Synthesis of liquid crystalline 4H-benzo[1,2,4]thiadiazines and generation of persistent radicals

Article abstract of DOI:10.1021/jo070122a

(Chemical Equation Presented) Four substituted 4H-benzo[1,2,4]thiadiazines 2 were prepared by condensation of the appropriate anilines and benzonitriles followed by oxidative cyclization. The preparation of three fluorinated derivatives 2b-2d proceeded sm

Full text of DOI:10.1021/jo070122a

Synthesis of Liquid Crystalline 4H-Benzo[1,2,4]thiadiazines and
Generation of Persistent Radicals
Jo´zef Zienkiewicz, Anna Fryszkowska,† Katarzyna Zienkiewicz, Fengli Guo,
Piotr Kaszynski,* Adam Januszko, and David Jones
Organic Materials Research Group, Department of Chemistry, Vanderbilt UniVersity,
NashVille, Tennessee 37235
piotr.kaszynski@Vanderbilt.edu
ReceiVed January 21, 2007
Four substituted 4H-benzo[1,2,4]thiadiazines 2 were prepared by condensation of the appropriate anilines
and benzonitriles followed by oxidative cyclization. The preparation of three fluorinated derivatives 2b-
2d proceeded smoothly, while the synthesis of 2a was problematic, presumably due to the relatively
high electron density of the benzene ring. The four-ring derivatives 2c and 2d exhibited liquid crystalline
properties (2c: Cr 95 SmA 158 I and 2d: Cr 142 SmA 212 I). 4H-Benzo[1,2,4]thiadiazines 2 were
oxidized with AgO to generate the corresponding persistent radicals 1 (g ) 2.0057). The stability of the
radicals followed the order 1b ∼ 1d > 1c . 1a, and the two fluorinated radicals 1b and 1d were isolated
as crude solids. The lower stability of 1c is presumably due to the presence of the reactive benzylic CH
position, and 1a lacks the stabilizing effect of the three fluorine atoms. ESR spectra for 1 were simulated
using DFT-derived hfcc as the starting point.
Introduction
spatial molecular arrangements and hence provide alternative
types of intermolecular interactions either in the fluid phase
(dynamic) or in the glass phase (static). Therefore, liquid crystals
are an attractive vehicle to impose partial molecular order and
to control intermolecular spin-spin interactions of paramagnetic
mesogens.5,6 To maximize these interactions, the spin source
should be placed in the rigid core and the unpaired electron
delocalized in the π-electron manifold.
Over the past two decades, there has been increasing effort
to combine paramagnetic and liquid crystalline properties to
enhance the effect of a magnetic field on optical properties
(magnetooptics) and to elucidate fundamental aspects of mo-
lecular magnetism.1 Liquid crystals (LCs) are partially oriented
anisotropic fluids2,3 that exhibit over two dozen distinct phases.4
They offer access to a number of thermodynamically controlled
The majority of paramagnetic LCs with permanent spins
studied thus far are metallomesogens,7 in which the spin
* Corresponding author. Phone: (615) 322-3458. Fax: (615) 343-1234.
† Visiting graduate student from the group of Prof. R. Ostaszewski at Warsaw
University of Technology, Poland.
(1) Dunmur, D.; Toriyama, K. In Handbook of Liquid Crystals; Demus,
D., Goodby, J. W., Gray, G. W., Spiess, H.-W., Vill, V., Eds.; Wiley-
VCH: New York, 1998; Vol. 1, pp 204-214.
(2) Demus, D. In Liquid Crystals. Applications and Uses; Bahadur, B.,
Ed.; World Scientific: Singapore, 1990; Vol. 1, pp 1-36.
(3) Demus, D. In Handbook of Liquid Crystals; Demus, D., Goodby, J.
W., Gray, G. W., Spiess, H.-W., Vill, V. Eds.; Wiley-VCH: New York,
1998; Vol. 1, pp 133-187.
(4) Goodby, J. W. In Handbook of Liquid Crystals; Demus, D., Goodby,
J. W., Gray, G. W., Spiess, H.-W., Vill, V., Eds.; Wiley-VCH: New York,
1998; Vol. 2A, pp 1-23.
(5) Haase, W.; Borchers, B. In Magnetic Molecular Materials; Gatteschi,
D., Kahn, O., Miller, J. S., Palacio, F., Eds.; Kluwer Academic Publishers:
Dordrecht, The Netherlands, 1991; pp 245-253.
(6) Griesar, K.; Athanassopoulou, M. A.; Bustamante, E. A. S.; Tomk-
iewicz, Z.; Zaleski, A. J.; Haase, W. AdV. Mater. 1997, 9, 45-48.
(7) Metallomesogens; Serrano, L. J., Ed.; VCH: New York, 1996.
10.1021/jo070122a CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/04/2007
3510
J. Org. Chem. 2007, 72, 3510-3520

Liquid Crystalline 4H-Benzo[1,2,4]thiadiazines
originates from transition metal centers. Many such compounds
exhibit significant paramagnetic anisotropy due to the spin orbit
coupling especially in the mesogenic complexes of some
lanthanides.8,9 Unfortunately, in metallomesogens, little spin is
transferred from the metal to the π-framework,10-12 which limits
the extent of intermolecular spin-spin magnetic exchange. In
contrast, properly designed all-organic paramagnetic mesogens
are expected to provide significant delocalization of the spin,
unfortunately at the expense of paramagnetic anisotropy. Such
all-organic mesogens have been much more difficult to realize
experimentally.13
FIGURE 1. Persistent benzo[1,2,4]thiadiazinyl I. Arrows indicate the
substitution sites to induce mesogenic behavior.
atom provides a modest paramagnetic anisotropy1 of the
radicals,25-27 which is greater than that of nitroxides.
Recently, we developed a methodology for the synthesis of
fused-ring 4H-benzo[1,2,4] thiadiazines28 and for the efficient
generation of the corresponding radicals.23 Investigation dem-
onstrated that the tetrafluoro derivative I (Figure 1) is moderately
reactive toward oxygen but is sufficiently stable for isolation
in the pure crystalline form and complete characterization. This
prompted us to investigate I as a structural element for
paramagnetic calamitic liquid crystals.13
To induce mesogenic properties, the anisometry of radical I
was increased by substitution with a hexyloxy group in position
7 and introduction of a substituent in the para position of the
phenyl ring (Figure 1). Therefore, we focused on a three-ring
derivative 1b, a trifluoro analogue of 1a, and four-ring deriva-
tives 1c and 1d, which could be available from the correspond-
ing thiadiazines 2.
There are very few LCs containing purely organic electrically
neutral spin sources. To date, only nitroxyl and related nitro-
nylnitroxide groups have been explored as spin sources for liquid
crystalline radicals. Since for stability reasons the nitroxyl group
must be substituted with quaternary centers, placing them in
the rigid core without compromising mesogenic properties was
a challenge for a long time.14-18 Recently, the first such
mesogens were prepared.19,20 Although this constitutes a
significant milestone in the investigation of all-organic para-
magnetic mesogens, the new design19 still has not addressed
the issue of spin delocalization. The nitroxide group is a
sterically and electronically isolated small spin source capable
of very limited intermolecular spin-spin interactions.
A more effective way to design liquid crystals with π-delo-
calized spins is to use heteroaromatic radicals. In this context,
we have focused on [1,2]thiazinyl as the fundamental structural
element for calamitic and discotic mesogens.13,21 We have
prepared several of its hetera- and fused-ring analogues and
investigated properties of such persistent radicals.22-24 Many
of these radicals exhibit a chemical stability sufficient for
studying their liquid crystalline derivatives. In addition, the S
Here, we report progress toward such a class of paramagnetic
calamitic liquid crystals and describe the preparation and liquid
crystalline properties of four substituted 4H-benzo[1,2,4]-
thiadiazines 2. We also report preliminary results on the
generation and characterization of radicals 1.
(8) Galyametdinov, Y.; Athanassopoulou, M. A.; Griesar, K.; Khari-
tonova, O.; Bustamante, E. A. S.; Tinchurina, L.; Ovchinnikov, I.; Haase,
W. Chem. Mater. 1996, 8, 922-926.
(9) Galyametdinov, Y. G.; Haase, W.; Malykhina, L.; Prosvirin, A.;
Bikchantaev, I.; Rakhmatullin, A.; Binnemans, K. Chem.sEur. J. 2001, 7,
99-105.
(10) Gillon, B.; Journaux, Y.; Kahn, O. Phys. B 1989, 156-157, 373-
375.
Results
(11) Gillon, B.; Cavata, C.; Schweiss, P.; Journaux, Y.; Kahn, O.;
Schneider, D. J. Am. Chem. Soc. 1989, 111, 7124-7132.
(12) Oshio, H.; Ichida, H. J. Phys. Chem. 1995, 99, 3294-3302.
(13) Kaszynski, P. In Magnetic Properties of Organic Materials; Lahti,
P. M., Ed.; Marcel Dekker: New York, 1999; pp 305-324.
(14) Tanaka, H.; Shibahara, Y.; Sato, T.; Ota, T. Eur. Polym. J. 1993,
29, 1525-1530.
Synthesis of 4H-Benzo[1,2,4]thiadiazines 2. Our initial
approach to the preparation of thiadiazine 2a followed the
method of Gilchrist, which relies on electrophilic cyclization
of N-arylbenzamidines with divalent sulfur electrophiles.29 Thus,
the reaction of amidine 3 with a bis(4-morpholinyl)chlorosul-
fonium intermediate followed by thermolysis of the resulting
crude ylide 4 in chlorobenzene repeatedly gave disappointingly
low yields (∼5%) of the desired thiadiazine 2a (Scheme 1).
Separation of pure 2a was complicated by the presence of
benzothiazole 5, which was formed presumably by thermolysis
of 2a, as was demonstrated for other benzo[1,2,4]thiadiazines.30
(15) Greve, S.; Vill, V.; Friedrichsen, W. Z. Naturforsch. B 2002, 57,
677-684.
(16) Nakatsuji, S.; Mizumoto, M.; Ikemoto, H.; Akutsu, H.; Yamada, J.
Eur. J. Org. Chem. 2002, 1912-1918.
