Fused-Ring Thiadiazines: Preparation and Crystallographic Characterization of 3-Phenyl Derivative of Benzo-, Pyridio[2,3-e]-, Pyrazino[2,3-e]-, and Tetrafluorobenzo-[1,2,4]thiadiazines

Article abstract of DOI:10.1021/jo035835h

Four bicyclic 4H-[1,2,4]thiadiazines 1a-d were prepared in 74-88% yields in two steps from the corresponding amidines 2. Three of them, 1a, 1b, and 1d, were obtained by thermal elimination of propene from the intermediate S-propylsulfilimines 12. The pyrazino derivative 1c was formed upon thermolysis of sulfoxide 14c obtained from 2c. The E_i mechanism was investigated using DFT methods. The elimination in the sulfilimine appears to be more favorable by about 2 kcal/mol than in the analogous sulfoxide. Crystal and molecular structures of three out of the four thiadiazines were established by single-crystal X-ray analysis. All thiadiazines were found as the 4H tautomers with the heterocyclic ring puckered along the S(1)...N(4) line. The benzo derivative 1a forms a unidimensional N(4)-H...N(2) chain, the pyrazino derivative 1c forms dimeric pairs with two synergistic hydrogen bonds, and the crystal structure of 1d is characterized by strong C₆F ₄...C₆H₅ quadrupolar interactions.

Full text of DOI:10.1021/jo035835h

F u sed -Rin g Th ia d ia zin es: P r ep a r a tion a n d Cr ysta llogr a p h ic
Ch a r a cter iza tion of 3-P h en yl Der iva tive of Ben zo-, P yr id io[2,3-e]-,
P yr a zin o[2,3-e]-, a n d Tetr a flu or oben zo-[1,2,4]th ia d ia zin es
J o´zef Zienkiewicz, and Piotr Kaszynski*
Organic Materials Research Group, Department of Chemistry, Vanderbilt University, Box 1822 Station B,
Nashville, Tennessee 37235
Victor G. Young, J r.
X-ray Crystallographic Laboratory, Department of Chemistry, University of Minnesota,
Twin Cities, Minnesota 55455
piotr@ctrvax.vanderbilt.edu
Received December 17, 2003
Four bicyclic 4H-[1,2,4]thiadiazines 1a -d were prepared in 74-88% yields in two steps from the
corresponding amidines 2. Three of them, 1a , 1b, and 1d , were obtained by thermal elimination of
propene from the intermediate S-propylsulfilimines 12. The pyrazino derivative 1c was formed
upon thermolysis of sulfoxide 14c obtained from 2c. The Ei mechanism was investigated using
DFT methods. The elimination in the sulfilimine appears to be more favorable by about 2 kcal/mol
than in the analogous sulfoxide. Crystal and molecular structures of three out of the four thiadiazines
were established by single-crystal X-ray analysis. All thiadiazines were found as the 4H tautomers
with the heterocyclic ring puckered along the S(1)‚‚‚N(4) line. The benzo derivative 1a forms a
unidimensional N(4)-H‚‚‚N(2) chain, the pyrazino derivative 1c forms dimeric pairs with two
synergistic hydrogen bonds, and the crystal structure of 1d is characterized by strong C6F4‚‚‚C6H5
quadrupolar interactions.
In tr od u ction
tuted nitrogen atoms appear to be convenient precursors
to persistent thiadiazinyl radicals.11,12
1,2,4-Benzothiadiazines1,2 and several recently inves-
tigated pyridio analogues3-5 belong to an important class
of pharmacologically active compounds.6 The most known
and studied are the derivatives with hexavalent sulfur
(e.g., cyclic sulfonamides), and much effort has been spent
on the study of 1,2,4-benzothiadiazines with tetravalent
sulfur. In contrast, only a handful of derivatives with
divalent sulfur (general structure I) have been reported
in the literature.3,7-10 Such compounds with unsubsti-
In the context of our interest in electrical and magnetic
properties of free radicals in organized media, we focused
on fused 1,2,4-thiadiazinyl radicals as the centerpiece of
calamitic liquid crystals.13,14 Initially, we concentrated on
the development of convenient and general synthetic
access to this class of heterocycles. In a subsequent
publication, we will evaluate the stability of the corre-
sponding 1,2,4-thiadiazinyl radicals as a function of the
ring structure.15
1,2,4-Th ia d ia zin e Rin g-Closu r e Meth od s. The few
known 1,2,4-benzothiadiazines were prepared using one
of four synthetic methods shown in Scheme 1. The only
direct method to I involves the condensation of ortho-
aminothiophenols II with hydroxamoyl chlorides (Method
A). A few reported examples show high yields of the
thiadiazines and suggest generality of the method.16,17
* Phone: (615) 322-3458, Fax: (615) 343-1234.
(1) Smalley, R. K. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: New
York, 1996; Vol. 6, pp 645-680.
(2) Pfeiffer, W.-D. In Hetarenes IV. Six-Membered and Larger
Heterorings with Maximum Unsaturation; Schaumann, E., Ed.; Thi-
eme: New York, 1998; Vol. E9c, pp 522-524.
(3) Gilchrist, T. L.; Rees, C. W.; Vaughan, D. J . Chem. Soc., Perkin
Trans. 1 1983, 55-59.
(4) de Tullio, P.; Pirotte, B.; Dupont, L.; Masereel, B.; Laeckmann,
D.; Podona, T.; Diouf, O.; Lebrun, P.; Delarge, J . Tetrahedron 1995,
51, 3221-3234.
(11) Markovskii, L. N.; Talanov, V. S.; Polumbrik, O. M.; Shermolov-
ich, Y. G. J . Org. Chem. USSR 1981, 17, 2338-2339.
(12) Shermolovich, Y. G.; Simonov, Y. A.; Dvorkin, A. A.; Polumbrik,
O. M.; Borovikova, G. S.; Kaminskaya, E. I.; Levchenko, E. S.;
Markovskii, L. N. Russ. J . Org. Chem. 1989, 25, 550-553.
(13) Patel, M. K.; Huang, J .; Kaszynski, P. Mol. Cryst. Liq. Cryst.
1995, 272, 87-97.
(14) Kaszynski, P. In Magnetic Properties of Organic Materials;
Lahti, P. M., Ed.; Marcel Dekker: New York, 1999; pp 305-324.
(15) Zienkiewicz, J .; Kaszynski, P.; Young, V. G., J r. In preparation.
(16) Abdelhamid, A. O.; Khalifa, F. A.; Ghabrial, S. S. Phosphorus
Sulfur 1988, 40, 41-46.
(17) Abdelhamid, A. O.; Negm, A. M.; Abdeen, T. M. S. Arch. Pharm.
(Weinheim Ger.) 1988, 321, 913-915.
(5) Neill, C. G.; Preston, P. N.; Wightman, R. H. Tetrahedron 1998,
54, 13645-13654.
(6) Ref 1, pp 679-680 and references therein.
(7) Kresze, G.; Seyfried, C.; Trede, A. Liebigs Ann. Chem. 1968, 715,
223-237.
(8) Levchenko, E. S.; Borovikova, G. S.; Borovik, E. I.; Kalinin, V.
N. Russ. J . Org. Chem. 1984, 20, 176-181.
(9) Finch, N.; Ricca, S., J r.; Werner, L. H.; Rodebaugh, R. J . Org.
Chem. 1980, 45, 3416-3421.
(10) Bo¨hnisch, V. W.; Gilchrist, T. L.; Rees, C. W. J . Chem. Soc.,
Perkin Trans. 1 1979, 2851-2854.
10.1021/jo035835h CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/09/2004
J . Org. Chem. 2004, 69, 2551-2561
2551

Zienkiewicz et al.
SCHEME 1
SCHEME 2
yields better than 70%. The use of SOCl2 results in
chlorination of the benzene ring,7 and the reduction of
VI with Bu3P may lead to ring contraction as a side
product.9
The limited range of substrates (mostly N-phenyl
benzamidine substituted with Cl or Me) used in the above
investigations does not allow prediction of the generality
of any of the methods. It is clear, however, that the
strongly chlorinating conditions of Method B1 preclude
it from use in more complex molecular systems. The
regiospecificity of ring closure in amidines IV (Methods
B1 and C) is largely governed by the nucleophilicity of
the ring rather than by a molecular design. In contrast,
the regiospecificity of ring formation is well defined in
Method A, although the preparation and stability of the
substituted thiophenols II can be problematic. Keeping
in mind our future needs for more complex molecular
systems with liquid crystal properties,14 we focused on
the development of Method B2. We adapted the method
of Hori21-23 for the formation of S-alkyl sulfilimines V
by oxidative cyclization of amidines III. The thermal
decomposition of the ylide V and the formation of
thiadiazine I occurs readily for S-alkyl derivatives at
temperatures as low as 80 °C.23,24 The generally higher
chemical stability of amino sulfides as compared to amino
thiols and the facile and high yield of alkene elimination
make this method particularly attractive and possibly
general for the synthesis of substituted fused thiadia-
zines.
