Interaction of methyl N-(3-oxoalkyl)carbamates, S-methyl-carbamates, and -dithiocarbamates with sodium borohydride. Synthesis of tetrahydro-1,3-oxazin-2-ones and -thiones

Article abstract of DOI:10.1023/A:1011660706513

The interaction of N-(3-oxoalkyl)carbamates, -thiocarbamates, and -dithiocarbamates with sodium borohydride has been studied. It was shown that reaction proceeds diastereoselectively, and reductive cyclization with the formation of tetrahydro-1,3-oxazin-2-ones and -thiones may occur. The tend to cyclization of the N-(3-hydroxyalkyl)carbamates, -thiocarbamates, and -dithiocarbamates formed as intermediates depends on the number of substituents in the alkyl chain.

Full text of DOI:10.1023/A:1011660706513

Chemistry of Heterocyclic Compounds, Vol. 37, No. 5, 2001
INTERACTION OF METHYL
N-(3-OXOALKYL)CARBAMATES,
S-METHYL -CARBAMATES, AND
-DITHIOCARBAMATES WITH
SODIUM BOROHYDRIDE.
SYNTHESIS OF TETRAHYDRO-
1,3-OXAZIN-2-ONES AND -THIONES
A. S. Fisyuk, E. A. Ryzhova, and B. V. Unkovskii
The interaction of N-(3-oxoalkyl)carbamates, -thiocarbamates, and -dithiocarbamates with sodium
borohydride has been studied. It was shown that reaction proceeds diastereoselectively, and reductive
cyclization with the formation of tetrahydro-1,3-oxazin-2-ones and -thiones may occur. The tend to
cyclization of the N-(3-hydroxyalkyl)carbamates, -thiocarbamates, and -dithiocarbamates formed as
intermediates depends on the number of substituents in the alkyl chain.
Keywords: N-(3-oxoalkyl)carbamates, N-(3-oxoalkyl)thiocarbamates, N-(3-oxoalkyl)dithiocarbamates,
tetrahydro-1,3-oxazines, diastereoselectivity, reductive cyclization.
The tetrahydro-1,3-oxazin-2-ones and -thiones are of interest as biologically active compounds [1], and
are used for the synthesis of polymers [2,3] and liquid crystals [4]. Some of them are naturally occurring [5]. A
series of reviews has been devoted to the methods of synthesis and properties of these compounds [6-9].
The N-(3-hydroxyalkyl)carbamates and their sulfur analogs 6 and 7 are converted by the action of bases
or on heating into tetrahydro-1,3-oxazin-2-ones and -thiones [5,10-14]. At the same time it has been reported
that N-(3-hydroxyalkyl)carbamates are formed on reducing the N-(3-oxoalkyl)carbamates [12,15] with complex
metal hydrides in basic media. We obtained compounds 3-5 with the aim of studying the stereoselectivity of the
borohydride reduction and the possibility of a one-stage conversion of N-3-oxoalkyl-substituted carbamates,
thiocarbamates, and dithiocarbamates into tetrahydro-1,3-oxazin-2-ones and -thiones.
Carbamates 3a,c,e, syn-3b, and anti-3d were synthesized by the reaction of the hydrochlorides of the
corresponding 1,3-amino ketones 2a,c,e, syn-2b, and anti-2d with methyl chloroformate in a two-phase system
(water–ether) at reduced temperature. The anti isomer of the hydrochloride of amino ketone 2d was obtained by
the procedure of [16], and syn-2b by crystallization from acetone of a mixture of syn and anti isomers of 2b
formed on hydrolysis of 1,3-isothiocyanato ketone 1b [17].
__________________________________________________________________________________________
Omsk State University, Omsk 644077, Russia; e-mail: fis@univer.omsk.su. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 5, pp. 649-662, May 2001. Original article submitted May 11, 1999.
0009-3122/01/3705-0597$25.00©2001 Plenum Publishing Corporation
597

