Efficient synthesis of 5-chalcogenyl-1,3-oxazin-2-ones by chalcogen-mediated yne-carbamate cyclisation: An experimental and theoretical study

Article abstract of DOI:10.1002/ejoc.201403169

A very efficient synthesis of 5-chalcogenyl-1,3-oxazin-2-ones has been accomplished by the chalcogen-mediated yne-carbamate cyclisation of chiral, non-racemic N-Cbz-protected propargylic amines using PhXY (X = Se, S, Te; Y = Br or Cl) as electrophile sources. The reactions gave good-toexcellent yields for a wide range of substrates. In all cases the reaction was totally regioselective, occurring by a 6-endo-dig process regardless of the nature of the reagent and of the substituents in the starting material. This methodology permits the formation of the 1,3-oxazin-2-one moiety as well as the simultaneous installation of a chalcogen functionality onto the heterocyclic ring. The experimental results have been rationalised by theoretical studies at the B3LYP/6-311G level of theory.

Full text of DOI:10.1002/ejoc.201403169

Job/Unit: O43169
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FULL PAPER
DOI: 10.1002/ejoc.201403169
Efficient Synthesis of 5-Chalcogenyl-1,3-oxazin-2-ones by Chalcogen-Mediated
Yne–Carbamate Cyclisation: An Experimental and Theoretical Study
Alicia Monleón,[a] Gonzalo Blay,[a] Luis R. Domingo,*[a] M. Carmen Muñoz,[b] and
José R. Pedro*[a]
Keywords: Cyclization / Regioselectivity / Nitrogen heterocycles / Chalcogens / Reaction mechanisms / Density functional
calculations
A very efficient synthesis of 5-chalcogenyl-1,3-oxazin-2-ones
has been accomplished by the chalcogen-mediated yne–
process regardless of the nature of the reagent and of the
substituents in the starting material. This methodology per-
carbamate cyclisation of chiral, non-racemic N-Cbz-pro- mits the formation of the 1,3-oxazin-2-one moiety as well as
tected propargylic amines using PhXY (X = Se, S, Te; Y = Br
or Cl) as electrophile sources. The reactions gave good-to-
excellent yields for a wide range of substrates. In all cases the
reaction was totally regioselective, occurring by a 6-endo-dig
the simultaneous installation of a chalcogen functionality
onto the heterocyclic ring. The experimental results have
been rationalised by theoretical studies at the B3LYP/6-
311G* level of theory.
ties.[6] Consequently, a number of methods have been re-
ported in recent years that lead to the synthesis of this kind
of compound.[7] However, the development of new and ef-
ficient protocols for the synthesis of functionalised chalco-
gen-substituted heterocycles remains an important chal-
lenge in organic chemistry.[8] Indeed, several important
heterocycles, such as indoles,[9] pyrroles,[10] benzofurans,[11]
Introduction
Carbamates are an important class of compounds that
show interesting properties and find wide utility in several
areas, such as pharmaceuticals,[1] agrochemicals[2] and ma-
terials.[3] Although there are a variety of methods for the
synthesis of this kind of compound,[4] the development of
practical and efficient methods for the preparation of cyclic
carbamates, especially those that are densely functionalised,
is of great interest.
On the other hand, the interest in organochalcogenide
compounds has increased considerably in the last decade,
because the introduction of chalcogen groups into organic
molecules modifies their physical and chemical properties
as well as biological activities. The polarisation of the
carbon–chalcogen bond leads to a wide range of applica-
tions in organic synthesis,[5] because it allows the introduc-
tion of new functionalities through the replacement of the
carbon–chalcogen bond by carbon–halogen, carbon–lith-
ium or carbon–carbon bonds. Organochalcogenides show
potential biological activities such as antiviral, antihyper-
tensive, antioxidant, antimicrobial and anticancer proper-
benzothiophenes,[12]
benzoselenophenes,[11b,13]
thio-
phenes,[14] furans[15] and benzopyrans,[16] have been synthe-
sised by electrophilic cyclisation of suitable unsaturated sys-
tems with a wide range of internal nucleophilic groups.
These strategies are of particular interest because valuable
hetero- and carbocycles can be readily formed under rela-
tively mild conditions.
Bearing in mind these bibliographic records and our own
experience,[17] we reasoned that the electrophilic cyclisation
reactions of N-Cbz-protected propargylic amines by using
selenium, sulfur or tellurium electrophilic reagents could
provide an interesting synthesis of functionalised chalco-
gen-substituted heterocycles, and a study of the regioselec-
tivity of the cyclisation reaction would be of significant
interest. When an N-Cbz-protected propargylic amine of
type 1 is subjected to an electrophilic O-cyclisation process,
two reaction modes are possible: the 6-endo-dig mode that
should yield 1,3-oxazin-2-ones 2 and the 5-exo-dig mode
that should yield 1,3-oxazolidin-2-ones 5 (Scheme 1). Sev-
eral authors have proved that both cyclisation modes are
possible in reactions carried out on related substrates, and
have shown that the regioselectivity of the reaction depends
on the structure of the starting material and the nature of
the reagent or catalyst.[18–22]
[a] Departament de Química Orgànica-Facultat de Química,
Universitat de València,
C/ Dr. Moliner 50, 46100 Burjassot, València, Spain
E-mail: jose.r.pedro@uv.es
domingo@utopia.uv.es
http://www.uv.es
[b] Departamento de Física Aplicada, Universitat Politècnica de
València,
Camí de Vera s/n, 46022 València, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403169.
