1,3-oxazinan-2-ones from amines and 1,3-diols through dialkyl carbonate chemistry

Article abstract of DOI:10.1055/s-0031-1290368

A one-pot green synthesis of 1,3-oxazinan-2-ones from amines and 1,3-diols in the presence of a dialkyl carbonate and potassium tert-butoxide is described. Four dialkyl carbonates were utilised: dimethyl carbonate, diethyl carbonate, diprop-2-yl carbonate, and tert-butyl methyl carbonate. The more hindered the dialkyl carbonate used, the higher the yield of 1,3-oxazinan-2-one. Four 1,3-diols were reacted having primary-primary, primary-secondary, primary-tertiary, and secondary-tertiary functionalities, with the yield of oxazinanone decreasing with increasing hindrance of the diol. In the case of the diols containing primary and either secondary or tertiary functionality, the substituent(s) were selectively found in the 6-position of the so-formed oxazinanone. The optimized conditions were then employed with different nucleophiles, namely phenylhydrazine, aniline, and n-octylamine.

Full text of DOI:10.1055/s-0031-1290368

LETTER
▌1809
letter
1
,3-Oxazinan-2-ones from Amines and 1,3-Diols through Dialkyl Carbonate
Chemistry
1
,3-Oxazinan-2-ones from Amines and 1,3-Diols
Con Robert McElroy, Fabio Aricò, Pietro Tundo*
Università Ca’ Foscari di Venezia, Dipartimento Scienze Ambientali, Informatica e Statistica, Dorsoduro 2137, 30123 Venice, Italy
Fax +39(041)2348620; E-mail: tundop@unive.it
Received: 16.01.2012; Accepted after revision: 19.04.2012
9
tiple steps. Recently, our group described a new route to
Abstract: A one-pot green synthesis of 1,3-oxazinan-2-ones from
amines and 1,3-diols in the presence of a dialkyl carbonate and po-
tassium tert-butoxide is described. Four dialkyl carbonates were uti-
1,3-oxazinan-2-ones, via the two-step reaction of a prima-
ry amine or phenylhydrazine with a dicarbonate deriva-
lised: dimethyl carbonate, diethyl carbonate, diprop-2-yl carbonate, tive of 1,3-diols synthesised by dimethyl carbonate
1
0
and tert-butyl methyl carbonate. The more hindered the dialkyl car- (DMC) chemistry (Scheme 1); the latter being an estab-
11
bonate used, the higher the yield of 1,3-oxazinan-2-one. Four 1,3-
diols were reacted having primary–primary, primary–secondary,
primary–tertiary, and secondary–tertiary functionalities, with the
yield of oxazinanone decreasing with increasing hindrance of the
diol. In the case of the diols containing primary and either secondary
or tertiary functionality, the substituent(s) were selectively found in
the 6-position of the so-formed oxazinanone. The optimized condi-
tions were then employed with different nucleophiles, namely phen-
ylhydrazine, aniline, and n-octylamine.
lished green reagent. The reaction mechanism was dis-
cussed representing the first example of a carbonate
reacting selectively and sequentially, firstly at the carbon-
yl centre to form a linear carbamate and then as a leaving
group to yield a cyclic carbamate.
In this paper, the cyclisation reaction is performed in one-
step by synthesising the bis(dialkyl)propane-1,3-diyl-
dicarbonate in situ, through a cascade reaction (Scheme
Key words: green chemistry, cyclisation, heterocycles, diols, dial-
kyl carbonates
2
); the general application of this methodology and the in-
fluence on the yield of differently substituted 1,3-diols
and dialkyl carbonates (DAC) were investigated. The syn-
thesis was carried out on different nucleophiles, that is, al-
iphatic and aromatic amines and phenylhydrazine.
1,3-Oxazinan-2-ones (Figure 1) are compounds of great
interest due to their biological activity. In fact, recently,
they have appeared in numerous patents as intermediates
in the synthesis of pharmaceutical drugs used in the treat-
1
All reactions followed Scheme 3 where substituents R ,
2
3
R , and R are selected so to modify the functionality of
the 1,3-diol. DAC selected for this study were DMC, di-
ethyl carbonate (DEC), diprop-2-yl carbonate (Di-PrC)
and tert-butyl methyl carbonate (Mt-BuC).
1
ment of Alzheimer, diseases mediated by the activation
2
of β3-adrenoceptorother, diseases related to kinases ac-
3
4
tivity, and for the regulation of cholesterol. They are also
5
used as herbicides with excellent crop-weed selectivity.