The dithiocarbamates 4a,c and anti-4d were synthesized by the alkylation of salts of dithiocarbamic
acids with methyl iodide. In the case of anti-4d the dithiocarbamic acid salt was obtained by the reaction of the
anti isomer of amino ketone 2d with carbon disulfide in the presence of triethylamine, and compounds 4b,c by
the interaction of 1,3-isothiocyanato ketones [18] and sodium hydrosulfide [19].
R1
R1
R2
3
2
O
R
2NaOH
3
O
O
R
R
O
+
Cl
OMe
–2NaCl, –2H2O
R4
R5
R4
R5
_
+
NH Cl
N
H
OMe
SMe
SMe
2a–e3
3a–e
HCl, ∆
R1
1
R
R1
R2
R2
R2
R3
R4
R5
3
R3
R4
R
O
S
MeI
–NaI
NaSH
MeOH
O
O
S
_
R4
R5
+
N
H
N
H
R5
Na
NCS
1a–e
S
4a, c
HCl, ∆
Me
Me
Me
H
H
H
H
H
O
O
S
MeI
NEt3
S
O
CS
+
2
_
+
N
H
anti-4d
N
H
SHNEt3
NH2
H
anti-2d
a R1 = R2 = Me, R3 = R4 = R5 = H; b R1 = R2 = R4 = Me, R3 = R5 = H;
c R1 = R4 = R5 = Me, R2 = R3 = H; d R1 = Me, R2 = R5 = H, R3 + R4 = (CH2)4;
e R1 + R2 = (CH2)4, R3 = H, R4 + R5 = (CH2)5
It has been reported [20] that 1,3-chloro ketones undergo the Ritter reaction with methyl thiocyanate in
the presence of Lewis acids to give 2-methylthio-4H-1,3-oxazines. We have shown that hydrolysis of
2-methylthio-4H-1,3-oxazines leads to an S-methyl N-(3-oxoalkyl)thiocarbamates. The S-methyl thiocarbamate
5c was obtained in this way.
Me
Me
O
O
SnCl4
Me
Me
Me
Me
N
CSMe
+
+
N
H
Cl
SMe
_
SnCl5
Me
_
OH
H2O
O
O
Me
Me
N
H
5c
SMe
Study of the interaction of sodium borohydride with N-(3-oxoalkyl)carbamates 3a-e, S-methyl
thiocarbamate 5e, and dithiocarbamates 4a,c in alcohol showed that the initial reaction products
N-(3-hydroxyalkyl)carbamates 6c,e, thiocarbamate 8c, and dithiocarbamate 7c were not isolated since they are
598

unstable under the reaction conditions and are converted into tetrahydro-1,3-oxazin-2-ones 9c,e and -thione 10c.
Compounds 6c and 7c were successfully obtained only in neutral medium which we maintained by the addition
of phosphate buffer to the reaction mixture.
R1
R1
R1
R2
R3
R4
R5
R2
R3
R4
R5
R2
R3
R4
R5
_
O
X
_
OH
X
O
X
NaBH4
OH
–H2O
N
H
YMe
N
H
YMe
N
H
A
YMe
6a–f; 7a,c,d; 8e
3a–e; 4a,c,d; 5e
R1
R1
OH
R2
ClCO2Me
+
R2
_
NH2
R3
R4
R3
–YMe
_
O
O
X
R4
N
H
X
N
H
<
YMe
R5
R5
9a–e; 10a,c,d
a R1 = R2 = Me, R3 = R4 = R5 = H; b R1 = R2 = R4 = Me, R3 = R5 = H;
c R1 = R4 = R5 = Me, R2 = R3 = H, d R1 = Me, R2 = R5 = H, R3 + R2 = (CH2)4;
e R1 = R2 = (CH2)4, R3 = H, R4 + R5 = (CH2)5; f R1 = R2 = R3 = R4 = R5 = H;
3, 6, 9 X = Y = O; 5, 8, 10 X = O, Y = S; 4, 7 X = Y = S
Several hours after adding sodium borohydride compounds 3c,e and 4c were practically completely
converted into tetrahydro-1,3-oxazines 9c,e and 10c. Methyl N-(3-hydroxy-2-methylbutyl)carbamate (6a) and
-dithiocarbamate (7a), with a lower number of substituents in the alkyl fragment, were less able to cyclization
than compounds 6c,e and 7c, what enabled them to be obtained from substances 3a and 4a without buffer. Only
an increase in the pH of the reaction mixture leads to conversion of compounds 6a and 7a into 1,3-oxazines 9a
and 10a. Attempts to realise cyclization of unsubstituted methyl N-(3-hydroxypropyl)carbamate 6f into a
tetrahydro-1,3-oxazin-2-one under analogous conditions were unsuccessfull. The anomalous behavior of
unsubstituted cyclic carbamates (instability on distillation, tendency to ring opening and polymerization) has
been noted by many investigators [2,3,21]. At the same time the substituted tetrahydro-1,3-oxazin-2-ones are
less capable to polymerization [2]. A thermodynamic concept based on a comparison of the enthalpy and
entropy of the linear and cyclic structures has been proposed to explain the accelerated cyclization of
polysubstituted bifunctional compounds [22]. It was shown that there were fewer sloped unbonded interactions
in a series of substituted hexanes and cyclohexanes with alkyl substituents in the cycle than in compounds with
open chains. This indicates that enthalpy factors favor to a large extent the cyclization of the methyl substituted
chain as compared with the unsubstituted ones. Branchings restrict internal rotation, reduces the entropy of
compounds with an open chain, but is unable to change significantly the entropy of cyclic compounds, having
less freedom for internal rotation.
The mechanism of formation of tetrahydro-1,3-oxazinones 9, 10 probably includes base catalyzed
cyclization of N-(3-hydroxyalkyl)carbamates and their sulfur analogs into the 2-gem-substituted tetrahedral
intermediate B stabilized by elimination of a methoxy or mercapto anion. An increase in the pH of the medium
increases the reaction rate due to the increase in concentration of anion A.
Interaction of dithiocarbamate 4d with NaBH4 leads to a mixture of (4a,8a-trans-4a,4-trans)- and (4a,8a-
trans-4a,4-cis)-4-methyloctahydro-2H-3,1-benzoxazine-2-thiones (10d) with a slight predominance of the latter
(2/3), as a result of the cyclization of N-(3-hydroxyalkyl)dithiocarbamates with configurations anti,anti-7d and
599

