Novel 2H-1,3-benzoxazine ring formation by intramolecular heterocyclization of N-(α-aryloxyalkyl)imidoyl chlorides

Article abstract of DOI:10.1515/hc-2017-0102

A convenient synthetic approach to derivatives of 2-trichloromethyl and 2-dichlorometylene-2H-1,3-benzoxazines, based on intramolecular heterocyclization of readily accessible N-(α-aryloxytrichloroethyl)imidoyl chlorides, was developed. Base induced dehyd

Full text of DOI:10.1515/hc-2017-0102

Heterocycl. Commun. 2017; aop
Petro P. Onys’ko*, Kateryna A. Zamulko, Olena I. Kyselyova and Yaroslav A. Syzonenko
Novel 2H-1,3-benzoxazine ring formation
by intramolecular heterocyclization
of N-(α-aryloxyalkyl)imidoyl chlorides
https://doi.org/10.1515/hc-2017-0102
therein]. 2H-1,3-Benzoxazines bearing a chloroalkyl group
at the C-2 atom, to the best of our knowledge, have not
been described so far. The importance of the CCl3 group
in natural biologically active products and synthetic
molecules has been noted [10, 11]. Existing synthetic
approaches to 1,3-benzoxazines have limitations and
drawbacks [4, 6, 7]. Specifically, synthesis of benzoxa-
zines from 2-hydroxyphenylketones involves generation of
unstable N-H ketimines as key intermediates [7]; methods
based on the use of salicylamides, ortho-hydroxybenzy-
lamines [12, 13], or 1-chlorotrifluoroethylisocyanates [14]
are limited to the synthesis of benzoxazin-4-ones. Recently
reported method, utilizing oxidative C-O bond forma-
tion, requires synthesis of 1-(aminoalkyl)-2-naphthols
Received May 30, 2017; accepted September 20, 2017
Abstract: A convenient synthetic approach to derivatives
of 2-trichloromethyl and 2-dichlorometylene-2H-1,3-ben-
zoxazines, based on intramolecular heterocyclization
of readily accessible N-(α-aryloxytrichloroethyl)imidoyl
chlorides, was developed. Base induced dehydrochlo-
rination of 4-phenyl- or 4-trifluoromethyl-2-trichlo-
romethylbenzoxazines
allows
preparation
of
2-dichloromethylene-1,3-benzoxazines, whereas dehydro-
chlorinationof4-fluoromethylanalogsundersimilarcondi-
tionsisaccompaniedbyformal1,5-H-shifttoaffordrespective
2-dichloromethyl-4-fluoromethylene-1,3-benzoxazines.
Keywords: 2H-1,3-benzoxazines; dichloromethylene; or 2-(aminoalkyl)phenols and is limited to compounds
imidoyl chlorides; intramolecular cyclization; polyfluoro- incorporating 1,3-benzoxazine moiety in a complex con-
alkyl; trichloromethyl.
densed heterocyclic system [15]. Thus, elaboration of new
synthetic methods for construction of a 1,3-benzoxazine
skeleton remains a challenging task.
Introduction
2H-1,3-Benzoxazines are of interest in medicine and Results and discussion
material sciences. Specifically, they are useful as anti-
inflammatory agents [1], photochromic substances [2] We report a novel synthesis of 2H-1,3-benzoxazines with
and photofading-preventive materials [3]. Derivatives of trichloromethyl group at the C-2 atom, based on readily
1,3-benzoxazines I-III (Figure 1) are effective potassium accessible N-(α-aryloxytrichloroethyl)imidoyl chlorides
channel regulators and are candidates as therapeutic (1). Thus, imidoyl chlorides 1 on heating in polyphos-
agents for hypertension, angina pectoris, asthma and phoric acid (PPA) or in the presence of AlCl3 (Lewis acid)
urinary incontinence [4–7]. 2,3-Disubstituted-1,3-ben- undergo intramolecular heterocyclization (‘intramolecu-
zoxazines show fungicidal activity [8]. Compounds lar imidoylation’) to afford benzoxazines 2 in 30–80%
incorporating hydrogenated benzo[e][1,3]oxazine or yields (Scheme 1). Apparently, electrophilic attack of the
naphtho[2,1-e][1,3]oxazine fragment have been reported imine carbon atom on the ortho position of the benzene
to show significant antimicrobial and cytotoxic activi- ring in imidoyl chlorides 1 is favored by electron-releasing
ties [9]. A benzoxazinone fragment is considered a phar- mesomeric effect of the alkoxy substituent (Scheme 1).
maceutically privileged scaffold [6 and references cited The presence of the electron-donating Me group(s) in
O-benzene ring is beneficial for ring closure, whereas the
electron-withdrawing C-4 fluorine atom in 1b (which is in
*Corresponding author: Petro P. Onys’ko, Institute of Organic
meta position to the reactive center) retards heterocycliza-
Chemistry, National Academy of Sciences, 5 Murmans’ka str.,
tion and reduces the yield of the respective oxazine 2b.
Kyiv 02660, Kyiv, Ukraine, e-mail: onysko@ukr.net
Heterocyclization of the dimethyl substrate 1e proceeds
Kateryna A. Zamulko, Olena I. Kyselyova and Yaroslav A. Syzonenko:
Institute of Organic Chemistry, National Academy of Sciences,
5 Murmans’ka str., Kyiv 02660, Kyiv, Ukraine
regioselectively, with the involvement of a sterically less
hindered C-6 atom of the oxybenzene ring. Remarkably,
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ꢀP.P. Onys’ko et al.: 1,3-Benzoxazine ring formation
CCl3
CCl3
N
N
O
N
O
O
O
N
O
O
N
O
N
N
Br
Cl
Ph
AlCl3
N
N
N
Ph
Cl
O
Cl
I (TCV-95)
III
3
II
4 (66%)
Figure 1ꢀBiologically active 2H-1,3-benzoxazines, potassium chan-
nels regulators.
Scheme 2ꢀPreparation of 2H-naphtho-1,3-oxazine 4.
Promotion of intramolecular heterocyclization in
Schemes 1 and 2 by AlCl3 or PPA catalyst is connected most
likely with generation of highly electrophilic iminium A
and nitrilium B type intermediates that undergo elec-
trophilic attack on the activated ortho-position of the
aryloxy substituent (Scheme 3). A similar pattern has been
reported previously for the preparation of dihydroiso-
quinolines from N-(2-arylethyl)imidoyl chlorides by the
Bischler-Napieralski reaction [22].
To the best of our knowledge, 1,3-benzoxazines
bearing a trichloromethyl group in the oxazine ring have
not been reported so far. The presence of an electron-
withdrawing CCl3 group in compounds 2 increases C-H
acidity of the neighboring carbon atom, offering addi-
tional synthetic opportunities. Thus, in the presence of
base, such as triethylamine or DBU, benzoxazines 2a–d
and 4 readily undergo dehydrochlorination to afford the
respective 2-(dichloromethylene)-2H-oxazines 5a–d and 6
(Scheme 4). Compounds 5 and 6 are the first representa-
tives of benzoxazines with 2-dichloromethylene group.
At the same time, reactions of benzoxazines 2f,g with
a methyl or fluoromethyl group at the C-4 atom, under
the same conditions afforded the respective 4-methylene
or 4-fluoromethylene substituted 6-methyl-2-dichloro-
methylbenzoxazine 7a,b, apparently resulting from the
formal 1,5-hydrogen shift in the primary dehydrochlo-
rination products C (Scheme 5). Obviously, the driving
force for the prototropic isomerization Cꢀ→ꢀ7 is the for-
mation of the energetically more favorable conjugated
imidoyl chlorides with various substituents at the imine
carbon atom are apt to heterocyclization expanding the
scope of the reaction and allowing variation of substitu-
ents in the benzene and oxazine rings. Thus, benzoxa-
zines with phenyl, methyl, fluoromethyl or trifluoromethyl
group at C-4 atom are readily accessible by this approach.
