Synthesis and crystal structure determination of 3-phenyl-2-(2- phenylhydrazino)-4H-1-benzothiopyran-4-one

Article abstract of DOI:10.1007/s10870-010-9692-z

A new type of substituted benzothiopyranone, 3-phenyl-2-(2-phenylhydrazino) -4H-1-benzothiopyran-4- one, has been prepared by the condensation-acid cyclization of polylithiated phenylacetic acid phenylhydrazide with lithiated methyl thiosalicylate. Absorption spectra, especially 13C NMR, provided good indication of its structure, which was conclusively established with X-ray rystal structure analysis. In comparison to the few benzothiopyran X-ray reports documented, the benzothiopyranone ring of the molecule was found to be essentially planar, with the 3-phenyl ring nearly perpendicular to the benzothiopyranone fused-ring system. Crystals of C₂₁H ₁₆N₂OS are orthorhombic, P2₁2₁2 ₁, a = 10.140(4) A , b = 10.432(4) A , c = 16.228(7) A , Z = 4, V = 1717(1) A ³, R1 = 0.0267 and wR ₂ = 0.0725 for reflections with I>2σ(I). The molecular packing in the crystal is the result of N-H...O hydrogen bonding. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s10870-010-9692-z

J Chem Crystallogr (2010) 40:536–540
DOI 10.1007/s10870-010-9692-z
ORIGINAL PAPER
Synthesis and Crystal Structure Determination of 3-Phenyl-2-
(2-phenylhydrazino)-4H-1-benzothiopyran-4-one
•
Clyde R. Metz John D. Knight Stefan J. Pastine
•
•
•
William T. Pennington Charles F. Beam
Received: 12 July 2008 / Accepted: 7 January 2010 / Published online: 30 January 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A new type of substituted benzothiopyranone,
3-phenyl-2-(2-phenylhydrazino)-4H-1-benzothiopyran-4-
one, has been prepared by the condensation-acid cycliza-
tion of polylithiated phenylacetic acid phenylhydrazide
with lithiated methyl thiosalicylate. Absorption spectra,
especially 13C NMR, provided good indication of its
structure, which was conclusively established with X-ray
crystal structure analysis. In comparison to the few ben-
zothiopyran X-ray reports documented, the benzothiopyr-
anone ring of the molecule was found to be essentially
planar, with the 3-phenyl ring nearly perpendicular to
the benzothiopyranone fused-ring system. Crystals of
(Fig. 1). BTP-4-ones (R2 = H, alkyl, other; R3 = aryl)
have been studied for their synthetic approaches such
placing substituted aryl moieties in the 3-position of the
thiopyranone ring by condensation via diazonium salts, or
by select oxidation of dihydrobenzothiopyranones [1–5],
for their use in other syntheses such as select oxidation of
the ring sulfur to sulfone or sulfoxides [6, 7], for their
spectrophotometric determination study of basicity [8, 9],
for their biological potential in medicine (e.g., aromatase
inhibition in select cancer studies) [10, 11], and for theo-
retical studies (e.g., Hu¨ckel MO and LCAO calculations)
[12, 13]. Two somewhat related benzothiopyranones have
received limited X-ray structural analysis [14–16], while
other BTP-4-ones (R3 = Ar) have not.
