Dienamine-Catalyzed Nitrone Formation via Redox Reaction

Article abstract of DOI:10.1021/acs.orglett.6b00770

The first catalytic method to directly introduce nitrone functionality onto aldehyde substrates is described. This reaction proceeds by an unprecedented organocatalytic redox mechanism in which an enal is oxidized to the -nitrone via dienamine catalysis, thereby reducing an equivalent of nitrosobenzene. This reaction is a unique example of divergent reactivity of an enal, which represents a novel strategy for rapidly accessing small libraries of N,O-heterocycles. Alternatively, divergent reactivity can be suppressed simply by changing solvents.

Full text of DOI:10.1021/acs.orglett.6b00770

Letter
pubs.acs.org/OrgLett
Dienamine-Catalyzed Nitrone Formation via Redox Reaction
Americo J. Fraboni and Stacey E. Brenner-Moyer*
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
*
S Supporting Information
ABSTRACT: The first catalytic method to directly introduce nitrone
functionality onto aldehyde substrates is described. This reaction proceeds by
an unprecedented organocatalytic redox mechanism in which an enal is oxidized
to the γ-nitrone via dienamine catalysis, thereby reducing an equivalent of
nitrosobenzene. This reaction is a unique example of divergent reactivity of an
enal, which represents a novel strategy for rapidly accessing small libraries of
N,O-heterocycles. Alternatively, divergent reactivity can be suppressed simply by changing solvents.
ldehydes are one of the most versatile functional groups in
organic chemistry, being readily transformable into other
Scheme 1. γ-Functionalization of Enals via Dienamine-
7
A
Catalyzed [4 + 2] Cycloaddition Reaction
functionalities and indispensible in asymmetric reactions. Like-
wise, nitrones are useful reactive intermediates that are character-
istically employed in dipolar cycloaddition reactions to generate
heterocycles. However, direct methods to introduce nitrone
functionality in the presence of an aldehyde, to generate
compounds with two handles for further functionalization, are
exceedingly rare. This is most likely due to the incompatibility of
the reactive aldehyde functional group with methods commonly
used to generate nitrones, which include oxidation of amines,
imines, or hydroxyl amines and CN bond formation via
Scheme 2. Dienamine-Catalyzed Nitrone Formation
1
condensation of hydroxyl amines with carbonyls. In addition to a
handful of examples of oxidation of pyridinecarboxaldehydes and
2
quinolonecarboxaldehydes to the corresponding nitrones, we
identified only two methods in the literature for the direct
introduction of a nitrone in the presence of an aldehyde. There is
one isolated example of reaction of a carbon−nitrogen ylide with
3
4
-nitrosobenzaldehyde, and the other method entailed N-
4
alkylation of aldoximes with enals. The latter strategy would be
less amenable, however, to ketoximes, in which competitive N-
and O-alkylation would be anticipated due to sterics. Herein we
We were curious to examine what other dienophiles could
participate in a [4 + 2] cycloaddition with a dienamine to afford γ-
functionalized α,β-unsaturated aldehydes, and we suspected that
the labile bond (circled in 4, Scheme 1) might need to be a
carbon−heteroatom bond. The electrophile selected for exami-
5
presentourserendipitous discoveryofadirect catalyticmethodto
introduce nitrone functionality to α,β-unsaturated aldehyde
substrates via a novel CN bond-forming strategy.
8
This discovery was made during investigations into dienamine-
catalyzed reactions, which are a relatively underexplored mode of
catalysis for chiral secondary amine organocatalysts. This is likely
due to the challenges associated with controlling the regiose-
lectivity of reactions with dienamines, which are nucleophilic at
both their α- and γ-positions. Often, cyclic dienamines and/or
steric bias are employed to influence the regioselectivity of
nation was nitrosobenzene (6a, Scheme 2)for tworeasons. First,
we were unsure whether γ-oxidation (7, X = O, Y = NPh) or γ-
amination (7, X = NPh, Y = O) would occur. Second, when
nitrosobenzene has been used as an electrophile in enamine9-
catalyzedα-functionalizationsusingrelatedcatalyst2b(Ar=Ph),
it has been shown that one can switch whether α-amination or α-
oxygenation occurs simply via the addition or omission,
8f,g
6
respectively, of a carboxylic acid additive.