The simple preparative access to benzoxazines bearing a
fluorine or trifluoromethyl substituent is of special impor-
tance, when taken into consideration that incorporation
of a fluorinated group in organic molecules often imparts
a variety of useful properties, including enhanced binding
interactions in a biological system, metabolic stability and
better performances of synthetic materials [16–21].
It is interesting to note that in the AlCl3-catalyzed
cyclization of fluoroacetimidoyl chloride 1g, the forma-
tion of a small amount (~5%) of 4-chloromethyl-6-me-
thyl-2-trichloromethyl-2H-1,3-benzoxazine (2h, Rꢀ=ꢀCH2Cl,
R′ꢀ=ꢀMe, R″ꢀ=ꢀH; Scheme 1) was also detected and con-
firmed by analysis of 1H and 13C NMR spectra. Unexpected
formation of compound 2h can be accounted for by the
AlCl3-promoted chlorine-fluorine exchange in start-
ing fluoroacetimidoyl chloride 1g under the reaction
conditions.
The developed methodology enables also the synthe-
sis of more complex condensed systems incorporating the
benzoxazine fragment as illustrated in Scheme 2.
R″
R′
O
CCl3
R″
R′
O
R
CCl3
i or ii
-HCl
N
N
Cl
R′′
R′
O
CCl3
NH
R
PPA
1a–g
2a–g (30–78%)
Cl
R
a: R = Ph; R′ = R′′ =H
A
b: R = Ph; R′ = F; R′′ =H
c: R = Ph; R′ = Me; R′′ =H
d: R = CF3; R′ = Me; R′′ =H
e: R = Ph; R′ = R′′ = Me
f: R = R′ = Me; R′′ =H
2
1
R′′
R′
O
CCl3
AlCl3
N
AlCl4
g: R = CH2F; R′ = Me; R′′ =H
R
Scheme 1ꢀSynthesis of 2H-1,3-benzoxazines. Reagents and condi-
tions: (i) AlCl3, dichloroethane; (ii) PPA, 80–100°C, 0.5 h, then
130–140°C, 0.5 h.
B
Scheme 3ꢀPPA or AlCl3-promoted synthesis of 1,3-benzoxazines.
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P.P. Onys’ko et al.: 1,3-Benzoxazine ring formationꢂ ꢂ3
Cl
with phosphorus pentachloride or the Ph3P-CCl4 system
led to the desired imidoyl chlorides 1 and 3.
O
R
DBU or Et3N
Cl
5a–d (41–89%)
2a–d
The spectral and analytical data of compounds 2 and
4–6 are in full agreement with their structures. In particu-
N
R′
13
lar, analysis of APT C NMR spectra of 2 and 5 confirm
Cl
quaternary character of the C-4a atom involved in cycliza-
tion. The couplings of the C-5 atom of fluorine-containing
O
DBU
Cl
4
4
products 2d,g and 5d (δCꢀ=ꢀ125.5–125.9, JCFꢀ=ꢀ2–5 Hz) and
N
4
6 (56%)
C-4 atom of 5b (δCꢀ=ꢀ160.2, JCFꢀ=ꢀ2 Hz) indicate clearly the
Ph
annelation of imino carbon atom with the phenoxy ring.
The signal of the proton in the C-N=C triad of the benzoxa-
zine system in compounds 2 and 4 is substantiated by the
characteristic chemical shifts of sp3 C-2 and sp2 C-4 atoms
(δCꢀ=ꢀ93.9–94.7 and 155.6–167.8, respectively) and low-field
resonance of the respective 2-C-proton (δHꢀ=ꢀ5.9–6.4). In
addition, the signals of C-4 atoms of compounds 2d and
2g reveal themselves in the 13C NMR spectra as characteris-
tic multiplets (155.6 ppm, 2JCFꢀ=ꢀ36 Hz and 162.9, 2JCFꢀ=ꢀ17 Hz)
due to the splitting by interaction with fluorine atoms.
The 2ꢀ→ꢀ5 transformation is accompanied by a substantial
downfield shift of C-2 atom signal (from 93.9–94.7 ppm to
146.4–147.5 ppm) resulting from the sp3- to sp2 change of its
hybridization.
Scheme 4ꢀDehydrochlorination of 2H-1,3-benzoxazines.
system C=NC=C. Noteworthy, proton shift in CH2F-substi-
tuted compound 2g proceeds stereoselectively affording
mainly the E-isomer of 7b (E/Zꢀ~ꢀ10:1). The assignment of
geometry was based mainly on comparison of the value
of a coupling constant between C-4 and fluorine nuclei
in the 13C NMR spectrum (2JCFꢀ=ꢀ9 Hz for E isomer) and
1
the relative chemical shifts of =CHF in H NMR spectrum
2
2
(δꢀ=ꢀ6.58, JHFꢀ=ꢀ76.3 Hz; δꢀ=ꢀ7.11, JHFꢀ=ꢀ78.8 Hz for E- and
Z-isomers, respectively), with our previous data for iso-
meric fluorovinylamides [23]. For the Z configuration, the
value of the 2JC-4,F constant would be expected in the range
of 30–40 Hz [23].
The starting imidoyl chlorides 1 and 3 were prepared
according to Scheme 6. Readily accessible hydroxy- Conclusions
amides 8 were converted into chlorides 9 [24, 25]. The
latter species were allowed to react with the respective A simple synthesis of 2-trichloromethyl- and 2-dichlo-
phenols in the presence of triethylamine to afford N-(α- rometylene-substituted 6-aryl-2H-1,3-benzoxazines, based
aryloxytrichloroethyl)amides 10. Reaction of amides 10 on intramolecular heterocyclization of readily accessible
O
CCl2
O
CHCl2
DBU
–HCl
1,5–H
2f, 2g
7a: R = H (37%)
7b: R = F (70%)
N
N
CH3
CH3
CH2R
CHR
7a,b
C
Scheme 5ꢀDehydrochlorination and prototropic isomerization of 4-methyl- and 4-fluoromethyl-2H-1,3-benzoxazines.
H
H
N
H
O
R
i
ii
iii
iv or v
Cl3C
N
R
Cl3C
R
Cl3C
N
R
1a–g, 3
H2NC
Cl3CCHO
OH
O
OAr O
Cl
O
(33–76%)
10a–h (50–80%)
8a–d
9a–d
8a, 9a: R = Ph
8b, 9b: R = CF3
8c, 9c: R = Me
8d, 9d: R = CH2F
10a: R = Ph; Ar = Ph
10e: R = Ph; Ar = 3,4-diMeC6H3
H4
10f: R = Me; Ar = 4-MeC6
10g: R = CH2F; Ar = 4-MeC6H4
10h: R = Ph; Ar = 1-naphthyl
10b: R = Ph; Ar = 4-FC6H4
10c: R = Ph; Ar = 4-MeC6H4
10d: R = CF3; Ar = 4-MeC6H4
Scheme 6ꢀPreparation of imidoyl chlorides 1 and 3. Reagents and conditions: (i) H2SO4, 95°C; (ii) PCl5, benzene; (iii) ArOH, Et3N, benzene,
reflux, 3 h; (iv) PCl5, 100–110°C, 1 h; (v) Ph3P, CCl4, dichloroethane, reflux 8 h.