The remaining three methods involve transformations
of tetravalent sulfur species, which are almost exclusively
obtained by the double reaction of electrophilic sulfur
species with amidines. The only exception is the re-
ported18 cyclization of N-(2-phenylthio)benzamidine (III,
R′′ ) Ph, Method B2), but the product was not designed
to be a substrate for I.
One of the most tested methods for preparation of I is
the reaction of amidines IV with morpholine sulfide or
disulfide in the presence of NCS followed by thermolysis
of the resulting ylide V (X ) 1-morpholinyl) at 140 °C.3,19
The overall yields of the process are less than 35%. For
example, 3-phenyl-4H-pyridio[2,3-e][1,2,4]thiadiazine was
obtained in 24% yield.3 Similar cyclization of amidine
with methane- and ethanesulfenyl chloride gave the ylide
V (X ) Me and Et, respectively).18 Only thermolysis of
the S-methyl ylide was reported, and it gave I in 52%
yield.3 The relatively high temperatures required for the
preparation of I in these reactions promotes ring contrac-
tion and formation of benzothiazole as byproducts.3,10
Cyclization of amidines20 or N-chloroamidines8,12 with
SCl2 in the presence of chlorine gave the corresponding
sulfiliminyl chlorides V (X ) Cl), which can be reduced
to I with thiophenols.8,15 The use of strongly chlorinating
conditions (SCl2 and Cl2) limits the general use of this
method.
Here we report the synthesis of four thiadiazines 1
from amidines 2 using Method B2 (Scheme 2). We
describe the mechanism for the formation of thiadiazines
1 supported by DFT calculations. The tautomerism of the
thiadiazines is investigated with X-ray crystallography
and computationally.
Resu lts
Syn th esis of Ben za m id in es 2. Synthesis of the
N-phenyl and N-pyridyl benzamidines 2a and 2b was
straightforward and is shown in Scheme 3. Thus, 2-chlo-
ronitrobenzene (3a ) and 2-chloro-3-nitropyridine (3b)
were reacted with 1-propanethiol in basic ethanol to form
the corresponding propylthio derivatives 4a 25 and 4b,
respectively. The pyridine derivative 4b was reported
only as a byproduct in a similar reaction of 3b.26 The nitro
The third method involves a cyclization of N-aryl
benzamidines IV with two equivalents of N-sulfinyl-
arenesulfonamide to form S-(N-sulfonylimine) derivative,
which is hydrolyzed to form S-oxide VI in good overall
yield.7,9 Alternatively, the oxide was obtained from ami-
dine IV with SOCl2.7 The S-oxide can be reduced to
thiadiazine I with thionyl chloride7 or with Bu3P9 in
(21) Hori, M.; Kataoka, T.; Shimizu, H.; Matsuo, K. Tetrahedron
Lett. 1979, 3969-3972.
(22) Shimizu, H.; Matsuo, K.; Kataoka, T.; Hori, M. Chem. Pharm.
Bull. 1984, 32, 4360-4371.
(18) Gilchrist, T. L.; Rees, C. W.; Vaughan, D. J . Chem. Soc., Perkin
Trans. 1 1983, 49-54.
(23) Shimizu, H.; Ikedo, K.; Hamada, K.; Ozawa, M.; Matsumoto,
H.; Kamata, K.; Nakamura, H.; J i, M.; Kataoka, T.; Hori, M. J . Chem.
Soc., Perkin Trans. 1 1991, 1733-1747.
(19) Gilchrist, T. L.; Rees, C. W.; Vaughan, D. J . Chem. Soc., Chem.
Commun. 1978, 1049-1050.
(24) Benin, V.; Kaszynski, P. J . Org. Chem. 2000, 65, 8086-8088.
(25) Foster, D. G.; Reid, E. E. J . Am. Chem. Soc. 1924, 46, 1936-
1948.
(20) Markovskii, L. N.; Darmokhval, E. A.; Levchenko, E. S. Russ.
J . Org. Chem. 1973, 9, 2055-2058.
2552 J . Org. Chem., Vol. 69, No. 7, 2004

Fused-Ring Thiadiazines
SCHEME 3
SCHEME 4
the product. Reduction of triazole 9 was accomplished
with iron, which offers mild reaction conditions as
compared to some described in the literature.28-30
Each step of the synthesis, formation of the azide and
its reduction, proceeded with about 60% yield, giving 5c
in an overall yield of 36% based on 8.
Several unsuccessful attempts were made to improve
the yield of amine 5c. In a reaction of the chloro
derivative 8 with ammonia in dioxane at 120 °C, no
product was observed. Similarly, a carbamination reac-
tion31 of 8 with t-BuOCONH2 or amination with ben-
zophenone imine31,32 gave only the starting material
recovered in over 80% yield.
Attempts at preparation of the amidine 2c from amine
5c and PhCN under conditions successfully used in the
preparation of 2a and 2b (NaH/THF) did not work, and
only unreacted starting amine 5c was recovered. When
LDA was used as the base following a general literature
procedure,33 the yield of N-pyrazine amidine 2c was
irreproducible and often less than 5%. In contrast, the
literature preparation the parent N-pyrazinyl benzami-
dine from 2-aminopyrazine and PhCN in the presence of
LDA was reproduced as reported.33 Presumably, the
failure of this base-assisted method is due to the exten-
sive delocalization of the negative charge onto the ring
nitrogen atom and chelation of the cation (Li+ or Na+)
by the N and S atoms.
group was subsequently reduced with iron, and the
resulting amines 5a 25 and 5b were condensed with
benzonitrile in the presence of NaH to give the benz-
amidines 2a and 2b, respectively, in good yields.
Benzamidine 2a was also prepared in an alternative
way from amide 6 according to a similar synthesis27
(Scheme 4). The crude imidoyl chloride 7 was generated
from amide 6 with solid PCl5 in toluene followed by a
reaction with aqueous ammonia. At room temperature,
a significant amount of 2-phenylbenzothiazole (1:1 with
the amidine) was observed, presumably formed by in-
tramolecular electrophilic attack on the sulfur center. At
-15 °C, the cyclization was completely suppressed and
the amidine 2a was isolated in 78% yield.
The preparation of N-pyrazinyl amidine 2c was more
challenging. The commercially available 2,3-dichloropy-
razine was thiolated in ethanol at ambient temperature
to give sulfide 8 in high yield with only traces of the 2,3-
bis(propylthio)pyrazine byproduct (Scheme 3). The ami-
nation step and the formation of 5c was less straight-
forward. Following a general method for introduction of
the amino group to the pyrazine ring,28 chloride 8 was
reacted with NaN3 in DMSO to give azide tautomer 9
(Scheme 3). The reaction proceeded at an appreciable rate
only above 120 °C, at which temperature the yield of 9
was partially compromised by thermal decomposition of
In search of a method to prepare amidine 2c, we
explored several other reactions. Thus, a direct reaction
of the amidinyl anion,27 generated in situ from benz-
amidine34 and NaH in THF, with the chloride 8 at reflux
gave no reaction. A similar negative result was obtained
in the attempted Pd(0)-catalyzed amidination reaction of
8 under general conditions for amidation.35
(29) Sato, N.; Matsuura, T.; Miwa, N. Synthesis 1994, 931-934.
(30) Brown, D. J . In The Chemistry of Heterocyclic Compounds;
Wiley & Sons: New York, 2002; Vol. 58, pp 272-273.
(31) Hartwig, J . F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K.
H.; Alcazar-Roman, L. M. J . Org. Chem. 1999, 64, 5575-5580.
(32) Wolfe, J . P.; Ahman, J .; Sadighi, J . P.; Singer, R. A.; Buchwald,
S. L. Tetrahedron Lett. 1997, 38, 6367-6370.
(33) Redhouse, A. D.; Thompson, R. J .; Wakefield, B. J .; Wardell, J .
A. Tetrahedron 1992, 48, 7619-7628.
(34) Barker, J .; Phillips, P. R.; Wallbridge, M. G. H.; Powell, H. R.
Acta Crystallogr. 1996, C52, 2617-2619.
(26) Lamotte, P. J .; Dupont, L.; Dideberg, O.; Dive, G.; J amoulle, J .
C. Acta Crystallogr. Sect. B 1980, B36, 2157-2159.
(27) Linschoten, M. R.; Gaisser, H.-D.; van der Goot, H.; Timmer-
man, H. Eur. J . Med. Chem.sChim. Ther. 1984, 19, 137-142.
(28) Shaw, J . T.; Brotherton, C. E.; Moon, R. W.; Winland, M. D.;
Anderson, M. D.; Kyler, K. S. J . Heterocycl. Chem. 1980, 17, 11-16.