We were thus
dienamine-catalyzed intermolecular reactions. There is one
interested whether a similar reversal of regioselectivity might also
be observed in γ-functionalizations. When this reaction was first
attempted, however, neither 8 nor 9 was observed, but rather only
nitrone 10.
example, however, of manipulating the reactivity of a linear
dienamine (i.e., as a diene) in a [4 + 2] cycloaddition, with
subsequentringopening, toyieldexclusivelyγ-functionalizedα,β-
7
unsaturated aldehydes (Scheme 1). The [4 + 2] mechanism
accounts not only for the regioselectivity of this reaction but also
for the high degree of stereocontrol despite the γ-position being
remote from the chiral center of the catalyst.
Received: March 16, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00770
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Reaction Optimization
b
,
c
d
entry
6 (equiv)
additive
time (h)
temp (°C)
yield (%)
dr (10a/10a′)
e
1
1
1
2
2
2
2
4
4
4
4
4
PhCO H
22
4.25
1
rt
rt
24
12:1
3:1
2
2
3
4
5
6
7
8
9
1
1
PhCO H
29
2
PhCO H
rt
31
3:1
2
PhCO H
65.5
14.5
41
−30
−30
rt
42
3:1
2
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
42 (2, 49)
4:1
f
f
f
f
40 (21, 23)
9:1
41
rt
48
43
49
53
54
9:1
−
g
39
rt
10:1
12:1
10:1
10:1
,
h
144
15
rt
f
f
,
i
i
0
1
rt
,
−
j
15.5
rt
a
b
1
Reaction conditions: 1a, 6a, 2b (0.1 equiv), additive (0.1 equiv), toluene (1 M). Determined by H NMR using 1,4-dioxane or cyclohexene as
c
internal standard. First number in parentheses is percentage of 1a remaining, second number in parentheses is percentage of side product (vide
infra) formed. Determined by H NMR. Catalyst 2a used. 1,4-Dioxane is reaction solvent. Reaction concentration = 2 M. Reaction
concentration = 0.5 M. 0.2 equiv of 2b and of AcOH used. Reaction scaled 10-fold, using 1a (2.5 mmol).
d
1
e
f
g
h
i
j
Seeking to optimize this transformation, and starting with
Scheme 3. Scope of Dienamine-Catalyzed Nitrone Formation
a
conditions (i.e., catalyst 2a, PhCO H additive) similar to those
Reaction
2
used for the dienamine-catalyzed γ-amination using diethyl
7
azodicarboxylate (3), a 24% yield of the nitrone product was
obtained with excellent diastereoselectivity (entry 1, Table 1).
Switching to the more reactive catalyst 2b shortened reaction
timeswhileimprovingreactionyield(entry2).Increasingtheratio
of 6a/1a to 2:1 improved the yield slightly and further reduced
reaction times (entry 3). Lowering the reaction temperature was
found to have a big impact on yield (entry 4). Use of AcOH as the
acid additive further shortened reaction times (entry 5). Under
these conditions, however, when nitrosobenzene was completely
consumed,only2%ofstartingenal1aremained,whilenearlyallof
the mass balance of the reaction could be accounted for by the
formation of a side product (vide infra), which was generated in
4
9% yield. Switching the reaction solvent to 1,4-dioxane
suppressed the formation of this side product significantly, and
as a result, 21% of unreacted starting enal 1a remained once
nitrosobenzene was completely consumed (entry 6). Interest-
ingly, in this solvent, the diastereoselectivity of this reaction was
alsosignificantlyimproved(entries6−11).Inanefforttodrivethe
reaction toward completion, more equivalents of nitrosobenzene
were used, which did further improve the yield of the nitrone
product(entry7).Increasedordecreasedreactionconcentrations
were not beneficial to this transformation (entries 8 and 9).
Increasing the catalyst loading to 20 mol %, however, afforded the
nitrone product in a still higher yield (entries 10 and 11). After
10
exhaustive optimization, the conditions summarized in entry 10
provided the nitrone product in the highest attainable yield.