The unsymmetrical carbonate Mt-BuC was used instead
of the di-tert-butyl carbonate as the latter is too sterically
1
2
hindered for any reaction to occur.
2
O
The base selected was potassium tert-butoxide as it gave
the best results, although other alkoxides (sodium
methoxide) are also efficient bases, but gave lower yields.
Carbonate derivatives of the 1,3-diols having the tert-
butoxy functionality were present in all the reaction mix-
tures, but only in small amounts.
1
3
O
NR
R = aromatic, aliphatic
6
4
5
Figure 1 The 1,3-oxazinan-2-one motif
For this study a primary amine, benzylamine, was selected
as substrate. It is noteworthy that the reactions do not re-
quire the presence of a solvent.
There are many routes to 1,3-oxazinan-2-ones, the major-
ity involve phosgene and isocyanate or alkyl halide
6
7
chemistry, while those that are considered green routes ei-
8
ther require not easy available starting materials or mul-
O
R
O
O
KOt-Bu
O
N
RNH2
+
+
2MeOH
+
CO2
MeO
O
O
OMe
Scheme 1 Intermolecular cyclisation of an amine with dimethyl propane-1,3-diyl-dicarbonate10
SYNLETT 2012, 23, 1809–1815
Advanced online publication: 29.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290368; Art ID: ST-2012-D0042-L
Georg Thieme Verlag Stuttgart · New York
©

1810
C. R. McElroy et al.
LETTER
R1 R2 R3
O
O
R4
R4
O
O
O
O
O
O
R3
4
R1 R2 R3
HO
R3 R1 R2
O
R1 R2
HO
(R O)2CO
O
O
NR5
R4
R4
NHR5
OH
O
O
O
O
O
R1
R2
R3
1
2
3
R , R , R = H, Me
R4 = Me, Et, i-Pr, t-Bu
R3 R1 R2
O
HO
O
NHR5
R5 = Bn, n-C8H17, Ph, PhNH
Scheme 2 An example of in situ cascade reaction to an 1,3-oxinan-2-one described in this paper; all reactions are equilibriums with exception
of the final cyclisation step
O
R3
R1 R2
HO
O
NH2
90 °C
O
N
+
+
4
OR4
KOt-Bu
R1 2
OH
R O
R3
–4
R
1
1
2
3
1
2
3
4
R , R , R = H
R1 = Me; R , R = H
2
3
R , R = Me; R3 = H
1
2
1
2
3
R , R , R = Me
Scheme 3 Synthesis of 1,3-oxazinan-2-ones via DAC chemistry
Benzylamine was reacted with propane-1,3-diol in the the reaction of dimethyl propane-1,3-diyl-dicarbonate
presence of different DAC to give 3-benzyl-1,3-oxazinan- with benzylamine (Scheme 1) gave an isolated yield of
2-one 1 (Scheme 3). As propane-1,3-diol contains two pri- oxazinanone 1 of 40%. However, when the reactions were
mary alcohols with identical reactivity, the sole variable is carried out utilising Di-PrC and Mt-BuC (Table 1, entries
the DAC used. The results are reported in Table 1.
3 and 4) oxazinanone 1 was isolated in higher yields than
those achieved employing the presynthesised bis(dialkyl-
carbonate) in a two-step reaction. It is noteworthy that in
the reaction depicted in Scheme 3, only three equivalents
When DMC or DEC were employed, 3-benzyl-1,3-oxazi-
nan-2-one (1) was isolated in 21% and 36% yield, respec-
tively (Table 1, entries 1 and 2). In our previous paper,
1
0
Table 1 Reaction of Benzylamine with 1,3-Propanediol in the Presence of a DAC and Potassium tert-Butoxide to Yield Oxazinone 1a
O
O
N
Entry
DAC
Conv. (%)
HPLC yield (area, %)
1
Isolated yield (%)
O
1
98
29
21
MeO
OMe
O
2
3
96
95
96
38
43
50
36
47
57
EtO
OEt
O
O
i-PrO
Oi-Pr
4
MeO
Ot-Bu
a
All reactions were carried out at 90 °C for 2 h, in the absence of a solvent with a 1.0:1.0:2.0:3.0 molar ratio of benzylamine/diol/base/DAC,
respectively. Due to the large number of parasitic reactions and their related products, HPLC data has not been calibrated, as to isolate every
byproduct would be too complex.
