Synthesis of spiroheterocycles derived from benzo[f]chromanone

Article abstract of DOI:10.1002/jhet.636

The syntheses of an important class of hitherto unreported spiro derivatives containing benzo[f]chromanone moiety involving very simple cyclocondensation reactions are described. Installation of pharmacologically active moieties like thiazolidine and thia

Full text of DOI:10.1002/jhet.636

1234
Synthesis of Spiroheterocycles Derived from Benzo[f]chromanone
Vol 48
Anita Pati, Snigdha Mohapatra, and Rajani K. Behera*
School of Chemistry, Sambalpur University, Jyoti Vihar, Burla 768 019, Orissa, India
*E-mail: rajanibehera@yahoo.co.in
Received May 28, 2010
DOI 10.1002/jhet.636
Published online 14 July 2011 in Wiley Online Library (wileyonlinelibrary.com).
The syntheses of an important class of hitherto unreported spiro derivatives containing benzo[f]chro-
manone moiety involving very simple cyclocondensation reactions are described. Installation of pharma-
cologically active moieties like thiazolidine and thiazolidinone is achieved by taking simple reagents
like ethylchloroacetate, 1, 2-dibromo ethane and thioglycollic acid.
J. Heterocyclic Chem., 48, 1234 (2011).
INTRODUCTION
we describe our endeavor towards the synthesis of spi-
ro[benzo[f]chroman-4,60-tetrazine] and spiro[benzo[f]-
chroman-4,20-thiazolidinone] derivatives.
Proliferation of research in spiro chemistry has now
attained considerable height, right from the unprece-
dented synthesis of spiro hydrocarbon by Bayer [1].
Spiro heterocycles in particular fused at a central carbon
atom display diverse biological and pharmaceutical
[2–7] activities due to their interesting conformational
features and structural implications. The presence of the
sterically constrained spiro structure in various natural
products also generates interest in the investigation on
spiro compound [8,9]. During the last few decades, sev-
eral papers have been published on spiro compounds,
which have been reviewed in depth by Sanigrahi [10]
and Pradhan et al. [11].
Recently various spirochromane derivatives have been
reported to exhibit ACC inhibiting activity in low nano-
molar range [12]. The antibiotics b-rubromycine and
c-rubromycine containing spirochromane unit are potent
inhibition of human telomerase and are active against
the reverse transcriptase of human immunodeficiency
virus [13].
RESULTS AND DISCUSSION
Benzo[f]chromanone was prepared by the base-
catalyzed nucleophilic addition reaction of b-naphthol
(1) to acrylonitrile followed by the hydrolysis of cya-
noethylether (2) and subsequent dehydration reaction
(Scheme 1) [15].
Spiro-s-tetrazine derivative (4) of benzo[f]chroman-4-
one was prepared by the reaction of benzo[f]chroman-4-
one with thiocarbohydrazide as per the procedure of
Lamon [16] (Scheme 2). The absence of carbonyl
absorption along with the appearance of bands at 3294
and 1195 cmꢀ1 assignable to m(NAH) and m(C¼¼S),
respectively, support the formation of the spiro tetrazine
product 4. In its PMR spectrum, an upfield shift of the
triplet from d 4.74 (in case of benzochromanone 3) to d
4.36 with J-value 6.4 Hz, due to the absence of the
long-range anisotropic effect of the carbonyl group has
been observed. In addition, a two-proton broad singlet at
d 10.06 assignable to two NH protons and two one pro-
ton broad singlets at d 10.70 and d 10.89, may be due
The above reports gave us an impetus to develop
simple synthetic strategy for preparing new spirohetero-
cycles efficiently from benzochromanone. In continu-
ance of our interest in the spirochemistry [14], herein
C
V
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November 2011
Synthesis of Spiroheterocycles Derived from Benzo[f]chromanone