(17) Several compounds containing the nitroxyl or nitronylnitroxide group
in the alkyl chains were found to exhibit liquid crystalline behavior:
Dvolaitzky, M.; Billard, J.; Poldy, F. Tetrahedron 1976, 32, 1835-1838.
See also refs 15 and 16.
(18) Shimono, S.; Tamura, R.; Ikuma, N.; Takimoto, T.; Kawame, N.;
Tamada, O.; Sakai, N.; Matsuura, H.; Yamauchi, J. J. Org. Chem. 2004,
69, 475-481.
(25) Preston, K. F.; Sandall, J. P. B.; Sutcliffe, L. H. Magn. Reson. Chem.
1988, 26, 755-759.
(19) Ikuma, N.; Tamura, R.; Shimono, S.; Kawame, N.; Tamada, O.;
Sakai, N.; Yamauchi, J.; Yamamoto, Y. Angew. Chem., Int. Ed. 2004, 43,
3677-3682.
(26) Preston, K. F.; Sutcliffe, L. H. Magn. Reson. Chem. 1990, 28, 189-
204.
(27) Fairhurst, S. A.; Sutcliffe, L. H.; Preston, K. F.; Banister, A. J.;
Partington, A. S.; Rawson, J. M.; Passmore, J.; Schriver, M. J. Magn. Reson.
Chem. 1993, 31, 1027-1030.
(20) Ikuma, N.; Tamura, R.; Shimono, S.; Uchida, Y.; Masaki, K.;
Yamauchi, J.; Aoki, Y.; Nohira, H. AdV. Mater. 2006, 18, 477-480.
(21) Patel, M. K.; Huang, J.; Kaszynski, P. Mol. Cryst. Liq. Cryst. 1995,
272, 87-97.
(28) Zienkiewicz, J.; Kaszynski, P.; Young, V. G., Jr. J. Org. Chem.
2004, 69, 2551-2561.
(22) Benin, V.; Kaszynski, P. J. Org. Chem. 2000, 65, 8086-8088.
(23) Zienkiewicz, J.; Kaszynski, P.; Young, V. G., Jr. J. Org. Chem.
2004, 69, 7525-7536.
(29) Gilchrist, T. L.; Rees, C. W.; Vaughan, D. J. Chem. Soc., Perkin
Trans. 1 1983, 49-54.
(30) Bo¨hnisch, V. W.; Gilchrist, T. L.; Rees, C. W. J. Chem. Soc., Perkin
Trans 1 1979, 2851-2845.
(24) Kaszynski, P. Molecules 2004, 9, 716-724.
J. Org. Chem, Vol. 72, No. 9, 2007 3511

Zienkiewicz et al.
SCHEME 1a
SCHEME 3a
a
i: NaH for 9, MeSO3H for 10, 46-76%.
(Scheme 2).28 In one instance, sulfoxide 8c was isolated in 18%
yield, presumably from hydrolysis of the unreacted chlorosul-
fonium intermediate. To increase the conversion, the NCS-
assisted cyclization reaction of 6c was first conducted at ambient
temperature for 12 h and then in boiling methylene chloride
for 1 h followed by the usual workup. Unfortunately, this led
to the formation of a complex mixture of products, and the
desired thiadiazine 2c was isolated only in about 12% yield.
This presumably resulted from temperature-enhanced reactivity
of NCS toward the benzylic-type position in 6c and also from
partial decomposition of the thermally labile ylide 7c to
thiadiazine 2c and its subsequent reaction with NCS.
a i: (1) (4-Morpholinyl)2S, NCS and (2) 5% NaOH. ii: PhCl, reflux.
SCHEME 2a
The preparation of the requisite amidines 6 was accomplished
by condensation28 of amines 9 and 10 with appropriate nitrile
11-13 either under basic (6a) or under acidic conditions (6b-
6d) (Scheme 3). In the latter reaction, typically a 5-fold excess
of nitrile was used to ensure the consumption of amine 10. The
unused nitrile was recovered in about 60% and reused for
another condensation reaction with amine 10. In one experiment,
the amount of nitrile 12 was reduced to 2 equiv without
significant compromising of the yield for 6c. Experiments
demonstrated that isomeric mixtures of amines containing 75-
90% of 10 could be used successfully for the condensation
reaction. In this case, pure amidines 6b and 6c were easily
isolated by chromatography followed by recrystallization.
The required amines 9 and 10 were prepared from 2,4-
dichloronitrobenzene (14) and pentafluoronitrobenzene (15),
respectively, in a series of nucleophilic aromatic substitution
reactions (Scheme 4). The order of introduction of the substit-
uents was dictated by the demonstrated regioselectivity of
alkylthiolation of 1433,34 and alkoxylation of 15.35 Thus,
propylthiolation of 14 under PTC conditions gave the pure
desired isomer 16. Subsequent reaction of 16 with n-hexanol
in DMSO in the presence of powdered KOH, according to an
analogous procedure,36 gave the nitro compound 17, which was
reduced to amine 9 with iron powder. The overall yield of the
amine for the three steps was 38%.
a i: (1) NCS, (2) 5% NaOH. ii: Toluene, reflux, 2b 41-46%, 2c 34%,
2d 30%. iii: NaIO4, 68%. iV: PhCl, reflux, 12%.
An analogous reaction31 of amidine 3 with SCl2 in the presence
of pyridine resulted in partial chlorination of the ring and was
not pursued further.
The difficulties with the isolation of pure thiadiazine 2a and
low yields of this process prompted us to develop a more reliable
method involving regiospecific cyclization of amidines substi-
tuted with an alkylsulfanyl group.28 According to this method,
amidine 6a was treated with NCS or with PhI(OAc)2/K2CO3,
but the formation of the expected ylide 7a was not confirmed
by NMR analysis (Scheme 2). It is possible that the oxidants
preferentially attacked the electron-rich benzene ring rather than
the amidinyl nitrogen atom. Therefore, the preparation of the
desired thiadiazine 2a was approached through sulfoxide 8a
following our success with an analogous synthesis of a pyrazine
derivative.28 Thus, thermolysis of 8a in refluxing toluene showed
a slow formation of the desired thiadiazine 2a along with the
thiazole 5 byproduct. The same reaction carried out in boiling
chlorobenzene gave about 50% conversion of the starting 8a
after 16 h, and the product 2a was isolated in 12% yield along
with 8% of thiazole 5. The required sulfoxide 8a was smoothly
obtained in 68% isolated yield by periodate oxidation32 of either
amidine 6a or its hydrochloride 6a‚HCl. 1H NMR and combus-
tion analyses demonstrated that sulfoxide 8a crystallizes with
one molecule of water.
Reaction of 15 with n-hexanol under PTC conditions,
according to an analogous literature procedure,37 gave 4-hexy-
loxytetrafluoronitrobenzene (18) and its ortho isomer in a 7:1
to 8:1 ratio. The structural assignment for the isomers was made
on the basis of MS and NMR results. The formation of the
(33) Hodgson, H. H.; Handley, F. W. J. Soc. Chem. Ind., London 1927,
46, 435-436.
Preparation of the fluorinated thiadiazines 2b-2d was more
straightforward. They were obtained in 30-46% isolated yields
by oxidative cyclization of amidines 6b-6d in the presence of
NCS and subsequent electrocyclic elimination of propene
(34) Kato, S.; Inada, S.; Aoki, Y.; Wakita, S. Agric. Biol. Chem. 1975,
39, 1475-1481.
(35) Kobrina, L. S.; Furin, G. G.; Yakobson, G. G. J. Org. Chem. 1970,
6, 510-517.
(36) Kaszynski, P.; Jawdosiuk, M. Mol. Cryst. Liq. Cryst. 1989, 174,
21-37.
(31) Levchenko, E. S.; Borovikova, G. S.; Borovik, E. I.; Kalinin, V. N.
J. Org. Chem. USSR 1984, 20, 176-181.
(32) Komeshima, N.; Osawa, T.; Nishitoba, T.; Jinno, Y.; Kiriu, T. Chem.
Pharm. Bull. 1992, 40, 351-356.
(37) Marriott, J. H.; Moreno Barber, A. M.; Hardcastle, I. R.; Rowlands,
M. G.; Grimshaw, R. M.; Neidle, S.; Jarman, M. J. Chem. Soc., Perkin
Trans. 1 2000, 4265-4278.
3512 J. Org. Chem., Vol. 72, No. 9, 2007

Liquid Crystalline 4H-Benzo[1,2,4]thiadiazines
SCHEME 4a
a i: PrSH, NaOH, Bu4N+Br-, benzene, 60%. ii: n-HexOH, KOH, DMSO, 67%. iii: Fe, AcOH, H2O, 9 94%, 10 91%. iV: n-HexOH, Bu4N+HSO4
CH2Cl2, 76%. V: PrSH, NaOH, EtOH, 92%.
,
-
TABLE 1. Transition Temperatures and Enthalpies for Selected
Compoundsa
compound
phase transition
2a
Cr 133 I
(36.2)
2b
2c
2d
3
Cr 93 I
(36.2)
Cr 95 SmA 158 I
(22.6) (3.75)
Cr 142 SmA 212 I
(31.6) (6.0)
Cr 130 (SmXb 125 SmB 130 )c SmA 136 I
(35.4)
(0.1)
(3.2)
(7.3)
5
Cr 99 N 125 I
(22) (0.9)
a Transition temperatures (°C) and enthalpies (kJ mol-1) were determined
by DSC (5 °C min-1) in the heating mode: Cr ) crystal; Sm ) smectic;
and I ) isotropic. b SmI or SmF phase. See text for details. c Monotropic
transitions.
FIGURE 2. A DSC trace of 2c. Heating and cooling rates are 5 °C/
min.
isomers and their ratio is consistent with other reports38 on
alkoxylation of 15 and the finding that the ratio of the two
isomers is temperature-dependent.35 Isomerically pure 18 was
obtained by repeated fractional distillation. Propylthiolation of
18 gave 19, which upon reduction with iron yielded amine 10
in good yield. Less satisfactory results were obtained with zinc/
AcOH or zinc/NH4Cl39 as the reducing reagents, and the amine
could not be separated from byproducts. For practical reasons,
a large-scale synthesis could be carried out on the isomeric
mixture of the nitrobenzenes and the isomers could be separated
on later stages of the synthesis, as was demonstrated for
amidines 6b and 6c. Thus, nitro derivative 18, containing about
10% of the ortho isomer, gave amine 10 as a 9:1 mixture of
two isomers, which was successfully used in the subsequent
condensation reactions.