Synlett 2012, 23, 1809–1815
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,3-Oxazinan-2-ones from Amines and 1,3-Diols
1811
of DAC are required to yield oxazinanone 1, and no sol- Table 1. It is noteworthy that the reaction of benzylamine
vent is used. The reduced amount of reagents/solvents with the presynthesised dimethyl 3-methylpropane-1,3-
represents a significant saving in terms of reaction vol- diyl-dicarbonate gave the 1,3-oxazinan-2-one 2 in only
1
0
ume, energy usage, and consumption of reagents.
18% yield. On the other hand, employing the one-pot
synthetic approach and more hindered DAC (Table 2, en-
tries 2–4), oxazinanone 2 was isolated in better yields up
to 45%.
Table 1 shows a significant trend in increasing yield of cy-
clic product from entriy 1 through to entry 4. The forma-
tion of the oxazinanone 1 is the consequence of a cascade
1
reaction (Scheme 2) that requires both alcohol and amine Significantly, H NMR analysis of the cyclic product syn-
functionalities to react with the DAC through a B 2 path- thesised confirmed that the methyl group is exclusively
Ac
way. Due to the many consecutive steps involved and the located in the 6-position of the oxazinanone ring. This
different DAC utilized, it is not easy to compare the dif- suggests that intramolecular attack on the soft electrophil-
ferent reaction pathways and intermediates from entries ic centre of the carbonate functionality (B 2 pathway)
Al
1–4 and thus to clearly justify the trend in yields observed.
preferentially occurs on a CH group (Scheme 4). As a
2
consequence, this cyclisation reaction results in high se-
lectivity towards substituents in the 6- and not in the 4-
position of the oxazinanone ring.
It is already known, however, that, when reacting an
amine with a DAC in the presence of a base, the more hin-
dered the DAC, the easier the formation of a carbamate,
1
3
as more hindered alcoxides are better leaving groups.
Conversely, when an alcohol is reacted with a DAC in ba-
sic conditions the trend of the leaving group is almost the
reverse of that observed with an amine.
O
O
O
1
4
–
R4O
R4O
O
O
O
N
O
O
N
N
H
Although it is not the objective of this paper to investigate
the reaction mechanism, the results shown here seem to be
5
2
1
3,14
in good agreement with the previous observations
O
O
O
even if the presence of many equilibrium reactions makes
the question not easy to clarify.
–
N
O
X
The cyclisation reaction was then investigated employing
butane-1,3-diol that incorporates primary and secondary
functionalities. In this case the product formed is 3-ben-
zyl-6-methyl-1,3-oxazinan-2-one (2). The aim is to ob-
6
7
Scheme 4 Selectivity towards 6-methyl oxazinanones
serve the effect, if any, of the influence of steric factors of Accordingly, in the case of butane-1,3-diol only one reac-
the substrate on the synthesis of the oxazinanone 2. The tion pathway selectively leads to the formation of the ox-
results are reported in Table 2.
azinanone, so a much lower yield of the cyclic product
would be expected. However, the yields observed in Table
The trend of increasing yield of the cyclic product when
utilising more hindered DAC is similar to the one seen in
2
are not dramatically lower than those in Table 1; this
Table 2 Reaction of Benzylamine with Butane-1,3-diol in the Presence of a DAC and Potassium tert-Butoxide to Yield Oxazinone 2a
Entry
DAC
Conv. (%)
HPLC yield (area, %)
O
O
N
2
Isolated yield (%)
O
1
98
28
14
MeO
OMe
O
2
3
98
98
96
39
46
51
27
44
45
EtO
OEt
O
i-PrO
Oi-Pr
O
4
MeO
Ot-Bu
a
All reactions were carried out at 90 °C for 2 h, in the absence of a solvent with a 1.0:1.0:2.0:3.0 molar ratio of benzylamine/diol/base/DAC,
respectively. Due to the large number of parasitic reactions and their related products, HPLC data has not been calibrated, as to isolate every
byproduct would be too complex.