˚
C21H16N2OS are orthorhombic, P212121, a = 10.140(4) A,
˚
b = 10.432(4) A, c = 16.228(7) A, Z = 4, V = 1717(1)
˚
3
A , R1 = 0.0267 and wR2 = 0.0725 for reflections with
˚
Strong-base monoanion and multiple anion syntheses
from this laboratory have resulted in several benzothio-
pyranone preparations: BTP-2-one 4 and BTP-4-ones 6 and
8 (Scheme 1). They involved a Claisen type condensation-
acid cyclization of lithiated methyl thiosalicylate 2 with a
variety of reactive but selective lithiated nucleophiles 3, 5,
or 7, where the condensation occurred at the carboalkoxy
carbon atom of 2. For example, (1) lithiated ethyl propio-
nate 3 was condensed-cyclized with lithiated thiosalicylate
2 to afford BTP-2-one 4 [17]; (2) trilithiated acetoacetan-
ilide 5 was condensed-cyclized with 2 to give BTP-4-one 6
[18]; (3) dilithiated carbomethoxyhydrazones 7 were con-
densed-cyclized with 2 to afford BTP-4-ones 8 [19]. Each
of these studies was straightforward, and structure confir-
mation was made from absorption spectra, comparison of
melting points with a known compound in a few instances,
and a reaction path described with a straightforward
mechanism. This was evident in the third project cited for
BTP-4-ones 8 [19], where carbomethoxyhydrazine, ini-
tially part of the carbomethoxyhydrazones functional group
were displaced by the sulfur of the thiophenol of a
I [ 2r(I). The molecular packing in the crystal is the result
of N–HÁÁÁO hydrogen bonding.
Keywords Phenylhydrazino-benzothiopyranone
synthesis Á X-ray analysis
Introduction
In comparison to benzopyranones, benzothiopyranones
(BTP-4-ones or BTP-2-ones) have received minimal study
C. R. Metz Á J. D. Knight Á S. J. Pastine Á C. F. Beam (&)
Department of Chemistry and Biochemistry,
College of Charleston, Charleston,
SC 29424, USA
e-mail: beamc@cofc.edu
W. T. Pennington
Department of Chemistry, Clemson University,
Clemson, SC 29634, USA
123

J Chem Crystallogr (2010) 40:536–540
537
Experimental Section
O
R4
S
R3
R3
O
Materials and Characterization
S
R2
Fourier transform infrared spectra were obtained on a
Nicolet Impact 410 FT-IR. Proton and 13C NMR spectra
were obtained with a Varian Associates Mercury Oxford
300 MHz nuclear magnetic resonance spectrometer, and
chemical shifts were recorded in d ppm downfield from an
internal tetramethylsilane standard. Combustion analyses
were performed by Quantitative Technologies, Inc., P.O.
Box 470, Salem Industrial Park, Whitehouse, NJ 08888
USA. The tetrahydrofuran (THF) was distilled from
sodium (benzophenone ketyl as an indicator of dryness)
prior to use, and organic chemicals were obtained from
Aldrich Chemical Co.
4H-1-benzothiopyran-4-ones
abbreviation, BTP-4-ones
2H-1-benzothiopyran-2-ones
abbreviation, BTP-2-ones
Fig. 1 Benzothiopyranones
C-acylated intermediate, not isolated, to form BTP-4-ones
8 instead of thiophenol-pyrazole (not illustrated).
While an X-ray crystal structural analysis would have
been an attractive addition in each of the projects illus-
trated in 4, 6, and 8 cited, they were not essential for
absolute structural verification.
Entry compounds, phenylacetic acid phenylhydrazides 9,
were prepared from a phenylacetic acid (or 4-methoxy-
phenylacetic acid for 13a) condensation with phenylhydr-
azine [21]. The preparation 3-phenyl-2-(2-phenylhydrazino)
-4H-1-benzothiopyran-4-one (BTP-4-one) 13 involved the
following reagents and procedure. Lithium diisopropyl-
amide (LDA) (0.079 mol) was prepared by the addition of
49 mL of 1.6 M n-butyllithium in hexanes (0.079 mol) to a
three-neck round-bottomed flask (e.g., 500 mL), equipped
with a nitrogen inlet tube, a side-arm addition funnel (e.g.,
125 mL), and a magnetic stir bar. The flask was cooled in an
An earlier strong base preparation of 3H-pyrazol-3-ones
12 (Scheme 2) resulted from the condensation–cyclization
of polylithiated phenylacetic acid phenylhydrazides 10
(from 9) with aromatic esters including lithiated methyl
salicylate, but the condensation–cyclization of lithiated
thiosalicylate 2 with lithiated hydrazide 10 gave products
that were later determined to be BTP-4-ones 13. Spectral
properties of 13 did not correlate with other pyrazolone 12
products [20]. Other potential cyclization products, in
addition to BTP-4-ones 13, include BTP-2-ones 14 (related
to 4) [17], or other pyrazolones 15.
