The synthesis and structure of chiral enamine N-oxides

Article abstract of DOI:10.1039/c3cc47928e

Chiral enamine N-oxides have been synthesised by a diastereoselective intermolecular reverse-Cope cycloaddition reaction between chiral hydroxylamines and activated acetylenes. Their structures have been investigated by NMR, X-ray crystallography and computational methods.

Full text of DOI:10.1039/c3cc47928e

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
The synthesis and structure of chiral enamine
N-oxides†
Cite this: Chem. Commun., 2014,
50, 7336
I. A. O’Neil,* M. McConville, K. Zhou, C. Brooke, C. M. Robertson and N. G. Berry
Received 15th October 2013,
Accepted 15th May 2014
DOI: 10.1039/c3cc47928e
www.rsc.org/chemcomm
Chiral enamine N-oxides have been synthesised by a diastereoselective
intermolecular reverse-Cope cycloaddition reaction between chiral
hydroxylamines and activated acetylenes. Their structures have been
investigated by NMR, X-ray crystallography and computational methods.
Scheme 1 Hydroxylamine addition to activated acetylene observed by
Winterfelt.
Chiral tertiary amine N-oxides have recently emerged as an
important class of compounds.1 A number of chiral N-oxide
derivatives of proline have been shown to catalyse a wide range
of synthetically useful transformations, giving products with
high e.e.s.2 These N-oxide catalysts are stable and simple to
prepare. Conversely, enamine N-oxides are a rare functional
group and there are only a handful of publications describing
their synthesis. Two methods have been used; the first is the
elimination of HX from a suitably b-functionalised tertiary
amine N-oxide.3 The second method, developed by Woodward
et al. involves the aminolysis of epoxides followed by chlorina-
tion, N-oxidation and dehydrochlorination.4 Enamine N-oxides
Scheme 2 Addition of prolinol-derived hydroxylamines to activated
acetylenes.
have also been isolated as intermediates in the synthesis of by the isomerization of the initially formed enamine N-oxides
indoles.5 The paucity of general methods for the synthesis of this to the corresponding nitrones. These then underwent a 1,3-
fascinating class of compounds means that very little of their dipolar cycloaddition with the activated alkyne. Holmes has
chemistry has been explored, although they are of considerable also utilised the intramolecular reaction of primary hydroxyla-
theoretical interest.6 In common with other tertiary amine mines with alkynes in the synthesis of alkaloids.8b
N-oxides, simple enamine N-oxides are hygroscopic.
Based on our previous work,9 we speculated that by using a chiral
In this communication, we wish to disclose a short and prolinol derived hydroxylamine in this reaction, the reverse-
highly efficient synthesis of chiral enamine N-oxides. Our route Cope cycloaddition10 would occur to give a single diastereoisomeric
was inspired by the observations of Winterfelt et al. who noted enamine N-oxide, where the N-oxide was hydrogen bonded to the side
that dimethylacetylene dicarboxylate underwent an intermole- chain hydroxyl group. This would generate a chiral N-oxide along with
cular reverse-Cope cycloaddition with diethylhydroxylamine to a geometrically defined alkene (Scheme 2). These compounds would
give the unstable enamine N-oxide (1) shown in Scheme 1.7 The be of intrinsic interest since they would be the first example of a chiral
reaction of primary hydroxylamines with activated alkynes has enamine N-oxide, in which the alkene also possessed one or more
also been described by Padwa and Wong.8a The final products electron withdrawing groups. Our initial studies focused on the
from these reactions were isoxazolidinones, which were formed addition of prolinol hydroxylamine to methyl propiolate. Prolinol
hydroxylamine (2) was prepared using our previously described