J . Org. Chem, Vol. 69, No. 7, 2004 2553

Zienkiewicz et al.
SCHEME 5
SCHEME 6
Finally, in a reaction36 between amine 5c and benzoni-
trile in the presence of AlCl3 at 200 °C, only starting
amine was recovered.
Since the chlorine atom in 8 showed low reactivity, it
was converted into fluoride 10 using excess KF in hot
DMSO. The reaction of crude fluoride 10 with sodium
benzamidinate gave the desired amidine 2c in good
overall yield. The higher reactivity of fluoro derivative
10 than the chloro analogue 8 is consistent with previous
findings for halopyrazines37 and the generally greater
mobility of F than Cl by a factor of 103 in nucleophilic
aromatic substitution reactions.38 The preparation of the
N-tetrafluorophenyl benzamidine 2d took advantage of
the known39 2-bromo-3,4,5,6-tetrafluoroaniline (11), which
was thiolated with cuprous propanethiolate in DMF to
yield 5d according to a similar reaction39 (Scheme 3).
Using Cs2CO3 as the base and 5 equiv of CuSPr added
in portions over a 12 h period at 120 °C, the maximum
yield of 5d was about 40% and typically above 30%. (This
is significantly lower than the yields of about 80%
reported for analogous reactions with CuSPh.39) No other
product was isolated in these reactions, also no reaction
was observed in the absence of base. When a catalytic
amount of Pd(AcO)2 was added to the reaction mixture,
the yield of 5d decreased to about 20% and 2,3,4,5-
tetrafluoroaniline, the debromination product, was ob-
served in about the same amounts (∼20%).
group. When the amidine 2d was reacted with NCS for
only several hours, a significant amount (about 45%
yield) of the N-chloroamidine 13d was isolated chromato-
graphically as the more mobile fraction and partially
characterized. An NMR sample of 13d in CDCl3 was
partially converted (about 50%) to the sulfilimine 12d
and subsequently to 1d upon standing at ambient tem-
perature for 24 h and almost completely transformed in
2 days. Thermolysis of sulfilimines 12 in boiling toluene
gave the thiadiazines 1 in overall yields of about 80%.
The yield of the thiadiazine 1d was approximately the
same using either pure 12d or the N-chloroamidine 13d .
The pyrazine amidine 2c behaved differently than
other amidines. Reaction of 2c with NCS, followed by
workup with 5% aq NaOH, did not give the expected
sulfilimine 12c. Instead, the product was identified as
sulfoxide 14c (Scheme 6) on the basis of spectroscopic
data, which did not fit the general pattern for 12. In the
1H NMR spectrum, the S-CH2 protons were shifted
downfield by about 0.3 ppm relative to those in sulfil-
imines 12. The adjacent CH2 group showed an unusually
strong diastereotopic splitting generally not observed in
12 but characteristic for sulfoxides.41
Both NMR and IR showed the presence of two N-H
protons. IR also showed a strong absorption band at 1037
cm-1, which can be attributed to the SdO stretching
vibration. All this evidence is consistent with structure
14c, whose thermolysis in toluene gave the desired
thiadiazine 1c in good yield. The reaction may proceed
either through sulfilimine 12c (path b) or sulfenic acid
15c (path a in Scheme 6), and both paths are discussed
below.
Initial attempts to condense amine 5d with benzoni-
trile in the presence of NaH gave no reaction. An attempt
to prepare amidine 2d via amide 6d as shown for 2a in
Scheme 4 proved to be impractical, and no desired
product could be identified in the mixture of products.
Finally, amidine 2d was successfully prepared in about
94% by using the condensation of aniline 5d with
benzonitrile under acidic conditions.40
F or m a tion of th e Th ia d ia zin es 1. With the excep-
tion of the pyrazine derivative, oxidative cyclization of
the amidines 2 with NCS according to a general proce-
dure23 gave the corresponding unstable sulfilimines 12
(Scheme 5). This is evident from the diastereotopic
splitting of the methylene group protons of the propyl
(35) Yin, J .; Buchwald, S. L. Org. Lett. 2000, 2, 1101-1104.
(36) Oxley, P.; Partridge, M. W.; Short, W. F. J . Chem. Soc. 1947,
1110-1116.
Mech a n istic In vestiga tion s. The elimination of pro-
pene from the S-propyl sulfilimines 12 was investigated
at the B3LYP/6-31++G(d,p)//B3LYP/6-31G(d,p) level of
theory. The sulfilimines were assumed to be at the syn-
(37) Chambers, R. D.; Musgrave, W. K. R.; Urben, P. G. J . Chem.
Soc., Perkin Trans. 1 1974, 2584-2589.
(38) Miller, J . Aromatic Nucleophilic Substitution; Elsevier: New
York, 1968; Chapter 5.
(39) Yakobson, G. G.; Furin, G. G.; Korbina, L. S.; Vorozhtsov, N.
N., J r. Russ. J . Gen. Chem. 1967, 37, 1221-1224.
(40) Inukai, Y.; Oono, Y.; Sonoda, T.; Kobayashi, H. Bull. Chem. Soc.
J pn. 1979, 52, 516-520.
(41) For instance: Rudnik, M.; Maslankiewicz, A. Heterocycles 1999,
51, 2731-2738. Komeshima, N.; Osawa, T.; Nishitoba, T.; J inno, Y.;
Kiriu, T. Chem. Pharm. Bull. 1992, 40, 351-356.
2554 J . Org. Chem., Vol. 69, No. 7, 2004

Fused-Ring Thiadiazines
F IGURE 1. Optimized (B3LYP/6-31G(d,p)) geometries of ground- and transition-state structures for selected compounds. Atoms
marked with an asterisk are used to define the dihedral angle θ.
clinal conformation on the basis of results for 12a for
which the syn orientation of the propyl group relative to
the N(2) atom is more stable than the anti orientation
by about 0.3 kcal/mol (Figure 1). Analysis of the theoreti-
cal models show that both conformers have almost
identical geometrical parameters. The exception is the
torsional angle about the exocyclic C-S bond: in the anti
conformer, 12a -a n ti, the dihedral angle is 177.5°, and
in the syn conformer, 12a -syn , the dihedral angle is
64.8°. In the latter, the distance between the ring
nitrogen atom N(2) and the hydrogen atom, which is to
be transferred from the propyl group to form 1a -2H, is
close to VDW separation and calculated to be 2.83 Å.
A search for the transition state for the elimination of
propene from 12a -syn to form the thiadiazine 1a -2H
resulted in both endo (12a -TSen d o) and exo (12a -
TSexo) transition structures (Figure 1). The DFT cal-
culations slightly favor the endo TS by about 0.05 kcal/
mol, which is about 22 kcal/mol above the starting 12a -
syn (Figure 2). The same small preference for the endo
TS over the exo TS was calculated for an analogous
transformation of 12c-syn .
F IGURE 2. B3LYP/6-31++G(d,p)//B3LYP/6-31G(d,p) Gibbs
free-energy profile (298 K) for the formation of 1a -2H and
subsequently 1a -4H thiadiazines in the gas phase. Transition-
and ground-state structures are shown in Figure 1.
thermodynamic stabilization of about 4 kcal/mol is
provided by tautomerization of 1a -2H to 1a -4H. The
overall process is exoergic by about 22 kcal/mol or
exothermic by 9.6 kcal/mol.
The endo TS was assumed for the formation of the
remaining 1-2H thiadiazines, and the activation param-
eters for all four processes are listed in Table 1. The
calculated activation energies are generally about 22 kcal/
mol, and all are within 0.5 kcal/mol. The highest value
for ∆Gq of 22.1 kcal/mol was calculated for the benzo
The elimination of propene from 12a -syn and the
formation of 1a -2H thiadiazine is modestly exothermic
and largely driven by the change in entropy. Additional
J . Org. Chem, Vol. 69, No. 7, 2004 2555

Zienkiewicz et al.
TABLE 1. Ca lcu la ted a Th er m od yn a m ic P a r a m eter s for Elim in a tion of P r op en e
PhS(O)C3H7
∆H ∆G298
a
b
c
d
∆H
0.0
∆G298
∆H
0.0
∆G298
∆H
0.0
21.0
23.2
-6.0
-14.5
∆G298
∆H
0.0
∆G298
reactant
TS
0.0
0.0
12, 14
12-TSen d o
14-TS
1-2H + C3H6
1-4H + C3H6
0.0
22.1
0.0
21.6
0.0
21.6
23.6
-18.0
-27.1
0.0
21.8
23.0
23.6
21.7
21.0
20.9
25.9 ( 1.9b
30.4 ( 1.9b
c
c
products
-5.9
-9.6
-18.1
-21.9
-5.7
-8.3
-17.7
-20.9
-6.4
-10.1
-18.2
-22.1
c
c
a
b
B3LYP/6-31++G(d,p)//B3LYP/6-31G(d,p) calculations. Emerson, D. W.; Korniski, T. J . J . Org. Chem. 1969, 34, 4115-4118. c Not
calculated.
