Dihydrooxazine oxides as key intermediates in organocatalytic michael additions of aldehydes to nitroalkenes

Article abstract of DOI:10.1002/anie.201204833

The organocatalytic enantioselective Michael addition of aldehydes to nitroalkenes through enamine catalysis has been studied intensively in recent years. Pioneering mechanistic studies by Seebach and Hayashi and co-workers, as well as by the Blackmond group, on reactions catalyzed by diaryl prolinol ethers have identified cyclobutane (CB) species 6a (Scheme 1) as a key intermediate and the resting state of the amine catalyst. Although these studies clearly demonstrated that the rate-determining step in the catalytic cycle takes place after the formation of 6a, and possibly involves the protonation of the iminium nitronate 5a, the detailed mechanism of the rate-determining step was not addressed. More recently, the Blackmond group suggested a modified catalytic cycle where the cyclobutane species 6a is first deprotonated to give the anion 10 a, followed by protonation to form the enamine 8a.

Full text of DOI:10.1002/anie.201204833

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DOI: 10.1002/anie.201204833
Reaction Mechanisms
Dihydrooxazine Oxides as Key Intermediates in Organocatalytic
Michael Additions of Aldehydes to Nitroalkenes**
Gokarneswar Sahoo, Hasibur Rahaman, ꢀdꢁm Madarꢁsz, Imre Pꢁpai,* Mikko Melarto,
Arto Valkonen, and Petri M. Pihko*
The organocatalytic enantioselective Michael addition of
aldehydes to nitroalkenes through enamine catalysis[1] has
been studied intensively in recent years.[2] Pioneering mech-
anistic studies by Seebach and Hayashi and co-workers,[3] as
well as by the Blackmond group,[4] on reactions catalyzed by
diaryl prolinol ethers[5] have identified cyclobutane (CB)
species 6a (Scheme 1) as a key intermediate and the resting
state of the amine catalyst. Although these studies clearly
demonstrated that the rate-determining step in the catalytic
cycle takes place after the formation of 6a, and possibly
involves the protonation of the iminium nitronate 5a, the
detailed mechanism of the rate-determining step was not
addressed. More recently, the Blackmond group suggested
a modified catalytic cycle where the cyclobutane species 6a is
first deprotonated to give the anion 10a, followed by
protonation to form the enamine 8a.[4b]
products in synthetically useful yields and enantio- and
diastereoselectivities.[6] The protonation of the dihydrooxa-
zine oxide intermediate also explains the sense of dia-
stereoselection of the protonation step.
At the outset, we decided to study the reaction with both
a-unsubstituted and a-substituted nitroalkenes. Recently,
Wennemers and Duschmalꢀ[7] reported a tripeptide catalyst
Herein, we present a model derived from a combination
of computational and experimental studies where the rate-
determining step of the reaction involves protonation of the
dihydrooxazine oxide (OO) species 11a instead of the
previously suggested species 5a[3,4a] or 10a.[4b] Furthermore,
we demonstrate that the sluggish reaction rates observed in
reactions with a-alkyl-substituted nitroalkenes (such as 4b)
are in fact due to slow protonation of the OO intermediate
(e.g. 11b; R = Me) and not a result of the intrinsically lower
reactivities of the nitroalkenes. Finally, as a practical appli-
cation of the insight obtained by these studies, we demon-
strate that a simple p-nitrophenol co-catalyst remarkably
accelerates reactions with a-alkyl nitroalkenes, to provide the
[*] Dr. G. Sahoo, Dr. H. Rahaman, M. Melarto, Dr. A. Valkonen,
Prof. Dr. P. M. Pihko
Department of Chemistry, Nanoscience Center
University of Jyvꢀskylꢀ, P. O. B. 35, FI-40014 JYU (Finland)
E-mail: Petri.Pihko@jyu.fi
Homepage: http://tinyurl.com/pihkogroup
Dr. ꢁ. Madarꢂsz, Dr. I. Pꢂpai
Institute of Organic Chemistry
Research Centre for Natural Sciences
Hungarian Academy of Sciences
P.O.B. 17, H-1525 Budapest (Hungary)
E-mail: papai@chemres.hu
[**] We thank Esa Haapaniemi and Mirja Lahtiperꢀ for assistance with
the NMR and HRMS measurements, respectively. This work was
supported by the Academy of Finland (project Nos. 123813 and
138854 to P.M.P.), the Hungarian Research Foundation (OTKA,
Grant NN-82955), and COST CM0905. A.V. thanks Academy Prof.
