Conversion of nitrosobenzenes to isoxazolidines: An efficient cascade process utilizing reactive nitrone intermediates

Article abstract of DOI:10.1039/b806374e

Reactive nitrones can be generated directly in situ by an unusual reaction of nitrosobenzene with styrene. The Royal Society of Chemistry.

Full text of DOI:10.1039/b806374e

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Conversion of nitrosobenzenes to isoxazolidines: an efficient cascade
process utilizing reactive nitrone intermediatesw
Jun Yong Kang, Alejandro Bugarin and Brian T. Connell*
Received (in College Park, MD, USA) 15th April 2008, Accepted 29th May 2008
First published as an Advance Article on the web 3rd July 2008
DOI: 10.1039/b806374e
Reactive nitrones can be generated directly in situ by an unusual
at RT for 12–48 h (eqn (2)). The reaction produces a slightly
higher yield of product in DMSO, however, for ease of
removal, we chose to employ MeCN as solvent, with minimal
loss in reaction rate and yield (o10%).
reaction of nitrosobenzene with styrene.
Efficiency is a central concept in modern organic synthesis.
Cascade reactions, where multiple bond-forming events occur
in one synthetic operation, not only encourage efficiency but
also reduce waste by eliminating extra steps and often tedious
purifications.1,2 In this communication, we report the efficient,
regioselective one-pot synthesis of a variety of isoxazolidines
from commercially available starting materials. Isoxazolidines
are often used as intermediates in the synthesis of complex
molecules,3,4 and are frequently present in biologically active
compounds.5–7 They are valuable intermediates because the
N–O bond can be easily cleaved under mild reducing condi-
tions to afford 1,3-amino alcohols, which themselves are
highly valuable synthetic building blocks.8 The most common
method for the synthesis of isoxazolidines involves the 1,3-
dipolar cycloaddition of a nitrone with an alkene to simulta-
neously generate an O–C and C–C bond, as well as up to three
stereocenters (eqn (1)).9–15
ð2Þ
Table 1 summarizes the results of several cycloaddition
reactions between various substituted styrenes and nitroso-
benzenes in MeCN after 48 h. Yields of the isoxazolidines were
best when a moderate excess of styrene (4 equiv.) was em-
ployed. Larger excesses did not significantly improve the
isolated yields of these isoxazolidines. Electron rich styrenes
generally give higher yields than electron deficient styrenes,
but the unsubstituted parent styrene was the best substrate in
this reaction, producing 49% of pure isoxazolidine (Table 1,
entry 1). A by-product in these reactions is the substituted
nitrone 4, which helped in our mechanistic analysis (vide infra).
We confirmed the structure of the products 3 by routine
analytical methods, including 2D NMR spectroscopy (see
ESIw). In addition, the structure of 3b was confirmed by single
crystal X-ray analysis, cementing our analysis and structural
assignment of these products.21
Experiments to probe the influence of temperature were
undertaken in refluxing MeCN (82 1C). The reactions at
elevated temperature afforded the more hindered trisubsti-
tuted isoxazolidines 5 in addition to the disubstituted isoxa-
zolidines which were formed at room temperature (Table 2).
ð1Þ
Because of the utility of the isoxazolidines, a wide variety of
synthetic approaches toward the precursor nitrones have been
reported.16,17 Among these synthetic methods, the acid-cata-
lyzed condensation of N-monosubstituted hydroxylamines
with carbonyl compounds and the oxidation of N,N-disub-
stituted hydroxylamines or secondary amines are the most
general.13 A neutral, non-oxidative pathway to nitrones, par-
ticularly reactive methylene nitrones, which are generally too
reactive to isolate, would be beneficial.18
Table 1 Room temperature cycloadditionsa
The high reactivity of aromatic nitroso compounds19 led us
to investigate their reactivity with olefins incapable of under-
going the nitroso ene reaction.20 This led us to a discovery of a
useful yet previously undeveloped reactivity pattern for nitro-
so compounds. We observed formation of isoxazolidines
simply by combining nitrosobenzene and styrene in MeCN
Entry
R1
R2
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
4-BrPh (1b)
Ph (2a)
3a
3b
3c
3d
3e
3f
3g
3h
3i
49
48
48
31
30
40
35
48
40
2-MePh (2b)
4-MeOPh (2c)
3-ClPh (2d)
4-t-BuPh (2e)
4-CF3Ph (2f)
2-BrPh (2g)
4-BrPh (2h)
Ph (2a)
Texas A&M University, Department of Chemistry, PO Box 30012,
College Station, TX 77842-3012, USA.
E-mail: connell@mail.chem.tamu.edu; Fax: +1-979-458-3249
w Electronic supplementary information (ESI) available: Experimental
procedures, 1H and 13C NMR spectra of new compounds. CCDC
reference numbers 682983 and 682984. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/b806374e
a
1 (0.25 mmol), 2 (1.0 mmol), and anhydrous MeCN (4 mL) were
b
used. Yield of isolated products; maximum possible yield: 50%.
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Table 2 Elevated temperature cycloadditionsa
ð5Þ
Entry
R1
R2
Product
Yield (%)b
ð6Þ
ð7Þ
1
2
3
4
5
6
7
8
9
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
4-BrPh (1b)
Ph (2a)
3a/5a
3b/5b
3c/5c
3d/5d
3e/5e
3f/5f
3g/5g
3h/5h
3i/5i
49/40
41/41
48/39
30/32
33/30
38/25
40/33
48/40
40/21
2-MePh (2b)
4-MeOPh (2c)
3-ClPh (2d)
4-t-BuPh (2e)
4-CF3Ph (2f)
2-BrPh (2g)
4-BrPh (2h)
Ph (2a)
a
1 (0.25 mmol), 2 (1.0 mmol), and anhydrous MeCN (4 mL) were