1235
Scheme 1
to the two CSNH protons were observed. The cyclocon-
densation of spiro-s-tetrazine derivative (4) with ethyl-
chloroacetate in presence of pyridine gives the corre-
sponding thiazolidinone derivative (6) (Scheme 2). The
absence of chlorine and ACOOH group in the chemical
analysis of the compound and the appearance of car-
bonyl stretching frequency at 1728 cmꢀ1 in its IR spec-
trum along with a prominent peak at 1616 cmꢀ1 assign-
able to C¼¼N stretching suggests the formation of the
expected product 6. In the PMR spectrum of the product
appearance of a two proton singlet at d 3.97 due to the
ACH2- group of the thiazolidinone ring along with a
two proton broad singlet (exchangeable with D2O) at d
9.70 due to the two NH protons confirms the structure
of the spiro thiazolo-s-tetrazine as 6. The spiro [thia-
zole-s-tetrazine] derivative was condensed with benzal-
dehyde in presence of piperidine in ethanol to form ben-
zylidine derivative (7) (Scheme 2). The bathocromic
shift of the carbonyl stretching frequency from 1728
cmꢀ1 to 1705 cmꢀ1 due to conjugation with the exocy-
clic double bond confirms the formation of the benzyli-
dene derivative (7). The one pot reaction of tetrazine de-
rivative (4), ethylchloroacetate and benzaldehyde in
presence of bases pyridine and piperidine in a sequential
manner yields the same benzylidene derivative (7)
(Scheme 2).The IR and PMR spectra of the product
formed in both the routes are completely super impos-
able. Spiro-s-tetrazine derivative (4) on condensation
with 1, 2-dibromo ethane gives dihydrospiro thiazolo-s-
tetrazine derivatives (5) (Scheme 2). The appearance of a
prominent peak at 1618 cmꢀ1 due to the C¼¼N stretching
in the IR spectrum and two proton triplets at d 2.90, 2.99,
4.36, and 4.61 with J-value 6 Hz in the PMR spectrum of
(5) in addition to all other peaks as observed in the PMR
spectrum of 4 support the proposed structure 5.
Hydrazone and thiosemicarbazone derivatives (8) of
benzochromanone 3 were prepared by the acid catalyzed
condensation of benzochromanone with benzoyl hydra-
zine/4-phenyl thiosemicarbazone (Scheme 3).
In the IR spectrum of compound 8a, the shifting of
the carbonyl stretching frequency from 1670 cmꢀ1 to
1660 cmꢀ1 along with the appearance of two bands at
3209 and 1633 cmꢀ1 assignable to m(NAH)str and
m(C¼¼N)str confirms the condensation of the carbonyl
group with benzoyl hydrazine. In the PMR spectrum of
compound 8a, the appearance of a broad singlet at d
9.75 assignable to the NH proton along with the two
triplets at d 4.37 and d 3.00 with J-value 6 Hz assigna-
ble to the two CH2 group of the chromane moiety con-
firms the formation of the product as 8a.
The facile synthesis of spirothiazolidinone derivative
(9) was achieved by the condensation of thioglycollic
acid with hydrazone/phenylthiosemicarbazone deriva-
tives of benzochromanone (Scheme 3). The absence of
the ACOOH group in the chemical analysis of com-
pound (9a) and the appearance of two carbonyl stretch-
ing frequencies, one at 1708 cmꢀ1 and another at 1664
cmꢀ1 along with the disappearance of the m (C¼¼N)str in
Scheme 2
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A. Pati, S. Mohapatra, and R. K. Behera
Vol 48
Scheme 3
1
200ꢁC. IR (KBr) (mmax/cmꢀ1): 1269 (C¼¼S), 3294 (NAH). H-
NMR (400 MHz, CDCl3): dH (ppm): 3.14 (2H, t, J3,2 6.4 Hz,
H-3), 4.36 (2H, t, J2,3 6.4 Hz, H-2), 7.07–7.82 (4H, m, ArH),
9.12 (1H, d, J 7.6 Hz, ArH), 9.38 (1H, d, J 8.4 Hz,
ArH),10.06 (2H, br s, NH),10.70 (1H, s, CSNH), 10.89 (1H, s,
CSNH). MS (CI): m/z 287 [MþH]þ. Anal. Calcd for
C14H14N4OS: C, 58.74; H, 4.90; N, 19.58. Found: C, 58.43; H,
4.56; N, 19.21.
the IR spectrum suggests the formation of the product.
