthesis 2009, 1583–1614.
6166 J. Org. Chem. Vol. 74, No. 16, 2009

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TABLE 3. Conjugate Addition of 1,3-Dicarbonyl Compounds to
Nitroolefins Catalyzed by 7b
FIGURE 3. Representation of the computed transition states. Ener-
gies correspond to the B3LYP/6-311þþG**// B3LYP/6-31G*
level. Single-point values in a toluene model (IEF-PCM) are shown
in brackets.
moieties of the catalyst. However, it has been recently
reported25,26 that an alternative H-bonding pattern between
the nucleophile and a thiourea-catalyst leads to more stable
complexes and transition states, and thus, lower activation
barriers. In order to obtain insight about the two possible
operational mechanisms for 2-aminobenzimidazole cata-
lysts 7, DFT calculations were performed at B3LYP/6-
311þþG**// B3LYP/6-31G* levels for the conjugate addi-
tion of 1,3-dicarbonyl compounds to β-nitrostyrene.
In our case, the deprotonation of the nucleophilic dicar-
bonyl compound renders a protonated catalyst that pos-
sesses three N-H units. Two competing mechanistic
pathways were envisioned for the C-C bond-forming step,27
differing on the N-H groups attached to the nucleophile and
electrophile in the initial ternary complex and during the
transition state. In TSa, the nitroolefin interacts with the
protonated amine, while the two benzimidazole N-H units
bind the deprotonated nucleophile (Figure 3). In TSb, the
opposite binding pattern was computed. For each of them,
the neutral and cationic forms of catalyst 7b, and the two
possible diastereoselective transition states providing the
R or S enantiomers were considered. Dimethylmalonate
and 2,4-pentanedione were chosen as nucleophiles.
aIsolated yield after flash chromatography. bDetermined by 1HNMR
on the crude reaction mixture. cDetermined by chiral HPLC analysis on
the crude reaction mixture (see Supporting Information). 5 mol % of
d
e
f
7b/TFA was used. 1 equiv of nucleophile was used. Absolute config-
uration for the new stereocenter in the major diastereomer was deter-
mined to be S by X-ray analysis23 (see Supporting Information). g>99%
i
ee after recrystallization (Et2O). hReaction conversion. 98% ee after
recrystallization (Et2O).
previously obtained with the most active guanidine-derived
catalyst 510 and cinchona alkaloid-derived organocata-
lysts.5c
Finally, under the optimized reaction conditions, the 7b-
catalyzed conjugate addition of other activated methylenes
such as malononitrile and ethyl 2-cyanoacetate afforded the
corresponding products in high yields (>99%) but with
negligible diastereo- and enantioselectivity (dr ≈1/1, <3% ee).
Finally, mechanistic studies were carried out to gain insight
into the H-bond activation pattern of the electrophile and the
origin of the observed stereoselectivities. Both substrates, the
nucleophile (malonate or diketone) and the electrophile
(nitrostyrene), bear polar groups capable of H-bond forma-
tion. In this regard, it has been generally accepted that the
mechanism of the Michael addition involves nitrostyrene
activation through binding to the Brønsted acidic N-H
The results obtained for neutral (X=N) and protonated
catalyst (X=NHþ) 7b are very similar (Figure 3).28 The
lowest energy transition states correspond to the addition of
(26) For a related H-bonding activation pattern in an aza-Henry reaction,
see: Gomez-Bengoa, E; Linden, A.; Lopez, R.; Mugica-Mendiola, I.;
Oiarbide, M.; Palomo, C. J. Am. Chem. Soc. 2008, 130, 7955–7966.
(27) The participation of the enolic form of the nucleophile was also
considered, but the activation energies are exceedingly higher than those
found for the deprotonated nucleophiles.
(25) For an extensive theoretical study on the reaction mechanism in the
ꢀ
presence of a chiral thiourea, see: Hamza, A.; Schubert, G.; Papai, I. J. Am.
Chem. Soc. 2006, 128, 13151–13160.
(28) Activation energies computed at B3LYP/6-311þþG**//B3LYP/6-
31G* level versus the initial nucleophile-catalyst-electrophile H-bond tern-
ary complexes. For computational details, see Supporting Information.
J. Org. Chem. Vol. 74, No. 16, 2009 6167

Almas-i et al.