procedure.11 Mixing equimolar amounts of this hydroxylamine with
Robert Robinson Laboratories, Department of Chemistry, University of Liverpool,
methyl propiolate in CDCl3 resulted in formation of an adduct (3), as
Crown St, Liverpool L69 7ZD, UK. E-mail: ion@liv.ac.uk
judged by 1H-NMR spectroscopy (Scheme 3).
† Electronic supplementary information (ESI) available. CCDC 963296 and
After 1 hour, the spectrum showed a characteristic pair of
doublets centred at 5.50 and 7.60 ppm with a rather low trans
963298. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3cc47928e
7336 | Chem. Commun., 2014, 50, 7336--7339
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Table 1 Stereoselective addition of diphenylprolinol hydroxylamine (4) to
activated acetylenes
Entry
Acetylene
t (h)
Product
Scheme 3 Addition of prolinol hydroxylamine to methyl propiolate.
1
0.25
2
3
0.25
Scheme 4 Addition of diphenylprolinol hydroxylamine to methyl propiolate.
(vide infra) coupling constant of 12.4 Hz. The product had clearly
been formed as a single stereoisomer. Attempts to purify the
crude reaction by chromatography failed. We then examined the
reaction between diphenylprolinol hydroxylamine (4) and methyl
propiolate in CDCl3 at room temperature (Scheme 4).
4
4
5
18
Again, after stirring at room temperature for 12 h an adduct
(5) had formed, with a characteristic pair of doublets centred at
6.23 and 6.58 ppm, with a coupling constant of 16.2 Hz.
Recrystallization of the reaction mixture gave crystals of a
suitable quality for X-ray analysis. The X-ray structure clearly
shows the N-oxide oxygen hydrogen bonded to the hydroxyl
group and a trans geometry for the alkene (Fig. 1). Remarkably,
this compound could be purified by flash chromatography.
We next examined a range of alkynes bearing electron with-
drawing groups in this reverse-Cope cycloaddition reaction.
The results are shown in Table 1. Given the higher stability of
the diphenylprolinol hydroxylamine adducts in our initial
studies, we chose to use this hydroxylamine. In all cases the
product was formed as a single stereoisomer as shown. The
reaction was carried out by simply stirring the two reactants
in CDCl3 at room temperature (Table 1).
18
We found that the reaction did not tolerate alkyl, aryl or silyl
substituents on mono activated alkynes. Hence, methyl but-2-ynoate,
methyl 3-phenylpropiolate and trimethyl(( p-tolylsulfonyl)ethynyl)silane
all failed to react with the diphenylprolinol hydroxylamine.
We have also briefly investigated the use of ephedrine
hydroxylamine in these reactions. Ephedrine (11) was treated
with acrylonitrile to give the N-cyanoethyl adduct (12) in 99%
yield. N-Oxidation with m-CPBA, followed by Cope elimination as
previously described, furnished the desired hydroxylamine (13) in
42% yield as a solid, after flash chromatography (Scheme 5).
Reaction of ephedrine hydroxylamine (13) with three representative
alkynes again gave the corresponding enamine N-oxides in excel-
lent yield, as single diastereoisomers (420 : 1) (Scheme 6).
1H-NMR analysis showed that in all cases the conversion
was essentially quantitative and simply removing the solvent
gave the enamine N-oxide in 490% yield. The adduct formed
with diethyl acetylene dicarboxylate was also crystalline and
X-ray analysis confirmed the structure of the product (Fig. 2).
Entry 4 gives the only example of an alkyne bearing an electron
donating OEt group.
Fig. 2 X-ray crystal structure of the chiral enamine N-oxide (7) from the
addition of diphenylprolinol hydroxylamine (4) to diethyl acetylene
dicarboxylate.
Fig. 1 X-ray crystal structure of the chiral enamine N-oxide (5) from the
addition of diphenylprolinol hydroxylamine (4) to methyl propiolate.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 7336--7339 | 7337