Eur. J. Org. Chem. 0000, 0–0
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A. Monleón, G. Blay, L. R. Domingo, M. C. Muñoz, J. R. Pedro
FULL PAPER
drawing (Cl) and -donating (Me) substituents were well tol-
erated at para and ortho positions, with yields ranging from
88 to 99%. In addition, the phenylseleno cyclisation of N-
Cbz-protected propargylic amines 1 derived from alkyl-sub-
stituted imines also gave the corresponding products in very
good yield (90%, Table 1, entry 4). Various N-Cbz-pro-
tected propargylic amines 1 bearing different aromatic and
aliphatic groups attached to the alkyne moiety afforded the
corresponding products 2 in excellent yields in the most
cases (Table 1, entries 5–7); although the aryl-substituted
starting materials 1e,f afforded the corresponding phenyl-
selenylated cyclisation products in excellent yields (96–
99%), the 2-phenylethyl-substituted 1g only gave a moder-
ate yield (71%).
Scheme 1. Electrophilic yne–carbamate chalcogen-cyclisation of N-
Cbz-protected propargylic amines.
In our previous paper[17] on the O-cyclisation reactions
of N-Cbz-protected propargylic amines promoted by
halogens, a totally regioselective 6-endo-dig process was ob-
served. However, in the metal-catalysed cyclisation of N-
Boc-protected propargylic amines described by Carretero
and co-workers,[20] the reaction took place by the intra-
molecular 5-exo-dig mode to afford five-membered-ring
products 5. Also, metal-catalysed 5-exo-dig cyclisation of
carbamate-protected propargylic alcohols[21] and ureas[22]
providing five-membered carbamates and carbamimidates,
respectively, have recently been described. Therefore good
control of the regioselectivity of the O-chalcogen cyclisation
reaction is essential for the selective preparation of 2 or 5
(Scheme 1). In this paper we report our experimental results
on such a reaction. To the best of our knowledge, there is
no protocol describing the simultaneous formation of the
1,3-oxazin-2-one system and the installation of a chalcogen
functionality onto the heterocycle ring by using N-Cbz-pro-
tected propargylic amines as substrates through yne–carb-
amate electrophilic cyclisation reactions. Also, the mecha-
nism of this reaction has been investigated theoretically.
Table 1. Electrophilic yne–carbamate cyclisation of N-Cbz-pro-
tected propargylic amines 1 to 5-chalcogenyl-1,3-oxazin-2-ones 2.[a]
Entry
1
R1
R2
PhXY Time Product Yield
[h]
[%][b]
1
2
3
4
5
6
7
8
1a Ph
Ph
Ph
Ph
Ph
PhSeCl 0.25
PhSeCl 0.25
PhSeCl 0.25
PhSeCl 0.5
PhSeCl 0.25
2a
2b
2c
2d
2e
2f
2g
3a
3b
3c
3h
3e
3f
4a
4i
4j
4k
4l
4g
99
88
99
90
99
96
71
92
93
78
90
99
79
75
87
58
65
75
80
1b 4-ClC6H4
1c 2-MeC6H4
1d n-Butyl
1e Ph
1f Ph
1g Ph
1a Ph
1b 4-ClC6H4
1c 2-MeC6H4
1h C6H5CH2CH2 Ph
1e Ph
1f Ph
1a Ph
1i 4-MeC6H4
1j Cyclohexyl
1k Ph
4-FC6H4
2-MeOC6H4 PhSeCl 0.25
PhCH2CH2 PhSeCl 0.5
Ph
Ph
Ph
PhSCl
PhSCl
PhSCl
PhSCl
PhSCl
0.5
1
0.5
0.5
1
9
10
11
12
13
14
15
16
17
18
19
4-FC6H4
2-MeOC6H4 PhSCl 0.25
Ph
Ph
Ph
4-ClC6H4
2-Thienyl
PhTeBr
PhTeBr
4
3
PhTeBr 20
PhTeBr
PhTeBr
4
2
4
1l Ph
1g Ph
PhCH2CH2 PhTeBr
[a] Reagents and conditions: 1 (0.1 mmol), phenylselenyl chloride
(0.15 mmol), acetonitrile (2.5 mL, entries 1–7); 1 (0.1 mmol), phen-
ylsulfenyl chloride in 1,2-dichloroethane (0.4 m, 0.15 mmol), aceto-
nitrile (2.5 mL, entries 8–13); 1 (0.1 mmol), phenyltellanyl bromide
in 1,2-dichloroethane (0.5 m, 0.15 mmol), acetonitrile (2.5 mL, en-
tries 14–19). [b] Yield of isolated product.
