Synthesis of densely functionalised 5-halogen-1,3-oxazin-2-ones by halogen-mediated regioselective cyclisation of N-Cbz-protected propargylic amines: A combined experimental and theoretical study

Article abstract of DOI:10.1002/chem.201302089

A very efficient synthesis of 5-halogen-1,3-oxazin-2-ones has been accomplished by the halocyclisation reaction of chiral nonracemic N-carbobenzyloxy (N-Cbz)-protected propargylic amines by using I₂, Br₂ and Cl₂ as electrophile sources. The nature of the halogen influences the reaction time and yield. However, in all cases the reaction is totally regioselective taking place through a 6-endo-dig process regardless of the nature of the halogen and of the substituents in the starting material. To rationalise the experimental results, theoretical studies at the B3LYP/6-311G* level have been performed. Copyright

Full text of DOI:10.1002/chem.201302089

FULL PAPER
DOI: 10.1002/chem.201302089
Synthesis of Densely Functionalised 5-Halogen-1,3-oxazin-2-ones by
Halogen-Mediated Regioselective Cyclisation of N-Cbz-Protected
ProACHTUNGTRENNUNGparACHTUNGTRENNUNGgylic Amines: A Combined Experimental and Theoretical Study**
Alicia Monleꢀn,[a] Gonzalo Blay,[a] Luis R. Domingo,*[a] M. Carmen MuÇoz,[b] and
Josꢁ R. Pedro*[a]
Abstract: A very efficient synthesis of 5-halogen-1,3-oxazin-2-ones has been ac-
complished by the halocyclisation reaction of chiral nonracemic N-carACTHNUTRGENNbUG oACHTUNGTRNEbNUGN enzyloxy
(N-Cbz)-protected propargylic amines by using I2, Br2 and Cl2 as electrophile sour-
ces. The nature of the halogen influences the reaction time and yield. However, in
all cases the reaction is totally regioselective taking place through a 6-endo-dig
process regardless of the nature of the halogen and of the substituents in the start-
ing material. To rationalise the experimental results, theoretical studies at the
B3LYP/6-311G* level have been performed.
Keywords: density functional calcu-
lations halocyclisation oxazi-
nones · propargylic amines · reac-
tion mechanisms · regioselectivity
·
·
Introduction
mate derivative as the internal nucleophilic group remains
relatively unexplored.[2a,16]
The electrophilic cyclisation of functionalised alkynes pos-
sessing a nucleophilic group in close proximity to the triple
bond constitutes an important strategy in the construction
of a wide variety of heterocycles and carbocycles.[1] Typical-
ly, the activation of the carbon–carbon triple bond is based
on the formation of a cationic metal complex (in transition-
metal-catalysed reactions)[2] or an incipient halonium ion (in
halogen-mediated reactions).[3] This second activation
method leads to the synthesis of halogen-containing hetero-
cycle or carbocycle derivatives, which are versatile precur-
sors in many synthetic processes. With regard to the internal
nucleophile, a wide range of nucleophilic groups, such as al-
cohols,[4] ethers,[5] thioethers,[6] selenoethers,[7] amines,[8]
imines,[9] oximes,[10] azides,[11] aldehydes and ketones,[12] car-
boxylic acids and their derivatives,[13] 1,3-dicarbonyl com-
pounds[14] and aromatic rings,[15] has been investigated. How-
ever, the use of functionalised alkynes possessing a carba-
Very recently, we have reported a convenient method for
the synthesis of chiral nonracemic N-benzyloxycarbonyl (N-
Cbz)-protected propargylic amines by the addition of termi-
nal alkynes to imines generated in situ from a-amido sul-
fones in the presence of diethylzinc and 1,1’-binaphthol
(BINOL)-type ligands as catalysts.[17] On the basis of early
reported results in the synthesis of halo derivatives of het-
erocycles by halocyclisation of conveniently functionalised
alkynes we envisioned that the N-Cbz-protected propargylic
amines must be suitable substrates to investigate a novel
route for preparing densely-functionalised 1,3-oxazin-2-ones
or oxazolidin-2-ones (cyclic carbamates) through an O-halo-
cyclisation process. Carbamates represent an important class
of compounds with interesting properties and have found
wide utility in several areas, such as pharmaceuticals[18] or
agrochemicals.[19] Cyclic carbamates are less known, al-
though they have been used as chiral auxiliaries[20] and, be-
sides, present interesting biological activity.[21] There is a va-
riety of methods[22] for the synthesis of this kind of com-
pounds, however, the development of practical and efficient
methods for the preparation of these cyclic carbamates, es-
pecially those densely functionalised, is of great interest.
When a substrate of the N-Cbz-protected propargylic
amine-type 1 is subjected to an O-cyclisation process, two
reaction modes are possible: the 6-endo-dig mode that
should yield the 1,3-oxazin-2-ones 2 and the 5-exo-dig mode
that should yield the oxazolidin-2-ones 3. Therefore, the
highly effective control of the regioselectivity of the O-halo-
cyclisation mode is essential for the selective preparation of
compounds 2 or 3 (Scheme 1). A metal-catalysed cyclisation
of N-butyloxycarbonyl (Boc)-protected propargylic amines
has been previously described by Carretero et al.,[2a] which
[a] A. Monleꢀn, Prof. Dr. G. Blay, Prof. Dr. L. R. Domingo,
Prof. Dr. J. R. Pedro
Department de Quꢁmica Orgꢂnica-Facultat de Quꢁmica
Universitat de Valꢃncia
C/Dr. Moliner 50, 46100 Burjassot (Valꢃncia) (Spain)
Fax : (+34)963544328
E-mail: domingo@utopia.uv.es
jose.r.pedro@uv.es
[b] Prof. Dr. M. C. MuÇoz
Departmento de Fꢁsica Aplicada
Universitat Politꢃcnica de Valꢃncia
Camꢁ de Vera s.n., 46022-Valꢃncia (Spain)
[**] Cbz=carbobenzyloxy.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302089.
