Hetero-Diels-Alder reaction of phosphinyl and phosphonyl nitroso alkenes with conjugated dienes: An aza-Cope rearrangement

Article abstract of DOI:10.1021/jo201116u

Phosphorylated nitroso alkenes react with cyclic dienes such as cyclopentadiene or cyclohexadiene to afford hetero Diels-Alder-type cycloadducts where the nitroso alkene participates as dienophile component and the cyclic olefin acts as the 4π-electron (diene) system. Subsequent aza-Cope rearrangement affords highly functionalized 5,6-dihydro-4H-1,2-oxazines. Conversely, the reaction of TMS-substituted cyclopentadiene (dienophile) with nitroso alkenes as heterodienes leads directly to bicyclic 1,2-oxazines. Theoretical studies are in agreement with the experimental results and with the new aza-Cope rearrangement proposed.

Full text of DOI:10.1021/jo201116u

ARTICLE
pubs.acs.org/joc
Hetero-DielsꢀAlder Reaction of Phosphinyl and Phosphonyl Nitroso
Alkenes with Conjugated Dienes: An Aza-Cope Rearrangement
Jesꢀus M. de los Santos, Roberto Ignacio, Gloria Rubiales, Domitila Aparicio, and Francisco Palacios*
Departamento de Química Orgꢀanica I, Facultad de Farmacia, Centro de Investigaciones y Estudios Avanzados “Lucio Lascaray”,
Universidad del País Vasco, Apartado 450, 01080 Vitoria, Spain
S Supporting Information
b
ABSTRACT: Phosphorylated nitroso alkenes react with cyclic
dienes such as cyclopentadiene or cyclohexadiene to afford
hetero DielsꢀAlder-type cycloadducts where the nitroso alkene
participates as dienophile component and the cyclic olefin acts
as the 4π-electron (diene) system. Subsequent aza-Cope re-
arrangement affords highly functionalized 5,6-dihydro-4H-1,2-
oxazines. Conversely, the reaction of TMS-substituted cyclo-
pentadiene (dienophile) with nitroso alkenes as heterodienes leads directly to bicyclic 1,2-oxazines. Theoretical studies are in
agreement with the experimental results and with the new aza-Cope rearrangement proposed.
Scheme 1. Hetero-DielsꢀAlder Reactivity Pattern of Nitroso
’ INTRODUCTION
Alkenes I with Dienes
The nitroso function has been widely recognized as a useful
source of nitrogen- and oxygen-containing molecules. The chem-
istry of nitroso compounds has been widely studied in recent
decades, especially because of their applications in the fields of
asymmetric synthesis and cycloaddition processes.1 In addition,
nitroso-DielsꢀAlder (nDA) reaction2,3 is a remarkable synthetic
transformation, providing easy access to synthetically useful
compounds such as 1,2-oxazines.
Nitroso alkenes4 are functionalized nitroso derivatives, which
have attracted a great deal of attention owing to their usefulness
as heterodienes for a [4 + 2]-cycloaddition reaction. These
nitroso alkenes I may react with dienes, in a DielsꢀAlder
reaction,5 either as dienophile (2π-electron) systems through
the nitroso group (mode i) or involving the carbonꢀcarbon
double bond (mode ii) or as 4π-electron (heterodiene) compo-
nents (mode iii) (see Scheme 1).
Acyclic and cyclic conjugated dienes, as a dienophile system,
also been used for the regioselective preparation of highly
functionalized N-hydroxypyrroles11 IV (see Scheme 2).
add to nitroso alkenes I involving reaction at the terminal carbon
and oxygen atoms (1,4-positions), most of which are unsubsti-
tutedat the terminal carbon atom (R1 = H) (route iii, Scheme 1).6
Likewise, cyclopentadiene and cyclohexadiene add to the nitroso
group of substituted nitroso alkenes I (R1 = Cl, Br, CO2R) (route i)
to give [4 + 2]-adducts7,8 which may isomerize at room temperature
to form epoxyaziridines.7 Clearly, the nitroso alkene substituents
play a crucial role. Early works of Gilchrist et al.9 also suggested
cycloadditions involving only the terminal carbonꢀcarbon dou-
ble bond of nitroso alkenes (route ii, Scheme 1).
We previously described the generation of phosphinyl II (R = Ph)
and phosphonyl nitroso alkenes II (R = OEt) and the conjugate
addition (1,4-addition) of some nucleophiles, such as amines
and amino-esters, for the preparation of R-amino phosphonate
derivatives10 III (see Scheme 2). Likewise, formal [3 + 2]
cycloaddition processes of phosphorated nitroso alkenes II have
Taking into account the interest of phosphorated substituted
heterocycles12 and following from our interest in the preparation
of three-,13 five-,14 and six-membered15 heterocycles and in the
reactivity of phosphorated nitroso alkenes,10,11 we report here
the combined theoretical and experimental study of the [4 + 2]-
cycloaddition reaction of phosphonyl and phosphinyl nitroso
alkenes II (R = Ph, OEt) to cyclic conjugated nucleophilic dienes
such as cyclopentadiene, cyclohexa-1,3-diene, and silyl-substi-
tuted cyclopentadiene. Moreover, we report the first example of a
tandem process involving an initial cycloaddition reaction fol-
lowed by a consecutive new [3,3]-sigmatropic rearrangement.
Received: May 31, 2011
Published: July 06, 2011
r
2011 American Chemical Society
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Scheme 2. Reactivity Pattern of Nitroso Alkenes II
Figure 1. NOE observed for 4-phophinyl-5,6-dihydro-4H-1,2-oxazine 7a.
Scheme 4. Mechanism for the Conversion of Adducts 4 into
1,2-Oxazines 7
Scheme 3. Hetero-DielsꢀAlder Reaction of Phosphorated
Nitroso Alkenes 1 with Cyclopentadiene 2a
in which the nitroso group of compound 1 may act as a
dienophile and the cyclopentadiene acts as diene. However,
the in situ heating of adducts 4a,b in refluxing chloroform for
48 h gave rise to a stable phosphinyl-5,6-dihydro-4H-1,2-oxazine
7a or the phosphonyl-5,6-dihydro-4H-1,2-oxazine 7b in good
yields. These products 7 could also be obtained from diene 2a
and nitroso derivatives 1, when these reagents were heated in
refluxing chloroform.
The regio- and stereochemistry of 1,2-oxazine 7a was based
upon the NOE, 1H, 13C, and 1Hꢀ H COSY NMR spectral data.
1
This process, in which the conjugated diene acts as a 4π-electron
component toward the nitrogenꢀoxygen double bond of the nitroso
alkene, provides an efficient access to a variety of phosphorus-
substituted cycloadducts V (see Scheme 2).
Namely, the stereochemistry of 7a was assigned on the basis of
NOE experiments. The 5,6-cis relationship of H-4a and H-7a in
the ring of 1,2-oxazine 7a was evident since a NOE was observed
between H-4a and H-7a (2.3%) (cis relative stereochemistry) and
between H-7a and H-7 (3.0%) after irradiation of proton H-7a
(Figure 1). These results clearly suggest a cis relative stereo-
chemistry between H-4a and H-7a. Conversely, a very small
NOE was observed between H-4 and H-4a (0.5%) suggesting a
trans relationship between both protons. Likewise, the regio-
chemistry of 7a was also confirmed by a NOE effect between H-4
and H-5 (1.3%). Comparable values were observed when
selective irradiations were performed with oxazine 7b.
