1,2-oxazine N-oxides as catalyst resting states in michael additions of aldehydes to nitro olefins organocatalyzed by α,α-diphenylprolinol trimethylsilyl ether: Preliminary communication

Article abstract of DOI:10.1002/hlca.201200283

By combining enamines, derived from aldehydes and diphenylprolinol trimethylsilyl ether (the Hayashi catalyst), with nitroethenes ((D ₆)benzene, 4-A molecular sieves, room temperature) intermediates of the corresponding catalytic Michael-addition cycles were formed and characterized (IR, NMR, X-ray analysis; Schemes 3-6 and Fig. 1-3). Besides cyclobutanes 2, 1,2-oxazine N-oxide derivatives 3-6 and 8 have been identified for the first time, some of which are very stable compounds. It may not be a lack of reactivity (between the intermediate enamines and nitro olefins) that leads to failure of the catalytic reactions (Schemes 3-5) but the high stability of catalyst resting states. The central role zwitterions play in these processes is discussed (Schemes 1 and 2). Copyright

Full text of DOI:10.1002/hlca.201200283

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1,2-Oxazine N-Oxides as Catalyst Resting States in Michael Additions of
Aldehydes to Nitro Olefins Organocatalyzed by a,a-Diphenylprolinol
Trimethylsilyl Ether
Preliminary Communication
by Dieter Seebach*, Xiaoyu Sun1), Christof Sparr1), Marc-Olivier Ebert, W. Bernd Schweizer, and
Albert K. Beck
Laboratorium fꢀr Organische Chemie, Departement fꢀr Chemie und Angewandte Biowissenschaften,
ETH-Zꢀrich, Hçnggerberg HCI, Wolfgang-Pauli-Strasse 10, CH-8093 Zꢀrich
(phone: þ 41-44-632-2990; fax: þ 41-44-632-1144, e-mail: seebach@org.chem.ethz.ch)
Dedicated to the memory of Robert I. Ireland, a dear friend and pioneering organic chemist
By combining enamines, derived from aldehydes and diphenylprolinol trimethylsilyl ether (the
Hayashi catalyst), with nitroethenes ((D6)benzene, 4-ꢁ molecular sieves, room temperature) inter-
mediates of the corresponding catalytic Michael-addition cycles were formed and characterized (IR,
NMR, X-ray analysis; Schemes 3 – 6 and Fig. 1 – 3). Besides cyclobutanes 2, 1,2-oxazine N-oxide
derivatives 3 – 6 and 8 have been identified for the first time, some of which are very stable compounds. It
may not be a lack of reactivity (between the intermediate enamines and nitro olefins) that leads to failure
of the catalytic reactions (Schemes 3 – 5) but the high stability of catalyst resting states. The central role
zwitterions play in these processes is discussed (Schemes 1 and 2).
In stoichiometric reactions of aldehyde- and ketone-derived enamines with nitro
olefins under anhydrous conditions, three types of products have been isolated, as long
ago as 48 years: amino-nitro-cyclobutanes A (formally [2 þ 2] cycloadducts), 1,2-
oxazine N-oxides B (formally [4 þ 2] cycloadducts), and ꢂproduct enaminesꢃ C [1]. The
common intermediate precursor of these products is assumed to be a zwitterion D that
is formed reversibly, and that may collapse, likewise reversibly, to the four- and six-
membered ring, or else, undergo a proton shift, as shown in Scheme 1 for an enamine
derived from an aldehyde and a disubstituted nitroethene [1]. In principle, not only the
collapse to a cyclic compound but also the proton shift could occur intramolecularly
within the zwitterion, as indicated in the bottom part of Scheme 1 (cf. the proposal
made in [1c]). As with other ꢂpolarꢃ cycloadditions, the evidence for the involvement of
an intermediary zwitterion is the non-stereospecific formation of the same diaste-
reoisomeric product (mixture), no matter whether starting materials of (E)- or (Z)-
configuration are employed [2]2). This was shown for the Michael addition of
diastereoisomerically pure (E)- and (Z)-morpholinoenamines to uniform (E)- or (Z)-
nitro olefins [1m].
1
)
)
Postdoctoral co-workers 2011/2012.
For this to be the case, the zwitterion involved may have a very short life-time; rotations around
single bonds occur in the order of 10ꢀ11 s.
2
ꢄ 2012 Verlag Helvetica Chimica Acta AG, Zꢀrich

