New chemical access for pyran core embedded derivatives from bisalkenylated 1,3-diketones and 1,3-diketoesters via tandem C-dealkenylation and cyclization

Article abstract of DOI:10.1016/j.tetlet.2010.10.030

New chemical access has been developed for the synthesis of pyran core embedded derivatives from 1,3diketones and 1,3-diketoesters, in which the active methylene group of 1,3-diketone or 1,3-diketoester was alkenylated with three equivalents of alkenyl br

Full text of DOI:10.1016/j.tetlet.2010.10.030

Tetrahedron Letters 51 (2010) 6576–6579
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New chemical access for pyran core embedded derivatives from
bisalkenylated 1,3-diketones and 1,3-diketoesters via tandem
C-dealkenylation and cyclization q
T. Narender a, , S. Sarkar a, K. Venkateswarlu a, J. K. Kumar b
⇑
a Medicinal and Process Chemistry Division, Central Drug Research Institute (CSIR), Lucknow 226 001, UP, India
b Natural Products Chemistry Lab, CIMAP Research Centre (CSIR), Boduppal, Hyderabad 500 039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
New chemical access has been developed for the synthesis of pyran core embedded derivatives from 1,3-
diketones and 1,3-diketoesters, in which the active methylene group of 1,3-diketone or 1,3-diketoester
was alkenylated with three equivalents of alkenyl bromides in presence NaH to give bisalkenyl 1,3-dike-
tones or 1,3-diketoesters and the resultant bisalkenyl 1,3-diketones or 1,3-diketoesters were reacted with
AlCl3 at room temperature to furnish pyran core embedded derivatives in good to excellent yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 2 August 2010
Revised 5 October 2010
Accepted 7 October 2010
Available online 20 October 2010
Keywords:
1,3-Diketone
1,3-Diketoester
3,4-Dihydro-2H-pyrans
AlCl3
Pyran core is embedded in several natural products of biological
importance such as coumarins (I),1 terpenoids (II),2 flavonoids
(III),3 anthraquinones (IV),4 alkaloids (V),5 (Fig. 1). Several groups
In continuation of our program on the synthesis of bioactive
natural products, we were interested in preparing 3,4-dihydro-
2H-pyran derivatives from enolizable b-diketones. The general
method for the synthesis of 3,4-dihydro-2H-pyran derivatives from
1,3-diketones involves the C-alkenylation of enolizable b-dike-
tones and subsequent cyclization in presence of acids such as
H2SO4, HCl, P2O5, acetic acid, Lewis acids etc.19 We therefore
carried out a prenylation reaction on cyclohexa-1,3-dione (1a)
and obtained mixture of C-2-prenyl-1,3-cyclohexadione (2a) and
C-2-bisprenyl-1,3-cyclohexadione (3a).20 Similar reaction was
attempted on bisprenylated 1,3-cyclohexadione 3a with different
Lewis acids to obtain dipyran system 5a (Scheme 1). None of them
described synthesis of these pyran intermediates using a,b-unsat-
urated aldehydes and 1,3-diketones by formal [3+3] cyclo-addition
in presence of Lewis acid as catalyst,6 or a reaction between an
activated a
,b-unsaturated iminium salt and 1,3-diketones,7 or pal-
ladium catalyzed tandom Stille-oxo-electrocyclization reaction be-
tween 2-iodenones and 4-cis-stannylenones.8–11 Recently Moreau
et al. synthesized 3,4-dihydro-2H-pyran derivatives by addition
of enolizable b-diketones to a,b-unsaturated aldehydes and subse-
quent selective hydrogentation of resultant dihydro-2H-chrome-
nones using chiral phosphoric acid catalysts.12 Enolizable 1,3-
diketones are important building blocks and their usefulness in
heterocyclic preparations,13 pyrazole,14 isoxazole,15 triazole16 and
benzopyran-4-ones17 has been largely illustrated. These 1,3-dike-
teones are also key structural units in many chelating ligands for
lanthanide and transition metals.18 Rich synthetic potential of
1,3-dicarbonyl compounds (1,3-DCC) is due to variety of chemical
reactions with participation of ketone-methelene (polyketide)
fragment and their ability to incorporate electrophilic or nucleo-
philic functionalities.
OH
O
HO
OH
OH
OH
O
O
O
OH
O
II
III
I
OH
OH
O
Cl
CHO
O
Cl
HO
O
N
H
V
HO
O
Cl
IV
q
CDRI communication No. 7978
⇑
Corresponding author. Tel.: +91 522 2612411; fax: +91 522 2623405.
E-mail address: t_narendra@cdri.res.in (T. Narender).
Figure 1. Pyran core embedded natural products (I–V).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.030

