Single-Step Modular Synthesis of Unsaturated Morpholine N-Oxides and Their Cycloaddition Reactions

Article abstract of DOI:10.1002/anie.201611791

A single-flask procedure for the generation of α-keto-N-alkenylnitrones through a Chan–Lam coupling and subsequent spontaneous 6π electrocyclization of these intermediates for the synthesis of 2H-1,4-oxazine N-oxides has been developed for a variety of α-ketooximes and alkenylboronic acids. This transformation provides a new approach to C-substituted unsaturated morpholine derivatives that are poised to undergo further functionalization for the preparation of a diverse array of novel heterocyclic structures. The scope of the new method for the synthesis of 2H-1,4-oxazine N-oxides is discussed, in addition to initial studies describing the cycloaddition reactivity of these new heterocyclic intermediates.

Full text of DOI:10.1002/anie.201611791

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International Edition: DOI: 10.1002/anie.201611791
German Edition: DOI: 10.1002/ange.201611791
Electrocyclization
Single-Step Modular Synthesis of Unsaturated Morpholine N-Oxides
and Their Cycloaddition Reactions
Jongwoo Son, Ki Hwan Kim, Dong-Liang Mo, Donald J. Wink, and Laura L. Anderson*
Abstract: A single-flask procedure for the generation of
a-keto-N-alkenylnitrones through a Chan–Lam coupling and
subsequent spontaneous 6p electrocyclization of these inter-
mediates for the synthesis of 2H-1,4-oxazine N-oxides has been
developed for a variety of a-ketooximes and alkenylboronic
acids. This transformation provides a new approach to
C-substituted unsaturated morpholine derivatives that are
poised to undergo further functionalization for the preparation
of a diverse array of novel heterocyclic structures. The scope of
the new method for the synthesis of 2H-1,4-oxazine N-oxides is
discussed, in addition to initial studies describing the cyclo-
addition reactivity of these new heterocyclic intermediates.
T
he prevalence of N-heterocyclic scaffolds in molecules that
exhibit important biological and electronic activity has
spurred the development of methods that provide access to
novel N-heterocyclic architectures.[1] In particular, substituted
morpholines are common motifs in biologically active mol-
ecules and are often prepared by displacement or addition
reactions involving 1,2-amino alcohols (Scheme 1A).[2,3]
While a variety of elegant and efficient synthetic routes to
substituted morpholines have been implemented using these
strategies, these approaches are usually limited to the
installation of functional groups and stereochemical informa-
tion prior to or during oxazine ring formation.[4] We wondered
if the electrocyclization of a-keto-N-alkenylnitrones might
provide a new route to novel dehydrogenated morpholines,
which could be easily functionalized for divergent synthetic
applications.
Scheme 1. Electrocyclization of N-alkenylnitrones for the synthesis of
2H-1,4-oxazine N-oxides. Cbz=benzyloxycarbonyl, PG=protecting
group, Tf=trifluoromethanesulfonyl, Ts=para-toluenesulfonyl.
oxime 1 or 2 with alkenylboronic acid 3—the unsaturation
pattern embedded in the resulting novel heterocyclic scaffolds
6 and 7 could be exploited to access a broad and diverse range
of substituted morpholines (Scheme 1C). While many new
methods focus on finding better routes to known heterocycles,
we have discovered that 2H-1,4-oxazine N-oxides 6 and 7 can
be prepared by this approach. To the best of our knowledge,
these types of unsaturated morpholine N-oxides have not
been previously reported and are poised to undergo further
synthetic manipulation.[7] Herein, we report the scope of this
transformation for the synthesis of 2H-1,4-oxazine N-oxides 6
and 7, as well as the facile conversion of these densely
functionalized motifs into more complicated heterocyclic
structures.