Scheme 1 Previous
benzothiopyranone (BTP-2-one
and BTP-4-one) related
investigations
methyl thiosalicylate
1
xs LDA
OH
COOCH3
CH3
Li
+
CH3CHCOOCH2CH3
SLi
2
3
S
O
4
O
Li
N
H
C
LiH2C
+
2
O
C
C
O
C
O
C6H5
Li
S
C
NHC6H5
5
6
H2
O
CH2Li
Li
N
2 +
H3CO
C
N
OCH3
C
OCH3
S
O
8
7
123

538
J Chem Crystallogr (2010) 40:536–540
Scheme 2 Reactions: actual
and potential products
SH
HLi Li
H2
C
H
N
C
N
Ph
Ph
O
C
Ph'
C
O
N
Ph'
C
O
N
Li
10
H
H
9
CH
11
N
Ph
Ph'
C
O
N
H
O
Ph'
O
NH
OH
O
Ph'
N
Ph'
O
Ph'
NH
Ph
H
N
OH
N
S
12
S
N
Ph
Ph
H
14
SH
13
15
Ph = C6H5
Ph' = C6H5 or 4-CH3OC6H4
ice water bath and 8.02 g (0.079 mol) of diisopropylamine,
dissolved in 25–30 mL of dry tetrahydrofuran (THF), was
added from the addition funnel at a fast drop wise rate during
a 5 min period (0 °C, nitrogen). The solution was stirred for
an additional 15–20 min, and then rapidly treated via a
powder funnel, with a slurry of 3.39 g (0.015 mol) of 9 and
50 mL of dry THF. After 2 h of polylithiation, 2.91 g
(0.016 mol) of methyl thiosalicylate 1 (97%), dissolved in
25–35 mL of THF was added, during 5 min, to the poly-
lithiated intermediate 10 (Scheme 2), and the solution was
stirred and condensed for 2 h. Finally, 100 mL of 3M
hydrochloric acid was added quickly, and the two-phase
mixture was well stirred and heated under reflux for
approximately 60 min. At the end of this period, the mixture
was poured into a large flask containing ice (ca., 100 g),
followed by the addition of 100 mL of solvent grade ether.
The mixture was then neutralized with solid sodium
bicarbonate, and the liquid layers or solid materials sep-
arated. If a solid appeared at this point, the biphasic
mixture could be filtered using a large Buchner funnel.
The aqueous layer was extracted with ether or THF
(2 9 75 mL), and the organic fractions were combined,
dried (MgSO4), filtered, evaporated, and recrystallized.
Yield of 13, 2.84 g (55%); mp 229–232 °C (ethanol/ben-
the condensation–cyclization of trilithiated 4-methoxy-
phenylacetic phenylhydrazide 10 and 2 [22].
Single Crystal X-Ray Structure Determination
Colorless crystals of C21H16N2OS 13 were recrystallized
from ethanol/benzene in order to give satisfactory crystals
for X-ray determination. Crystal data for X-ray studies were
collected at room temperature on a Siemens R3mV diffrac-
tometer at Clemson University using the x/2h scan mode.
Details of the data collection are reported in Table 1 [23].
The unit cell dimensions were determined by a least-
squares refinement based on the setting angles of 50
carefully centered reflections in the range 31.91°
\ 2h \ 44.98°. Diffraction data were collected for 3068
unique reflections with -12 \ h \ 12, -12 \ k \ 0, and
-19 \ l \ 0. A total of 2939 reflections with I [ 2.0r(I)
were used in the structure determination. Weights based on
counting statistics were applied to the data. No correction
was made for absorption.
The non-hydrogen atoms were refined anisotropically.
The positions for all hydrogen atoms were obtained from
difference maps; the hydrogen atoms were refined with
isotropic thermal parameters. The final least-squares
refinement on F2 converged with R1 = 0.0278 and
wR2 = 0.0733 (all data). The final Fourier map had no hole
zene). IR (KBr) 3456, 1646 and 1599 cm-1 1H NMR
.
