1,1-Dichloro-2,2,2-trihaloethyl isocyanates and N-(1-chloro-2,2,2- trihaloethylidene)urethanes in the synthesis of 4-trihalomethyl-2H-1,3- benzoxazin-2-ones

Article abstract of DOI:10.1023/B:COHC.0000023776.49961.0f

4-Trihalomethyl-2H-1,3-benzoxazin-2-ones have been synthesized by the reaction of 1,1-dichloro-2,2,2-trihaloethyl isocyanates or N-(1-chloro-2,2,2- trihaloethylidene)urethanes with 3-dialkylamino-(alkoxy)phenols. The character of the products from the add

Full text of DOI:10.1023/B:COHC.0000023776.49961.0f

Chemistry of Heterocyclic Compounds, Vol. 40, No. 1, 2004
1,1-DICHLORO-2,2,2-TRIHALOETHYL
ISOCYANATES AND N-(1-CHLORO-2,2,2-
TRIHALOETHYLIDENE)URETHANES IN
THE SYNTHESIS OF 4-TRIHALOMETHYL-
2H-1,3-BENZOXAZIN-2-ONES
M. V. Vovk, A. V. Bol'but, P. S. Lebed', and V. I. Boiko
4-Trihalomethyl-2H-1,3-benzoxazin-2-ones have been synthesized by the reaction of 1,1-dichloro-2,2,2-
trihaloethyl isocyanates or N-(1-chloro-2,2,2-trihaloethylidene)urethanes with 3-dialkylamino-
(alkoxy)phenols. The character of the products from the addition of nucleophiles has been shown to
depend on the nature of the nucleophile and the trihalomethyl group.
Keywords: N-alkylideneurethanes, m-dialkylamino(alkoxy)phenols, isocyanates, 4-trihalomethyl-2H-
1,3-benzoxazin-2-ones.
In previous papers [1-3] we have shown the possibility of using thermal cyclocondensation of
derivatives of 1-chloro-2-trifluoromethylalkyl isocyanates and N-alkylidene-O-arylurethanes to prepare
trifluoromethyl-containing 3,4- and 2,3-dihydro-1,3-benzoxazines. With the objective of synthesizing non-
hydrogenated analogs of known heterocyclic systems we have studied the reaction of 1,1-dichloro-2,2,2-
trihalomethyl isocyanates 1a,b, and the N-(1-chloro-2,2,2-trihaloethylidene)urethanes 2a-d made from them,
with phenols 3a-d activated by dialkylamino or alkoxy groups.
It was found that interaction of the isocyanates 1a,b with the m-dialkylaminophenols 3a,b in benzene in
the presence of an organic base led to the formation of the N-alkylideneurethanes 4a-c, the structures of which
were confirmed by the absence in the IR spectra of the reaction mixtures of the absorption band of the N=C=O
groups in the 2260-2270 cm-1 region and the appearance of the absorption band of the C=O group in the
1760-1770 cm-1 region. According to the 19F NMR spectrum, measured for compound 4b, the
N-alkylideneurethanes 4a-c even at 20-25°C began to be converted slowly into 4-trihalomethyl-2H-1,3-
benzoxazin-2-ones 5a-c by intramolecular electrophilic attack of the imidoyl carbon at position 6 of the benzene
ring, activated by the dialkylamino group. This process was completed by boiling the reaction mixture for 0.5 h.
In the case of 1-aryl-1-chloro-2,2,2-trifluoroethyl isocyanates the analogous reaction occurred only on heating in
toluene for 10 h [2].
The decrease in the nucleophilicity of the phenoxy nucleus in N-alkylideneurethanes 4d,e which resulted
from replacing the dialkylamino groups by poorer donating alkoxy group led to considerably slower cyclization.
The required compounds 5d,e were isolated in yields of 41 and 9% respectively only after prolonged boiling of
the reaction mixture in xylene.
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094, Ukraine; e-mail:
hetfos@ukrpack.net, mvovk@i.com.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1,
pp. 107-112, January, 2004. Original article submitted February 21, 2001.
0009-3122/04/4001-0101©2004 Plenum Publishing Corporation
101