Kari Rissanen for funding through the Academy of Finland (KR
project Nos. 130629, 122350, and 140718).
Scheme 1. Summary of the proposed mechanisms for the conjugate
addition of aldehydes to nitroalkenes by enamine catalysis and the
structure of the dihydrooxazine oxide species characterized in this
study. Species labeled ‘observed’ have previously been identified and
characterized by 1D and 2D NMR spectra and by HRMS.[3,4] rds=rate-
determining step, TMS=trimethylsilyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204833.
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that provides acceptable reaction rates and excellent enan-
tioselectivities for reactions with a-alkyl nitroalkenes, such as
4b. They suggested that the lower reactivity of 4b is a result of
suboptimal conjugation of the phenyl ring with the nitro-
alkene. If, however, the turnover-limiting step occurs later in
the catalytic cycle, as suggested by the groups of Seebach,
Hayashi, and Blackmond for 4a,[3,4] the lower reactivity of a-
alkyl nitroalkenes might not be related to the reactivity of the
starting nitroalkene at all. Instead, we should consider the
reactivity of the intermediates. To resolve this issue, we
decided to investigate the reactions with both 4a and 4b by
a combination of computational and experimental studies.
Our initial computational analysis[8] focused on the
identification of the reaction intermediate formed upon the
À
C C bond formation process between enamine 3 and nitro-
Figure 2. A plot of concentration versus time for different species in
olefin 4a.[9] We found that the conjugate addition leads to
spontaneous ring closure between the oxygen atom of the
nitro group and the iminium carbon atom resulting in an OO
species (11a). The zwitterionic iminium nitronate 5a could
not be located as a low-lying energy minimum on the
potential energy surface even with the inclusion of solvent
effects. The computations also showed that 11a can easily
transform into CB 6a in a single step. Similar results were
obtained for the addition of enamine 3 to a-substituted
nitroolefin 4b. The energetics of these transformations are
illustrated in Figure 1.
the reaction between 2 and 4a in [D8]toluene with an excess of 1.
Reaction conditions: [2]0 and [4a]0 =0.086m, [1]0 =0.172m (see the
Supporting Information for more details).
the product enamine 8a (green curve) are both in line with
previous studies.[3,4] Importantly, however, we also observed
a second minor intermediate (dark grey curve) that appears to
form and decay contemporaneously with the cyclobutane 6a,
thus indicating that these species are linked together and
likely involved in a rapid equilibrium. This new species was
confirmed to be the dihydrooxazine oxide 11a by 2D NMR
experiments (COSY, HMQC; see the Supporting Informa-
tion).[12]
When the corresponding reaction with 4b was monitored,
the analogous OO species 11b was observed by NMR
spectroscopy, but the cyclobutane 6b was not detected. This
result confirmed the computationally predicted stability order
between 11b and 6b. In the absence of added acid, 11b was
stable for hours (see Figure 3), and its identity could be
established by an array of NMR experiments (COSY,
NOESY, HMQC, HMBC) as well as by HRMS (see the
Supporting Information). The similarity between the
1H NMR spectra of 11a and 11b provides further evidence
for their identity (see the Supporting Information).
