A new LiBr-catalyzed, facile and efficient method for the synthesis of 14-alkyl or aryl-14H-dibenzo[a,j]xanthenes and tetrahydrobenzo[b]pyrans under solvent-free conventional and microwave heating

Article abstract of DOI:10.1055/s-2006-947339

An efficient method for the synthesis of 14-alkyl or aryl-14H-dibenzo[a,j] xanthenes and tetrahydrobenzo[b]pyrans under solvent-free conventional and microwave heating using lithium bromide, is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-947339

1928
LETTER
A New LiBr-Catalyzed, Facile and Efficient Method for the Synthesis of
14-Alkyl or Aryl-14H-dibenzo[a,j]xanthenes and Tetrahydrobenzo[b]pyrans
under Solvent-Free Conventional and Microwave Heating
S
ynthesis of 14-Al
n
kyl or
A
ryl-1
i
4
H
-dib
l
enzo[a.j]xan
Sthenes aini, Sanjay Kumar, Jagir S. Sandhu*
Department of Chemistry, Punjabi University, Patiala 147 002, India
Fax +91(175)2283073; E-mail: j_sandhu2002@yahoo.com
Received 8 May 2006
Abstract: An efficient method for the synthesis of 14-alkyl or aryl-
14H-dibenzo[a,j]xanthenes and tetrahydrobenzo[b]pyrans under
solvent-free conventional and microwave heating using lithium bro-
mide, is described.
Key words: xanthenes, tetrahydrobenzo[b]pyrans, solvent-free,
lithium bromide, microwave irradiation
Scheme 1
Xanthenes and particularly benzoxanthenes constitute an
important group of oxygen heterocycles which have ex-
tended conjugation conferring interesting spectroscopic
properties and as such have many applications in laser
methodologies.1,2 Benzoxanthene derivatives have shown
good promise as sensitizers in photodynamic therapy
(PDT), a well known method of controlling the localized
tumours.3 Additionally, these compounds also have
promising antibacterial,4 antiviral5 and antiinflammatory
activities6 and can be used as luminescent sensors.7
In a typical example, benzaldehyde (2 mmol), b-naphthol
(4 mmol) and LiBr (0.3 mmol) were mixed and stirred for
5 minutes at room temperature and then the temperature
was raised to 130 °C and maintained for 65 minutes
(Method A). After completion of reaction (TLC), the re-
action mixture was cooled to room temperature and water
(20 mL) was added. The solid thus obtained was filtered
and recrystallized with ethanol to afford colorless crystals
of 14-phenyl-14H-dibenzo[a,j]xanthene (3a), in 82%
yield, mp 184–85 °C (lit.10a mp 185 °C; entry 1, Table 1).
Similarly, other aldehydes were reacted with b-naphthol
to afford various xanthene derivatives 3b–k (Table 1).
When the reaction was carried out under microwave irra-
diation (Method B), equivalent results were obtained and
the xanthene derivatives were obtained in 77–86% yield
(Table 1). The reaction proved to be very reproducible
and could be carried out in a domestic microwave oven as
well as a purpose designed Prolabo Microwave Module
Synthwave S-402.
Methods reported for the production of xanthenes include
aryne cycloaddition to phenols,8 intramolecular coupling
of aldehydes and ketones,9 cyclodehydration,10 and from
precursors like formamide,11 toxic carbon monoxide,12
protected aldehydes13 and finally 2-napthol-1-methanol.14
Several of these methods involve harsh reaction condi-
tions or long reaction time leaving considerable scope for
development of further clean, facile and efficient process
for the synthesis of these important molecules. We and
others15 have been using LiBr as a mild Lewis acid in
many chemical transformations,16 including the Friedel–
Crafts reaction, preparation of acylals, opening of
epoxides, Knoevenagel condensation, Bigginelli conden-
sation, Ehrlich–Sachs reaction. In most of these reported
reactions, the LiBr is almost neutral.16 We have also been
active in the area of microwave heating under solvent free
conditions.17,18 In continuation of our investigations with
LiBr and microwave heating we describe herein a new ef-
ficient and facile method for the production of xanthenes
using LiBr under solvent free condition by applying con-
ventional as well as microwave heating (Scheme 1).