Recently, our group has shown that N-alkenylnitrones can
be accessed by Chan–Lam couplings of oximes and alkenyl-
boronic acids and that these compounds undergo a variety of
novel rearrangements, as well as addition and rearrangement
reactions.[5] In related studies, Nakamura and co-workers
have investigated the electrocyclization of N-allenylnitrones,
accessed through a 2,3-rearrangement from O-propargylox-
imes, to give substituted pyridines (Scheme 1B).[6] The
inherent stability of pyridines makes them resistant to further
functionalization; however, we anticipated that if a related
electrocyclization could be triggered with a-keto-N-alkenyl-
nitrones 4 and 5—generated in situ through the coupling of
Our initial investigation of the synthesis of a-keto-N-
alkenylnitrones 4 began by testing the reactivity of oxime 1a
and boronic acid 3a under a variety of Chan–Lam coupling
conditions. As shown in Table 1, entry 1, we were delighted to
discover that when 1a and 3a were mixed in the presence of
Cu(OAc)2 in 1,2-dichloroethane (DCE) for 2 h, oxazine
N-oxide 6a was isolated in 79% yield. This preliminary
result suggested that the 6p electrocyclization of N-alkenyl-
[*] J. Son, K. H. Kim, Dr. D.-L. Mo, Dr. D. J. Wink, Prof. L. L. Anderson
Department of Chemistry
University of Illinois at Chicago
845 W. Taylor St., Chicago, IL (USA)
E-mail: lauralin@uic.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201611791.
À
nitrone (E)-4a can spontaneously occur after an initial C N
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Table 1: Optimization of the synthesis of 2H-1,4-oxazine N-oxide 6a
from a-ketooxime 1a and alkenylboronic acid 3a.
Entry
Catalyst
Base
Solvent
6a [%][a]
1
2
3
4
5
6
7
8
9
10
Cu(OAc)2 (1 equiv)
CuO (1 equiv)
CuBr2 (1 equiv)
Cu(OAc)2 (1 equiv)
Cu(OAc)2 (1 equiv)
Cu(OAc)2 (1 equiv)
Cu(OAc)2 (1 equiv)
Cu(OAc)2 (1 equiv)
Cu(OAc)2 (1 equiv)
Cu(OAc)2 (10 mol%)
Py
Py
Py
NEt3
DABCO
K2CO3
Py
Py
Py
DCE
DCE
DCE
DCE
DCE
DCE
toluene
THF
79
45
6
26
46
48
61
51
43
47
EtOH
DCE
Py
[a] Reaction conditions: 1a (1 equiv), 3a (5 equiv), base (3 equiv),
Na2SO4 (6.6 equiv), 0.1m in solvent, 258C. DABCO=1,4-diazabicyclo-
[2.2.2]octane, DCE=1,2-dichloroethane, py=pyridine.
bond-forming event. Surprisingly, Cu(OAc)2 was uniquely
well-suited to this reaction. A variety of other CuI and CuII
salts were tested but none exhibited significant conversion of
1a into 6a (entries 1–3), and none provided the proposed
N-alkenylnitrone intermediate (E)-4a. The single-flask syn-
thesis of 6a from 1a and 3a was also dependent on the choice
of base, and replacement of pyridine with NEt3, DABCO, or
K2CO3 led to attenuated yields (entries 4–6). The trans-
formation was tolerant of a variety of different solvents but
optimal results were achieved in DCE (entries 1 and 7–9).
Decreasing the copper loading of the reaction mixture to
10 mol% also provided the desired product, albeit in
moderate yield (entry 10). The data described in Table 1
indicated that the conditions in entry 1 were most appropriate
to further explore the scope of the synthesis of 6 from 1 and 3
through this single-flask coupling and electrocyclization
process.
The scope of the synthesis of unsaturated oxazine
N-oxides 6 was initially investigated by varying the substitu-
ents on the oxime. As shown in Scheme 2, aldoximes with aryl
ketone substituents with alkyl, ether, thioether, or halogen
groups at the 4-position of the arene were well-tolerated and
gave 6a–6e in good yield. Oximes with electron-poor aryl
ketone substituents gave products such as 6 f in attenuated
yield. In addition to para-substituted aryl ketones, a furanyl
ketone was also tolerated in this transformation to give 6g,
and a sterically hindered mesityl ketone was smoothly
converted into 6h. Aldoximes with alkyl ketone substituents
were tested but a competing elimination reaction was favored
over the formation of the corresponding oxazine.[8] In
addition to a-ketoaldoximes, cyano-substituted oximes 2
were also treated with Cu(OAc)2 and 3a and shown to form
oxazine N-oxides 7. Cyano-substituted oximes with aryl
ketone substituents generally gave higher yields than their
aldoxime analogues for the synthesis of oxazine N-oxides
such as 7a–7c. The conversion of 2 into 7 also tolerated
thiophenyl-substituted ketones to give 7e and tetrahydro-
Scheme 2. Oxime scope of the oxazine N-oxide synthesis.