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Table 1. Electrophilic cyclisation of N-Cbz-protected propargylic amines
to 5-halogen-1,3-oxazin-2-ones.[a]
Entry
1
R1
R2
X2 Time Product Yield
[h]
[%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
1a Ph
1b 4-ClC6H4
Ph
Ph
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
18
30
24
24
4
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
82
76
94
94
94
45
70
98
91
93
97
98
97
65
93
82
79
91
80
86
80
62
50
61
59
1c 4-MeC6H4 Ph
1d 2-MeC6H4 Ph
1e cyclohexyl Ph
1 f nBu
1g PhCH2CH2 Ph
1h Ph 4-FC6H4
1i Ph
Scheme 1. Halocyclisation of N-Cbz-protected propargylic amines (Bn=
benzyl).
Ph
4
20
18
2
1
52
1
took place according to an intramolecular 5-exo-dig process
to afford the five-membered ring products 3. Also, a metal-
catalysed 5-exo-dig cyclisation of propargylic ureas to pro-
vide cyclic five-membered carbamimidates has been recently
described by Toste and Campbell.[2b] In this paper we report
for the first time a halogen-mediated regioselective cyclisa-
tion of N-Cbz-protected propargylic amines to provide the
six-membered isomers, 1,3-oxazin-2-ones 2, through a 6-
endo-dig route with a regioselectivity that contrasts with the
previously reported in metal-catalysed cyclisation reactions
of propargylic amine derivatives.[2a,b] Additionally, the mech-
anism of this reaction has been theoretically investigated.
4-MeOC6H4
2-MeOC6H4
3,5-(MeO)2C6H3 I2
2-thienyl
C6H5CH2CH2
tBu
Ph
Ph
1j Ph
1k Ph
1l
Ph
I2
I2
I2
1m Ph
1n Ph
1a Ph
1b 4-ClC6H4
1d 2-MeC6H4 Ph
1e cyclohexyl Ph
1h Ph
1o Ph
1m Ph
1a Ph
30
24
Br2 0.5 4a
Br2 0.3 4b
Br2 0.5 4d
Br2
1
4e
4-FC6H4
Br2 0.5 4h
Br2 0.5 4o
Br2
Cl2 0.15 5a
Cl2 0.15 5c
Cl2 0.15 5e
Cl2 0.15 5i
4-ClC6H4
PhCH2CH2
Ph
1
4m
1c 4-MeC6H4 Ph
1e PhCH2CH2 Ph
1i
Ph
4-MeOC6H4
Results and Discussion
[a] All iodocyclisation reactions were run with 0.1 mmol of the starting
material and 2.0 equivalents of iodine in 2.5 mL of acetonitrile at 08C.
All bromocyclisation reactions were run with 0.1 mmol of the starting
material and 1.2 equivalents of bromine in 12.5 mL of acetonitrile at 08C.
All chlorocyclisation reactions were run with 0.1 mmol of the starting
material and 1.2 equivalents of chlorine in 12.5 mL of acetonitrile at
ꢀ208C. [b] Yield of the isolated product.
The required starting materials, that is, the N-Cbz-protected
propargylic amines 1, are readily prepared by the addition
of terminal alkynes to imines generated in situ from a-
amido sulfones in the presence of diethylzinc and BINOL-
type ligands as catalysts, following our previously reported
method.[17] In order to determine the general conditions for
the halocyclisation reaction of N-Cbz-protected propargylic
amines 1, N-Cbz-1,3-diphenylprop-2-yn-1-amine (1a) was
submitted to iodocyclisation conditions in the presence of
iodine/NaHCO3 in dichloromethane at room temperature,
such as it has been described for the iodocyclisation of sev-
eral functionalised alkynes. Under these conditions we ob-
tained the corresponding iodinated 1,3-oxazin-2-one (2a)
with an endocyclic double bond as the only isolated product
(67% yield). After a brief optimisation process, including
the solvent, the temperature, the base and the stoichiometry,
we observed that the best result in product 2a was obtained
with iodine (2 equiv) in acetonitrile at 08C and the absence
of NaHCO3 (82% yield). These optimised reaction condi-
tions allowed us to synthesise a wide range of 4,6-disubsti-
tuted 3,4-dihydro-5-iodo-1,3-oxazin-2-ones 2 through a 6-
endo-dig O-cyclisation process in good to excellent yields.