With optimized conditions in hand, the scope of this one-pot
methodwasinvestigated (Scheme3). EnalswithalkylRgroupsall
afforded nitrone products (10a−c) in modest yield and
outstanding dr. Notably, the sterically demanding isopropyl R
group generated the corresponding nitrone product (10d) in the
highestyieldamongallsubstratesexamined.Aδ-phenylgroupand
a
Reaction conditions: 1, 6 (4 equiv), 2b (0.2 equiv), AcOH (0.2
1
equiv),1,4-dioxane (1 M), rt, 14−18 h. Yield and dr determined by H
NMR using cyclohexene as internal standard. Reaction conditions: 1,
6
b
(2 equiv), 2b (0.1 equiv), AcOH (0.1 equiv), toluene (1 M), −30
c
°
C. Reaction conditions: 1, 6 (2 equiv), 2b (0.1 equiv), CHCl (0.5
M), rt.
3
-
heteroatom were tolerated, although the latter afforded no
diastereoselectivity (10e−f). A γ-phenyl group furnished the
nitrone product in low yield but, interestingly, favored formation
B
DOI: 10.1021/acs.orglett.6b00770
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Organic Letters
Letter
Scheme 4. Proposed Mechanism
11
of the opposite diastereomer of the nitrone (10g′). Other
commercially available nitrosobenzenes were also examined in
this transformation. The electron-poor p-nitronitrosobenzene
provided the corresponding nitrone product in slightly reduced
yield and dr compared to nitrosobenzene (10h). Use of the
electron-rich 4-nitrosoresorcinol 1-monomethyl ether provided
interesting results. The major diastereomer of the nitrone, with
the aromatic ring cis to the enal moiety, evidently underwent a
subsequentoxa-Michaeladditionandreoxidationtoenal10i. The
other major product, 11, presumably arose from aza-Michael
addition of N-arylhydroxylamine (vide infra), followed by
dehydrationtoformanimineandtautomerizationtotheenamine.
Our working hypothesis for the mechanism of the reaction is
illustratedinScheme4.Enal1acondenseswithcatalyst2btoform
iminiumion12, whichisinequilibriumwithdienamine13vialoss
or gain of a proton. Both of these species were detected by HRMS
analysis of the reaction mixture. Dienamine 13 reacts with 2 equiv
of nitrosobenzene (6a) to generate 15. The detection of iminium
species 14 by HRMS suggests that dienamine 13 undergoes two
successive reactions with a nitrosobenzene monomer, as opposed
to reacting directly with the dimer of nitrosobenzene, which is
known to be in equilibrium with the monomeric form in
Scheme 5. Subsequent Elaboration of Nitrone Products
For medicinal chemists, this divergent reactivity may be useful,
asitrepresentsaninterestingnewmeansofrapidlyaccessingsmall
libraries of medicinal compounds. In toluene, and using
conditions summarized in entry 5 in Table 1, compounds 10a
and 17 are generated in an approximately 1:1 ratio and in a
10
combined yield of 91% in one step. Both compounds are
isolable, and each provides access to a structurally related N,O-
heterocycle(i.e., 18inScheme5and17),whicharecompoundsof
14
1
2
importance in medicinal chemistry.
solution. The reaction of 14 with nitrosobenzene must be very
Forsyntheticchemists,however,thisdivergentreactivitywould
be undesirable and, as mentioned previously, can be suppressed
simply by switching the reaction solvent to 1,4-dioxane. It should
be noted that, although the yields of nitrone products in 1,4-
dioxane are moderate (Scheme 3), alternative strategies to
synthesize compounds containing nitrone and aldehyde
functionalities would necessitate the use of protecting groups
and entail multiple steps, which may curtail the overall yield of
desired product relative to this one step catalytic process.
In an effort to further hamper divergent reactivity, the
possibility of oxidizing N-phenylhydroxylamine in situ to
regenerate nitrosobenzene, thereby recycling this amine by-
productandcircumventingformationofbyproduct17,wasbriefly
fast(i.e.,fasterthanhydrolysisofthecatalyst),asnoaldehydepeak
corresponding to the enal arising from hydrolysis of the catalyst in
1
1
4 (i.e., 8) was observed in the H NMR spectra of the crude
reaction at any time point. It is still unclear whether a [4 + 2]
cycloaddition and subsequent ring opening is, in fact, operative in
the formation of 14. We propose that deprotonation of 15
liberates the nitrone 10a, along with 1 equiv of the product of
reduction of nitrosobenzene, N-phenylhydroxylamine. Further
evidence in support of this mechanism is the observation of 17 as
the major byproduct of this reaction (vide supra). Compound 17
can be formed from the conjugate addition of N-phenylhydroxyl-
amine to 1a (via iminium 12) followed by intramolecular
1
3
hemiacetalization.