FIGURE 3. Optical texture for 2d at 190 °C. Magnification 150×.
for 2c is shown in Figure 2. Optical microscopy for both
thiadiazines revealed typical smectic A phases with the char-
acteristic fan-shaped textures obtained upon cooling from the
isotropic phase (Figure 3). The three-ring thiadiazines 2a
and 2b showed only melting transitions and, upon cooling,
crystallization at about 15 °C below the melting point. Interest-
ingly, fluorination of 2a results in a 40 °C lower melting point
of 2b.
Liquid Crystalline Properties. Phase transition temperatures
and enthalpies for 4H-benzo[1,2,4]thiadiazines 2, amidine 3,
and benzothiazole 5 are collected in Table 1. Phase structures
were assigned by comparison of microscopic textures observed
under polarized light with those published for reference
compounds.40-42
Thermal and optical analysis of amidine 3 revealed the
formation of a narrow temperature range enantiotropic
SmA phase and two monotropic smectic phases. The first
monotropic phase was identified as a SmB phase (hexatic) on
the basis of a typical broken focal-conic texture and low
viscosity (see Supporting Information). Upon cooling, the
homeotropic regions of the SmB phase displayed a schlieren
texture. This, combined with a very small enthalpy of transition
(0.1 kJ/mol), suggested the formation of a tilted SmI
phase, although a SmF phase cannot be excluded. None of the
amidines 6 substituted with the PrS group exhibited mesogenic
behavior.
Out of the four thiadiazines, only the four-ring derivatives
2c and 2d exhibited liquid crystalline properties. The DSC trace
(38) Castle, M. D.; Plevey, R. G. J. Fluorine Chem. 1972, 2, 431-
433.
(39) Miller, A. O.; Furin, G. G. J. Fluorine Chem. 1987, 36, 247-
272.
(40) Demus, D.; Richter, L. Textures of Liquid Crystals, 2nd ed.; VEB:
Leipzig, 1980.
(41) Dierking, I. Textures of Liquid Crystals; Wiley-VCH: Weinheim,
2003.
(42) Gray, G. W.; Goodby, J. W. G. Smectic Liquid CrystalssTextures
and Structures; Leonard Hill: Philadelphia, 1984.
J. Org. Chem, Vol. 72, No. 9, 2007 3513

Zienkiewicz et al.
SCHEME 5a
a i: AgO, K2CO3, MeCN/toluene 1:1. ii: O2.
Benzothiazole 5 exhibited only an enantiotropic nematic
phase. It is a new member of a homologous series of benzothia-
zoles that exhibit nematic (lower homologues) and also SmA
phases.43
Generation of Radicals. Radicals 1 were generated from the
corresponding benzo[1,2,4]thiadiazines 2 using AgO in a MeCN/
toluene or MeCN/benzene mixture according to an earlier
established procedure23 (Scheme 5). The three fluorinated
radicals 1b-1d were significantly more stable than 1a. Their
solutions were filtered through a Florisil pad to remove the
inorganic salts, and solvents were removed from solutions of
1b and 1d under reduced pressure, leaving the black-green solid
of the crude radicals. Radical 1c appeared to be less stable than
the two other fluorinated derivatives and decomposed in solution
after filtration. Radical 1a persisted in solution for a few hours
but largely decomposed during the attempted filtration.
All three fluorinated radicals were moderately sensitive to
molecular oxygen, and their solutions were bleached in air over
several hours. In the case of radical 1b, the S-oxide 20b was
isolated as the main decomposition product, which is consistent
with the results for the parent radicals.23
FIGURE 4. ESR spectra for 1a (top) and 1d (bottom) recorded in
benzene at ambient temperature. The radicals were generated with AgO/
K2CO3.
TABLE 2. Experimental Isotropic hfcc (G) for Radicals 1a
1a
1b
1c
1d
aN2
5.82
5.04
1.12
0.76
0.70
0.41
0.34
0.76
5.91
4.87
1.88
1.42
1.64
0.24
0.23
0.44
5.86
4.92
1.90
1.44
1.63
0.22
0.12
0.40
5.83
4.90
1.94
1.38
1.74
0.13
0.05
0.30
aN4
aX5b
aX6b
aX8b
aH(Ph)c ortho
aH(Ph)c meta
aH(CH2)d
Electron Spin Resonance. The room temperature benzene
solution spectrum of radicals 1a consists of a pseudo-quintet
centered at about 3488 G, which arises from the principal coupl-
ing to the two nitrogen atoms and unresolved couplings to the
hydrogen atoms (Figure 4, top). The solution spectra of 1b-
1d have more features due to the presence of the fluorine atoms.
They appear similar to each other since the structural differences
are in the remote part of the molecule. Spectra of 1b and 1c
consist of 17 lines centered at about 3488 G, while the spectrum
of 1d exhibits several additional shoulder features (Figure 4,
bottom). The measured g value for all four radicals 1a-1d is
2.0057, which is practically the same as for the parent radicals.23
Simulations of the experimental spectra were performed using
computed and appropriately scaled23 hfcc values for two
nitrogen, hydrogen or fluorine atoms in positions 5, 6, and 8,
and also H atoms of the 3-phenyl substituent and the two
hydrogens of the CH2O group at the 7 position as the starting
point (see Supporting Information). The resulting hfcc were
structurally assigned on the basis of trends in the calculated
values (Table 2).
a Obtained from simulation of the experimental spectra recorded in
benzene solutions at ambient temperature (g ) 2.0057). The correlation
value r2 g 0.994. b X is H (1a) or F (1b-1d). c Average value for the two
hydrogen atoms. d Average value for two hydrogen atoms near the ring.
the spectrum of 1a (Figure 4, top). Interestingly, the fluorine
atoms decrease the spin density on the N(4) atom, and
consequently, the aN4 for the fluorinated radicals is lower by
about 0.15 G relative to that for 1a. In radical 1a, only one
hydrogen atom, H(5), has a significant hfcc of 1.6 G, and the
couplings to the remaining eight H atoms are e0.55 G. In
contrast, in radicals 1b-1d, there is a significant coupling to
all three 19F nuclei, and the aF is in the range of 1.4-2.0 G.
The aF value for F(6) is markedly larger (∼1.4 G) than that
predicted by theory (0.16 G), which is consistent with our
previous findings.23 The couplings to the remaining six H atoms
in 1b-1d are similar to those observed for radical 1a (aH
0.6 G), and they contribute to the line broadening.
e
Computational Analysis. To provide the initial guess for
the numerical simulation of the experimental ESR spectra,
hyperfine coupling constants were calculated for model com-
pounds 21 using the previously developed protocol.44 For the
purpose of calculations, the alkoxy groups in 1 were replaced
with a methoxy group, and the 4-pentylcyclohexyl in 1c was
substituted with the isopropyl group. A model for 1d was not
Results in Table 2 show that all four radicals exhibit two
similar couplings aN of about 6 and 5 G to the thiadiazinyl
nitrogen atoms N(2) and N(4), which give the basic quintet in
(43) Zhenrong, L.; Li, Y. Thermochim. Acta 1991, 178, 305-309.
3514 J. Org. Chem., Vol. 72, No. 9, 2007

Liquid Crystalline 4H-Benzo[1,2,4]thiadiazines
considered. The orientation of the substituents in 21 was set in
accordance with solid-state structures of compounds containing
the relevant molecular fragments. Thus, the methoxy group at
the 7 position of 21a was fixed coplanar with the heterocyclic
ring, and in 21b and 21c, it was initially set at about 60° to the
heterocycle plane, in accordance with over two dozen solid-
state structures featuring the 2,6-difluoroalkoxyphenyl frag-
ment.45 For all three compounds, two conformers were consid-
ered with the Me group syn and anti relative to the sulfur atom.
The MeO group on the phenyl substituent in 21a and 21b was
set to be coplanar, while the isopropyl group in 21c was
orthogonal to the benzene ring plane as it was found in the solid-
state structures of simple 4-isopropylphenyl derivatives.46 The
geometries of syn and anti conformers of 21a were optimized
at the Cs point group symmetry and for 21b and 21c without
symmetry constraints (C1 symmetry) at the B3LYP/6-31G(d)
level of theory. Results show that the 7-MeO group is oriented
at about 10° for the anti and about 30° for the syn conformer
relative to the heterocyclic ring in the equilibrium geometry of
21b and 21c. The 3-phenyl substituent remains coplanar with
the thiadiazinyl ring, which is consistent with the solid-state
structure for the parent radical I.23
FIGURE 5. Total spin density map calculated for 21a with the B3LYP/
cc-DVZ//B3LYP/6-31G(d) method and averaged for two conformers.
The numerals show the heterocycle numbering system.
The resulting hfcc values for pairs of conformers were
averaged for each nucleus and appropriately scaled.23 The values
for hydrogen atoms on the 3-phenyl ring were obtained as an
average of four hfcc (two ortho or two meta positions in two
conformers). The average aH values for the 7-MeO group were
calculated using two hydrogen atoms closest to the ring in each
conformer. These results served as starting points for the eight-
parameter fitting of experimental spectra, and numerical values
are listed in the Supporting Information.
Spin densities calculated for 21a are generally similar to those
obtained for the parent radical23 (Figure 5). The largest
differences are observed for the sulfur atom and carbon atoms
in positions 6, 7, and 8. The introduction of the MeO group to
the parent radical decreases the spin density on the sulfur and
C(7) atoms by 10 and 21%, respectively. At the same time, the
small negative spin density on C(6) becomes positive and that
on C(8) becomes more negative.
Discussion
Analysis of synthetic results reveals some limitations of the
methods previously used for the 3-phenyl substituted parent
heterocycles.28 The NCS-assisted ring closure worked well for
fluorinated thiadiazines 2b and 2d, but it proved to be
problematic for 2c and failed for 2a. The difficulties with
oxidative ring closure in 6c to form 2c presumably originate
from the presence of the benzylic-type position, which is
relatively reactive in free radical processes. Thus, higher
temperature and presumably light may promote chlorination of
the tertiary carbon in the phenylcyclohexane fragment by NCS
and N-chloro intermediates. The failure of the formation of 2a
was at first surprising since the parent amidine, which lacks
alkoxy substituents, was smoothly converted to the correspond-
ing 3-phenyl-4H-benzo[1,2,4]thiadiazine.28 Apparently, the pres-
ence of the hexyloxy substituent in 6a increases the reactivity
of the benzene ring toward electrophiles, and the oxidant attacks
it preferentially to the amidine NH2 group.