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Scheme 1. Formation of Cyclobutanes A, 1,2-Oxazin N-oxides B, and Product Enamines C from
Enamines and Nitro Olefins under Anhydrous Conditions. The zwitterion D plays a central role in its
equilibration with the reactants, and the products A and B. The formation of the product enamine C
could possibly occur intramolecularly, see D ! aci-C ! C.
Acidic hydrolysis of all three types of (isolable) products A, B, and C has been
shown to lead to g-nitro aldehydes H3), which, for the cyclobutane A and the
heterocycle B, is assumed to, again, occur through the zwitterion intermediate D, by
protonation (! E) and deprotonation (! F), respectively [1]; to draw the zwitterion
out of its equilibria with the reactants and the cyclic compounds, a hydration of the
iminium moiety (!G) may also be considered (Scheme 2)4). In the mechanistic
picture, as outlined in Schemes 1 and 2 the zwitterion plays the central role; the
3
)
The statements made herein about aldehyde-derived enamines are cum grano salis also applicable
to ketone-derived enamines.
4
)
Although the relative and absolute configurations of the product g-nitro aldehydes are not
discussed herein, it is interesting to note that the configuration of the stereogenic center (bearing
NO2 and R2) results by a protonation step (cf. [3][4]) in all three routes from D to H, the
configuration in the b-position to the aldehyde group (bearing R1) is determined in the C,C-bond-
forming step, again in all three routes, and the configuration in the a-position to the aldehyde group
(bearing R3) is created in the C,C-bond-forming step en route D ! E ! H and D ! G ! H, and by
diastereoselective protonation en route D ! F ! H, and, of course, also when the product enamine
C is hydrolyzed (C ! H).

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Scheme 2. Trapping the Zwitterion D (from an aldehyde-derived enamine and a nitro olefin) to Form g-
Nitroaldehydes H in the Presence of H2O (and acid) through Intermediates E – G
product-forming bimolecular reactions D ! E, F, G compete with the unimolecular
dissociation (back to enamine and nitro olefin) and with the intramolecular conversions
to the cyclic (A, B) and the open-chain (C) isomers of the short-lived zwitterion5).
In Michael additions of aldehydes to nitro olefins catalyzed by diphenylprolinol
trimethylsilyl ether (the Hayashi catalyst 1 [5]), a,b-disubstituted g-nitro aldehydes are
formed with exceptionally high stereoselectivities, but the rate of conversion drops
dramatically with increasing size and number of substituents on the nitro olefin
component and in the a-position of the aldehyde used6): thus, propanal and 3-
methylbutanal do not react with 3,3-dimethyl-1-nitrobut-1-ene under catalytic con-
ditions; on the other hand, the preformed enamine shown in Scheme 3 forms the
cyclobutyl derivative 2 with this tBu-substituted nitro olefin under anhydrous
conditions, as we have already shown in our previous paper7). We have now isolated
2 and obtained an X-ray crystal structure depicted in Scheme 38). Thus, in this case the
failure of the catalytic reaction is not due to lack of reactivity between the
5
)
For the hydrolysis of the oxazine derivatives B under acidic conditions routes not involving the
zwitterion have to be considered: a) protonation at an O-atom, followed by ring opening, would
lead directly to the nitronic acid/iminium ion, the aci-nitro form of the nitro derivative E; b) a Nef
reaction could eventually lead to a dialdehyde (R2 ¼ H) or an oxo aldehyde (R2=H).
This is surprising considering that the stoichiometric reactions of enamines with nitro olefins under
aprotic conditions are exothermic (ꢂreact vigorouslyꢃ [1a] and are often carried out below 08 [1b], or
at ꢀ 758 with slow warming [1m]), even with highly substituted reactants.
6
)
7
8
)
)
See Tables 3 and 4, and Fig. 3 in [1s].
The crystallographic data for compounds 2, 3, and 6 (Schemes 3 – 5) have been deposited with the
Cambridge Crystallographic Data Centre (CCDC Nos. 883666 – 883668, resp.). These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.