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1809–1815

1812
C. R. McElroy et al.
LETTER
Table 3 Reaction of Benzylamine with 3-Methylbutane-1,3-diol in the Presence of a DAC and Potassium tert-Butoxide to Yield Oxazinanone 3a
O
O
N
Entry
DAC
Conv. (%)
HPLC yield (area, %)
3
Isolated yield (%)
O
1
97
28
16
MeO
OMe
O
2
3
96
94
94
39
46
51
21
29
32
EtO
OEt
O
O
i-PrO
Oi-Pr
4
MeO
Ot-Bu
a
All reactions were carried out at 90 °C for 2 h, in the absence of a solvent with a 1.0:1.0:2.0:3.0 molar ratio of benzylamine/diol/base/DAC,
respectively. Due to the large number of parasitic reactions and their related products, HPLC data has not been calibrated, as to isolate every
byproduct would be too complex.
might be attributed to the reversible nature of the cascade In this case, analysis of the reaction by GC–MS indicated
reactions leading up finally to the formation of the product that the major product was methyl N-benzylcarbamate
2
(Scheme 2). As the compound 5 is consumed, while 6 is most likely as a result of the steric hindrance both of the
not, the concentration gradient might push the equilibrium diol and of the α-carbon in the intramolecular cyclisation
of a number of reactions to give more of the intermediate step (Scheme 4). A very small yield of cyclic product 4
1
6
which leads irreversibly to the oxazinanone 2.
was detected (0.3%). Therefore nucleophilic displace-
ment of the carbonate group upon attack of a hindered car-
bon is probably not energetically favored. This confirms
that cyclisation occurs preferably via intramolecular nu-
Finally, it must be mentioned that the presence of the sec-
ondary alcohol does effect, to an extent, the yields of ox-
azinanone 2 being lower than those of oxazinanone 1.
cleophilic attack on a CH group (Scheme 2).
2
Benzylamine was then reacted with 3-methylbutane-1,3-
diol, containing primary and tertiary functionalities, in the
presence of a DAC and the base to give 3-benzyl-6,6-di-
methyl-1,3-oxazinan-2-one (3).
The general applicability of the one-pot synthesis to 1,3-
oxazinan-2-ones was then investigated employing several
nucleophiles, that is, aniline, phenylhydrazine, and n-oc-
tylamine. These substrates were reacted with differently
substituted 1,3-diols in the presence of the preferred DAC,
Mt-BuC, (Scheme 5).
The results, reported in Table 3 confirmed once again the
influence of the steric factors previously observed.
Due to the difficulty in isolating 3-benzyl-6,6-dimethyl-
1
,3-oxazinan-2-one (3), for this set of reactions only the
O
1
5
R2
HO
R1
HPLC data has been scrutinised.
R3
O
90 °C
1
O
N
R NH2+
+
The same trend of increasing yield with increasing steric
hindrance of the DAC previously observed in Tables 1
and 2, is also seen in Table 3. The yields for oxazinone 3
are lower compared to those observed for oxazinanones 1
and 2, most likely as a result of the low reactivity of the
tertiary alcohol in transesterification reactions. Also in
OH
KOt-Bu
MeO
Ot-Bu
R2
R3
8–15
8 R1 = Ph; R , R3 = H
2
12 R1 = PhNH; R2 = Me; R = H
3
9 R1 = Ph; R2 = Me; R3 = H 13 R1 = PhNH; R , R = Me
2
3
0 R1 = Ph; R , R3 = Me
2
14 R1 = Oct; R , R3 = H
2
1
11 R1 = PhNH; R2 = R3 = H 15 R1 = Oct; R2 = Me; R = H
3
1
this case, H NMR confirmed that the two methyl substit-
uents are solely in the 6-position.
Scheme 5 Reaction of a 1,3-diol with an amine or phenylhydrazine
to give the 1,3-oxazinan-2-ones 8–15
To further support the results observed the diol 2-methyl-
pentane-2,4-diol was reacted with benzylamine and Mt-
BuC in the presence of potassium tert-butoxide to give 3-
benzyl-4,6,6-trimethyl-1,3-oxazinan-2-one (4). The Mt-
BuC was selected as in the previous reactions. It has been
shown to give the highest yield of oxazinanone.
Table 4 shows that this cascade synthetic approach to ox-
azinanones can be employed efficiently to several amines
and also to phenylhydrazine, giving adequate to good
Synlett 2012, 23, 1809–1815
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,3-Oxazinan-2-ones from Amines and 1,3-Diols
1813
Table 4 Reaction of Amines and Phenylhydrazine with a 1,3-Diol in the Presence of Methyl tert-Butyl Carbonate with Potassium tert-Butoxidea
Entry
Nucleophile
Diol
GC–MS area (%)
Isolated yield (%)
1
2
3
4
5
6
7
aniline
propane-1,3-diol
butane-1,3-diol
46
62
34
61
76
52
51
32
8 34
9 41
aniline
aniline
3-methylbutane-1,3-diol
propane-1,3-diol
butane-1,3-diol
10 32
11 24
12 53
13 18
14 25
15 17
phenylhydrazine
phenylhydrazine
phenylhydrazine
n-octylamine
n-octylamine
3-methylbutane-1,3-diol
propane-1,3-diol
butane-1,3-diol
8
a
All reactions were carried out at 90 °C for 2 h, in the absence of a solvent with a 1.0:1.0:2.0:3.0 molar loading of amine/phenylhydrazine/di-
ol/base/dialkyl carbonate, respectively. Due to the large number of parasitic reactions and their resultant products for each entry, the HPLC data
has not been calibrated, as to isolate every byproduct would be too complex.