The high electron density of the benzene ring may also
explain the low yield of 2a obtained from sulfoxide 8a. In this
reaction, the formation of 2a is slow and apparently comparable
to the rate of its decomposition to benzothiazole 5. A similar
reaction of a pyrazine analogue of 8a proceeded significantly
faster and at lower temperatures, and no thiazole formation was
observed. This difference in reactivity can be attributed to the
dissimilarity in the electron density of the benzene and pyrazine
rings in the two compounds. According to our postulate,28 the
first and also the rate-determining step in this process is the
elimination of propene from the sulfoxide and the formation of
sulfenic acid, which subsequently undergoes intramolecular
condensation with the amidinyl NH2 group to close the
thiadiazine ring (Scheme 6). Thus, it appears that 8a forms
sulfenic acid 22a at a slower rate than the pyrazine analogue
Single-point calculations at the B3LYP/cc-pVDZ level of
theory gave the spin densities and Fermi contacts for each
conformer. Inspection of the calculated coupling constants
demonstrated that the orientation of the MeO group in the 7
position has an effect on all nuclei in the ring, but as expected,
the most profound effect is on the methylene group and the
atoms (H in 21a and F in 21b and 21c) in the ortho positions.
In the syn conformers, the two H atoms of the OMe group have
approximately twice as large aH values than in the anti
conformers. This results from a balance of through bond and
through space spin polarization induced by atoms X(6) and X(8)
with spin densities of opposite signs. The X(6) and X(8) atoms
are little affected (e0.7 MHz) by the orientation of the OMe
group. In contrast, the aX5 value varies significantly between
the two conformers, and for 21a, the difference between the
syn and the anti form is 1.3 MHz, while for 21b, it is 2.5 MHz.
The aN2 value is also affected by conformational differences
but to a smaller extent. The aN2 value is smaller in the syn
conformer by 0.8 MHz for 21a and by 0.5 MHz for the
fluorinated radicals.
(44) Kaszynski, P. J. Phys. Chem. A 2001, 105, 7615-7625.
(45) For example: Smith, C. E.; Smith, P. S.; Thomas, R. L.; Robins,
E. G.; Collings, J. C.; Dai, C.; Scott, A. J.; Borwick, S.; Batsanov, A. S.;
Watt, S. W.; Clark, S. J.; Viney, C.; Howard, J. A. K.; Clegg, W.; Marder,
T. B. J. Mater. Chem. 2004, 14, 413-420.
(46) (a) For example: Kravers, M. A.; Antipin, M. Y.; Struchkov, Y. T.
Cryst. Struct. Commun. 1979, 8, 455-456. (b) Wo´jcik, G.; Holband, J.
Acta Crystallogr., Sect. B 2002, B58, 684-689. (c) Emsley, J.; Ma, L. Y.
Y.; Bates, P. A.; Motevalli, M.; Hursthouse, M. B. J. Chem. Soc., Perkin
Trans 2 1989, 527-533.
J. Org. Chem, Vol. 72, No. 9, 2007 3515

Zienkiewicz et al.
SCHEME 6a
TABLE 3. Homolytic Bond Dissociation Enthalpy for Selected
Compounds
a i: Heat, -C3H6. ii: -H2O.
does. This is consistent with results of previous studies for a
series of para substituted phenyl propyl sulfoxides,47 which
demonstrated higher activation energies for the formation of
sulfenic acid from substrates having electron donating groups
relative to those with electron withdrawing substituents. Thus,
for 4-methoxyphenyl propyl sulfoxide, ∆Hq is 2.4 kcal/mol
higher than for the 4-nitro analogue, which translates to a nearly
4-fold difference in reaction rates.47
Overall, the present methods appear to be too harsh for the
formation of electron-rich benzo[1,2,4]thiadiazines (such as 2a),
and careful control of reaction conditions must be used for
substrates with groups susceptible to free radical processes (such
as 2c). The strongly basic or acidic conditions used for the
formation of amidines 6 impose further restrictions on the type
and variety of functional groups that can be introduced with
this synthetic protocol.
a Calculated as ∆H for the reaction at the B3LYP/6-311+G(2d,2p)//
B3LYP/6-31G(d) level of theory with B3LYP/6-31G(d) thermodynamic
corrections. b Ref 52. c Ref 53.
the presence of a very long alkyl chain induces a monotropic
mesophase.51
The three-ring thiadiazines 2a and 2b do not form meso-
phases, although it is possible that longer alkyl chains may
induce liquid crystalline behavior. In contrast, relatively wide-
range enantiotropic SmA phases were observed for the four-
ring derivatives 2c and 2d above 90 °C. As expected from
general trends in mesogenic compounds,48 the transition tem-
peratures for the biphenyl derivative 2d are significantly higher
(by ∼50 °C) than those for the less rigid cyclohexyl derivative
2c. Similarly, high transition temperatures can be expected for
radicals 1c and 1d, which is unfavorable for their stability and
future magnetic investigation. Therefore, other substituents
should be considered to induce a mesophase with the clearing
temperature below 110 °C.
The finding that amidine 3 exhibits liquid crystalline behavior
was unexpected and deserves comment. A comparison of 3,
the first mesogenic benzamidine,48 to its Schiff base and ester
analogues demonstrates the importance of intermolecular hy-
drogen bonding between the amidinyl groups in the stabilization
of lamellar phases. The Schiff base and ester show only nematic
phases with TNI of 11949 and 91.5 °C,50 respectively. In contrast,
the amidine exhibits three smectic polymorphs with a clearing
temperature TSI of 136 °C. Interestingly, the analogous N-
phenylbenzamides appear to be much less mesogenic, and only
The qualitative stability of the radicals follows the order 1b
∼ 1d > 1c . 1a. The observed difference in stability of 1a
versus its fluorinated analogue 1b is consistent with our previous
findings for the parent radicals and demonstrates again the
significant stabilization effect of the fluorine atoms.23
The initial choice of the cyclohexyl substitutent in 1c was
driven by a desire to obtain low transition temperatures and
was based on general structure-property relationships in liquid
crystals.48 While this was accomplished, the presence of the
cyclohexyl group appears to compromise the radical stability.
For example, 1c decays faster than the two other fluorinated
radicals 1b and 1d, presumably via hydrogen abstraction from
the benzylic position. To assess the H donor ability of 1c,
homolytic bond dissociation enthalpies (HBDE) were calculated
for model compounds. Results collected in Table 3 show that
the benzo[1,2,4]thiadiazinyl radical I is more stable by about
12 kcal/mol than the 1-phenylcyclohexyl relative to their R-H
precursors, and consequently, the H donation by the benzyl
group to the thiadiazinyl is not favorable. It is, however, more
favorable by 8.5 kcal/mol than the H donation by the alkoxy
group. In both cases, the abstraction leads to irreversible
transformations, which result in slow decay of the thiadiazinyl.
(47) Emerson, D. W.; Korniski, T. J. J. Org. Chem. 1969, 34, 4115-
4118.
(48) Vill, V. LiqCryst 4.6; LCI Gmbh: Hamburg, 2004 and references
therein.
(49) van der Veen, J.; Grobben, A. H. Mol. Cryst. Liq. Cryst. 1971, 15,
239-245.
The calculations reproduced well the experimental energies
for aniline52 and phenylcyclohexane,53 lending credance to the
results for the parent 5,6,7,8-tetrafluoro-3-phenyl-4H-benzo-
[1,2,4]thiadiazine (I-H). Aniline is a close model for benzo-
(50) Steinstra¨sser, R. Z. Naturforsch. B 1972, 27, 774-779.
(51) (a) Mori, A.; Uno, K.; Kubo, K.; Kato, N.; Takeshita, H.; Hirayama,
K.; Ujiie, S. Liq. Cryst. 2004, 31, 285-294. (b) Mori, A.; Hirayama, K.;
Kato, N.; Takeshita, H.; Ujiie, S. Chem. Lett. 1997, 509-510.
(52) McMillen, D. F.; Golden, D. M. Ann. ReV. Phys. Chem. 1982, 33,
493-532.
(53) Denisov, E. T. Russ. J. Phys. Chem. 1993, 67, 2178-2183.
3516 J. Org. Chem., Vol. 72, No. 9, 2007

Liquid Crystalline 4H-Benzo[1,2,4]thiadiazines
added at -20 °C. The mixture was stirred at ambient temperature
for 1 h, washed with 5% aqueous NaOH, and dried (Na2SO4). The
solvent was evaporated, and the semicrystalline residue (525 mg)
was crystallized (EtOH, -5 °C) to give 140 mg of starting amidine
3. The filtrate was concentrated and dried under vacuum to give
380 mg of a brown oil, which was dissolved in dry PhCl (5 mL).
The solution was gently refluxed for 4 h under N2, and the solvent
was removed. The viscous residue was dissolved in CH2Cl2 and
passed through a silica gel plug. The resulting yellow solution was
evaporated, and the solid was separated by column chromatography
(SiO2, hexane/CH2Cl2, 1:1). The crude product was recrystallized
(hexanes) to give 20 mg (5% yield) of thiadiazine 2a as yellow
crystals. The second fraction contained benzothiazole 5.
Method B. A solution of sulfoxide 8a (166 mg, 0.362 mmol) in
dry PhCl was refluxed for 16 h, and the solvent was evaporated.