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4ꢀ ꢀP.P. Onys’ko et al.: 1,3-Benzoxazine ring formation
N-[2,2,2-Trichloro-1-(4-methylphenoxy)ethyl]benzimidoyl chlo-
N-(α-aryloxytrichloroethyl)benzimidoyl
chlorides,
1
ride (1c)ꢁYield 76%; colorless oil; bp 150°C/0.07 mm Hg; H NMR
catalyzed by Lewis (AlCl3) or Bronsted (PPA) acid, was
developed. Remarkably, imidoyl chlorides with various
substituents at the imine carbon atom are apt to heterocy-
clization expanding the scope of the reaction and allow-
ing variation of substituents in the benzene and oxazine
rings. Benzoxazines with aryl, methyl, fluorine, fluoro-
methyl, trifluoromethyl, trichloromethyl, dichlorome-
thyl, methylene, fluoromethylene and dichloromethylene
groups are readily accessible by this approach. The simple
preparative access to benzoxazines bearing fluorine-
containing substituents is of special importance because
incorporation of a fluorinated group in organic molecules
modulates their pharmacological properties.
(CDCl3): δ 2.29 (s, 3H, Me), 6.17 (s, 1H, CHN), 7.02 (d, 2H, 3JHHꢀ=ꢀ8.7 Hz,
Ar), 7.1 (d, 2H, 3JHHꢀ=ꢀ8.7 Hz, Ar), 7.45 (t, 2H, 3JHHꢀ=ꢀ8 Hz, Ar), 7.56 (t, 1H,
3JHHꢀ=ꢀ7 Hz, Ar), 8.14 (d, 2H,3JHHꢀ=ꢀ8 Hz, Ar). Anal. Calcd for C16H13Cl4NO:
C, 50.96; H, 3.47; Cl, 37.60; N, 3.71. Found: C, 51.06; H, 3.60; Cl, 37.56;
N, 3.90.
N-[2,2,2-Trichloro-1-(3,4-dimethylphenoxy)ethyl]benzimidoyl
chloride (1e)ꢁCrude compound was used; yield 73%; colorless oil;
1H NMR (CDCl3): δ 2.18 (s, 3H, CH3), 2.21 (s, 3H, CH3), 6.17 (s, 1H, CH),
6.86 (d, 1H, 3JHHꢀ=ꢀ8 Hz, Ar), 6.93 (s, 1H, Ar), 7.03 (d, 1H, 3JHHꢀ=ꢀ8 Hz, Ar),
3
3
7.44 (t, 2H, JHHꢀ=ꢀ7.5 Hz, Ar), 7.55 (t, 1H, JHHꢀ=ꢀ7.5 Hz, Ar), 8.14 (d, 2H,
3JHHꢀ=ꢀ7.5 Hz, Ar).
General procedure for the preparation of imidoyl
chlorides 1d,f,g and 3
Experimental
A mixture of respective amide 10 (1 mmol), Ph3P (0.39 g, 1.5 mmol)
1H nuclear magnetic resonance (NMR) spectra were recorded on a Var- and CCl4 (0.29 mL, 3 mmol) in dichloroethane (10 mL) was heated at
ian VXR-300 spectrometer at 299.95 MHz and 19F NMR spectra were reflux for 8 h. After cooling to room temperature the volatiles were
recorded on a Gemini 200 Varian instrument at 188.14 MHz. 13C NMR removed under reduced pressure and the residue was extracted with
spectra were obtained on a Bruker Avance DRX 500 spectrometer hexane (5ꢀ×ꢀ3 mL).
operating at 125.76 MHz. Chemical shifts are reported relative to inter-
nal transmission magnetic spectroscopy (TSM) (1H, 13C), and CFCl3 N-[2,2,2-Trichloro-1-(4-tolyloxyethyl)trifluoroacetimidoyl chlo-
(19F). APCI MS spectra were recorded using an Agilent 1100 instru- ride (1d)ꢁYield 57%; colorless oil; bp 65–67°C/0.045 mm Hg; 1H NMR
ment. Melting points are uncorrected. Solvents were dried before use (CDCl3): δ 2.32 (s, 3H, Me), 5.92 (s, 1H, CHN), 6.95 (d, 2H, 3JHHꢀ=ꢀ8.7 Hz,
according to standard methods. Elemental analysis was carried out on CH2,6Ph), 7.14 (d, 2H, 3JHHꢀ=ꢀ8.7 Hz, CH3,5Ph); 13C NMR (CDCl3): δ 20.7 (Me),
1
a Carlo Erba 1106 instrument in the analytical laboratory of Institute 96.9 (CHN), 97.1 (CCl3), 116.4 (q, JCFꢀ=ꢀ277 Hz, CF3), 118.2 (C2,6Ar), 130.5
2
of Organic Chemistry, NAS of Ukraine. Compounds 8a,c [26], 8b,d (C3,5Ar), 134.4 (C4Ar), 154.01 (C1Ar), 140.9 (q, JCFꢀ=ꢀ44 Hz, C=N); 19F NMR
[27], 9a [28], 9c [29], 9d [30] have been described previously.
(CDCl3): δ –72.33. Anal. Calcd for C11H8Cl4F3NO: C, 35.80; H, 2.19; Cl,
38.43; N, 3.80. Found: C, 35.94; H, 2.33; Cl, 38.34; N, 3.97.
N-[2,2,2-Trichloro-1-(4-tolyloxyethyl)acetimidoyl
chloride
General procedure for the preparation of imidoyl
chlorides 1a–c,e
1
(1f)ꢁYield 38%; colorless oil; bp 99–101°C/0.06 mm Hg; H NMR
(CDCl3): δ 2.30 (s, 3H, Me), 2.55 (s, 3H, Me), 5.89 (s, 1H, CHN), 6.96
3
3
(d, 2H, JHHꢀ=ꢀ8.5 Hz, C2,6Ph), 7.11 (d, 2H, JHHꢀ=ꢀ8.5 Hz, C3,5Ph); 13C NMR
A mixture of the appropriate amide 10 and a 5% molar excess of PCl5 (CDCl3): δ 20.7 (MeAr), 30.5 (MeC=N), 97.3 (CHN), 98.5 (CCl3), 117.7
was heated at 100–110°C for 1 h. After removal of POCl3, the residue (C2,6Ar), 130.2 (C3,5Ar), 133.2 (C4ArC), 151.6 (C=N), 154.4 (C1Ar). Anal. Calcd
was distilled under reduced pressure (1a–c) or used in subsequent for C11H11Cl4NO: C, 42.10; H, 3.69; Cl, 45.02; N, 4.45. Found: C, 41.94; H,
synthesis without purification (1e).
3.52; Cl, 45.21; N, 4.67.
N-(2,2,2-Trichloro-1-phenoxyethyl)benzimidoyl
chloride N-[2,2,2-Trichloro-1-(4-tolyloxyethyl)fluoroacetimidoyl
chlo-
1
(1a)ꢁYield 72%; colorless oil; bp 162–164°C/0.02 mm Hg; H NMR ride (1g)ꢁYield 33%; colorless oil; bp 70–75°C/0.05 mm Hg; 1H
3
2
(CDCl3): δ 6.22 (s, 1H, CHN), 7.08 (t, 1H, JHHꢀ=ꢀ7 Hz, Ph), 7.12 (d, 2H, NMR (CDCl3): δ 2.35 (s, 3H, Me), 5.09 (d, 2H, JHFꢀ=ꢀ47 Hz, CH2F), 6.04
3JHHꢀ=ꢀ8 Hz, Ph), 7.31 (t, 2H, 3JHHꢀ=ꢀ8 Hz, Ph), 7.45 (t, 2H, 3JHHꢀ=ꢀ7 Hz, Ph), (s, 1H, CHN), 7.01 (d, 2H, JHHꢀ=ꢀ8 Hz, Ar), 7.17 (m, 2H, Ar); 19F NMR
3
7.56 (t, 1H, 3JHHꢀ=ꢀ7 Hz, Ph), 8.14 (d, 2H, 3JHHꢀ=ꢀ7 Hz, Ph); 13C NMR (CDCl3): (CDCl3): δ –215.4 (t, 2JFHꢀ=ꢀ47 Hz); 13C NMR (CDCl3): δ 20.6 (Me), 82.1 (d,
δ 97.1 (CHN), 98.8 (CCl3), 117.7 (C2,6PhO), 123.5 (C4PhO), 128.5 (C3,5PhC), 129.7 1JCFꢀ=ꢀ189 Hz, CH2F), 96.4 (CHN), 97.9 (CCl3), 117.7 (C2,6Ar), 130.3 (C3,5Ar),
(C2,6PhC), 129.9 (C3,5PhO), 133.1 (C4PhC), 134.44 (C1PhC), 151.2 (C=N), 156.6 133.5 (C4Ar), 149.6 (d, JCFꢀ=ꢀ22 Hz, C=N) 154.1 (C1Ar). Anal. Calcd for
2
(C1PhO). Anal. Calcd for C15H11Cl4NO: C, 49.62; H, 3.05; Cl, 39.06; N, 3.86. C11H10Cl4FNO: C, 39.67; H, 3.03; Cl, 42.58; N, 4.21. Found: C, 39.80; H,
Found: C, 49.81; H, 3.11; Cl, 39.34; N, 3.93.