Based on these results, it is very unlikely that the
zwitterion 5 is involved in the catalytic cycle, but instead,
the OO species 11 may play a key role, presumably in the
protonation step. 11 is predicted to be in a rapid equilibrium
with CB 6 for both reactions, but notable differences are seen
in their relative stabilities for the R = H and R = Me cases. In
the reaction with 4a (R = H), the cyclobutane 6a is favored
thermodynamically, whereas the stability order is reversed for
6b/11b (R = Me), as the OO species 11b is favored.[10]
Guided by these computational findings, we embarked on
the experimental study of the reaction progress, with the hope
of identifying the OO species 11a and/or 11b.[11] Figure 2
shows the conversion versus time profile for the reaction
between 2 and 4a with an excess of catalyst 1. The initial spike
of the CB formation (6a; blue curve) and the conversion into
When the reaction between 2 and 4b was carried out with
40 mol% of 1, addition of acid p-nitrophenol (12) caused the
linear decay of aldehyde 2 and concomitant linear increase in
the concentration of the product aldehyde 9b (Figure 3). The
concentration of the OO species 11b remained constant
during this time, suggesting that it is a steady-state inter-
mediate. Similar observations were made when the reaction
was carried out in CDCl3, and in experiments with nitroalkene
4c (Ar= p-FC6H4). From 4c, we obtained a third OO species
11c, which was also fully characterized by 2D NMR
spectroscopy and HRMS (see the Supporting Information).
A set of control experiments were conducted to probe the
reversibility of the formation of 11. First, experiments starting
from aldehyde 9c and catalyst 1 in the presence or absence of
p-nitrophenol led to the formation of 11c and the product
enamine 8c, thus confirming that 11c is a thermodynamically
stable species that can also be generated from the product
(Figure 4a).
Figure 1. Free-energy diagram computed for the reactions of enamine
3 with nitroalkanes 4a (R=H; blue) and 4b (R=Me; red). Relative
solution-phase Gibbs free energies (in kcalmolÀ1; with respect to
reactants 1 + 2 + 4) are given in parentheses.[8]
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of the CB species 6a and the decay of 11a are accompanied by
a steady increase in the concentration of either 11b (see
Figure 4c) or 11c, but the product enamine (8a) was
generated only slowly. A complementary crossover experi-
ment starting from 11b and 4a led to a very slow but steady
formation of product enamine 8a and a slow decay of 11b
(see the Supporting Information). The crossover experiments
demonstrate that the CB and OO species are involved in
a dynamic equilibrium and they can revert into the reactants,
albeit at a slow rate. The presence of the methyl group a to the
nitro group (as in 11b and 11c) renders the OO species more
stable relative to CB and no CB species corresponding to 11b
or 11c could be detected. The OO species 11b and 11c are so
stable that they convert into products only upon the addition
of p-nitrophenol or upon the addition of nitrostyrene (4a),
which traps the enamine 3 that is slowly released in
a reversible reaction from 11b, thus providing an exit via
the formation of product enamine 8a.
Figure 3. A plot of concentration versus time for different species in
the reaction between 2 and 4b in [D8]toluene. Reaction conditions: [2]0
and [4b]0 =0.172m, [1]0 and [12]0 =0.068m (see the Supporting
Information for more details).
To gain further mechanistic insight into the protonation
step of the catalytic cycle, reaction pathways corresponding to
the protonation of 6a/6b and 11a/11b with p-nitrophenol (12)
were explored computationally and other alternative path-
ways were considered as well (see the Supporting Informa-
tion). Our results indicate that the protonation takes place
preferentially on the C3 carbon of the OO species, and the
attack on the Si face of the six-membered ring was found to be
clearly favored kinetically (see Figure 5). The computations
The dynamic exchange between the CB species 6a and the
OO species 11 was established by crossover experiments
where either nitroalkene 4b or 4c was added to a reaction
mixture containing a maximum concentration of 6a/11a
(Figure 4b and c). These experiments revealed that the decay
Figure 5. Diastereoselective protonation of intermediate 11b. Protona-
tion barriers (in kcalmolÀ1, with respect to the 11b···12 adduct) are
given in parenthesis. Bond distances indicated by dashed lines are
given in ꢃ. For clarity, all hydrogen atoms (except those involved in the
proton transfer) are omitted, and the bulky CPh2OTMS group of the
catalyst is represented by simple lines. Blue N, red O.