The resulting brown residue was separated by column chromatog-
raphy (SiO2, hexane/CH2Cl2, 1:1), and a yellow fraction containing
2a and benzothiazole 5 was collected. Unreacted sulfoxide 8a (81
mg, 48% yield) was eluted with AcOEt and recrystallized from
AcOEt/hexane. Product 2a was purified by PTLC (hexane/CH2-
Cl2, 3:2, multiple times reversed to separate the fluorescent benzo-
thiazole 5) and recrystallized (Et2O/heptane) to give 17 mg (12%
yield or 24% yield based on consumed 8a) of thiadiazine 2a as
fine yellow crystals: mp 131-132 °C; 1H NMR δ 0.90 (t, J ) 6.7
Hz, 3H), 0.98 (t, J ) 7.4 Hz, 3H), 1.20-1.42 (m, 6H), 1.49 (sextet,
J ) 7.5 Hz, 2H), 1.65-1.82 (m, 4H), 3.84 (t, J ) 6.6 Hz, 2H),
3.97 (t, J ) 6.5 Hz, 2H), 6.33 (d, J ) 2.5 Hz, 1H), 6.36 (d, J ) 8.5
Hz, 1H), 6.47 (dd, J1 ) 8.5 Hz, J2 ) 2.5 Hz, 1H), 6.6 (bs, 1H),
6.87 (d, J ) 8.8 Hz, 2H), 7.56 (d, J ) 8.8 Hz, 2H); 13C NMR δ
13.8, 14.0, 19.2, 22.6, 25.6, 29.1, 31.1, 31.5, 67.8, 68.5, 109.3,
112.7, 114.4, 114.7, 122.6, 126.3, 127.5, 129.6, 156.9, 157.0, 161.2;
IR (KBr) νmax 3362, 1607, 1513, 1467; FAB-HRMS: Calcd for
C23H30N2O2S m/z: 398.2028; found: 398.2029. Anal. Calcd. for
C23H30N2O2S: C, 69.31; H, 7.59; N, 7.03. Found: C, 69.09; H,
7.63; N, 7.02.
[1,2,4]thiadiazines since both compounds form N-centered
radicals with significant delocalization onto the adjacent benzene
ring. Previously reported values for radicals were based on a
reaction with MeO•, but this model was inadequate. The results
in Table 3 suggest that the previously reported HBDE values24
for I-H and other radicals are overestimated by about 7.5 kcal/
mol, and the recalculated values are listed in the Supporting
Information.
Conclusion
The facile preparation of three substituted 5,6,8-trifluoro-4H-
benzo[1,2,4]thiadiazines 2b-2d indicates straightforward access
to other such derivatives from amine 10, the common precursor,
in an acid-promoted condensation with benzonitriles, followed
by oxidative cyclization. Results of thermal analysis of 2a-2d
provide the starting point for further manipulation with the
substituents in 2 to control the transition temperatures and the
phase structure. The availability of the 4H-benzo[1,2,4]-
thiadiazines 2 opened access to potentially liquid crystalline
radicals 1. Preliminary experiments demonstrated that some
radicals 1 can be efficiently generated from 2 and presumably
purified in a strictly anerobic atmosphere. Future studies will
focus on 1d, which appears to be particularly stable and likely
mesogenic since 2d exhibits a liquid crystalline phase. It is
desirable, however, to lower transition temperatures through
manipulation with the alkoxy substituents.
Experimental Section
4-(E-4-Pentylcyclohexyl)benzonitrile54 (12) and 4′-pentyloxy-4-
biphenylcarbonitrile55 (13) were obtained commercially. 4-Butoxy-
benzonitrile56 (11) was prepared by alkylation of 4-hydroxyben-
zonitrile in the presence of K2CO3 in MeCN.
3-(4-Butoxyphenyl)-5,6,8-trifluoro-7-hexyloxy-4H-benzo[1,2,4]-
thiadiazine (2b). A solution of NCS (326 mg, 2.4 mmol) in CH2-
Cl2 (5 mL) was added dropwise to a stirred solution of amidine 6b
(1.190 g, 2.4 mmol) in CH2Cl2 (10 mL) at -78 °C. The mixture
was slowly warmed up and stirred for 12 h at ambient temperature.
The mixture was washed with 5% aqueous NaOH; the organic layer
was separated, washed with water, and dried (MgSO4); and the
solvent was evaporated. The resulting crude ylide 7b (1.04 g) was
dissolved in dry toluene, and the solution was stirred at reflux for
24 h. The solvent was removed under reduced pressure. The
resulting residue was dissolved in CH2Cl2 and passed through a
silica gel plug. The crude product was purified by column
chromatography (SiO2; hexane/CH2Cl2, 1:1) followed by recrys-
tallization (hexane) to give 462 mg (43% yield) of pure thiadiazine
Generation of Radicals 1. Benzo[1,2,4]thiadiazine 2 (0.1 mmol)
was dissolved in dry toluene (3 mL), and dry MeCN (3 mL) was
added. Solid AgO57 (125 mg, 1 mmol) and K2CO3 (138 mg, 1
mmol) were added, and the mixture was vigorously stirred at
ambient temperature for 90 s under Ar. The resulting black-green
reaction mixture was diluted with toluene and filtered through a
short jacketed column (5 cm of Florisil and 0.5 cm of silica) at
0 °C. Solvents were removed under reduced pressure (∼1 Torr) at
temperatures below 0 °C, leaving a black-green solid of the crude
radical.
3-(4-Butoxyphenyl)-7-hexyloxy-4H-benzo[1,2,4]thiadiazine (2a).
Method A. A solution of NCS (134 mg, 1.0 mmol) in dry CH2Cl2
(2 mL) was added to a solution of dimorpholine sulfide58 (204 mg,
1.0 mmol) in dry CH2Cl2 (4 mL) at -20 °C. After 1 h, a solution
of amidine 3 (368 mg, 1.0 mmol) in CH2Cl2 (6 mL) was slowly
1
2b as a yellow solid: mp 95 °C; H NMR δ 0.90 (t, J ) 6.7 Hz,
3H), 0.98 (t, J ) 7.4 Hz, 3H), 1.29-1.36 (m, 4H), 1.44-1.56 (m,
4H), 1.70-1.81 (m, 4H), 4.00 (t, J ) 6.6 Hz, 2H), 4.04 (t, J ) 6.7
Hz, 2H), 6.6 (brs, 1H), 6.91 (d, J ) 8.8 Hz, 2H), 7.57 (d, J ) 8.8
Hz, 2H); 19F NMR δ -163.8 (dd, J1 ) 20.9 Hz, J2 ) 9.9 Hz, 1F),
-153.4 (dd, J1 ) 20.9 Hz, J2 ) 2.2 Hz, 1F), -134.1 (dd, J1 ) 9.9
Hz, J2 ) 2.2 Hz, 1F); IR (KBr) νmax 3198, 1590, 1437 cm-1. Anal.
Calcd. for C23H27F3N2O2S: C, 61.04; H, 6.01; N, 6.19. Found: C,
60.77; H, 5.93; N, 6.10.
(54) 4-(E-4-Pentylcyclohexyl)benzonitrile (12): 1H NMR δ 0.89 (t, J
) 6.9 Hz, 3H), 0.99-1.12 (m, 2H), 1.20-1.37 (m, 9H), 1.38-1.50 (m,
2H), 1.88 (brd, J ) 11.3 Hz, 4H), 2.52 (tt, J1 ) 12.2 Hz, J2 ) 3.0 Hz, 1H),
7.29 (d, J ) 8.3 Hz, 2H), 7.57 (d, J ) 8.1 Hz, 2H).
(55) 4′-Pentyloxy-4-biphenylcarbonitrile (13): 1H NMR δ 0.93 (t, J )
7.1 Hz, 3H), 1.35-1.50 (m, 4H), 1.78 (quint, J ) 7.0 Hz, 2H), 3.98 (t, J
) 6.6 Hz, 2H), 6.98 (d, J ) 8.7 Hz, 2H), 7.53 (d, J ) 8.7 Hz, 2H), 7.64
(d, J ) 8.4 Hz, 2H), 7.67 (d, J ) 8.4 Hz, 2H).
5,6,8-Trifluoro-7-hexyloxy-3-(4-(E-4-pentylcyclohexylphenyl)-
4H-benzo[1,2,4]thiadiazine (2c). Benzo[1,2,4]thiadiazine 2c was
prepared as described for 2b. The crude product was purified by
flash chromatography (SiO2; hexane/CH2Cl2, 4:1) and crystallization
(hexanes) to give yellow crystals of 2c in 34% yield: mp 98 °C;
1H NMR δ 0.89 (t, J ) 7.0 Hz, 3H), 0.90 (t, J ) 7.0 Hz, 3H),
0.98-1.12 (m, 2H), 1.15-1.39 (m, 13H), 1.40-1.52 (m, 4H), 1.72
(quintet, J ) 7.0 Hz, 2H), 1.87 (brd, J ) 11.3 Hz, 4H), 2.51 (bt,
J ) 12.0 Hz, 1H), 4.04 (t, J ) 6.6 Hz, 2H), 6.6 (brs, 1H), 7.27 (d,
J ) 8.3 Hz, 2H), 7.55 (d, J ) 8.3 Hz, 2H); 19F NMR δ -163.8
(dd, J1 ) 20.6 Hz, J2 ) 10.2 Hz, 1F), -153.4 (dd, J1 ) 20.6 Hz,
(56) 4-Butoxybenzonitrile (11): 1H NMR δ 0.97 (t, J ) 7.4 Hz, 3H),
1.48 (sextet, J ) 7.6 Hz, 2H), 1.78 (quintet, J ) 7.0 Hz, 2H), 3.99 (t, J )
6.5 Hz, 2H), 6.92 (d, J ) 8.9 Hz, 2H), 7.56 (d, J ) 8.8 Hz, 2H). (a) Marquet,
J.; Cayo´n, E.; Martin, X.; Casado, F.; Gallardo, I.; Moreno, M.; Lluch, J.
M. J. Org. Chem. 1995, 60, 3814-3825. (b) Partridge, M. W. J. Chem.
Soc. 1949, 3043-3046.
(57) Hammer, R. N.; Kleinberg, J.; Holtzclaw, H. F., Jr.; Johnson, K.
W. R. Inorg. Synth. 1953, 4, 12-14.
(58) The sulfide was prepared in 77% yield according to a literature
procedure: 1H NMR δ 3.28 (t, J ) 4.7 Hz, 8H), 3.64 (t, J ) 4.7 Hz, 8H);
13C NMR δ 57.7, 67.8. Blake, E. S. J. Am. Chem. Soc. 1943, 65, 1267-
1269.
J. Org. Chem, Vol. 72, No. 9, 2007 3517

Zienkiewicz et al.