3.21; Cl, 42.69; N, 4.36.
N-[2,2,2-Trichloro-1-(4-fluorophenoxy)ethyl]benzimidoyl chloride N-[2,2,2-Trichloro-1-(1-naphthyloxy)ethyl]benzimidoyl chloride
(1b)ꢁYield 51%; colorless oil; bp 133–135°C/0.2 mm Hg; 1H NMR (CDCl3): (3)ꢁYield 60%; colorless powder; mp 93–94°C; H NMR (CDCl3): δ
1
δ 6.11 (s, 1H, CHN), 7.0 (t, 2H, 1JHHꢀ=ꢀ3JHFꢀ=ꢀ8 Hz, Ar), 7.1 (m, 2H, Ar), 7.47 (t, 6.44 (s, 1H, CHN), 7.05 (d, 1H, JHHꢀ=ꢀ8 Hz, Ar), 7.34–7.57 (m, 5H, Ar),
3
2H, 3JHHꢀ=ꢀ7 Hz, Ar), 7.58 (t, 1H, 3JHHꢀ=ꢀ7 Hz, Ar), 8.14 (d, 2H, 3JHHꢀ=ꢀ7 Hz, Ar); 7.65 (d, 1H, 3JHHꢀ=ꢀ7.2 Hz, Ar), 7.69 (d, 1H, 3JHHꢀ=ꢀ7.2 Hz, Ar), 7.80 (m, 1H,
19F NMR (CDCl3): δ –119.9. Anal. Calcd for C15H11Cl4NO: C, 47.28; H, 2.65; Ar), 8.13 (d, 2H, 3JHHꢀ=ꢀ7.2 Hz, Ar), 8.45 (m, 1H, Ar); 13C NMR (CDCl3): δ
Cl, 37.22; N, 3.68. Found: C, 47.55; H, 2.80; Cl, 37.34; N, 3.80.
96.9 (CHN), 98.8 (CCl3), 109.2 (C2naphth), 122.7, 123.0, 125.4, 125.8, 126.7,
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P.P. Onys’ko et al.: 1,3-Benzoxazine ring formationꢂ ꢂ5
127.4 (naphthyl), 126.2 (C8anaphth), 128.5 (C3,5Ph), 130.0 (C2,6Ph), 132.1 (C4Ph),
134.5 (C4anaphth), 134.7 (C1Ph), 152.3 (C1naphth). Anal. Calcd for C19H13Cl4NO:
C, 55.24; H, 3.17; Cl, 34.33; N, 3.39. Found: C, 55.39; H, 3.24; Cl, 34.38;
N, 3.55.
NMR (CDCl3): δ –69.37. Anal. Calcd for C11H7Cl3F3NO: C, 39.73; H, 2.12;
Cl, 31.98; N, 4.21. Found: C, 39.94; H, 2.30; Cl, 31.81; N, 4.25.
6,7-Dimethyl-4-phenyl-2-trichloromethyl-2H-1,3-benzoxazine
1
(2e)ꢁYield 39% (method A); yellow powder; mp 106–108°C; H NMR
(CDCl3): δ 2.18 (s, 3H, CH3), 2.29 (s, 3H, CH3), 5.90 (s, 1H, CHN), 6.91 (s, 1H,
13
Ar), 7.06 (s, 1H, Ar), 7.5 (m, 3H, Ar), 7.64 (d, 2H, 3JHHꢀ=ꢀ7.8 Hz, Ar); C NMR
General procedures for the preparation
of 1,3-benzoxazines 2a–g and 4
(CDCl3): δ 19.1 (Me), 20.4 (Me), 94.3 (C-2), 99.6 (CCl3), 115.1 (C-4a), 117.3
(C-8), 128.5 (C3,5Ph), 128.7 (C-6), 128.8 (C-5), 129.2 (C2,6Ph), 130.4 (C4Ph), 136.2
(C1Ph), 144.4 (C-7), 153.1 (C-8a), 167.1 (C-4). Anal. Calcd for C17H14Cl3NO: C,
57.57; H, 3.98; Cl, 29.99; N, 3.95. Found: C, 57.71; H, 4.12; Cl, 30.21; N, 4.12.
Method A A mixture of the imidoyl chloride 1a–d, 1d–g (1 mmol) and
AlCl3 (0.27 g, 2 mmol) in dichloroethane (5 mL) was stirred at room
temperature for 24 h. The mixture was poured into ice water (15 mL),
extracted with CH2Cl2, dried over MgSO4 and crystallized from etha-
nol (2b,e) or purified by column chromatography (silica-gel, hexane-
EA, 9:1) (2d,f,g). Compound 4 was obtained from imidoyl chloride 3.
4,6-Dimethyl-2-trichloromethyl-2H-1,3-benzoxazine (2f)ꢁYield
45% (method A); colorless oil; 1H NMR (CDCl3): δ 2.32 (s, 3H, Me), 2.45
(s, 3H, Me), 5.79 (s, 1H, CHN), 6.88 (d, 1H, 3JHHꢀ=ꢀ8.8 Hz, Ar), 7.2 (m, 2H,
Ar); 13C NMR (CDCl3): δ 20.7 (6-Me), 22.0 (4-Me), 94.1 (C-2), 99.5 (CCl3),
115.9 (C-8), 126.0 (C-5), 135.0 (C-7), 117.2 (C-4a), 131.7 (C-6), 151.5 (C-8a),
165.7 (C-4). Anal. Calcd for C11H10Cl3NO: C, 47.43; H, 3.62; Cl, 38.18; N,
5.03. Found: C, 47.62; H, 3.85; Cl, 38.25; N, 5.23.
Method B A mixture of the imidoyl chloride 1a–c (1.5 mmol) and
PPA (2.5 g) was heated at 80–100°C for 0.5 h and then at 130–140°C
for 0.5 h. After cooling, the mixture was poured into ice water. The
precipitated product was separated by filtration and washed suc-
cessively with water, aqueous NaHCO3, and water. Analytically pure
sample was obtained by crystallization from ethanol.