anti,syn-7d formed as intermediates. The borohydride reduction of 2-aminoacetylcyclohexane 2d in methanol
[23] leads to the predominant formation of the anti,anti isomer of the 1,3-aminoalcohol 11d (diastereomeric
purity 30%), and proceeds probably through a cyclic transition state (control by chelation) characteristic for
1,3-amino ketones [15,16,23].
Me
Me
Me
Me
OH
Me
Me
Me
NHR OH
Me
NHR OH
Me
MeO2CNH
MeO2CNH
anti,anti -6,7,11d
anti,syn-6,7,11d
syn,anti-6b
syn,syn-6b
6 R = CO2Me; 7 R = CS2Me; 11 R = H
The slightly expressed stereoselectivity of the reduction of dithiocarbamate 4d indicates the occurrence
of nucleophilic attack of the carbon atom of the carbonyl group by hydride anion from both sides, but the
change in the predominant direction of the attack corresponds to an open model of 1,2-asymmetric induction,
which is effected from the less hindered side and not from the side of the amino group, as in the case of
1,3-aminoketones in [15,23]. The reductive cyclization of the carbamates anti-3d and syn-3b in alcohol occurs
analogously, but with somewhat higher stereoselectivity. Reaction of compounds anti-3d and syn-3b with
sodium borohydride gave a mixture of oxazines 4a,8a-trans-4,4a-cis-9d and 4a,8a-trans-4,4a-trans-9d,
4,5-cis-5,6-trans-9b, and 4,5-cis-5,6-cis-9b in ratios 4 : 1 with overall yields of 78 and 80%.
The differences in the stereoselectivity of the reduction of amino ketone 2d and
N-(3-oxoalkyl)carbamate 3d enabled us to obtain the pure diastereomers 4a,4-cis-4a,8a-trans-9d and
4a,4-trans-4a,8a-trans-10d. We note that the known procedure for obtaining tetrahydro-1,3-oxazine-2-thiones,
based on the interaction of 1,3-isothiocyanato ketones and sodium borohydride [24], for the synthesis of the
is not useful, since the addition of thiocyanic acid to 1-acetyl-Δ1
individual isomers of 10d
-cyclohexene was not
stereospecific [16] and did not permit the preparation of the individual syn and anti isomers of isothiocyanato
ketone 1d. Compound 4a,8a-trans-4a,4-cis-9d was isolated by crystallization of the products of reductive
cyclization 3d.
4a,8a-trans-4,4a-trans-9,10d
4a,8a-trans-4,4a-cis-9,10d
600

4,5-cis-5,6-cis-9b
syn-4b
4,5-cis-5,6-trans-9b
20%
80%
By reacting the diastereomers of aminoalcohol 11d, formed on borohydride reduction of amino ketone
anti-2d, with carbon disulfide and methyl iodide [25] a mixture of the anti and syn isomers of methyl
[anti-2-(1-hydroxyethyl)cyclohexyl]dithiocarbamate (7d) was obtained in an overall yield of 70%, from which a
pure isomer with the configuration of anti,anti-7d was isolated. The dithiocarbamate anti,anti-7d was converted
by the action of a solution of sodium hydroxide in methanol into (4a,8a-trans-4a,4-trans)-4-methyloctahydro-
2H-3,1-benzoxazine-2-thione (10d).
4a,8a-trans-4,4a-trans-10d
anti,anti-7d
Study of the products of reductive cyclization of carbamate 3b and dithiocarbamate 4b showed that the
cis and trans isomers of oxazines 9b and 10b are formed in practically equal ratios. The oxazine trans-10b was
isolated from this mixture of isomers by crystallization.
In the IR spectra of liquid samples of compounds 6a,c,f and 7a,c, recorded in a thin film, a broad intense
band was observed at 3200-3500 cm-1 assigned to H-bonded OH and NH groups. At the same time the spectrum
of crystalline dithiocarbamate 7d recorded in Nujol shows two absorption bands at 3320 and 3100 cm-1 of the
OH and NH groups. The characteristic absorptions of 1,3-oxazin-2-ones 9 and -thiones 10 were in agreement
with the known data [26]. In the IR spectra of tetrahydro-1,3-oxazin-2-ones 9 recorded in Nujol the lines
observed at 1700 and 3255-3280 cm-1 resulted from intermolecular hydrogen bonding of NC=O and NH groups
[26]. On dilution of these compounds in chloroform, the bands of NC=O and NH groups free from association
appeared in the IR spectra at 1710-1720 and 3440-3460 cm-1 (Table 1).
The dithiocarbamates anti-4d and anti,anti-7d were in the form of Z- and E-isomers in a ratio of 4 : 1 in
chloroform solution, the existence of which is caused by restricted rotation about the HN–CS2Me bond. The
signal of the proton on the carbon atom of the cyclohexane ring bound to the nitrogen of the Z-isomer is
observed at lower field (4.43-4.92) than the signals of the E-isomer (3.67-4.18), which indicates restricted
rotation about the C–NHCS2Me bond [27].
E-anti,anti-7d
Z-anti,anti-7d
601

