Water-compatible hydrogen-bond activation: A scalable and organocatalytic model for the stereoselective multicomponent aza-henry reaction

Article abstract of DOI:10.1002/chem.201303448

A study was conducted to demonstrate that H-bond based asymmetric organocatalysis can be performed under the so-called in the presence of water conditions. Nitroalkane, catalyst, dimethylcyclohexylamine, benzaldehyde and aniline were mixed to a 0°C cooled and vigorously stirred aqueous solution of NaOAc/AcOH saturated with NaCl. The organic residues were taken into dichloromethane and decanted off. The combined organic fractions were dried over Na₂SO₄, filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel) using a mixture of hexanes/ethyl acetate. From a synthetic point of view, the reaction furnishes enantioenriched b-nitroamines decorated with aromatic or aliphatic substituents at the amine center and a different set of alkyl chains or rings attached to the carbon bearing the nitro functionality. Importantly, the reaction can be scaled up without losing yield and stereoselectivity and with full recovery of the catalyst.

Full text of DOI:10.1002/chem.201303448

DOI: 10.1002/chem.201303448
Water-Compatible Hydrogen-Bond Activation: A Scalable and
Organocatalytic Model for the Stereoselective Multicomponent Aza-Henry
Reaction
Fabio Cruz-Acosta, Pedro de Armas,* and Fernando Garcꢀa-Tellado*[a]
Dedicated to the Professor Julio Delgado Martꢀn
The water paradigm has changed in organic chemistry.[1]
Multiple organic reactions have been implemented in the
form of water-compatible processes with a net gain in effi-
ciency and instrumental simplicity.[2] Most of these reactions
are currently performed either as homogeneous solutions or
easily-stirred aqueous suspensions. Homogeneity requires
either the use of water soluble reactants or the aid of an or-
ganic co-solvent and are governed by hydrophobic and/or
hydrogen-bond (H-bond) interactions.[3] Aqueous suspen-
sions involve reactants that are insoluble in water and at
least one of them is a liquid[4] (the so-called “on water”[4a] or
in the presence of water[4b] conditions). Although there is no
general agreement on the chemical bases governing these
reactions nor the exact place where they occur, experimen-
tal evidences suggest that these reactions must be occurring
at the organic-water interface[5] and, as a consequence, they
should be influenced by the properties of water molecules
and reactants at these interfaces.[6] Although several proto-
cols based on covalent organocatalysis have been successful-
ly developed in water or in the presence of water,[7] the im-
plementation of non-covalent based protocols has proved to
be more problematic due to the polar properties of the
water molecule and its hydrogen bond disruptor capacity.
However, recent reports[8] have shown that the development
of these reactions can be feasible in a productive manner. In
a seminal communication, Schreiner and col.[8a] established
that hydrogen bonding thiourea-based catalysis can be ac-
complished in the presence of water and even amplified by
hydrophobic hydration.[9] More recently, Rueping et. al.[8b]
reported the first example of an asymmetric Brønsted acid
catalyzed organic reaction in the presence of water, using
the hydrophobic hydration as the driving force of the reac-
tion. Although it is well established that water should favor
multicomponent reactions (MCR),[10] the number of success-
fully developed water-compatible MCR[11] remains scarce.[12]
However, the implementation of robust and efficient water-
compatible MCR manifolds still remains challenging. We
describe herein our efforts in the development and imple-
mentation of the first example of an H-bond based organo-
catalytic multicomponent manifold operating “in the pres-
ence of water” conditions.[4b] The manifold performs a multi-
component and stereoselective version of the organocata-
lyzed aza-Henry reaction[13] (Scheme 1A) and it utilizes ani-
line, aromatic or aliphatic aldehydes, primary or secondary
nitroalkanes, N,N-dimethylcyclohexylamine as the catalytic
base, and a chiral thiourea[14] or squaramide[15] catalyst as
the chiral source to afford the corresponding a,b-disubstitut-
ed b-nitroamine derivatives 3 in good yield and high stereo-
selectivity (up to ꢀ99.5:0.5 e.r. and ꢀ99.5:0.5 d.r., anti-
adduct[16]). The catalysis is performed through H-bond inter-
actions between the nitroalkane and the chiral catalyst. Im-
portantly, each family of catalysts delivers the b-nitroamine
3 with complementary enantioselectivity, allowing for the se-
lective access to the two enantiomeric series of these impor-
[a] F. Cruz-Acosta, Dr. P. de Armas, Dr. F. Garcꢀa-Tellado
Departamento de Quꢀmica Biolꢁgica y Biotecnologꢀa
Instituto de Productos Naturales y Agrobiologꢀa
Consejo Superior de Investigaciones
Cientꢀficas Astrofꢀsico Francisco Sꢂnchez 3,
38206 La Laguna, Tenerife (Spain)
Fax : (+34)922260135
E-mail: parmas@ipna.csic.es
fgarcia@ipna.csic.es
Homepage: https://www.ipna.csic.es/dept/qbb/qob/
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303448.