4-(Fluoromethyl)-6-methyl-2-trichloromethyl-2H-1,3-benzox-
1
azine (2g)ꢁYield 30% (method A); colorless oil; H NMR (CDCl3): δ
2.24 (s, 3H, Me), 5.29 (d, 2H, 2JHFꢀ=ꢀ47 Hz, CH2F), 5.77 (s, 1H, CHN), 6.83
3
3
(d, 1H, JHHꢀ=ꢀ8 Hz, Ar), 7.16 (d, 1H, JHHꢀ=ꢀ8 Hz, Ar), 7.23 (s, 1H, Ar); 13C
4-Phenyl-2-trichloromethyl-2H-1,3-benzoxazine (2a)ꢁYield 42%
1
NMR (CDCl3): δ 20.7 (Me), 83.1 (d, JCFꢀ=ꢀ174 Hz, CF), 94.0 (C-2), 98.7
1
(method A), 58% (method B); light yellow solid; mp 94–96°C; H
4
(CCl3), 114.8 (C-4a), 116.1 (C-8), 125.8 (d, JCFꢀ=ꢀ5 Hz, C-5), 132.1 (C-6),
3
NMR (CDCl3): δ 5.95 (s, 1H, CHN), 7.02 (t, 1H, JHHꢀ=ꢀ8 Hz, Ar), 7.11 (d,
135.7 (C-7), 151.8 (C-8a), 162.9 (d, 2JCFꢀ=ꢀ17 Hz, C-4); 19F-{H} NMR (CDCl3):
δ –223.6. Anal. calcd for C11H9Cl3FNO: C, 44.55; H, 3.06; Cl, 35.86; N,
4.72. Found: C, 44.74; H, 3.21; Cl, 35.99; N, 4.87.
3
3
1H, JHHꢀ=ꢀ8 Hz, Ar), 7.33 (d, 1H, JHHꢀ=ꢀ8 Hz, Ar), 7.51 (m, 4H, Ar), 7.66
(m, 2H, Ar); 13C NMR (CDCl3): δ 94.1 (C-2), 99.2 (CCl3), 116.5 (C-8), 117.2
(C-4a), 122.1 (C-5), 128.3 (C4Ph), 128.4 (C3,5Ph), 129.1 (C2,6Ph), 130.5 (C-6),
134.5 (C-7), 135.7 (C1Ph), 154.9 (C-8a), 167.1 (C-4); LC-APCI-MS: m/z 292
[M-1]. Anal. Calcd for C15H10Cl3NO: C, 55.16; H, 3.09; Cl, 32.56; N, 4.29.
Found: C, 55.31; H, 3.17; Cl, 32.12; N, 4.29.
4-Chloromethyl-6-methyl-2-trichloromethyl-2H-1,3-benzoxa-
zine (2h, the presumed by-product)ꢁ1H NMR (CDCl3): δ 2.25 (s, 3H,
Me), 4.42 (s, 2H, CH2Cl), 5.79 (s, 1H, CHN), 6.82 (d, 1H, 3JHHꢀ=ꢀ8 Hz, Ar),
7.16 (d, 1H, 3JHHꢀ=ꢀ8 Hz, Ar), 7.23 (s, 1H, Ar); 13C NMR (CDCl3): δ 20.7 (Me),
43.2 (CH2Cl), 94.0 (C-2), 98.8 (CCl3), 114.5 (C-4a), 116.2 (C-8), 125.8 (C-5),
132.0 (C-6), 135.7 (C-7), 152.0 (C-8a), 163.2 (C-4).
6-Fluoro-4-phenyl-2-trichloromethyl-2H-1,3-benzoxazine
(2b)ꢁYield 30% (method A), 20% (method B); gray solid; mp 91.5–
1
93°C; H NMR (CDCl3): δ 5.92 (s, 1H, CHN), 7.07 (m, 2H, Ar), 7.2 (m,
1H, Ar), 7.5 (m, 3H, Ar), 7.66 (m, 2H, Ar); 13C NMR (CDCl3): δ 94.6 (C-2),
4-Phenyl-2-(trichloromethyl)-2H-naphtho-1,3-oxazine (4)ꢁYield
66% (method A); yellowish solid; mp 161–162°C; 1H NMR (CDCl3): δ 6.40
(s, 1H, CHN), 7.41 (d, 1H, 3JHHꢀ=ꢀ8 Hz, Ar), 7.53–7.9 (m, 9H, Ar), 8.44 (d, 1H,
3JHHꢀ=ꢀ8 Hz, Ar); 13C NMR (CDCl3): δ 94.7 (C-2), 99.3 (CCl3), 112.0 (C-4a),
121.1 (C-7), 122.8 (C-9), 123.5 (C1Ph), 123.6 (C-6), 126.8 (C-5), 127.8 (C-10),
128.6 (C3,5Ph), 129.4 (C4Ph), 129.4 (C2Ph), 130.7 (C-8), 135.9 (C-6a), 136.7
(C-10a), 152.7 (C-10b), 167.8 (C-4). Anal. Calcd for C19H12Cl3NO: C, 60.59;
H, 3.21; Cl, 28.24; N, 3.72. Found: C, 60.81; H, 3.31; Cl, 28.18; N, 3.89.
2
3
99.1 (CCl3), 114.4 (d, JCFꢀ=ꢀ24 Hz, C-5), 117.8 (d, JCFꢀ=ꢀ7 Hz, C-4a), 118.0
(d, 3JCFꢀ=ꢀ7 Hz, C-8), 121.2 (d, 2JCFꢀ=ꢀ24 Hz, C-7), 128.7, 129.0 (C2,6Ph, C3,5Ph),
130.8 (C4Ph), 135.4 (C1Ph), 151.0 (d, 4JCFꢀ=ꢀ2 Hz, C-8a), 157.2 (d, 1JCFꢀ=ꢀ243 Hz,
C-6), 166.1 (C-4); 19F NMR (CDCl3): δ –119.7; LC-APCI-MS: m/z 344
[Mꢀ+ꢀ1]. Anal. Calcd for C15H9Cl3FNO: C, 52.28; H, 2.63; Cl, 30.86; N,
4.06. Found: C, 52.41; H, 2.77; Cl, 31.05; N, 4.26.
6-Methyl-4-phenyl-2-trichloromethyl-2H-1,3-benzoxazine
(2c)ꢁYield 78% (method B); white solid; mp 91–92°C; 1H NMR
3
(CDCl3): δ 2.28 (s, 3H, Me), 5.89 (s, 1H, CHN), 7.0 (d, 1H, JHHꢀ=ꢀ8.1 Hz,
General procedure for the preparation of 2-dichlorometh-
ylenebenzoxazines 5a–c and 6
3
Ar), 7.11 (s, 1H, Ar), 7.3 (d, 1H, JHHꢀ=ꢀ8.1 Hz, Ar), 7.51 (m, 3H, Ar), 7.65
(m, 2H, Ar); 13C NMR (CDCl3): δ 20.8 (Me), 94.3 (C-2), 99.5 (CCl3), 116.3
(C-5), 117.1 (C-4a), 128.4 (C-8), 128.5, 129.2 (C2,3Ph), 130.5 (C4Ph), 131.6
(C-6), 135.1 (C-7), 136.1 (C1Ph), 152.9 (C-8a), 167.2 (C-4). Anal. Calcd for
C16H12Cl3NO: C, 56.42; H, 3.55; Cl, 31.22; N, 4.11. Found: C, 56.59; H,
3.67; Cl, 30.75; N, 4.30.
A solution of the benzoxazine 2a–c or 4 (0.5 mmol) and DBU (0.08 g,
0.5 mmol) in chloroform (2 mL) was allowed to stand at room temper-
ature for 6 days. The solvent was evaporated under reduced pressure.
The solid residue was triturated with water, filtered and crystallized
from aqueous ethanol (1:1).