(DMSO-d6): d (ppm) 6.80–6.84, 7.20–7.70, 8.25–8.28 (m,
14H, ArH), and 8.81 (s broad, 1H); 13C NMR (DMSO-d6):
d (ppm) 110.1, 112.8, 119.9, 126.4, 126.7, 127.0, 127.6,
128.7, 128.9 [possible isochronous], 130.5, 131.2, 133.2,
135.3, 148.1, 161.7, and 176.2. Anal. calcd. for
C21H16N2OS: C, 73.23; H, 4.68; N, 8.13. found: C, 72.98;
H, 4.60; N, 7.96. 3-(4-Methoxyphenyl-2-(2-phenylhydraz-
ino)-4H-1-benzothiopyran-4-one 13a (R3 = 4-CH3OC6H4)
was prepared in 45% yield by the procedure above from
-3
˚
deeper than -0.169 e A
and no peak greater than
0.127 e A-3. Structure solution, refinement, and the calcu-
lation of derived results were performed using the SHELX-
97 [24] package of computer programs and the analysis of
the crystal packing results was performed using Mercury
[25]. Neutral atom scattering factors were those of Cromer
and Waber [26], and the real and imaginary anomalous
dispersion corrections were those of Cromer [27].
˚
123

J Chem Crystallogr (2010) 40:536–540
539
Table 1 Crystallographic data, 3-phenyl-2-(2-phenylhydrazino)-4H-
1-benzothiopyran-4-one 13
CCDC deposit number [23]
Color/shape
689210
Colorless/parallelopiped
0.44 9 0.56 9 0.82
Crystal dimensions (mm)
Formula
C
21H16N2OS
Formula mass
T (°C)
Crystal system
344.43
22(1)
Orthorhombic
Space group
P212121
˚
a (A)
10.140(4)
˚
b (A)
10.432(4)
˚
c (A)
16.228(7)
3
V (A )
˚
1716(1)
Z
4
dcalc (g cm-3
)
1.333
˚
k (A)
0.71073
l (mm-1
)
0.199
Fig. 2 Thermal ellipsoid plot, 3-phenyl-2-(2-phenylhydrazino)-4H-
1-benzothiopyran-4-one 13 (50% ellipsoids for non-hydrogen atoms)
F(000)
720
h range (°)
Reflections collected
2.32–25.14
3542
˚
Table 2 Selected bond distances (A), bond angles (°), and dihedral
Independent reflections
Independent reflections I [ 2r(I)
Max and min transmission
Data, restraints, parameters
Final R indices I [ 2r(I)
R indices all data
3068
angles (°), 3-phenyl-2-(2-phenylhydrazino)-4H-1-benzothiopyran-4-
one 13
2939
0.9174, 0.8537
3068, 0, 290
S1–C3
1.731(2)
1.235(2)
1.348(2)
1.402(2)
1.428(2)
1.365(2)
1.397(2)
101.72(7)
116.4(2)
118.8(1)
124.3(1)
118.0(1)
125.9(1)
115.2(1)
118.6(1)
122.5(1)
S1–C4
1.739(2)
1.387(2)
0.84(2)
O1–C1
N1–N2
R1 = 0.0267, wR2 = 0.0725
R1 = 0.0278, wR2 = 0.0733
1.044
N1–C3
N1–H1
N2–C10
N2–H2
0.84(2)
Goodness of fit on F2
C1–C2
C1–C9
1.477(2)
1.488(2)
1.388(2)
118.7(1)
121.2(1)
120.0(1)
117.6(1)
112.1(1)
122.1(1)
124.9(1)
123.0(1)
117.6(2)
-3
)
˚
Largest diff peak and hole (e A
0.127, -0.169
C2–C3
C2–C16
C4–C5
C4–C9
C3–S1–C4
N1–N2–C10
O1–C1–C9
C1–C2–C3
C3–C2–C16
S1–C3–C2
S1–C4–C5
C1–C9–C8
N2–C10–C11
N2–N1–C3
O1–C1–C2
C2–C1–C9
C1–C2–C16
S1–C3–N1
N1–C3–C2
S1–C4–C9
C1–C9–C4
N2–C10–C15
Results and Discussion
During the current investigation (Scheme 2) phenylacetic
acid phenylhydrazide 7 was trilithiated to 10 with excess
LDA followed by condensation with lithiated methyl
thiosalicylate 2, and acid cyclization of C-acylated inter-
mediate 11. Intermediate compound 11 was not isolated,
and an acid cyclization with dilute hydrochloric acid (3M)
was implemented. BTP-4-one 13 (R2 = NHNHPh,
R3 = Ph), was isolated in 55% yield, and indicative but
inconclusive absorption spectra (IR, 1H-NMR and 13C-
NMR) plus X-ray crystal analysis confirmed that 13 was an
isomer of the originally targeted product, a substituted 3H-
pyrazol-3-one 12. It also ruled out the possibility of the
product being a 4-hydroxy 2H-1-benzothiopyran-2-one 14.