yields. Notably oxazinanones 9 and 12 were achieved in groups, entering groups and protecting groups. Compar-
6
2% and 76% yields, respectively (according to GC–MS).
ing the results from entries 1–4 in each Table, the more
hindered the DAC the greater the yield of oxazinaone ob-
served.
In particular, while n-octylamine follows a similar trend
to that of benzylamine in terms of decreasing yield as the
hindrance of the diol increases, aniline and phenylhydra-
zine showed a different trend. This is possibly a result of
steric hindrance between the rigid aromatic system of the
amine/hydrazine and the methyl group(s) on the carbon α
to the carbamate. In all cases, H NMR analysis of the ox-
azinanones confirmed that methyl substituent(s) were
found solely in the 6-position.
One-Pot Reaction. Synthesising the 1,3-dicarbonate in
situ removes a lengthy step from the production of the ox-
azinanone, requires far less equivalents of DAC and re-
duces the energy consumption for the process. This one-
pot reaction has many variables: temperature, reaction
time, base, 1,3-diol, DAC, and amine. The present work
has established the effect of DAC and 1,3-diols on the re-
action yields; it should be noted that the latter are already
definitely higher than those previously reported in the lit-
erature. However, reaction conditions such as different
DAC, time, temperature, and base should be investigated
individually for each novel 1,3-oxazin-2-ones in order to
achieve optimised yields.
1
Table 4 shows a disparity between the observed and iso-
lated yields since products 8–13 were isolated by crystal-
lisation and not by column chromatography as in Tables
1–3, thus, it is expected that a certain amount of the com-
pounds remain within the liquor. Also, in the case of oxa-
zinanones 7–9 the large hydrophobic chain present in the
compound made its separation from other byproducts via
column chromatography somewhat difficult.
Experimental Data
All experimental procedures described were carried out under air
and in oven-dried glassware. All reagents were ACS grade and were
employed without further purification. Alkyl carbamates DPrC and
Mt-BuC were synthesised and purified as described in our previous
In conclusion, a one-pot synthesis of oxazinanones from
amines or phenyl hydrazine, 1,3-diols and DAC through a
cascade reaction in the presence of a base and without any
solvent has been described. According to the results ob-
14 1
13
paper. H NMR and C NMR spectra were obtained on a Bruker
tained we can make several observations on this novel AVANCE 300 spectrometer at 25 °C and referred to deuterated
synthetic approach to 1,3-oxazinan-2-ones:
CHCl as internal standard. Melting point analyses carried out are
uncorrected. HPLC analyses were carried out at 20 °C on a C18 5
μm column (4.6 × 150 mm) using an eluting system of acidified
3
Structure of the 1,3-Diol. A very high level of selectivity
is found when reacting a 1,3-diol with both primary func-
tionality and a substituent α to the other OH group. For cy-
clisation to occur through nucleophilic displacement,
H O–MeCN (65:35) at 0.8 mL/min and detecting at λ = 210 nm. A
2
typical sample size was 100 μL of a solution comprising of 0.1 g of
the reaction mixture, 5 mL of 18.8 mM solution of nitrobenzene in
primary CH functionality α to the carbonate must be MeCN as standard, and 20 mL of MeCN–H O (50:50). GC–MS
2
2
analyses were performed at 70 eV (MS) with a 30 m HP 5 capillary
GC column. A typical sample size was 0.2 μL of a solution of 1 mg
present, as substituents on the oxazinanone ring are found
in the 6-position, never in the 4-position. Comparing the
results from Tables 1–4, it is evident that in the case of al-
of the reaction mixture in 1 mL of CH Cl .
2
2
iphatic amines, the more hindered the diol the lower the General Synthesis of an 1,3-Oxazinan-2-one
To an oven dried 50 mL round-bottom flask equipped with a mag-
yield of oxazinanone.