’ RESULTS AND DISCUSSION
Experimental Study. The reaction of 1,2-oxazabuta-1,3-
dienes 1 with conjugated dienes was explored. Thus, as outlined
in Scheme 3, the addition of cyclopentadiene 2a to the highly
reactive 4-phosphinyl (1a, R = Ph) or 4-phosphonyl nitroso
alkene (1b, R = OEt), generated in situ from R-bromooximes,10
in CH2Cl2 at room temperature was performed. The highly
colored 1,2-oxazabuta-1,3-dienes 1 disappeared very quickly, and
instead of the hetero-DielsꢀAlder 1,2-oxazine 3, the 2-oxa-3-
azabicyclic derivatives 4 were observed in the reaction mixture as
sole adducts (Scheme 3). N-Vinyl bicyclic compounds 4 were
very sensitive to hydrolysis because all attempts to isolate these
adducts 4 by chromatographic methods were unsuccessful, and
the cleavage of the enaminic CꢀN bond in these intermediates
afforded the R-ketophosphine oxide 6a or R-ketophosphonate
6b and bicyclic amine 5 (Scheme 3, and Experimental Section).
Formation of adducts 4a,bmay be explained by a [4 + 2]-cycloaddition,
1,2-Oxazines 7 generated by the reaction of the nitroso alkenes
1 and the cyclopentadiene 2a seems to be the result of an initial
[4 + 2]-cycloaddition, in which the nitroso alkene acts as a
dienophile, through the nitroso group, while the cyclopentadiene
acts as diene to afford 2-oxa-3-azabicyclic compounds 4. These
adducts 4 may undergo an aza-Cope rearrangement16 to give 1,2-
oxazines 8 (Scheme 4). Compounds 8, with the bulky phos-
phorus substituent at C-4 in anti position with respect to H-4a
and H-7a, may suffer an imine-enamine tautomeric process (8 to
9) to give 1,2-oxazines 7 with the bulky phosphorus substituent
in syn position with respect to H-4a and H-7a, as confirmed by
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Scheme 5. Hetero-DielsꢀAlder Reaction of Phosphorated
Scheme 6. Hetero-DielsꢀAlder Reaction of Phosphorated
Nitroso Alkenes 1 with 1,3-Cyclohexadiene 2b
Nitroso Alkenes 1 with Substituted Cyclopentadiene 2c
the NOE experiments. The isolation of thermodynamically more
stable oxazine 7 toward 8 is in agreement with the calculated free
energy differences (see computational studies in Supporting
Information), which show that oxazines 7 are approximately 2
kcal/mol more stable than the corresponding oxazines 8. As far as
we know, this process represents the first example of a tandem
reaction of an initial [4 + 2]-cycloaddition reaction of the nitroso
alkene and subsequently a new [3,3]-sigmatropic (aza-Cope)
rearrangement to give 1,2-oxazine derivatives 7.
The process was extended to the reaction of 4-phosphorated-
1,2-oxazabuta-1,3-dienes 1 toward cyclohexa-1,3-diene 2b in
CH2Cl2 at room temperature to give hetero-DielsꢀAlder cy-
cloadducts 10a,b in excellent yield (Scheme 5). Similar behavior
as before was observed, and all attempts to isolate these cycloadducts
10a,b by chromatographic methods were unsuccessful (see
Experimental Section). Although cycloadducts 10a,b were fully
characterized from the crude reaction, in this case neither heating
these adducts in refluxing chloroform nor the use of Lewis acids
Figure 2. NOE observed for 4-phophinyl-5,6-dihydro-4H-1,2-oxazine
14a/15a.
derivatives 14a,b/15a,b in good yields and in a regio- and sterose-
lective fashion (Scheme 6). No formation of the regioisomeric
oxazine 16 was detected at all. 1H and 31P NMR spectral data for
crude compounds 14/15 reveals that a mixture of diastereoi-
somers in a ratio of 50:50 for compound 14a/15a and 92:8 for
compound 14b/15b are present in the crude reaction media.
However, the in situ heating of a mixture of cycloadducts 14/
15 in refluxing chloroform afforded a stable phosphorus
substituted 1,2-oxazines 14 in good yields. These oxazines
14 can also be obtained from conjugated nitroso alkenes 1
and olefine 2c, when these reagents were heated in refluxing
chloroform.
The regio- and stereochemistry of 1,2-oxazines 14/15 was
based upon the NOE and 1H NMR spectral data. The 4,5,6-cis
relationship between H-4, H-4a, and H-7a in the ring of 1,2-
oxazine 15a was evident since a NOE was observed between
H-4a and H-7a (4.4%) and between H-4a and H-4 (3.8%) after
irradiation of proton H-4a (cisꢀcis relative stereochemistry)
(Figure 2). Conversely, only a NOE was observed between
H-4a and H-7a (2.7%) in 1,2-oxazine 14a when proton H-4a
was irradiated, suggesting a cis relative stereochemistry between
H-4a and H-7a, and no NOE was observed between H-4a and
H-4 (trans relative stereochemistry). Likewise, the regiochem-
istry of 14a was also confirmed by a NOE between H-4 and H-5
(3.8%). Clearly different chemical shifts for H-5 were found for
both diastereoisomers. When the diphenylphosphinyl group at
C-4 adopts an anti position with respect to H-4a and H-7a
such as TiCl4, BF3 Et2O, or AlMe3 afforded phosphorated 1,2-
3
oxazines 11 (Scheme 5).
Evidence for the formation of the 2-oxa-3-azabicycle derivative
12 and thus for the formation of cycloadducts 10 was found
through treatment of crude compound 10b with trifluoroacetic
acid (TFA) in MeOH at room temperature. Under these
conditions salt 12 was obtained (Scheme 5). Likewise, the
treatment of adduct 10b with ZnCl2 was explored in order to
test whether NꢀO bond cleavage could be achieved in order to
obtain substituted amino alcohol 13. Hence, compound 10b was
subjected to ZnCl2 treatment in MeOH to afford the amino
alcohol derivative 13 (Scheme 5). Even though phosphorated
1,2-oxazines 11 cannot be obtained by heating the cycloadducts
10 (Scheme 5), isolation of salt 12 and amine 13 support the
formation of 2-oxa-3-azabicyclic cycloadducts 10 by the reaction
of nitroso alkenes 1 and cyclohexa-1,3-diene 2b.
1
(compound 15a), H-5 resonates at 2.70 ppm, while in the H
NMR spectrum the absorption of H-5 for compound 14a is
shifted to higher field (δH 1.60 ppm). Similar values were observed
for 1,2-oxazines 14b/15b.
In order to determine the scope and limitations of the
cycloaddition reaction between nitroso alkenes and cyclic con-
jugated dienes and to investigate the regio- and stereochemistry
of the additions, we extended the study to the reaction of
4-phosphorated-1,2-oxazabuta-1,3-dienes 1 with other cyclic
conjugated dienes, such as 5-(trimethylsilyl)cyclopenta-1,3-
diene 2c. Thus, reaction of nitroso alkenes 1 with substituted
cyclopentadiene 2c in CH2Cl2 at room temperature showed a
different reactivity pattern, affording a mixture of 1,2-oxazine
The formation of silylated oxazines 15, without detection of
the regioisomeric oxazines 16, can be explained by a regioselec-
tive [4 + 2]-cycloaddition reaction with the nitroso alkene as
the 4π-electron system6 (route iii of Scheme 1). As before in the
case of oxazine 8 and 7 (Scheme 4, vide supra), epimerization of
the bulky phosphorus substituent at C-4 of compound 15 to
oxazine 14 is thermodynamically favored because the latter is
about 4 kcal/mol more stable than the former oxazines 15 (see
Computational Studies).
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To the best of our knowledge, these novel strategies are the
first examples of the preparation of 4-phosphorated 1,2-oxazines.
