Inorganic-base-mediated hydroamination of alkenyl oximes for the synthesis of cyclic nitrones

Article abstract of DOI:10.1002/anie.201308617

A method based on hydroamination mediated by inorganic base was developed for the synthesis of cyclic nitrones from alkenyl oximes. DFT calculations of the reaction pathway suggested that this hydroamination could proceed through an unprecedented nucleophilic amination of the unactivated alkene by the oxime nitrogen atom. The transition state of this reaction is stabilized by an ionic interaction between a metal cation such as K⁺ and the oxime oxygen and negatively charged alkene moiety. Basic ring building: A method for the synthesis of cyclic nitrones by using alkenyl oximes was developed based on hydroamination mediated by an inorganic base. DFT calculations for the reaction pathway suggested that this hydroamination could proceed through nucleophilic amination of the unactivated alkene by the oxime nitrogen atom, with the transition state stabilized by ionic interaction with a metal cation such as K⁺. Copyright

Full text of DOI:10.1002/anie.201308617

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Chemie
DOI: 10.1002/anie.201308617
Hydroamination
Inorganic-Base-Mediated Hydroamination of Alkenyl Oximes for the
Synthesis of Cyclic Nitrones**
Xingao Peng, Benny Meng Kiat Tong, Hajime Hirao,* and Shunsuke Chiba*
Abstract: A method based on hydroamination mediated by
inorganic base was developed for the synthesis of cyclic
nitrones from alkenyl oximes. DFT calculations of the reaction
pathway suggested that this hydroamination could proceed
through an unprecedented nucleophilic amination of the
unactivated alkene by the oxime nitrogen atom. The transition
state of this reaction is stabilized by an ionic interaction
between a metal cation such as K+ and the oxime oxygen and
negatively charged alkene moiety.
Retro-Cope hydroamination of alkenyl oximes has also
been studied. This reaction could potentially provide cyclic
À
nitrones through Nsp2 Csp3 bond formation, but the oxime
substrates have been limited mostly to aldoximes for the
formation of 6-membered rings (Scheme 2a).[7–11] Moreover,
H
ydroamination of unsaturated carbon–carbon bonds
(alkenes or alkynes) is one of the most efficient methods to
construct nitrogen-containing heterocyclic scaffolds in an
atom- and step-economical manner.[1] The catalytic hydro-
amination of alkenyl amines has been extensively developed
using various metal catalysts (alkali metals, transition metals,
and f-block elements) as well as Brønsted acids (Scheme 1a).
An analogous type of hydroamination, retro-Cope-type
Scheme 2. Hydroamination with alkenyl oximes.
Scheme 1. Hydroamination of alkenyl amines and alkenyl hydroxyl-
owing to their 1,3-dipole reactivity, the resulting nitrones are
prone to further intermolecular [3+2] cycloaddition with
another molecule of the alkenyl oxime. Given that cyclic
nitrones are versatile synthons for various synthetic trans-
formations[12] and for medicinal and biological applications,[13]
it would be highly desirable to develop an efficient and
controllable hydroamination of alkenyl ketoximes that ena-
bles the selective synthesis of cyclic nitrones. Herein, we
report an operationally simple yet mechanistically distinct
hydroamination of alkenyl oximes in a reaction catalyzed or
mediated by an inorganic base (especially K3PO4), which
allows the facile construction of a variety of cyclic nitrones
(Scheme 2b).
It appears from the previously accumulated knowledge
about retro-Cope hydroamination of alkenyl oximes that the
conversion of g,d-unsaturated ketoximes into the correspond-
ing 5-membered cyclic nitrones is particularly challenging.
Indeed, heating oxime 1a[14] in various solvents at 110–1508C
for 24 h resulted in the recovery of 1a and provided only
amines.
hydroamination (1,3-azaprotio cyclotransfer) of alkenyl
hydroxylamines, is a powerful but mechanistically distinct
alternative that proceeds through a concerted pericyclic
À
À
mechanism whereby C N and C H bonds are formed
concurrently to afford hydroxylamines (Scheme 1b).[2–6]
[*] Dr. X. Peng, B. M. K. Tong, Prof. H. Hirao, Prof. S. Chiba
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637371 (Singapore)
E-mail: shunsuke@ntu.edu.sg
[**] This work was supported by funding from Nanyang Technological
University and the Singapore Ministry of Education (Academic
Research Fund Tier 2: MOE2012-T2-1-014).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308617.