R
20 0C
–HCl
HO
R
CHal3 –CCl2–N=C=O
+
1a,b
3a–d
CHal3
N
O
∆
CHal3 –CCl=N–C–O
–HCl
R
O
O
5a–e
4a–d
1a Hal = F, b Cl, 3a R = Me2N, b Et2N, c MeO, d EtO,
4, 5 a R = Me2N, Hal = Cl, b R = Et2N, Hal = F, c R = Et2N, Hal = Cl,
d R = MeO, Hal = F, e R = EtO, Hal = Cl
In the IR spectra of the 1,3-benzoxazinones 5 the absorption bands of the exocyclic C=O groups appear
1
at 1735-1760 and the endocyclic C=N bond at 1630-1635 cm-1. In the H NMR spectra there are doublets for
proton C(8)H (6.44-6.83) and proton C(5)H (7.65-8.17 ppm), and also a doublet of doublets for C(6)H
(6.65-6.91 ppm) which confirms annelation at position 6 of the benzene ring. In the 19F NMR spectra of
compounds 5a,b,d there are singlets for the CF3 group in the range 67.2-68.0 ppm, typical for this group
attached to sp2-carbon atoms [4]. The cyclic structure of 5 was also confirmed by measuring the 13C NMR
spectrum for compound 5c: 12.32 (CH3), 45.04 (CH2), 94.87 (CCl3), 95.96 (C(8)), 99.64 (C(5a)), 109.10 (C(6)),
129.53 (C(5)), 151.71 (C(8a)), 153.98 (C(4)), 161.41 (C(7)), 169.59 (C=O).
To obtain the isomeric with 5 2-trihalomethyl-4H-1,3-benzoxazin-4-ones of type 6 we investigated the
reaction of N-(1-chloro-2,2,2-trihalo)ethylidene-O-methylurethanes 2a,b [5] with the phenol 3b. The reason for
choosing this solution was the results obtained previously for the cyclization of compounds 2a,b with arylamines
[6]. However, as we had established, the products of substitution of the chlorine atom 7a,b did not undergo
electrophilic attack at the o-position of the phenoxy substituent by the methoxycarbnyl group even on prolonged
heating in mesitylene. Therefore N-alkylidene-O-(4-nitrophenyl)urethane 2c was chosen to increase the
electrophilicity of the carbonyl group in reaction with the phenol 3b. We observed the unexpected conversion of
the imidate 7c in a yield of 51% not into a structure of type 6, but into compound 5c (the reaction occurs over a
day at room temperature but in just 0.5 h in boiling dioxane). We suggest that in this case a mild
transphenoxylation occurs into the heterodiene system of bonds, which most probably occurs by an anionic
mechanism [7] through the stage of the 1,1-diphenoxyalkyl isocyanate A, Cyclization of the intermediate
rearrangement product B is evidently facilitated by the ability of the 4-nitrophenoxy group as a leaving group
(Scheme 1).
Reaction of alcohols with the benzoxazin-2-ones 5b,c gave stable 2,3-dihydro-4-alkoxy derivatives
10a-c which confirmed the ability of trihalomethyl group no matter what the halogen, to retain exocyclic alkoxy
substituents.
The increased electrophilicity of compound 5b, caused by the presence of the CF3 group, led to its
reaction with ammonia occurring at both electrophilic centers with opening of the oxazine ring, as a result of
which we were unable to isolate individual products of the reaction. At the same time the reaction of
cyclohexylamine with compound 5c, which contains a CCl3 group, leaves the cyclic system unaffected. The
initially formed 4-amino-3,4-dihydro derivative 11, like its hydroxy analog 8b, loses a molecule of chloroform
1
and is converted into compound 12 which, according to its H NMR spectrum in CDCl3, exists as the 4-amino
derivative 12.
102