JOCArticle
malonate or diketone to the nitrolefin with formation of two
H-bonds between the nucleophile and the amino-benzimidazole
and one H-bond between the nitroolefin and the protonated
(KBr) 2929, 2855, 1700, 1644, 1606, 1580, 1468, 1270, 1116,
1030; δH (CD3OD) 1.19-1.49 (m, 4H), 1.74-1.77 (m, 2H),
1.98-2.11 (m, 2H), 2.50-2.58 (m, 1H), 3.34-3.40 (m, 1H),
6.93-6.97 (m, 2H), 7.15-7.18 (m, 2H); δC 26.0, 26.2, 33.8, 34.9,
55.6, 60.4, 112.7, 121.3, 139.1, 156.9; m/z 230 [Mþ, 10%], 160
(24), 134 (100), 133 (59), 97 (28); HRMS calcd for C13H18N4
[M]þ 230.1531, found 230.1532.
amine
(TSa-R
and
TSa-Hþ-R).
These
transi-
tion states were taken as relative E=0. TSb-type transition
states, which involve the opposite H-bonding pattern, are in
general 2-6 kcal/mol higher in energy. This result is fully
concordant with the previously reported examples,25,26 in
that it favors the alternative TSa activation mechanism over
the classical TSb.
A mixture of 7a (168 mg, 0.73 mmol, 1 equiv), 80% HCO2H
(3.5 mL), and a 36% aqueous solution of HCHO (127 μL, 1.61
mmol, 2.2 equiv) was stirred at 120 °C for 16 h. Then, the solvent
was removed under reduced pressure. Saturated NaHCO3
solution (15 mL) and 10% NaOH solution (until pH 8) were
added in this order, and the resulting mixture was extracted with
CH2Cl2 (3 ꢀ 15 mL). The organic phases were dried over MgSO4
and evaporated under reduced pressure to give a crude mixture,
which was purified by flash chromatography (EtOAc/MeOH)
and then recrystallized in CH2Cl2 to afford pure 7b (87 mg,
46%) as a white solid; mp 248-250 °C (CH2Cl2); [R]20D -55.3 (c
1.0, CH2Cl2); IR (KBr) 2923, 2856, 2818, 2775, 1700, 1633, 1576,
1499, 1461, 1375, 1265, 1064; δH (CDCl3) 1.09-1.42 (m, 4H),
1.65-1.70 (m, 1H), 1.82-1.87 (m, 2H), 2.22 (s, 6H), 2.33 (td,
J = 10.9, 3.2 Hz, 1H), 2.65-2.69 (m, 1H), 3.44 (td J = 10.4, 4.0
Hz, 1H), 5.46 (br s, 1H), 6.91-6.96 (m, 2H), 7.14-7.20 (m, 2H);
δC (CD3OD) 23.7, 25.8, 26.4, 34.8, 40.5, 54.7, 67.7, 112.6, 121.2,
139.1, 156.6; m/z 258 [Mþ, 1.5%], 133 (30), 125 (100), 84 (20);
HRMS calcd for C15H22N4 [M]þ 258.1844, found 258.1844.
Typical Experimental Procedure for the Conjugate Addition of
Diethyl Malonate to β-Nitrostyrene Catalyzed by 7b. Synthesis of
8a. To a stirred solution of 7b (30 mg, 0.116 mmol, 10 mol %)
and β-nitrostyrene (173 mg, 1.16 mmol) in toluene (2.3 mL) were
added trifluororacetic acid (8.7 μL, 0.116 mmol, 10 mol %) and
then diethyl malonate (357 μL, 2.32 mmol). Once the reaction
was completed (TLC), the mixture was quenched with water
(10 mL) and extracted with EtOAc (3 ꢀ10 mL). The organic
phases were dried over MgSO4 and evaporated under reduced
pressure to give crude 8a, which was purified by flash chroma-
tography (EtOAc/hexane) to give pure 8a (348 mg, 97%, er=
96/4) as a colorless oil: Rf 0.27 (hexane/EtOAc 4/1); [R]20D -3.5
(c 1.0, CH2Cl2); absolute configuration for 8a was assigned as
(R) by comparison of the optical rotation with reported litera-
Notably, only pathway a is able to account for the experi-
mental enantioselectivity, since a-R transition states lie an
average of 3.8 kcal/mol lower in energy than a-S ones,
predicting the formation of the experimental major R enan-
tiomer. Meanwhile, b-type transition states present more
similar activation energies (average Eb-S - Eb-R of 0.6 kcal/
mol), showing that, in this case, the formation of quasi-
racemic products would be wrongly predicted. This finding
can be taken as a further proof that activation mode a is
probably responsible for the mechanism and the observed
enantioselectivity. The fact that the conjugate addition
performed with other activated methylenes such as malono-
nitrile and ethyl 2-cyanoacetate afforded the correspon-
ding products but with negligible selectivity would also
support the activation mode of catalyst 7b for the studied
reaction.