So the optimised conditions were used for the iodocyclisa-
tion of several N-Cbz-protected propargylic amines 1 derived
from the addition of phenylacetylene to N-Cbz-protected
imines of substituted benzaldehydes (Table 1, entries 1–4) in
good to excellent results. Both electron-donating (Me) and
electron-withdrawing (Cl) substituents in ortho and para po-
sitions of the aromatic ring were well tolerated, with yields
ranging from 76 to 94%. On the other hand, the iodocyclisa-
tion of N-Cbz-protected propargylic amines 1 derived from
alkyl-substituted imines gave the corresponding products in
variable yields (Table 1, entries 5–7). Whereas the cyclohex-
yl-substituted starting material 1e afforded the iodocyclisa-
tion product with an excellent yield, the n-butyl-substituted
and the 2-phenylethyl-substituted starting materials 1 f and
1g gave moderate yields. Then we examined the reactivity
of various N-Cbz-protected propargylic amines 1 bearing
different aromatic, heteroaromatic and aliphatic groups at-
tached to the alkyne moiety affording the corresponding
products 2 in excellent yield in most cases (Table 1, en-
tries 8–14).
The structures of products 2 were established on the basis
of NMR spectroscopic analysis. In particular, the four
carbon atoms in the 6-membered-ring-containing cyclic car-
bamate gave characteristic signals. So, the carbonyl group
corresponds to the signal at d=149–150 ppm (when R1 is ar-
omatic) and d=151–152 ppm (when R1 is aliphatic), the
ꢀ
quaternary olefinic =C O carbon atom gives a signal at d=
ꢀ
148–150 ppm, the signal of the quaternary olefinic I C=
carbon atom appears at high field at d=69–72 ppm and the
benzylic CH group appears at d=60–65 ppm. Moreover, the
structural and configurational assignments of 2j and 2l were
confirmed by means of X-ray diffraction analysis
(Figure 1).[23,24] In all cases, the 6-endo-dig O-cyclisation led
to 3,4-dihydro-5-iodo-1,3-oxazin-2-ones 2. Determination of
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Halogen-Mediated Regioselective Cyclisation of Protected Propargylic Amines
FULL PAPER
Finally, the chlorocyclisation reaction of several N-Cbz-
protected propargylic amines (Table 1, entries 22–25) was
carried out in the same way as the bromocyclisation reaction
with chlorine in acetonitrile at ꢀ208C. A very short reaction
time (0.15 h) was required, and the chlorocyclisation prod-
ucts 5 were obtained with moderate yields (50–60%). As for
the iodinated and brominated analogues, the four carbon
atoms in the chlorinated 6-membered-ring-containing cyclic
carbamate gave characteristic signals. So, the carbonyl group
corresponds to the signal at d=149–151 ppm, the quaternary
ꢀ
olefinic =C O carbon atom gives a signal at d=144–
ꢀ
146 ppm, the quaternary olefinic Cl C= carbon atom ap-
pears at d=107–109 ppm and the benzylic CH group ap-
pears at d=56–61 ppm.
The 3,4-dihydro-5-halogen-1,3-oxazin-2-ones 2, 4 and 5
prepared by this method offer a great potential as precursors
for compounds of increasing molecular complexity, particu-
larly when one considers the different ways to transform the
resulting halogen functionalities through palladium- and
copper-catalysed reactions.[25]
Figure 1. ORTEP plots for the X-ray structures of compounds 2j (top)
and 2l (bottom). The thermal ellipsoids are drawn at the 50% probability
level.
In order to understand the mechanism of the regioselec-
tive halogen-mediated cyclisation of protected propargylic
amines 1 to yield the corresponding 6-membered 1,3-oxazin-
2-ones 2 a computational study by using density functional
theory (DFT) methods at the B3LYP/6-311G* level (see
computational methods in the Experimental Section) was
carried out (Scheme 2). In the theoretical study, the R1
group and the benzyl group present in the N-Cbz-protected
propargylic amines 1a–1o were modelled by methyl groups.
Starting from the protected propargylic amine 1p a study of
the potential energy surface for the title reactions indicates
that these halogen-mediated cyclisation reactions take place
through a two-step mechanism. In the first step, the halogen
molecule X2 electrophilically attacks on the C1 or C2
carbon atom of the triple bond of these propargylic amines
to yield the cationic intermediates IN1-endo-X or IN1-exo-
X through TS1-endo-X or TS1-exo-X. In the second step,
the methyl group present in the carboxylate substituent is
eliminated in these cationic intermediates assisted by the
halide ion Xꢀ yielding the final 1,3-oxazin-2-one 2p or the
oxazolidin-2-one 3p (Scheme 2). For the reaction in the
the enantiomeric excesses (ee) by chiral HPLC of the prod-
ucts showed no epimerisation at the stereogenic centre re-
gardless of the reaction time.
When we applied the optimised conditions for the iodo-
cyclisation to the reaction between N-Cbz-1,3-diphenylprop-
2-yn-1-amine (1a) and bromine in acetonitrile at 08C a
shorter reaction time was required but, besides 3,4-dihydro-
5-bromo-1,3-oxazin-2-one (4a) corresponding to the cyclisa-
tion process, a second product was observed, probably re-
sulting from a simple addition of Br2 to the triple bond. To
our delight, in the presence of only 1.2 equivalents of bro-
mine (instead of 2.0 equiv) and by using a more diluted re-
action mixture (1:5) this secondary addition reaction was
completely avoided and the bromocyclisation product 4a
was obtained with good yield (93%) (Table 1, entry 15). The
reaction scope was then explored under the new optimised
conditions for the bromocyclisation. The reaction has
proven to be a general route to a variety of 3,4-dihydro-5-
bromo-1,3-oxazin-2-ones
4 (Table 1, entries 16–21). The
structural characterisation of products 4 was carried out by
spectroscopic methods. As for
the iodinated products, the
four carbon atoms in the bro-
minated 6-membered-ring-con-
taining cyclic carbamate gave
characteristic signals. So, the
carbonyl group corresponds to
the signal at d=149–151 ppm,
ꢀ
the quaternary olefinic =C O
carbon atom gives a signal at
d=145–148 ppm, the quaterna-
ꢀ
ry olefinic Br C= carbon atom
appears at d=97–99 ppm and
the benzylic CH group appears
at d=58–63 ppm.
