Bronsted acid-catalyzed C-C bond forming reaction for one step synthesis of oxazinanones

Article abstract of DOI:10.1016/j.tetlet.2011.06.054

An efficient Bronsted acid-catalyzed synthesis of oxazinanones (2) from corresponding Boc-imines (1) in one-step has been developed. Oxazinanones are obtained via an unprecedented tandem elimination-cycloaddition reaction. The reaction is remarkably signi

Full text of DOI:10.1016/j.tetlet.2011.06.054

Tetrahedron Letters 52 (2011) 4353–4356
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Tetrahedron Letters
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Brønsted acid-catalyzed C–C bond forming reaction for one step
synthesis of oxazinanones
⇑
Nazim Uddin, Joseph S. Ulicki, F. Holger Foersterling, M. Mahmun Hossain
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient Brønsted acid-catalyzed synthesis of oxazinanones (2) from corresponding Boc-imines (1) in
one-step has been developed. Oxazinanones are obtained via an unprecedented tandem elimination-
cycloaddition reaction. The reaction is remarkably significant given its novelty, mild reaction conditions,
simplicity and low cost of the catalyst system.
Received 10 December 2010
Revised 10 June 2011
Accepted 13 June 2011
Available online 2 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Brønsted acid catalysis
Boc-imines
Oxazinanones
Tandem elimination-cycloaddition
Nitro-Mannich (or aza-Henry) reactions involve catalytic for-
mation of b-nitro amines from Boc-imines and nitroalkanes.
Recently, there has been a surge of research in this area of organic
chemistry due to the importance of b-nitro amines in organic syn-
theses.1 For example, the organocatalytic nitro-Mannich reaction2,3
has newly become an essential reaction in this area of research,
while Brønsted acids4,5 have been found to be especially effective
catalysts. Johnston et al. have investigated several aspects of the
chiral Brønsted acid-catalyzed nitro-Mannich reactions of Boc-
imines and nitromethane.4b,c At about the same time, using various
nitroalkanes to aromatic N-Boc imines, Jacobsen et al. reported
thiourea-catalyzed nitro-Mannich reactions.5d These reactions ulti-
mately form b-nitro amines in excellent yields and in high
enantioselectivity.
Our group is actively working with strong Brønsted acid-
catalyzed organic reactions in the synthesis of important building
blocks of biologically active compounds.6 In order to expand the
scope of strong Brønsted acid-catalyzed reactions in organic chem-
istry; we investigated nitro-Mannich reactions using Boc-imine
with nitromethane in the presence of fluoroboric acid (HBF4ÁOEt2).
Surprisingly, nitromethane did not participate in the reaction and
no formation of b-nitro amine product was observed. Instead, we
observed the formation of 1,3-oxazinan-2-one in high yield
(Scheme 1).
nones occurs when employing various Boc-imines in the
presence of a strong Brønsted acid.
The major difference in our reaction conditions compared to the
aforementioned nitro-Mannich reactions is the use of fluoroboric
acid. In order to determine whether fluoroboric acid is exclusively
unique, we screened several Brønsted acids (Table 1). Several
attempts, including a control reaction and reactions employing
weaker acids such as acetic acid or triflyl amide, did not yield
any oxazinanone product. However, by employing stronger acids
such as trifluoroacetic acid, oxazinanone product was efficiently
produced in yields of 40% (Table 1, entries 4 and 5). Indeed,
Brønsted acids with lower pKas7 provided even greater yields of
oxazinanone product. Ultimately, the stronger triflic and fluorobo-
ric acids were found to be the most effective catalysts for the reac-
tion as shown in Table 1. A 10 mol % catalyst loading was also
found to be most effective; however, an increase in the catalyst
loading does not improve the yield (Table 1, entries 1–3 and 7–9).
In order to optimize the yield of the product, we investigated
the reaction in different solvents. A preliminary screening revealed
that polar aprotic solvents, with the exception of DMF, gave higher
yields of the product (entries 1–3, Table 2). A plausible explanation
O
Boc
Boc
Herein, we report on an unprecedented catalytic tandem elim-
ination-cycloaddition reaction in which the formation of oxazina-
N
HN
HN
O
10 mol% HBF4 OEt2
CH3NO2 , rt
+
NO2
β-nitroamine (0%)
2 (75 %)
1
⇑
Corresponding author. Tel.: +1 414 229 6698; fax: +1 414 229 5530.
E-mail address: mahmun@uwm.edu (M.M. Hossain).
Scheme 1. HBF4ÁOEt2 reaction of Boc-imine and nitromethane.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.054