Scheme 1
O
O
O
NEt2
O
N
OR'
CHal3
N
HO
CHal –CCl=N–C–OR'
+
3
–HCl
–ROH
Et2N
CHal3
2a-c
Et2N
O
3b
6
7a-c
R'= 4-O2NC6H4
O
C
N
O
Et2N
O
N
CCl3
O
CCl3
R'O
Et2N
OR'
B
A
CCl3
R'= 4-O2NC6H4OH
N
O
O
Et2N
5c
2, 7 a Hal = F, R'= Me, b Hal = Cl, R' = Me,
c Hal = Cl, R' = 4-O2NC6H4
4-Trihalomethyl-2H-1,3-benzoxazin-2-ones of type 5 are little studied [8,9] benzannelated systems with
two electrophilic centers – the carbon atoms of the C=O and C=N groups. The reactions of benzoxazinones 5
with some nucleophilic reagents might be used as a suitable variant for the synthesis of new dihydro derivatives.
In particular, mild hydrolysis of compound 5b, which contains a CF3 group, occurs by addition of water to the
C=N group with the formation of the stable product 8a, whereas the CCl3 group does not stabilize its analog 8b,
which undergoes haloform elimination to give the 2,4-dioxo derivative 9.
O
OH
NH
CHal3
Hal = Cl
–CHCl3
NH
X=OH
Et2N
Et2N
O
O
O
O
9
8a,b
CHal3
AlkO
CHal3
NH
X=OAlk
HX
N
O
Et2N
O
Et2N
O
O
5b,c
10a-c
NHR
N
RNH
CCl3
NH
–CHCl3
X=
H2NR
Et2N
O
O
Et2N
O
O
12
11
8 a Hal = F, b Hal = Cl; 10 a Hal = F, Alk = Me, b Hal = Cl, Alk = Me, c Hal = Cl, Alk = i-Pr; 12 R = cyclo-C6H11
103

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
(method)
mp, °C
C
H
N
5a
5b
5c
С11Н9Cl3N2O2
С13Н13F3N2O2
С13Н13Cl3N2O2
С10Н6F3NO3
43.31
42.96
54.21
54.55
46.90
46.52
48.61
48.99
43.11
42.82
51.44
51.32
61.48
61.53
53.06
52.83
2.69
2.95
4.39
4.58
4.24
3.90
2.32
2.47
2.69
2.61
5.18
4.97
5.92
6.02
5.27
5.38
9.27
9.11
10.07
9.79
8.03
8.35
5.50
5.71
4.17
4.54
9.52
9.21
12.17
11.96
8.62
8.80
187-188
155-156
185-186
97-98
52
44
56 (A), 51 (B)
5d
5e
41
9
С11Н8Cl3NO3
С13Н15F3N2O3
С12Н14N2O3
125-126
134-135
206-207
119-120
180-181
168-169
211-212
8a
9
95
94
73
71
70
75
10a
10b
10c
12
С14Н17F3N2O3
С14Н27Cl3N2O3
С16Н12Сl3N2O3
С18Н25N3O2
46.08
45.76
48.86
48.56
68.71
68.54
4.41
4.66
5.11
5.35
8.27
7.99
7.53
7.62
6.72
7.08
13.03
13.32
EXPERIMENTAL
IR spectra of KBr disks or solutions in chloroform or dioxane were recorded on a UR-20 apparatus.
19
1H and F NMR spectra of CDCl3 solutions with TMS (1H) or CCl3F (19F) internal standards were recorded on
Varian-Gemini machine (300 and 188 MHz respectively). The characteristics of compounds 5a-e, 8a, 9, 10a-c,
and 12 are cited in Table 1. Compounds 5a,b,d were recrystallized from a benzene–dioxane mixture, 5c,e, 8a, 9,
12 from dioxane, 10a,b from methanol, and 10c from 2-propanol.
N-(1,2,2,2-Tetrachloro)ethylidene-O-(4-nitrophenyl)urethane (2c). Triethylamine (0.505 g, 5 mmol)
in benzene (5 ml) was added dropwise to a mixture of isocyanate 1b (1.22 g, 5 mmol) and 4-nitrophenol
(0.696 g, 5 mmol) and the mixture was stirred for 2h. The precipitate of triethylammonium chloride was filtered
off, the filtrate was evaporated and the residue recrystallized from a 6:1 mixture of hexane and benzene.
1
Yield 89%; mp 91-92°C. IR spectrum (CH2Cl2), ν, cm-1: 1700 (C=N), 1780 (C=O). H NMR spectrum (C6D6),
δ, ppm (J, Hz): 6.55 (2H, d, J = 9.3, 2,6-H); 7.62 (2H, d, J = 9.3, 3,5-H). Found, %: Cl 40.76; N 7.82.
C9H4Cl4N2O4. Calculated, %: Cl 40.99; N 8.10
N-[1-(3-Diethylaminophenoxy)-2,2,2-trihalomethylethylidene]-O-methylurethanes (7a,b). A mixture
of phenol 3a (0.826 g, 5 mmol) and triethylamine (0.505 g, 5 mmol) was added dropwise to a solution of
N-alkylidenurethane 2a,b (5 mmol) in benzene (15 ml) and the mixture stirred for 2 h. The precipitate of
triethylammonium chloride was filtered off, the filtrate was evaporated and the oily precipitate was purified by
freezing out from a 1:10 mixture of diethyl ether and hexane at -18°C.
Compound 7a. Yield 85%. IR spectra (CH2Cl2), ν, cm-1: 1695 (C=N), 1765 (C=O). 1H NMR spectrum
(C6D6): δ, ppm (J, Hz): 0.74 (6H, t, J = 7.2, 2CH3); 2.76 (4H, q, J = 7.2, 2CH2); 3.16 (3H, s, OCH3); 6.26 (1H,
dd, J1,2 = 8.7, J1,3 = 2.1, 4-H); 6.34 (1H, dd, J1,2 = 7.8, J13 = 1.7, 6-H); 6.38 (1H, t, J = 2.1, 2-H); 6.92 (1H, t,
J = 8.7, 5-H). 19F NMR spectrum (C6D6), δ, ppm: 71.3. Found, %: F 17.83, N 8.67. C14H17F3N2O3.
Calculated, %: F 17.91; N 8.80.
104