examined. A preliminary screen of stoichiometric MnO as well as
2
This is, thus, a unique example of divergent reactivity of an enal
in an organocatalyzed redox reaction. Under the conditions
summarized in entry 5 in Table 1, 1 equiv of enal is oxidized to the
γ-nitroneviadienaminecatalysis,whileasecondequivalentofenal
reacts with the reduced byproduct, N-phenylhydroxylamine, via
iminium catalysis.
catalytic conditions developed by Read de Alaniz and co-workers
10,15
(
CuCl , air, and pyridine) was undertaken.
While the latter
2
did completely suppress the formation of byproduct 17, no
improvement in the yield of 10a was achieved.
Finally, subsequent transformations of 10 were investigated
(Scheme 5). Under unoptimized conditions, a 1,3-dipolar
C
DOI: 10.1021/acs.orglett.6b00770
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Organic Letters
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cycloadditionof10awithdiethylacetylenedicarboxylate(DEAD)
atlowtemperatureprovided2,3-dihydroisoxazole18in54%yield.
Interestingly, when this cycloaddition was run at higher
temperatures, or when 18 was isolated, redissolved in toluene,
and heated, pyrrole 19 was formed, albeit in extremely low yields
(2) (a) Jeong, J.; Lee, D.; Chang, S. Chem. Commun. 2015, 51, 7035−
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Wagner,R.;Maring,C.J.;Kati,W.M.;Liu,Y.;Masse,S.V.;Middleton,T.;
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(
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2
(
876−1879. (d) Adam, W.; Zhao, C.-G.; Jakka, K. Organic Reactions
16
nitrones derived from ketones, under heating, is precedented.
008, 69, 1−346.
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17
was converted to ketone 20 in 63% yield. 2,3-Dihydroisoxazole
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1
functionality that can be further manipulated.
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204.
In conclusion, we have developed the first catalytic method to
directly introduce nitrone functionality in the presence of an
aldehyde.Inthisorganocatalyticredoxreaction,anenalisoxidized
to the corresponding γ-nitrone via dienamine catalysis, thereby
reducing 1 equiv of nitrosobenzene to N-phenylhydroxylamine.
Whenthereactionsolventistoluene,theN-phenylhydroxylamine
reacts with unreacted enal to form 5-hydroxyisoxazolidines via
iminium catalysis and subsequent intramolecular hemiacetaliza-
tion. This is an unprecedented, and potentially useful, example of
divergent reactivity of enals in an organocatalytic redox reaction.
Alternatively, when the reaction solvent is 1,4-dioxane, this side
reactionissuppressedandnitroneproductsareobtainedinhigher
yields. Importantly, the reaction products have two handles for
further functionalization, and we have shown that the nitrone can
be manipulated orthogonally to the aldehyde. Further inves-
tigations into organocatalytic reactions using nitrosobenzene are
underway in our laboratory.
(
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Crystallographic data (CIF)
(10) See the Supporting Information for full details.
(11) CCDC 1451744 contains the supplementary crystallographic data
for this paper. These data are provided free of charge by the Cambridge
Crystallographic Data Centre.
AUTHOR INFORMATION
Corresponding Author
■
*
(
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E-mail: seb244@rutgers.edu.
Notes
(
́
dova, A. Chem.
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
This work was supported by the National Science Foundation
CAREER-1148295) and by Rutgers University. The Bruker 500
MHzspectrometerusedinthesestudieswasfurnishedbyanNSF-
MRI grant (CHE-1229030). We gratefully acknowledge Dr.
Roman Brukh (Rutgers University) for assistance with mass
spectrometry for the mechanistic studies and Dr. William
Brennessel (University of Rochester) and Dr. Furong Sun
UniversityofIllinois)fortheacquisitionofX-raycrystallographic
and mass spectrometry data, respectively, for compound
characterization.
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