6-Methyl-2-trichloromethyl-4-trifluoromethyl-2H-1,3-benzoxa-
zine (2d)ꢁYield 41% (method A); colorless oil; 1H NMR (CDCl3): δ 2.34
(s, 3H, Me), 5.99 (q, 1H, 5JHHꢀ=ꢀ1.5 Hz, CHN), 6.97 (d, 1H, 3JHHꢀ=ꢀ8.7 Hz, Ar),
7.3 (m, 2H, Ar); 13C NMR (CDCl3): δꢀ=ꢀ20.8 (Me), 93.9 (C-2), 97.8 (CCl3),
111.7 (C-4a), 115.5 (C-8), 119.2 (q, 1JCFꢀ=ꢀ279 Hz, CF3), 125.9 (q, 4JCFꢀ=ꢀ2.5 Hz,
2-Dichloromethylene-4-phenyl-2H-1,3-benzoxazine (5a)ꢁYield
1
41%; white solid; mp 125–126°C; H NMR (CDCl3): δ 7.05 (m, 2H, Ar),
7.5 (m, 5H, Ar), 7.7 (m, 2H, Ar). Anal. Calcd for C15H9Cl2NO: C, 62.09;
H, 3.13; Cl, 24.44; N, 4.83. Found: C, 62.21; H, 3.28; Cl, 24.27; N, 5.08.
C-5), 132.7 (C-6), 136.9 (C-7), 152.9 (C-8a), 155.6 (q, 2JCFꢀ=ꢀ36 Hz, C-4); 19
F
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ꢀꢀꢀꢁ
6ꢀ ꢀP.P. Onys’ko et al.: 1,3-Benzoxazine ring formation
2-Dichloromethylene-6-fluoro-4-phenyl-2H-1,3-benzoxazine E-isomerꢁ1H NMR (C6D6): δ 2.04 (s, 3H, Me), 6.10 (s, 1H, CHCl2), 6.58
1
2
(5b)ꢁYield 60%; white solid; mp 155–156°C; H NMR (CDCl3): δ 7.0 5 (d, 1H, JHFꢀ=ꢀ76.3 Hz, CHF), 6.55 (s, 1H, 5-H), 6.68 (1H) and 6.74 (1H),
(m, 1H, Ar), 7.15 (m, 2H, Ar), 7.54 (m, 3H, Ar), 7.7 (m, 2H, Ar); 13C NMR two doublets, JHHꢀ=ꢀ9 Hz (7-H and 8-H); 13C NMR (C6D6): δ 20.5 (Me),
3
(CDCl3): δ 102.1 (CCl2), 114.0 (d, JCFꢀ=ꢀ25 Hz, C-5), 117.0 (d, JCFꢀ=ꢀ8 Hz, 66.8 (CHCl2), 114.4 (d, 3JCFꢀ=ꢀ3 Hz, C-4a), 116.3 (C-8), 120.8 (d, 6JCFꢀ=ꢀ1 Hz,
2
3
C-4a), 117.3 (d, 3JCFꢀ=ꢀ7 Hz, C-8), 121.3 (d, 2JCFꢀ=ꢀ24 Hz, C-7), 128.8 (C2,6Ph), C-7), 121.2 (d, JCFꢀ=ꢀ9 Hz, C-4), 130.5 (d, JCFꢀ=ꢀ2.5 Hz, C-5), 135.6 (d,
2
4
128.9 (C3,5Ph), 130.9 (C4Ph), 135.0 (C1Ph), 147.5 (C-2), 151.2 (d, JCFꢀ=ꢀ2 Hz, 5JCFꢀ=ꢀ1 Hz, C-6), 140.4 (d, JCFꢀ=ꢀ269 Hz, =CF), 146.6 (d, JCFꢀ=ꢀ7 Hz) and
4
1
4
C-8a), 157.9 (d, JCFꢀ=ꢀ243 Hz, C-6), 160.2 (d, JCFꢀ=ꢀ2 Hz, C-4); 19F NMR 150.4 (d, JCFꢀ=ꢀ5 Hz) (C-2 and C-8a); 19F NMR (C6D6): δꢀ=ꢀ–150.6 (d,
(CDCl3): δ –118.3. Anal. Calcd for C15H8Cl2FNO: C, 58.47; H, 2.62; Cl, 2JFHꢀ=ꢀ76.3 Hz).
23.01; N, 4.55. Found: C, 58.60; H, 2.88; Cl, 23.00; N, 4.85.
1
4
4
Z-isomerꢁ1H NMR (C6D6): δ 2.06 (s, 3H, Me), 6.00 (s, 1H, CHCl2), 7.11
2-Dichloromethylene-6-methyl-4-phenyl-2H-1,3-benzoxazine (d, 1H, JHFꢀ=ꢀ80 Hz, CHF); 13C NMR (C6D6): δ 20.5 (Me), 66.6 (CHCl2),
2
(5c)ꢁYield 58%; white solid; mp 130–130.5°C; H NMR (CDCl3): δ 115.8 (C-8), 131.1 (d, JCFꢀ=ꢀ2 Hz, C-5); 19F NMR (C6D6): δꢀ=ꢀ–142.9 (d,
1
4
2.27 (s, 3H, Me), 6.97 (d, 1H, 3JHHꢀ=ꢀ8.4 Hz, Ar), 7.19 (s, 1H, Ar), 7.26 (d, 2JFHꢀ=ꢀ80 Hz). Analysis for mixture. Calcd for C11H8Cl2FNO: C, 50.80; H,
3
1H, JHHꢀ=ꢀ8.4 Hz, Ar), 7.5 (m, 3H, Ar), 7.7 (m, 2H, Ar). Anal. Calcd for 3.10; Cl, 27.26; N, 5.39. Found: C, 50.97; H, 3.15; Cl, 27.39; N, 5.50.
C16H11Cl2NO: C, 63.18; H, 3.65; Cl, 23.31; N, 4.60. Found: C, 63.33; H,
3.82; Cl, 23.38; N, 4.66.
N-(1,2,2,2-Tetrachloroethyl)trifluoroacetamide (9b)ꢁA solution
of acetamide 8b (10 g, 0.04 mol) and phosphorus pentachloride (8 g,
2-Dichloromethylene-6-methyl-4-trifluoromethyl-1,3-benzo- 0.04 mol) in benzene (50 mL) was heated until evolution of hydro-
xazine (5d)ꢁA solution of benzoxazine 2d (0.2 g, 1.1 mmol) and gen chloride ceased. After cooling to room temperature, the precipi-
Et3N (0.17 mL, 1.7 mmol) in dichloromethane (0.5 mL) was stirred at tated solid was separated by filtration and purified by sublimation
1
room temperature overnight. The mixture was washed with water in vacuo: yield 70%; white solid; mp 49–50°C; H NMR (CDCl3): δ
(2ꢀꢀ×ꢀꢀ3 mL) and dried (MgSO4). After evaporation of solvent the resi- 6.45 (d, 1H, 3JHHꢀ=ꢀ10 Hz, CHN), 7.09 (br s, 1H, NH); 19F NMR (CDCl3): δ
due was extracted with hot hexane: yield 89%; red solid; mp 155– –76.3. Anal. Calcd for C4H2Cl4F3NO: C, 17.23; H, 0.72; Cl, 50.85; N, 5.02.
156°C; 1H NMR (CDCl3): δ 2.33 (s, 3H, Me), 6.91 (d, 1H, 3JHHꢀ=ꢀ8.4 Hz, Ar), Found: C, 17.35; H, 0.79; Cl, 50.99; N, 5.14.
7.24 (m, 1H, Ar), 7.29 (m, 1H, 3JHHꢀ=ꢀ8.4 Hz, Ar); 13C NMR (CDCl3): δ 20.7
1
(Me), 111.5 (CCl2), 115.7 (C-8), 116.2 (C-4a), 119.5 (q, JCFꢀ=ꢀ277 Hz, CF3),
4
125.5 (q, JCFꢀ=ꢀ3 Hz, C-5), 132.4 (C-6), 136.8 (C-7), 146.4 (C-2), 148.2 (q, General procedure for the preparation of N-substituted
2JCFꢀ=ꢀ36 Hz, C-4), 153.1 (C-8a); 19F NMR (CDCl3): δꢀ=ꢀ–69.17. Anal. Calcd
for C11H6Cl2F3NO: C, 44.62; H, 2.04; Cl, 23.95; N, 4.73. Found: C, 44.85;
H, 2.25; Cl, 23.99; N, 4.89.
amides 10a–h
A
solution of chloride 9a–d (20 mmol), respective phenol
(20 mmol) and triethylamine (2.8 mL, 20 mmol) in anhydrous
benzene (50 mL) was heated under reflux for 3 h. The precipitated
product was separated by filtration, successively washed with
benzene and water and crystallized from ethanol (10a–f,h). Com-
pound 10g was purified by column chromatography (silica-gel,
hexane-ethyl acetate, 9:1).