Conclusions
We have developed a recyclable chiral 2-aminobenzimi-
dazole-derived organocatalyst 7b, bearing a chiral (1R,2R)-
1,2-diaminocyclohexane moiety, which in the presence of
TFA is a very active catalyst for the highly enantioselective
conjugate addition of different 1,3-dicarbonyl compounds to
a broad range of conjugated nitroalkenes. Unlike the major-
ity of the most active organocatalysts reported so far,
organocatalyst 7b is not specific to one type of nucleophile
but efficiently promotes the conjugate addition of different
activated methylenes such as malonate esters, ketoesteres,
and 1,3-diketones to nitroalkenes. Computational studies
support the bifunctional Brønsted acid-base organocataly-
tic character of 7b with the activation of the nitroolefin better
achieved by the protonated tertiary amine motif. Further
studies are in progress to explore the scope of organocata-
lysts 7 as hydrogen-bond donor scaffolds in other catalytic
asymmetric reactions.
ture29 value: [R]23 þ7.3 (c 1.07, CHCl3), [95% ee, (S)-enan-
D
tiomer]; δH (400 MHz) 1.04, 1,26 (2t, J = 7.1, 6H), 3.82 (d, J =
9.4 Hz, 1H), 4.00 (q, J = 7.1 Hz, 2H), 4.18-4.28 (m, 3H), 4.86
(dd, J = 13.1, 9.0 Hz, 1H), 4.93 (dd, J=13.1, 5.2 Hz, 1H), 7.22-
7.37 (m, 5H); δC (100 MHz) 13.7, 13.9, 42.9, 54.9, 61.8, 62.1,
77.6, 128.0, 128.3, 128.9, 136.2, 166.8, 167.4; m/z 263,
[Mþ - NO2, 25%], 189 (100), 171 (44), 161 (43), 115 (54), 104
(26), 103 (28), 102 (26), 91 (29), 76 (37).
Acknowledgment. Financial support from the MEC
(Projects CTQ2004-00808/BQU, CTQ2007-62771/BQU and
Consolider INGENIO 2010 CSD2007-00006), from the Gen-
eralitat Valenciana (GV/2007/142) and the University of
Alicante is acknowledged. D.A. thanks the EU and the
Spanish MEC for a predoctoral fellowship. We also thank
SGI/IZO-SGIker UPV/EHU for allocation of computational
resources and Dr. Tatiana Soler for solving the X-ray struc-
tures of 7b and (2S)-8m.
Experimental Section
For general experimental details, see Supporting Informa-
tion.
Experimental Procedure for the Synthesis of 7b. A mixture of
2-chloro-1H-benzo[d]imidazole (233 mg, 1.53 mmol, 1 equiv),
(1R,2R)-cyclohexane-1,2-diamine (698 mg, 6.12 mmol, 4 equiv),
and TEA (213 μL, 1.53 mmol, 1 equiv) was heated under argon
atmosphere at 195-200 °C during 16 h. The reaction mixture
was then allowed to reach 50 °C, and water (20 mL) was added.
The reaction was quickly extracted with CH2Cl2 (3 ꢀ 20 mL)
before the temperature of the reaction reached rt in order to
avoid solubility problems. The organic phases were dried
over MgSO4 and evaporated under reduced pressure to give a
crude mixture, which was purified by flash chromatography
(EtOAc/MeOH) to give pure 7a (229 mg, 65%) as a pale yellow
solid: mp 235-240 °C (Et2O); [R]20D -55.0 (c 1.0, MeOH); IR
Supporting Information Available: Experimental proce-
dures and spectroscopic data for all the products and X-ray
structures for compounds 7b and (S,R)-8m in CIF format. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(29) Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129,
11583–11592.
6168 J. Org. Chem. Vol. 74, No. 16, 2009