1,2-Oxazines are of biological importance and have been used as
intermediates during the synthesis of glycosidase inhibitor
analogues,17 and functionalized pyrroles.18 They have found
numerous applications in the total synthesis of natural and
biologically active nitrogen-containing compounds, such as
alkaloids,19 pheromones20 or unnatural R-amino acids.21 1,2-
Oxazines are important structural constituents of many fun-
gicides and broad spectrum bactericides,22 as well as marine-
derived trichodermamides.23
Table 1. Hardnessesa (η, in au), Chemical Potentialsa (μ, in au),
Global Electrophilicitiesa (ω, in eV), and Maximum Number
of Accepted Electronsa (ΔNmax, in au) for Nitroso Alkenes 1a,
b and Cyclic Dienes 2aꢀc
entry
compound
η
μ
ω
ΔNmax
1
2
3
4
5
1a
1b
2a
2b
2c
0.11528
0.11748
0.20159
0.18841
0.20447
ꢀ0.17024
ꢀ0.17219
ꢀ0.11069
ꢀ0.11175
ꢀ0.10408
0.126
0.126
0.030
0.033
0.026
1.477
1.466
0.549
0.593
0.509
a Computed at the B3LYP/6-31G* level of theory according to the
approach and equations described previously.24
’ COMPUTATIONAL STUDIES
As has been shown in Scheme 1 for conjugated nitroso derivatives
I, nitroso alkenes 1 may potentially act in DielsꢀAlder reactions
not only as heterodienes (route iii) but also as dienophiles
(routes i and ii). Similarly, the presence of a second double bond
in the cyclic conjugated dienes open a new reactivity pattern to
the olefin, and these reagents may act as dienes (routes i and ii) or
dienophiles (route iii). Therefore, the aim of the present study
for the [4 + 2]-cycloaddition reactions of nitroso alkenes 1a
(R=Ph) and1b (R = OEt) with cyclic dienes such as cyclopentadiene
2a, cyclohexa-1,3-diene 2b, and 5-(trimethylsilyl)cyclopenta-1,3-
diene 2c was to elucidate whether nitroso alkenes 1 may play the
role of dienophiles or heterodienes in the cycloaddition reaction
with dienes 2 and to explore the regiocontrol and exo/endo
stereocontrol of these processes in order to find a possible
mechanism that may explain the different reactivity observed in
each case.
The molecular DFT-based parameters, electronic chemical
potential (μ), chemical hardness (η), global electrophilicity (ω),
and maximum number of accepted electrons (ΔNmax), for
nitroso alkenes 1a and 1b and cyclic dienes 2aꢀc are reported
in Table 1. These parameters indicate that nitroso alkenes
(Table 1, entries 1 and 2) are more electrophilic than cyclic
dienes (Table 1, entries 3ꢀ5). Thus, cyclic dienes 2aꢀc are
harder than nitroso alkenes 1a and 1b, the chemical potentials for
compounds 1 are lower than for compounds 2aꢀc, the com-
puted electrophilicities of 1 are larger than those computed for
cyclic dienes 2, and the ΔNmax values for 1a,b are the largest.
The presence of a TMS group in the cyclic diene 2c increases
the hardness and the chemical potential and decreases the
electrophilicity toward dienes 2a and 2b.
We next computationally examined the regio- and diastereos-
electivity of the [4 + 2]-cycloaddition reactions between nitroso
alkenes 1 and cyclic conjugated dienes 2. The approach of
compounds 1 to dienes 2 could lead to eight different cycloadducts
(Scheme 7). The cycloadducts are defined as endo/exo in the
standard way, on the basis of the orientation of the dienophile
with respect to the dienic system. Thus, nitroso alkenes 1 could
react with dienes 2 via transition structures TS1, where the
nitroso alkene acts as the 2π-electron system through the nitroso
moiety (nitroso DielsꢀAlder reaction, nDA), or via transition
structures TS2, with the nitroso alkene as the dienophile through
the CꢀC double bond (DielsꢀAlder reaction, DA), or via TS3
or TS4 transition structures, where the nitroso alkenes act as
heterodienes with two possible approaches, a or b, to the cyclic
diene 2 (so-called hetero-DielsꢀAlder reaction a or b, HDAa or
HDAb, respectively) (Scheme 7). Moreover, when nitroso
alkenes 1 act as dienophiles, the approach to dienic system could
be in the s-cis conformation 1a,b via transition structures TS1 and
TS2 or in the s-trans conformation 10a,b via transition structures
TS10 and TS20 (Scheme 7), since these approaches could afford
the same cycloadducts, respectively. Note that when R0 ¼ H
there are two possibilities for each pathway described above;
path syn or anti refers to the TMS group orientation of the dienophile
or the diene. It is also interesting to note that all of our attempts to
locate TS2-endo corresponding to the DA reaction through the
CꢀC double bond with endo approach met with no success, since all
the starting geometries converged to TS4-endo (Scheme 7) upon the
optimization at the B3LYP/6-31G* + ZPVE level.25
First, we studied the reaction of nitroso alkenes 1a (R = Ph) or
1b (R = OEt) with cyclopentadiene 2a. According to our results,
in all cases when nitroso alkenes 1 act as dienophile, the approach
to diene in s-cis conformation 1a,b through transition structures
TS1 and TS2 presents lower activation barriers than the
approach in the s-trans conformation 10a,b through transition
structures TS10 and TS20, respectively (for a full comparison of
energetics see Supporting Information). Moreover, the pathways
involving TS1-endo, TS3-endo, and TS4-endo transition state
structures (Table 2, entries 2, 4, 8, 10, 12, and 14) exhibit
activation barriers lower than those of the corresponding TS1-
exo, TS2-exo, TS3-exo, and TS4-exo transition state structures
(Table 2, entries 1, 3, 5ꢀ7, 9, 11, and 13). All of the processes are
exothermic and occur in a concerted manner but slightly
asynchronous (Table 2). The computational results indicate that
the formation of cycloadducts 4a,b-endo through transition state
structures TS1aa,ba-endo, for the nDA, have activation barriers
(Table 2, entries 2 and 4) lower than those observed when
nitroso alkenes 1 act as heterodienes reacting through TS3-endo
or TS4-endo for the HDA (Table 2, entries 8, 10, 12, and 14) to
give cycloadducts 8 or 26, respectively. With the inclusion of
methylene chloride as the solvent, the preference for TS1aa,ba-
endo for the nDA is more favored than TS4aa,ba-endo (1.8 kcal/
mol for R = Ph and 0.7 kcal/mol for R = OEt, see Supporting
Information). From these data, we could conclude that cycload-
ducts 4-endo will be the sole compounds to be obtained under
kinetic control, which is in agreement with the experimental
results. The endo transition structures with the lower activation
energies for each approach giving rise to the cycloaddition
reaction of 1a with 2a are summarized in Figure 3.
Experimentally, at room temperature only the nDA adducts
4a,b-endo are formed, but the heating of these adducts in
refluxing chloroform gives cycloadducts 7a,b. This may be
explained by a sigmatropic rearrangement of the nDA adducts
4a,b-endo to HDAa adducts 8a,b, which eventually gives 7a,b
through an imineꢀenamine tautomeric process. In fact, we have
located transition structures (TS5) that are associated with a
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Scheme 7. Possible Cycloadducts Corresponding to the Approach of Nitroso Alkenes 1 to Dienes 2
Table 2. Activation Energiesa (ΔEa, kcal/mol), Reaction
Energiesa (ΔErxn, kcal/mol), Synchronicitiesb (Sy) Associa-
ted with the Formation of Some Reaction [4 + 2]-Cycload-
ducts between Nitroso Alkenes 1a,b and Cyclopentadiene 2a
(For a Full Comparison of Energetics see Supporting Infor-
mation)
[3,3]ꢀshift and provide a pathway for the conversion of
cycloadducts 4a,b-endo into cycloadducts 8a,b through a hetero
ꢀClaisen rearrangement, allowing us to explain the experimental
results (Figure 4). This process is exothermic and occurs in a
concerted manner with an asynchronous bond formation (see
Table 2, entries 15 and 16). These TS5-aa,ba show activation
energies of 21.7 kcal/mol (21.9 kcal/mol in chloroform) for the
conversion of compound 4a-endo into 8a and of 23.0 kcal/mol
(22.9 kcal/mol in chloroform) for the conversion of compound
4b-endo into 8b. M06ꢀ2X calculated energetics which are
expected to be more accurate, also predicted analogous activation
barriers (for a full comparison of energetics see Table 3 in
Supporting Information). Hence, computational predictions
are consistent with our experimental results.