4-Phenyl-2-(dichloromethylene)-2H-naphtho[2,1-e][1,3]-oxa-
1
zine (6)ꢁYield 56%; red solid; mp 168°C; H NMR (CDCl3): 7.37–7.63
3
(m, 10H), 8.45 (d, 1H, JHHꢀ=ꢀ8 Hz). Anal. Calcd for C19H11Cl2NO: C,
67.08; H, 3.26; Cl, 20.84; N, 4.12. Found: C, 67.17; H, 3.20; Cl, 20.72;
N, 4.09.
N-(2,2,2-Trichloro-1-phenoxyethyl)benzamide (10a)ꢁYield 80%;
mp 175–176°C, lit. mp 175–176°C [31].
General procedure for the preparation of 2-dichlorometh-
ylbenzoxazines 7a,b
N-[2,2,2-Trichloro-1-(4-fluorophenoxy)ethyl]benzamide
(10b)ꢁYield 77%; white solid; mp 137–138°C; 1H NMR (CDCl3): δ 6.55
(d, 1H, JHHꢀ=ꢀ9.9 Hz, CHN), 6.95 (d, 1H, JHHꢀ=ꢀ9.9 Hz, NH), 7.01 (t, 2H,
3JHHꢀ=ꢀ3JHFꢀ=ꢀ7.8 Hz, Ar), 7.12 (m, 2H, Ar), 7.49 (t, 2H, 3JHHꢀ=ꢀ7.5 Hz, Ar), 7.59
(t, 1H, 3JHHꢀ=ꢀ7.5 Hz, Ar), 7.82 (d, 2H, 3JHHꢀ=ꢀ7.5 Hz, Ar); 19F NMR (CDCl3):
δꢀ=ꢀ–119.9. Anal. Calcd for C15H11Cl3FNO2: C, 49.68; H, 3.06; Cl, 29.33; N,
3.86. Found: C, 49.90; H, 3.21; Cl, 29.41; N, 3.94.
A solution of benzoxazine 2f,g (0.43 mmol) and DBU (0.1 g,
0.65 mmol) in dichloromethane (2 mL) was stirred at room tempera-
ture for 12 h. The mixture was washed with water and dried (MgSO4).
The solvent was evaporated under reduced pressure and the residue
was extracted with hot hexane.
3
3
2-Dichloromethyl-6-methyl-4-methylene-4H-1,3-benzoxazine
1
(7a)ꢁYield 37%; colorless oil; H NMR (CDCl3): δ 2.38 (s, 3H, Me),
N-[2,2,2-Trichloro-1-(4-methylphenoxy)ethyl]benzamide
(10c)ꢁYield 75%; white solid; mp 116–117°C; 1H NMR (CDCl3): δ 2.29 (s,
3H, Me), 6.59 (d, 1H, 3JHHꢀ=ꢀ9.9 Hz, CHN), 6.91 (d, 1H, 3JHHꢀ=ꢀ9.9 Hz, NH),
7.04 (d, 2H, 3JHHꢀ=ꢀ8.7 Hz, Ar), 7.12 (d, 2H, 3JHHꢀ=ꢀ8.7 Hz, Ar), 7.48 (t, 2H,
5.11 (s, 1H, =CHa), 5.30 (s, 1H, =CHb), 6.19 (s, 1H, CHCl2), 7.02 (d, 1H,
3
3JHHꢀ=ꢀ8.5 Hz, 8-H), 7.17 (d, 1H, JHHꢀ=ꢀ8.5 Hz, 7-H), 7.33 (s, 1H, 5-H); 13C
NMR (CDCl3): δ 21.1 (Me), 66.7 (CHCl2), 103.4 (=CH2), 116.40 (C-8), 117.8
(C-4a), 123.6 (C-5), 131.4 (C-7), 136.1 (C-6), 139.2 (C-4), 146.9 (C-8a),
150.3 (C-2). Anal. Calcd for C11H9Cl2NO: C, 54.57; H, 3.75; Cl, 29.29; N,
5.79. Found: C, 54.71; H, 3.88; Cl, 29.27; N, 5.91.
3
3
3JHHꢀ=ꢀ7.5 Hz, Ar), 7.58 (t, 1H, JHHꢀ=ꢀ7.5 Hz, Ar), 7.81 (d, 2H, JHHꢀ=ꢀ7.5 Hz,
Ar). Anal. Calcd for C16H14Cl3NO2: C, 53.58; H, 3.93; Cl, 29.65; N, 3.91.
Found: C, 53.71; H, 4.10; Cl, 29.50; N, 4.05.
2-Dichloromethyl-6-methyl-4-(fluoromethylene)-4H-1,3-benzo- N-[2,2,2-Trichloro-1-(4-methylphenoxy)ethyl]trifluoroaceta-
1
xazine (7b)ꢁThis compound was purified by column chromatog- mide (10d)ꢁYield 50%; colorless oil; H NMR (CDCl3): δ 2.32 (s, 3H,
3
3
raphy (silica gel, benzene) and isolated as a mixture (10:1) of E/Z Me), 6.30 (d, 1H, JHHꢀ=ꢀ10 Hz, CHN), 6.94 (d, 2H, JHHꢀ=ꢀ8.5 Hz, Ar),
3
3
isomers; yield 70%; colorless oil.
7.02 (d, 1H, JHHꢀ=ꢀ10 Hz, NH), 7.12 (d, 2H, JHHꢀ=ꢀ8.5 Hz, Ar); 13C NMR
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ꢁꢀꢀꢀ
P.P. Onys’ko et al.: 1,3-Benzoxazine ring formationꢂ ꢂ7
(CDCl3): δ 20.6 (Me), 85.2 (CHN), 97.8 (CCl3), 116.3 (C2,6Ar), 130.6 (C3,5Ar),
133.8 (C4Ar), 153.3 (C=O), 157.0 (q, 1JCFꢀ=ꢀ39 Hz, C1Ar); 19F-{H} NMR (CDCl3):
δ –76.4. Anal. Calcd for C11H9Cl3F3NO2: C, 37.69; H, 2.59; Cl, 30.34; N,
4.00. Found: C, 37.86; H, 2.68; Cl, 30.57; N, 4.15.
[6] Hiramatsu, K.; Honjo, T.; Rauniar, V.; Toste, F. D. Enantiose-
lective synthesis of fluoro-dihydroquinazolones and -benzo-
oxazinones by fluorination-initiated asymmetric cyclization
reactions. ACS Catalysis. 2016, 6, 151–154.
[7] Hideya, M.; Hiroyuki, I.; Susumu, K.; Tadataka, O.; Yukio,
M.; Miichiro, A. Process development of potassium chan-
nel opener, TCV-295, based on convenient ring formation of
2H-1,3-benzoxazine and selective N-oxidation of the pyridyl
moiety. Tetrahedron 2001, 57, 7501–7506.
[8] Tang, Z.; Zhu, Zh.; Xia, Z.; Liu, H.; Chen, J.; Xiao, W.; Ou, X.
Synthesis and fungicidal activity of novel 2,3-disubstituted-
1,3-benzoxazines. Molecules. 2012, 17, 8174–8185.