TABLE 1. Characteristics of Compounds 3-7, 9, 10
IR spectrum, ν, cm-1
Found, %
——————
Empirical
formula
mp, °C (solvent),
bp, °C/mm Hg
Compound
1
Yield, %
Calculated, %
(C=O)
OH
9
NC=X
7
NH
8
C
3
H
4
(S)N
5
2
6
10
69
54
94
97
C7H13NO3
C8H15NO3
C8H15NO3
C10H17NO3
52.86
52.82
8.23
8.23
—
—
—
72-73/0.4
76-77/0.6
73-75/0.6*3
1710
1710
1710
1690
3280
3280
3280
3270
(1730)*2
(1725)*2
(1725)*2
(1705)*4
3a*
55.49
8.67
3b
55.47
8.73
3c*
—
—
anti-3d
60.32
60.28
8.64
8.60
7.32
7.03
95-96
(alcohol)
C14H23NO3
66.33
9.13
5.52
91-92*5
1700
3320
(1715)*4
92
3e
66.37
9.15
5.53
30-50/1.0
4a*
C7H13NOS2
C8H15NOS2
43.83
43.95
—
6.91
6.85
—
7.31
7.32
115-118/0.05
1510
1550
3230
3180
(1705)*2
(1710)*4
77
84
—
—
—
100-101
4c
(acetone)*6
anti-4d
C10H17NOS2
C8H15NO2S
51.87
51.91
7.33
7.41
91-92
1530
1670
3220
3410
(1690)*7
(1710)*8
37
71
(alcohol–water)
50.63
7.99
75-76
5c
50.77
7.99
(hexane)
6f*
6a*
6c*
7a*
7c*
С5Н11NО3
С7H15NO3
С8H17NO3
С7H15NOS2
С8H17NOS2
45.12
45.11
8.30
8.33
10.56
10.52
98-100/4
1710*2
1695*2
1695*2
1520*2
1530*2
3040-3500
60
86
92
76
85
52.38
9.37
8.72
93-96/0.30
3130-3500
3140-3480
3040-3500
3040-3500
52.16
9.38
8.69
8.09
7.99
55.20
54.84
9.56
9.78
88-90/0.26
43.52
7.69
(33.02)
93-95/0.09
43.49
7.82
(33.17)
46.42
46.34
8.23
8.26
—
98-100/0.03-0.06

TABLE 1 (continued)
1
2
3
4
5
6
7
8
9
10
anti,
С10H19NOS2
51.43
51.46
8.28
8.21
5.99
6.00
132-133
(alcohol)
1550*4
3100
3320
36
(68)*9
anti-7d
9a*9
С6H11NO2
С7H13NO2
С9H15NO2
С13H21NO2
С6H11NOS
55.72
8.60
10.82
78-79
1700
3280
3460
—
—
—
—
—
81
(acetone)
1720*10
55.80
8.58
10.84
—
—
—
—
—
—
126-127
1700
3255
87
9c
(acetone)*11
1710*10
3440
(80)*12
cis,
63.49
63.88
8.81
8.93
163-164
1680*4
1700*8
1570*4
3260
64*13
(acetone)
(80)*9
trans-9d
9e*9
69.92
9.54
212-213
3275
3450
3120
93
69.92
9.48
(acetone)
trans-10a
10c
—
—
—
—
110-112
47*13
(alcohol)*14
93*9
С7H13NOS
С9H15NOS
—
—
210-211 (alcohol)*14
1560*4
1575*4
3165
3140
—
—
99
93
trans,
58.22
58.34
8.16
8.16
206-208
(alcohol)
trans-10d
_______
* nD20 3a 1.4505, 3c 1.4483, 4a 1.5680, 6a 1.4605,
6c 1.4500, 6d 1.4564, 7a 1.5630, 7c 1.5395.
*2 Thin film.
*8 In chloroform.
*9 Mixture of isomers.
*10 Solution (2%) in CHCl3.
*11 Lit. [32] 125-126°C.
*12 Obtained from 6a.
*3 Lit. [30] bp 70°C/0.2 mm Hg.
*4 In nujol.
*5 Sublimation, 30-50°C/12 mm Hg.
*6 Lit. [31] mp 101°C.
*13 According to data of NMR spectrum.
*14 Lit. [24] 10a 111-112°C, 10c 212-213°C (alcohol).
*7 KBr pellet.