In the PMR spectrum the appearance of a two proton
singlet at d 3.70 due to the ACH2 protons of the thiazo-
lidinone ring along with all other peaks as observed for
compound (8a) confirms the formation of spirothiazoli-
dinone product (9a). Similarly the structures of 8b and
9b have also been established.
Spiro [Benzo[f]chroman-4,30(4H)[2H] thiazolo[3,2-b]-s-
tetrazine]-6(70H)-one (6). A mixture of tetrazine (4) (0.001
mole, 0.286 g), ethylchloroacetate (0.001 mole, 0.1 mL) and
five drops pyridine in dioxane (15 mL) was heated under
reflux for 9 h. Then it was isolated with ice cold water. The
precipitate thus obtained was filtered and recrystallized from
ethanol to get compound 6. Yield 60%, mp 255ꢁC. IR
(KBr)(mmax/cmꢀ1): 1616 (C¼¼N), 1728 (C¼¼O), 3317 (NAH).
1H NMR (400 MHz, CDCl3): dH (ppm): 2.96 (2H, t, J3,2 6.4
Hz, H-3), 3.97 (2H, s, CH2CO), 4.28 (2H, t, J2, 3 6.4 Hz, H-
2), 7.03–7.78 (m, 3H, ArH), 7.87 (1H, d, J 8.4 Hz, ArH), 9.47
(1H, d, J 7.6 Hz, ArH), 9.63 (1H, d, J 8.4 Hz, ArH), 9.70 (2H,
br s, NH). MS (CI): m/z 327 [MþH]þ. Anal. Calcd for
C16H14N4O2S: C, 58.90; H, 4.29; N, 17.18. Found: C, 58.55;
H, 3.92; N, 16.89.
CONCLUSIONS
In conclusion, we have described efficient and simple
methods for the synthesis of spiro[benzochroman-4,60-
tetrazine] and spiro[benzochroman-4,20-thiazolidinone]
derivatives whose structures have been established on
the basis of their IR and PMR spectral data. Taking into
consideration the literature reports on the biological
activities of the benzo[f]chromanone, tetrazine, and thia-
zolidinone moieties, the spiro compounds containing
these moieties can be expected as the potent antimicro-
bial agents. Thus, the biological study is in progress.
70-Benzylidene spiro[benzo[f]-chroman-4,30(40H)[2H]thiazolo
[3,2-b]-s-tetrazine]-60-one(7). Method – A To a solution of
thiazolidinone (6) (0.001mole, 0.33 g) in dioxane (15 mL),
benzaldehyde (0.001 mole, 0.1 mL) was added and refluxed
for 6 h. The reaction mixture was poured into ice cold water.
The brown precipitate thus obtained was filtered, dried and
purified by column chromatography using ethyl acetate and
EXPERIMENTAL
The melting points were determined in open capillaries on a
sulfuric acid bath and are uncorrected. Purity of the products
was checked by TLC on silica gel G (BDH) using toluene-eth-
ylacetate (4:1) as eluent. IR spectra were recorded on a Shi-
madzu FT-IR Prestige-21 spectrophotometer using KBr as
background and under DRS technique. NMR spectra were
recorded on Varian 200 and 400 MHz FT NMR spectrometer
and were recorded in CDCl3, unless otherwise stated. Mass
spectra were recorded on a LCMS spectrometer, model HP-
5899A. Elemental analyses were performed on Flash 2000 ele-
mental analyzer, and results were within 60.4% of calculated
values. All other reagents and solvents were obtained from
commercial sources and used without further purification.