Additional spectral data was obtained by the preparation
of another benzothiopyranone 13a from 4-methoxyphen-
ylacetic hydrazide 9a. Its preparation also indicated that the
preparation of 13 was not an isolated single result.
The molecular structure of C21H16N2OS 13 is shown in
Fig. 2 and selected bond distances and angles are listed in
Table 2. The bond lengths agree with the assignment of the
double bond shown in 13 between C2 and C3 and the single
bonds shown for C1–C9, C1–C2, C3–S1, and S1–C4.
The least squares best planes representing the fused
rings are nearly coplanar with an angle of 3.38° between
them. The two phenyl groups are nearly perpendicular to
the heterocyclic ring containing S1 with angles of 86.35°
123

540
J Chem Crystallogr (2010) 40:536–540
7. Patonay T, Adam W, Levai A, Kover P, Nemeth M, Peters EM,
Peters K (2001) J Org Chem 66:2275
and 88.75° for the rings containing C10 and C16,
respectively.
8. Tolmachev AI, Shulezhko LM, Kisilenko AA (1967) Zhurnal
Obshchei Khimii 37:367; Chem Abstr 67:53984
9. David RD, Sabo V, Rakosh M (1967) Visnik Kiivs’kogo Uni-
versitetu, Seriya Fiziki ta Khimii 176; Chem Abstr 69:72439
10. Kim Y-W, Hackett JC, Brueggemeier RW (2004) J Med Chem
47:4032
11. Bargagna A, Longobardi M, Mariani E, Schenone P, Losasso C,
Esposito G, Falzarano C, Marmo E (1990) Farmaco 45:405
12. Tolmachev AI, Dyadyusha GG, Shulezhk LM (1970) Teore-
ticheskaya i Eksperimental’naya Khimiya 6:185; Chem Abstr 73:
55511
13. Volovenko YM, Litenko VA, Zamkovoi VI, Babichev FS (1988)
Ukrainskii Khimicheskii Zhurnal 54:1294; Chem Abstr
111:77193
14. Nakazumi H (1993) Senryo to Yakuhin 38:269; Chem Abstr
120:163828
15. Nakazumi H, Watanabe S, Kitao T (1992) J Chem Res Synop 212
16. Nelson A (2003) Sci Syn 14:787
17. Davis SE, Church AC, Tummons RC, Beam CF (1997) J Het-
erocycl Chem 34:1159
18. Angel AJ, Finefrock AE, French KL, Hurst DR, Williams AR,
Rampey ME, Studer-Martinez SL, Beam CF (1999) Can J Chem
77:94
19. French KL, Angel AJ, Williams AR, Hurst DR, Beam CF (1998)
J Heterocycl Chem 35:45
The packing of the molecules in the unit cell results
from the formation of N–HÁÁÁO intermolecular hydrogen
bonding between each molecule and two additional mole-
cules. Each O1 forms two hydrogen bonds with a second
˚
molecule with bond lengths of 2.128 A and 2.651 A for
˚
O1ÁÁÁH1–N1 and O1ÁÁÁH2–N2, respectively.
