A modular approach to α,β-unsaturated N-aryl ketonitrones

Article abstract of DOI:10.1016/j.tetlet.2012.06.083

A modular approach to α,β-unsaturated N-aryl ketonitrones has been developed. Specifically, condensation of anilines and enals followed by alkylation of the resulting α,β-unsaturated imines provided N-allyl anilines, which were subjected to oxidation with

Full text of DOI:10.1016/j.tetlet.2012.06.083

Tetrahedron Letters 53 (2012) 4679–4682
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Tetrahedron Letters
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A modular approach to
a,b-unsaturated N-aryl ketonitrones
⇑
Tyler S. Hood, C. Bryan Huehls, Jiong Yang
Department of Chemistry, Texas AM University, College Station, TX 77843-3255, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A modular approach to
tion of anilines and enals followed by alkylation of the resulting
a
,b-unsaturated N-aryl ketonitrones has been developed. Specifically, condensa-
,b-unsaturated imines provided N-allyl
anilines, which were subjected to oxidation with OxoneÒ to form
,b-unsaturated N-aryl ketonitrones.
Received 27 May 2012
Accepted 15 June 2012
Available online 21 June 2012
a
a
This modular approach is general and provides rapid access to diversely substituted
a,b-unsaturated
N-aryl ketonitrones with a single purification step in good yields.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
a,b-Unsaturated N-aryl ketonitrone
Cycloaddition
Hydroxylamine
Oxidation
Synthesis
Nitrones are widely recognized as important building blocks in
organic synthesis. Much of this popularity can be traced to their
facile [3+2] cycloadditions with alkene and alkyne dipolarophiles
to form products such as isoxazolidines and 2,3-dihydroisoxazoles
that not only are common structural components but are also valu-
able intermediates to other important motifs.1 Nitrones are also
excellent electrophiles for reactions with organometallic reagents
to give nitrogen-containing compounds and enantioselective ver-
sions of these transformations are known.2 Utility of nitrones in
transformations other than dipolar [3+2] cycloadditions and alky-
lations has been reported as well.3 These include a recent discovery
R2
O
CO2R
R4
R1
R3
O
N
R3
CO2R
R1
R2
R4
N
Scheme 1. Reaction of a,b-unsaturated N-aryl ketonitrones and activated alkynes.
limited substitution. Such an approach would allow us to acquire
knowledge of the general stability of these relatively unexplored
species, examine their reactivity with dipolarophiles, and explore
their potential as reagents in other transformations.
A number of methods have been known for the preparation of
nitrones,7 but the most convenient and commonly used are by con-
densing N-monosubstituted hydroxylamines and carbonyl com-
pounds or by oxidation of the corresponding hydroxylamines,
imines, or amines.8 The reaction of N-substituted hydroxylamines
and aldehydes is typically facile and gives aldonitrones in high
yields. However, except for the intramolecular variant, condensa-
tion of N-substituted hydroxylamines and ketones typically re-
quires harsh conditions and is of limited scope. Indeed, despite
by our laboratory that
a,b-unsaturated N-aryl ketonitrones, when
combined with activated alkynes, afforded C3-quaternary indole-
nines with concomitant formation of up to two contiguous quater-
nary and tertiary chiral centers (Scheme 1).4 The ketonitrones
employed in our study were prepared by reaction of aryl nitro
compounds with crotylmagnesium chloride as described by Bartoli
to give a,b-unsaturated N-aryl ketonitrones that are b-unsubstitut-
ed,5 or by reaction of silyl dienolates and excess of nitrosobenzene
as we have previously reported to give those with b-alkoxycarbon-
yl substituents (Scheme 2).6 To the best of our knowledge, no other
approaches to these species have been reported. Our interest in
expanding the power and scope of this transformation and explor-
sporadic reports of condensing N-alkyl hydroxylamines and
a,b-
unsaturated ketones to give the corresponding ketonitrones,9 di-
ing other potential reactivities of a,b-unsaturated N-aryl ketonitro-
nes required access to these species with diverse substitution
patterns. This led us to consider developing a general and synthet-
rect condensation of N-aryl hydroxylamines and
a,b-unsaturated
ketones had been unsuccessful.10 Thus, our efforts focused on
developing an approach based on oxidation of N-allyl anilines,
which could be synthesized in a modular approach by condensing
ically useful approach to
a,b-unsaturated N-aryl ketonitrones
beginning from readily available starting materials since the cur-
rent methods would only allow synthesis of these species with
anilines and
a,b-unsaturated aldehydes to give N-allylideneani-
lines, followed by alkylation with organometallic reagents. This
method was successfully applied in the synthesis of a range of
⇑
Corresponding author. Tel.: +1 979 845 2889; fax: +1 979 845 4718.
E-mail address: yang@mail.chem.tamu.edu (J. Yang).
a,b-unsaturated ketonitrones as shown in Table 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.083