Results and Discussion
The required starting materials, N-Cbz-protected prop-
argylic amines 1, were readily prepared by the addition of
terminal alkynes to imines generated in situ from α-amido
sulfones in the presence of diethylzinc and BINOL-type
ligands as catalyst following our previously reported
Under similar reaction conditions, we next evaluated the
method.[23] To establish the appropriate reaction conditions phenylsulfenyl cyclisation reaction of several N-Cbz-pro-
for the electrophilic cyclisation we treated N-Cbz-1,3-di- tected propargylic amines 1. Thus, the starting material dis-
phenylprop-2-yn-1-amine (1a) with phenylselenyl chloride solved in acetonitrile was treated with 1.5 equiv. of a freshly
(1.5 equiv.) in acetonitrile (2.0 mL) at 0 °C. Under these re- prepared 0.4 m solution of phenylsulfenyl chloride in 1,2-
action conditions we obtained the corresponding 5-phenyl- dichloroethane at 0 °C.[24] The reaction proceeded to give
selenylated-1,3-oxazin-2-one 2a with an endocyclic double good-to-excellent yields of 5-phenylthio-1,3-oxazin-2-ones 3
bond as the only product with total regioselectivity and in (Table 1, entries 8–13). Aromatic groups with an electron-
quantitative yield (99%). These reaction conditions allowed withdrawing substituent at the para position provided the
us to synthesise a wide range of 4,6-disubstituted 3,4-di- cyclisation products in excellent yields (93–99%; Table 1,
hydro-5-phenylselenylated-1,3-oxazin-2-ones 2 through a 6- entries 9 and 12), whereas the utilisation of propargylic
endo-dig O-cyclisation process in good-to-excellent yields. amines with aromatic groups bearing an electron-donating
Several N-Cbz-protected propargylic amines 1 derived from group at the ortho position gave the desired products in
the addition of phenylacetylene to N-Cbz-imines of substi- somewhat lower yields (78–79%; Table 1, entries 10 and 13).
tuted benzaldehydes (Table 1, entries 1–3) were transformed The cyclisation reaction of a propargylic amine derived
into the corresponding 5-phenylselenylated 1,3-oxazin-2- from an aliphatic aldehyde occurred in high yield (90%;
ones 2 in good-to-excellent yields. Both electron-with- Table 1, entry 11).
2
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Chalcogen-Mediated Yne–Carbamate Cyclisation
Finally, N-Cbz-protected propargylic amines 1 dissolved
in acetonitrile were treated with a freshly prepared 0.5 m
solution of phenyltelluryl bromide in 1,2-dichloroethane.[25]
These yne–carbamate cyclisation reactions required longer
times and provided the 5-phenyltellanyl-1,3-oxazin-2-ones 4
in moderate-to-high yields (58–87%; Table 1, entries 14–
19). The cyclisation of propargylic amines derived from
benzaldehyde and p-tolylaldehyde yielded the correspond-
ing products in good yields (75–87%; Table 1, entries 14
and 15). However, the utilisation of the propargylic amine
derived from cyclohexanecarbaldehyde 1j provided the de-
sired 1,3-oxazin-2-one 4j in moderate yield (58%; Table 1,
entry 16). Both aromatic and heteroaromatic groups at-
tached to the alkyne moiety were tolerated by this pro-
cedure (Table 1, entries 17 and 18). In addition, 2-phenyl-
ethyl-substituted 1g gave the corresponding 1,3-oxazin-2-
one 4g in 80% yield (Table 1, entry 19).
Scheme 2. Oxidation of 3a to yield 6a.
The structures of 5-phenylchalcogenyl-1,3-oxazin-2-ones
2–4 were elucidated by X-ray diffraction analysis and spec-
troscopic methods. Due to the failure to obtain appropriate
monocrystals of products 2–4, 5-phenylthio-1,3-oxazin-2-
one 3a was subjected to oxidative conditions,[9a] yielding a
diastereomeric mixture of the corresponding sulfoxide de-
Figure 1. ORTEP plot of the X-ray structure of compound 6a. The
thermal ellipsoids are drawn at the 50% probability level.
rivative 6a, from which the major diastereomer was isolated 150 ppm, the quaternary olefinic S–C= appears at high field
(Scheme 2). An X-ray diffraction analysis of this dia- at δ = 106–107 ppm and the CH appears at δ = 54–60 ppm.