Analogously, we next investigated the regioselectivity in the
reaction of 1,3-cyclohexadiene 2b (Scheme 7, R0 = H, n = 2) and
nitroso alkenes 1a,b. Similarly to cycloadditions with 2a, when
nitroso alkenes 1 act as dienophile, the approach to nitroso
alkene in s-cis conformation 1a,b through transition structures
TS1 and TS2 presents activation barriers lower than those of the
approach to nitroso alkene in the s-trans conformation 10a,b
through transition structures TS10 and TS20 (for a full compar-
ison of energetics see Supporting Information). The pathways
involving endo transition state structures (Table 3, entries 2, 4, 8,
10, 12 and 14) exhibit activation barriers lower than those
involving exo transition state structures (Table 3, entries 1, 3,
5ꢀ7, 9, 11, and 13). All of the processes are exothermic and occur
in a concerted but asynchronous manner (see Table 3). Similarly
to the cyclopentadiene study, computational results indicate that
Syc
a
entry
reaction
TS
ΔEaa
ΔErxn
1
1a + 2a f 4a-exo
1a + 2a f 4a-endo
1b + 2a f 4b-exo
1b + 2a f 4b-endo
1a + 2a f 18a-exo
1b + 2a f 18b-exo
1a + 2a f 7a
TS1aa-exo
TS1aa-endo
TS1ba-exo
TS1ba-endo
TS2aa-exo
TS2ba-exo
TS3aa-exo
TS3aa-endo
TS3ba-exo
TS3ba-endo
TS4aa-exo
TS4aa-endo
TS4ba-exo
TS4ba-endo
TS5aa
14.4
7.4
ꢀ10.8
ꢀ13.0
ꢀ8.7
0.93
0.80
0.92
0.79
0.78
0.74
0.92
0.87
0.91
0.91
0.91
0.89
0.92
0.91
0.82
0.82
2
3
13.4
9.4
4
ꢀ13.8
ꢀ12.3
ꢀ11.6
ꢀ34.8
ꢀ32.7
ꢀ38.4
ꢀ36.3
ꢀ31.3
ꢀ29.6
ꢀ35.5
ꢀ35.2
ꢀ19.3
ꢀ21.9
5
11.7
14.2
13.0
10.0
14.3
9.8
6
7
8
1a + 2a f 8a
9
1b + 2a f 7b
10
11
12
13
14
15
16
1b + 2a f 8b
1a + 2a f 25a
1a + 2a f 26a
1b + 2a f 25b
1b + 2a f 26b
4a-endo f 8a
16.1
9.2
10.8
9.6
21.7
4b-endo f 8b
TS5ba
23.0
a Computed at the B3LYP/6-31G* + ZPVE level of theory. b Computed
at the B3LYP/6-31G* level of theory according to approach and
equations described previously.26 c For a perfectly synchronous reaction
Sy = 1.
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the nDA reaction between nitroso alkenes 1a (R = Ph) or 1b
(R = OEt) with cyclohexa-1,3-diene 2b through the TS1-endo, to
give cycloadduct 10a,b-endo, have the lowest activation barriers.
This may explain the kinetically favored formation of cycloadducts
10a,b-endo as compared to the formation of other cycloadducts, in
agreement with the experimental results.
Our experimental results show that heating of compounds
10a,b-endo in refluxing chloroform did not afford compounds 21
or 22. In this case, we also located the transition structures
(TS5ab,bb) corresponding to the hetero Claisen rearrangement
that could provide a pathway for the conversion of cycloadducts
10a,b-endo into cycloadducts 22a,b through a [3,3]-sigmatropic
rearrangement (Figure 5), but these transition structures lie in
higher activation energies (Table 3, entries 15 and 16) than for
cyclopentadiene derivatives (Table 2, entries 15 and 16) and the
processes are less exothermic than in the latter case. M06ꢀ2X
calculated energetics, which are expected to be more accurate,
predicted that activation barriers for TS5ab,bb for cyclohexa-1,3-
diene derivatives are bigger than for the corresponding cyclo-
pentadiene derivatives (see Figure 5 and Supporting Information
for a full comparison of energetics computed with different
methods). These results indicate that the conversion of com-
pounds 10a,b-endo into compounds 22a,b are not favored.
Moreover, the NꢀO and CꢀN bond distances in compounds
4-endo derived from cyclopentadiene are higher than in com-
pounds 10-endo derived from cyclohexa-1,3-diene. Conversely,
the CꢀNꢀO and NꢀOꢀC bond angles in compounds 4-endo
are lower than those observed for compounds 10-endo
(Figure 6). These structural differences could explain both the
greater stability observed for compounds 10-endo as compared
with compounds 4-endo and why heating these compounds in
refluxing chloroform did not afford compounds 22.
Table 3. Activation Energiesa (ΔEa, kcal/mol), Reaction
Energiesa (ΔErxn, kcal/mol), Synchronicitiesb (Sy) Asso-
ciated with the Formation of [4 + 2]-Cycloadducts of the
Reaction between Nitroso Alkenes 1a,b and Cyclohexa-1,3-
Diene 2b
Syc
a
entry
reaction
TS
ΔEaa
ΔErxn
1
1a + 2b f 10a-exo
1a + 2b f 10a-endo
1b + 2b f 10b-exo
1b + 2b f 10b-endo
1a + 2b f 19a-exo
1b + 2b f 19b-exo
1a + 2b f 21a
TS1ab-exo
TS1ab-endo
TS1bb-exo
TS1bb-endo
TS2ab-exo
TS2bb-exo
TS3ab-exo
TS3ab-endo
TS3bb-exo
TS3bb-endo
TS4bb-exo
TS4ab-endo
TS4bb-exo
TS4ab-endo
TS5ab
19.3
7.5
ꢀ16.8
ꢀ18.9
ꢀ16.0
ꢀ19.3
ꢀ13.0
ꢀ18.6
ꢀ33.1
ꢀ30.8
ꢀ38.6
ꢀ34.8
ꢀ34.9
ꢀ30.7
ꢀ37.7
ꢀ34.5
ꢀ11.9
ꢀ15.5
0.92
0.79
0.91
0.80
0.74
0.75
0.91
0.91
0.91
0.91
0.91
0.91
0.91
0.90
0.85
0.85
2
3
18.1
7.3
4
5
14.1
15.4
12.9
10.7
11.8
11.3
18.3
12.1
13.7
12.2
28.3
30.6
6
7
8
1a + 2b f 22a
9
1b + 2b f 21b
1b + 2b f 22b
1b + 2b f 27a
10
11
12
13
14
15
16
1a + 2b f 28a
1b + 2b f 27b
1a + 2b f 28b
Figure 3. Fully optimized endo transition structures with the lower
activation energies for the reaction of nitroso alkene 1a and cyclopenta-
diene 2a. Selected bond lengths are given in Å. The numbers given in
parentheses correspond to the relative energy differences (in kcal/mol)
of TS3aa-endo and TS4aa-endo with respect to TS1aa-endo calculated at
B3LYP/6-31G* + ΔZPVE level of theory. Numbers in square brackets
are the relative energies differences calculated a B3LYP(PCM)/6-31G*
using methylene chloride as the solvent.