Scheme 2. Possible reaction routes for the regioselective halogen-mediated cyclisation of protected propargylic
amines that were studied by DFT methods.
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L. R. Domingo, J. R. Pedro et al.
presence of bromine (Br2) the two regioisomeric channels
were studied, whereas for the reaction in the presence of
chlorine (Cl2) only the most favourable channel yielding the
6-membered 1,3-oxazin-2-one 2p was considered. Relative
energies in the gas phase as well as in acetonitrile are given
in Table 2. Total energies are given in Table S1 in the Sup-
porting Information. Because some species involved in the
reactions are charged, the energy discussion will be done by
using the relative energies in acetonitrile.
determining step, the methyl elimination is the RDS of the
reaction.
For the reaction in presence of chlorine, TS1-endo-Cl as-
sociated with the electrophilic attack of Cl2 on the C2
carbon atom of the propargylic amine 1p is located
ꢀ12.8 kcalmolꢀ1 below the separated reagents; formation of
the 1,3-oxazin-2-one intermediate IN1-endo-Cl is strongly
exothermic by ꢀ41.3 kcalmolꢀ1. The activation energy asso-
ciated with the elimination of the methyl group in inter-
mediate IN1-endo-Cl through TS2-endo-Cl is 12.2 kcal
molꢀ1, the overall process is exothermic by ꢀ51.4 kcalmolꢀ1.
The fact that TS1-endo-Cl is located below the separated re-
agents is a consequence of the strong solvation of the chlo-
ride ion Clꢀ, which develops along the electrophilic attack.
Note that in the gas phase TS1-endo-Cl is located 9.5 kcal
molꢀ1 above the reagents. A comparison of the relative ener-
gies of the transition states (TSs) associated with the elec-
trophilic attack of halogens Br2 or Cl2 on the propargylic
amine 1p in the gas phase and in acetonitrile indicates that
the addition of Cl2 to these propargylic amines is favoured
over the addition of Br2.
Table 2. Relative energies in acetonitrile (in [kcalmolꢀ1], relative to 1p
or 1q plus the halogen X2) of the stationary points involved in the halo-
gen-mediated cyclisation reactions of protected propargylic amines 1p
and 1q.
Bromination of 1p
Chlorination of 1p
Bromination of 1q
MC1-Br
ꢀ1.0
MC1-Cl
TS1-endo-Cl
ꢀ1.2
CM2-Br
ꢀ4.1
TS1-endo-Br
TS1-exo-Br
IN1-endo-Br
IN1-exo-Br
TS2-endo-Br
TS2-exo-Br
2p+MeBr
3p+MeBr
0.5
8.4
ꢀ12.8
ꢀ41.3
ꢀ29.1
ꢀ51.4
TS3-endo-Br
TS3-exo-Br
IN3-endo-Br
IN3-exo-Br
2.0
3.3
ꢀ20.0
ꢀ19.4
ꢀ7.3
IN1-endo-Cl
TS2-endo-Cl
2p+ MeCl
ꢀ27.5
ꢀ25.4
ꢀ8.5
Finally, the role of the phenyl substituent attached to the
alkyne moiety was analysed by studying the two regioiso-
meric channels associated with the addition of bromine on
the C1 and C2 carbon atoms of the methyl-substituted pro-
ꢀ28.6
ꢀ31.8
ACHUTNGERNpNUG arAHCTUNGTRNENgUGN ylic amine 1q (see Scheme 3). The activation energies
In an earlier step of the reaction, the halogens X2 form a
weak molecular complex (MC) with the p system of the
triple bond of propargylic amine 1p. These MCs are located
at ꢀ1.0 (MC1-Br) and ꢀ1.2 kcalmolꢀ1 (MC1-Cl) for Br2 and
Cl2, respectively, below the separated reagents. For the reac-
tion in presence of bromine, the activation energies associat-
ed with the electrophilic attack of Br2 on the C2 and C1
carbon atoms of the propargylic amine 1p are 0.5 (TS1-
endo-Br) and 8.4 kcalmolꢀ1 (TS1-exo-Br); formation of the
corresponding cationic intermediates are exothermic by
ꢀ20.0 (IN1-endo-Br) and ꢀ19.4 kcalmolꢀ1 (IN1-exo-Br).
Elimination of the methyl group from these cationic inter-
mediates takes place through a bimolecular nucleophilic
substitution of the methyl group assisted by the bromide ion
Brꢀ generated in the first step of the reaction. From the cor-
responding intermediates, the activation energies associated
with the extrusion of the methyl group are: 12.7 (TS2-endo-
Br) and 10.9 kcalmolꢀ1 (TS2-exo-Br). Formation of 2p and
3p plus MeBr is exothermic by ꢀ28.6 and ꢀ31.8 kcalmolꢀ1,
respectively.