View Article Online
ChemComm
Communication
Scheme 5 Synthesis of ephedrine hydroxylamine (13) from ephedrine.
Fig. 4 Favoured TS for the reaction of ephedrine hydroxylamine and
methyl propiolate (carbon — grey, hydrogen — white, oxygen — red).
Hydrogen bond indicated by dotted line. Distances are stated in Å. Graphic
generated using CylView (http://www.cylview.org/Home.html).
interaction is crucial in the relative stability of the TS relative to
the other five transition states found (Fig. 4). These calculations
thus provide further evidence to the stereochemistry assigned
in Scheme 6.
Scheme 6 Addition of ephedrine hydroxylamine (13) to activated
acetylenes.
In summary, the intermolecular reverse-Cope cycloaddition of
chiral prolinol hydroxylamine derivatives with activated alkynes,
gives stable, chiral, enamine N-oxides in high yield and with very
high selectivity. We are currently investigating the chemistry of
these novel chiral compounds.
We gratefully acknowledge generous financial support from
MRC Technologies and helpful discussions with Dr Dave Tapolczay
and Dr Justin Bryans.
Since none of these compounds were suitable for X-ray analysis,
we have tentatively assigned the stereochemistry as shown, based
on a 1H-NMR study of the ethynyl p-tolylsulfone adduct. This
proposal is confirmed via molecular modelling studies.
Computational studies using density function theory (M06-2x/
6-311++(d,p)) were performed on the reaction between ephedrine
hydroxylamine and methyl propiolate.12–14 In total six transition
states for the reaction were identified corresponding to three
conformations accessible via rotation about the central carbon–
carbon bond in ephedrine and also considering the approach of
the alkyne from the ‘‘top’’ or ‘‘bottom’’ (Fig. 3).
Notes and references
1 I. A. O’Neil, ‘‘Amine N-Oxides,’’ Houben-Weyl, ‘‘The Science of
Synthesis’’, Thieme, Stuttgart, 2008, vol. 40b, pp. 855–891.
2 I. A. O’Neil, C. D. Turner and S. B. Kalindjian, Synlett, 1997, 777;
X. Liu, L. Lin and X. Feng, Acc. Chem. Res., 2011, 44, 574.
3 J. S. Krower and J. P. Richmond, J. Org. Chem., 1978, 43, 2464;
I. A. O’Neil, D. Wynn and J. Y. Q. Lai, Tetrahedron Lett., 2000, 41, 271.
4 D. Bernier, A. J. Blake and S. Woodward, J. Org. Chem., 2008, 73, 4229.
5 J. R. Hwu, H. V. Patel, R. J. Lin and M. O. Gray, J. Org. Chem., 1994,
59, 1577.
6 W. Adam, M. Ahrweiler, K. Paulini, H. Reisig and V. Voerckel, Chem.
Ber., 1992, 125, 2719; E. H. Krenske, E. C. Davison, I. T. Forbes,
J. A. Warner, A. L. Smith, A. B. Holmes and K. N. Houk, J. Am. Chem.
Soc., 2012, 134, 2434.
One of the verified TS was 3.26 kcal molÀ1 lower in energy
than any of the others, and is thus proposed as the most likely
route to the product observed. Examination of this TS revealed
a hydrogen bond between the alcohol moiety and the oxygen
of the hydroxylamine functionality. It is proposed that this
7 E. Winterfelt and W. Krohn, Chem. Ber., 1969, 102, 2336. See also J. R. Hwu,
H. V. Patel, R. J. Lin and M. O. Gray, J. Org. Chem., 1994, 59, 1577.
8 (a) A. Padwa and G. S. K. Wong, J. Org. Chem., 1986, 51, 3125;
(b) E. H. Krenske, E. C. Davis, I. T. Forbes, J. A. Warner, A. L. Smith,
A. B. Holmes and K. N. Houk, J. Am. Chem. Soc., 2012, 134, 2434.
9 I. A. O’Neil, N. D. Miller, J. Peake, J. V. Barkley, C. M. R. Low and
S. B. Kalindjian, Synlett, 1993, 515; I. A. O’Neil, N. D. Miller,
J. V. Barkley, C. M. R. Low and S. B. Kalindjian, Synlett, 1995, 617;
I. A. O’Neil, N. D. Miller, J. V. Barkley, C. M. R. Low and
S. B. Kalindjian, Synlett, 1995, 619.
10 I. A. O’Neil, E. Cleator, J. M. Southern, J. Bickley and D. J. Tapolczay,
Tetrahedron Lett., 2001, 42, 8251.
11 I. A. O’Neil, E. Cleator and D. J. Tapolczay, Tetrahedron Lett., 2001,
42, 8247.
12 All stationary points were fully optimized with Gaussian 09(13)
using M06-2X/6-311++(d,p). An ultrafine grid density was used for
numerical integration in all DFT calculations. Harmonic vibrational
frequencies were computed for all optimized structures to verify that
Fig. 3 Six TS for the reaction of ephedrine hydroxylamine and methyl
propiolate identified computationally (M06-2x/6-311++(d,p)).
7338 | Chem. Commun., 2014, 50, 7336--7339
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
they were either minima or transition states, possessing zero
imaginary frequencies and one imaginary frequency, respectively.
Calculations were performed with M06-2X functional,14 which is
constructed to include nonlocal effects of electronic dispersion
and is found to give good estimates for reaction enthalpies in
bond-forming reactions. A full report of all computed structures
and energies is reported in full in the ESI†.
Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery Jr.,
J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers,
K. N. Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J. Normand,
K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi,
M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross,
V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,
O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski,
R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth,
P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas,
J. B. Foresman, J. V. Ortiz, J. Cioslowski and D. J. Fox, Gaussian 09,
Revision B.01, Gaussian, Inc., Wallingford, CT, 2010.
13 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci,
G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian,
A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada,
M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, 14 Y. Zhao and D. G. Truhlar, Theor. Chem. Acc., 2008, 120, 215.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 7336--7339 | 7339