F IGURE 4. Thermal ellipsoid diagram of molecules A and
B′ of thiadiazine 1c with the ellipsoids drawn at 50% prob-
ability. Hydrogen atoms are given arbitrary radii.
vanced than in the sulfilimine 12c-TSen d o. This is
evident from the slightly shorter C-C distance and the
longer C‚‚‚H separation in the transition state of 14c-
TS, both by about 0.04 Å. However, the S‚‚‚C separation
is more complete in the sulfilimine 12c-TSen d o than in
sulfoxide 14c-TS. The geometrical parameters for the
pyrazine sulfilimine 12c-TSen d o are almost the same
as those shown for the benzo analogue 12a -TSen d o in
Figure 1.
The conformer of 14c shown in Figure 1 in which the
N-H interacts with the ring nitrogen atom was found
to be more stable than the one in which the N-H forms
a hydrogen bond with the sulfinyl group by more than 5
kcal/mol. In the former conformer, a close S-O‚‚‚H-CPh
interaction is maintained in the transition state 14c-TS.
Cr ysta l a n d Molecu la r Str u ctu r es. Yellow, triclinic
crystals of 1c and monoclinic crystals of 1a and 1d were
obtained by slow evaporation of CH2Cl2 solutions at
ambient temperature, and their solid-state structures
were determined by X-ray diffraction.42
Molecular structures for 1a and 1c are shown in
Figures 3 and 4, and a partial packing diagram for 1d is
presented in Figure 5. Selected bond lengths and angles
are shown in Table 2.
All molecules in crystals of 1a , 1c, and 1d are the 4H
tautomers, which adopt a puckered conformation with
the folding axis along the S(1)‚‚‚N(4) line (e.g., 1a in
F IGURE 3. Thermal ellipsoid diagram of thiadiazine 1a with
the ellipsoids drawn at 50% probability. Hydrogen atoms are
given arbitrary radii.
derivative 12a , which compares to 23.6 kcal/mol obtained
for the analogous elimination of propene from phenyl
propyl sulfoxide.
Analysis of the transition state 12a -TSen d o shows
that the S-C bond is elongated by about 0.63 Å and the
H‚‚‚N distance is shortened by 1.41 Å relative to 12a -
syn (Figure 1). The N-S‚‚‚C-C angle is changed from
65° in 12a -syn to 6.8° in 12a -TSen d o, and all five atoms
S-N‚‚‚H‚‚‚C-C involved in the transition state adopt an
almost planar arrangement. The largest deviation from
planarity of 10.4° is calculated for N‚‚‚H‚‚‚C-C atoms.
The exo transition structure, 12a -TSexo, is characterized
by almost identical key geometrical parameters except
for the orientation of the methyl group. The high degree
of planarization in the TS is reflected in the negative
activation entropy for the reaction.
Elimination of propene from 14c to form the sulfenic
acid 15c was found to proceed through transition state
14c-TS (Figure 1). The calculated activation energy ∆Gq
is 23.7 kcal/mol, which is 2 kcal/mol higher than that
calculated for the pyrazino derivative 12c and nearly the
same as that calculated for PhS(O)Pr (Table 1). A
comparison of the geometrical parameters shows that the
formation of propene in sulfoxide 14c-TS is more ad-
(42) Crystal data for 1a : C13H10N2S monoclinic, P21/c, a ) 6.932(3)
Å, b ) 15.657(6) Å, c ) 10.350(4) Å, â ) 100.866(7)°, V ) 1103.2(7) Å3,
Z ) 4, T ) 173 (2) K, λ ) 0.71073 Å, R (F2) ) 0.0320 and Rw(F2) )
0.0845 (for 1789 reflections with I > 2σ(I)). Crystal data for 1c:
C
11H8N4S triclinic, P1h, a ) 8.4404(14) Å, b ) 12.304(2) Å, c ) 20.759-
(3) Å, R ) 80.261(3)°, â ) 81.795(3)°, γ ) 85.807(3)°, V ) 2100.5(6) Å3,
Z ) 8, T ) 173 (2) K, λ ) 0.71073 Å, R (F2) ) 0.0422 and Rw(F2) )
0.1007 (for 5737 reflections with I > 2σ(I)). Crystal data for 1d :
C
13H6F4N2S monoclinic, C2/c, a ) 14.189(5) Å, b ) 6.783(3) Å, c )
24.549(9) Å, â ) 102.298(6)°, V ) 2308.5(15) Å3, Z ) 4, T ) 173 (2) K,
λ ) 0.71073 Å, R (F2) ) 0.0470 and Rw(F2) ) 0.1200 (for 1462 reflections
with I > 2σ(I)). For details, see Supporting Information.
2556 J . Org. Chem., Vol. 69, No. 7, 2004

Fused-Ring Thiadiazines
ence between the two sets of data for all bonds is -0.009
with the std ) 0.012.
The puckering of the thiadiazine ring is most pro-
nounced in the benzo derivative 1a (about 31° at the S(1)
center, Figure 3), modest in molecule D of the pyrazo
derivative 1c (about 15°), and small, about 7°, in the
tetrafluorobenzo 1d (Figure 5) and molecules A-C of 1c
(Figure 4). These experimental angles are generally
smaller than the values calculated for the molecules in
the gas phase. Exceptions are 1a and molecule D of 1c
for which the puckering angles are greater than calcu-
lated. This coincides with the largest observed torsional
angles between the phenyl and the thiadiazine rings,
which for 1a significantly exceeds the calculated value
of about 30°. These torsional angles are significantly
smaller in the crystal of 1d and close to 0° in molecule A
of 1c, which makes these molecules the most planar in
the series. The observed planarization relative to the
calculated values is most likely due to the compression
of the puckering and torsional angles in the crystal.
The benzene ring in 1a fused with the thiadiazine ring
is slightly puckered with the largest deviation from
planarity of 4.9(2)° observed for C(5)-C(6)-C(10)-C(9)
atoms. In contrast, the tetrafluorobenzene ring in 1d is
planar within 1.5°, and the pyrazine rings in 1c are
planar within 2.2°.
Each unique molecule in the solid structure of 1 is
related to its enantiomeric form through an inversion
center. In the crystal structure of 1c, four molecules are
found per asymmetric unit. They form dimers through
pairs of synergistic hydrogen bonds between N(4)-H and
N(7). The N(4)‚‚‚N(7) distances vary between 2.959 and
3.267 Å and the angles N(4)-H-N(7) between 152.5 and
168.3°, all observed in the A-B′ pair shown in Figure 4.
The pyrazine rings in the A-B′ pair form an angle of 56°
measured as C(9)C(8)N(7)-C(9)′C(8)′N(7)′ interplanar
angle. The analogous value for the C-D′ pair is 43°. Some
additional pseudosymmetry is observed, but no pseudo-
inversion centers are apparent. Each unique molecule of
1c is near a unique crystallographic inversion center.
In the crystal structure for 1a , the molecules form one-
dimensional hydrogen bonds between N(4)-H and N(2)
parallel to the c axis. The N(4)‚‚‚N(2) separation is 3.023
Å and the N(4)-H-N(2) angle is 147.9°.
F IGURE 5. Partial packing diagram for 1d showing molec-
ular stacking along the b axis.
Figure 3). This is consistent with general trends in eight-
π-electron six-membered heterocycles such as the [1,2,4,5]-
thiatriazine43 and related compounds.44
The unit cell of 1c consists of four unique molecules in
a pseudo-endo conformation in which the benzene ring
interacts with H-N(4) in the endo face of the puckered
thiadiazine ring (Figure 4). In contrast, only one unique
molecule was found in crystal structures of 1a and 1d .
The former adopts the pseudo-endo conformation (Figure
3), while the latter prefers the pseudo-exo conformation
in the solid state (Figure 5). Calculations for 1d show
that both pseudo-endo and pseudo-exo conformers have
almost identical interatomic distances and intra-ring
angles, and their energies are within 0.1 kcal/mol. The
heterocycle puckering angles R are calculated to be
smaller in the pseudo-exo conformer by about 5° for the
N center and 9° for the S center, which results in a higher
degree of ring planarization. Similar calculations at the
B3LYP/6-31G(d,p) level located only the pseudo-endo
conformer of 1c.