1
Compound 7b. Yield 53%. IR spectrum (CH2Cl2), ν, cm-1: 1690 (C=N), 1770 (C=O). H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.17 (6H, t, J = 7.2, 2CH3); 3.34 (4H, q, J = 7.2, 2CH2); 3.37 (3H, s, OCH3);
6.39 (1H, t, J = 2.1, 2-H); 6.42 (1H, dd, J1,2 = 8.3, J1,3 = 2.0, 4-H); 6.54 (1H, dd, J1,2 = 8.4, J1,3 = 2.1, 6-H); 7.18
(1H, t, J = 8.3, 5-H). Found, %: Cl 29.07; N 7.71. C14H17Cl3N2O3. Calculated, %: Cl 28.93; N 7.62.
4-Trihalo-2H-1,3-benzoxazin-2-ones (5a-e). A. A mixture of phenol 3a-c (5 mmol) and triethylamine
(0.505 g, 5mmol) was added to a solution of isocyanate 1a,b (5 mmol) in benzene (10 ml) and the mixture was
stirred for 3 h at room temperature. The precipitate of triethylammonium chloride was separated to give benzene
solutions of the N-alkylideneurethanes 4a-e. In the case of 4a-c the solution was boiled for 0.5 h. For compounds
4d,e the benzene was evaporated and xylene (15 ml) was added to the residue and boiled for 8 h (compound 4d)
and for 30 h (compound 4e). After removal of the solvent, diethyl ether (20 ml) was added to the residue and the
solid substance was filtered off after 24 h.
B. A mixture of phenol 3b (0.826 g, 5 mmol) and triethylamine (0.505 g, 5 mmol) in dioxane (10 ml)
was added to a solution of N-alkylideneurethane 2c (1.73 g, 5 mmol) in dioxane (15 ml) and the mixture was
stirred for 2h. The precipitate of triethylammonium chloride was filtered off, and the filtrate was kept for 24 h or
boiled for 0.5 h. The solvent was removed and diethyl ether (20 ml) was added to the residue which was kept for
24 h and the solid product formed was filtered off.
4-Hydroxy-4-trifluoromethyl-2,3-dihydro-4H-1,3-benzoxazin-2-one (8a) and 2,3-Dihydro-4H-1,3-
benzoxazin-2,4-dione (9). Water (0.1 ml) was added to a solution of compound 5b,c (3 mmol) in DMSO (3 ml)
and the solution was kept at room temperature for 24 h. The mixture was then diluted with water (10 ml) and the
precipitate formed was filtered off and recrystallized.
4-Alkoxy-4-trichloromethyl-2,3-dihydro-4H-1,3-benzoxazin-2-ones (10a-c). Compounds 5a,b were
dissolved in methanol or 2-propanol (5 ml), 3 drops of triethylamine were added, and the mixture was kept for
48 h. The precipitate was filtered off and recrystallized.
4-Cyclohexylamino-2H-1,3-benzoxazin-2-one (12). Cyclohexylamine (0.198 g, 2 mmol) was added to
a solution of compound 5c (0,671 g, 2 mmol) in dioxane (10 ml) and the mixture was kept for 48 h. The
precipitate was filtered off and recrystallized.
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