thus predict diastereoselective protonation for reactions with
a-substituted nitroalkanes. The diastereoselectivity appears
to be governed by differential stabilizing electrostatic inter-
actions in the iminium–phenolate ion-pair intermediate (see
the Supporting Information). The free-energy barriers of
protonation for the reactions with 4a and 4b, are calculated to
be 20.6 and 23.9 kcalmolÀ1, respectively; these values are
consistent with the observed reaction rates. The nature of the
protonation transition states indicates that the barriers arise
predominantly from the ring opening of the OO species.[13] As
a result of the enhanced stability of 11b relative to 11a, the
ring opening is less favored for 11b, thus resulting in a larger
kinetic barrier for the protonation process. The iminium
Figure 4. a) Reversibility experiments. b) Crossover experiments. c) A
plot of concentration versus time for the crossover experiment starting
from cyclobutane 6a and a-alkylnitroalkene 4b, showing the dom-
inance of the dihydrooxazine oxide species 11b. For reaction condi-
tions, see the Supporting Information. M.S.=molecular sieves.
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intermediate 7a or 7b is deprotonated by the conjugate base
of 12 to form enamine 8a or 8b (see the Supporting
Information for computational details of this process).
a-Alkyl nitrostyrenes such as 4b, and a-alkyl nitroalkenes
in general, have been perceived as a challenging substrate
class for enamine-catalyzed conjugate additions.[7,14] We now
offer an explanation why this is the case: the resulting OO
intermediates (e.g. 11b) are very stable and convert into
products only with the addition of acid, such as 12.
The fact that 12 restores catalytic activity is synthetically
useful, and we also explored briefly the preparative value of
this simple protocol using 10 mol% of catalyst 1 and 40 mol%
of 12. Further solvent and additive screens indicated that 12 is
indeed an optimal co-catalyst, and somewhat faster rates are
obtained for reactions in CHCl3 rather than those in toluene.
Under these reaction conditions, a variety of aldehydes 2 and
a-alkyl nitroalkenes 4 were screened (Table 1).
to nitroalkenes catalyzed by diaryl prolinol ethers. The
previously identified cyclobutanes and the OO species can
rapidly interconvert, but the computations indicate that only
the OO species are on the catalytic cycle and become
protonated in the rate-determining step. The experimentally
observed stability of the OO species explains the sluggish
reaction rates observed with a-alkyl nitroalkenes, and this
obstacle can be overcome with a suitable choice of an acid co-
catalyst, to afford the products with high enantio- and
diastereoselectivities. The observed stereoselectivity of the
protonation step is consistent with the computational model.
A revised catalytic cycle is presented in Scheme 2.
Table 1: Enantio- and diastereoselective Michael addition of aldehydes to
a-alkyl nitro alkenes.[a]
Entry R1
R2
R3
t
Yield d.r.[c]
[h] [%][b]
e.r.[d]
1
2
3
4
Me
nBu
nC8H19 Ph
Ph
Ph
Me 30 68[f] 92:7:1:<1
>99.5:<0.5
>99.5:<0.5
>99.5:<0.5
Me 25 94
Me 24 94
90:6:4:<1
89:7:4:<1
Scheme 2. Revised mechanism for the Michael addition of aldehydes
to nitroalkenes catalyzed by 1.