stereomer allowed us to establish its structure and un- In the case of 5-phenylselenyl-1,3-oxazin-2-ones 2, the carb-
equivocally confirmed the existence of the six-membered onyl group gives a signal at δ = 150–151 ppm (when R2
ring, as illustrated in Figure 1.[26]
is aromatic) and δ = 154 ppm (when R2 is aliphatic), the
A
13C NMR spectroscopic analysis was carried out to quaternary olefinic =C–O resonates at δ = 149–152 ppm,
ensure that all the chalcogen-mediated cyclisation reactions the quaternary olefinic Se–C= appears at high field at δ =
proceeded by a 6-endo-dig mechanism. We compared the 103–105 ppm and the CH appears at δ = 55–60 ppm. Fi-
13C NMR signals of the four carbon atoms in the six-mem- nally, the 13C NMR spectra of 5-phenyltellanyl-1,3-oxazin-
bered ring containing the cyclic carbamate (Table 2). In the 2-ones 4 shows the signal of the carbonyl group at δ = 150–
case of the 5-phenylthio-1,3-oxazin-2-ones 3, the carbonyl 151 ppm (when R1 and R2 are aromatic) and δ = 152–
group gives a signal at δ = 152–153 ppm (when R2 is aro- 154 ppm (when R1 or R2 is aliphatic), the quaternary ole-
matic), the quaternary olefinic =C–O resonates at δ = 149– finic =C–O resonates at δ = 150–152 ppm, the quaternary
Table 2. 13C NMR signals of the four carbon atoms in the six-membered ring containing the cyclic carbamate in compounds 2–4.
Entry
2–4
X
R1
R2
δ [ppm]
C=O[a]
=C–O[a]
X–C=
CH
1
2
3
4
5
6
7
8
3a
3b
3c
3h
3e
3f
2a
2b
2c
2d
2e
2f
S
S
S
S
S
S
Se
Se
Se
Se
Se
Se
Se
Te
Te
Te
Te
Te
Te
Ph
Ph
Ph
Ph
Ph
152.93
153.03
153.31
153.42
151.99
157.44
151.50
151.61
151.84
151.74
150.61
157.44
153.95
151.86
151.85
152.19
150.91
149.95
154.56
150.06
149.94
149.89
151.01
149.80
150.14
150.27
150.12
150.03
151.65
150.11
150.14
149.88
150.38
150.33
152.19
150.09
146.27
150.08
106.79
106.48
106.32
106.68
106.83
105.93
103.85
103.49
103.38
104.23
104.01
105.93
103.11
89.14
58.78
58.13
55.22
53.93
58.88
60.17
60.21
59.62
56.75
55.75
60.35
60.17
60.16
62.54
62.37
62.50
62.85
63.22
63.21
4-ClC6H4
2-MeC6H4
PhCH2CH2
Ph
Ph
Ph
4-ClC6H4
2-MeC6H4
n-butyl
Ph
Ph
Ph
4-FC6H4
2-MeOC6H4
Ph
Ph
Ph
9
10
11
12
13
14
15
16
17
18
19
Ph
4-FC6H4
2-MeOC6H4
PhCH2CH2
Ph
Ph
Ph
4-ClC6H4
2-thienyl
PhCH2CH2
2g
4a
4i
Ph
4-MeC6H4
cyclohexyl
Ph
Ph
Ph
89.49
88.53
89.82
88.46
4j
4k
4l
4g
89.41
[a] Signals could be exchanged.
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A. Monleón, G. Blay, L. R. Domingo, M. C. Muñoz, J. R. Pedro
FULL PAPER
olefinic Te–C= appears at high field at δ = 88–89 ppm and Table 3. Relative energies in acetonitrile (relative to 1a plus PhSeCl)
of the stationary points involved in the cyclisation reaction of pro-
tected propargylic amine 1a with PhSeCl.
the CH appears at δ = 62–63 ppm. Only in the case of sub-
strates with an ortho substituent or with a heterocyclic ring
are small deviations from these values observed (see
E [kcalmol–1]
Table 2, entries 6, 12, and 18).
1a + PhSeCl
MC
TS1-endo
TS1-exo
IN1-endo
IN1-exo
0.0
–0.8
4.5
11.1
–12.6
–12.5
–4.6
–5.1
–22.6
–24.4
Determination of the enantiomeric excesses by chiral
HPLC analysis of the products showed no epimerisation at
the stereogenic centre regardless of the nature of the reagent
and of the reaction time.
The 3,4-dihydro-5-chalcogenyl-1,3-oxazin-2-ones 2–4 ob- TS2-endo
tained by the electrophilic yne–carbamate cyclisation reac-
tions are versatile compounds for the construction of more
complex structures, especially considering the reactivity of
organochalcogen derivatives towards halogens and Li/Se
exchange reactions.[27]
TS2-exo
2a + PhCH2Cl
5a + PhCH2Cl
To understand the mechanism of the chalcogen-mediated
yne–carbamate cyclisation of N-Cbz-protected propargylic
amine 1a, and particularly its regioselectivity to yield the
six-membered 5-phenylselanyl-1,3-oxazin-2-one 2a, a theo-
retical study using density functional theory (DFT) at the
B3LYP/6-311G* level of theory in acetonitrile was carried
out (Scheme 3). It is important to note that this theoretical
study was carried out by using the same starting material
as in the experimental work, without any kind of approxi-
mation by using a model compound.
A study of the potential energy surface of the title reac-
tion indicates that the cyclisation takes place through a two-
step mechanism. In the first step, the selenium atom of
PhSeCl electrophilically attacks the C1 or C2 carbon atom
of the triple bond of the propargylic amines to provide the
cationic intermediate IN1-endo or IN1-exo via the corre-
sponding transition states TS1-endo or TS1-exo, respec-
tively. In the second step, the benzyl group on the carb-
amate substituent is eliminated assisted by the halide anion
Cl– to yield the final 1,3-oxazin-2-one 2a or 1,3-oxazolidin-
2-one 5a. The total and relative energies in acetonitrile are
given in Table 3 (Figure 2).