From these energy results some relevant conclusions can
be drawn: 1) the electrophilic attack of bromine on the
triple bond of the propargylic amine 1p is completely regio-
selective, TS1-endo-Br being 7.9 kcalmolꢀ1 lower in energy
than TS1-exo-Br, 2) the high exothermic character of the
first step makes this step irreversible, 3) the activation
energy associated with the second step is higher than that
associated with the first step, thus, the elimination of the
methyl substituent is the rate-determining step (RDS) of the
reaction. Consequently, although the electrophilic attack of
bromine to the propargylic amine 1p is the regioselectivity-
Scheme 3. Two regioisomeric channels associated with the addition of
bromine to the propargylic amine 1q.
associated with the formation of intermediates IN3-endo-Br
and IN3-exo-Br through TS3-endo-Br and TS3-exo-Br are
2.0 and 3.3 kcalmolꢀ1, respectively, the formation of these
intermediates is exothermic by ꢀ27.5 and ꢀ25.4 kcalmolꢀ1,
respectively (see Table 2). Consequently, the cyclisation re-
action with the methyl-substituted propargylic amine 1q
should be slightly slower, and should present a low regiose-
lectivity. Note that the reaction with the phenyl-substituted
propargylic amine 1p is completely regioselective. Thus, the
phenyl substituent induces a total regioselectivity in these
halogen-mediated cyclisation reactions of protected propar-
gylic amines as a consequence of the stabilisation of the in-
cipient carbocationic C1 centre generated along the electro-
philic attack on the conjugated C2 carbon atom.
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Halogen-Mediated Regioselective Cyclisation of Protected Propargylic Amines
FULL PAPER
The geometries of the TSs involved in the regioisomeric
channels associated with the bromine-mediated cyclisation
of the phenyl-substituted propargylic amine 1p are given in
Figure 2, whereas those associated with the reaction mediat-
quency n˜ =ꢀ221.78 cmꢀ1 is associated with the movement of
ꢀ
ꢀ
the Br6, C2, O3 and C1 atoms along the Br6 C2 and O3
C1 bond formation, whereas at TS1-endo-Br in acetonitrile,
the unique imaginary frequency n˜ =ꢀ28.85 cmꢀ1 is mainly
ꢀ
associated with the rotation of the N C bond favouring the
approach of the O3 and C1 atoms. This change of the mech-
anism can be understood as a strong stabilisation of both
the bromine anion and the incipient benzyl carbocationic C1
centre at TS1-endo-Br in the polar solvent acetonitrile. At
the most favourable TS1-endo-Cl associated with the first
step of the chlorine-promoted cyclisation process, the
ꢀ
lengths of the forming bonds are 1.771 (Cl6 C2) and
ꢀ
2.752 ꢅ (O3 C1) ꢅ (see Figure S1 in the Supporting Infor-
ꢀ
mation). At TS1-endo-Cl, the Cl6 C2 bond formation is
more advanced than the Br6 C2 bond formation at TS1-
ꢀ
endo-Br.
At the TSs associated with the elimination of the methyl
group in IN1-endo-Br and IN1-endo-Br, the lengths of the
ꢀ
ꢀ
O4 C5 breaking bond and the C5 Br7 forming bond are
1.908 and 2.600 ꢅ, respectively, at TS2-endo-Br, and 1.887
and 2.624 ꢅ, respectively, at TS2-exo-Br. In these asynchro-
ꢀ
nous TSs, the O4 C5 breaking bonds are more advanced
ꢀ
ꢀ
than the C5 Br7 forming bond. Similar O4 C5 breaking-
ꢀ
bond and C5 Cl7 forming-bond processes are found at TS2-
endo-Cl (see Figure S1 in the Supporting Information).
The geometry of the TSs involved in the first step of the
regioisomeric channel associated with the bromine-mediated
cyclisation of the protected methyl-substituted propargylic
amine 1q are given in Figure 3. At the TSs, the lengths of
Figure 2. Geometry of the TSs involved in the regioisomeric channels as-
sociated with the bromine-mediated cyclisation of the protected propar-
gylic amine 1p. The lengths of the forming and breaking bonds are given
in ꢅngstrom.
ed by chlorine are given in Figure S1 in the Supporting In-
formation. At the TSs associated with the first step of the
bromine-mediated cyclisation process the lengths of the
ꢀ
ꢀ
Br6 C2(1) and the O3 C1(2) forming bond are 2.180 and
2.867 ꢅ at TS1-endo-Br and 2.247 and 2.193 ꢅ at TS1-exo-
Br, respectively. For the corresponding intermediates IN1-
ꢀ
endo-Br and IN1-exo-Br the lengths of the Br6 C2(1) and
ꢀ
the O3 C1(2) bond are 1.910 and 1.440 as well as 1.933 and
1.437 ꢅ, respectively. These geometrical parameters indicate
ꢀ
that at the most favourable TS1-endo-Br, the Br6 C2 bond
ꢀ
formation is very advanced, whereas the O3 C1 bond for-
Figure 3. Geometry of the TSs involved in the first step of the regioiso-
meric channels associated with the bromine-mediated cyclisation of the
protected propargylic amine 1q. The lengths of the forming and breaking
bonds are given in ꢅngstrom.