Me
p-FC6H4 Me 23 70[f] 92:8:<1:<1 >99.5:<0.5
5
6
7
8
nBu
p-FC6H4 Me 21 93
92:6:2:<1
89:10:1:<1
>99.5:<0.5
>99.5:<0.5
>99.5:<0.5
>99.5:<0.5
>99.5:<0.5
>99.5:<0.5
>99.5:<0.5
>99.5:<0.5
nC8H19 p-FC6H4 Me 18 85
Me
nBu
nHex p-ClC6H4 Me 18 93
Me
nBu
nC8H19 p-tolyl
nBu
Ph[e]
nC8H19 Ph[e]
p-ClC6H4 Me 21 71[f] 84:1:15:<1
p-ClC6H4 Me 17 94
An important lesson of this study is that significant
differences in reaction rates with different substrates can also
result from differential stability of the intermediates, and
different intermediates may dominate even in seemingly
similar reactions. Fortunately, the experimental and especially
the computational tools to characterize the intermediates
have now advanced to a level where their combined use can
provide a very detailed picture of the catalytic reactions, and
offer synthetically relevant insights.
91:6:3:<1
91:6:3:<1
9
10
11
12
13
14
p-tolyl
p-tolyl
Me 24 63[f] 91:1:8:<1
Me 27 84
Me 25 87
Et 61 92
Et 65 89
90:6:4:<1
90:6:4:<1
85:15:<1:<1 >99.5:<0.5
83:17:<1:<1 >99.5:<0.5
[a] Reaction conditions: 2 (200 mol%), 4 (100 mol%), 1 (10 mol%), 12
(40 mol%). [b] Yields are of the isolated aldehyde. [c] Determined by
1H NMR spectroscopy. [d] e.r. was determined by HPLC analysis of the
corresponding enoate or the derived alcohol (see the Supporting
Information for details). [e] With 300 mol% of 2 and 80 mol% of 12.
[f] The product aldehyde is volatile.
Received: June 20, 2012
Revised: October 10, 2012
Published online: November 13, 2012
Keywords: aminocatalysis · computational chemistry ·
.
heterocycles · intermediate characterization · NMR spectroscopy
The products were isolated in good to excellent yields, and
in all cases the isolated products displayed excellent enantio-
selectivities (> 99.5: < 0.5 e.r. in all tested cases) and typically
good diastereoselectivities for the syn, anti product 9.[15] The
experimental diastereoselectivity of the protonation step
matches that predicted by the computational studies, thus
providing another cross-check for the protonation mechanism
emerging from the computations.
[1] For reviews of enamine catalysis, including a discussion of
different activation modes, see: a) A. Erkkilꢁ, I. Majander, P. M.
Pihko, Chem. Rev. 2007, 107, 5416; b) S. Mukherjee, J. W. Yang,
S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471; for a detailed
NMR study of enamine intermediates derived from 1, see:
c) M. B. Schmid, K. Zeitler, R. M. Gschwind, Chem. Sci. 2011, 2,
1793.
In conclusion, we present here spectroscopic and compu-
tational evidence that dihydrooxazine oxides (OO) are key
on-cycle intermediates in the Michael additions of aldehydes
[2] For recent reviews, see: a) P. Melchiorre, M. Marigo, A. Carlone,
G. Bartoli, Angew. Chem. 2008, 120, 6232; Angew. Chem. Int. Ed.
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Communications
2008, 47, 6138; b) S. Bertelsen, K. A. Jørgensen, Chem. Soc. Rev.
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118, 8042; Angew. Chem. Int. Ed. 2006, 45, 7876; d) S. Sulzer-
Mossꢀ, A. Alexakis, Chem. Commun. 2007, 3123.
[10] The enhanced stability of 11b relative to 11a arises from the
electron-donating properties of the a-methyl substituent; in
contrast this group destabilizes the four-membered ring struc-
ture in 6b. For a detailed analysis, see the Supporting Informa-
tion.