Figure 2. Relative energies in acetonitrile (in kcalmol–1, relative to
1a plus PhSeCl) of the stationary points involved in the cyclisation
of 1a with PhSeCl.
energies associated with the electrophilic attacks of PhSeCl
In an earlier step of the reaction, PhSeCl forms a weak on the C1 and C2 carbon atoms of propargylic amine 1a
molecular complex (MC) with the π system of the triple are 4.5 (TS1-endo) and 11.1 kcalmol–1 (TS1-exo), respec-
bond of propargylic amine 1a. The MC is located tively, and the formation of the corresponding cationic in-
–0.8 kcalmol–1 below the separated reagents. The activation termediates are exothermic by –12.6 (IN1-endo) and
Scheme 3. Two regioisomeric reaction pathways associated with the yne–carbamate phenylselenocyclisation of propargylic amine 1a.
4
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Chalcogen-Mediated Yne–Carbamate Cyclisation
–12.5 kcalmol–1 (IN1-exo). Elimination of the benzyl group In the corresponding intermediates IN1-endo and IN1-exo,
from these cationic intermediates takes place by a nucleo- the lengths of the Se6–C2(1) and O3–C1(2) bonds are 1.931
philic substitution of the benzyl group assisted by the chlor- and 1.439 Å, and 1.944 and 1.432 Å, respectively. These
ide anion Cl– generated in the first step of the reaction. geometrical parameters indicate that the Se6–C2(1) bond
From the corresponding intermediates, the activation ener- formation is very advanced in the TS1s, with the O3–C2(1)
gies associated with the extrusion of the benzyl group are bond formation more delayed.
8.0 (TS2-endo) and 7.4 kcalmol–1 (TS2-exo), respectively.
In the TSs associated with the elimination of the benzyl
The formation of 1,3-oxazin-2-one 2a and oxazolidin-2-one group from IN1-endo and IN1-exo, the lengths of the O4–
5a plus PhCH2Cl is exothermic by –22.6 and C5 breaking bond and the C5–Cl7 forming bond are 2.015
–24.4 kcalmol–1, respectively.
and 2.775 Å, respectively, in TS2-endo and 1.981 and
Some important conclusions can be drawn from these 2.821 Å, respectively, in TS2-exo. Thus, in these asynchro-
data. 1) The electrophilic attack of the chalcogen PhSeCl nous TSs, the O4–C5 breaking bonds are more advanced
on the triple bond of the propargylic amine 1a is completely than the C5–Cl7 forming bond.
regioselective, TS1-endo being 6.6 kcalmol–1 lower in en-
From the theoretically calculated energies and geometries
ergy than TS1-exo. 2) The highly exothermic character of of the TSs and INs involved in the two regioisomeric path-
the first step makes this step irreversible. 3) The activation ways, an explanation for the origin of the 6-endo-dig over
energy associated with the second step (8.0 kcalmol–1) is 5-exo-dig selectivity can be given. The energy profiles given
higher than that associated with the first step in Figure 2 show that the formation of IN1-endo and IN1-
(4.5 kcalmol–1), thus, the elimination of the benzyl substitu- exo is irreversible. Consequently, the 6-endo-dig versus 5-
ent is the rate-determining step (RDS) of the reaction. Con- exo-dig selectivity is resolved during the first step of the
sequently, although the electrophilic attack of the chalcogen reaction. This first step is associated with two chemical pro-
PhSeCl on the propargylic amine 1a is the regioselectivity- cesses: 1) the electrophilic attack of the chalcogen PhSeCl
determining step, the benzyl elimination is the RDS of the on the C1 or C2 carbon of the triple bond of the proparg-
reaction. 4) These results are similar to those of our pre- ylic amine 1a and 2) a ring-closing process yielding the cor-
viously reported study on halogen-mediated cyclisation of responding cyclic intermediates. Analysis of the TS geome-
N-Cbz-protected propargylic amines.[17]
tries indicates that at this stage of the reaction, the electro-
The geometries of the transitions states (TSs) and inter- philic attack of the chalcogen is very advanced. Conse-
mediates (INs) involved in the regioisomeric pathways asso- quently, the relative energies of TS1-endo and TS1-exo can
ciated with the chalcogen-mediated yne–carbamate cycli- be correlated with the local nucleophilic activation of the
sation of propargylic amine 1a are given in Figure 3. In the C1 and C2 carbon atoms of the triple bond of 1a because
TSs associated with the first step of the chalcogen-mediated the subsequent ring closure is directed by the creation of
cyclisation reaction, the lengths of the Se6–C2(1) and O3– a new electrophilic centre during the electrophilic attack.