Spiro [Benzo[f]chroman-4,60-hexahydro-s-tetrazine] -3-
thione (4). To a solution of thiocarbohydrazide (1.06 g, 0.01
mole) in hot water (20 mL), benzochromanone (3) (1.98 g,
0.01 mole) in ethanol (5 mL) was added drop wise under stir-
ring. The product began to precipitate during the course of
addition. Then the reaction mixture was kept overnight in re-
frigerator and the resultant pale yellow solid was filtered,
washed well with hot water and ethanol and finally recrystal-
lized from acetic acid to get compound 4.Yield 72%, mp
toluene as eluent. Yield 58%, mp 225ꢁC. IR(KBr)(mmax
/
cmꢀ1):1616(C¼¼N), 1705(C¼¼O), 3292(NAH).1H-NMR (400
MHz, CDCl3): dH (ppm): 3.10 (2H, t, J3,2 6.4 Hz, H-3), 4.38
(2H, t, J2, 3 6.4 Hz, H-2), 7.06–7.77 (m, 8H, ArH), 7.89 (1H,
d, J 8.4 Hz, ArH), 8.01 (1H, br s, ¼ CHPh), 9.43 (1H, d, J 8.8
Hz, ArH), 9.67 (1H, s, NH), 9.69 (1H, d, J 8.4 Hz, ArH). MS
(CI): m/z 415 [MþH]þ. Anal. Calcd for C23H18N4O2S: C,
66.66; H, 4.34; N, 13.53. Found: C, 66.45; H, 3.98; N, 13.4.
Method – B. A mixture of tetrazine (4) (0.001 mole, 0.29
g), ethylchloroacetate (0.001 mole 0.1 mL) and pyridine in
dioxane was heated under reflux for 4 h. Then to the reaction
mixture, benzaldehyde (0.001 mole, 0.1 mL) and few drops of
piperidine was added and further refluxed for 5 h. The reaction
mixture was cooled and poured into ice cold water. The crude
product thus obtained was purified by column chromatography
using ethyl acetate and toluene as eluent. Yield 65%, mp
225ꢁC, Mixed mp 225ꢁC. Anal. Calcd for C23H18N4O2S: C,
66.66; H, 4.34; N, 13.53. Found: C, 66.31; H, 4.11; N, 13.23.
Journal of Heterocyclic Chemistry
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Synthesis of Spiroheterocycles Derived from Benzo[f]chromanone
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The spectral and analytical data of the product 7 obtained
by Method-B is same as the product obtained in Method-A.
60,70-Dihydrospiro[benzo[f]chroman-4,30 (40H) [2H]thia-
zolo [3,2-b]-s-tetrazine] (5). A mixture of spiro-s-tetrazine of
benzochromanone (4) (2.86 g, 0.01 mole) and 1, 2-dibromo-
ethane (0.85 mL, 0.01 mole) in 1, 4-dioxane was refluxed for
6 h in an oil bath. The reaction mixture was cooled to room
temperature and then poured into ice cold water. The greenish
yellow precipitate thus obtained was filtered, dried and finally
recrystallized from methanol. Yield 67%, mp 195ꢁC. IR (KBr)
(mmax/cmꢀ1): 1618(C¼¼N), 3338 (NAH). 1H-NMR (200 MHz,
CDCl3): dH (ppm): 2.90 (2H, t, J 6 Hz, S-CH2), 2.99 (2H, t, J
6 Hz, CH2), 4.36 (t, 2H, J ¼ 6 Hz, N-CH2), 4.61(t, 2H, J ¼ 6
Hz,O-CH2), 7.03–7.78 (m,4H,ArH), 9.29 (d,1H, J ¼ 8.8 Hz,
ArH), 9.69 (d,1H, J ¼ 8.8 Hz, ArH), 10.61(2H, br s, NH). MS
(CI): m/z 313 [MþH]þ. Anal. Calcd for C16H16N4OS: C,
61.54; H, 5.13; N, 17.95. Found: C, 61.35; H, 4.92; N, 17.58.