[11] For previous studies on dihydrooxazine oxides, see: a) F. Felluga,
P. Nitti, G. Pitacco, E. Valentin, Tetrahedron 1989, 45, 2099; b) F.
Felluga, P. Nitti, G. Pitacco, E. Valentin, J. Chem. Soc. Perkin
Trans. 1 1992, 2331; for a suggestion of the OO species as
a reversible catalyst sink, see: c) M. P. Lalonde, Y. Chen, E. N.
Jacobsen, Angew. Chem. 2006, 118, 6514; Angew. Chem. Int. Ed.
2006, 45, 6366.
[3] K. Patora-Komisarska, M. Benohoud, H. Ishikawa, D. Seebach,
Y. Hayashi, Helv. Chim. Acta 2011, 94, 719, and references
therein.
[4] a) J. Burꢀs, A. Armstrong, D. G. Blackmond, J. Am. Chem. Soc.
2011, 133, 8822; b) J. Burꢀs, A. Armstrong, D. G. Blackmond, J.
Am. Chem. Soc. 2012, 134, 6741; corrigendum (for the assign-
ment of 10a): J. Burꢀs, A. Armstrong, D. G. Blackmond, J. Am.
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[5] a) Y. Hayashi, H. Gotoh, T. Hayashi, M. Shoji, Angew. Chem.
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[6] For a previous study on the effect of H-bond co-catalysts in these
reactions, see: H. Rahaman, ꢂ. Madarꢃsz, I. Pꢃpai, P. M. Pihko,
Angew. Chem. 2011, 123, 6247; Angew. Chem. Int. Ed. 2011, 50,
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[7] J. Duschmalꢀ, H. Wennemers, Chem. Eur. J. 2012, 18, 1111.
[8] DFT calculations were carried out using the dispersion-cor-
rected range-separated hybrid wB97X-D functional. The 6–
311G(d,p) basis set was used for geometry optimizations,
vibrational analysis, and the estimation of solvent effects,
whereas the electronic energies were obtained in single-point
energy calculations using the large 6-311 ++ G(3df,3pd) basis
set. The solvation free energies (in chloroform) were computed
by using the SMD continuum model. The reported energies refer
to solvent-phase Gibbs free energies. For further details, see the
Supporting Information.
[12] During the reviewing of this manuscript, 11a and other 1,2-
oxazine N-oxides were independently identified by Seebach
et al.: D. Seebach, X. Sun, C. Sparr, M.-O. Ebert, W. B.
Schweizer, A. K. Beck, Helv. Chim. Acta 2012, 95, 1064.
[13] The protonation of the OO species 11a and 11b takes place in
concert with ring opening, but the two events are asynchronous.
The protonation process begins with the ring opening, which
renders the C3 carbon more basic and facilitates the proton
transfer from the phenolic OH. For further details, see the
Supporting Information.
[14] For previous examples with cyclic nitroalkenes, see: a) L. Guo,
Y. Chi, A. M. Almeida, I. A. Guzei, B. K. Parker, S. H. Gellman,
J. Am. Chem. Soc. 2009, 131, 16018; b) B. Stevenson, W. Lewis, J.
Dowden, Synlett 2010, 672; with nitroalkenes bearing additional
hydrogen-bond-donor groups: c) Y. Wang, S. Zhu, D. Ma, Org.
Lett. 2011, 13, 1602; for a very recent example with acyclic a-
alkylnitroalkenes with a benzoic acid co-catalyst, see: d) L.
Wang, X. Zhang, D. Ma, Tetrahedron 2012, 68, 7675.
[15] The stereochemistry of 9b was confirmed by X-ray analysis.
CCDC 884143 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
À
[9] The C C bond formation step between 3 and 4a was inves-
tigated in previous computational studies, however, intermedi-
ates related to the identified transition states were not discussed,
see: a) C. B. Shinisha, R. B. Sunoj, Org. Biomol. Chem. 2008, 6,
3921; b) J.-Q. Zhao, L.-H. Gan, Eur. J. Org. Chem. 2009, 2661.
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