–
C1(2) forming bonds are 2.020 and 2.204 Å, respectively, in Analysis of the nucleophilic Pk Parr functions[28] in prop-
TS1-endo, and 2.093 and 2.154 Å, respectively, in TS1-exo. argylic amine 1a indicates that the β-conjugated C2 carbon,
–
Pk = 0.30, is the most nucleophilic centre in this molecule.
–
Note that the nucleophilic Pk Parr function at the C1
carbon presents a low value of 0.01. Consequently, it is ex-
pected that the more favourable electrophilic attack of the
chalcogen on the C2 carbon of 1a generates the electro-
philic centre at C1 carbon, and this behaviour forces the
concomitant ring closure at this carbon via TS1-endo. Con-
sequently, we can conclude that the 6-endo-dig selectivity is
determined by the electronic response of the propargylic
amine 1a to the electrophilic attack of the chalcogen more
than the steric factor associated with the formation of the
six-membered TS1-endo compared with the five membered
TS1-exo.
Conclusions
A very efficient synthesis of 5-chalcogenyl-1,3-oxazin-2-
ones has been developed by an yne–carbamate chalcogen-
mediated regioselective cyclisation of chiral, non-racemic
N-Cbz-protected propargylic amines. A broad range of sub-
Figure 3. Geometries of the TSs and INs involved in the regioiso-
strates have been transformed under these cyclisation condi-
meric pahways associated with the chalcogen-mediated cyclisation
tions in the presence of PhSeCl, PhSCl or PhTeBr as elec-
trophile reagents. All the reactions proceeded through a 6-
of N-Cbz-protected propargylic amine 1a. The lengths of the form-
ing and breaking bonds are given in Ångstroms.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Pages: 9
A. Monleón, G. Blay, L. R. Domingo, M. C. Muñoz, J. R. Pedro
FULL PAPER
plete (TLC). The reaction mixture was then concentrated under
reduced pressure. Purification by flash chromatography on silica
gel afforded compound 3.
endo-dig mode of cyclisation to give good-to-excellent
yields. This methodology permits the formation of the 1,3-
oxazin-2-one moiety and the simultaneous installation of a
chalcogen functionality onto the heterocyclic ring and pro-
vides a useful alternative to the reported literature protocols
for preparing cyclic carbamates. In addition, DFT calcula-
tions were performed to rationalise the experimental results.
(S)-4,6-Diphenyl-5-(phenylthio)-3,4-dihydro-2H-1,3-oxazin-2-one
(3a): M.p. 158–159 °C. [α]2D0 = +328.0 (c = 1.00, CHCl3, 87% ee).
1H NMR (300 MHz, CDCl3): δ = 7.72–7.68 (m, 2 H), 7.41–7.22
(m, 13 H), 6.10 (br. s, 1 H), 4.87 (d, J = 2.3 Hz, 1 H) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 152.9 (C), 150.1 (C), 140.6 (C),
133.7 (C), 131.5 (C), 130.1 (CH), 129.4 (CH), 129.1 (CH), 129.0
(CH), 128.8 (CH), 128.7 (CH), 127.9 (CH), 127.1 (CH), 127.0
(CH), 106.8 (C), 58.8 (CH) ppm. HRMS (ESI): m/z (%) =
360.1051/361.1083 (100.0/25.3) [M + H]+; calcd. for C22H18NO2S:
360.1058/361.1092. The enantiomeric excess (87%) was determined
by chiral HPLC (Chiralcel AD-H): hexane/iPrOH, 90:10, 1 mL/
min, major enantiomer: tr = 12.3 min, minor enantiomer: tr =
23.4 min.
Experimental Section
General Methods: Reactions were carried out under nitrogen in
round-bottomed flasks oven-dried overnight at 120 °C. Commer-
cial reagents were used as purchased. The N-Cbz-protected prop-
argylic amines 1 were prepared from the corresponding α-amido
sulfones and alkynes as described in the literature.[23] Solvents were
dried when necessary: dichloromethane was distilled from CaH2.
Reactions were monitored by TLC analysis by using Merck silica
gel 60 F-254 thin-layer plates. Flash column chromatography was
performed on Merck silica gel 60 (0.040–0.063 mm). Melting points
were determined with a Büchi M-560 apparatus. 1H and 13C NMR
spectra were recorded at 300 and 75.5 MHz, respectively, with a
Typical Procedure for the Phenyltellanyl Cyclisation of the N-Cbz-
Protected Propargylic Amines 1: The phenyltelluryl bromide solu-
tion was prepared by the addition of bromine (10 μL, 0.2 mmol) to
a flask containing diphenyl ditelluride (81.9 mg, 0.2 mmol) in 1,2-
dichloroethane (0.4 mL) at 0 °C. The reaction mixture was stirred
for 15 min at this temperature.[25] A 0.5 m solution of phenyltelluryl
bromide in 1,2-dichloroethane (0.3 mL, 0.15 mmol) was added to
a solution of N-Cbz-protected propargylic amine 1 (0.10 mmol) in
acetonitrile (2 mL) at 0 °C. The solution was stirred until the reac-
tion was complete (TLC). The reaction mixture was then concen-
trated under reduced pressure. Purification by flash chromatog-
raphy on silica gel afforded compound 4.