10a-endo f 22a
10b-endo f 22b
TS5bb
a Computed at the B3LYP/6-31G* + ZPVE level of theory. b Computed
at the B3LYP/6-31G* level of theory according to approach and
equations. described previously.26 c For a perfectly synchronous reaction
Sy = 1.
Figure 4. Stationary points (B3LYP/6-31G* level) found in the conversion of cycloadduct 4b-endo to cycloadduct 8b. Bond lengths and energies are
given in Å and kcal/mol, respectively. Bold numbers over the arrows correspond to the relative energies calculated at B3LYP/6-31G* + ZPVE level.
Numbers within parentheses correspond to relative energies calculated to M06-2X/6-31G*//B3LYP/6-31G* + ZPVE level.
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Figure 5. Stationary points (B3LYP/6-31G* level) found in the conversion of cycloadduct 10b-endo to cycloadduct 22b. Bond lengths and energies are
given in Å and kcal/mol, respectively. Bold numbers over the arrows correspond to the relative energies calculated at the B3LYP/6-31G* + ZPVE level.
Numbers within parentheses correspond to relative energies calculated to M06-2X/6-31G*//B3LYP/6-31G* + ZPVE level.
Figure 6. Structural data for optimized compounds 4- and 10-endo. Bond lengths are given in Å.
Table 4. Activation Energiesa,b (ΔEa, kcal/mol), Reaction Energiesa,b (ΔErxn, kcal/mol), and Synchronicitiesc (Sy) Associated
with the Formation of [4 + 2]-Cycloadducts-A of the Reaction between Nitroso Alkenes 1a,b and TMS-Cyclopentadiene 2c
Syd
a
b
entry
R
reaction
TS
ΔEaa
ΔErxn
ΔEab
ΔErxn
1
Ph
1a + 2c f 17a-exo-A
1a + 2c f 17a-endo-A
1b + 2c f 17b-exo-A
1b + 2c f 17b-endo-A
1a + 2c f 20a-exo-A
1b + 2c f 20b-exo-A
1a + 2c f 23a-A
TS1ac-exo-A
TS1ac-endo-A
TS1bc-exo-A
TS1bc-endo-A
TS2ac-exo-A
TS2bc-exo-A
TS3ac-exo-A
TS3ac-endo-A
TS3bc-exo-A
TS3bc-endo-A
TS4ac-exo-A
TS4ac-endo-A
TS4bc-exo-A
TS4bc-endo-A
14.6
8.7
ꢀ5.0
ꢀ6.9
9.3
5.4
10.7
7.1
2.7
5.2
9.7
5.8
11.5
7.7
9.9
0.1
8.1
2.3
ꢀ17.7
ꢀ20.0
ꢀ16.2
ꢀ20.3
ꢀ25.5
ꢀ22.9
ꢀ42.7
ꢀ45.3
ꢀ46.3
ꢀ44.2
ꢀ44.3
ꢀ44.3
ꢀ48.1
ꢀ46.2
0.86
0.78
0.94
0.78
0.78
0.78
0.92
0.88
0.92
0.90
0.91
0.86
0.89
0.87
2
Ph
3
OEt
OEt
Ph
15.9
10.1
10.8
11.6
14.2
11.2
14.5
11.9
16.1
9.1
ꢀ3.2
4
ꢀ8.1
5
ꢀ5.2
6
OEt
Ph
ꢀ4.5
7
ꢀ25.9
ꢀ28.0
ꢀ32.1
ꢀ29.8
ꢀ30.0
ꢀ26.6
ꢀ33.3
ꢀ30.3
8
Ph
1a + 2c f 24a-A
9
OEt
OEt
Ph
1b + 2c f 23b-A
1b + 2c f 24b-A
1a+ 2c f 14a-A
10
11
12
13
14
Ph
1a + 2c f 15a-A
OEt
1b + 2c f 14b-A
13.3
OEt
1b + 2c f 15b-A
9.0
a Computed at the B3LYP/6-31G* + ZPVE level of theory. b Computed at the M06ꢀ2X/6-31G*//B3LYP/6-31G* + ZPVE level. c Computed at the
B3LYP/6-31G* level of theory according to approach and equations described previously.26 d For a perfectly synchronous reaction Sy = 1.
Finally, we investigated the regioselectivity in the reaction of
TMS-cyclopentadiene 2c (Scheme 7, R0 = TMS, n = 1) and
nitroso alkenes 1. It is important to note that for each cycload-
duct shown in Scheme 7, there are two possible approaches of
compound 2c, named “A” (if the group TMS is placed in anti)
and “B” (when placed at syn) referring to the orientation of the
TMS group and the dienophile or the diene. Transition struc-
tures endo and exo, syn and anti were located for nDA, DA, and
HDA cycloadditions, but all exo structures lie higher in energy
than the corresponding endo structures (see Supporting In-
formation). Also, all syn structures lie higher in energy than the
corresponding anti structures (see Supporting Information). It is
also interesting to note that, as in the previous studies with dienes
2a and 2b, all of our attempts to locate TS2-endo corresponding
to the DA reaction through the CꢀC double bond with endo
approach met with no success, since all of the starting geometries
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Figure 7. endo-A transition structures with the lower activation energies and adducts for the cycloaddition of nitroso alkene 1b and 2c. Bond lengths and
energies are given in Å and kcal/mol, respectively. Bold numbers over the arrows correspond to the relative energies calculated at the B3LYP/6-31G* +
ZPVE level. Numbers within parentheses correspond to relative energies calculated to M06-2X/6-31G*//B3LYP/6-31G* + ZPVE level.
Experimentally, the reaction of 2c with 1a,b gives epimeric
mixtures of compounds 14a,b-A and 15a,b-A, which after heating
leads to 14a,b-A as the only compounds through an imineꢀ
enamine tautomeric process. Calculated free energy differences
computed at B3LYP(PCM)/6-31G* using chloroform as solvent
indicate that these compounds 14a,b-A are about 4 kcal/mol
more stable than compounds 15a,b-A (Scheme 8 and Supporting
Information), and this result is in accord with the easy epimer-
ization of these compounds.
Scheme 8. Transformation of Compounds 15a,b-A in 14a,b-A
converged to TS4-endo upon the optimization at the B3LYP/6-
31G* + ZPVE level. Similarly, when nitroso alkenes 1 act as
dienophiles the approach in s-cis conformation 1 through transi-
tion structures TS1 and TS2 present activation barriers lower
than that observed for the approach in the s-trans conformation
10 through transition structures TS10 and TS20 (for a full
comparison of energetics see Supporting Information).
’ CONCLUSIONS
In conclusion, the first synthesis of functionalized 1,2-oxazines
containing a phosphine oxide or phosphonate group at the C-4
position of the heterocyclic system by means of a hetero-
DielsꢀAlder cycloaddition reaction of 4-phosphinyl or 4-phos-
phonyl nitroso alkenes, respectively, is described. Computational
and experimental studies indicate that conjugated nitroso alkenes
1 participate as 2π-electron components (heterodienophile),
through the nitroso group, toward cyclic nucleophilic dienes,
such as cyclopentadiene or cyclohexa-1,3-diene to afford the
corresponding cycloadducts 4 or 10, respectively, in a nitroso
DielsꢀAlder reaction (nDA) that takes place via an asynchronous
concerted mechanism through endo transition states. Cycload-
ducts 4, derived from cyclopentadiene, undergo a new aza-Cope
type [3,3]-sigmatropic rearrangement to give 1,2-oxazines 7.