N-[2,2,2-Trichloro-1-(3,4-dimethylphenoxy)ethyl]benzamide
(10e)ꢁYield 79%, white solid, mp 155°C. 1H NMR (CDCl3): δꢀ=ꢀ2.18 (s,
3H, CH3), 2.23 (s, 3H, CH3), 6.59 (d, 1H, 3JHHꢀ=ꢀ9 Hz, CHN), 6.8–6.94 (m,
3H, Ar), 7.06 (d, 1H, 3JHHꢀ=ꢀ9 Hz, NH), 7.47 (t, 2H, 3JHHꢀ=ꢀ7.8 Hz, Ar), 7.56
(m, 1H, 3JHHꢀ=ꢀ7.8 Hz, Ar), 7.81 (d, 2H, 3JHHꢀ=ꢀ7.8 Hz, Ar). Anal. Calcd for
C17H16Cl3NO2: C, 54.79; H, 4.33; Cl, 28.54; N, 3.76. Found: C, 54.89; H,
4.56; Cl, 28.20; N, 3.85.
[9] Mathew, B. P.; Kumar, A.; Sharma, S.; Shukla, P. K.; Nath, M. An
eco-friendly synthesis and antimicrobial activities of dihydro-
2H-benzo- and naphtho-1,3-oxazine derivatives. Eur. J. Med.
Chem. 2010, 45, 1502–1507.
[10] Nishimine, T.; Taira, H.; Tokunaga, E.; Shiro, M.; Shibata,
N. Enantioselective trichloromethylation of MBH-fluorides
with chloroform based on silicon-assisted C–F activation and
carbanion exchange induced by a Ruppert–Prakash reagent.
Angew. Chem. Int. Ed. 2016, 55, 359–363.
[11] Gribble, G. W. Naturally occurring organohalogen compounds.
Acc. Chem. Res. 1998, 31, 141–152.
[12] Sainsbury, M.; Boulton, A. J. (Ed) Comprehensive Heterocyclic
Chemistry II; Elsevier: Oxford, 1996, 6, 279.
[13] Lundquist, D. K.; Belen’kii, L. I.; Kochetkov, N. K. Comprehen-
sive Organic Chemistry [Russian Edition]; Khimiya: Moscow,
1985; 9, 575–580.
[14] Vovk, M. V.; Bol’but, A. V.; Chernega, A. N. 1-Aryl-1-chloro-2,2,2-
trifluoroethylisocyanates – convenient reagents for synthesis
of 2-aryl-2-trifluoromethyl-2,3-dihydro-4H-benzo[e][1,3]oxazin-
4-ones. J. Fluorine Chem. 2002, 116, 97–101.
N-[2,2,2-Trichloro-1-(4-methylphenoxy)ethyl]acetamide
(10f)ꢁYield 60%; white solid; mp 107–108°C; 1H NMR (CDCl3): δ 2.11
(s, 3H, Me), 2.31 (s, 3H, Me), 6.37 (d, 1H, 3JHHꢀ=ꢀ10 Hz, CHN), 6.44 (d, 1H,
3
3
3JHHꢀ=ꢀ10 Hz, NH), 6.97 (d, 2H, JHHꢀ=ꢀ8 Hz, Ar), 7.12 (d, 2H, JHHꢀ=ꢀ8 Hz,
Ar); 13C NMR (CDCl3): δ 20.6 (MeAr), 23.3 (MeC=O), 84.5 (CHN), 99.1
(CCl3), 116.1 (C2,6Ar), 130.3 (C3,5Ar), 132.6 (C4Ar), 153.8 (C1Ar), 170.0 (C=O).
Anal. Calcd for C11H12Cl3NO2: C, 44.55; H, 4.08; Cl, 35.86; N, 4.72.
Found: C, 44.73; H, 4.20; Cl, 35.97; N, 4.81.
N-[2,2,2-Trichloro-1-(4-methylphenoxy)ethyl]fluoroacetamide
(10g)ꢁYield 80%; white solid; mp 46–48°C; 1H NMR (CDCl3): δ 2.30
2
2
(s, 3H, Me), 4.91 (dd,1H, JHFꢀ=ꢀ47 Hz, JHHꢀ=ꢀ15 Hz, CHAF), 4.84 (dd,
2
2
3
1H, JHFꢀ=ꢀ47 Hz, JHHꢀ=ꢀ15 Hz, CHBF), 6.39 (d, 1H, JHHꢀ=ꢀ10 Hz, CHN),
6.97 (d, 2H, JHHꢀ=ꢀ8 Hz, Ar), 7.12 (m, 3H, Ar, NH); 13C NMR (CDCl3): δ
3
1
20.6 (Me), 79.7 (d, JCFꢀ=ꢀ187 Hz, CH2F), 84.1 (CHN), 98.6 (CCl3), 116.2
(C2,6Ar), 130.4 (C3,5Ar), 133.1 (C4Ar), 153.6 (C1Ar), 167.8 (d, JCFꢀ=ꢀ19 Hz,
2
C=O); 19F-{H} NMR (CDCl3): δ –226.5. Anal. Calcd for C11H11Cl3FNO2:
C, 42.00; H, 3.52; Cl, 33.81; N, 4.45. Found: C, 42.19; H, 3.75; Cl, 33.95;
N, 4.50.
[15] Deb, M. L.; Borpatra, P. J.; Saikia, P. J.; Baruah, P. K. Iodine/
Hydrogen peroxide promoted intramolecular oxidative C–O
bond formation in ethanol at room temperature: a green
approach to 1,3-oxazines. Synlett 2017, 28, 461–466.
[16] Smart, B. E. Fluorine substituent effects (on bioactivity).
J. Fluorine Chem. 2001, 109, 3–11.
[17] Ismail, F. M. D. Important fluorinated drugs in experimental and
clinical use. J. Fluorine Chem. 2002, 118, 27–33 and references
therein.
N-[2, 2, 2-Trichloro-1-(1-naphthyloxy)ethyl]benzamide
1
(10h)ꢁYield 50%; light red solid; mp 177–178°C; H NMR (CDCl3): δ
3
3
6.87 (d, 1H, JHHꢀ=ꢀ10 Hz, CHN), 7.02 (d, 1H, JHHꢀ=ꢀ10 Hz, NH), 7.23 (d,
1H, 3JHHꢀ=ꢀ7.2 Hz, Ar), 7.36–7.59 (m, 7H, Ar), 7.82 (m, 3H, Ar), 8.33 (m, 1H,
Ar). Anal. Calcd for C19H14Cl3NO2: C, 57.82; H, 3.58; Cl, 26.95; N, 3.55.
Found: C, 57.75; H, 3.41; Cl, 26.90; N, 3.73.
[18] Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. Eds. Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applica-
tions. Elsevier: Amsterdam, 1993.
[19] O’Hagan, D. Fluorine in health care: organofluorine
containing blockbuster drugs. J. Fluorine Chem. 2010, 131,
1071–1081.
[20] Zhou, Y.; Wang, J.; Gu, Zh.; Wang, Sh.; Zhu, W.; Acena, J.-L.;
Soloshonok, V.; Izawa, K.; Liu, H. Fluorine in pharmaceuti-
cal industry: fluorine-containing drugs introduced to the
market in the last decade (2001–2011). Chem. Rev. 2014, 114,
2432–2506.
[21] Zhou, Y.; Wang, J.; Gu, Zh.; Wang, Sh.; Zhu, W.; Acena, J.-L.;
Soloshonok, V.; Izawa, K.; Liu, H. Next generation of fluorine-
containing pharmaceuticals, compounds currently in phase
II–III clinical trials of major pharmaceutical companies: new
structural trends and therapeutic areas. Chem. Rev. 2016, 116,
422–518.
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8ꢀ ꢀP.P. Onys’ko et al.: 1,3-Benzoxazine ring formation
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