Structure of the DAC. The role of the DAC in the cascade
cyclisation reaction is multifunctional. They act as leaving
netic stirrer bar and condenser was added the amine/hydrazine (10
mmol), the 1,3 diol (10 mmol), and the required alkyl carbonate–
DMC (2.7 g, 30 mmol), DEC (3.54 g, 30 mmol), DPrC (4.38 g, 30
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1809–1815

1814
C. R. McElroy et al.
LETTER
mmol), or Mt-BuC (3.96 g, 30 mmol), which were reacted at 90 °C
for 2 h in the presence of KOt-Bu (2.24 g, 20 mmol). The reaction
6-Methyl-3-phenylamino-1,3-oxazinan-2-one (12)
White crystalline product (1.092 g, 5.30 mmol, yield 53%); mp
1
was then quenched with H O (5 mL) and the mixture extracted with
156.5–157.5 °C. H NMR (300 MHz, CDCl ): δ = 1.35–1.37 (d, J =
3
2
CH Cl (2 × 10 mL), dried over Na SO and the solvent removed
6.3 Hz, 3 H), 1.82–2.03 (m, 2 H), 3.39–3.46 (m, 1 H), 3.53–3.63 (m,
2
2
2
4
under vacuum to give a yellow/orange oil, which was further puri-
fied depending upon the product.
1 H), 4.37–4.44 (m, 1 H), 6.68–6.75 (m, 3 H) 6.82–6.86 (t, J = 7.3
1
3
Hz, 1 H), 7.15–7.20 (t, J = 8.2 Hz, 2 H). C NMR (75 MHz,
CDCl ): δ = 21.1, 29.8, 48.2, 74.4, 113.5, 121.2, 129.7, 145.8,
3
+
Additional Purification for 1, 2, and 14
The oil was then purified via column chromatography on silica us-
155.0. HRMS: m/z calcd for C H N O + H : 207.1134; found:
11
14
2
2
2
07.1152.
ing Et O to remove the byproducts and then MeOH to give the prod-
2
uct.
6,6-Dimethyl-3-phenylamino-1,3-oxazinan-2-one (13)
White crystalline product (0.404 g, 1.84 mmol, yield 18%); mp
1
Additional Purification for 3 and 15
The oil was then purified via column chromatography on silica us-
ing Et O–cyclohexane (1:1) to give adequate separation of the by-
products and the product.
184.3–185.0 °C. H NMR (300 MHz, CDCl ): δ = 1.47 (s, 6 H),
3
2
.01–2.06 (t, J = 6.4 Hz, 2 H), 3.63–3.67 (t, J = 6.4 Hz, 2 H), 6.71–
2
6.74 (d, J = 6.7 Hz, 2 H), 6.86–6.91 (t, J = 7.4 Hz, 1 H), 7.19–7.26
13
(
t, J = 7.5 Hz, 2 H). C NMR (75 MHz, CDCl ): δ = 27.6, 33.6,
3
4
6.4, 79.6, 113.7, 121.6, 129.8, 146.9, 154.3. HRMS: m/z calcd for
Purification for 8–13
+
C H N O + H : 221.1290; found: 221.1306.
12
16
2
2
The product was then precipitated out in Et O and recrystallised in
2
PrOH.
3
-Octyl-1,3-oxazinan-2-one (14)
1
Yellow oil (0.541 g, 2.54 mmol, yield 25%). H NMR (300 MHz,
Spectroscopic data for products 1, 8, and 11 has previously been re-
ported.
10
CDCl ): δ = 0.61–0.66 (t, J = 6.4 Hz, 3 H), 1.03–1.05 (m, 10 H),
3
1
.29–1.38 (quin, J = 6.9 Hz, 2 H), 1.76–1.84 (quin, J = 6.1 Hz, 2 H),
13
3
-Benzyl-1,3-oxazinan-2-one (1)
3.04–3.11 (m, 4 H), 3.97–4.01 (t, J = 5.3 Hz, 2 H). C NMR (75
The product was recrystallised in Et O to give a white crystalline
MHz, CDCl ): δ = 14.2, 22.4, 22.7, 26.8, 27.1, 29.3, 29.4, 31.9,
45.2, 49.5, 66.6, 153.6.
2
3
solid (DMC: 0.402 g, 2.09 mmol, yield 21%; DEtC: 0.684 g, 3.58
mmol, yield 36%; Di-PrC: 0.892 g, 4.67 mmol, yield 47%; MCt-Bu:
1.086 g, 5.69 mmol, yield 57%).