In the course of optimization of the reaction conditions,
increase in reaction time did not prove fruitful. About 15
mol% of LiBr seems to be the optimum amount of Lewis
acid and higher amounts of catalyst (20 mol%) did not
improve the yields while decreasing the amount of cata-
lyst decreases the yield. The reaction works well with
aromatic aldehydes (entry 1–9, Table 1) as well as aliphat-
ic aldehydes (entries 10 and 11, Table 1), giving various
xanthene derivatives in 77–86% yields. As can be seen in
Table 1, the method is general and tolerates a variety of
functional groups.
Encouraged by these results we were delighted to observe
this protocol, could safely be extended to a three-compo-
nent coupling reaction involving equimolar quantity of al-
dehyde 1, 5,5-dimethyl-1,3-cyclohexanedione (4) and
active methylene compounds 5. Tetrahydrobenzo[b]pyr-
ans 6a–e were obtained in excellent yields (Scheme 2,
Table 2) without the formation of any side products.
SYNLETT 2006, No. 12, pp 1928–1932
Advanced online publication: 24.07.2006
DOI: 10.1055/s-2006-947339; Art ID: D03806ST
© Georg Thieme Verlag Stuttgart · New York
0
1
.0
8
.2
0
0
6

LETTER
Synthesis of 14-Alkyl or Aryl-14H-dibenzo[a,j]xanthenes
1929
Table 1 LiBr-Mediated Synthesis of 14-Alkyl or Aryl-14H-dibenzo[a,j]xanthenes19
Entry
Aldehyde
Producta
Method Ab
Time (min)
Method Bb
Time (min)
Mp (°C)
Yield (%)c
82
Yield (%)c
83
1
2
3
3a
3b
3c
65
60
70
4.0
3.5
4.5
184–8510a
295–9710a
203–04
83
80
81
82
4
5
6
7
3d
3e
3f
65
60
65
60
81
84
80
84
3.5
3.0
3.5
3.5
80
86
80
85
190–92
287–8910b
214–15
3g
309–1010a
8
9
3h
3i
70
65
81
82
4.0
3.0
84
82
210–11
227–2910a
10
11
EtCHO
3j
75
75
78
77
4.5
4.5
79
78
112–13
MeCHO
3k
172–7313
a The products were characterized by comparison of their melting points and spectral (IR, 1H NMR) data with those of authentic samples.
b Method A: reaction carried out under thermal condition in solvent-free conditions. Method B: reactions carried out under microwave irradi-
ation in solvent-free conditions.
c Isolated yields after recrystallization.
Results of the investigation involving thermal (method A) Similarly, other tetrahydrobenzo[b]pyrans 6b–e were
as well as microwave (method B) irradiation are presented obtained (Table 2) by the reaction of aldehydes, 5,5-di-
in Table 2.
methyl-1,3-cyclohexanedione and active methylene com-
pounds. When the reaction was carried out under
microwave irradiation (Method B), equivalent results
were obtained and the tetrahydrobenzo[b]pyran deriva-
tives were obtained in 81–86% yield (Table 2).
In a typical example, benzaldehyde (2 mmol), 5,5-di-
methyl-1,3-cyclo-hexanedione (2 mmol), malononitrile
(2 mmol) and LiBr (0.3 mmol) were mixed and stirred for
5 minutes at room temperature. The reaction mixture was
then maintained at 90 °C for 55 minutes (Method A). It is worth mentioning here that we did not observe the
After completion of the reaction (TLC), the reaction formation of 3,3,6,6-tetramethyl-9-aryl-1,8-dioxo-octa-
mixture was cooled to room temperature and water (20 hydroxanthenes 7 which would arise by the reaction of
mL) was added. The solid thus obtained was filtered 5,5-dimethyl-1,3-cyclohexanedione with aldehyde. Evi-
and recrystallized with ethanol to afford colorless crystals dently it appears that R1CH2CN being activated competes
of 2-amino-3-cyano-4-phenyl-7,7-dimethyl-5-oxo-4H- successfully in condensation with the aldehyde so the
5,6,7,8-tetrahydrobenzo[b]pyran (6a), 84% yield, mp formation of 3,3,6,6-tetramethyl-9-aryl-1,8-dioxo-octa-
232–234 °C (lit.21 mp 233–234 °C; entry 1, Table 2). hydroxanthenes 7 is suppressed.