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a very small amount of cyclic nitrone 2a (0–6%; Table 1,
entry 1). By contrast, the treatment of oxime 1a with K3PO4
(10 mol%) in toluene at 1108C brought the reaction to
completion in 12 h, thereby yielding cyclic nitrone 2a in 98%
Table 1: Hydroamination of g,d-unsaturated ketoxime 1a.[a]
Entry Base
[equiv]
Solvent
T
[8C]
t
[h]
Yield of 2a [%][b]
1
none
various
solvents[c]
toluene
o-xylene
PhCl
DMSO
DMF
PhCl
110–150 24
0–6 (58–92)[d]
2
3
4
5
6
7
8
9
K3PO4 (0.1)
K3PO4 (0.1)
K3PO4 (0.1)
K3PO4 (0.1)
K3PO4 (0.1)
K2CO3 (0.1)
KOtBu (0.1)
KOtBu (0.1)
110
120
120
120
120
120
120
60
12
10
4
24
24
24
0.6 96
20
7
98
98
98
59 (29)[d]
12 (72)[d]
21 (77)[d]
PhCl
PhCl
97
10
11
NaOMe (0.1) PhCl
NaH (0.1) PhCl
120
120
67 (30)[d]
88
7
[a] The reactions were carried out using 0.2 mmol of 1a in the solvents
(0.1m). [b] Yield of isolated product. [c] The reactions were examined in
toluene (1108C, no product, 92% recovery of 1a), o-xylene (1508C, 4%
yield of 2a with 70% recovery of 1a), PhCl (1308C, 5% yield of 2a with
78% recovery of 1a), and DMSO (1208C, 6% yield of 2a with 58%
recovery of 1a). [d] Yield of recovered 1a shown in parentheses.
Figure 1. Energy diagrams (in kcalmolÀ1) for the reaction of neutral
oxime 1a (a) and anionic oxime 1a’ (b), as obtained at the B3LYP-
(SCRF)/6-311+G(d,p) level. Zero-point-energy (ZPE) effects are
included. Key bond distances are given in ꢀ in the three-dimensional
models of the transition states.
yield (entry 2). Solvent screening (entries 3–6) revealed that
chlorobenzene was optimal for this transformation (at 1208C
for 4 h, 98% yield; entry 4) and the reactions in polar solvents
such as DMSO and DMF became very sluggish (entries 5 and
6). With K2CO3 as the catalyst, the reaction was less efficient
than with K3PO4 (entry 7). The use of a stronger base, KOtBu,
as the catalyst allowed the reaction temperature to be lowered
to 608C (entries 8 and 9). Other stronger inorganic bases such
as NaH and NaOMe also worked reasonably well (entries 10
and 11).
To obtain detailed information pertaining to the role of
the inorganic base in the formation of cyclic nitrone 2a from
oxime 1a, we performed density functional theory (DFT)
calculations to analyze the energy profiles for the reactions of
oxime 1a in its neutral and anionic forms at the B3LYP-
(SCRF)/6-311 + G(d,p) level (Figure 1), taking into account
the chlorobenzene solvent effect.[15–18] In the cyclization of
neutral oxime 1a (in the absence of the base), the oxime
nitrogen and the hydroxy hydrogen attack the two carbon
atoms of the alkene in a concerted fashion (i.e. through retro-
Cope hydroamination) to yield the five-membered cyclic
nitrone 2a. However, the transition state for this reaction (TS-
1) is highly unstable, and thus the energy barrier is very high
(31.3 kcalmolÀ1; Figure 1a).
ure 1b). Interestingly, in the transition state TS-2, K+ interacts
with the oxime oxygen atom and stays close to the ipso-
carbon atom of the phenyl group. While the ipso-carbon has
a positive charge according to the Mulliken population
analysis (Figure S1 in the Supporting Information), the
adjacent three carbon atoms are negatively charged. The K+
ion thus effectively stabilizes these negative charges that
accumulate as the cyclization reaction progresses. The
resultant carbanion intermediate 2a’ will subsequently
accept a proton from oxime 1a to yield 2a and regenerate
anionic oxime 1a’. Our computational results therefore
suggest an essential role for metal cations such as K+ and
Na+ in this unprecedented stepwise hydroamination reaction.
We next explored the substrate scope of this K3PO4-
mediated hydroamination with regard to the g,d-unsaturated
ketoximes 1 for the synthesis of 5-membered cyclic nitrones 2
(Scheme 3). For the substituent R1, the reactions tolerated the
installation of not only electron-rich and electron-deficient
benzene rings (Scheme 3, 2b and 2c) but also sterically bulky
aryl groups (2d and 2e), as well as a 2-thienyl moiety (2 f).