4680
T. S. Hood et al. / Tetrahedron Letters 53 (2012) 4679–4682
Scheme 2. Approaches to
a
,b-unsaturated N-aryl ketonitrones.
Table 1
Synthesis of
a
,b-unsaturated N-aryl ketonitrone 3
Ar
O
Oxone, aq. Na2EDTA,
NaHCO3, CH3CN-THF
ArNH2, MgSO4,
ether;
R2 NHAr
R2
N
R2
R3Li, ether
R1
R3
R1
R3
R1
O
1
2
3
Entry
1
Aldehyde 1
N-Allyl aniline 2 (yield)
a
,b-Unsaturated N-aryl ketonitrone 3 (yield, E:Z ratio)
Ph
Ph
O
O
O
O
O
NH
N
N
N
N
N
N
N
Ph
O
2a (79%)
3a (80%, 3.6:1)
3b (67%, 2.7:1)
3c (62%, 3.7:1)
3d (34%, 2:1)
3e (22%, 3.3:1)
3f (82%,2:1)
Ph
Ph
2'-tolyl
NH
2'-tolyl
Ph
4'-tolyl
Ph
2
3
4
5
6
7
8
2b (91%)
2c (44%)
2d (64%)
2e (78%)
2f (71%)
2g (88%)
2h (74%)
Ph
4'-tolyl
NH
Ph
4'-Cl-Ph
NH
4'-Cl-Ph
Ph
Ph
Ph
Ph
NH
Ph
Ph
Ph
Ph
O
NH
Ph
Ph
n-Bu
Ph
n-Bu
Ph
Ph
O
NH
Ph
3g (52%, P5:1)
3h (74%, 4:1)
Ph
Ph
Ph
Ph
O
O
NH
NH
N
N
4'-MeO-Ph
O
4'-MeO-Ph
2'-tolyl
4'-MeO-Ph
Ph
4'-MeO-Ph
2'-tolyl
4'-MeO-Ph
Ph
9
2i (73%)
2j (83%)
3i (49%, 2:1)
3j (70%, 4:1)a
O
NH
N
10
O