naphthalene substituents to give 7 f. Consistent with 6 f,
cyano-substituted oximes with electron-deficient aryl ketone
substituents gave attenuated yields for the preparation of
oxazine N-oxides such as 7g. In contrast to aldoximes 1,
pivaloyl-substituted 2h was tested and smoothly converted
into oxazine 7h. The structures of 6c and 7c were confirmed
by X-ray crystallography.[9] The synthesis of 6c was also
performed on 1 g scale, and purification by crystallization
gave the desired product in 66% yield.[10] The results shown in
Scheme 2 indicate that the Chan–Lam coupling and electro-
cyclization process to convert mixtures of oximes and
alkenylboronic acids into 1,4-oxazine N-oxides is general for
a variety of a-ketooximes and provides a reliable method to
access unsaturated morpholines 6 and 7.
After investigating the tolerance of the unsaturated
morpholine N-oxide synthesis with respect to the oxime, we
decided to look at the scope of the alkenylboronic acid
reaction partner. As shown in Scheme 3, a variety of electron-
rich and electron-poor aryl groups were tolerated at the
R1 position of alkenylboronic acid 3 for the synthesis of 6 and
7.[11] The alkyl group at the R2 position could also be tethered
to the R1 position (see 6n and 7n). The same alkenylboronic
acids were equally effective with both aldoxime 1c and cyano-
À
substituted oxime 2c. Surprisingly, the C N bond coupling
and electrocyclization process seemed to require the combi-
nation of an aryl group at the R1 position and an alkyl group
at the R2 position. Alterative reaction conditions were
explored to expand the scope of 3 for the synthesis of oxazine
N-oxides.
The scope of the oxime and alkenylboronic acid coupling
and electrocyclization reaction can be expanded to include
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treated with alkenylboronic acid 3a under the optimized
reaction conditions, alkenylnitrone 11b was isolated after 2 h
(Scheme 5). Surprisingly, 11b was formed as the E isomer and
Scheme 5. Isolation of an N-alkenylnitrone.
resisted further conversion when resubjected to the reaction
conditions. In contrast, when the reaction mixture used to
form 11b was stirred for 18 h, oxazine 10b was isolated in
75% yield (Scheme 4B). Further screening showed that when
11b was treated with an excess of Cu(OAc) and Cu(OAc)2,
10b was formed in 31% yield.[13] These data provide support
for the intermediacy of N-alkenylnitrones in the conversion of
oximes 1, 2, and 9 into oxazine N-oxides 6 and 7 and oxazine
10, respectively, but also suggest that rapid electrocyclization
is needed to trap the active N-alkenylnitrone isomer prior to
isomerization to the more stable isomer and that stabilization
of the active isomer may require copper coordination to
promote oxazine synthesis.[6,14]
To the best of our knowledge, 2H-1,4-oxazine N-oxides 6
and 7 have not previously been reported, and discussions of
oxazines similar to 10 are rare and limited to their use as
latent azadienes.[7c,d] Due to the demand for new heterocycles
for medicinal and material applications, we decided to
explore the reactivity of 6 and 7 to determine how they
might be applied in the preparation of new structurally
diverse libraries. We decided to focus our study on the
reactivity of 6 and 7 in [3+2] and [4+2] cycloaddition
reactions (Scheme 6). When oxazines 6c and 7c were treated
with N-phenylmaleimide in the presence of a Lewis acid
catalyst, the dipolar cycloaddition products 12 and 13 were
isolated in good yields with excellent diastereoselectivity.
Similarly, 7c underwent a [3+2] cycloaddition with a benzyne
intermediate to form the fused oxazine-benzoxazolidine 14.