Synlett 2006, No. 12, 1928–1932 © Thieme Stuttgart · New York

1930
A. Saini et al.
LETTER
Scheme 2
Table 2 LiBr-Mediated Synthesis of Tetrahydrobenzo[b]pyrans20
Entry
Aldehyde
R1
Producta
Method Ab
Method Bb
Mp (°C)21
Time (min) Yield (%)c Time (min) Yield (%)c
1
2
3
4
5
CN
6a
6b
6c
6d
6e
55
50
60
60
60
84
86
82
80
82
8.0
7.5
8.5
8.5
8.5
84
86
81
82
85
232–234
216–218
199–200
191–193
257–258
CN
CN
CO2Et
CO2Et
a Melting points, IR, 1H NMR were in accordance with those of authentic samples.
b Reaction condition: aldehyde 1 (2 mmol), 5,5-dimethyl -1,3-cyclohexanedione (4, 2 mmol), active methylene compound 5 (2 mmol) and LiBr
(0.30 mmol) were heated to reflux (Method A) or irradiated in a microwave oven at 500 W (Method B) for the appropriate time as shown in
Table 2.
c Isolated yields after recrystallization.
In conclusion, we have developed a quick, clean and sim-
ple method for the synthesis of 14H-dibenzo[a,j]xan-
thenes and tetrahydrobenzo[b]pyrans under solvent-free
conditions using thermal as well as microwave heating.
Further merits of this method are its generality, shorter
reaction times and easy work-up. The catalyst used here is
near neutral in nature unlike previously used Brønsted
acids or strong dehydrating agents such as POCl3.
References and Notes
(1) Green, G. R.; Evans, J. M.; Vong, A. K. In Comprehensive
Heterocyclic Chemistry II, Vol. 5; Katritzky, A. R.; Rees, C.
W.; Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1995,
469.
(2) (a) Sirkeciolgu, O.; Talini, N.; Akar, A. J. Chem. Res.,
Synop. 1995, 502. (b) Ahmad, M.; King, T. A.; Ko, D.-K.;
Cha, B. H.; Lee, J. J. Phys. D: Appl. Phys. 2002, 35, 1473.
(c) Ion, R. M.; Fara, V. L. Proc. Indian Acad. Sci. 1999, 107,
825.
(3) (a) Ion, R. M. Progr. Catal. 1997, 2, 55. (b) Ion, R. M.;
Frackowiak, D.; Planner, A.; Wiktorowicz, K. Acta Biochim.
Pol. 1998, 45, 833.
(4) Hideo, T. Jpn. Tokkyo Koho JP56005480, 1981; Chem.
Abstr. 1981, 95, 80922b.
Acknowledgment
Authors thank the Council of Scientific and Industrial Research,
New Delhi, India for financial support to this research project.
Assistance by Dr D. Prajapati, Scientist, RRL Jorhat is duly
acknowledged.
Synlett 2006, No. 12, 1928–1932 © Thieme Stuttgart · New York

LETTER
Synthesis of 14-Alkyl or Aryl-14H-dibenzo[a,j]xanthenes
1931
(5) Lambert, R. W.; Martin, J. A.; Merrett, J. H.; Parkes, K. E.
B.; Thomas, G. J. PCT Int. Appl. WO9706178, 1997; Chem.
Abstr. 1997, 126, 212377y.
(6) Poupelin, J. P.; Saint-Ruf, G.; Foussard-Blanpin, O.;
Narcisse, G.; Uehida-Ernouf, G.; Lacroix, R. Eur. J. Med.
Chem. 1978, 13, 67.