Alkyl groups (2g and 2h) and a morpholino moiety (2i) could
also be introduced at R1, although the reaction of aldoxime 1j
(R1 = H) afforded nitrone 2j in only 24% yield along with the
corresponding nitrile in 47% yield through the dehydration of
aldoxime 1j. Investigation into the effect of the substituents
attached to the alkene (R2 and R3) revealed that the
By contrast, the energy barrier for the reaction of anionic
oxime 1a’ (with K+) is much lower (15.8 kcalmolÀ1; Fig-
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installed as R2, but the reaction of oxime 1n, which bears
a 2,6-dimethylphenyl group, was very slow. Oxime 1o, which
is a trisubstituted E-alkene with Ph as R2 and Me as R3,
afforded the corresponding nitrone 2o as a 1.2:1 diastereo-
meric mixture, a result that supports a stepwise hydroamina-
tion mechanism involving a carbanion intermediate like 2a’ in
Figure 1b. Hydroamination of the terminal alkene of oxime
1p (R2 and R3 = H) required a higher temperature (1508C)
and a stoichiometric amount of K3PO4 to give nitrone 2p in
54% yield (87% yield based on recovered oxime 1p).[19]
Spirocyclic nitrones were also effectively constructed by
using the K3PO4-mediated hydroamination (2q and 2r).
Besides a-geminal disubstituted oximes, a-monophenyl-sub-
stituted and nonsubstituted oximes 1s and 1t were also
examined. While oxime 1s is a 1:1 syn/anti mixture and oxime
À
1t is the pure syn isomer (the oxime N O bond lies on the
same side as the alkene),[20,21] the stoichiometric use of K3PO4
gave the corresponding nitrones 2s and 2t in 50% and 76%
yields, respectively (the reaction of oxime 1t was conducted in
5 mmol scale). These results suggest that the stereochemistry
À
of the oxime N O bond does not influence the hydroamina-
tion. The K3PO4-mediated hydroamination turned out to be
advantageous even for the formation of nitrones with 6-
membered rings. The cyclization of d,e-unsaturated oxime 1u
proceeded in the presence of 1 equiv of K3PO4 to give 6-
membered cyclic nitrone 2u in 65% yield. In the absence of
K3PO4, the cyclization also occurred through concerted retro-
Cope hydroamination, although the reaction was rather
sluggish (35% yield of 2u with 36% recovery of 1u even
after 37 h heating).
Dialkenyl oxime 1v underwent K3PO4-mediated hydro-
amination to give 5-membered cyclic nitrone 2v, which
subsequently underwent 1,3-dipolar cycloaddition with
another alkene tether to give triheterocyclic system 3v in
83% yield as a single diastereomer (Scheme 4).
Scheme 3. Substrate scope for the synthesis of nitrones 2. [a] Unless
otherwise noted, the reactions were carried out using 0.2 mmol of 1 in
the presence of K3PO4 (10 mol%) in PhCl (0.1m) at 1208C under an
N2 atmosphere. [b] Yields of isolated product are noted. [c] The
reaction time is noted in parantheses. [d] 100 mol% of K3PO4 was
used. [e] The corresponding nitrile was formed in 47% yield through
the dehydration of aldoxime 1j. [f] 40 mol% of K3PO4 was used.
[g] From pure E-alkenyl oxime 1o, nitrone 2o was formed as a 1.2:1
mixture of diastereomers. [h] The reaction was conducted using
100 mol% of K3PO4 at 1508C in o-xylene and oxime 1p was recovered
in 38% yield. [i] 5 mmol of oxime 1t was used.
Scheme 4. A domino sequence of hydroamination–[3+2] cycloaddition.
The further application of this finding to develop other
types of amino functionalization of alkenes with oxime
derivatives, as well as asymmetric variants with chiral bases,
is currently under investigation.
electronic nature of the alkene significantly influences the
hydroamination process. It took a very long time (48 h) for
the reaction of oxime 1k, which bears an electron-rich
methoxyphenyl group on the alkene, to be completed, even
with 40 mol% of K3PO4, whereas the reaction of oxime 1l,
which has an electron-deficient group (trifluoromethyl
phenyl), proceeded very rapidly and was completed within
1 h. Sterically bulky aryl groups (2m and 2n) could be
Received: October 3, 2013
Published online: January 13, 2014
Keywords: density functional calculations · 1,3-dipoles ·
.
hydroamination · nitrones · oximes
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1, 1122; c) C. OꢂMahony, F. Heaney, J. Chem. Soc. Perkin Trans.