4-(Benzamido/phenylthiourido)iminobenzo[f]chroman-4-
one(8). General procedure. To a solution of benzochroma-
none (3) (0.005 mole) in methanol (15 mL), benzoic acid hy-
drazide/4-phenylthiosemicarbazone (0.005 mole) and few
drops of glacial acetic acid were added. The mixture was then
heated under reflux for 7 h. The precipitate thus obtained was
filtered, washed properly with methanol and recrystallized
from methanol.
3.85 (s, 2H, CH2CO), 4.42 (2H, t, J2, 3 6 Hz, H-2), 7.23–7.84
(10H, m, ArH), 9.51–9.54 (1H, m, ArH), 9.56(1H, br s,
NHCS), 9.72 (1H, br s, NHCSPh). MS (CI): m/z 422 [MþH]þ.
Anal. Calcd. for C22H19N3O2S2: C, 62.70; H, 4.51; N, 9.98.
Found: C, 62.51; H, 4.26; N, 9.65.
Acknowledgments. The authors are thankful to Department of
Science and Technology for FIST grant and University Grant
Commission (UGC), New Delhi for financial support. One of the
authors (AP) is grateful to University Grant Commission (UGC),
New Delhi for research fellowship.
REFERENCES AND NOTES
[1] Baeyer, A. Ber Dtsch ChemGes 1900, 33, 3771. Retrieved
from ‘‘http://en.wikipedia.org/wiki/Spiro_compound’’Category: Organic
chemistry
[2] Gomez-Monterrey, I.; Campiglia, P.; Carotenuto, A.; Stiuso,
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di Bosco, A. M.; Grieco, P.; Novellino, E. J Med Chem 2007, 50,
1787.
Compound 8a. Yield 56%, mp 185 ꢁC. IR (KBr) (mmax/cmꢀ1):
[4] Bolognese, A.; Correale, G.; Manfra, M.; Esposito, A.;
Novellino, E.; Lavecchia, A. J Med Chem 2008, 51, 8148.
[5] Singh, C.; Kanchan, R.; Sharma, U.; Puri, S. K. J Med
Chem 2007, 50, 521.
1
1633 (C¼¼N), 1660 (C¼¼O), 3209 (NAH). H-NMR (200 MHz,
CDCl3): dH (ppm): 3.00 (2H, t, J3,2 6 Hz, H-3), 4.37 (2H, t, J2, 3 6
Hz, H-2), 7.04–7.88 (9H, m, ArH), 8.97–9.06 (2H, m, ArH), 9.75
(1H, br s, NH). MS (CI): m/z 317 [MþH]þ. Anal. Calcd for
C20H16N2O2: C, 75.95; H, 5.06; N, 8.86. Found: C, 75.57; H,
4.87; N, 8.56.
[6] Yang, L.; Butora, G.; Jiao, R. X.; Pasternak, A.; Zhou, C.;
Parsons, W. H.; Mills, S. G.; Vicario, P. P.; Ayala, J. M.; Cascieri, M.
A.; MacCoss, M. J Med Chem 2007, 50, 2609.
Compound 8b. Yield 60%, mp 190ꢁC. IR (KBr) (mmax/cmꢀ1):
[7] Kumar, R. R.; Perumal, S.; Senthilkumar, P.; Yogeeswari,
P.; Sriram, D. J Med Chem 2008, 51, 5731.