J2 ) 2.5 Hz, 1F), -134.2 (dd, J1 ) 9.9 Hz, J2 ) 2.5 Hz, 1F); IR
(KBr) νmax 3335, 3133, 1443 cm-1. Anal. Calcd. for C30H39F3N2-
OS: C, 67.64; H, 7.38; N, 5.26. Found: C, 67.26; H, 7.30; N,
5.26.
in 43% yield after crystallization from an AcOEt/hexane mixture:
mp 150-152 °C; 1H NMR δ 0.91 (t, J ) 7.3 Hz, 3H), 0.96 (t, J )
7.3 Hz, 3H), 1.01 (t, J ) 7.3 Hz, 3H), 1.21-1.41 (m, 4H), 1.42-
1.86 (m, 10H), 2.85 (t, J ) 7.2 Hz, 2H), 3.80-3.94 (m, 4H), 6.66-
7.10 (m, 6H), 7.30-7.78 (m, 2H), 8.3 (bs, 1H).
5,6,8-Trifluoro-7-hexyloxy-3-(4′-penyloxybiphenyl-4-yl)-4H-
benzo[1,2,4]thiadiazine (2d). Benzo[1,2,4]thiadiazine 2d was
prepared as described for 2b. The crude product was purified by
flash chromatography (SiO2, CH2Cl2) and crystallization (MeCN/
toluene) to give yellow-orange crystals of 2d in 30% yield: mp
143-144 °C; 1H NMR δ 0.90 (t, J ) 6.9 Hz, 3H), 0.94 (t, J ) 6.9
Hz, 3H), 1.29-1.50 (m, 10H), 1.73 (quintet, J ) 7.1 Hz, 2H), 1.82
(quintet, J ) 7.1 Hz, 2H), 4.00 (t, J ) 6.7 Hz, 2H), 4.05 (t, J )
6.7 Hz, 2H), 6.6 (brs, 1H), 6.98 (d, J ) 8.8 Hz, 2H), 7.54 (d, J )
8.8 Hz, 2H), 7.61 (d, J ) 8.6 Hz, 2H), 7.68 (d, J ) 8.6 Hz, 2H);
19F NMR δ -164.2 (dd, J1 ) 20.5 Hz, J2 ) 10.2 Hz, 1F), -153.8
(d, J ) 20.6 Hz, 1F), -134.6 (d, J ) 9.6 Hz,1F); IR (film) νmax
3335, 1442 cm-1. Anal. Calcd. for C30H33F3N2O2S: C, 66.40; H,
6.13; N, 5.16. Found: C, 66.33; H, 6.18; N, 5.11.
4-Butoxy-N-(2,3,5-trifluoro-4-hexyloxy-6-(propylsulfanyl)phe-
nyl)benzamidine (6b). Methanesulfonic acid (550 mg, 5.71 mmol)
was added in one portion to a stirred solution of aniline 10 (355
mg, 1.11 mmol, 83% isomerically pure) and nitrile 11 (970 mg,
5.50 mmol) at 150 °C. The stirring was continued for 30 min. The
mixture was cooled and neutralized with sat. NaHCO3 (50 mL),
and organic materials were extracted with Et2O (3×). The combined
extracts were washed with water, dried (Na2SO4), and passed
through a silica gel plug. Crude product was recrystallized (hexane)
to give 271 mg (50% yield) of isomerically pure amidine 6b as
1
white crystals: mp 91-93 °C; H NMR δ 0.91 (t, J ) 7.0 Hz,
3H), 0.95 (t, J ) 7.3 Hz, 3H), 0.99 (t, J ) 7.3 Hz, 3H), 1.29-1.36
(m, 4H), 1.44-1.55 (m, 6H), 1.71-1.83 (m, 4H), 2.80 (t, J ) 7.2
Hz, 2H), 4.02 (t, J ) 6.4 Hz, 2H), 4.12 (t, J ) 6.5 Hz, 2H), 4.75
(brs, 2H), 6.96 (t, J ) 8.7 Hz, 2H), 7.87 (t, J ) 8.6 Hz, 2H); 19F
NMR δ -150.9 (dd, J1 ) 21.9 Hz, J2 ) 10.9 Hz, 1F), -149.9 (dd,
J1 ) 21.9 Hz, J2 ) 5.5 Hz, 1F), -124.9 (dd, J1 ) 10.9 Hz, J2 )
5.5 Hz, 1F); IR (KBr) νmax 3444 and 3123 (NH2), 1640, 1601, 1446,
1403, 1253 cm-1. Anal. Calcd. for C26H35F3N2O2S: C, 62.88; H,
7.10; N, 5.64. Found: C, 63.00; H, 7.23; N, 5.60.
4-Butoxy-N-(4-hexyloxyphenyl)benzamidine (3). A mixture of
4-hexyloxyaniline (3.68 g, 20 mmol), nitrile 1156 (3.50 g, 20 mmol),
dry benzene (20 mL), and 60% NaH (0.90 g, 22 mmol) was refluxed
for 2 days. The resulting viscous mixture was poured into diluted
HCl, and organic products were extracted (CH2Cl2). The organic
layer was washed with sat. NaHCO3 and dried (Na2SO4). The
solvent was evaporated, and the residue was recrystallized (isooc-
tane/toluene) to give 6.00 g (82% yield) of amidine 3 as an off-
N-(2,3,5-Trifluoro-4-hexyloxy-6-(propylsulfanyl)phenyl)-4-
(4E-pentylcyclohexyl)benzamidine (6c). Benzamidine 6c was
obtained in 66% yield from amine 10 and nitrile 1254 according to
the procedure described for 6b. Chromatographic separation
recovered excess nitrile in 60% (SiO2; hexane/CH2Cl2, 4:1) and
gave amidine 6c (hexane/CH2Cl2, 3:2). Using 2 equiv of 12 and
2.5 equiv of MeSO3H, amidine 6c was isolated in 76% yield.
Analytical sample of isomerically pure 6c was obtained by
recrystallization from isooctane: mp 111 °C; 1H NMR δ 0.90 (t, J
) 6.9 Hz, 3H), 0.92 (t, J ) 7.2 Hz, 3H), 0.95 (t, J ) 7.3 Hz, 3H),
1.00-1.12 (m, 2H), 1.18-1.39 (m, 11H), 1.40-1.65 (m, 8H), 1.77
(quintet, J ) 7.0 Hz, 2H), 1.89 (brd, J ) 9.9 Hz, 4H), 2.53 (bt, J
) 12.0 Hz, 1H), 2.81 (t, J ) 7.2 Hz, 2H), 4.11 (t, J ) 7.2 Hz, 2H),
4.8 (brs, 2H), 7.29 (d, J ) 8.1 Hz, 2H), 7.84 (d, J ) 8.1 Hz, 2H);19F
NMR δ -150.9 (dd, J1 ) 21.9 Hz, J2 ) 10.8 Hz, 1F), -149.8 (dd,
J1 ) 21.9 Hz, J2 ) 5.5 Hz, 1F), -124.9 (dd, J1 ) 10.9 Hz, J2 )
1
white solid: mp 132-133 °C; H NMR δ 0.91 (t, J ) 7.0 Hz,
3H), 0.98 (t, J ) 7.4 Hz, 3H), 1.30-1.39 (m, 4H), 1.42-1.57 (m,
4H), 1.78 (quintet, J ) 7.0 Hz, 2H), 1.79 (quintet, J ) 7.0 Hz,
2H), 3.94 (t, J ) 6.6 Hz, 2H), 4.00 (t, J ) 6.5 Hz, 2H), 4.8 (bs,
2H), 6.80-6.95 (m, 6H), 7.80 (d, J ) 7.9 Hz, 2H); 13C NMR δ
13.8, 14.0, 19.2, 22.6, 25.8, 29.4, 31.2, 31.6, 67.8, 68.3, 114.2-
(2C), 115.5, 122.5, 128.1, 142.8, 154.6, 155.0, 161.0; IR (KBr)
νmax 1636, 1607, 1565, 1514, 1466, 1388, 1253, 1209. Anal. Calcd
for C23H32N2O2; C, 74.96; H, 8.75; N, 7.60. Found: C, 74.85; H,
8.74; N, 7.57.
3-(4-Butoxyphenyl)-7-hexyloxybenzothiazole (5). Compound
5 was isolated as a less polar fraction (blue fluorescence on TLC)
in chromatographic separation of 2a. Colorless crystals (isooc-
tane): mp 98-99 °C; 1H NMR δ 0.92 (t, J ) 6.6 Hz, 3H), 0.99 (t,
J ) 7.4 Hz, 3H), 1.30-1.42 (m, 4H), 1.45-1.57 (m, 4H), 1.76-
1.87 (m, 4H), 4.02 (t, J ) 6.6 Hz, 2H), 4.03 (t, J ) 6.5 Hz, 2H),
6.97 (d, J ) 8.9 Hz, 2H), 7.06 (dd, J1 ) 8.9 Hz, J2 ) 2.5 Hz, 1H),
7.32 (d, J ) 2.5 Hz, 1H), 7.89 (d, J ) 8.1 Hz, 1H), 7.95 (d, J )
8.8 Hz, 2H); 13C NMR (C6D6) δ 14.4, 14.7, 19.9, 23.4, 26.5, 30.0,
31.9, 32.4, 68.2, 69.0, 105.7, 115.6, 116.7, 124.5, 129.6, 137.3,
150.2, 153.2, 158.1, 162.0, 165.6; IR (KBr) νmax 1606, 1453, 1254
cm-1. Anal. Calcd. for C23H29NO2S: C, 72.02; H, 7.62; N, 3.65.
Found: C, 71.95; H, 7.70; N, 3.65.