1 1998, 341; d) C. OꢂMahony, F. Heaney, Chem. Commun. 1996,
167; e) R. Bishop, P. R. Brooks, S. C. Hawkins, Synthesis 1988,
997.
[1] Selected reviews: a) P. S. Hanley, J. F. Hartwig, Angew. Chem.
2013, 125, 8668; Angew. Chem. Int. Ed. 2013, 52, 8510; b) K. D.
Hesp, M. Stradiotto, ChemCatChem 2010, 2, 1192; c) T. E.
Mꢀlller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem. Rev.
2008, 108, 3795; d) R. Severin, S. Doye, Chem. Soc. Rev. 2007, 36,
1407; e) S. Hong, T. J. Marks, Acc. Chem. Res. 2004, 37, 673; f) J.
Seayad, A. Tillack, C. G. Hartung, M. Beller, Adv. Synth. Catal.
2002, 344, 795; g) T. E. Mꢀller, M. Beller, Chem. Rev. 1998, 98,
675.
[2] Review: N. J. Cooper, D. W. Knight, Tetrahedron 2004, 60, 243.
[3] Recent selected reports on intramolecular retro-Cope hydro-
amination of alkenyl hydroxylamines: a) A. R. Brown, C.
Uyeda, C. A. Brotherton, E. N. Jacobsen, J. Am. Chem. Soc.
2013, 135, 6747; b) E. H. Krenske, E. C. Davison, I. T. Forbesm,
J. A. Warner, A. L. Smith, A. B. Holems, K. N. Houk, J. Am.
Chem. Soc. 2012, 134, 2434; c) M.-E. Lebrun, J. Y. Pfeiffer, A. M.
Beauchemin, Synlett 2009, 1087.
[4] Reports on a catalytic tethering strategy for intermolecular
retro-Cope-type hydroamination by Beauchemin et al.: a) M. J.
MacDonald, C. R. Hesp, D. J. Schipper, M. Pesant, A. M.
Beauchemin, Chem. Eur. J. 2013, 19, 2597; b) N. Guimond,
M. J. MacDonald, V. Lemieux, A. M. Beauchemin, J. Am. Chem.
Soc. 2012, 134, 16571; c) M. J. MacDonald, D. J. Schipper, P. J.
Ng, J. Moran, A. M. Beauchemin, J. Am. Chem. Soc. 2011, 133,
20100.
[5] Reports on intermolecular retro-Cope-type hydroamination of
hydroxylamines with alkenes, allenes, and alkynes: a) S. Zhao, E.
Bilodeau, V. Lemieux, A. M. Beauchemin, Org. Lett. 2012, 14,
5082; b) J. Moran, J. Y. Pfeiffer, S. I. Gorelsky, A. M. Beauche-
min, Org. Lett. 2009, 11, 1895; c) J. Bourgeois, I. Dion, P. H.
Cebrowski, F. Loiseau, A.-C. Bꢁdard, A. M. Beauchemin, J. Am.
Chem. Soc. 2009, 131, 874; d) J. Moran, S. I. Gorelsky, E.
Dimitrijevic, M.-E. Lebrun, A.-C. Bꢁdard, C. Sꢁguin, A. M.
Beauchemin, J. Am. Chem. Soc. 2008, 130, 17893; e) A. M.
Beauchemin, J. Moran, M.-E. Lebrun, C. Sꢁguin, E. Dimitrijevic,
L. Zhang, S. I. Gorelsky, Angew. Chem. 2008, 120, 1432; Angew.
Chem. Int. Ed. 2008, 47, 1410.
[6] Analogous retro-Cope hydroamination with hydrazides and
hydrazines: a) F. Loiseau, C. Clavette, M. Raymond, J.-G.
Roveda, A. Burrell, A. M. Beauchemin, Chem. Commun.
2011, 47, 562; b) J.-G. Roveda, C. Clavette, A. D. Hunt, S. I.
Gorelsky, A. M. Beauchemin, J. Am. Chem. Soc. 2009, 131, 8740;
c) P. H. Cebrowski, J.-G. Roveda, J. Moran, S. I. Gorelsky, A. M.
Beauchemin, Chem. Commun. 2008, 492.