(7) Callan, J. F.; De Silva, P.; Magri, D. C. Tetrahedron 2005,
61, 8551.
(8) (a) Knight, D. W.; Little, P. B. Synlett 1998, 1141.
(b) Knight, D. W.; Little, P. B. J. Chem. Soc., Perkin Trans.
1 2001, 14, 1771.
Method B.
A mixture of aldehyde (2 mmol,), b-naphthol (4 mmol) and
LiBr (0.3 mmol) were irradiated in a domestic microwave
oven at 500 W for the appropriate time according to Table 1.
After completion of reaction (TLC), the reaction mixture
was cooled to r.t. and H2O (20 mL) was added and the
mixture stirred for 5 min. The solid thus obtained was
filtered and the crude product obtained was purified by
recrystallization from EtOH.
(20) General Procedure for the Synthesis of
Tetrahydrobenzo[b]pyran – Method A.
A mixture of aldehyde (2 mmol,), 5,5-dimethyl-1,3-cyclo-
hexanedione (2 mmol), active methylene compound (2
mmol) and LiBr (0.6 mmol) was mixed and stirred for 5 min
at r.t. and then heated at 90 °C for the appropriate time given
in Table 2. After completion of reaction (TLC), the reaction
mixture was cooled to r.t., H2O (20 mL) was added and the
mixture stirred for 5 min. The solid thus obtained was
filtered and the crude product obtained was purified by
recrystallization from EtOH.
(9) Jha, A.; Beal, J. Tetrahedron Lett. 2004, 45, 8999.
(10) (a) Sarma, R. J.; Baruah, J. B. Dyes Pigm. 2005, 64, 91.
(b) Bekaert, A.; Andrieux, J.; Plat, M. Tetrahedron Lett.
1992, 33, 2805. (c) Buechler, C. A.; Cooper, D. E.;
Scrudder, E. O. J. Org. Chem. 1943, 8, 316.
(11) Papini, P.; Cimmarusti, R. E. Gazz. Chim. Ital. 1947, 77,
142.
(12) Ota, K.; Kito, T. Bull. Chem. Soc. Jpn. 1976, 49, 1167.
(13) Van Allan, J. A.; Giannini, D. D.; Whitesides, T. H. J. Org.
Chem. 1982, 47, 820.
Method B.
A mixture of aldehyde (2 mmol), 5,5-dimethyl-1,3-cyclo-
hexanedione (2 mmol), active methylene compound (2
mmol) and LiBr (0.6 mmol) was irradiated in a domestic
microwave oven at 500 W for the appropriate time according
to Table 2. After completion of reaction (TLC), the reaction
mixture was cooled to r.t., H2O (20 mL) was added and the
mixture stirred for 5 min. The solid thus obtained was
filtered and the crude product obtained was purified by
recrystallization from EtOH.
(14) Sen, R. N.; Sarkar, N. N. J. Am. Chem. Soc. 1925, 47, 1079.
(15) (a) Ono, F.; Negoro, R.; Sato, T. Synlett 2001, 1581.
(b) Pushin, A. N.; Trachentro, S. E.; Martynov, I. V. Dokl.
Akad. Nauk SSSR 1988, 299, 154. (c) Seeback, D.; Thaler,
A.; Blaser, D.; Ko, S. Y. Helv. Chem. Acta 1991, 74, 1102.
(d) Prajapati, D.; Lekhok, K. R.; Sandhu, J. S.; Ghosh, A. C.
J. Chem. Soc., Perkin Trans. 1 1996, 959. (e) Baruah, P. P.;
Gadhwal, S.; Prajapati, D.; Sandhu, J. S. Synlett 2002, 1038.
(f) Laskar, D. D.; Prajapati, D.; Sandhu, J. S. Synth.
Commun. 2001, 1427.
(21) (a) Wang, X. S.; Shi, D. Q.; Tu, S. J.; Yao, C. S. Synth.
Commun. 2003, 33, 119..(b) Selected Characterization
Data. 14-Phenyl-14H-dibenzo[a,j]xanthene (3a, Table 1,
Entry 1).