The intra-ring bond lengths and angles for the thia-
diazine rings in 1 are typical for analogous compounds43
and consistent with the 4H tautomer. The theoretical gas-
phase geometry for the three molecules matches the
experimental solid-state results, and the comparison is
shown in Table 2. Generally, the calculations slightly
overestimate the experimental C-C and C-N bond
lengths by an average of 0.006 Å (std ) 0.009 Å). In
contrast, the bonds involving the sulfur atoms are over-
estimated by about 0.025 Å (std ) 0.007 Å) except for
the S-N bonds in the highly planarized 1d and molecule
A of 1c. These two distances are shorter than calculated
by about 0.04 Å, while in the more puckered 1a this
distance was only 0.008Å shorter than predicted. The
difference between the experimental and calculated C-F
distances is within the experimental error (mean )
+0.003 Å and std ) 0.001 Å). Overall, the mean differ-
No hydrogen bonding was found in 1d . Instead, the
molecules form approximately parallel stacks with al-
ternating phenyl and tetrafluorobenzene rings as shown
in Figure 5. The rings are approximately parallel to each
other in the stack with the alternating separation
between the rings of about 3.5 and 3.3 Å. The two sides
of the individual rectangular stack are twisted relative
to each other due to the conformational requirements of
the molecules.
Discu ssion a n d Con clu sion
Thiadiazines 1 were efficiently obtained from amidines
2 in a two-step process. The synthesis of thiadiazines 1a ,
1b, and 1d involved sulfilimines 12 and is a successful
extension of the Hori and Gilchrist methods. In contrast,
the preparation of the pyrazine derivative 1c is the first
example of a new method that involves a sulfoxide rather
than a sulfilimine. Both of these methods simplify
synthetic access to fused thiadiazines and offer a degree
(43) Farrar, J . M.; Patel, M. K.; Kaszynski, P.; Young, V. G. J r. J .
Org. Chem. 2000, 65, 931-940, and references therein.
(44) For example: Rees, C. W.; White, A. J . P.; Williams, D. J .;
Rakitin, O. A.; Konstantinova, L. S.; Marcos, C. F.; Torroba, T. J . Org.
Chem. 1999, 64, 5010-5016. Kim, D. C.; Yoo, K. H.; Shin, K. J .; Park,
S. W.; Kim D. J . J . Heterocycl. Chem. 1997, 34, 57-63.
J . Org. Chem, Vol. 69, No. 7, 2004 2557

Zienkiewicz et al.
TABLE 2. Selected Exp er im en ta l a n d Ca lcu la ted Bon d Len gth s [Å] a n d An gles [d eg] for Th ia d ia zin esa
1a 1c
1d
exp
calcd
exp
1.687(2)b
calcd
exp
calcd
S(1)-N(2)
1.7243(14)
1.294(2)
1.3785(19)
1.416(2)
1.393(3)
1.7629(17)
1.393(2)
1.390(2)
1.489(2)
2.910
117.20(11)
125.14(14)
121.51(13)
101.96(7)
149.09(15)
147.85(13)
43.7(2)
1.732
1.288
1.395
1.410
1.403
1.784
1.395
1.394
1.488
2.943
1.719
1.286
1.393
1.391
1.416
1.787
1.323
1.317
1.488
3.033
1.677(2)
1.285(3)
1.377(4)
1.398(3)
1.400(4)
1.763(3)
1.370(4)
1.372(4)
1.488(4)
3.039
124.4(2)
125.4(3)
123.7(2)
103.67(13)
171.4(3)
173.1(2)
11.3(4)
1.718
1.285
1.401
1.404
1.402
1.784
1.392
1.389
1.487
3.031
122.0
125.7
121.7
N(2)-C(3)
1.283(3)b
1.384(3)b
1.384(3)b
1.413(3)b
1.762(3)b
1.320(3)b
1.314(3)b
1.486(3)b
C(3)-N(4)
N(4)-C(5)
C(5)-C(6)
S(1)-C(6)
C(5)-X(7)c
C(6)-X(10)c
C(3)-CPh
b
S(1)‚‚‚N(4)
3.018
S(1)-N(2)-C(3)
N(2)-C(3)-N(4)
C(3)-N(4)-C(5)
C(6)-S(1)-N(2)
X(7)-C(5)-N(4)-C(3)c
X(10)-C(6)-S(1)-N(2)c
N(4)-C(3)-C(11)-C(12)
118.6
122.6(2)b
123.4(2)b
124.4(2)b
104.5(1)b
169.0(2)b
171.4(2)b
0.9(4), 23.5(3),
122.3
124.1
122.2
102.3
149.2
152.5
29.6
124.6
124.9
103.3
166.5
167.9
27.7
102.7
155.8
160.3
25.0
19.7(3), 25.8(3)
8.1, 5.3, 8.2, 15.5
9.0, 5.5, 6.7, 15.1
S(1): Rd
N(4): Rd
30.7
25.4
25.6
25.6
12.2
12.1
7.5
7.5
16.8
18.9
a
b
Gas-phase calculations at the B3LYP/6-31G(d,p) level of theory. Average for four molecules. c X ) C for 1a and 1d and X ) N for
d
1c. Ring puckering angle defined as 180 - (X - * - *) angle in which asterisks are the midpoints between the C(6)‚‚‚N(2) and C(5)‚‚‚C(3)
atoms.
F IGURE 6. Two general methods for the formation of cyclic
sulfenamides.
of regiochemical control in the ring closure, which is
absent in Methods B1 and C (Scheme 1). The formation
of the thiadiazines through sulfoxides is particularly
valuable since the latter can be prepared from sulfides
using a range of mild oxidants.45
These methods, schematically shown in Figure 6, can,
F IGURE 7. Optimized (B3LYP/6-31G(d,p)) geometries and
in principle, be extended to other S-N systems and open
calculated Wiberg bond order indices for amidine 16 and its
new possibilities in synthesis of heterocyclic sulfenam-
ides.
anion 16-.
The formation of sulfilimines 12 most likely involves
a chlorosulfonium cation generated either by direct
chlorination with NCS or by chlorine transfer from
nitrogen in N-chloroamidine, as suggested by the isola-
tion of 13d . The subsequent attack of the amidinyl
nitrogen atom on the chlorosulfonium group results in
the formation of the N-S bond and thiadiazine ring
closure. This last step fails, however, for the pyrazine
(see 14c in Figure 1). Calculations for N-pyrazinobenz-
amidine (16) show a significant increase in the exocyclic
CPyraz-N bond order upon deprotonation due to delocal-
ization of the negative charge onto the pyrazine ring
nitrogen atom in 16- (Figure 7). Such an increase in the
double-bond character further hinders the rotation about
the CPyraz-N bond and makes the direct interaction
between the chlorosulfonium cation and the amidinyl
derivatives, and 12c is not formed from 2c under
ordinary conditions. Instead, the chlorosulfonium cation
nitrogen atom inaccessible at ambient temperature.
The strong intramolecular hydrogen bonding and the
high degree of conjugation with the pyrazine ring may
also inhibit the N-chlorination of 2c, and direct chlorina-
tion of the S center may occur instead. This is desired,
since the generation of the N-chloro amidine 13c could
lead to the formation of the triazolopyrazine 17, a more
thermodynamically stable (by ∆H ) 36.1 kcal/mol) isomer
of 12c (Figure 1). Such triazolopyrazines are efficiently
formed during pyrolysis of imidoyl azides,46 oxidation of
derived from 2c is hydrolyzed under workup conditions
leading to the isolation of sulfoxide 14c as the sole
product. The problem with the formation of the N-S bond
in 12c presumably results from the strong intramolecular
bonding between the ring nitrogen atom and the amidinyl
group, which may deactivate the amidine as a nucleophile
(45) Kresze, G. In Organische Schwefel-Verbindungen; Klamann, D.,
Ed.; Verlag: New York, 1985; Vol. E11; pp 702-752.
2558 J . Org. Chem., Vol. 69, No. 7, 2004

Fused-Ring Thiadiazines
amidines with Pb(AcO)4,47 or dehydration of N-hydroxy-
amidines.48
A comparison of the three experimental structures
shows that the geometry of the thiadiazine ring is
sensitive to the electronic structure of the fused ring. The
N(4)-C(5) distance is shortened in the tetrafluorobenzo
and pyrazino derivatives by 0.01 and 0.03 Å relative to
that in 1a . In the former, the shortening of the bond
length occurs in response to the strongly electron-
deficient benzene ring. In the pyrazino derivative 1c, the
large contraction of the N-C bond appears to be due to
extensive conjugation with the pyrazine ring N atoms.
At the same time, the pyrazine ring C(5)-N(7) distance
is expanded relative to C(6)-N(10), and the C(5)-C(6)
bond acquires more single-bond character relative to that
in 1a . These observed geometrical changes are consistent
with the computational results. The shortening of the
N(4)-C(5) distance also appears to parallel the increasing
planarization of the N(4) center, which would be expected
for strong interactions of the N(4) lone pair with the
adjacent ring. Indeed, the sinus of the pyramidalization
angle RN(4) is approximately proportional to dN(4)-C(5) (R2
) 0.96) for all four theoretical models 1 in the absence
of crystal packing forces.