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Scheme 3. Reaction between Aldehydes and ꢀ2-(tert-Butyl)-1-nitroetheneꢁ (¼ 3,3-dimethyl-1-nitrobut-1-
ene) Does not Take Place under the Standard Conditions of Catalysis with the sec-Amine 1 [1s]; the
ꢀIntermediateꢁ (cf. Schemes 1 and 2) Cyclobutanes Are Too Stable and Become Catalyst Traps (MS ¼
molecular sieves). Crystal structure of cyclobutane 28): orthorhombic space group P212121, all-trans
configuration; the virtual lone-pair lobe at the amino N-atom is antiperiplanar to the ꢂpolarꢃ CꢀC(NO2)
bond (nN ! sC*,C interaction), an arrangement, from which cyclobutane ring opening with formation of
the corresponding zwitterion is expected to occur (cf. B in Scheme 3 of [1s]); N and O on the exocyclic
bond of the pyrrolidine ring are antiperiplanar.
corresponding enamine and the nitro olefin, but it is rather caused by the fact that a
cyclobutane is formed that is too stable to undergo ring opening back to the zwitterion,
to be hydrolyzed according to Scheme 2, with the recovery of the amine catalyst. In the
cyclobutane 2, the catalyst ꢂrests foreverꢃ as a substituent.
In our search for reasons of lacking reactivity in Michael additions of aldehydes to
nitro olefins with the Hayashi catalyst 1, we have also studied (E)-2-nitro-1-phenyl-
prop-1-ene, an a,b-disubstituted nitro olefin, which is assumed to show poor reactivity
for steric reasons9), and we deliberately first chose the reaction with isovaleraldehyde
i
(¼ 3-methylbutanal), providing an enamine intermediate with an Pr group in b-
9
)
For a thorough discussion, entitled ꢂAdapting to Substrate Challenges: Peptides as Catalysts for
Conjugated Addition Reactions of Aldehydes to a,b-Disubstituted Nitroolefinsꢃ, with an extensive list
of references, see [4].

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position (Scheme 4). Indeed, there was no catalytic reaction under the standard
conditions. When, however, a solution of the enamine in C6D6 (cf. Scheme 3) was
Scheme 4. Reactions of Isovaleraldehyde (¼ 3-Methylbutanal) and Its 1-Derived Enamine with
Disubstituted Nitro Olefins. There is no catalytic reaction with (E)-2-nitro-1-phenylprop-1-ene, but the
enamine yields the 1,2-oxazine N-oxide 3 (see crystal structure with ap-conformation of the exocyclic
bond on the pyrrolidine ring; monoclinic space group P21, only dominant conformation (75%) of the
disordered Me3Si group shown)8). The 1,2-oxazine N-oxide 3 and the starting materials are in
equilibrium (see the T-dependent ratio). Six-membered-ring heterocycles 4 and 5 have also been isolated
or identified, respectively. The zwitterion D-1, which supposedly is involved in the formation and
dissociation of 3, is also shown.

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treated with the nitro olefin in the presence of 4-ꢁ molecular sieves, instantaneous
formation of the 1,2-oxazine N-oxide 3 was evidenced by NMR analysis. A temperature-
dependent heterocycle/starting materials ratio was established (by NMR integration of
appropriate enamine and oxazine signals). The [4 þ 2] cycloadduct 3 is very sensitive to
moisture. Still, we were able to prepare single crystals for X-ray structure analysis
(Scheme 4) of the major diastereoisomer. In view of the mechanistic scenario, as
outlined in Schemes 1 and 2, we have to conclude that, in this case, the reaction of the
corresponding zwitterion D-1 (Scheme 4), with formation of products of type E – G (or
with proton transfer to a nitro enamine C), is too slow under the catalytic conditions,
i.e., its collapse to the heterocycle 3, and its dissociation back to enamine and nitro
olefin are much faster. The oxazine derivative 4 (from (E)-4-methyl-2-nitropent-2-ene)
was also isolated; it is stable enough to be purified by preparative TLC. Finally, 1-
nitrocyclohexene gave the bicyclic nitronate 5 in a slow reaction; in this case, the
analogous catalytic reaction has been shown to take place (20 mol-% 1, 10 mol-% m-
nitrobenzoic acid, 54 h, r.t., in CH2Cl2) [6]10).
We also looked at the reaction of the most simple aldehyde propanal and its Me-
substituted enamine with the a,b-disubstituted nitro olefin (Scheme 5). The catalytic
Scheme 5. Reactions of Propanal and Its 1-Derived Enamine with (E)-2-Nitro-1-phenylprop-1-ene, and
Crystal Structure of the Product 1,2-Oxazine N-Oxide 6 (monoclinic space group P21)8). Unlike the
situation in the structure of 3 (Scheme 4), in the crystal structure of 6 the exocyclic bond of the
pyrrolidine has a synclinal-exo conformation. As in the structure of 3 (Scheme 4), the virtual lone-pair
lobe on the pyrrolidine N-atom is antiperiplanar to the neighboring ꢂpolarꢃ CꢀO bond (see the N
pyramidalization), establishing a stereoelectronic (nN ! sC*,O) stabilization; this is also the arrangement
from which ring opening with formation of the corresponding zwitterion is expected to occur.
10
)
Besides the crystal structure of 3 and 6, and the NMR analyses, the characteristic nitronate ester IR
band at ca. 1615 cmꢀ1 of the products 3 – 6 is a further piece of evidence for their identity.