1
Bruker Avance 300 DPX spectrometer. H and 13C NMR spectra
were internally referenced to the CDCl3 signal (δ = 7.26 and
77.0 ppm, respectively). Chemical shifts are reported in ppm. The
type of carbon was determined by DEPT experiments. HRMS were
recorded with a Waters Q-TOF premier spectrometer (ESI). Spe-
cific optical rotations were measured by using sodium light (D line,
λ = 589 nm). Chiral HPLC analyses were performed by using an
Agilent 1100 Series chromatograph equipped with a UV diode-
array detector and chiral stationary columns from Daicel.
(S)-4,6-Diphenyl-5-(phenyltellanyl)-3,4-dihydro-2H-1,3-oxazin-2-one
(4a): M.p. 61–63 °C. [α]2D0 = +50.8 (c = 0.39, CHCl3, 87% ee). H
1
NMR (300 MHz, CDCl3): δ = 7.52–7.47 (m, 4 H), 7.43–7.39 (m, 3
H), 7.35–7.30 (m, 4 H), 7.23–7.16 (m, 4 H), 5.97 (br. d, J = 1.6 Hz,
1 H), 4.86 (d, J = 2.4 Hz, 1 H) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 151.9 (C), 150.4 (C), 140.9 (C), 138.7 (CH), 134.4 (C), 130.0
(CH), 129.5 (CH), 129.1 (CH), 128.9 (CH), 128.7 (CH), 128.6
(CH), 128.0 (CH), 127.3 (CH), 113.0 (C), 89.1 (C), 62.5 (CH) ppm.
HRMS (ESI): m/z (%): 458.0395/456.0379 (100.0/93.1) [M +
H]+; calcd. for C22H18NO2Te: 458.0400/456.0382. The enantio-
meric excess (87%) was determined by chiral HPLC (Chiralcel OD-
H): hexane/iPrOH, 90:10, 1 mL/min, major enantiomer: tr =
13.1 min, minor enantiomer: tr = 16.5 min.
Typical Procedure for the Phenylseleno Cyclisation of the N-Cbz-
Protected Propargylic Amines 1: Phenylselenyl chloride (101.4 mg,
0.15 mmol) was added to a solution of N-Cbz-protected proparg-
ylic amine 1 (0.10 mmol) in acetonitrile (2 mL) at 0 °C. The solu-
tion was stirred until the reaction was complete (TLC). The reac-
tion mixture was then concentrated under reduced pressure. Purifi-
cation by flash chromatography on silica gel afforded compound
2.
(S)-4,6-Diphenyl-5-(phenylselanyl)-3,4-dihydro-2H-1,3-oxazin-2-one
(2a): M.p. 157–160 °C. [α]2D0 = +157.1 (c = 1.00, CHCl3, 86% ee).
1H NMR (300 MHz, CDCl3): δ = 7.62–7.59 (m, 2 H), 7.44–7.23
(m, 13 H), 6.16 (br. d, J = 1.9 Hz, 1 H), 4.86 (d, J = 2.4 Hz, 1
H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 151.5 (C), 150.3 (C),
140.8 (C), 132.5 (C), 131.9 (CH), 130.0 (CH), 129.5 (CH), 129.2
(CH), 128.94 (CH), 128.89 (C), 128.8 (CH), 127.9 (CH), 127.7
(CH), 127.2 (CH), 103.9 (C), 60.1 (CH) ppm. HRMS (ESI): m/z
Preparation of (S)-4,6-Diphenyl-5-[(R)-phenylsulfinyl]-3,4-dihydro-
2H-1,3-oxazin-2-one (6a): A 30 % H2O2 solution (10.2 μL,
0.10 mmol) was added to a solution of (S)-4,6-diphenyl-5-(phen-
ylthio)-3,4-dihydro-2H-1,3-oxazin-2-one (3a; 18.0 mg, 0.05 mmol)
and phenol (54 μL, 0.60 mmol) in 1,1,1,3,3,3-hexafluoro-2-prop-
anol (0.4 mL).[9a] The reaction mixture was stirred at room tem-
perature until the disappearance of the reactant, monitored by
TLC, and then the excess H2O2 was quenched with saturated aque-
ous Na2SO3. The phenol was neutralised with 10 % aqueous
NaOH. The aqueous layer was extracted with EtOAc (2ϫ 3 mL)
and the combined organic layers were dried with anhydrous MgSO4
and concentrated under vacuum to afford the crude product, which
was purified by flash column chromatography on silica gel using
hexane/ethyl acetate as the eluent to afford 6a (99% yield, 1:2.5 dr).
Only the major diastereoisomer was characterised.
(%)
= 408.0500/406.0507 (100.0/51.2) [M +
H]+; calcd. for
C22H18NO2Se: 408.0503/406.0511. The enantiomeric excess (86%)
was determined by chiral HPLC (Chiralcel OD-H): hexane/iPrOH,
90:10, 1 mL/min, major enantiomer: tr = 13.0 min, minor enantio-
mer: tr = 23.1 min.