Scheme 1. Water-compatible aza-Henry reaction.
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Table 1. Scope of the water-compatible stereoselective 3CR aza-Henry.
tant building blocks in an efficient, instrumentally simple,
and scalable manner.
À
The aza-Henry reaction is an important C C bond-form-
ing reaction in organic chemistry. Since the pioneer works of
Shibashaki et. al.[17] (1999, metal-catalyzed) and Takamoto
et. al.[18] (2004, organocatalyzed), many other catalytic asym-
metric versions have been implemented.[13] In spite of these
advances, a number of problems remain to be solved.
Among others, the restrictive nature of the aldimine (mainly
aromatic) and the nitroalkane (mainly primary) and the
large amounts of nitroalkane needed to reach good reaction
rates (5–10 fold excess). Currently, the aldimines are pre-
formed (usually as its moisture-sensitive N-BOC-derivative)
or formed in situ from the corresponding a-amide sulfona
precursor and a base.[19] To our knowledge, the implementa-
tion of the stereoselective three component version of this
reaction (3CR) has remained elusive.[20] We tackled this
challenge by designing a 3CR involving aldehydes, aniline,
nitroalkanes, and a catalytic amount of a small organic H-
bonding donor molecule in the presence of an organic base
and water. The design of the manifold was drafted based on
our own experience on the favored formation and activation
of N-phenylaldimines in the presence of water[21] and the re-
ported properties of the water molecules at the organic-
water interface,[22] which present a very weak bonding char-
acter and a low reactivity. Under these conditions, nitroal-
kanes could be recognized and activated by small H-bond-
ing donor organic catalysts (e.g., thioureas[14] or squar-
ACHTUNGTRENNUNG
amides[15]). The H-bond interaction between nitroalkane and
catalyst should reduce the pKa of the nitroalkane favoring
the formation of the corresponding nitronate species by the
organic base. If this proposal were feasible, then the cata-
lysts should be designed to be easily implemented with
chiral information, which should be transferred completely
to the resulting b-nitroamine. As a proof of concept, we de-
signed a reaction prototype involving water and n-hexanal,
nitroethane, aniline, N,N-dimethylcyclohexylamine (catalytic
amount), and thiourea catalyst thu or the squaramide cata-
lyst sqa (Scheme 1B). We chose n-hexanal as the model al-
dehyde because of its lipophilic nature and because its
N-phenylimine derivative should share the same stability
and reactivity profiles than the other members of the ali-
phatic series, which have proved to be difficult to control in
these reactions in organic media.[13] We were delighted to
observe that this catalytic reaction could be accomplished in
the presence of water, confirming that our initial hypothesis
was correct. After considerable experimental work, a set of
optimal experimental conditions could be established for
this reaction (Scheme 1B). The reaction was pH-sensitive
with an optimal value of 5.5 (see the Supporting Informa-
tion, Table 1S), which is close to the value reported for the
air-water interface (c.a. 4,8)[23] and that accepted as suitable
for imine formation (c.a. 4,5);[24] therefore, it must be also
an appropriate value for the formation of the iminium
ion.[24] The pH was kept constant using an aqueous solution
of NaOAc/AcOH saturated with NaCl (buffer). No reaction
could be observed under neat conditions and both the base
Reported yields are isolated yields. Enantiomeric and diastereomeric
ratios were determined by chiral HPLC analysis and they refer to the
anti-isomer and to the anti/syn ratio respectively.
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P. de Armas, F. Garcia-Tellado, F. Cruz-Acosta
and the catalyst were needed to accomplish the reaction
with efficiency. The addition order of the different reactants
was critical, the optimal sequence being: nitroalkane, cata-
lyst, base, aldehyde, and aniline. The nitroalkane amount
and the catalyst and base loadings were also examined, es-
tablishing a minimal threshold of 14 mol% for the catalysts,
a 10 mol% for the base and a two-fold excess for the nitro-
alkane (see the Supporting Information, Table 2S). Al-
though the reaction was optimized using n-hexanal and ni-
troethane, other aldehydes (aliphatic and aromatic) and ni-
troalkanes (primary or secondary) were smoothly accepted.