TABLE 2. 1H NMR Spectra of Compounds 3-7, 9, and 10
Chemical shifts of protons, δ, ppm and CC, 2,3J, Hz
С6-Н(3J)
СН-ОН
YMe
Compound
1
R1 (3J)
R2 (2,3J)
R3 (2,3J)
R4(2,3J)
R5(2,3J)
NH (3J)
(ОН)
2
3
4
5
6
7
8
9
—
2.10
1.08 d
(6.5)
2.74 m
3.25-3.12 m
5.38
br. s
3.37 s
3a
(6.5, 6.5, 6.5)
syn-3b
3s
anti-3d
—
—
—
2.13
2.03
2.14
1.11
2.61 m (6.8, 6.8)
2.06 d (7.2)
4.06-3.88 m
3.68 m
4.88 br. d (8.0)
5.18 br. s
5.97 br. d (9.0)
3.58 s
3.48 s
3.56 s
2.76
1.29
2.34
2.12-1.10 m
(4.0, 11.5, 11.5)
—
2.12-1.10 m
3.03 dd
2.12-1.10 m
4.97
br. s
3.58 s
3e
(5.0, 13.0)
—
—
—
2.15
2.01
2.20 s
1.13 d (7.5)
3.05 m
3.90-3.57 m
1.53
8.00 br. s
7.37 br. s
2.52 s
2.47 s
2.59 s
4a
3.36
2.81
4s
Z-anti-4d
2.51 m *
2.20-1.60* m
2.20-1.60* m
4.92 m
7.69 d
(11.5, 11.5, 3.3)
(11.5, 11.5, 7.3, 4.0)
(7.3)
E-anti-4d
—
—
2.19
2.06
2.66-2.55*
4.18 m
8.37 d
(8.6)
5.79 br. s
5.62 br. s
2.67 s
(11.5, 11.5, 8.6, 3.3)
1.33
3.50-2.87 m
2.21 s.
3.58 s *
5s
syn-6a
3.79 m
1.05 d
0.76 d
(7.0)
0.80 d (7.0)
1.68-1.35 m *
1.68-1.35 m *
(6.5, 3.0)
(6.5)
anti-6a
6s
3.52-3.64* m
1.10 d (6.5)
3.50-2.87 m
5.62 br. s
6.48 br. s
3.58 s *
3.97 m
1.05 d
1.63 dd
1.33 dd
1.28 s
1.25 s
3.43 s
(9.0, 6.0, 2.5)
(6.0)
(14.5, 9.0)
(14.5, 2.5)
(3.83 br. s)
3.56 m
3.14 m
3.52 m
5.86
br. s
3.52 s
6f
(4.00 br. s)
4.18 m
1.25 d
(6.5)
1.92 dd
1.59 dd
1.69 s
1.65 s
8.90
2.49 s
7s
(9.5, 6.5, 2.0)
(9.5, 15.0)
(2.0, 15.0)
br. s
(2.56 br. s)
Z-anti,anti-7d
3.90 m
1.20 d
2.30-1.05 m
4.43 m
7.52 d
(8.2)
2.62 s
(6.5, 5.0)
(6.5)
(10.8, 10.8, 8.2,
4.0)

TABLE 2 (continued)
1
2
3
4
5
6
7
8
9
3.99 m
1.17 d
(6.5)
2.30-1.05
m
3.67 m
(10.5, 10.5, 8.2,
5.0)
8.14 d
(8.2)
2.68 s
E-anti-,anti-7d
(6.5, 5.0)
trans-9a
cis-9a
4.00 m
1.32 d
(6.5)
0.97 d
(6.5)
0.92 d (6.5)
1.76 m
2.06 m
3.45-2.85 m*
6.80
br. s
—
—
—
—
—
—
—
(10.0, 6.5)
4.42 m
1.26 d
3.45-2.85 m*
6.74
(3.5, 6.5)
(6.5)
br. s
trans,cis-9b
cis,cis-9b
9s
4.28 m
1.40 d
(6.4)
1.00 d
(7.1)
1.93 m
1.19 d
(6.7)
3.63
6.99
br. s
(6.4, 8.0)
(5.3, 7.1, 8.0)
(3.0, 6.7, 5.3)
4.56 m
1.38 d
0.95 d
1.80 m
1.23 d
3.79 m
6.70
(2.0, 6.5)
(6.5)
(7.1)
(6.6)
(4.0, 6.6)
br. s
4.38
1.26 d
(7.0)
1.50 dd
1.38 dd
1.23 s
1.23 s
7.31
br. s
7.13 br. s
(12.0, 7.0, 3.5)
(12.0, 3.5)
(12.0, 12.0)
trans,cis-9d
trans,trans-9d
4.44 m
1.28 d
1.97-2.12
1.90-0.96 m
1.90-0.96 m
2.33-0.90 m
2.33-0.90 m
1.91 m
3.15 m
(4.6, 6.6)
(6.6)
m
(4.0, 10.4, 10.4)
3.78 m
1.32 d
(6.6)
1.97-2.12
m
2.89 m
7.13 br. s
(6.6, 10.6)
(3.8, 10.5, 10.5)
trans-9e
cis-9e
trans-10a
3.98 m
4.55 m
6.23 br. s
6.23 br. s
—
—
—
4.15 m
1.41 d
(6.3)
1.04 d
(7.0)
3.38 m
2.96 m
8.99
(9.6, 6.3)
(12.8, 5.2, 5.0)
(12.8, 10.5)
br. s
cis-10a
4.57 m
1.38 d
1.02 d
2.21 m
3.46 m
3.12 m
8.91
br. s
—
—
—
—
(3.0, 6.6)
(6.6)
(6.6)
(12.8, 5.2, 1.9)
(12.8, 5.2, 3.2)
4.47 m
1.44 d
(6.0)
1.85 dd
1.63 dd
1.36 s
1.33 s
8.61
10s
(11.4, 6.0, 2.5)
(13.4, 2.5)
(13.4, 11.4)
br. s
trans,cis-10d
trans, trans-10d
4.60 m
1.34 d
2.18-2.00
1.91-0.96 m
3.19 m
8.85
br. s
8.85
br. s
(4.7, 6.7)
(6.7)
m
(4.2, 10.5, 10.5)
4.22 m
(6.4, 10.4)
1.41 d
(6.4)
2.18-2.00
m
1.91-0.96 m
3.08
(4.2, 10.5, 10.5)
_______
* Signals overlap.