mation is rather delayed. At the most unfavourable TS1-
exo-Br, the O3 C2 bond formation is more advanced than
the O3 C1 bond formation at TS1-endo-Br, showing a more
synchronous bond-formation process. Note that in the gas
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
phase the lengths of the Br6 C2(1) and the O3 C1(2) form-
ing bond are 2.156 and 1.806 ꢅ at TS1-endo-Br and 2.214
and 1.760 ꢅ at TS1-exo-Br, respectively, indicating that both
bond-formation processes are coupled. Consequently, polar
solvent effects change the mechanism of the first step of the
the Br6 C2(1) and O3 C1(2) forming bonds are 2.204 and
2.453 ꢅ, respectively, at TS3-endo-Br, and 2.208 and
2.251 ꢅ, respectively, at TS3-exo-Br. At the most favourable
ꢀ
TS3-endo-Br, the Br6 C2 bond length indicates that the
Br6 C2 bond formation at this TS is more advanced than
ꢀ
ꢀ
most favourable reactive channel from a synchronous Br6
C2 and O3 C1 bond formation in the gas phase to a highly
asynchronous process in acetonitrile. This behaviour is illus-
trated by the analysis of the atomic movements at the
unique imaginary frequency associated with each TS; at
TS1-endo-Br in the gas phase, the unique imaginary fre-
that at TS1-endo-Br, 2.867 ꢅ. This behaviour accounts for
the role of the phenyl substituent in TS1-endo-Br, stabilising
the incipient carbocationic C1 centre along the electrophilic
attack of bromine on the C1 carbon atom.
Finally, an analysis of the reactivity of the protected prop-
argylic amines 1p and 1q was performed by using the reac-
ꢀ
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L. R. Domingo, J. R. Pedro et al.
tivity indices defined within the conceptual DFT method.[26]
The global and local reactivity indices, named global electro-
philicity w, global nucleophilicity N, nucleophilic Parr func-
tions Pk and the local nucleophilicity indices Nk of the
propargylic amines 1p and 1q are given in Figure 4.
Conclusion
In summary, a very efficient synthesis of 5-halogen-1,3-
oxazin-2-ones has been developed involving a halogen-medi-
ated regioselective cyclisation of chiral nonracemic N-Cbz-
protected propargylic amines. A wide variety of substrates
undergoes this cyclisation process in good to excellent
yields. The halogens I2, Br2 and Cl2 have been utilised as e-
lectrophiles and the results obtained demonstrate the impor-
tance of the nature of the halogen on the reaction time and
yield, but not on the regioselectivity. This synthetic ap-
proach allows a simultaneous construction of the 1,3-oxazin-
2-one system and the installation of a halogen functionality
at the 5-position of the heterocyclic ring and it constitutes a
useful complement to the literature-known protocols for
preparing cyclic carbamates. In addition DFT calculations
were performed to obtain an insight into various aspects of
the reactivity of protected propargylic amines under halo-
cyclisation reaction conditions.
ꢀ
Figure 4. Maps of the atomic spin density of the cation radicals of the
ꢀ
propargylic amines 1p and 1q and the nucleophilic Parr functions Pk at
the C1 and C2 carbon atoms, and global electrophilicity w, global nucleo-
philicity N, and local nucleophilicity indices Nk, in [eV], of compounds
1p and 1q.
The propargylic amines 1p and 1q have low electrophilic-
ity values, 1.24 (1p) and 0.62 eV (1q), being classified as mo-
derate and marginal electrophiles,[27] respectively. On the
other hand, the corresponding nucleophilicity N indices, 2.78
(1p) and 2.17 eV (1q), indicate that they will behave as mo-
derate nucleophiles.[28] The higher nucleophilic character of
the phenyl-substituted propargylic amine 1p compared to
the methyl-substituted propargylic amine 1q accounts for
the lower activation energy found for the bromine-mediated
addition to compound 1p than to compound 1q.
Experimental Section
General methods: Reactions were carried out under a nitrogen atmo-
AHCTUNGERTGsNNUN phere in round bottom flasks oven-dried overnight at 1208C. Commer-
cial reagents were used as purchased. The N-Cbz-protected propargylic
amines 1 were prepared from the corresponding a-amido sulfone and
alkyne as described in the literature.[17] Solvents were dried when neces-
sary: Dichloromethane was distilled from CaH2. Reactions were moni-
tored 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 in a Buchi M-560
apparatus. 1H NMR spectroscopy was run at 300 MHz for 1H and at
75.5 MHz for 13C NMR in a Bruker Avance 300 DPX spectrometer.
1H NMR spectra and 13C NMR spectra were internally referenced to
CDCl3 signal (d=7.26 and 77.0 ppm, respectively). Chemical shifts are
reported in [ppm]. The carbon-atom type was determined by DEPT ex-
periments. High-resolution mass spectra were recorded on a Waters Q-
TOF premier spectrometer (ESI). Specific optical rotations were mea-
sured by using sodium light (D-line, l=589 nm). Chiral HPLC analyses
were performed in an Agilent 1100 Series chromatograph equipped with
a UV diode-array detector by using chiral stationary columns from
Daicel.