With a non-chiral robust and reliable organocatalytic mul-
ticomponent manifold at hand, we studied the chiral imple-
mentation of this protocol using the reaction of benzalde-
hyde, aniline, and nitroethane as a model (Table 1, 3aa/
ent-3aa). We explored a survey of chiral catalyst structures
incorporating a thiourea unit or a squaramide motive (see
the Supporting Information, Figure 1S and 2S). After a con-
siderable experimental effort, we arrived to the Jacobsenꢄs
catalyst thu*-I[25] and de novo catalyst sqa*-I as the best cat-
alysts in terms of chemical efficiency, chiral induction and
preparation, and 08C as the optimal temperature for this re-
action (Tables 3S). Under these conditions, both catalysts
funneled the reaction towards the corresponding b-nitroa-
mine derivatives 3 with anti-configuration, but with comple-
mentary enantioselectivity.[26] Benzaldehyde reacted with
aniline and nitroethane in the presence of N,N-dimethylcy-
clohexylamine (10 mol%) and catalyst thu*-I (14 mol%) to
afford the b-nitroamine 3aa in 88% yield and excellent ste-
reoselectivity (95:5 e.r.; 20:1 d.r.). Under the same reaction
conditions, the catalyst sqa*-I delivered the enantiomeric
product ent-3aa with similar efficiency (85% yield), but
better stereoselectivity (97:3 e.r.; ꢀ66:1 d.r.). This discovery
allowed us to gain access to the two enantiomeric series of
the resulting b-nitroamine products. A set of electronically
diverse aromatic aldehydes reacted with nitroethane to
afford the corresponding b-nitroamines with excellent enan-
tioselectivity in most cases and diastereomeric ratios ranging
from modest (4:1) to excellent (ꢀ99.5:0.5). Remarkably, an
increase in the aromatic surface of the aldehyde did not
translate into a higher stereoselectivity or efficiency (com-
pare b-nitroamines 3aa/ent-3aa with 3ga/ent-3ga). The re-
action accepted both primary and secondary nitroalkanes al-
though with different effectiveness (compare b-nitroamines
3aa–3ac with 3ad–3af and their corresponding enantio-
mers).
that the nitroalkane amount could be reduced to a slight
10% excess (1.1 equiv). Under these new conditions, 1-ni-
tropentane reacted with a representative set of linear alde-
hydes to deliver the expected a,b-dialkyl b-nitroamines
3hc–3oc [ent-(3hc–3oc)] with good yield (74% average
yield), but moderate to good stereoselectivity [(75–85): (25–
15) e.r.; (4–8):1 d.r.]. It is interesting to note that 3-phenyl-
propanal and n-butanal, which markedly differ in the lipo-
philic nature of the group at the end of the chain (Ph versus
Me), afforded the corresponding products 3kc and 3oc (and
their enantiomers) with similar stereoselectivity, but with
different efficiency: the less lipophilic n-butanal rendered
the corresponding b-nitroamine with roughly 20% higher
yield than the more lipophilic 3-phenyl-propanal. Nitro-
ethane and 1-nitrobutane smoothly reacted with n-pentanal
to give the corresponding a,b-dialkyl b-nitroamines 3la–3lb
[ent-(3la–3lb)] in good yields, but moderate enantioselectiv-
ity. Branching in the nitroalkane proved to be harmful for
the reaction both in terms of yields (ꢁ20%) and stereose-
lectivity (almost-racemate). An interesting outcome was ob-
served in the reactions of cyclohexanecarboxaldehyde and
the 3-pentanecarboxaldehyde with 1-nitropentane in the
presence of each catalyst (see square inside Table 1). The
flash chromatography of each one of the obtained diastereo-
meric mixtures allowed us to obtain each one of the all of
possible stereoisomers associated with these structures in
pure and enantioenriched form. These examples highlight
the potential of this methodology for the synthesis of stereo-
chemically diverse libraries of nitrogen-containing small
molecules for mapping bioactivity in the chemical space.[28]
The reaction was scaled up (up to 20 mmol) without sig-
nificant erosion in yield or stereoselectivity [Eq. (1)]. A
simple decantation-trituration protocol allowed us the isola-
tion of b-nitroamine ent-3aa (87%; ꢀ95% pure; 98:2 e.r.;
30:1 d.r.) and the full recovery of the chiral catalyst. Re-
markably, a large scale reaction using the recycled waters
and recovered catalyst afforded ent-3aa with roughly the
same efficiency and stereoselectivity (see the Supporting In-
formation for details).
Although we have performed this study using aniline, the
reaction can be performed using 2-methoxyaniline, which in-
troduces the synthetic advantage of the direct transforma-
tion of the products into their free amine form[29] (See the
Supporting Information for experimental details).