(16) (a) Firouzabadi, H.; Karimi, B.; Eslami, S. Tetrahedron Lett.
1999, 4055. (b) Firouzabadi, H.; Iranpoor, N.; Karimi, M.
Synthesis 1999, 58.
Mp 184–85 °C. IR (KBr): 3030, 1612, 1242 cm–1. 1H NMR
(200 MHz, CDCl3): d = 6.75 (s, 1 H), 7.10–8.10 (m, 17 H).
Anal. Calcd for C27H18O: C, 90.47; H, 5.06. Found: C, 90.55;
H, 5.15.
(17) (a) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(b) Hayes, B. L. Aldrichimica Acta 2004, 37, 66.
(c) Nüchter, M.; Ondruschka, B.; Bonrath, W.; Gum, A.
Green Chem. 2004, 4, 128. (d) Mavanadadi, F.; Lidstrom,
P. Curr. Top. Med. Chem. 2004, 4, 773. (e) Al-Obeidi, F.;
Austin, R. E.; Okonya, J. F.; Bond, D. R. S. Mini Rev. Med.
Chem. 2003, 3, 449. (f) Wilson, N. S.; Roth, G. P. Curr.
Opin. Drug Discovery Dev. 2002, 5, 620. (g) Lidstrom, P.;
Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57,
9225.
(18) (a) Laskar, D. D.; Gohain, M.; Prajapati, D.; Sandhu, J. S.
New J. Chem. 2002, 193. (b) Sarmah, U.; Boruah, R. C.;
Sandhu, J. S. Tetrahedron Lett. 2002, 43, 143. (c) Laskar,
D. D.; Prajapati, D.; Sandhu, J. S. Chem. Res., Synop. 2001,
313. (d) Thakuria, J. A.; Baruah, M.; Sandhu, J. S. Chem.
Lett. 1999, 995. (e) Gadhwal, S.; Baruah, M.; Sandhu, J. S.
Synlett 1999, 1573. (f) Karmakar, D.; Prajapati, D.; Sandhu,
J. S. J. Chem. Res., Synop. 1998, 382. (g) Borah, H. N.;
Boruah, R. C.; Sandhu, J. S. J. Chem. Res., Synop. 1998,
272. (h) Konwar, D.; Boruah, R. C.; Sandhu, J. S.
Tetrahedron Lett. 1997, 38, 4267. (i) Baruah, B.; Prajapati,
D.; Baurah, A.; Sandhu, J. S. Tetrahedron Lett. 1997, 38,
449.
14-(4-Methoxyphenyl)14-H-dibenzo[a,j]xanthene (3c,
Table 1, Entry 3).
Mp 203–04 °C. IR (KBr): 3035, 1621, 1581, 1252. cm–1. 1H
NMR (200 MHz, CDCl3): d = 3.50 (s, 3 H), 6.45 (s, 1 H),
6.73 (d, J = 9.3 Hz, 2 H), 7.36–7.92 (m, 12 H), 8.36 (d,
J = 9.3 Hz, 2 H). Anal. Calcd for C28H20O2: C, 86.57; H,
5.19. Found: C, 86.35; H, 5.29.
14-(3-Bromophenyl)-14-H-dibenzo[a,j]xanthene (3d,
Table 1, Entry 4).
Mp 190–92 °C. IR (KBr): 3040, 1613, 1245. cm–1. 1H NMR
(200 MHz, CDCl3): d = 6.62 (s, 1 H), 7.21–20 (m, 16 H).
Anal. Calcd for C27H17BrO: C, 74.15; H, 3.92. Found: C,
74.21; H, 3.86. UV (CHCl3): lmax = 245, 266, 335 nm.
14-(4-Nitrophenyl)-14H-dibenzo[a,j]xanthene (3g, Table
1, Entry 7).
Mp 309–10 °C. IR (KBr): 3070, 1615, 1540, 1355, 1245.
cm–1. 1H NMR (200 MHz, CDCl3): d = 7.20–7.90 (m, 12 H),
8.15 (d, J = 9.0 Hz, 2 H), 8.55 (d, J = 9.0 Hz, 2 H). Anal.