However both computational and experimental results indicate
that cycloadducts 10 derived from cyclohexa-1,3-diene may be
stable and its subsequent [3,3]-sigmatropic rearrangement is not
favored by kinetic or thermodynamic control. Conversely, ni-
troso alkenes 1 could act as 4π-electron system (heterodiene) in
a HDA process when they react with TMS-cyclopentadiene,
which participate as the 2π-electron component, to give 1,2-
oxazine derivatives 15, and as in the preceding cases, the reaction
takes place via an asynchronous concerted mechanism through
endo transition states. It should be also emphasized that the use of
The activation barriers for the reaction of nitroso alkene 1a
(R = Ph) to give compounds 17a-endo-A and 15a-A, through
TS1ac-endo-A and TS4ac-endo-A, respectively, are very simi-
lar (Table 4, entries 2, and 12), and thus both mechanisms are
predicted to be competitive. However, for nitroso alkene 1b
(R = OEt) TS4bc-endo-A has the lower activation barrier, and
compound 15b-A could be the result expected under kinetic
control conditions (Table 4, entry 14). M06-2X calculated
energetics predicted that the transition structures TS4ac,bc-
endo-A for the HDAb are favored kinetically, in both cases (see
Table 4 entries 12 and 14, Figure 7 and Supporting Informa-
tion for a full comparison of energetics). Moreover, at all of
levels of theory examined, thermodynamics favor cycload-
ducts 15a,b-A over 17a,b-endo-A (Table 4, Figure 7). There-
fore, in these cases cycloadducts 15a,b-A could be the only
compounds obtained under both kinetic and thermodynamic
control. These results are in agreement with the regioselectivity
observed experimentally for the reaction of nitroso alkenes 1 and
cyclic diene 2c.
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ARTICLE
these very reactive phosphorylated heterodienes also opens a
novel route to other functionalized cyclic and acyclic phosphorus
compounds due to the marked ability of nitroso alkenes to add
nucleophiles. These 1,2-oxazine derivatives may be important
synthons in organic synthesis for the preparation of biologi-
cally active compounds of interest to medicinal chemistry.17ꢀ23
δ 7.90ꢀ7.81 (m, 4H), 7.59ꢀ7.47 (m, 6H), 5.72ꢀ5.69 (m, 1H),
5.11ꢀ5.09 (m, 1H), 4.55ꢀ4.49 (m, 1H), 3.83ꢀ3.77 (m, 1H), 3.21
2
3
(dd, JPH = 13.8 Hz, JHH = 3.3 Hz, 1H), 2.59ꢀ2.56 (m, 2H), 1.81
(d, 4JPH = 1.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 163.5 (d, 2JPC
=
4.0 Hz), 132.3, 132.3, 132.2, 132.1, 131.5, 131.4, 131.3, 130.5, 130.4,
128.9, 128.7, 128.6, 76.6, 45.9 (d, 2JPC = 2.0 Hz), 41.8 (d, 1JPC = 65.1
Hz), 39.6, 22.9 (d, 3JPC = 1.8 Hz); 31P NMR (120 MHz, CDCl3) δ 27.6;
HRMS (EI) m/z calcd for C20H20NO2P [M+] 337.1232, found [M+]
337.1234.
’ EXPERIMENTAL SECTION
Diethyl (4R*,4aS*,7aR*)-3-Methyl-4,4a,7,7a-tetrahydro-
cyclopenta[e][1,2]oxazin-4-ylphosphonate (7b)
General Methods. Et3N was distilled and then dried over molec-
ular sieves 70 Å. CH2Cl2 and cyclopentadiene were freshly distilled. All
other solvents and reagents were obtained from commercial sources and
used without further purification. All reactions were performed under an
atmosphere of dry nitrogen. Melting points are uncorrected. IR-FT
spectra were obtained as solids in KBr or as neat oils in NaCl. Mass
spectra (MS) were made by electron impact (EI) at an ionizing voltage
of 70 eV or by chemical ionization (CI) and high resolution mass spectra
Obtained as colorless oil (196 mg, 72%) from 1-bromo-2-hydroxyimi-
nopropyl phosphonic acid diethyl ester10 (287 mg, 1.0 mmol), Et3N
(168 μL, 1.2 mmol), and cyclopentadiene 2a (79 mg, 1.2 mmol) as
described in the general procedure. The crude product was purified by
flash chromatography (SiO2, AcOEt/pentane 20:80). IR (NaCl) νmax
2984, 1636, 1237, 1020 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 5.88ꢀ
5.80 (m, 1H), 5.56ꢀ5.54 (m, 1H), 4.74 (td, J = 7.6 Hz, J = 2.5 Hz, 1H),
4.22ꢀ4.11 (m, 4H), 3.79ꢀ3.63 (m, 1H), 2.75ꢀ2.61 (m, 3H), 2.14 (d,
4JPH = 1.8 Hz, 3H), 1.37ꢀ1.34 (m, 6H); 13C NMR (100 MHz, CDCl3)
δ 163.9 (d, 2JPC = 5.2 Hz), 131.8, 130.7 (d, 3JPC = 11.1 Hz), 76.4 (d, 3JPC
= 4.9 Hz), 62.6 (d, 2JPC = 6.7 Hz), 46.4 (d, 2JPC = 4.2 Hz), 39.7, 37.9 (d,
1
(HRMS) was measured by EI method. H (300, 400 MHz), 13C (75,
100 MHz) and 31P NMR (120 MHz) spectra were recorded on a 300 or
400 MHz spectrometers, respectively, in CDCl3, d6-DMSO or CD3OD,
as specified below. Chemical shifts (δH) are reported in parts per million
(ppm), relative to TMS as internal standard. All coupling constants (J)
values are given in Hz. Chemical shifts (δC) are reported in parts per
million (ppm) relative to CDCl3, d6-DMSO, or CD3OD as internal
standard in a broad band decoupled mode. The abbreviations used are as
follows: s, singlet; bs, broad singlet, d, doublet; dd, double doublet; t,
triplet; q, quartet, m, multiplet. Flash column chromatography was
performed using commercial grades of silica gel finer than 230 mesh.
Analytical thin layer chromatography was performed on precoated
Merck silica gel 60 F254 plates, and spot visualization was accomplished
by UV light (254 nm) or KMnO4 solution. The starting materials such
as phosphorylated R-bromooximes10 were prepared according to the
literature procedures.
General Procedure for the Reaction of Phosphorated
Nitroso Alkenes 1 with Cyclopentadiene 2a. To a stirred
solution of R-bromooxime10 (1.0 mmol) in CH2Cl2 (5 mL) were added
cyclopentadiene 2a (1.2 mmol) and triethylamine (1.2 mmol) at room
temperature and under a nitrogen atmosphere. The reaction was allowed
to stir at room temperature for 30 min. The solvent was removed by
rotary evaporation, and the residue was stirred with diethyl ether. The
triethyl amine hydrobromic salt was filtered through a sintered glass
vacuum filtration funnel with Celite. The filtrate was concentrated to
dryness in vacuum. The isolation of adducts 4 by chromatographic
methods afforded bicyclic oxazine 5,27 together with the corresponding
R-ketophosphine oxide 6a13b,28 or ketophosphonate 6b.29 These com-
pounds were shown to exhibit spectral data consistent with those
reported in the literature. Crude adducts 4 were dissolved in CHCl3
and stirred under reflux for 48 h. The solvent was removed by rotary
evaporation, and the crude compounds were purified by flash chroma-
tography to give 1,2-oxazines 7.
1JPC = 141.7 Hz), 22.1 (d, 3JPC = 1.5 Hz), 16.4 (d, 3JPC = 3.5 Hz); 31
P
NMR (120 MHz, CDCl3) δ 24.0; MS (CI) m/z 274 (M+ + 1, 100);
HRMS (EI) m/z calcd for C12H20NO4P [M+] 273.1130, found [M+]
273.1135.