TABLE 3. 13C NMR Spectra of Compounds 3, 4, 6, 7, 9, and 10
Chemical shifts of carbon atoms, δ, ppm (CHCl3)
Compound
C–O
NC=O
OCH3
C–N
signals of other carbon atoms
(С=O)
(NC=S)
(SCH3)
3a*
(208.8)
(205.1)
(210.1)
(211.8)
156.3
154.8
155.7
155.0
51.2
51.3
56.9
56.4
46.8
51.3
51.2
55.8
42.8, 27.8, 13.8
3c*
50.7, 31.1, 27.3, 27.3
anti-3d
3e
50.8, 32.4, 28.1, 26.0, 24.3, 24.1
50.9, 43.6, 31.1, 30.2, 28.9, 28.0, 25.4,
25.2, 21.0, 21.0
(210.3)
(206.5)
64.3
58.5
64.2
75.5
78.3
70.1
71.4
198.1
196.7
155.5
156.8
(195.3)
154.2
154.5
154.5
153.2
17.0
17.7
50.6
50.7
(17.5)
—
—
—
—
47.2
57.2
51.8
37.1
58.8
44.4
45.3
49.8
54.2
44.7, 27.4, 13.4
49.8, 30.7, 26.7, 26.7
49.5, 27.9, 25.2, 24.7
31.4
49.4, 26.4, 24.6, 22.6
28.5, 15.8, 10.9
31.6, 18.4, 13.5
41.5, 30.2, 28.9, 20.5
4a
4c
6c
6f
7c
cis-9a
trans-9a
9c
cis-9e
46.7, 38.3, 36.9, 35.0, 34.1, 32.3, 32.1,
30.1
trans-9e
74.7
154.3
—
54.4
25.0, 24.9, 24.6, 24.6, 24.3, 23.6, 21.6,
21.3, 20.2, 20.2, 19.9, 18.9
cis,trans-9d
cis-10a
trans-10a
10c
76.1
77.7
80.6
73.5
153.5
(185.8)
(186.1)
(186.4)
—
—
—
—
49.4
45.7
46.1
53.1
40.9, 32.2, 25.6, 25.1, 23.4, 15.2
27.6, 15.8, 11.2
30.5, 18.0, 13.8
41.6, 30.3, 29.4, 21.1
_______
* Solvent CCl4.
The chemical shifts and the values of coupling constants (CC) of the cis- and trans-isomers of oxazines 9
and 10 were in agreement with known data for these heterocyclic systems [11,15,28]. The values of the coupling
constants for compounds trans,cis-9d and 10d at 3J4a-H,8a-H = 10.5 and 3J4a-H,4-H = 4.5 indicate the transoid linking of
the rings in 4-methyloctahydro-2H-3,1-benzoxazines and the axial orientation of the 4-CH3 methyl group. On the other
hand oxazines cis-9,10a and cis,cis-9b have the axial methyl group at C(5) (3J6-Ha,5-He = 2.0-3.5 and 3J4-Ha,5-He = 4.0-5.2),
3
3
and trans,cis-9b (3J6-Ha,5-Ha = 8.0 and J4-He,5-Ha = 5.3) at C(4). The coupling constant J4-Ha,NH = 3.0 Hz
characteristic for equatorially oriented 4-H proton also proves the above orientation of compound trans,trans-9b.
Consequently we have studied the behavior of N-(3-oxoalkyl)carbamates and -dithiocarbamates under
borohydride reduction and have shown that, depending on the pH of the medium and the structure of the
reactant, this may lead to the formation of N-(3-hydroxyalkyl)carbamates and -dithiocarbamates or tetrahydro-
1,3-oxazin-2-ones or -thiones. The results obtained enabled us to develop a one-step method of obtaining
tetrahydro-1,3-oxazin-2-ones from N-(3-oxoalkyl)carbamates [29]. Taking into account the availability of
N-(3-oxoalkyl)carbamate esters, the stereoselectivity of borohydride reduction, and the simplicity of carrying
out reductive cyclization, the present method is of preparative interest for obtaining tetrahydro-1,3-oxazin-2-
ones. The pH-controlled borohydride reduction of N-(3-oxoalkyl)carbamates and -dithiocarbamates may be used
for obtaining the corresponding hydroxy derivatives and competes successfully with known methods.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker WM 250 (250.2 MHz) and Tesla BS 467 (60 MHz)
spectrometers in CDCl3 solution with HMDS as internal standard, and the 13C NMR spectra on a Bruker WP 80
(20.13 MHz) spectrometer. The IR spectra were recorded on Specord IR 75 and UR 10 instruments. The
606