Building upon recent studies devoted to the bonding
changes in polar reactions,[29] Domingo and Pꢆrez have pro-
posed two new electrophilic, Pþk , and nucleophilic, Pkꢀ, Parr
functions, based on the analysis of the atomic spin density
(ASD) at the corresponding anion and cation radicals, to
study the regio- and chemoselectivity in polar reactions.[30]
Analysis of the nucleophilic Parr functions Pꢀk in the propar-
gylic amines 1p and 1q indicates that the phenyl-substituted
propargylic amine 1p presents a strong nucleophilic activa-
tion of the C1 carbon atom, 0.30, when compared to the C1
carbon atom, 0.01, whereas the methyl-substituted propar-
gylic amine 1q shows a similar nucleophilic activation at the
two acetylenic C1 and C2 carbon atoms (see Figure 4). As a
consequence, analysis of the local nucleophilicity indices of
the phenyl-substituted propargylic amine 1p indicates that
the C2 carbon atom is the most nucleophilic centre of this
molecule, N2 =0.84 eV, whereas the corresponding values
for methyl-substituted propargylic amine 1p show that the
C2 carbon atom, N2 =0.46 eV is slightly more nucleophilical-
ly activated than the C1 carbon atom, N2 =0.45 eV. This
local analysis is in complete agreement with the entire regio-
selectivity found in the bromine-mediated cyclisation of the
phenyl-substituted propargylic amines 1p. A lower regiose-
lectivity should be observed in the reaction of compound
1q.[31]
Typical procedure for the iodocyclisation of the N-Cbz-protected propar-
gylic amines 1: A solution of iodine (0.2 mmol) in acetonitrile (1.0 mL)
was added to
a solution of the N-Cbz-protected propargylic amine
1 (0.1 mmol) in acetonitrile (1.5 mL) at 08C. The solution was stirred
until the reaction was complete (TLC). The reaction mixture was
quenched with a saturated aqueous solution of sodium bisulfate (1.0 mL),
extracted with CH2Cl2 (3ꢇ15 mL), dried over MgSO4 and concentrated
under reduced pressure. Purification by flash chromatography on silica
gel afforded compound 2.[32]
(S)-5-Iodo-4,6-diphenyl-3,4-dihydro-2H-1,3-oxazin-2-one (2a): M.p. 65–
688C; [a]2D0 = +64.7 (c=1.00 in CHCl3, 87% ee); the enantiomeric excess
(87%) was determined by chiral HPLC (Chiralcel OD-H), hexane/
iPrOH 90:10, 1 mLminꢀ1, major enantiomer: tr =13.9 min, minor enantio-
mer: tr =23.1 min; 1H NMR (300 MHz, CDCl3): d=7.65–7.61 (m, 2H),
7.42–7.39 (m, 8H), 6.49 (brs, 1H), 5.19 ppm (d, J=2.1 Hz, 1H);
13C NMR (75.5 MHz, CDCl3): d=149.8 (C), 148.9 (C), 140.2 (C), 133.6
(C), 130.0 (CH), 129.4 (CH), 129.2 (CH), 129.1 (CH), 128.0 (CH), 127.5
(CH), 71.4 (C), 64.9 ppm (CH); HRMS (ESI): m/z calcd for C16H13NO2I:
377.9986 [M+H]+; found: 377.9984.
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Halogen-Mediated Regioselective Cyclisation of Protected Propargylic Amines
FULL PAPER
Typical procedure for the bromocyclisation of the N-Cbz-protected pro-
pargylic amines 1: Bromine (0.12 mmol) was added to a solution of the
N-Cbz-protected propargylic amine (0.1 mmol) in acetonitrile
lenciana (ACOMP2012-212 and ISIC2012/001) is gratefully acknowl-
edged. A.M. thanks the Generalitat Valenciana for a predoctoral grant.
G
ACHTUNGTRENNUNG
1
(12.5 mL) at 08C. The solution was stirred until the reaction was com-
plete (TLC). The reaction mixture was concentrated under reduced pres-
sure. Purification by flash chromatography on silica gel afforded com-
pound 4.
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(S)-5-Bromo-4,6-diphenyl-3,4-dihydro-2H-1,3-oxazin-2-one (4a): M.p.
52–548C; [a]2D0 = +62.7 (c=1.00 in CHCl3, 87% ee); 1H NMR (300 MHz,
CDCl3): d=7.72–7.69 (m, 2H), 7.43–7.41 (m, 8H), 6.12 (brs, 1H),
5.19 ppm (d, J=2.1 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=149.3 (C),
146.2 (C), 139.6 (C), 131.6 (C), 130.1 (CH), 129.3 (CH), 129.2 (CH),
128.9 (CH), 128.1 (CH), 127.4 (CH), 98.3 (C), 62.3 ppm (CH); HRMS
(ESI): m/z (%) calcd for C16H13BrNO2: 330.0130/332.0109 [M+H]+;
found: 330.0110/332.0090 (100/96.5).
General procedure for the chlorocyclisation of the N-Cbz-protected
propargylic amines 1: A solution of chlorine[33] (0.19m, 0.12 mmol) in ace-
tonitrile was added to a solution of the N-Cbz-protected propargylic
amine 1 (0.1 mmol) in acetonitrile (12.5 mL) at ꢀ208C. The solution was
stirred until the reaction was complete (TLC). The reaction mixture was
concentrated under reduced pressure. Purification by flash chromatogra-
phy on silica gel afforded compound 5.
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(S)-5-Chloro-4,6-diphenyl-3,4-dihydro-2H-1,3-oxazin-2-one (5a): Viscous
oil; [a]2D0 = +45.3 (c=0.83 in CHCl3, 87% ee); 1H NMR (300 MHz,
CDCl3): d=7.76–7.73 (m, 2H), 7.44–7.40 (m, 8H), 5.98 (brs, 1H),
5.12 ppm (d, J=2.0 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=149.0 (C),
144.9 (C), 139.2 (C), 130.5 (C), 130.0 (CH), 129.4 (CH), 129.2 (CH),
128.6 (CH), 128.1 (CH), 127.3 (CH), 108.9 (C), 60.4 ppm (CH); HRMS
(ESI) m/z calcd for C16H13ClNO2: 286.0629 [M+H]+; found: 286.0632.