Calcd for C27H17NO3: C, 80.38; H, 4.25; N, 3.47. Found: C,
80.29; H, 4.10; N, 3.55. UV (CHCl3): lmax 245, 259, 335 nm.
14-(4-Methylphenyl)-14H-dibenzo[a,j]xanthene (3i,
Table 1, Entry 9).
(19) General Procedure for the Synthesis of 14-Alkyl or Aryl
Dibenzo[a,j]xanthenes – Method A.
A mixture of aldehyde (2 mmol), b-naphthol (4 mmol) and
LiBr (0.3 mmol) were mixed and stirred for 5 min at r.t. and
then temperature was raised to 130 °C and maintained for
the appropriate time given in Table 1. After completion of
reaction (TLC), the reaction mixture was cooled to r.t. and
H2O (20 mL) was added and the mixture stirred for 5 min.
The solid thus obtained was filtered and the crude product
obtained was purified by recrystallization from EtOH.
Mp 227–29 °C. IR (KBr): 3038, 1618, 1240 cm–1. 1H NMR
(200 MHz, CDCl3): d = 2.30 (s, 3 H), 6.55 (s, 1 H), 7.15–
7.95 (m, 16 H). Anal. Calcd for C28H20O: C, 90.29; H, 5.41.
Found: C, 90.41; H, 5.49.
14-Ethyl-14H-dibenzo[a,j]xanthene (3j, Table 1, Entry
10).
Mp 112–13 °C. IR (KBr): 3045,2901, 1615, 1221 cm–1. 1H
NMR (200 MHz, CDCl3): d = 0.98 (t, J = 6.1 Hz, 3 H) 1.64
Synlett 2006, No. 12, 1928–1932 © Thieme Stuttgart · New York

1932
A. Saini et al.
LETTER
(d, J = 6.1 Hz, 3 H), 5.60 (q, J = 6.1 Hz, 1 H) 7.09–7.97 (m,
12 H). Anal. Calcd for C23H18O: C, 89.00; H, 5.85. Found:
C, 89.12; H, 5.76.
Ethyl-2-Amino-4-phenyl-7,7-dimethyl-5-oxo-4H-5,6,7,8-
tetrahydrobenzo[b]pyran Carboxlate (6d, Table 2,
Entry 4).
2-Amino-3-cyano-4-phenyl-7,7-dimethyl-5-oxo-4H-
5,6,7,8-tetrahydrobenzo[b]pyran (6a, Table 2, Entry 1).
Mp 232–234 °C. IR (KBr): 3392, 3288, 2934, 2198, 1685,
1601 cm–1. 1H NMR (200 MHz, CDCl3): d = 0.97 (s, 3 H),
1.04 (s, 3 H), 2.18 (d, J = 14.5 Hz, 1 H), 2.23 (d, J = 14.5 Hz,
1 H), 2.50–2.60 (br s, 2 H), 4.30 (s, 1 H), 6.10 (s, 2 H), 7.20–
7.40 (m, 5 H). Anal. Calcd for C18H18N2O2: C, 73.45; H,
6.16; N, 9.52. Found: C, 73.58; H, 6.08; N, 9.40.
Mp 191–193 °C. IR (KBr): 3420, 2960, 2925, 1749, 1598,
1358 cm–1. 1H NMR (200 MHz, CDCl3): d = 1.0 (s, 3 H),
1.06 (s, 3 H), 1.21 (t, J = 7.5 Hz), 2.14 (d, J = 14.0 Hz, 1 H),
2.25 (d, J = 14.0 Hz, 1 H), 2.49 (br s, 2 H), 4.19 (q, J = 7.5
Hz), 4.27 (s, 1 H), 5.84 (s, 2 H), 7.10–7.35 (m, 5 H). Anal.
Calcd for C20H23NO4: C, 70.38; H, 6.74; N, 4.11. Found: C,
70.30; H, 6.83; N, 4.07.
Synlett 2006, No. 12, 1928–1932 © Thieme Stuttgart · New York