6-Methyl-3-octyl-1,3-oxazinan-2-one (15)
Yellow oil (0.378 g, 1.67 mmol, yield 17%). H NMR (300 MHz,
1
3
-Benzyl-6-methyl-1,3-oxazinan-2-one (2)
CDCl ): δ = 0.62–0.66 (m, 3 H), 1.05–1.15 (m, 10 H), 1.12–1.14 (d,
3
The product was recrystallised in Et O (at –18 °C) to give a yellow
J = 6.3 Hz, 3 H), 1.51–1.60 (m, 2 H), 1.76–1.80 (m, 1 H), 1.81–1.84
2
1
3
crystalline solid (DMC: 0.284 g, 1.39 mmol, yield 14%; DEtC:
(m, 1 H), 2.92–3.21 (m, 4 H), 4.08–4.19 (m, 1 H). C NMR (75
0
.563 g, 2.75 mmol, yield 28%; Di-PrC: 0.897 g, 4.38 mmol, yield
MHz, CDCl ): δ = 14.3, 21.1, 22.8, 26.9, 27.3, 29.2, 29.4, 29.5,
3
+
4
4%; MCt-Bu: 0.928 g, 4.53 mmol, yield 45%); mp 52.4–54.3 °C.
32.0, 44.6, 49.4, 73.5, 153.8. HRMS: m/z calcd for C H NO + H :
1
3
25
2
1
H NMR (300 MHz, CDCl ): δ = 1.30–1.33 (d, J = 6.3 Hz, 3 H),
224.1287; found: 224.1300.
3
1
4
.64–1.77 (m, 1 H), 1.87–1.95 (m, 1 H), 3.07–3.25 (m, 2 H), 4.28–
.38 (m, 1 H), 4.42–4.61 (m, 2 H), 7.22–7.32 (m, 5 H). 1 C NMR
3
(
1
75 MHz, CDCl ): δ = 20.7, 28.7, 43.5, 52.3, 73.4, 127.5, 127.9,
Supporting Information for this article is available online at
3
+
28.6, 136.7, 154.1. HRMS: m/z calcd for C H NO + H :
http://www.thieme-connect.com/ejournals/toc/synlett. SnuIpofoipmngr irtSatnoIuipfog
r
t
iornat
1
2
15
2
206.1182; found: 206.1202.
3
-Benzyl-6,6-dimethyl-1,3-oxazinan-2-one 3
References and Notes
The product was then recrystallised in Et O (–18 °C) to give a white
2
1
(
1) (a) Ghosh, A. K.; Bilcer, G.; Schiltz, G. Synthesis 2001,
2203. (b) List, B.; Castello, C. Synlett 2001, 1687. (c) Fuchs,
K.; Eickmeier, C.; Heine, N.; Peters, S.; Dorner-Ciossek, C.;
Handschuh, S.; Nar, H.; Klinder, K. US 2010144681 A1,
2010.
crystalline solid, mp 65.7–68.3 °C. H NMR (300 MHz, CDCl ): δ
3
=
1.36 (s, 6 H), 1.81–1.86 (t, J = 6.5 Hz, 2 H), 3.16–3.20 (t, J = 6.4
1
3
Hz, 2 H), 4.57 (s, 2 H), 7.24–7.36 (m, 5 H). C NMR (75 MHz,
CDCl ): δ = 27.0, 32.4, 41.5, 52.3, 78.0, 127.5, 127.9, 128.6, 136.8,
3
+
153.7. HRMS: m/z calcd for C H NO + H : 220.1338; found:
13
17
2
2
20.1354.
(2) Berger, R.; Chang, L.; Edmonson, S. D.; Goble, S. D.;
Harper, B.; Kar, N. F.; Kopka, I. E.; Li, B.; Morriello, G. J.;
Moyes, C. R.; Shen, D. M.; Wang, L.; Wendt, H.; Zhu, C.
WO 2009123870 A1, 2009.
3
-Phenyl-1,3-oxazinan-2-one (8)
White crystalline product (0.610 g, 3.41 mmol, yield 34%).
(
(
3) Li, Y.; Yao, W.; Rodgers, J. WO 200964835 A1, 2009.
4) Ali, A.; Sinclair, P. J.; Taylor, G. E. US 2009018054 A1,
2009.
6
-Methyl-3-phenyl-1,3-oxazinan-2-one (9)
White crystalline product (0.791 g, 4.14 mmol, yield 41%); mp
6
1
78.3–78.6 °C (lit. 78–79 °C). H NMR (300 MHz, CDCl ): δ =
3
(5) Tomokazu, H.; Yasuko, Y.; Toshihiko, S.; Koki, M.
EP 2085392 A1, 2009.