1,3-amino ketone hydrochlorides were obtained by the procedures of [16,17], and methyl
N-(3-oxoalkyl)dithiocarbamates 4a,c by the procedure of [19].
Methyl N-(3-Oxoalkyl)carbamates (3a-e). The 1,3-amino ketone hydrochloride (0.145 mol), water
(10.3 ml), and ether (36.6 ml) were placed in a four-necked flask fitted with a mechanical stirrer and two
dropping funnels. The mixture was cooled to -5 to -20°C, and a solution of sodium hydroxide (5.8 g, 0.145 mol)
in water (9 ml) was added with vigorous stirring, then methyl chloroformate (0.075 mol) was added dropwise.
Thereafter NaOH (5.9 g, 0.145 mol) in H2O (9 ml) and methyl chloroformate (0.075 mol) were added
simultaneously from the two dropping funnels, maintaining the same temperature. The mixture was stirred at
room temperature for 30 min. The precipitated NaCl was dissolved in H2O (10 ml), the organic layer was
separated, and the aqueous layer extracted with chloroform (3 × 25 ml). The combined extract was dried over
MgSO4, and the solvent was distilled off. The residue was purified by distillation in vacuum or by crystallization.
S-Methyl N-(anti-2-Acetylcyclohexyl)dithiocarbamate (4d). A solution of sodium methylate,
prepared from sodium (0.078 g, 3.37 mmol) in methanol (2 ml), was added with stirring to a solution of the anti
isomer of amino ketone hydrochloride 2d (0.603 g, 3.38 mmol) in methyl alcohol (6 ml) at 0-5°C. Then carbon
disulfide (0.257 g, 3.38 mmol) in methanol (1.5 ml) and triethylamine (0.341 g, 3.37 mmol) in methanol (1 ml)
were added simultaneously from two dropping funnels. The reaction mixture was stirred for 30 min at the same
temperature, methyl iodide (0.480 g; 3.38 mmol) was added, and the mixture was left for 4 h. The solvent was
distilled off, and water (5 ml) and chloroform (5 ml) were added to the residue. The organic layer was separated,
and the aqueous one extracted with chloroform (2 × 5 ml). The combined chloroform extract was washed with
water (3 × 5 ml), and dried with sodium sulfate. The solvent was distilled off. Dithiocarbamate 4d (0.293 g) was
obtained by recrystallization from aqueous alcohol.
S-Methyl N-(1,1-Dimethyl-3-oxobutyl)thiocarbamate (5c). A sample of SnCl4 (4.7 g, 0.04 mol) was
added dropwise with stirring to a solution of 4-chloro-4-methylpentan-2-one (5.4 g, 0.04 mol) and methyl
thiocyanate (2.7 ml, 0.04 mol) in absolute chloroform (25 ml) at 0°C. The reaction mixture was stirred for
15 min at 0°C, then left overnight at room temperature. The mixture was neutralized with saturated aqueous
sodium carbonate solution and left for 20 h. The organic layer was then separated, and the aqueous one
extracted with ether (2 × 25 ml). The combined organic layer was dried with anhydrous magnesium sulfate, the
solvent was removed, and the residue was recrystallized from hexane. Compound 5c (5.4 g) was obtained.
Methyl N-(3-Hydroxypropyl)carbamate (6f). 3-Aminopropanol (21.7 g, 0.289 mol), water (20 ml),
and ether (70 ml) were mixed in a flask fitted with a stirrer and two dropping funnels. The mixture was cooled
to -10°C and methyl chloroformate (11 ml, 0.144 mol) was added with vigorous stirring. A solution of sodium
hydroxide (11.4 g, 0.295 mol) in water (18 ml) and methyl chloroformate (11.4 ml, 0.149 mol) were added from
the two dropping funnels. The mixture was stirred for 30 min at room temperature, the organic layer was
separated off, the aqueous layer was saturated with potassium carbonate, and then extracted with chloroform
(4 × 50 ml). The combined extract was dried with sodium sulfate, the solvent was distilled off, and the residue
was distilled in vacuum. Compound 6f (23.2 g) was obtained.
S-Methyl N-[anti-2-(anti-1-Hydroxyethyl)cyclohexyl]dithiocarbamate (7d). Triethylamine (3.86 ml,
27.8 mmol) and carbon disulfide (1.67 ml, 27.8 mmol) were added simultaneously from two dropping funnels
during 30 min to a solution of a mixture of isomers of 1-(anti-2-aminocyclohexyl)ethanol [16] (3.97 g,
27.8 mmol) containing 65% anti and 35% syn isomers in pyridine (4.7 ml) at 0°C. The reaction mixture was
stirred for 1 h at 0°C, then methyl iodide (1.73 ml, 27.8 mmol) was added dropwise, and the mixture was left at
0-5°C overnight. The reaction mixture was poured into 1 M sulfuric acid solution (100 ml), and extracted with
chloroform (3 × 100 ml). The combined chloroform extract was washed with 1 M sulfuric acid solution (until
the disappearance of pyridine according to TLC), with 5% sodium bicarbonate solution, with water, and then
dried with sodium sulfate. The solvent was evaporated and a mixture (4.41 g, 68.1%) of the anti,syn and
anti,anti isomers of 7d was obtained. The compound was crystallized twice from aqueous alcohol. S-Methyl
N-[anti-2-(anti-1-hydroxyethyl)cyclohexyl]dithiocarbamate (2.31 g, 35.6%) was isolated.
607