Crystal structures for the three thiadiazines show that
hydrogen bonding and quadrupolar interactions between
fluorinated and nonfluorinated rings are powerful tools
for crystal engineering. The presence of the N(7) atom
in the pyrazine ring makes it possible to form dimeric
pairs with two synergistic interactions in 1c similar to
those in nucleic bases. In the absence of the nitrogen
atom in position 7, thiadiazine 1a forms an infinite
hydrogen-bonded chain, which presumably causes a
significant opening of the angle between the phenyl and
the thiadiazine rings (Figure 3). Fluorination of the
benzene ring in 1d leads to changing of the packing
diagram, and the hydrogen bond motif is replaced by
quadrupolar interactions between π-faces of the fluori-
nated and nonfluorinated benzene rings as the main
driving force in the molecular arrangement (Figure 5).
Similar crystal packing is observed in the solid structure
of a radical derived from 1d .15
Elimination of propene from 12 proceeds through a
concerted electrocyclic Ei mechanism characteristic for
sulfilimines and sulfoxides among other functional
groups.49,50 The evidence for the concerted mechanism is
provided by experimental data50-52 and supported by
recent computational results for sulfoxides.53,54
Our DFT calculations show that propene elimination
from 12 requires lower activation energy than from
phenyl propyl sulfoxide (Table 1). This is consistent with
experimental data for sulfilimines and sulfoxides, which
both typically easily eliminate in boiling toluene, as
observed for 12. Experimentally measured55 activation
energy and entropy for PhS(O)Pr are higher than calcu-
lated (Table 1), which suggests that the actual activation
parameters for the formation of 1-2H from 12 are also
higher. A comparison of computational methods shows
that MP2 level calculations give activation enthalpies
close to the experimental values.53 Also the use of
perturbation methods may show significantly higher than
0.05 kcal/mol stabilization of the endo transition state
12-TSen d o relative to 12-TSexo, as was found for
Diels-Alder reaction.56
The formation of thiadiazine 1c from sulfoxide 14c
most likely proceeds through elimination of propene and
subsequent intramolecular condensation of the resulting
unstable sulfenic acid 15c to form 1c. Our DFT calcula-
tions demonstrate that this is energetically possible
under the reaction conditions, and sulfenic acids are
known to react easily with nucleophiles.57
The alternative path b (Scheme 6), in which 14c forms
sulfilimine 12c, is not plausible since sulfoxides do not
readily undergo nucleophilic additions.
X-ray analysis of 1 provides the first experimental
molecular structures for thiadiazines. To date, the only
reported derivatives were 1,1-dioxides, which constitute
an important class of biologically active compounds,58 and
one 1-oxide.59
The finding of 1-4H tautomers in the crystal structures
is consistent with their calculated higher thermodynamic
stability as compared to the 1-2H tautomers.
Exp er im en ta l Section
3-P h en yl-4H-ben zo[1,2,4]th ia d ia zin e3 (1a ). A solution of
crude sulfilimine 12a (0.65 g, 2.3 mmol) in dry toluene (10 mL)
was stirred at reflux for 12 h. The solvent was removed and
the residue dissolved in CH2Cl2 and passed through a silica
gel plug. The crude product was purified by silica gel column
chromatography (CH2Cl2-hexanes in a 1:3 ratio) followed by
recrystallization from a hexanes-toluene (9:1) mixture, which
gave 1a (0.44 g, 85% yield; other runs 79-85% yield) as a
yellow solid: mp 119.5-120.5 °C (lit.3 119-120 °C); 1H NMR
(300 MHz, CDCl3) δ 6.44 (dd, J 1 ) 7.0 Hz, J 2 ) 2.0 Hz, 1H),
6.59 (br s, 1H), 6.74 (dd, J 1 ) 7.0 Hz, J 2 ) 2.0 Hz, 1H), 6.89-
6.99 (m, 2H), 7.39-7.47 (m, 3H), 7.63-7.68 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 114.1, 121.0, 122.9, 125.5, 125.8, 127.4,
128.6, 130.8, 133.8, 136.5, 156.8; IR 3239 (N-H), 1602 (thia-
diazine CdN), 1461 and 1424 (ring in-plane) cm-1; FAB m/z
226 (M+, 100). Anal. Calcd for C13H10N2S: C, 69.00; H, 4.45;
N, 12.38. Found: C, 69.11, H, 4.35, N, 12.33.
(46) Sambaish, T.; Reddy, K. K. Indian J . Chem. Sect. B 1992, 31B,
444-445.
(47) Badger, G. M.; Nelson, P. J .; Potts, K. T. J . Org. Chem. 1964,
29, 2542-2545.
(48) Tamura, Y.; Kim, J .-H.; Ikeda, M. J . Heterocycl. Chem. 1975,
12, 107-110.
(49) Oae, S.; Furukawa, N. Tetrahedron 1977, 33, 2359-2367.
(50) Oae, S.; Furukawa, N. Sulfilimines and Related Derivatives;
ACS Monograph 179; Americal Chemical Society: Washington, DC,
1983.
(51) Kwart, H.; George, T. J .; Louw, R.; Ultee, W. J . Am. Chem. Soc.
1978, 100, 3927-3928.
(52) McNab, H. In Comprehensive Organic Functional Group Trans-
formations; Katritzky, A. R., Meth-Cohn, O., Eds.; Pergamon: New
York, 1995; Vol. 1, pp 778-780.
(53) Cubbage, J . W.; Guo, Y.; McCulla, R. D.; J enks, W. S. J . Org.
Chem. 2001, 66, 8722-8736.
(54) J ursic, B. S. THEOCHEM 1997, 389, 257-263.
(55) Emerson, D. W.; Korniski, T. J . J . Org. Chem. 1969, 34, 4115-
4118.
N-(2-P r op ylth iop h en yl)ben za m id in e (2a ). Meth od A.
NaH (1.24 g of 60% suspension in mineral oil, 31.0 mmol) was
washed with pentane (20 mL) and suspended in dry THF (20
mL). A solution of 2-propylthioaniline (5a , 5.00 g, 30 mmol)
in THF (15 mL) was added dropwise within 10 min. The
mixture was stirred at room temperature until no more gas
evolved, and a solution of benzonitrile (3.20 g, 31.0 mmol) in
(56) Calvo-Losada, S.; Sua´rez, D. J . Am. Chem. Soc. 2000, 122, 390-
391.
(57) Kice, J . L. Adv. Phys. Org. Chem. 1980, 17, 65-181.
(58) Pirotte, B.; Ouedraogo, R.; de Tullio, P.; Khelili, S.; Somers, F.;
Boverie, S.; Dupont, L.; Fontaine, J .; Damas, J .; Lebrun, P. J . Med.
Chem. 2000, 43, 1456-1466 and references therein.
(59) Kresze, G.; Schwo¨bel, A.; Hatjiissaak, A.; Ackermann, K.;
Minami, T. Liebigs Ann. Chem. 1984, 904-910.
J . Org. Chem, Vol. 69, No. 7, 2004 2559

Zienkiewicz et al.
dry THF (10 mL) was added dropwise. Stirring was continued
at room temperature for 2 h and at reflux for 10 h. Another
portion of NaH (0.6 g) was added, and the mixture was stirred
for additional 12 h. Most of the solvent was removed under
reduced pressure. Ice-water (50 mL) was added, and the
organic materials were extracted with diethyl ether (20 mL),
dried (Na2SO4), and passed through a silica gel plug, which
was washed with a hexanes-ethyl acetate mixture (2:1). Pure
amidine 2a was obtained by column chromatography (CH2-
Cl2) followed by recrystallization from hexanes-toluene (4:1)
to give 6.5 g (80% yield; other runs 79-85% yield) of a white
solid: mp 77-78 °C; 1H NMR (400 MHz, CDCl3) δ 1.03 (t, J )
7.3 Hz, 3H), 1.69 (sextet, J ) 7.3 Hz, 2H), 2.87 (t, J ) 7.3 Hz,
2H), 4.8 (s, 2H), 6.92 (d, J ) 7.6 Hz, 1H), 7.04 (t, J ) 7.6 Hz,
1H), 7.16 (t, J ) 7.3 Hz, 1H), 7.31 (d, J ) 7.6 Hz, 1H), 7.41-
7.50 (m, 3H), 7.95 (d, J ) 7.5 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 13.7, 22.3, 33.8, 121.2, 123.4, 126.1, 126.9, 127.6,
128.5, 129.5, 130.6, 135.5, 147.6, 154.5; IR 3460 and 3332 (N-
H), 1632 and 1573 (amidine) cm-1; MS m/z 270 (M+, 25), 104
(100); FAB m/z 271 (MH+, 100). Anal. Calcd for C16H18N2S:
C, 71.07; H, 6.71; N, 10.36. Found: C, 71.17; H, 6.70; N, 10.57.