1
1370 (C¼¼S), 1642 (C¼¼N), 3240 (NAH). H-NMR (200 MHz,
CDCl3): dH (ppm): 3.21 (2H, t, J3,2 6 Hz, H-3), 4.42 (2H, t, J2, 3
6 Hz, H-2), 7.12–7.93 (9H, m, ArH), 8.89–9.23 (2H, m, ArH),
9.42 (1H, br s, NHCS), 9.68 (1H, br s, NHPh). MS (CI): m/z 348
[MþH]þ. Anal. Calcd. for C20H17N3OS: C, 69.16; H, 4.90; N,
12.10. Found: C, 68.84; H, 4.58; N, 11.78.
[8] Dolbier, W. R. Mechanisms of Molecular Migrations,
Thyagarajan, B. S., Ed.; Wiley-Interscience: New York, 1971,
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[9] (a) Kobayashi, J.; Touda, M.; Agemi, K.; Shigemori, H.;
Ishibashi, M.; Saski, T.; Mikami, Y. Tetrahedron 1991, 47, 6617. (b)
Waldmann, H. Synlett 1995, 133.
Spiro[benzo[f]chroman-4,20-(30-(benzamido/phenylthiourido)-
40-thiazolidinone] (9). General procedure. A mixture of hy-
drazone derivative (8) (0.002 mole) and mercaptoacetic acid
(0.006 mole) in 1, 4-dioxane (20 mL) was refluxed for 14 h.
Then was cooled to room temperature and saturated solution
of NaHCO3 was added to it. The crude precipitate thus
obtained was purified by column chromatography using ethyl
acetate and toluene as eluent.
[10] Sanigrahi, M. Tetrahedron 1999, 59, 9007.
[11] Pradhan, R.; Patra, M.; Behera, A. K.; Mishra, B. K.;
Behera, R. K. Tetrahedron 2006, 62, 779.
[12] Shinde, P.; Srivastava, S. K.; Odedara, R.; Tuli, D.; Munshi,
S.; Patel, J.; Zambad, S. P.; Sonawane, R.; Gupta, R. C.; Chauthai-
wale, V.; Dutt, C. Bioorg Med Chem Lett 2009, 19, 949.
[13] Tsang, K. Y.; Brimble, M. A. Tetrahedron 2007, 63, 6015.
[14] (a) Behera, R. K.; Behera, A. K.; Pradhan, R.; Patra, M.
Ind J Chem 2006, 45B, 933; (b) Behera, R. K.; Behera, A. K.; Prad-
han, R.; Pati, A.; Patra, M. Synthetic Commun 2006, 36, 3729; (c)
Behera, R. K.; Behera, A. K.; Pradhan, R.; Pati, A.; Patra, M. Res J
Chem Environ 2006, 10, 18; (d) Behera, R. K.; Behera, A. K.; Prad-
han, R.; Pati, A.; Patra, M. Phosphorus, Sulfur, and Silicon 2009, 184,
753; (e) Behera, R. K.; Pati, A.; Patra, M.; Behera, A. K. Phosphorus,
Sulfur, and Silicon 2009, 184, 2827.
Compound 9a. Yield 60%, mp 168ꢁC. IR (KBr) (mmax/cmꢀ1):
1
1602(C¼¼N),1664(PhC¼¼O),1708(CH2C¼¼O),3211(NAH). H-NMR
(200 MHz, CDCl3): dH (ppm): 2.99(2H, t, J3,2 6 Hz, H-3), 3.70
(s, 2H, CH2CO), 4.34 (2H, t, J2, 3 6 Hz, H-2), 7.03–7.93 (10H, m,
ArH), 9.43–9.47 (1H, m, ArH), 9.73(1H, br s, NH). MS (CI): m/z
391 [MþH]þ. Anal. Calcd. for C22H18N2O3S: C, 67.69; H, 4.16;
N, 7.18. Found: C, 67.47; H, 3.96; N, 6.85.
Compound 9b. Yield 65%, mp 210ꢁC. IR (KBr) (mmax
/
[15] Fitton, A. O.; Smalley, R. K. Practical Heterocyclic Chem-
istry; Academic Press: London, 1968, p 98.
1
cmꢀ1): 1622 (C¼¼N), 1712 (CH2C¼¼O), 3231(NAH). H-NMR
(200 MHz, CDCl3): dH (ppm): 3.02 (2H, t, J3,2 6 Hz, H-3),
[16] Lamon, R.W. J Org Chem 1969, 34, 756.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet