Catalyst functional group cooperativity in the amino acid-catalysed nitroaldol condensation reaction

Article abstract of DOI:10.1007/s11164-012-0853-x

Several amino acids and their derivatives have been evaluated as organic catalysts for the nitroaldol reaction. It was found that when an unprotected amino group and an unprotected carboxylate group were present in the organocatalyst, both the nitroaldol reaction and subsequent elimination could occur to afford nitroalkenes from aromatic aldehydes and nitromethane. The best results were obtained by use of γ-amino acids derived from l-glutamine. It is suggested that the amino group is important for intermediate Schiff base formation and that the free carboxylate group facilitates the elimination step.

Full text of DOI:10.1007/s11164-012-0853-x

Res Chem Intermed
DOI 10.1007/s11164-012-0853-x
Catalyst functional group cooperativity in the amino
acid-catalysed nitroaldol condensation reaction
•
Leman Karadeniz Stephen T. Astley
Received: 19 July 2012 / Accepted: 5 October 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract Several amino acids and their derivatives have been evaluated as
organic catalysts for the nitroaldol reaction. It was found that when an unprotected
amino group and an unprotected carboxylate group were present in the organo-
catalyst, both the nitroaldol reaction and subsequent elimination could occur to
afford nitroalkenes from aromatic aldehydes and nitromethane. The best results
were obtained by use of c-amino acids derived from L-glutamine. It is suggested that
the amino group is important for intermediate Schiff base formation and that the
free carboxylate group facilitates the elimination step.
Keywords Nitroaldol condensation Á Amino acid catalysts Á Diamines Á
Nitroalkenes
Introduction
The possible applications of organic catalysts bearing both Lewis acidic and Lewis
basic sites is an area of increasing interest [1–5]. These catalysts are particularly
useful for single-step electrophile–nucleophile combinations in which both reactants
can be independently activated. The Henry (nitroaldol) reaction is one such example
[6–11]. In this C–C bond-forming reaction, coupling of a nitroalkane and an
aldehyde occurs. Bifunctional organocatalysts that have been used to independently
activate both these groups include cinchona [12, 13] and guanidine [14, 15]
derivatives, which are two classes of catalyst which have recently been found to be
effective for a wide range of organic transformations.
By comparison, histidine [16, 17] and related amino acids may have been
important catalysts in biochemical processes ever since life in its most primitive
L. Karadeniz Á S. T. Astley (&)
˙
Department of Chemistry, Faculty of Science, Ege University, 35100 Bornova, Izmir, Turkey
e-mail: astleys@yahoo.co.uk
123

L. Karadeniz, S. T. Astley
form evolved on Earth. Therefore, despite the bifunctional nature and wide
availability of amino acids, with the exception of proline [18, 19], the potential
catalytic activity of amino acids does not seem to have been thoroughly exploited.
Thus, as a result of our ongoing interest in the asymmetric Henry reaction [20, 21],
we were very interested in recent publications which described tandem reactions
involving nitroaldol condensation steps, catalysed by amino acid-containing
catalysts, which occurred over several days at room temperature [22, 23]. These
publications, and other publications describing the nitroaldol condensation reaction
catalysed by diamines [24, 25], made us wonder whether amino acids containing a
second nitrogen centre, for example histidine, could have a structure particularly
beneficial for catalysis of nitroaldol reactions.
Herein we report the preparation of a variety of amino acid-derived catalysts
related to histidine in that they contain a second basic nitrogen centre separated
from the alpha amino acid functionality, and the interesting observation that for
gamma amino acids a selective nitroaldol condensation occurs readily under
unusually mild conditions.
Experimental procedure
All chemicals were purchased from Merck, Sigma–Aldrich, Alfa Aesar, or Fluka
and were used without any purification. Solvents were used as received from
commercial suppliers. Silica gel F254 (Merck 5554) precoated plates were used for
thin-layer chromatography. For column chromatography, silica gel 60 (Merck 7743)
was used. IR spectra were recorded as either KBr discs or thin films between NaCl
plates on a Perkin Elmer 100 FTIR spectrometer. 1H NMR spectra were obtained by
use of a 400-MHz Varian NMR spectrometer at ambient temperature. Catalysts 1–4
were prepared by standard protection [26], Hofmann degradation [27, 28], and
deprotection procedures [29].
General procedure for the Henry elimination reaction
In a typical procedure, aldehyde (1 mmol), nitromethane (5 mmol), and the catalyst
(10 mol%) were dissolved in 2 mL solvent and stirred at 30 °C. The reaction was
monitored by TLC. After completion of the reaction, the solvent was evaporated in
vacuo and the crude product was purified by column chromatography on silica gel
1
(hexane–EtOAc). The E stereochemistry was readily assigned on the basis of H
NMR spectra. The structures of the known products were characterized by
comparison with literature data.
1-Chloro-2-[(E)-2-nitrovinyl]benzene (7a)
Yellow oil, 93 % yield. 1H NMR (CDCI3) d (ppm) 8.40 (d, 1H, J = 12 Hz), 7.59 (d,
1H, J = 12 Hz), 7.57 (d, 1H, J = 8 Hz), 7.50 (d, 1H, J = 8 Hz), 7.42 (t, 1H,
J = 8 Hz), 7.33 (t, 1H, J = 8 Hz). IR (NaCl) 1634, 1520, 1339 cm-1
.
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Catalyst functional group cooperativity in the amino acid
1-Methyl-4-[(E)-2-nitrovinyl]benzene (7b) [30]
Yellow solid, 98 % yield. 1H NMR (CDCI3) d (ppm) 7.99 (d, 1H, J = 12 Hz), 7.56
(d, 1H, J = 12 Hz), 7.44 (d, 2H, J = 8 Hz), 7.26 (d, 2H, J = 8 Hz), 2.41 (s, 3H).
IR (KBr) 1633, 1497, 1341 cm-1
.
1-Ethyl-4-[(E)-2-nitrovinyl]benzene (7c)
Yellow solid, 77 % yield. Melting point: 80–81 °C. 1H NMR (CDCI3) d (ppm) 7.99
(d, 1H, J = 12 Hz), 7.57 (d, 1H, J = 12 Hz), 7.47 (d, 2H, J = 8 Hz), 7.28 (d, 2H,
J = 8 Hz), 2.70 (q, 2H, J = 8, 16 Hz) 1.26 (t, 3H, J = 8 Hz). IR (KBr) 1634, 1519,
1505, 1342 cm-1
.
1-Methoxy-4-[(E)-2-nitrovinyl]benzene (7d) [31]
Yellow solid, 93 % yield. 1H NMR (CDCI3) d (ppm) 7.98 (d, 1H, J = 12 Hz), 7.52
(d, 1H, J = 12 Hz), 7.50 (d, 2H, J = 8 Hz), 6.96 (d, 2H, J = 8 Hz), 3.87 (s, 3H).
IR (KBr) 1604, 1517, 1497 cm-1
.
1-Nitro-2-[(E)-2-nitrovinyl]benzene (7e) [32]
Yellow solid, 50 % yield. 1H NMR (CDCl3) d (ppm) 8.54 (d, 1H, J = 12 Hz), 8.21
(d, 1H, J = 8 Hz), 7.75 (td, 1H, J = 8, 4 Hz), 7.69 (t, 1H, J = 8 Hz), 7.60 (dd, 1H,
J = 8, 4 Hz), 7.43 (d, 1H, J = 12 Hz). IR (KBr) 1544, 1520, 1347 cm-1
.
1-Nitro-3-[(E)-2-nitrovinyl]benzene (7f) [32]
1
Yellow solid, 54 % yield. H NMR (CDCl3) d (ppm) 8.42 (bs, 1H), 8.35 (d, 1H,
J = 8 Hz), 8.05 (d, 1H, J = 12 Hz), 7.88 (d, 1H, J = 8 Hz), 7.75–7.60 (m, 2H). IR
(KBr) 1639, 1556, 1509, 1347 cm-1
.
1-Nitro-4-[(E)-2-nitrovinyl]benzene (7 g) [32]
1
Yellow solid, 60 % yield. H NMR (CDCl3) d (ppm) 8.32 (d, 2H, J = 8 Hz), 8.04
(d, 1H, J = 12 Hz), 7.73 (d, 2H, J = 8 Hz), 7.64 (d, 1H, J = 12 Hz). IR (KBr)
1637, 1601, 1519, 1340 cm-1
.
Results and discussion
The series of organocatalysts used in this study are shown in Fig. 1.
As is apparent for histidine (1a), all the catalysts contain a nitrogen functionality
separated from the alpha amino acid group by one or more methylene groups.
Catalysts 3 and 4 were prepared from asparagine and glutamine by use of Hoffman
rearrangement procedures [27, 28]. The amino acids were used as catalysts in their
underivatised form but also with protected amine groups. The catalytic effects of
123