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N. Uddin et al. / Tetrahedron Letters 52 (2011) 4353–4356
Table 1
Table 3
Optimization of catalyst
Optimized HBF4ÁOEt2-catalyzed reactions of Boc-imine
O
O
Boc
Boc
N
N
HN
O
HN
O
10 mol% HBF4 OEt2
CH2Cl2, 2-3 hr, rt
10 mol% acid
CH2Cl2, rt
R
R
Entry Catalyst
pKa(H2O) Catalyst loading (mol %) Yield (%)
Entry
1
Imine
Product
Yielda (%)
75
1
2
3
Triflic acid
Triflic acid
Triflic acid
À14
10
20
50
20
30
20
10
20
30
—
70
70
70
40
40
0
75
75
72
0
Boc
O
N
HN
O
4
5
Trifluoroacetic acid 0.52
Trifluoroacetic acid
6
7
8
9
10
11
Triflyl amide
Fluoroboric acid
Fluoroboric acid
Fluoroboric acid
No acid
6.33
À0.4
Boc
O
N
HN
O
2
3
4
70
75
75
O
Acetic acid
4.76
10
0
O
Boc
O
N
HN
O
Table 2
Cl
Optimization of the solvent system
Cl
O
O
Boc
Boc
N
N
HN
O
HN
O
10 mol% HBF4 OEt2
Solvent, rt
F
F
Boc
Boc
O
Entry
Solvent
Yield (%)
N
HN
O
1
2
3
4
5
6
7
8
Dichloromethane
THF
Acetonitrile
DMF
70
60
70
0
5
6
72
72
O
Toluene
0
N
75% Toluene in dichloromethane
Methanol
Nitromethane
35
20
70
HN
O
O
Boc
O
N
HN
for the apparent absence of yield in DMF is explained by the forma-
tion of an iminium ion, produced in consequence of the proton-
ation of DMF by fluoroboric acid. The presence of this ion
effectively reduces the acidic strength of the fluoroboric acid cata-
lyst itself (entry 4, Table 2). Reactions in a polar protic solvent such
as methanol displayed low yield; conversely, non-polar aprotic tol-
uene exhibited no reaction at all. However, a 3:1 toluene: dichloro-
methane mixture provided a 35% yield of the product (Table 2,
entry 6). Overall, the polar aprotic solvents THF, dichloromethane,
acetonitrile, and nitromethane were found to be the best solvents.
In order to determine the scope of this unprecedented reaction,
a number of various Boc-imines were subjected to the newly opti-
mized reaction conditions. Both aromatic and aliphatic Boc-imine
provided the corresponding oxazinanones in good yields. However,
aromatic imines (Table 3, entries 1–8) were found to be more reac-
tive in these cyclization reactions, resulting in high yields of oxaz-
inanones (65–75%). Electron donating or electron withdrawing
groups did not appreciably affect the yields of the products. An ali-
phatic N-Boc-imine (Table 3, entry 9) could also be used in these
reactions with a moderate yield of 50%.
7
70
Boc
Boc
O
N
HN
HN
O
8
9
74
50
O
O
O
N
O
a
Isolated yields, the average of at least two runs. In a typical reaction, the N-Boc-
imines (1.5 mmol) were dissolved in 5 ml CH2Cl2 under a N2 atmosphere and stirred
2–3 h at room temperature with 10 mol % of the Brønsted acid such as fluorobric
acid or triflic acid. Acid was removed from the reaction mixture by passing the
a plug of neutral alumina. The solvent was removed under
reduced pressure and the pure oxazinanone was recrystallized from 5% to 10%
CH2Cl2 in pentane.
solution through
To understand the mechanism of the reaction, we investigated
the reaction by NMR spectroscopy.1H NMR revealed the presence
of 2-methylpropene (Fig. 1) in the reaction mixture which is likely
formed from the decomposition of the protonated N-Boc imine 3
(Scheme 2). The resulting 2-methylpropene reacts with Boc-imine
in the presence of acid, followed by cyclization to form the oxazin-
anone product 2. Evidence of this process is also supported directly
by observation using NMR. Indeed, the formation of the phenyl-
methaniminium ion (5, Fig. 1) in the reaction mixture is believed
to result from the rapid decarboxylation of 4 in Scheme 2. Several
other intermittent species are observed by low temperature NMR,
the exact nature of which is still under investigation.
In order to substantiate the formation of 2-methypropene as an
intermediate, the reaction was carried out by adding excess
2-methylpropene. The yield of oxazinanone product
2 was