Scheme 3. Alkenylboronic acid scope of the oxazine N-oxide synthesis.
alkyl-substituted alkenylboronic acids such as 3h by changing
the reaction solvent. As shown in Scheme 4A, when methanol
was used as the reaction medium, 2-butenylboronic acid 3h
and oxime 2c were converted into oxazine 8a. This trans-
formation occurs with a concomitant deoxygenation in
contrast to formation of the predicted oxazine N-oxide.
À
The N O bond of 14 can be cleaved under hydrogenation
Scheme 4. Oxazine synthesis through coupling, electrocyclization, and
conditions to give phenol-substituted morpholine 15. Dime-
thylacetylene dicarboxylate also functioned as a dipolarophile
when mixed with 7b; however, the initial dipolar cyclo-
addition product rearranged to give furan-fused morpholine
16 under the reaction conditions. The structure of 16 was
confirmed by X-ray crystallography.[9] Deoxygenation and
elimination of 6c was achieved by activation with AcCl to
give 17, and mild hydrogenation conditions allowed for the
deoxygenation of 6c and 7c to give oxazines 18 and 19,
respectively. The transformations shown in Scheme 6 illus-
trate the versatility of 6 and 7 as precursors to novel
heterocyclic compounds through both predictable and sur-
prising pathways.
deoxygenation.
Further investigation of the scope of the oxime substrate
showed that a similar Chan–Lam coupling, electrocyclization,
and deoxygenation sequence was observed for ester-substi-
tuted oximes such as 9 (Scheme 4B).[7] The use of copper
catalysts and reagents for nitrone and pyridine N-oxide
deoxygenation reactions has previously been reported.[12]
Selective formation of oxazines 8 and 10 over oxazine
N-oxides 6 and 7 appears to be a consequence of extended
reaction times, and when cyano-substituted oxime 2g was
treated with 3a for 4 h, the analogous oxazine product was
isolated in contrast to the synthesis of 7g described in
Scheme 2.
In addition to examining the dipolar cycloaddition
reactivity of 6 and 7, we were also interested in investigating
the [4+2] cycloaddition reactivity of 2H-1,4-oxazine N-oxides.
Whereas 6 and 7 were resistant to [4+2] cycloadditions with
both electron-rich and electron-poor dienophiles, oxazines 18
Reaction monitoring was used to detect the proposed
N-alkenylnitrone intermediates prior to electrocyclization
and oxazine formation. When b-ketoester oxime 9b was
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6 and 7 has facilitated access to these unsaturated morpholine
N-oxide intermediates, and further investigations of this
method and the derivatization of these products are currently
ongoing in our laboratory to address the demand for new
heterocyclic structures for medicinal and material applica-
tions.
Acknowledgements
We are grateful to the National Science Foundation for
generous financial support (NSF-CHE 1212895 and 1464115).
We thank Furong Sun (UIUC) for high-resolution mass
spectrometry data.
Conflict of interest
The authors declare no conflict of interest.
Keywords: Chan–Lam coupling · electrocyclization ·
morpholines · nitrones · oxazine N-oxides
Scheme 6. Functionalization of 2H-1,4-oxazine N-oxides.
and 19 were reactive towards N-phenylmaleimide. As shown
in Scheme 7, when 18 was treated with N-phenylmaleimide,
the bicyclic [4+2] cycloaddition product 20 was isolated in
good yield and excellent diastereoselectivity. Oxazine 19
similarly underwent a [4+2] cycloaddition with the same
dienophile but the initial cycloaddition product rearranged to
the corresponding pyridine 21 under the reaction conditions.
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Scheme 7. Cycloaddition of 2H-1,4-oxazines.
These transformations are in contrast to the reactivity
reported for similar oxazines generated from 2H-azirines
and diazoesters, which favor ring opening and rearrange-
ment.[7c,d] The preparation of cycloaddition products 20 and 21
also further supports the unique utility of oxazines such as 6–8
and 10 for the diversity-oriented synthesis of new heterocyclic
structures.
In summary, we have discovered that a-keto-N-alkenylni-
trones can be generated from a-ketooximes through a Chan–
Lam coupling and spontaneously undergo a 6p electrocycliza-
tion to give 2H-1,4-oxazine N-oxides 6 and 7 in a single step.