General Procedure for the Reaction of Phosphorated
Nitroso Alkenes 1 with Cyclohexa-1,3-diene 2b. To a stirred
solution of R-bromooxime10 (1.0 mmol) in CH2Cl2 (5 mL) were added
1,3-cyclohexa-1,3-diene 2b (1.2 mmol) and triethylamine (1.2 mmol) at
room temperature and under a nitrogen atmosphere. The reaction was
allowed to stir at room temperature for 30 min. The solvent was
removed by rotary evaporation, and the residue was stirred with diethyl
ether. The triethyl amine hydrobromic salt was filtered through a
sintered glass vacuum filtration funnel with Celite. The filtrate was
concentrated to dryness in vacuum, and the crude cycloadducts 10 were
characterized without further purification steps.
(1R*,4S*)-3-((E)-1-(Diphenylphosphoryl)prop-1-en-2-yl)-
2-oxa-3-azabicyclo [2.2.2]oct-5-ene(10a)
(4R*,4aS*,7aR*)-4-(Diphenylphosphoryl)-3-methyl-4,4a,7,7a-
tetrahydrocyclopenta [e][1,2]oxazine (7a)
Obtained as colorless oil (337 mg, 96%) from 1-bromo-1-
(diphenylphosphoryl) propan-2-one oxime10 (351 mg, 1.0 mmol),
Et3N (168 μL, 1.2 mmol), and cyclohexa-1,3-diene 2b (114 μL,
1.2 mmol) as described in the general procedure. IR (NaCl) νmax 3423,
1
2975, 1721, 1601, 1251, 1193 cmꢀ1; H NMR (300 MHz, d6-DMSO)
δ 7.62ꢀ7.46 (m, 10H), 6.62ꢀ6.57 (m, 1H), 6.41ꢀ6.37 (m, 1H), 5.08 (d,
2JPH = 21.6 Hz, 1H), 4.77ꢀ4.74 (m, 1H), 4.60ꢀ4.59 (m, 1H), 1.99 (s,
Obtained as colorless oil (233 mg, 69%) from 1-bromo-1-
(diphenylphosphoryl) propan-2-one oxime10 (351 mg, 1.0 mmol),
Et3N (168 μL, 1.2 mmol), and cyclopentadiene 2a (79 mg, 1.2 mmol)
as described in the general procedure. The crude product was purified by
flash chromatography (SiO2, AcOEt/pentane 40:60). IR (NaCl) νmax
2955, 1636, 1436, 1256, 1105, 1020 cmꢀ1; 1H NMR (300 MHz, CDCl3)
3H), 1.45ꢀ1.11 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 161.0 (d, 2JPC
=
11.0 Hz), 137.0 (d, 1JPC = 103.2 Hz), 136.8 (d, 1JPC = 103.6 Hz), 130.9,
130.3, 130.2, 129.2, 128.6, 128.4, 91.1 (d, 1JPC = 118.7 Hz), 69.9, 50.8,
23.8, 20.6, 16.3 (d, 3JPC = 5.5 Hz); 31P NMR (120 MHz, d6-DMSO) δ
21.8; MS (CI) m/z 352 (M+ + 1, 18), 201 (100); HRMS (EI) m/z calcd
for C21H22NO2P [M+] 351.1388, found [M+] 351.1391.
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Diethyl (E)-2-((1R*,4S*)-2-Oxa-3-azabicyclo[2.2.2]oct-5-
en-3-yl)prop-1-enylphosphonate(10b)
and the residue was stirred with diethyl ether. The triethyl amine
hydrobromic salt was filtered through a sintered glass vacuum filtration
funnel with Celite. The solvent was removed by rotary evaporation, and
the crude compounds were purified by flash chromatography to afford a
mixture of oxazines in a ratio of 50:50 for compounds 14a/15a and 92:8
for compounds 14b/15b. The in situ heating of these mixtures of
cycloadducts 14/15 in refluxing chloroform afforded 1,2-oxazines 14.
(4S*,4aR*,5R*,7aR*)-4-(Diphenylphosphoryl)-3-methyl-5-
(trimethylsilyl)-4,4a,5,7a-tetrahydrocyclopenta[e][1,2]oxazine
(15a)
Obtained as brown oil (273 mg, 95%) from 1-bromo-2-hydroxyimino-
propyl phosphonic acid diethyl ester10 (287 mg, 1.0 mmol), Et3N
(168 μL, 1.2 mmol), and cyclohexa-1,3-diene 2b (114 μL, 1.2 mmol)
as described in the general procedure. IR (NaCl) νmax 3423, 2978, 1716,
1
1598, 1254, 1025, 951, 797 cmꢀ1; H NMR (300 MHz, CDCl3) δ
6.14ꢀ6.10 (m, 1H), 5.89ꢀ5.84 (m, 1H), 4.32 (d, 2JPH = 13.8 Hz, 1H),
4.29ꢀ4.25 (m, 1H), 4.10ꢀ4.04 (m, 1H), 3.79ꢀ3.50 (m, 4H), 1.71 (s,
3H), 1.18ꢀ0.82 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 160.3 (d,
2JPC = 19.6 Hz), 130.0, 127.4, 86.3 (d, 1JPC = 203.3 Hz), 69.5, 59.8 (d,
2JPC = 5.6 Hz), 50.3, 23.1, 19.9, 15.3 (d, 3JPC = 7.0 Hz), 7.7; 31P NMR
(120 MHz, CDCl3) δ 24.9; HRMS (EI) m/z calcd for C13H22NO4P
[M+] 287.1286, found [M+] 287.1289.
Obtained as colorless solid from 1-bromo-1-(diphenylphosphoryl)
propan-2-one oxime10 (351 mg, 1.0 mmol), Et3N (168 μL, 1.2 mmol),
and 5-(trimethylsilyl) cyclopenta-1,3-diene 2c (199 μL, 1.2 mmol) as
described in the general procedure before heating in refluxing chloro-
form. The crude product was purified by flash chromatography (SiO2,
AcOEt/pentane 50:50) to get oxazine 15a.1H NMR (300 MHz, CDCl3)
δ 7.94ꢀ7.39 (m, 10H), 5.94ꢀ5.91 (m, 1H), 5.53ꢀ5.50 (m, 1H),
5.48ꢀ5.46 (m, 1H), 3.73ꢀ3.69 (m, 1H), 3.39ꢀ3.32 (m, 1H), 2.77ꢀ
2.75 (m, 1H), 2.01 (s, 3H),ꢀ 0.27 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
169.6, 140.2, 131.9, 131.9, 131.8, 131.7, 131.6, 131.6, 131.5, 130.7, 130.6,
130.1, 130.0, 129.1, 129.0, 129.0, 128.9, 128.9, 128.8, 128.7, 128.5, 128.4,
124.5, 88.5 (d, 2JPC = 10.2 Hz), 42.9, 37.6, 36.0 (d, 1JPC = 79.7 Hz), 20.8
(d, 3JPC = 2.6 Hz), ꢀ 3.0; 31P NMR (120 MHz, CDCl3) δ 24.3.
(4R*,4aR*,5R*,7aR*)-4-(Diphenylphosphoryl)-3-methyl-5-
(trimethylsilyl)-4,4a,5,7a-tetrahydrocyclopenta[e][1,2]oxazine
(14a)
General Procedure and Spectral Data of (1R*,4S*)-2-Oxa-
3-azoniabicyclo[2.2.2]oct-5-ene 2,2,2-trifluoroacetate (12)
To a stirred solution of cycloadduct 10b freshly prepared (287 mg,
1.0 mmol) in MeOH (5 mL) was added some drops of trifluoroacetic
acid at room temperature. The reaction was allowed to stir at room
temperature for 2 h. The solvent was removed by rotary evaporation, and
the residue was purified by flash chromatography (SiO2, AcOEt/MeOH
98:2) to afford 10 (50 mg, 22% from R-bromoketone10) as colorless oil.