5.5 Hz, 1F); IR (KBr) νmax 3413 and 3174 (NH2), 1642, 1398 cm-1
;
FAB-MS m/z: 577 ([M + H]+, 68%), 257 (100%); FAB-HRMS:
Calcd for C33H48F3N2OS ([M + H]+) m/z: 577.3439; Found:
577.3439. Anal. Calcd for C33H47F3N2OS: C, 68.72; H, 8.21; N,
4.86. Found: C, 68.05; H, 8.15; N, 4.78.
N-(2,3,5-Trifluoro-4-hexyloxy-6-(propylsulfanyl)phenyl)-4-(4-
pentyloxyphenyl)benzamidine (6d). Benzamidine 6d was obtained
in 46% yield from amine 10 (0.79 g, 2.45 mmol) and nitrile 1355
(1.30 g, 4.9 mmol) in the presence of MeSO3H (0.47 g, 4.9 mmol)
as described for 6b. Chromatographic separation on a silica gel
plug recovered excess nitrile 13 (3.2 mmol; SiO2, hexane/CH2Cl2,
2:1 eluent) as the first fraction, followed by amidine 6d (0.78 g;
CH2Cl2 eluent). The product was crystallized (hexane/toluene) and
recrystallized (isooctane) to give 0.66 g (46% yield) of 6d as a
4-Butoxy-N-(4-hexyloxy-2-(propylsulfanyl)phenyl)benzami-
dine (6a). Amidine 6a was obtained in 50-60% yield from amine
9 and nitrile 1156 as described for 3 using either benzene or THF
as the solvent. The oily crude product was crystallized (hexanes)
and recrystallized (isooctane) to give amidine 6a as a white solid:
1
mp 76-77 °C; H NMR δ 0.91 (t, J ) 6.8 Hz, 3H), 0.98 (t, J )
1
7.4 Hz, 3H), 1.02 (t, J ) 7.3 Hz, 3H), 1.28-1.45 (m, 4H), 1.46-
1.56 (m, 4H), 1.65-1.82 (m, 6H), 2.85 (t, J ) 7.4 Hz, 2H), 3.94
(t, J ) 6.6 Hz, 2H), 4.00 (t, J ) 6.5 Hz, 2H), 4.7 (bs, 2H), 6.68
(dd, J1 ) 8.4 Hz, J2 ) 2.1 Hz, 1H), 6.80 (d, J ) 8.4 Hz, 1H), 6.85
(d, J ) 2.2 Hz, 1H), 6.92 (d, J ) 8.8 Hz, 2H), 7.86 (d, J ) 8.4 Hz,
2H); 13C NMR δ 13.7, 13.8, 14.0, 19.2, 22.2, 22.6, 25.7, 29.3, 31.2,
31.6, 33.8, 67.8, 68.3, 111.4, 114.2, 121.8, 127.8, 128.3, 129.2,
129.9, 140.5, 154.6, 155.3, 161.0; IR (KBr) νmax 3500, 3436, and
3349 (NH2), 1636, 1607, 1466, 1253. Anal. Calcd. for C26H38N2O2S;
C, 70.55; H, 8.65; N, 6.33. Found: C, 70.37; H, 8.64; N, 6.30.
4-Butoxy-N-(4-hexyloxy-2-(propylsulfanyl)phenyl)benzami-
dine Hydrochloride (6a‚HCl). Acidic workup of a condensation
reaction of amine 9 with nitrile 11 with dil HCl and without washing
with sat. NaHCO3 solution gave hydrochloride of benzamidine 6a
grayish solid: mp 115-116 °C; H NMR δ 0.91 (t, J ) 6.9 Hz,
3H), 0.95 (t, J ) 7.2 Hz, 3H), 0.97 (t, J ) 7.2 Hz, 3H), 1.39-1.55
(m, 12H), 1.78 (quintet, J ) 7.3 Hz, 2H), 1.82 (quintet, J ) 7.0
Hz, 2H), 2.82 (t, J ) 7.2 Hz, 2H), 4.01 (t, J ) 6.6 Hz, 2H), 4.12
(t, J ) 6.6 Hz, 2H), 4.8 (brs, 2H), 6.99 (d, J ) 8.6 Hz, 2H), 7.57
(d, J ) 8.1 Hz, 2H), 7.66 (d, J ) 8.3 Hz, 2H), 7.98 (d, J ) 8.3 Hz,
2H); IR (film) νmax 3480 and 3396 (NH2), 1633, 1605, 1450 cm-1
.
Anal. Calcd for C33H41F3N2O2S: C, 67.55; H, 7.04; N, 4.77.
Found: C, 67.63; H, 7.02; N, 4.73.
4-Butoxy-N-(4-hexyloxy-2-(propylsulfinyl)phenyl)benzami-
dine (8a). Sodium periodate (290 mg, 1.36 mmol) was added to a
solution of amidine 6a (298 mg, 0.674 mmol) in MeOH (25 mL)
and water (0.5 mL) at 0 °C. The mixture was stirred overnight at
rt, diluted with water, extracted with CH2Cl2, and washed with sat.
3518 J. Org. Chem., Vol. 72, No. 9, 2007

Liquid Crystalline 4H-Benzo[1,2,4]thiadiazines
NaHCO3 solution. Combined organic layers were dried (MgSO4),
and the solvent was evaporated to give the crude product as a light
brown solid (100%). Crystallization (AcOEt/hexane) followed by
recrystallization (MeCN) gave 210 mg (68% yield) of sulfoxide
8a as white crystals: mp 163-164 °C; 1H NMR δ 0.91 (t, J ) 6.8
Hz, 3H), 0.99 (t, J ) 7.4 Hz, 3H), 1.00 (t, J ) 7.4 Hz, 3H), 1.31-
1.36 (m, 4H), 1.41-1.55 (m, 4H), 1.57 (s, 2H), 1.74-1.95 (m,
6H), 2.79 (ddd, J1 ) 13.1 Hz, J2 ) 8.9 Hz, J3 ) 5.1 Hz, 1H), 3.08
(ddd, J1 ) 13.1 Hz, J2 ) 9.1 Hz, J3 ) 7.1 Hz, 1H), 4.02 (t, J ) 6.5
Hz, 4H), 5.0 (bs, 2H), 6.88 (d, J ) 8.5 Hz, 1H), 6.95 (d, J ) 8.8
Hz, 2H), 6.99 (dd, J1 ) 8.6 Hz, J2 = 2.8 Hz, 1H), 7.44 (d, J ) 2.8
Hz, 1H), 7.77 (d, J ) 8.8 Hz, 2H); 13C NMR δ 13.2, 13.8, 14.0,
15.8, 19.2, 22.6, 25.7, 29.2, 31.2, 31.6, 55.6, 67.9, 68.6, 109.4,
114.4, 118.9, 122.5, 126.9, 128.1, 136.5, 138.7, 154.8, 156.1, 161.5;
IR (KBr) νmax 3418 and 3220 (NH2), 1630, 1610, 1251 cm-1. Anal.
Calcd. for C26H38N2O3S: C, 68.09; H, 8.35; N, 6.11. Calcd. for
C26H38N2O3S‚H2O: C, 65.51; H, 8.46; N, 5.88. Found: C, 65.59;
H, 8.12; N, 5.92.
mmol), and Bu4NBr (1.0 g, 3.0 mmol) was vigorously stirred at
ambient temperature for 45 min. The organic layer was separated,
and the aqueous phase was extracted with hexanes. Combined
organic layers were dried (MgSO4), and the solvent was evaporated.
The residue (25.0 g) was recrystallized (EtOH) to give 13.3 g of
product 16 (60% yield) as yellow crystals: mp 76-77 °C (lit.34
74.5-75 °C); 1H NMR δ 1.11 (t, J ) 7.4 Hz, 3H), 1.78 (sextet, J
) 7.3 Hz, 2H), 2.92 (t, J ) 7.1 Hz, 2H), 7.17 (dd, J1 ) 8.8 Hz, J2
) 2.1 Hz, 1H), 7.32 (d, J ) 2.1 Hz, 1H), 8.15 (d, J ) 8.9 Hz, 1H);
13C NMR δ 13.7, 21.0, 34.4, 124.3, 125.9, 127.4, 140.3, 140.8,
144.0; IR (KBr) νmax 1592, 1555, 1507, 1335, 1302, 1121; MS m/z
231 (M+, 20), 125 (100). Anal. Calcd. for C9H10ClNO2S; C, 46.65;
H, 4.35; N, 6.05. Found C, 46.94; H, 4.38; N, 5.96.
4-Hexyloxy-1-nitro-2-(propylsulfanyl)benzene (17). Nitro com-
pound 16 (2.02 g, 8.7 mmol) was added to a suspension of
powdered KOH (0.85 g, 15.1 mmol) in DMSO (3 mL) and
n-hexanol (0.92 g, 9.0 mmol). The mixture was stirred at 75 °C
for 30 min, cooled, and poured into water. Organic products were
extracted with Et2O (2×), and combined extracts were dried
(MgSO4) and passed through a silica gel plug. The solvent was
evaporated, and the oily residue was crystallized (EtOH) to give
N-(2,3,5-Trifluoro-4-hexyloxy-6-(propylsulfinyl)phenyl)-4-
(4E-pentylcyclohexyl)benzamidine (8c). Compound 8c was ob-
tained as the second, more polar fraction in chromatographic
separation of thiadiazine 2c. Recrystallization from hexanes gave
1
1.72 g (67% yield) of 17 as yellow crystals: mp 53 °C; H NMR
1
δ 0.91 (t, J ) 6.8 Hz, 3H), 1.12 (t, J ) 7.4 Hz, 3H), 1.30-1.43
(m, 6H), 1.44-1.54 (m, 2H), 1.89 (sextet, J ) 7.3 Hz, 2H), 2.90
(t, J ) 7.3 Hz, 2H), 4.04 (t, J ) 6.5 Hz, 2H), 6.68 (dd, J1 ) 9.2
Hz, J2 ) 2.5 Hz, 1H), 6.79 (d, J ) 2.4 Hz, 1H), 8.26 (d, J ) 9.2
Hz, 1H); 13C NMR δ 13.8, 14.0, 21.1, 22.5, 25.6, 28.9, 31.5, 34.2,
68.8, 109.6, 111.6, 128.7, 139.0, 141.4, 163.0; IR (KBr) νmax 1597,
1562, 1497, 1307, 1284, 1252 cm-1; MS m/z 297 (M+, 16), 149
(100). Anal. Calcd. for C15H23NO3S; C, 60.58; H, 7.79; N, 4.71.
Found: C, 60.95; H, 7.75; N, 4.73.