L. Karadeniz, S. T. Astley
Fig. 1 The amino acids and derivatives used as catalysts
these amino acids in the Henry reaction, using the reaction between 2-chlorobenz-
aldehyde and nitromethane as a model, are summarised in Table 1.
When amino acids 1a (histidine), 2a (tryptophan), or 4a were used as catalysts,
slow reactions were observed to afford the nitroaldol condensation product (7).
Yields were poor for 1a and 2a but reasonable for 4a. The same product was also
obtained in low yield for 3a, but in this case larger amounts of the intermediate b-
nitroalcohol were obtained. (Scheme 1).
We subsequently prepared the derivatives 1b–4b in which the a-amino groups
were protected with Cbz (benzyloxycarbonyl) groups and were interested to note
that, with the exception of 4b, these amino acid derivatives failed to catalyse
formation of the nitroalkene to any significant extent. Thus, by protecting the a-
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Catalyst functional group cooperativity in the amino acid
Table 1 Effect of different organocatalysts in the nitroaldol reaction of 2-chlorobenzaldehyde and
nitromethane
Entry
Catalyst
Timea
Yieldb (%) 6a
Yieldb (%) 7a
1
1a
1b
2a
2b
3a
3b
4a
4b
4c
4d
4e
10 days
10 days
10 days
10 days
6 days
10 days
24 h
–
15
–
4.2
1
2
3
11
–
4
–
5
57
–
5.5
–
6
7
–
71
93
95
–
8
48 h
–
9
10 days
10 days
10 days
–
10
11
–
–
–
Reaction conditions: 2-chlorobenzaldehyde (1 mmol), nitromethane (5 mmol), catalyst (10 mol%)
a
Detected by TLC
b
Isolated yield after column chromatography
Scheme 1 Standard Henry reaction followed by dehydration
amino groups of 1, 2, and 3, the low catalytic behaviour of these substrates was
completely turned off, whereas for 4 there was very little change in the reactivity.
This clearly indicates that for 1, 2, and 3 the a-amino group is essential for any type
of catalytic activity, whereas for 4 the c-amino group may be much more important
than the a-amino group in determining catalytic activity. Interestingly, the presence
of the b-amino group in 3 results in no apparent catalytic activity.
To further test this hypothesis and to obtain further understanding of the catalytic
behaviour of 4, we prepared the derivatives 4c–4e, by incorporating different
protecting groups at the three sites of functionality in 4. Thus, it can be seen that
reaction of the gamma amino group with a Cbz group (4d) or esterifying the
carboxylate group (4e) led to complete termination of the catalytic activity. By
contrast, replacing H in 4a, or Cbz in 4b with a Boc (tert-butoxycarbonyl)
123

L. Karadeniz, S. T. Astley
protecting group in 4c led to a high yield of product being formed. Thus, it seems
that both the gamma amino group and the carboxylic acid group are necessary for
beneficial catalytic activity. Considering these observations, a likely mechanism is
proposed below (Scheme 2).
According to the mechanism suggested, the first step is preparation of an imine
involving the gamma amino group. This imine can then undergo nucleophilic attack
from a deprotonated nitromethane anion. Subsequent proton transfer may then be
followed by elimination, and it is suggested that this step is facilitated by the
carboxylate group. This suggestion is similar to a mechanism that has recently been
proposed for Knoevenagel condensation reactions using heterogeneously bound
NH2 groups [33].
These results are consistent with the results of Yoshida [23] and indicate that
amino acids may have unique bifunctional activity which can enable both steps of
this process to proceed. By comparison, when more traditional reagents are used the
overall reaction usually requires much harsher conditions for the elimination step
than for the first C–C bond-forming step. Thus, the first step often proceeds in the
presence of a base at mild temperature whereas a typical procedure for the
elimination process could consist of heating an acetic acid solution of the aldehyde
with the appropriate nitroalkane and ammonium acetate at 100 °C for several hours
[34]. Alternatively, reagents such as methane sulfonylchloride [35], phthalic
Scheme 2 Proposed mechanism for c-amino acid-catalysed nitroaldol condensation
123