[7] a) R. Grigg, J. Markandu, S. Surendrakumar, M. Thornton-Pett,
W. J. Warnock, Tetrahedron 1992, 48, 10399; b) R. Grigg, J.
Markandu, T. Perrior, S. Surendrakumar, W. J. Warnock, Tetra-
hedron 1992, 48, 6929.
[8] There are several reports on retro-Cope hydroamination of
alkenyl a-carbonyl ketoximes derived from a-keto esters and
amides for the construction of 6-membered heterocycles: a) L.
Doyle, F. Heaney, Tetrahedron 2010, 66, 7041; b) F. Heaney, J.
Fenlon, P. McArdle, D. Cunningham, Org. Biomol. Chem. 2003,
[9] Retro-Cope hydroamination of alkynyl oximes: R. Grigg, T. R.
Perrior, G. J. Sexton, S. Surendrakumar, T. Suzuki, J. Chem. Soc.
Chem. Commun. 1993, 372.
[10] Acid-catalzyed intramolecular hydroamination of alkynyl
oximes for the synthesis of pyridines and pyrazines: T. Rizk,
E. J.-F. Bilodeau, A. M. Beauchemin, Angew. Chem. 2009, 121,
8475; Angew. Chem. Int. Ed. 2009, 48, 8325.
[11] Acid-catalyzed hydroiminiumation of alkenyl imines: a) R.
Jazzar, J. B. Bourg, R. D. Dewhurst, B. Donnadieu, G. Bertrand,
J. Org. Chem. 2007, 72, 3492; b) R. Jazzar, R. D. Dewhurst, J.-B.
Bourg, B. Donnadieu, Y. Canac, G. Bertrand, Angew. Chem.
2007, 119, 2957; Angew. Chem. Int. Ed. 2007, 46, 2899.
[12] Reviews: a) J. Revuelta, S. Cicchi, A. Goti, A. Brandi, Synthesis
2007, 485; b) R. C. F. Jones in Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Towards Heterocycles and
Natural Products (Eds.: A. Padwa, W. H. Pearson), Wiley, New
York, 2002, chap. 1, pp. 1 – 81.
[13] a) R. A. Floyd, R. D. Kopke, C.-H. Choi, S. B. Foster, S. Doblas,
R. A. Towner, Free Radical Biol. Med. 2008, 45, 1361; b) Y. Han,
B. Tuccio, R. Lauricella, F. A. Villamena, J. Org. Chem. 2008, 73,
7108; c) F. A. Villamena, J. L. Zweier, Antioxid. Redox Signaling
2004, 6, 619; d) C. E. Thomas, D. F. Ohlweiler, A. A. Carr, T. R.
Nieduzak, D. A. Hay, G. Adams, R. Vaz, R. C. Bernotas, J. Biol.
Chem. 1996, 271, 3097.
[14] The structures of oximes 1a and 1t as well as nitrones 2e and 2r
were confirmed by X-ray crystallography (see the Supporting
Information).
[15] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648; b) C. Lee, W.
Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785; c) S. H. Vosko, L.
Wilk, M. Nusair, Can. J. Phys. 1980, 58, 1200.
[16] a) R. Krishnan, J. S. Binkley, R. Seeger, J. A. Pople, J. Chem.
Phys. 1980, 72, 650; b) P. C. Hariharan, J. A. Pople, Theor. Chim.
Acta 1973, 28, 213; c) T. Clark, J. Chandrasekhar, G. W.
Spitznagel, P. V. Schleyer, J. Comput. Chem. 1983, 4, 294.
[17] J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev. 2005, 105, 2999.
[18] Gaussian 09, revisionB.01, M. J. Frisch. et al., Gaussian, Inc.:
Wallingford, CT, 2010.
[19] The energy barrier for the reaction of anionic oxime 1p’ (with
K+) was somewhat higher (25.5 kcalmolÀ1) than that for 1a’,
while the energy barrier for the retro-Cope reaction pathway of
neutral oxime 1p (31.1 kcalmolÀ1) was as high as that for 1a
(Figure S2 in the Supporting Information).
[20] Unsymmetrical oximes have two stereoisomers; syn and anti
isomers. Herein, the syn isomer is defined as oximes bearing the
À
N O bond on the same side as the alkenyl moiety and vice versa
for the anti isomer.
[21] Amidoxime 1i was an inseparable mixture of syn/anti isomers
(1:11), while the stereochemistry of each isomer was not
assigned. Except for oximes 1i, 1s and 1t, all the oximes
1 were the anti isomer (see the Supporting Information).
1962
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