T. S. Hood et al. / Tetrahedron Letters 53 (2012) 4679–4682
4681
Table 1 (continued)
Entry
Aldehyde 1
N-Allyl aniline 2 (yield)
a,b-Unsaturated N-aryl ketonitrone 3 (yield, E:Z ratio)
3'-MeO-Ph
NH
3'-MeO-Ph
O
N
11
2k (89%)
2l (75%)
3k (70%, >10:1)a
3l (20%, 3:1)
O
Ph
Ph
O
NH
N
O
12
a
Estimated yield based on integration of 1H NMR spectra of the crude product.
The condensation of anilines and
a
,b-unsaturated aldehydes
are all commercially available and is operationally simple. It allows
access to diversely substituted unsaturated ketonitrones which en-
able further exploration of the reactivity of these relatively unex-
plored species.
was carried out in diethyl ether at room temperature with MgSO4
as the dehydrating agent.11 While all the anilines that we tested
condensed with equal amounts of cinnamaldehydes efficiently,
slight excess of aliphatic
a,b-unsaturated aldehydes (1.2 equiv)
had to be used for optimal yields and product purity. Since these
N-allylideneanilines were somewhat unstable, only simple filtra-
tion and concentration in vacuo were performed to prepare these
intermediates for the subsequent transformation. Uniformly high
yields were obtained for alkylation of these non-enolizable imines
with alkyl and phenyl lithium reagents to give N-allyl anilines (2)
that were mostly pure based on crude 1H NMR spectra.12 They
were subjected to oxidation by OxoneÒ under the conditions re-
Acknowledgements
We thank Mr. Daniel Jasinski of Texas A&M University for assis-
tance in preparing some of the substrates. Financial support was
provided by the Texas A&M University and the Robert A Welch
Foundation (A-1700).
Supplementary data
ported by Busqué and Figueredo to give
a,b-unsaturated N-aryl
ketonitrones (3).8a This modular approach allowed synthesis of
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.
083.
a
,b-unsaturated N-aryl ketonitrones with diverse substitutions.
These include substitution of the N-aryl groups by 20-methyl
(3b), 40-methyl (3c), 40-chloro (3d), and 30-methoxy (3k) groups
and substitution of the ketonitrone by ethyl (3e), n-Bu (3f), and
References and notes
phenyl (3g) groups. All the
a,b-unsaturated N-aryl ketonitrones
thus prepared are b-substituted by the phenyl, 40-methoxyphenyl,
or methyl groups (those with an unsubstituted b-position could be
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more conveniently prepared by the Bartoli method5). The
a
- and b-
positions of the
a,b-unsaturated N-aryl ketonitrones could be fur-
ther substituted with the methyl group (3k and 3l). The ketonitro-
nes thus formed showed varying degrees of stability. Most of them
could be purified by column chromatography, but with slight to
moderate levels of decomposition over silica gel. Thus, the yields
for formation of 3 were somewhat underestimated in Table 1.
Ketonitrones 3j, 3k, and 3l decomposed extensively over silica
gel. Indeed, characterization of the crude material prior to purifica-
tion indicated that the actual yield was much higher than obtained
after chromatography.
While the C@C double bonds of 3 appeared to be all generated
in the E-geometry when relevant, their nitrone C@N double bonds
were formed as E,Z-mixtures in ratios ranging from 2:1 to >10:1.
Determination of the C@N double bond geometry was straightfor-
ward when the a0-substituent was a methyl since it had been
established by Bartoli that the geometry was directly correlated
with the 1H NMR chemical shift of the methyl group.5 A chemical
shift of 2.25–2.31 ppm was associated with a C@N double bond
in the E-configuration while a chemical shift of 1.76–1.91 ppm
was indicative of a Z-double bond. The geometry of ketonitrones
with a0-ethyl- and butyl- groups could be similarly assigned. When
substituted by a phenyl group at the a0-position (3g), only one dia-
stereomeric nitrone, tentatively assigned as the E-isomer,13 was
observed.
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In summary,
synthesized in a modular fashion that involves condensing anilines
and ,b-unsaturated aldehydes to give N-allylideneanilines, fol-
a,b-unsaturated N-aryl ketonitrones can now be
a
lowed by alkylation with alkyl or phenyl lithium reagents and oxi-
dation with OxoneÒ. This procedure uses starting materials that

4682
T. S. Hood et al. / Tetrahedron Letters 53 (2012) 4679–4682
9. (a) Pfeiffer, J. Y.; Beauchemin, A. M. J. Org. Chem. 2009, 74, 8381–8383; (b)
Franco, S.; Merchan, F. L.; Merino, P.; Tejero, T. Synth. Commun. 1995, 25, 2272–
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10. Hood, T. S.; C. B. Huehls, Yang, J. unpublished results.
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7054.
13. This is based on the observation that, when R3 = alkyl, the two vinyl protons of
the ,b-unsaturated showed large chemical difference in the Z-isomer
d = 1.0–1.5 ppm) while a smaller chemical shift difference ( d< 0.5 ppm)
was observed for the E-isomer. A chemical shift difference of d = 1.5 ppm was
observed for 3f. It was assigned as the E-isomer because R3 = Ph.
a
a
(
D
D
D