Catalyst functional group cooperativity in the amino acid
anhydride [36, 37], dicyclohexyl carbodiimide [38], or pivaloyl chloride [39, 40], in
addition to a high temperature and a lengthy reaction time, may be used.
Next, it was decided to further study the reaction of 2-chlorobenzaldehyde with
nitromethane by varying some of the operating conditions in the presence of catalyst
4b. Table 2 illustrates the effect of the reaction solvent on the yield of 1-chloro-2-
[(E)-2-nitrovinyl]benzene.
It is apparent the reaction solvent has a very significant effect on the reaction.
When the reaction solvent was changed from ethanol to n-BuOH, IPA, EtOH–H2O
(10:1), MeOH, acetone, dichloromethane, or n-PrOH the reaction yield decreased
and the reaction required a longer time (Table 2, entries 1–5, 9, 12, and 13). No
product was obtained in THF, toluene, ethyl acetate, DMF, and acetonitrile (entries
6–8, 10, and 11). Thus, alcohols as solvents seem to be important in this reaction,
and this is consistent with the suggested mechanism in which proton transfer occurs
from the carboxylic acid group to the gamma N atom. Finally, using the optimized
reaction conditions and catalyst 4b, different aldehydes were tested to extend the
substrate scope, as shown in Table 3.
Table 2 Effect of the reaction solvent on the yield of 1-chloro-2-[(E)-2-nitrovinyl]benzene in the
reaction of 2-chlorobenzaldehyde with nitromethane
Entry
Solvent
Timea
Yieldb (%) 7a
1
EtOH
48 h
5 days
5 days
5 days
5 days
–
93
67
52
58
52
–
2
n-BuOH
IPA
3
4
EtOH–H2O (10:1)
MeOH
5
6
THF
7
Toluene
–
–
8
Ethyl acetate
Acetone
–
–
9
5 days
–
24
–
10
11
12
13
DMF
Acetonitrile
Dichloromethane
n-PrOH
–
–
7 days
5 days
14
78
Reaction conditions: 2-chlorobenzaldehyde (1 mmol), nitromethane (5 mmol), catalyst (10 mol%), 30 °C
a
Determined by TLC
b
Isolated yield after column chromatography
123

L. Karadeniz, S. T. Astley
Table 3 Condensation reaction of nitromethane with different aldehydes
Entry
R
Timea (h)
Product
Yieldb (%) 7
1
2
3
4
5
6
7
5a: 2-Cl
48
72
72
72
96
96
72
7a
7b
7c
7d
7e
7f
93
98
77
93
50
54
60
5b: 4-Me
5c: 4-Et
5d: 4-MeO
5e: 2-NO2
5f: 3-NO2
5g: 4-NO2
7g
Reaction conditions: aldehyde (1 mmol), nitromethane (5 mmol), catalyst (10 mol%), 30 °C
a
Determined by TLC
b
Isolated yield after column chromatography
It is apparent the L-glutamine-derived catalyst 4b generally worked well for
various aromatic aldehydes, although the presence of electron-donating substituents
on the aldehyde does seem to favour the reaction to some extent.
Conclusion
We report a simple, mild, and inexpensive method for one-pot synthesis of
nitroalkenes. The key feature of the organocatalysts used in the procedure seems to
be the presence of a gamma amino acid which can act as a bifunctional catalyst
allowing selective formation of (E)-nitroalkenes in high yields starting from
nitromethane and a variety of aromatic aldehydes.
Acknowledgments We are grateful to the Research Grant Office of Ege University (2007 Fen 044) and
¨
the Scientific and Technological Research Council of Turkey (TUBITAK, 107T778) for financial support.
˙
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