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reaction again failed completely, but when the nitro olefin was added to a solution (in
C6D6 over 4-ꢁ molecular sieves) of the enamine in an NMR tube, the 1,2-oxazine N-
oxide 6 had formed more or less quantitatively, before we arrived at the NMR
spectrometer to record the spectrum. The oxazine derivative 6 with Me2 and Ph
substituents is much more stable than the Me-, Ph-, and iPr-substituted one, i.e., 3 (c.f.
Scheme 4), and crystals suitable for X-ray analysis were readily obtained (see the
structure in Scheme 5). When a solution of compound 6 in C6D6 (over 4-ꢁ molecular
sieves) was heated to 508 there was no sign of dissociation to enamine and nitro olefin,
i
while 3, with the more bulky Pr substituent, is in equilibrium with its precursors at
room temperature (Scheme 4). Thus, the failure of the Hayashi catalyst 1 in the case
shown in Scheme 5 is not caused by missing reactivity between the intermediate
enamine and the nitro olefin but by the chemical property of the corresponding oxazine
derivative 6, which provides an irreversible trap for the amine catalyst, just like the
cyclobutane 2 discussed above (cf. Schemes 2 and 5).
With the characteristic NMR data available for both, the cyclobutanes [1s] and the
1,2-oxazine N-oxides derived from aldehyde enamines and nitro olefins, we revisited the
spectra obtained in our original work [1s] on cyclobutane formation in the Michael
additions with catalyst 1, to look for minor, hitherto not assigned peaks. Of particular
interest was the combination of the simplest reactants, propanal and nitrostyrene, the
prototype case also studied by Blackmond and co-workers [1q][1r]. When mixing the
enamine and the nitro olefin in a 1:1 ratio (NMR tube, C6D6, 4-ꢁ molecular sieves, r.t.),
the reactants disappeared immediately, and the signals from the cyclobutane 7 appeared,
as assigned previously [1q][1s] (Fig. 1,c). Besides the cyclobutane (cf. Fig. 1,b),
however, another compound was formed, giving rise to NMR signals matching, in shift
and multiplicity, those of the oxazine derivativesꢃ H1-, H2-, H3-, and H5-atoms (Fig. 1,a, c,
and d); furthermore, a low-field signal (d 5.9 ppm) was detected, which is characteristic
for the H-atom next to the N-atom in 1,2-oxazine N-oxides that are unsubstituted at C(3)
[7][8] (i.e., H4 in Fig. 1,d)11). Since some NMR peaks from the two compounds
overlapped (see, e.g., those of H2-atoms near 1.9 ppm), we recorded a 2D-COSY
spectrum for safer peak assignment to overcome this problem. As is evident from Fig. 2,
there are cross-peaks A, B, and C between H1 and H2, H2 and H3, and H3 and H4,
respectively, of the new species, as expected for the 1,2-oxazine N-oxide 8. Thus, in this
case a mixture (ca. 4 :1) of the four- and of the six-membered rings, 7 and 8, respectively,
is formed (see Scheme 6). When the solution was kept at r.t. for 15 h, the cyclic
compounds completely disappeared12), and the product enamine 9 was formed
quantitatively (10 :1 mixture of diastereoisomers (NMR analysis); see Fig. 1,e, and
bottom part of Scheme 6). To see, whether the four- and six-membered-ring compounds
11
)
)
In CD2Cl2, the chemical-shift range of HꢀC(3) and C(3) in 1H- and 13C-NMR spectra of 1,2-oxazine
derivatives of this kind are 6.3 – 6.4 ppm and 113 – 117 ppm, respectively [7]; the 13C signal of C(3) in
8 is observed at d 112 ppm.
The ratio 7/8 remained constant over this period of time. For one of several possible mechanisms of
this conversion, see Scheme 1: A, B ! D ! aci-C. After mixing the enamine with nitrostyrene in
K2CO3-dried CD2Cl2 and immediately recording an NMR spectrum, we detected only signals
corresponding to the product enamine 9 (no sign of starting material, or of four- or six-membered
ring was detected in this solvent!). Note that successful catalytic additions of aldehydes to
nitrocyclohexene by Gelman and co-workers were carried out in CH2Cl2 [6].
12

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Fig. 2. Absolute-value COSY spectrum of the mixture of the [2 þ 2] and the [4 þ 2]cycloadducts 7 and 8.
Peak designation as in Fig. 1. The cross-peaks A, B, and C, marked in red, clearly show that there are four
consecutive H-atoms, H1, H2, H3, and H4, in the six-membered ring just like in the cyclobutane. The
spectrum was recorded immediately after mixing the enamine solution with nitrostyrene, and the
recording was completed within 20 min.
equilibrate with each other, we also recorded an EXSY spectrum of a (D6)benzene
solution containing 7 and 8 (Fig. 3), which provided unambiguous evidence for exchange
between these two species. In accordance with the general mechanistic picture outlined
in Scheme 1, we would suggest that this equilibrium, as well as the conversion to the
product enamine 9, take place through the intermediate zwitterion of type D.
At this point, we have to refer to a recent paper by Blackmond and co-workers [1r],
in which the compound identified as 1,2-oxazene N-oxide 8 by us was assigned13) as
being nitronate anion 10, equilibrating with the cyclobutane 7 by protonation/
deprotonation (Scheme 7). The authors realized that a direct, elimination-type
cyclobutane ring opening, as depicted in J, is unfavorable and make the statement:
13
)
... using a 2D-NOSY spectrum, identical to that shown in Fig. 3 (proof of equilibration).

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1075

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Fig. 3. EXSY Spectrum of the mixture 7/8 (C6D6, r.t., mixing time 500 ms). Immediately after mixing the
reactants, the spectrum was recorded which took 1 h to be completed. Peak numbering and colors refer
to the H-atoms in positions as shown in the formulae, see also Figs. 1 and 2. For an identical spectrum, see
[1r]. The spectrum establishes equilibration between 7 and 8.
... ꢂa step that may represent sequences of elementary reactions combined into one
kinetically meaningful stepꢃ ([1r] and Footnote 14 therein). Apart from the incorrect
structural assignment, we consider this proposal unlikely from a purely intuitive
chemical point of view, since it claims the occurrence and observation by NMR of a free
nitronate anion under strictly anhydrous conditions in toluene solution (the counterion
would have to be H-1þ)14), and it suggests an energetically uphill conversion of an
open-chain enamino-nitronate to a cyclobutane upon protonation.
This acid H-1þ is proposed to eventually protonate the nitronate anion moiety of 10 to produce –
irreversibly – the product enamine 9 [1r]. On the other hand, this acid H-1þ would also have to
protonate the enamine moiety of 10 to generate the cyclobutane in the proposed equilibrium. With
14
)
pKaH O values of protonated pyrrolidine of 11.3, and of nitroethane of 8.6 (CH2) and ca. 4.5 (aci-nitro
2
form), pyrrolidine should actually deprotonate the nitro compound in H2O. There is no NMR
evidence for such a deprotonation of enamino-nitro compound 9 in C6D6 (see Scheme 7).

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Scheme 7. Proposed Equilibrium between the Cyclobutane 7 and an Enamino-nitronate 10 [1r]. The
structure of the anion 10 was deduced from the same NMR data, which allowed us to assign the oxazine
structure 8 to the species equilibrating with 7. Unfavorable direct ring opening, J, of the cyclobutane.
When the solution of 9 was treated (by us) with 1, no nitronate was generated (no change of the NMR
spectrum within 10 h), see also Footnote 13.
The rather far-reaching conclusions drawn in [1r], concerning the catalytic cycle of
amine-catalyzed Michael additions of aldehydes to nitro olefins, require revision.
Full experimental details of our investigations, together with more examples of
isolation and indentification of intermediates in this type of reactions, will be presented
in a forthcoming full paper [9].
We are grateful to Prof. D. Blackmond for pointing out to D. S. that there was an error in the
discussion of the kinetics of the various reactions of zwitterion D in our original manuscript (corrected at
the galley-proof stage).
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