The scope of this method has been shown to include a variety
of aldoximes and cyano-substituted oximes in combination
with alkenylboronic acids. Initial functionalization studies
have shown that 6 and 7 can be used as intermediates for
rapidly accessing complicated heterocyclic structures such as
12–21. The development of a single-step modular synthesis of
[4] For examples of intramolecular hydroamination followed by
asymmetric reduction, see Refs. [3j] and [3k].
[5] a) D.-L. Mo, D. A. Wink, L. L. Anderson, Org. Lett. 2012, 14,
5180; b) D.-L. Mo, L. L. Anderson, Angew. Chem. Int. Ed. 2013,
52, 6722; Angew. Chem. 2013, 125, 6854; c) D.-L. Mo, W. H.
Pecak, M. Zhao, D. J. Wink, L. L. Anderson, Org. Lett. 2014, 16,
3696; d) D.-L. Mo, D. J. Wink, L. L. Anderson, Chem. Eur. J.
2014, 20, 13217; e) W. H. Pace, D.-L. Mo, T. W. Reidl, D. J. Wink,
L. L. Anderson, Angew. Chem. Int. Ed. 2016, 55, 9183; Angew.
Chem. 2016, 128, 9329.
4
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[6] a) I. Nakamura, D. Zhang, M. Terada, J. Am. Chem. Soc. 2010,
are provided free of charge by The Cambridge Crystallographic
132, 7884; b) I. Nakamura, D. Zhang, M. Terada, J. Am. Chem.
Soc. 2011, 133, 6862.
Data Centre.
[10] See the Supporting Information for details.
[7] For examples of related 2H-1,4-oxazines prepared by the
addition of 2H-azirines to diazoesters and their use as transient
2-azadienes, see: a) V. A. Khlebnikov, M. S. Novikov, A. F.
Khlebnikov, N. V. Rostovskii, Tetrahedron Lett. 2009, 50, 6509;
b) N. V. Rostovskii, M. S. Novikov, A. F. Khlebnikov, V. A.
Khlebnikov, S. M. Korneev, Tetrahedron 2013, 69, 4292;
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Khlebnikov, G. L. Starova, M. S. Avdontseva, Beilstein J. Org.
Chem. 2015, 11, 302; d) M. S. Novikov, A. F. Khlebnikov, N. V.
Rostovskii, S. Tcyrulnikov, A. A. Suhanova, K. V. Zavyalov,
D. S. Yufit, J. Org. Chem. 2015, 80, 18.
[11] The attenuated yields for 6m and 7m are due to poor separation.
[12] For copper-promoted deoxygenation, see: a) A. Saini, S. Kumar,
J. Sandhu, Synlett 2006, 395; for copper-catalyzed deoxygenation
À
in combination with C H functionalization, see: b) B. Du, P.
Qian, Y. Wang, H. Mei, J. Han, Y. Pan, Org. Lett. 2016, 18, 4144.
[13] The remainder of the product mixture contained hydrolysis
products; 4p electrocyclization products were not observed.
[14] See the Supporting Information for an independent synthesis of
an analogous N-allenylnitrone and electrocyclization.
[8] A pivaloyl-substituted aldoxime gave pivaloyl cyanide when
subjected to the reaction conditions.
[9] CCDC 1506785 (6c), 1506786 (7c), and 1507227 (16) contain the
supplementary crystallographic data for this paper. These data
Manuscript received: December 4, 2016
Final Article published: && &&, &&&&
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Communications
Electrocyclization
A new approach to substituted morpho-
lines involves the preparation and func-
tionalization of 2H-1,4-oxazine N-oxides.
J. Son, K. H. Kim, D.-L. Mo, D. J. Wink,
À
L. L. Anderson*
&&&& — &&&&
A Chan–Lam C N bond coupling was
used to generate a-keto-N-alkenylni-
trones that spontaneously undergo
a 6p electrocyclization to give unsatu-
rated morpholine N-oxides, which can be
further functionalized through a variety of
cycloaddition reactions.
Single-Step Modular Synthesis of
Unsaturated Morpholine N-Oxides and
Their Cycloaddition Reactions
6
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