Typical Procedure for the Phenylsulfenyl Cyclisation of the N-Cbz-
Protected Propargylic Amines 1: The phenylsulfenyl chloride solu-
tion was first prepared by adding sulfuryl chloride (80 μL,
1.0 mmol) to a solution of diphenyl sulfide (240.2 mg, 1.1 mmol)
in 1,2-dichloroethane (3 mL) at room temperature. The solution
(S)-4,6-Diphenyl-5-[(R)-phenylsulfinyl]-3,4-dihydro-2H-1,3-oxazin-
2-one (6a): M.p. 159–161 °C. [α]2D0 = +43.0 (c = 0.70, CHCl3, 87%
ee). 1H NMR (300 MHz, [D6]DMSO): δ = 8.35–8.32 (m, 2 H), 8.14
(br. d, J = 2.3 Hz, 1 H), 8.09–8.04 (m, 8 H), 7.92–7.77 (m, 5 H),
5.21 (br. d, J = 2.8 Hz, 1 H) ppm. 13C NMR (75.5 MHz, [D6]-
DMSO): δ = 168.4 (C), 158.9 (C), 153.8 (C), 152.5 (C), 141.9 (CH),
was stirred for 5 min and the volume was diluted to 5 mL.[24]
A
freshly prepared 0.4 m solution of phenylsulfenyl chloride in 1,2-
dichloroethane (0.375 mL, 0.15 mmol) was added to a solution of
N-Cbz-protected propargylic amine 1 (0.10 mmol) in acetonitrile
(2 mL) at 0 °C. The solution was stirred until the reaction was com-
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O43169
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Date: 22-12-14 11:20:16
Pages: 9
Chalcogen-Mediated Yne–Carbamate Cyclisation
arenko, A. K. Kiemer, C. Jacob, Tetrahedron 2012, 68, 10577–
141.6 (CH), 141.4 (C), 140.1 (CH), 140.0 (CH), 139.4 (CH), 139.2
(CH), 138.7 (CH), 137.3 (CH), 135.1 (CH), 130.1 (C), 63.6
(CH) ppm. HRMS (ESI): m/z (%) = 375.9906/376.9911 (100/24.4)
[M + H]+; calcd. for C22H18NO3S: 376.1002/377.1036.
10585; e) J. Vargas, S. Narayanaperumal, K. Gul, B. B. Rav-
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Acknowledgments
Financial support from the Ministerio de Economía y Competitivi-
dad (MINECO), Gobierno de España, from the European Union
(EU) (Fondos Europeos para el Desarrollo Regional (FEDER),
grant numbers CTQ2009-13083 and CTQ2013-47494-P) and from
the Generalitat Valenciana (grant numbers ACOMP2012-212 and
ISIC2012/001 and a pre-doctoral grant to A. M.) is gratefully ac-
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Eur. J. Org. Chem. 0000, 0–0
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A. Monleón, G. Blay, L. R. Domingo, M. C. Muñoz, J. R. Pedro
FULL PAPER
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[26] X-ray data for compound 6a: crystallised from ethyl acetate/n-
hexane at 0 °C. C22H17NO3S, Mr = 375.43, orthorhombic,
space group = P212121, a = 9.7840(4), b = 10.5230(4), c =
18.1390(6) Å,
V = Z = 4, ρcalcd. =
1867.54(12) Å3,
1.335 Mgm–3, μ = 0.195 mm–1, F(000) = 784. A colourless crys-
tal of 0.04ϫ0.06ϫ0.10 mm3 was used; 2666 [R(int) = 0.0548]
independent reflections were collected with an Enraf–Nonius
CCD diffractometer by using graphite-monochromated Mo-Kα
radiation (λ = 0.71073 Å) operating at 50 kV and 30 mA. The
cell parameters were determined and refined by a least-squares
fit of all reflections. The first 100 frames were re-collected at
the end of the data collection to monitor crystal decay; no ap-
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43169
/KAP1
Date: 22-12-14 11:20:16
Pages: 9
Chalcogen-Mediated Yne–Carbamate Cyclisation
Yne–Carbamate Cyclisation
A. Monleón, G. Blay, L. R. Domingo,*
M. C. Muñoz, J. R. Pedro* ............... 1–9
Efficient Synthesis of 5-Chalcogenyl-1,3-
oxazin-2-ones by Chalcogen-Mediated
Yne–Carbamate Cyclisation: An Exper-
imental and Theoretical Study
5-Chalcogenyl-1,3-oxazin-2-ones (chalcog-
enyl = SePh, SPh, TePh) have been syn-
thesised in good yields and with total re-
gioselectivity from chiral, non-racemic N-
Cbz-protected propargylic amines through
a 6-endo-dig cyclisation process. The exper-
imental results have been rationalised by
computational studies at the B3LYP/6-
311G* level of theory.
Keywords: Cyclization / Regioselectivity /
Nitrogen heterocycles / Chalcogens / Reac-
tion mechanisms / Density functional cal-
culations
Eur. J. Org. Chem. 0000, 0–0
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9