Meth od B. PCl5 (0.11 g, 0.53 mmol) was added in one
portion to a stirred solution of N-(2-propylthiophenyl)benz-
amide60 (6, 0.136 g, 0.5 mmol), prepared from amine 5b, in
toluene (5 mL) at -15 °C. When PCl5 completely dissolved,
30% aqueous ammonia (1 mL) was added in one portion and
stirring continued for 15 min. The organic layer was separated
and dried (Na2SO4) and solvent evaporated under reduced
pressure. The crude product was dissolved in CH2Cl2 and
passed through a silica gel plug. Column chromatography
(CH2Cl2) followed by recrystallization from a hexanes-toluene
mixture (in a 9:1 ratio) gave 2a (0.105 g, 78% yield) identical
with that prepared in Method A.
N-(3-P r op ylth iop yr a zin -2-yl)ben za m id in e (2c). NaH
(0.12 g of 60% suspension in mineral oil, 3 mmol) was washed
with pentane (10 mL) and suspended in dry THF (10 mL), and
the suspension was warmed to 50 °C. Benzamidine hydrochlo-
ride (0.22 g 1.4 mmol) was added in one portion and stirring
continued for 15 min until no more gas was evolving. A
solution of 2-fluoro-3-propylthiopyrazine (10, 0.20 g, 1.2 mmol)
in dry THF (2 mL) was added dropwise, and the mixture was
stirred for 3 h. Most of the solvent was removed under reduced
pressure; ice-water (20 mL) was added, and the organic
material was extracted with diethyl ether (10 mL), dried (Na2-
SO4), and passed through a silica gel plug, which was washed
with a hexanes-ethyl acetate mixture (2:1). Column chroma-
tography (CH2Cl2) followed by recrystallization from hexanes-
toluene (4:1) gave pure 2c (0.18 g, 55% yield) as a yellow
solid: mp 69.5-70.5 °C; 1H NMR (400 MHz, CDCl3) δ 1.09 (t,
J ) 7.3 Hz, 3H), 1.78 (sextet, J ) 7.3 Hz, 2H), 3.09 (t, J ) 7.4
Hz, 2H), 6.2 (s, 1H), 7.42-7.54 (m, 3H), 7.86 (d, J ) 2.9 Hz,
1H), 7.96 (d, J ) 2.9 Hz, 1H), 8.02-8.05 (m, 2H), 10.2 (brs,
1H); 13C NMR (75 MHz, CDCl3) δ 13.8, 22.3, 31.1, 127.1, 128.6,
131.2, 133.8, 135.9, 136.2, 154.6, 156.4, 159.7; IR 3460 and
3399 (N-H), 1615 (amidine), 1535, 1479, and 1370 (pyrazine
in-plane) cm-1; MS m/z 272 (M+, 33), 104 (100). Anal. Calcd
for C14H16N4S: C, 61.74; H, 5.92; N, 20.57. Found: C, 62.00;
H, 5.90; N, 20.74.
N-(2,3,4,5-Tet r a flu or o-6-p r op ylt h iop h en yl)b en za m i-
d in e (2d ). Methanesulfonic acid (1.63 g, 17.0 mmol) was added
in one portion to a stirred solution of 3,4,5,6-tetrafluoro-2-
propylthioaniline (5d , 0.81 g, 3.4 mmol) and benzonitrile (1.75
g, 17.0 mmol) at 150 °C. After 30 min, the mixture was cooled
and neutralized with a 5% solution of NaHCO3 (10 mL).
Organic materials were extracted with ethyl ether (2 × 20 mL),
washed with water, dried (Na2SO4), and passed through a
silica gel plug. The crude product was purified by column
chromatography (CH2Cl2-hexanes in a 2:1 ratio) followed by
recrystallization from a hexanes-toluene (4:1) mixture to give
2d (1.09 g, 3.2 mmol, 94% yield; other runs 90%-94% yield) as
a white solid: mp 93.5-94.5 °C; 1H NMR (400 MHz, CDCl3) δ
0.96 (t, J ) 7.3 Hz, 3H), 1.55 (sextet, J ) 7.3 Hz, 2H), 2.84 (t,
J ) 7.2 Hz, 2H), 4.8 (s, 2H), 7.47-7.54 (m, 3H), 7.92 (d, J )
7.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 13.1, 23.2, 36.4, 111.9
(m), 127.0, 128.7, 131.3, 134.5, 156.3, (the 13C-F signals were
not located); 19F NMR (282 MHz, CDCl3) δ -132.3 (dd, J 1
)
24 Hz, J 2 ) 10 Hz, 1F), -150.3 (dd, J 1 ) 20 Hz, J 2 ) 10 Hz,
1F), -156.0 (t, J ) 21 Hz, 1F), -164.0 (t, J ) 23 Hz, 1F); IR
3469 and 3314 (N-H), 1637 (amidine), 1493, 1456 cm-1; MS
m/z 342 (M+, 20), 104 (100). Anal. Calcd for C16H14F4N2S: C,
56.13; H, 4.12; N, 8.18. Calcd for C16H14F4N2S‚0.5H2O: C,
54.69; H, 4.30; N, 7.97. Found: C, 54.90; H, 4.16; N, 7.71.
2-P r op ylth ion itr oben zen e (4a ).25 A solution of 2-chlo-
ronitrobenzene (3a , 15.7 g, 0.10 mol), 1-propanethiol (8.36 g,
0.11 mol), and NaOH (4.4 g, 0.11 mol) in EtOH (50 mL) was
stirred for 2 h at room temperature, and EtOH was evapo-
rated. Water was added, and organic materials were extracted
with CH2Cl2, dried (Na2SO4), and passed through a silica gel
plug. The solvent was removed, and the residue was Kugelrohr
distilled (110 °C/0.3 Torr, lit.25 172 °C/7 Torr) to give 4a (18.9
g, 96% yield) as a yellow liquid: 1H NMR (300 MHz, CDCl3) δ
1.06 (t, J ) 7.4 Hz, 3H), 1.75 (sextet, J ) 7.4 Hz, 2H), 2.91 (t,
J ) 7.4 Hz, 2H), 7.21 (td, J 1 ) 7.7 Hz, J 2 ) 1.3 Hz, 1H), 7.38
(dd, J 1 ) 8.2 Hz, J 2 ) 1.0 Hz, 1H), 7.53 (td, J 1 ) 7.7 Hz, J 2
)
1.5 Hz, 1H), 8.14 (dd, J 1 ) 8.3 Hz, J 2 ) 1.4 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 13.6, 21.2, 34.1, 124.1, 125.9, 126.4, 133.3,
138.0, 145.8; MS m/z 197 (M+, 62), 138 (100).
2-P r op ylth ioa n ilin e (5a ).25,61 This compound was pre-
pared according to a modified literature procedure.25 Nitro
derivative 4a (3.0 g, 15.2 mmol) was added to a stirred hot
suspension of fine iron dust (5.6 g, 0.1 mol) in water (8 mL)
containing AcOH (0.5 mL). The mixture was stirred at 100 °C
for 30 min and cooled, and the product was extracted with
hexanes. Organic extracts were dried (Na2SO4) and passed
through a silica gel plug. Solvents were removed and the oily
residue was Kugelrohr distilled (85 °C/0.3 Torr, lit.62 98 °C/1
Torr) to give 5a (1.88 g, 74% yield) as a light yellow liquid:
1H NMR (300 MHz, CDCl3) δ 1.01 (t, J ) 7.3 Hz, 3H), 1.61
(sextet, J ) 7.3 Hz, 2H), 2.75 (t, J ) 7.3 Hz, 2H), 4.3 (s, 2H),
6.68-6.74 (m, 2H), 7.13 (td, J 1 ) 7.6 Hz, J 2 ) 1.6 Hz, 1H),
7.37 (dd, J 1 ) 7.6 Hz, J 2 ) 1.5 Hz, 1H).
3,4,5,6-Tetr a flu or o-2-p r op ylth ioa n ilin e (5d ). A mixture
of 2-bromo-3,4,5,6-tetrafluoroaniline39 (11, 3.2 g, 13.1 mmol),
cuprous 1-propanethiolate (1.82 g, 13.1 mmol), and Cs2CO3
(0.85 g, 2.6 mmol) in dry DMF was stirred vigorously for 3 h
at 120 °C. Additional portions of cuprous 1-propanethiolate
(4 × 1.82 g) and Cs2CO3 (4 × 0.85 g) were added every 3 h.