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Computational methods: DFT calculations were carried out by using the
B3LYP[34] exchange-correlation functionals, together with the standard 6-
311G* basis set.[35] Optimisations were carried out by using the Berny an-
alytical gradient optimisation method.[36] Stationary points were charac-
terised by frequency calculations in order to verify that the TSs have one
and only one imaginary frequency. Intrinsic reaction coordinate (IRC)[37]
paths were traced in order to check the energy profiles connecting each
TS to the two associated minima of the proposed mechanism by using
the second-order Gonzꢈlez–Schlegel integration method.[38] Solvent ef-
fects of acetonitrile were taken into account through full optimisations
by using the polarisable continuum model (PCM) as developed by
Tomasi et al.[39] in the framework of self-consistent reaction field
(SCRF).[40] All calculations were carried out with the Gaussian 09 suite
of programs.[41]
The global electrophilicity index[42] w is given by the following simple ex-
pression:[42] w=(m2/2h), in terms of the electronic chemical potential m[43]
and the chemical hardness h.[43] Both quantities may be approached in
terms of the one-electron energies of the frontier molecular orbital
HOMO and LUMO, eH and eL, as mꢁ(eH+eL)/2 and hꢁ(eLꢀeH), respec-
tively.[43] Recently, we have introduced an empirical (relative) nucleophi-
licity index[44] N, defined as N=EHOMO(Nu)ꢀE
HOMOACHTNUGTREN(NUNG TCE). The nucleo-
philicity refers to tetracyanoethylene (TCE), as it presents the lowest
HOMO energy in a large series of molecules already investigated in the
context of polar cycloadditions. This choice allows us to conveniently
handle a nucleophilicity scale of positive values.[44a]
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The nucleophilic Pꢀk Parr functions[30] were obtained through the analysis
of the Mulliken ASD of the radical cation by single-point energy calcula-
tions over the optimised neutral geometries by using the unrestricted
UB3LYP formalism for radical species. With these values at hand, the
local nucleophilicity indices Nk were evaluated by using the following ex-
pressions: Nk =NPꢀk .[30]
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Acknowledgements
Financial support from the MINECO (Gobierno de EspaÇa) and
FEDER (European Union) (CTQ2009-13083) and from Generalitat Va-
Chem. Eur. J. 2013, 00, 0 – 0
ꢄ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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L. R. Domingo, J. R. Pedro et al.
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carbon atoms. Final R(wR) values were R=0.0304 and wR=0.0798.
b) CCDC-941482 (2j) and CCDC-941483 (2l) contain the supple-
mentary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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[24] X-ray data for compound 2l: crystallised from ethyl acetate/n-
hexane at ꢀ208C; C14H10N1O2S1I1; Mr =383.19; triclinic; space
¯
group=P1; a=5.6330(2), b=10.5035(4); c=12.6292(6) ꢅ.; a=
112.356(4), b=93.186(4), g=93.5068; V=687.25(5) ꢅ3; Z=2; 1calcd
1.852 Mgmꢀ3; m=2.478 mmꢀ1; F
(000)=372. A colourless crystal of
0.04ꢇ0.08ꢇ0.10 mm3 was used; 4658 [R
(int)=0.0322] independent
=
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
reflections were collected on a Enraf Nonius CCD diffractomer by
using graphite-monochromated MoKa radiation (l=0.71073 ꢅ) oper-
ating 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, and no appreciable decay was observed. The structure was
solved by direct methods and Fourier synthesis. It was refined by
full-matrix least-squares procedures on F2 (SHELXL-97[45]). All
non-hydrogen atoms were refined anisotropically. All hydrogen
atoms were included in calculated positions and refined riding on
the respective carbon atoms. Final R(wR) values were R=0.0385
and wR=0.0930.[23b]
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Halogen-Mediated Regioselective Cyclisation of Protected Propargylic Amines
FULL PAPER
Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X.
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J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
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Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O.
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Received: May 31, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
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www.chemeurj.org
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L. R. Domingo, J. R. Pedro et al.
Cyclisation Reactions
A. Monleꢀn, G. Blay, L. R. Domingo,*
M. C. MuÇoz, J. R. Pedro* . &&&& — &&&&
Synthesis of Densely Functionalised 5-
Halogen-1,3-oxazin-2-ones by
Halogen-Mediated Regioselective
Cyclisation of N-Cbz-Protected Pro-
Regioselective O-halocyclisation: A
halocyclisation reaction of chiral non-
racemic N-carbobenzyloxy (Cbz)-pro-
tected propargylic amines by using I2,
Br2 and Cl2 as electrophile sources (see
scheme, Bn=benzyl) provides a very
efficient synthesis of 5-halo-1,3-oxazin-
2-ones. The reaction is totally regiose-
lective, taking place through a 6-endo-
dig process. The experimental results
have been rationalised by theoretical
studies at the B3LYP/6-311G* level.
A
ACHTUNGTRENNUNGgylic Amines: A Combined Experi-
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10
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www.chemeurj.org
ꢄ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!