At this stage of the work, we do not have a theoretical-
supported model able to explain the role played by the
water molecules in the reaction mechanism and in the chiral
information transfer process. These reactions are performed
Next, we studied the extension of this catalytic system to
aliphatic aldehydes (Table 1). We found that the catalyst
thu*-I was consistently much less
efficient when the aldehyde was
aliphatic. Fortunately, the cata-
lyst performance could be in-
creased changing the N-terminal
N-methyl-1,1-diphenylmethana-
mine motive by the more com-
pact
(R)-2-phenylpyrrolidine
unit (thu*-II).[27] We also found
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Multicomponent aza-Henry Reaction
COMMUNICATION
were isolated in 88 and 85% yield, respectively, as amorphous pale
under non homogeneous conditions and involve a complex
sequence of steps, which make gaining a full understanding
of the reaction mechanism and the role of water very chal-
lenging. However, reactive water, in parallel to the complex
fluids in which biological reactions occur, must be well re-
moved from the place where these reactions take place (oth-
erwise, the activated imines could not survive). If these reac-
tions are taking place at the organic-water interface, as
postulated by Huck and co-workers,[5] and the water mole-
cules in this interface behave similarly to the water mole-
cules at the vapor–water interface as postulated by Rich-
mond and Chandler,[23] then the low reactivity and weak
binding character of these water molecules should enable
the observed H-bond interaction between the chiral catalyst
and the nitroalkane and the subsequent reactions affording
the b-nitroamine product. Therefore, more experimental
and theoretical work is needed to fully understand and in-
strumentalize the rich potential that this chemistry can
offer, and importantly, to take advantage of its capacity to
mimic the biological chemistry accomplished in confined
spaces in which pure water is absent.[10]
yellow solids. 1H NMR (400 MHz, CDCl3): d=7.36–7.28 (m, 5H), 7.13–
3
3
7.08 (m, 2H), 6.72 (appt, J(H,H) =7.4 Hz, 1H), 6.56 (appd, J(H,H) =7.7 Hz,
3
3
2H), 5.01 (dd, J(H,H) =6.5, 4.9 Hz, 1H), 4.90 (dq, J(H,H) =6.8, 4.9 Hz, 1H),
4.43 (brd, 3J(H,H) =6.5 Hz, 1H), 1.56 ppm (d, 3J(H,H) =6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=146.0, 137.5, 129.2 (2C), 129.0 (2C),
128.4, 126.8 (2C), 118.8, 114.1 (2C), 86.4, 77.3, 76.6, 60.8, 13.8 ppm; IR
(CHCl3): n˜ =3419, 1605, 1552 cmÀ1; HRMS (EI/TOF): m/z calcd for:
C15H16N2O2: 256.1212 [M]; found: 256.1205. The e.r. and d.r. were deter-
mined by HPLC using a Chiralpack AD-H column [hexane/isopropanol
(90:10 v/v)]; flow rate 0.5 mLminÀ1
. 3aa: tmajor =26.6 min, tminor =
20.6 min (e.r.: 95:5, d.r.: 20:1). ent-3aa: tmajor =20.8 min, tminor =26.2 min
(e.r.: 3:97, d.r.: ꢀ66:1).
Acknowledgements
We thank the Spanish MICINN (FEDER) for financial support
(CTQ2011-28417-C02-02) and CSIC for a JAE-PRE grant (F. C.-A.). We
thank Prof. Julio Delgado for his enthusiastic comments on this work and
Mrs. Sonia Rodriguez Dꢀaz for her aid with the synthesis of catalysts and
HPLC analysis.
Keywords: asymmetric organocatalysis · hydrogen bond ·
multicomponent reactions · nitro-mannich · water
In summary, we have demonstrated that H-bond based
asymmetric organocatalysis can be performed under the so-
called “in the presence of water” conditions.[4b] As a proof
of concept, we have described the first example of a stereo-
selective multicomponent aza-Henry reaction catalyzed by
a combination of a chiral H-bond donor organic molecule
(thiourea or squaramide) and a Lewis base (N,N-dimethyl-
cyclohexylamine) in the presence of water. Each family of
catalysts selectively funnels the reaction towards one of the
two enantioenriched forms of the corresponding b-nitro-
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[26] The relative and absolute configurations were assigned following es-
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[27] R. R. Knowles, S. Lin, E. N. Jacobsen, J. Am. Chem. Soc. 2010, 132,
5030–5032.
[28] For a selected example: N. Kumagai, G. Muncipinto, S. L. Schreiber,
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[29] For a recent example, see: P. Fu, M. L. Snapper, A. H. Hoveyda, J.
Am. Chem. Soc. 2008, 130, 5530–5541.
Received: September 2, 2013
Published online: November 4, 2013
16554
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