Conclusions
X-ray analysis is important for the conclusive structure
determination of 3-phenyl-2-(2-phenylhydrazino)-4H-1-
benzothiopyran-4-one 13, which unexpectedly resulted
from the condensation–cyclization of trilithiated phenyla-
cetic acid phenylhydrazide 10 with lithiated methyl thio-
salicylate 2. The product 13 resulted from an anionic
nucleophile 10 and an anionic electrophile 2 condensation,
involving the carbanion-type center of the dilithiated
phenylhydrazide 10 with the carbomethoxy carbon of the
lithiated thiosalicylate 2, followed by a selective cycliza-
tion. It is not an isolated result.
20. Downs JR, Pastine SJ, Townsend JD, Greer HA, Kelley W Jr,
Schady DA, Lentz-McConaughy T, Metz CR, Beam CF, Alm-
quist CD, Pennington WT, Walsch RDB (2001) J Heterocycl
Chem 38:695
21. Downs JR, Grant SP, Townsend JD, Schady DA, Pastine SJ,
Embree MC, Metz CR, Pennington WT, Walsch RDB, Beam CF
(2004) Can J Chem 82:659
Acknowledgements We wish to thank the following sponsors: the
Research Corporation, the National Science Foundation grants CHE #
9708014 and # 0212699 for Research at Undergraduate Institutions,
the United States Department of Agriculture, NRICGP # 2003-35504-
12853, and the Petroleum Research Fund, Administered by the
American Chemical Society. The College of Charleston awarded
summer grants through its Summer Undergraduate Research Forum
(SURF-2006) to J. D. Knight.
22. 3-(4-Methoxyphenyl-2-(2-phenylhydrazino)-4H-1-benzothiopy-
ran-4-one 13a mp 178–180 °C (ethanol/benzene). IR 3377 and
3317, and 1658 cm-1 1H NMR (CDCl3): d (ppm) 3.90 (s, 3H,
.
ArOCH3), 6.98–702, 7.25–7.78, 8.53–8.56 (m, 13H, ArH); 13C
NMR (CDCl3): d (ppm) 55.6, 113.0, 124.2, 126.6, 127.5, 127.7,
129.6, 129.8, 131.6, 132.5, 133.1, 133.7, 136.1, 139.9, 152.0,
157.1, 159.9, and 182.5. Anal. calcd. for C22H18N2O2S: C, 70.57;
H, 4.85; N, 7.48. found: C, 70.97; H, 4.37; N, 7.88
References
23. CCDC 689210 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif
24. Sheldrick GM (1997) SHELX-97, crystallographic computing
system—Windows version. University of Gottingen, Germany
25. Cambridge Crystallographic Data Centre (CCDC) (2005) Mer-
cury, Cambridge, England
1. Nakazumi H, Endo T, Sonoda H, Kitao T (1985) J Heterocycl
Chem 22:821
2. Baker W, Clarke GG, Harborne JB (1954) J Chem Soc, Abstracts
998; Chem Abstr 49:20054
3. Patonay T, Cavaleiro JAS, Levai A, Silva AMS (1997) Hetero-
cycl Commun 3:223
4. Katekar GF, Thomson RM (1972) Aust J Chem 25:647
5. Volovenko YM, Litenko VA, Dashkovskaya EV, Babichev FS
(1982) Khimiya Geterotsiklicheskikh Soedinenii 1047; Chem
Abstr 97:182164
26. International Tables for X-Ray Crystallography (1974) Vol IV,
Tables 2.2 B and 2.3.1. Kluwer Acadmenic Publisher, Dordrecht
27. Farrugia LJ (1997) J Appl Cryst 30:565
6. Szabo V, Borda J, Vegh V (1979) Acta Chimica Academiae
Scientiarum Hungaricae 98:457; Chem Abstr 91:20258
123