After 12 h the reaction mixture was cooled and passed through
a Celite plug, which was washed with CH2Cl2. Most of the
solvent was evaporated, and the residue was passed through
a silica gel plug. The resulting solution was washed with water
and dried (Na2SO4). The crude product was purified by column
chromatography (hexanes-CH2Cl2, in a 4:1 ratio) followed by
Kugelrohr distillation (108 °C/0.3 Torr) to give 5d (1.2 g, 38%
yield; other runs 32-38% yield) as a colorless liquid: 1H NMR
(300 MHz, CDCl3) δ 0.97 (t, J ) 7.3 Hz, 3H), 1.56 (sextet, J )
7.3 Hz, 2H), 2.67 (t, J ) 7.3 Hz, 2H), 4.5 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 13.0, 23.1, 36.7, 102.3 (d, J ) 21 Hz), 132.7
(dddd, J 1 ) 244 Hz, J 2 ) 19 Hz, J 3 ) 14 Hz, J 4 ) 3 Hz), 134.6
(td, J 1 ) 12 Hz, J 2 ) 6 Hz), 136.1 (dddd, J 1 ) 228 Hz, J 2 ) 13
Hz, J 3 ) 4 Hz, J 4 ) 2 Hz), 141.4 (dtd, J 1 ) 251 Hz, J 2 ) 14 Hz,
J 3 ) 5 Hz), 149.0 (ddt, J 1 ) 240 Hz, J 2 ) 10 Hz, J 3 ) 4 Hz); 19
F
NMR (282 MHz, CDCl3) δ -133.3 (ddd, J 1 ) 26 Hz, J 2 ) 10
Hz, J 3 ) 5 Hz, 1F), -156.6 (td, J 1 ) 21 Hz, J 2 ) 4 Hz, 1F),
-161.3 (ddd, J 1 ) 21 Hz, J 2 ) 10 Hz, J 3 ) 7 Hz, 1F), -173.1
(td, J 1 ) 23 Hz, J 2 ) 7 Hz, 1F); IR 3488 and 3369 (N-H) cm-1
;
MS m/z 239 (M+, 54), 197 (100). Anal. Calcd for C9H9F4NS:
C, 45.18; H, 3.79; N, 5.85. Found: C, 45.09; H, 3.75; N, 5.93.
(61) Takeuchi, H.; Hirayama, S.; Mitani, M.; Koyama, K. J . Chem.
Soc., Perkin Trans. 1 1988, 521-527.
(62) Parcell, R. F. U.S. Patent 2,836,595, 1956.
(60) Heesing, A.; Homann, W. K.; Mu¨llers, W. Chem. Ber. 1980, 113,
152-164.
2560 J . Org. Chem., Vol. 69, No. 7, 2004

Fused-Ring Thiadiazines
2-Ch lor o-3-p r op ylth iop yr a zin e (8). This compound was
prepared from 2,3-dichloropyrazine (5.0 g, 33.6 mmol) accord-
ing to procedure as described for 4a . Kugelrohr distillation (103
°C/0.3 Torr) gave 8 (6.03 g, 95% yield; other runs 93%-96%
yield) as a bright yellow liquid: 1H NMR (400 MHz, CDCl3) δ
1.03 (t, J ) 7.4 Hz, 3H), 1.72 (sextet, J ) 7.3 Hz, 2H), 3.11 (t,
J ) 7.4 Hz, 2H), 7.96 (d, J ) 2.6 Hz, 1H), 8.25 (d, J ) 2.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 13.4, 22.1, 32.2, 137.4,
141.5, 146.3, 156.9; IR 1337, 1145 and 1053 (ring in-plane)
cm-1; MS m/z 191 and 188 (M+, 17 and 45), 146 (100). Anal.
Calcd for C7H9ClN2S: C, 44.56; H, 4.81; N, 14.85. Found: C,
44.81; H, 4.80; N, 14.87.
8-P r op ylth iotetr a zolo[1,5-a ]p yr a zin e (9). A solution of
NaN3 (2.6 g 40 mmol) and 2-chloro-3-propylthiopyrazine (8,
3.75 g, 20 mmol) in dry DMSO (40 mL) was stirred at 120 °C
for 12 h, cooled, and poured into ice water (50 mL). Organic
materials were extracted with CH2Cl2, washed with water,
dried (Na2SO4), and passed through a silica gel plug. Solvents
were removed, and the crude product was purified by column
chromatography (hexanes-CH2Cl2 in a 1:1 ratio) to give 9 (2.15
g, 55% yield) as a dark yellow oil: 1H NMR (400 MHz, CDCl3)
δ 1.10 (t, J ) 7.4 Hz, 3H), 1.84 (sextet, J ) 7.2 Hz, 2H), 3.37
(t, J ) 7.2 Hz, 2H), 8.02 (d, J ) 4.6 Hz, 1H), 8.42 (d, J ) 4.6
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 13.3, 22.0, 31.5, 113.6,
132.6, 143.0, 155.5; IR 1496, 1455, 1300, 1100 and 974 (all-
in-plane ring) cm-1; MS m/z 167 (M+ - N2, 22) 125 (100). Anal.
Calcd for C7H9N5S: C, 43.06; H, 4.65; N, 35.87. Found: C,
43.36; H, 4.64; N, 35.65.
2-F lu or o-3-p r op ylth iop yr a zin e (10). A mixture of KF (2.1
g, 36 mmol) and 2-chloro-3-propylthiopyrazine (8, 1.35 g, 7.2
mmol) in dry DMSO (30 mL) was stirred for 12 h at 150 °C.
Most of the solvent was removed under reduced pressure (22
Torr), and the residue was cooled and dissolved in water.
Organic materials were extracted with diethyl ether (2 × 20
mL). Combined organic solutions were washed with water (2
× 20 mL), dried (Na2SO4), and passed through a silica gel plug,
and solvent was removed. Kugelrohr distillation (90 °C/0.3
Torr) gave 10 (1.16 g, 94% yield) as a colorless liquid: 1H NMR
(300 MHz, CDCl3) δ 1.04 (t, J ) 7.4 Hz, 3H), 1.74 (sextet, J )
7.3 Hz, 2H), 3.17 (t, J ) 7.3 Hz, 2H), 7.78 (dd, J 1 ) 2.6 Hz, J 2
) 2.0 Hz, 1H), 8.24 (dd, J 1 ) 4.4 Hz, J 2 ) 2.7 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 13.3, 22.2, 30.6, 134.5 (d, J ) 7 Hz),
140.7 (d, J ) 4.5 Hz), 146.3 (d, J ) 32 Hz), 156.2 (d, J ) 253
Hz); 19F NMR (282 MHz, CDCl3) δ -74.4; IR 1324, 1141 and
1062 (ring in-plane) cm-1; MS m/z 172 (M+, 69), 130 (100).
Anal. Calcd for C7H9FN2S: C, 48.82; H, 5.27; N, 16.27.
Found: C, 48.96; H, 5.39; N, 15.93.
3-P h en yl-1-p r op yl-1λ4-ben zo[1,2,4]th ia d ia zin e (12a ). A
solution of NCS (0.41 g, 3 mmol) in dry CH2Cl2 (5 mL) was
added dropwise to a stirred solution of amidine 2a (0.77 g, 2.9
mmol) in CH2Cl2 (15 mL) at -78 °C. The solution was
gradually warmed to room temperature (3 h) and stirred for
an additional 22 h until no more starting amidine was detected
by TLC. The mixture was washed with 5% aqueous NaOH (10
mL), and the organic layer was separated, washed twice with
water, and dried (Na2SO4). The solvent was evaporated to give
crude 12a (0.73 g, 95% yield) as a dark brown oil, which was
used in the next step without further purification: 1H NMR
(300 MHz, CDCl3) δ 0.99 (t, J ) 7.4 Hz, 3H), 1.61 (sextet, J )
7.4 Hz, 2H), 2.58 (dt, J 1 ) 12.4 Hz, J 2 ) 7.7 Hz, 1H), 2.93 (ddd,
J 1 ) 12.4 Hz, J 2 ) 8.0 Hz, J 3 ) 6.9 Hz, 1H), 7.20-7.24 (m,
2H), 7.40-7.48 (m, 4H), 7.52-7.55 (m, 1H), 8.28-8.31 (m, 2H);
13C NMR (75 MHz, CDCl3, major signals) δ 12.9, 15.8, 50.7,
106.2, 125.1, 125.3, 126.4, 127.9, 128.4, 130.5, 133.0, 138.7,
144.8, 164.9.
Ack n ow led gm en t. Financial support for this work
was received from the National Science Foundation
(CHE-0096827).
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal details, procedures, and characterization for other com-
pounds (CuSPr, 1b, 1c, 1d , 2b, 4b, 5b, 5c, 6, 12b, 12d , 13d ,
14c), domputational details, tables of computational results,
crystal data, structure solution and refinement, atomic coor-
dinates, bond lengths and angles, and anisotropic thermal
parameters. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O035835H
J . Org. Chem, Vol. 69, No. 7, 2004 2561