b
used. Yield of isolated products; maximum possible yield: 50%.
It is noteworthy that the alkenes without adjacent electron
stabilizing groups, including allyl alcohol, allyl bromide, and
1-octene, do not produce nitrones or cycloadducts under the
standard reaction conditions. Nitrosobenzenes appear to be
converted to nitrones only upon reaction with styrenes.
A preliminary proposed reaction pathway is outlined in
Scheme 1. The combination of nitrosobenzene and styrene in a
2 : 1 ratio produces two nitrone molecules, one substituted (4a)
and one unsubstituted (4aa) via an unstable intermediate 2 : 1
adduct of nitrosobenzene and styrene such as bis-nitroxide
radical 1aa. While we do not have direct evidence for 1aa and
cannot rule out other possibilities, we propose a bis-nitroxide
radical intermediate not only due to their rich chemistry23–26
but also more importantly the implication of nitroxide radical
formation in the early stages of the nitroso ene reaction,27,28
which may have a parallel in this reaction.
We confirmed the structure and stereochemistry of these endo
[3 + 2] cycloadducts by the usual methods. In addition, the
structure of 5b, including the relative cis stereochemistry of the
newly formed 5-membered ring, was confirmed by X-ray
crystallography.21
We were intrigued by the mechanism of this reaction and in
hopes of developing a synthetically useful cascade process, we
undertook a mechanistic analysis of the reaction. Our hypo-
thesis was that a nitrone-involved dipolar cycloaddition was
responsible for formation of the isoxazolidines.22 Our goal was
to determine if and how nitrones were being formed under the
reaction conditions.
In a room temperature experiment employing CD3CN as
solvent, the reaction of nitrosobenzene 1a with styrene 2a
produced 2,5-diphenylisoxazolidine 3a and N-benzylideneaniline
oxide 4a, with no deuterium incorporation in either product.
When the deuterated styrenes 2aa, 2ab, and 2ac were individu-
ally subjected to the usual reaction conditions (PhNO, MeCN,
RT), the products incorporated deuterium as indicated in
eqn (3)–(5). These data point to cleavage of the CQC bond of
the styrene moiety as a key step in the mechanism. As additional
confirmation, we utilized two 13C labelled styrenes (eqn (6)–(7)).
These experiments confirmed that cleavage of the alkene bond
must be occurring along the reaction pathway, and accounted
for all the carbons in the starting material and products.
Regardless of the exact nature of the 2 : 1 adduct, the
formation of unsubstituted nitrone 4aa cannot be disputed,
and this reactive dipole undergoes an immediate cycloaddition
at RT with the excess styrene present. The substituted nitrone
4a is not reactive towards dipolar cycloaddition at room
ð3Þ
ð4Þ
Scheme 1 Proposed reaction sequence.
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Table 3 Trapping of the unsubstituted nitrone with dipolarophilesa
with good yields and under convenient reaction conditions,
but in contrast to typical syntheses that require 3 or more total
steps, this cascade provides direct access to 5-substituted
isoxazolidines in a single step from commercially available
starting materials.
Texas A&M University and the Robert A. Welch Founda-
tion are acknowledged for support of this research. We thank
Dr Daniel Singleton for enlightening insight.
Entry
EWG
Product
Yield (%)b
1
2
3
4
5
6
CHO (6a)
CN (6b)
CO2Me (6c)
C(O)NMe2 (6d)
C(O)Et (6e)
7a
7b
7c
7d
7e
7f
86c
65
78
82
74
81
Notes and references
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temperature and can be isolated from the reaction mixture
before undergoing cycloaddition with styrene. However, 4a
will undergo cycloaddition with styrene when heated.
With this data in hand, we pursued the synthetically useful
goal of trapping the reactive nitrone 4aa in situ with a
dipolarophile that is more reactive than the styrene employed
for generation of the 4aa. For instance, when nitrosobenzene,
acrylamide, and styrene are combined at RT (Table 3 entry 4),
the desired 5-substituted oxazolidine can be isolated in 82%
yield in a single step from inexpensive, commercially available
materials. No cycloadduct derived from the more plentiful,
but less reactive dipolarophile styrene was observed when the
reaction was started at 0 1C and allowed to warm to RT. Other
reasonable cycloadducts can be isolated as shown in Table 3
with use of an appropriate monosubstituted dipolarophile.
The reactions are highly regioselective, with no evidence of
formation of the 4-substituted products observed (1H NMR
spectroscopy). Methyl methacrylate, a disubstituted olefin, is
also a suitable dipolarophile, yielding the expected cycload-
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methyl crotonate, were unreactive in this cycloaddition at
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nitrones from nitrosobenzenes and monosubstituted aromatic
styrenes, which can undergo a cyclization with electron-defi-
cient alkenes to afford isoxazolidines in a single reaction flask.
A [3 + 2] dipolar cycloaddition is clearly implicated by the
available mechanistic data. The reaction allows for the rapid
assembly of various substituted isoxazolidines directly from
nitrosobenzenes, electron deficient alkenes, and styrene. The
synthetically useful reactions described in Table 3 proceed
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3524 | Chem. Commun., 2008, 3522–3524