1
IR (NaCl) νmax 3417, 1670, 1197, 1145 cmꢀ1; H NMR (300 MHz,
CD3OD) δ 6.90 (ddd, J = 7.8 Hz, J = 5.8 Hz, J = 1.2 Hz, 1H), 6.64 (ddd,
J = 7.8 Hz, J = 6.3 Hz, J = 1.2 Hz, 1H), 4.95ꢀ5.00 (m, 1H), 4.55ꢀ4.50
(m, 1H), 2.30ꢀ2.15 (m, 2H), 1.62ꢀ1.56 (m, 2H); 13C NMR (75 MHz,
2
1
CD3OD) δ 163.2 (q, JFC = 32.6 Hz), 137.3, 130.0, 118.4 (q, JFC
=
294.0 Hz), 72.3, 50.2, 23.1, 18.4; 19F RMN (282 MHz, CD3OD) δ ꢀ
76.4; MS (CI) m/z 111 (M+ ꢀ CF3CO2, 100); HRMS (EI) m/z calcd
for C8H10F3NO3 [M+] 225.0613, found [M+] 225.0617.
General Procedure and Spectral Data of (1S*,4R*)-4-Ami-
nocyclohex-2-enol (13)
Obtained as colorless solid (360 mg, 88%) from 1-bromo-1-
(diphenylphosphoryl) propan-2-one oxime10 (351 mg, 1.0 mmol),
Et3N (168 μL, 1.2 mmol), and 5-(trimethylsilyl) cyclopenta-1,3-diene
2c (199 μL, 1.2 mmol) as described in the general procedure. The crude
product was purified by flash chromatography (SiO2, AcOEt/pentane
50:50). Mp 131ꢀ133 °C; IR (KBr) νmax 3052, 2949, 2909, 1636, 1436,
1191, 1111 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.97ꢀ7.43 (m, 10H),
5.87ꢀ5.84 (m, 1H), 5.55ꢀ5.51 (m, 1H), 5.15ꢀ5.12 (m, 1H), 3.47
(dddd, J = 12.9 Hz, J = 9.3 Hz, J = 3.9 Hz, J = 1.2 Hz, 1H), 3.08 (d, 2JPH
=
13.5 Hz, 1H), 1.75 (d, 4JPH = 2.1 Hz, 3H), 1.66ꢀ1.62 (m, 1H), ꢀ 0.15
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 165.0 (d, 2JPC = 5.0 Hz), 137.1,
132.3, 132.3, 132.2, 132.2, 131.9, 131.8, 131.7, 131.6, 131.5, 130.7, 130.3,
129.1, 129.0, 128.8, 128.7, 128.5, 128.3, 127.7, 83.4, 47.6 (d, 1JPC = 61.1
Hz), 45.2 (d, 2JPC = 9.5 Hz), 39.4 (d, 3JPC = 2.5 Hz), 24.0 (d, 3JPC = 1.0
Hz), ꢀ 3.4; 31P NMR (120 MHz, CDCl3) δ 27.1; HRMS (EI) m/z calcd
for C23H28NO2PSi [M+] 409.1627, found [M+] 409.1629.
Diethyl (4R*,4aR*,5R*,7aR*)-3-Methyl-5-(trimethylsilyl)-
4,4a,5,7a-tetrahydrocyclopenta[e][1,2]oxazin-4-ylphospho-
nate (14b)
To a stirred solution of cycloadduct 10b freshly prepared (287 mg,
1.0 mmol) in dry MeOH (5 mL) was added a solution of ZnCl2 (134 mg,
1.0 mmol) at 0 °C. The reaction was allowed to stir from 0 °C to room
temperature and was kept for an additional 2 h at room temperature. The
crude reaction mixture was filtered through a sintered glass vacuum
filtration funnel with Celite, the solvent was removed to dryness in
vacuum, and the crude compound was purified by flash chromatography
(SiO2, AcOEt) to afford amino alcohol 13 (19 mg, 17% from R-
bromooxime10) as colorless oil. Spectral data are in agreement with
those reported in the literature.30
General Procedure for the Reaction of Phosphorated
Nitroso Alkenes 1 with 5-(Trimethylsilyl)cyclopenta-1,3-
diene 2c. To a stirred solution of R-bromooxime10 (1.0 mmol) in
CH2Cl2 (5 mL) were added 5-(trimethylsilyl)cyclopenta-1,3-diene 2c
(1.2 mmol) and triethylamine (1.2 mmol) at room temperature and
under a nitrogen atmosphere. The reaction was allowed to stir at room
temperature for 30 min. The solvent was removed by rotary evaporation,
Obtained as colorless oil (300 mg, 87%) from 1-bromo-2-hydroxyimi-
nopropyl phosphonic acid diethyl ester10 (287 mg, 1.0 mmol), Et3N
6724
dx.doi.org/10.1021/jo201116u |J. Org. Chem. 2011, 76, 6715–6725

The Journal of Organic Chemistry
ARTICLE
(168 μL, 1.2 mmol), and 5-(trimethylsilyl)cyclopenta-1,3-diene 2c
(199 μL, 1.2 mmol) as described in the general procedure. The crude
product was purified by flash chromatography (SiO2, AcOEt/pentane
50:50) affording a mixture of diastereoisomers in a ratio of 92:8. Major
(7) (a) Francotte, E.; Merꢀenyi, R.; Vandenbulcke-Coyette, B.; Viehe,
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diastereoisomer: IR (NaCl) νmax 2984, 2949, 1630, 1242, 1025, 837 cmꢀ1
;
1H NMR (300 MHz, CDCl3) δ 5.89ꢀ5.85 (m, 1H), 5.56ꢀ5.52 (m,
1Hm), 5.23ꢀ5.20 (m, 1H), 4.22ꢀ4.02 (m, 4H), 3.35ꢀ3.25 (m, 1H), 2.54
(d, 2JPH = 24.9 Hz, 1H), 2.12 (d, 4JPH = 2.4 Hz, 3H), 1.61ꢀ1.57 (m, 1H),
1.31 (td, 3JHH = 7.2 Hz, 4JPH = 1.2 Hz, 6H), ꢀ 0.01 (s, 9H); 13C NMR
2
(75 MHz, CDCl3) δ 164.1 (d, JPC = 6.4 Hz), 137.4, 127.3, 83.0, 63.1
(d, 2JPC = 6.5 Hz), 62.4 (d, 2JPC = 7.0 Hz), 45.2 (d, 2JPC = 13.0 Hz), 42.2 (d,
1JPC = 135.2 Hz), 39.2 (d, 3JPC = 5.0 Hz), 23.6 (d, 3JPC = 1.9 Hz), 16.4 (d,
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3JPC = 6.0 Hz), 16.3 (d, JPC = 6.5 Hz), ꢀ 3.5; 31P NMR (120 MHz,
3
CDCl3) δ 23.7minor, 21.6major; HRMS (EI) m/z calcd for C15H28NO4PSi
[M+] 345.1525, found [M+] 345.1526.
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’ ASSOCIATED CONTENT
S
Supporting Information. Spectra data for all new com-
b
pounds; computational methods; Cartesian coordinates, harmo-
nic analysis data, and energies for all the stationary points
discussed in the text. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: francisco.palacios@ehu.es.
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’ ACKNOWLEDGMENT
This work was financially supported by the Universidad del
País Vasco-Departamento de Educaciꢀon, Universidades e In-
vestigaciꢀon del Gobierno Vasco (GIU-09/57; IT-422-10) and
Direcciꢀon General de Investigaciꢀon del Ministerio de Ciencia e
Innovaciꢀon (DGI, CTQ2009-12156 BQU). We also thank
SGIker technical support for computational resources, and
NMR spectra (MCINN, GV/EJ, European Social Found).
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