2,3,5,6-Tetrafluoro-4-hexyloxynitrobenzene (18). 1 M aqueous
NaOH (100 mL) and Bu4N+HSO4- (2.1 g, 6.1 mmol) were added
to a solution of pentafluoronitrobenzene (15, 13.0 g, 61.0 mmol)
and n-hexanol (6.20 g, 60.8 mmol) in CH2Cl2 (100 mL) at 0 °C.
The mixture was stirred vigorously at 0 °C for 1.5 h. The organic
layer was separated, and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with water,
dried (MgSO4), and passed through a silica gel plug. The
solvent was evaporated, and the resulting crude product (18.0 g,
82% pure by GCMS) was fractionally distilled (94-99 °C/0.3 Torr)
to give 12.70 g (76% yield) of 91% pure (by GCMS) product 18
as a yellow liquid. The product was redistilled, and pure 18 was
obtained as a fraction boiling at 96 °C/0.2 Torr: 1H NMR δ 0.90
(t, J ) 6.8 Hz, 3H), 1.31-1.38 (m, 4H), 1.42-1.51 (m, 2H), 1.81
(quintet, J ) 7.0 Hz, 2H), 4.39 (tt, J1 ) 6.4 Hz, J2 ) 1.3 Hz, 2H);
13C NMR δ 13.9, 22.4, 25.1, 29.8, 31.3, 75.8 (t, J ) 4.1 Hz), 124.5
(m), 140.5 (dm, J1 ) 251 Hz), 141.6 (dm, J1 ) 262 Hz), 141.7 (tt,
J1 ) 11 Hz, J2 ) 3 Hz); 19F NMR δ AA′XX′ -155.4 (d, J ) 16.2
Hz, 2F), -147.6 (d, J ) 16.2 Hz, 2F); IR (neat) νmax 1550, 1498
cm-1; MS m/z 295 (M+, 3), 85 (100). Anal. Calcd. for C12H13F4-
NO3: C, 48.82; H, 4.44; N, 4.74. Found: C, 49.29; H, 4.38;
N, 4.76.
3,5,6-Trifluoro-4-hexyloxy-1-nitro-2-(propylsulfanyl)ben-
zene (19). A solution of 1-propanethiol (1.50 g, 19.7 mmol) and
NaOH (0.786 g, 19.7 mmol) in EtOH (25 mL) was added dropwise
within 15 min to a solution of nitro compound 18 (5.80 g, 19.7
mmol) in EtOH (20 mL) at 0 °C. The mixture was stirred for 45
min, the solvent was evaporated, and the oily residue was treated
with water. Organic material was extracted with Et2O (2×), dried
(MgSO4), and passed through a silica gel plug. The solvent was
removed, and the crude mixture (6.82 g) was fractionally distilled
collecting a fraction (148 °C/0.3 Torr) to give 6.36 g (92% yield)
of pure 19 as a yellow liquid: 1H NMR δ 0.90 (t, J ) 6.9 Hz, 3H),
0.97 (t, J ) 7.3 Hz, 3H), 1.31-1.37 (m, 4H), 1.42-1.50 (m, 2H),
1.52-1.60 (m, 2H), 1.79 (quintet, J ) 7.0 Hz, 2H), 2.86 (t, J )
7.3 Hz, 2H), 4.27 (tt, J1 ) 6.5 Hz, J2 ) 0.9 Hz, 2H); 19F NMR δ
-148.5 (dd, J1 ) 21.3 Hz, J2 ) 10.5 Hz, 1F), -146.4 (dd, J1 )
21.3 Hz, J2 ) 8.7 Hz, 1F), -122.1 (dd, J1 ) 10.5 Hz, J2 ) 8.7 Hz,
8c (18% yield) as white crystals: mp 135-136 °C; H NMR δ
0.90 (t, J ) 7.0 Hz, 3H), 0.91 (t, J ) 6.9 Hz, 3H), 1.06 (t, J ) 7.4
Hz, 3H), 1.15-1.42 (m, 13H), 1.40-1.52 (m, 4H), 1.76 (sextet, J
) 7.0 Hz, 2H), 1.88 (d, J ) 11.0 Hz, 8H), 2.52 (bt, J ) 11.0 Hz,
1H), 3.15-3.29 (m, 1H), 3.46 (ddd, J1 ) 14.7 Hz, J2 ) 8.6 Hz, J3
) 6.3 Hz, 1H), 4.13 (t, J ) 6.5 Hz, 2H), 5.05 (s, 2H), 7.29 (d, J
) 8.1 Hz, 2H), 7.76 (d, J ) 7.6 Hz, 2H); IR (KBr) νmax 3423,
3341, 3227, 1676, 1643, 1598, 1559, 1480, 1456 cm-1; FAB-MS
m/z: 593 ([M + H]+, 68%), 163 (100%). FAB-HRMS: Calcd for
C33H48F3N2O2S m/z: 593.3389; found: 593.3370.
4-Hexyloxy-2-propylsulfanylaniline (9). Amine 9 was obtained
in 94% yield by reduction of 17 with Fe dust according to the
procedure described for amine 10 (reaction time 1 h). Short-path
distillation (175 °C/0.3 Torr) gave amine 9 as a colorless oil of
purity >95% (by GCMS): 1H NMR δ 0.90 (t, J ) 6.9 Hz, 3H),
0.99 (t, J ) 7.3 Hz, 3H), 1.28-1.38 (m, 4H), 1.39-1.52 (m, 2H),
1.60 (sextet, J ) 7.0 Hz, 2H), 1.74 (quintet, J ) 7.0 Hz, 2H), 2.74
(t, J ) 7.3 Hz, 2H), 3.87 (t, J ) 6.6 Hz, 2H), 4.0 (bs, 2H), 6.66 (d,
J ) 8.7 Hz, 1H), 6.72 (dd, J1 ) 8.7 Hz, J2 ) 2.7 Hz, 1H), 6.96 (d,
J ) 2.7 Hz, 1H); 13C NMR δ 13.3, 14.0, 22.6, 22.9, 25.7, 29.4,
31.6, 36.7, 68.8, 115.9, 116.4, 119.5, 120.7, 141.7, 151.7; IR (neat)
νmax 3436 and 3345 (NH2), 1590, 1492, 1472, 1268, 1229 cm-1
;
MS m/z 267 (M+, 71), 141 (100). Anal. Calcd. for C15H25NOS; C,
67.37; H, 9.42; N, 5.24. Found: C, 67.46; H, 9.43; N, 5.24.
1,2,5-Trifluoro-4-hexyloxy-6-(propylsulfanyl)aniline (10). To
a vigorously stirred suspension of Fe dust (2.41 g, 43 mmol) in
water (4 mL), acetic acid (0.25 mL) was added. The mixture was
warmed up to 100 °C and nitro derivative 19 (1.427 g, 4.1 mmol)
was added portionwise within 10 min. The mixture was stirred at
100 °C for 30 min and then cooled and poured to sat. NaHCO3 (30
mL). Organic products were extracted with Et2O (5×). Combined
organic layers were dried (MgSO4), the solvent was removed, and
the resulting liquid residue was short-path distillated (150 °C/0.3
Torr) to give 1.19 g (91% yield) of amine 10 as a colorless liquid:
1H NMR δ 0.90 (t, J ) 6.7 Hz, 3H), 0.98 (t, J ) 7.3 Hz, 3H),
1.27-1.35 (m, 4H), 1.40-1.47 (m, 2H), 1.53 (sextet, J ) 7.3 Hz,
2H), 1.73 (quintet, J ) 7.2 Hz, 2H), 2.67 (t, J ) 7.3 Hz, 2H), 4.00
(t, J ) 6.5 Hz, 2H), 4.45 (brs, 2H); 19F NMR δ -161.7 (dd, J1 )
20.5 Hz, J2 ) 10.5 Hz, 1F), -150.70 (dd, J1 ) 20.5 Hz, J2 ) 5.9
Hz, 1F), -126.6 (dd, J1 ) 10.5 Hz, J2 ) 5.9 Hz, 1F); IR (neat)
ν
max 3480 and 3370 (NH2), 1478 cm-1; MS m/e (relative intensity)
321 (M+, 17), 195 (100). Anal. Calcd. for C15H22F3NOS: 56.05;
H, 6.90; N, 4.36. Found: C, 56.31; H, 6.75; N, 4.48.
4-Chloro-1-nitro-2-(propylsulfanyl)benzene (16).34 A mixture
of 15% aqueous NaOH (20 mL), benzene (30 mL), 1-propanethiol
(7.60 g, 100 mmol), 2,4-dichloronitrobenzene (14, 19.2 g, 100
J. Org. Chem, Vol. 72, No. 9, 2007 3519

Zienkiewicz et al.
1F); IR (neat) νmax 1547, 1492, 1454, 1371, 1122, 1063 cm-1; MS
m/z 351 (M+, 7), 161 (100). Anal. Calcd. for C15H20F3NO3S: C,
51.27; H, 5.74; N, 3.99. Found: C, 51.52; H, 5.75; N, 4.03.
3-(4-Butoxyphenyl)-5,6,8-trifluoro-7-hexyloxy-1-oxo-4H-benzo-
[1,2,4]thiadiazine (20b). Compound 20b was isolated as the sole
product of decomposition of 1b in air: 1H NMR δ 0.92 (t, J ) 6.8
Hz, 3H), 1.01 (t, J ) 7.4 Hz, 3H), 1.30-1.40 (m, 4H), 1.41-1.55
(m, 4H), 1.72-1.86 (m, 4H), 4.04 (t, J ) 6.6 Hz, 2H), 4.09 (t, J )
6.5 Hz, 2H), 6.92 (d, J ) 8.9 Hz, 2H), 7.93 (d, J ) 8.9 Hz, 2H),
10.6 (brs, 1H); FAB-MS m/z: 469 ([M + H]+, 100%), 210 (89%);
FAB-HRMS: Calcd for C23H28F3N2O3S ([M + H]+) m/z: 469.1773;
found: 469.1780.
Acknowledgment. Financial support for this work was
received from the National Science Foundation (CHE-9528029
and CHE-0096827). We thank Monika J. Sienkowska for her
assistance with the generation of radical 1c.
Supporting Information Available: Computational details;
general experimental methods; ESR experimental, simulated, and
difference spectra for 1a-1d; texture photomicrographs for 3; and
computational results for 21 and related compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO070122A
3520 J. Org. Chem., Vol. 72, No. 9, 2007