N. Uddin et al. / Tetrahedron Letters 52 (2011) 4353–4356
4355
O
O
O
O
N
HN
O
HN
O
10 mol% HBF4 OEt2
CH2Cl2, rt
+
+
1
2 (30%)
6 (60%)
Scheme 4. HBF4ÁOEt2reaction of Boc-imine and styrene.
with Boc-imines to form the corresponding oxazinanones in good
yield (Table 4). Interestingly, -methylstyrene (Table 4, entry 4)
a
produced an oxazinanone possessed of a fairly congested tertiary
carbon center with the highest yield of all. As shown in the earlier
proposed mechanism (Scheme 2), the high yield of this product is
accounted for by the increased relative stability of the tertiary ben-
zylic carbocation. This latter result, concerning tolerance of steric
congestion and the lack of discrimination concerning styrenes con-
taining either EWG or EDG groups (Table 4, entries 2 and 3), further
exemplifies the robustness and versatility of this reaction. In 1990,
Overman reported a closely related reaction which involved intra-
molecular Boc-iminium ion-alkyne cycloaddition to form tricyclic
systems containing the oxazinanone ring system.9
In all these intermolecular reactions, we observed formation of
only the syn-diastereomer. The configuration of the product was
determined by comparing the spin–spin coupling constants with
known reported syn-compounds.10 The six-membered transition
state A, where both bulky aryl groups are equatorial positions
(syn) will be favorable over transition state B with one aryl group
Figure 1. 1H NMR (d = 1.77 and 4.71 ppm) of 2-methylpropene and phenylmeth-
animinium ion (d = 8.55 and 11.9 ppm) in reaction mixture.
O
O
H
H
H
H
OH
N
H
H
N
N
O
- CO2
H
+
3
5
4
H
H
H
O
O
Table 4
H
HBF4ÁOEt2-catalyzed reactions of Boc-imine and styrene derivatives
2
+
3
+
O
N
HN
O
O
Boc
+
HN
O
N
10 mol% HBF4 OEt2
CH2Cl2 , RT
Scheme 2. Proposed mechanism
R
R
improved upto 95%, corroborating our proposed mechanism. In
addition, to verify the incorporation of added 2-methylpropene
in the product, a reaction was conducted with fresh Boc-imine
and 2-methylpropene-1,1-d2 in the presence of fluoroboric acid.
The results were just as expected, 82% of the product was incorpo-
rated with deuterium (Scheme 3) confirming our assumptions of 2-
methylpropene in the reaction.
To further understand the mechanism of the reaction, a compet-
itive experiment was carried out in the presence of 1.2 equiv of sty-
rene. In this situation, both alkenes, 2-methylpropene from 1 and
styrene, competed with fresh Boc-imine to form the corresponding
oxazinanone product. The reaction provided 4,6-diphenyl-(1,3)-
oxazinan-2-one 6 along with 4-phenyl-6,6-dimethyl-(1,3)-oxaz-
inan-2-one, 2 (Scheme 4), which strongly supports the proposed
mechanism. Recently, a similar mechanism was proposed for the
formation of selective oxazinanone ring systems using triflic
acid-catalyzed reactions of vinylidene cyclopropanes with Boc-
imines.8
Entry
1
Styrene
Product
Yielda (%)
O
O
HN
72
70
70
O
O
HN
Cl
2
3
Cl
O
O
O
HN
HN
O
4
5
75
68
This intermolecular reaction facilitated the generation of oxaz-
inanones simply by Boc-imines reacting with different styrene
derivatives. More exactly, several styrene derivatives were reacted
O
O
HN
Boc
O
N
O
D
D
HN
Ph
O
HN
Ph
O
10 mol% HBF4 OEt2
CH2Cl2, 2-3 hr, rt
a
+
Isolated yields, the average of at least two runs. In a typical reaction, the N-Boc-
+
imines (1.3 mmol) and styrene derivative (1.6 mmol) were dissolved in 5 ml CH2Cl2
under a N2 atmosphere and stirred 2–3 h at room temperature with 10 mol % tet-
rafluorobric acid. Acid was removed from the reaction mixture by passing the
H
H
D
D
Excess
solution through
a plug of neutral alumina. The solvent was removed under
82%
18%
reduced pressure and the pure oxazinanone was recrystallized from 10% CH2Cl2 in
pentane.
Scheme 3. HBF4ÁOEt2 reaction of Boc-imine and 2-methylpropene-1,1-d2.

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N. Uddin et al. / Tetrahedron Letters 52 (2011) 4353–4356
References and notes
O
H
O
O
H
O
δ+
N
Ar
N
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Ar
Ar
δ+
Ph
Ph
H
H
H
O
H
Syn-6
A
H
+
favored
O
N
Ph
H
3
O
O
H
O
H
δ+
O
N
N
H
H
δ+
Ar
Ph
Ph
Ar
Ar
H
H
B
Anti-6
disfavored
Scheme 5. Proposed rationale for the stereoselective formation of 4,6-
diphenyloxazinanone.
at an axial position (Scheme 5). As a result, syn-4,6-diaryloxazina-
none 6 is expected to be the only or a major product.
To our knowledge, the reaction depicted in Scheme 1 is the first
recorded tandem elimination-cycloaddition reaction for the syn-
thesis of an oxazinanone ring system. To date, all of the reported
syntheses for making the oxazinanones 2 require three or more
steps.11 The chiral oxazinanones are employed as auxiliaries for
asymmetric enolate alkylation and aldol reactions,11b and also in
the synthesis of oxazolidinone derivatives.12 Oxazinanone deriva-
tives are of interest because they exhibit antibacterial activity
against gram-positive bacteria and are useful as PR modulators.13
Chiral Brønsted acid-catalyzed syntheses of optically active ana-
logs of oxazinanones are currently under investigation.
In summary, a new C–C bond formation reaction has been
developed using Brønsted acid catalysis. Cyclic oxazinanones are
produced from Boc-imines in one step, resulting in medium to high
yields. The atom-economic process presented here in Scheme 1 is
unprecedented in the area of organic chemistry and should extend
the scope of C–C bond forming reactions.
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We thank Professors James M. Cook, Alan W. Schwabacher, and
Dr. Matthew E. Dudley of the University of Wisconsin-Milwaukee
for their suggestions.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.054.