Methyl N-(3-Hydroxyalkyl)carbamate (6c) and -Dithiocarbamate (7c). Sodium borohydride
(22 mmol) in water (8 ml) was added dropwise with stirring to a mixture containing sodium dihydrophosphate
(10.42 g), sodium hydrophosphate (23.82 g), and carbamate 3c (22 mmol) or dithiocarbamate 4c (22 mmol) in
methanol (150 ml). After 1 h the reaction mixture was diluted with water (150 ml) and ether (100 ml). The
organic layer was separated, and the aqueous layer extracted with ether (3 × 70 ml). The combined ether extract
was washed with water (2 × 100 ml), dried with magnesium sulfate, the ether was distilled off, and the residue
was distilled in vacuum.
Methyl N-(3-Hydroxyalkyl)carbamate (6a) and -Dithiocarbamate (7a). Compounds 3a and 4a were
reduced analogously to compounds 3c and 4c in the absence of the buffer mixture. The reaction mixture was
acidified to about pH 7 with conc. HCl 1 h after adding the sodium borohydride, and the methanol was removed
in vacuum. Water (5-10 ml) was added to the residue, and the solution was extracted with ether (3 × 30 ml). The
combined ether extract was washed with water, with saturated NaCl solution, dried with magnesium sulfate, the
ether was distilled off, and the residue was distilled in vacuum.
Tetrahydro-1,3-oxazin-2-ones (9a-e) and -thiones (10a,c). Sodium borohydride (24.5 mmol) was
added portionwise into a solution of carbamate 6a-e (24.5 mmol) or dithiocarbamate 7a,c (24.5 mmol) in
alcohol (40 ml). The mixture was stirred for 1 h, 5 M sodium hydroxide solution (20 ml) in alcohol was added,
and the mixture was left overnight. The solvent was distilled off, water (20 ml) was added to the residue, and the
solution was extracted with chloroform (3 × 30 ml). The combined chloroform extract was washed with water,
with saturated NaCl solution, then dried with calcium chloride, and the solvent was distilled off. Compounds 9c
and 10c were obtained analogously from 3c, 4c, and 5c, without adding sodium hydroxide solution. Pure
(4a,8a-trans-4a,4-cis)-4-methyloctahydro-2H-3,1-benzoxazin-2-one 9d and trans-5,6-dimethyltetrahydro-1,3-
oxazine-2-thione 10a were isolated from the mixture of isomers after 2-3 recrystallizations from alcohol or
acetone.
Interaction of S-Methyl N-(anti-2-Acetylcyclohexyl)dithiocarbamate (4d) with Sodium
Borohydride. Sodium borohydride (16 mg, 0.42 mmol) in methanol (0.6 ml) was added to a solution of
compound 4d (100 mg, 0.43 mmol) in alcohol (0.5 ml). The reaction mixture was stirred for 4 h and left for a
day. The alcohol was then distilled off, water (2 ml) was added to the residue, and the mixture was extracted
with chloroform (3 × 10 ml). The chloroform extract was washed with water, then with saturated NaCl solution,
and dried with sodium sulfate. The solvent was distilled off, the residue was washed with ether to obtain a
mixture of isomers (70 mg, 87.9%) containing according to the data of 1H NMR spectroscopy 60% (4a,8a-trans-
4a,4-cis)- and
mp 143-144°C.
40%
(4a,8a-trans-4a,4-trans)-4-methyloctahydro-2H-3,1-benzoxazine-2-thione
(10d);
(4a,8a-trans-4a,4-trans)-4-Methyloctahydro-2H-3,1-benzoxazine-2-thione (10d). The N-[anti-2-
(anti-1-hydroxyethyl)cyclohexyl]dithiocarbamate 7d (0.207 g, 0.89 mmol) was dissolved in 2 M sodium
hydroxide solution in methanol (2.0 ml), the mixture was kept at room temperature for 3 h, the solvent was
distilled off, the residue was dissolved in water (2 ml), and the mixture was extracted with chloroform
(3 × 10 ml). The combined chloroform extract was washed with water, with saturated NaCl solution, dried with
magnesium sulfate, and the solvent was distilled off to give 4a,8a-trans-4a,4-trans-10d (0.152 g).
The work was carried out with the financial support of the Russian Fund for Fundamental Investigations
(grant No. 99-03-33013).
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