1.47–1.49 (d, J = 6.3 Hz, 3 H), 1.94–2.19 (m, 2 H), 3.62–3.82 (m, 2
1
3
H), 4.53–4.64 (m, 1 H), 7.24–7.43 (m, 5 H). C NMR (75 MHz,
CDCl ): δ = 21.4, 29.7, 48.5, 74.5.3, 126.3, 127.2, 129.6, 143.2,
(
6) (a) Fujiwara, M.; Baba, A.; Matsuda, H. J. Hetrocycl. Chem.
3
1
989, 26, 1659. (b) Shibata, I.; Nakamura, K.; Baba, A.;
Matsuda, H. Bull. Chem. Soc. Jpn. 1989, 62, 853.
(7) (a) Jung, J.; Avery, M. A. Tetrahedron Lett. 2006, 47, 7969.
b) Wang, G.; Ella-Menye, J.; Sharma, V. Bioorg. Med.
153.4.
6
,6-Dimethyl-3-phenyl-1,3-oxazinan-2-one (10)
White crystalline product (0.654 g, 3.19 mmol, yield 32%), mp
(
1
1
2
7
7
23.3–123.7 °C. H NMR (300 MHz, CDCl ): δ = 1.51 (s, 6 H),
.03–2.07 (t, J = 6.4 Hz, 2 H), 3.69–3.73 (t, J = 6.4 Hz, 2 H), 7.23–
.43 (m, 5 H). C NMR (75 MHz, CDCl ): δ = 27.7, 33.4, 46.4,
9.0.3, 126.4, 127.2, 129.7, 143.3, 153.1. HRMS: m/z calcd for
3
Chem. Lett. 2006, 16, 2177. (c) Trifunovic, S.; Dimitrijevic,
D.; Vasic, G.; Vukicevic, R. D.; Radulovic, N.; Vukicevic,
M.; Heinemann, F. W. Synthesis 2010, 943.
13
3
(8) (a) Kayaki, Y.; Mori, N.; Ikariya, T. Tetrahedron Lett. 2009,
+
C H NO + Na : 228.1964; found: 228.1935.
1
2
15
2
50, 6491. (b) Rice, G. T.; White, M. C. J. Am. Chem. Soc.
2
009, 131, 11707. (c) Nahra, F.; Liron, F.; Prestat, G.;
3
-Phenylamino-1,3-oxazinan-2-one (11)
Mealli, C.; Messaoudi, A.; Poli, G. Chem.–Eur. J. 2009, 15,
White crystalline product (0.468 g, 2.44 mmol, yield 24%).
11078. (d) Mangelinckx, S.; Nural, Y.; Dondas, H. A.;
Synlett 2012, 23, 1809–1815
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,3-Oxazinan-2-ones from Amines and 1,3-Diols
1815
Denolf, B.; Sillanpaa, R.; De Kimpe, N. Tetrahedron 2010,
6, 4115.
9) (a) Kim, Y. J.; Varma, R. S. Tetrahedron Lett. 2004, 45,
205. (b) Ella-Menye, J.; Sharma, V.; Wang, G. J. Org.
Chem. 2005, 70, 463.
(13) Tundo, P.; McElroy, C. R.; Aricò, F. Synlett 2010, 1567.
(14) Tundo, P.; Aricò, F.; Rosamilia, A. E.; Rigo, M.; Maranzana,
A.; Tonachini, G. Pure Appl. Chem. 2009, 81, 1971.
(15) 3-Benzyl-6,6-dimethyl-1,3-oxazinan-2-one (3) was isolated
by combining the reaction products from entries 2–4 (Table
3) prior to column chromatography. Due to many byproducts
6
(
7
(
10) McElroy, C. R.; Aricò, F.; Benetollo, F.; Tundo, P. Pure
Appl. Chem. 2012, 84, 707.
having similar R values to that of 3, only a small amount was
f
(
(
11) Tundo, P.; Selva, M. Acc. Chem. Res. 2002, 35, 706.
12) Benzylamine (0.16 g, 1.5 mmol), propane-1,3-diol (0.12 g,
isolated.
(16) Product 4 was attributed to this low yield compound as
HPLC retention time and GC–MS data were consistent with
such an oxazinanone.
1.5 mmol), di-tert-butyl carbonate (0.79 g, 4.5 mmol), and
KOt-Bu (0.34 g, 3 mmol) were reacted at 90 °C for 2 h; the
only product of the reaction was a small quantity of dibenzyl
urea.
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1809–1815

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