T. Narender et al. / Tetrahedron Letters 51 (2010) 6576–6579
6577
provided the anticipated dipyran 5a, however AlCl3 surprisingly
provided the 2-methyl-2,3,4,6,7,8-hexahydro-chromen-5-one (4a)
in reasonably good yields (Scheme 1).21 To best of our knowledge,
this unusual reaction (tandem dealkenylation and cyclization) with
AlCl3 was not reported earlier in the literature. To confirm the for-
mation of 4a from 3a, a similar reaction was carried out with other
bisprenylated diketones such as 5,5-dimethyl 2,2-diprenyl 1,3-
diketone (3b), 4,4-dimethyl-2,2-diprenyl-1,3-cyclohexadione (3c)
and bisprenylated 1,3-cyclopentadione (3d) which also gave
respective pyran derivatives (4b–d) under the same conditions in
reasonably good yields (Scheme 1). In case of 3c the corresponding
cyclized product 4c exclusively formed, might be due to steric
effect.
To explore the generality of the reaction, we focused to change
the alkenyl groups on 1,3-diketones. Bisgeranylated 1,3-cyclohex-
adione (3e), 4,4-dimethyl-1,3-cyclohexadione (3f) and 5,5-di-
methyl-cyclohexadiones (3g) and bisfarnesylated 4,4-dimethyl-
1,3-cyclohexadione (3h) were prepared from 1a–c and subjected
to further reaction with AlCl3, which again provided the respective
pyran derivatives 4e–h (Scheme 2) by tandem dealkenylation fol-
lowed by cyclization. It is noteworthy to mention here that in addi-
tion to formation of pyran system the side chain of geranyl and
farnasyl units further cyclized to give tricyclic (4e–g) and tetracy-
clic compound (4h) due to double and triple cyclization reactions,
respectively.
To demonstrate the applicability of this procedure to prepare
naturally occurring flavonoid derivatives III (Scheme 3) we synthe-
sized 3i from 1b and carried out cyclization with AlCl3 which
resulted in the synthesis of 7,7-dimethyl-2-phenyl-2,3,4,6,7,8-
hexahydro-chromen-5-one (4i).
Few mixed alkenylated 1,3-diketones such as 3j, 3k, 3l, and 3m
were prepared and subsequently reacted with AlCl3 to give 4a and
4b, respectively (Scheme 4). This indicates that AlCl3 preferentially
dealkenylates the bulky groups only.
O
R1
R2
O
O
R3
R4
R1
R2
1a: R1,R2,R3,R4=H
1b: R1,R2=CH3; R3,R4=H
O
a
: R1,R2=H; R3,R4=CH3
O
5a: R1,R2=H
1c
O
d
R1
R2
+
R1
R2
OH
R3 R4
O
2a: R1,R2,R3,R4=H
R3 R4
3a: R1,R2,R3,R4=H; 64%
c
3b: R1,R2=CH3; R3,R4=H; 65%
3c: R1,R2=H; R3,R4=CH3; 56%
O
O
b
O
R1
O
R2
R1
R2
or
R3
To broaden the reaction utility, 1,3-diketoesters were chosen for
alkenylation (Scheme 5). Compounds 3n and 3o were synthesized
from 3-oxo-butyric acid ethyl ester (1e) and subsequently reacted
with AlCl3, which surprisingly provided 2,2,6-trimethyl-3,4-dihy-
dro-2H-pyran (4j) and 2,5,5,8-tetramethyl-4,5,6,7,8,8a-hexahy-
dro-4H-chromene (4k), respectively, instead of 6a or 6b and 6c
or 6d. Interestingly the decarboxylation reaction appears to be tak-
ing place before or after tandem dealkenylation and cyclization
steps (Scheme 5).
O
R
R4
R3 R4
O
O
4c: R1,R2=H; R3,R4=CH3; 64%
4a: R1,R2,R3,R4=H; 75%
4b: R1,R2=CH3; R3,R4=H; 90%
O
O
O
c
a
O
O
O
4d;70%
3d;45%
1d
The reaction mechanism in the formation of pyran system ap-
pears to be the retro-Claisen rearrangement of one of the alkenyl
group of 3a to give intermediate VI and subsequent tandem dealk-
enylation and cyclization of second alkenyl group with enolic hy-
Scheme 1. Synthesis of pyran derivatives (4a–d) from bisalkenylated 1,3-cyclo-
hexadione (3a–d). Reagents and conditions: (a) NaH in DMF at À20 °C, prenylbr-
omide b and d, AlCl3 and other Lewis acids in dry dioxane at rt for 3–5 h; (c) only
AlCl3 in dry dioxane at rt for 3–5 h.
O
R1
R2
O
AlCl3
Dioxane; rt, 10-12h
O
R3 R4
R1
R2
4e: R1,R2,R3
,
R4=H; 58%
O
R4
R3
4f: R1 R2=CH3; R3,R4=H; 68%
,
OH
4g: R1
62%
, ,
R2=H; R3 R4=CH3;
3e: R1,R2,R3,R4=H; 53%
3f: R1,R2=CH3; R3,R4=H; 56%
3g: R1,R2=H; R3,R4=CH3;
O
O
O
R1
AlCl3
O
R2
Dioxane; rt, 12h
R1
R2
4h: R1,R2=CH3;
58%
O
3h: R1,R2=CH3;
52%
HO
HO
O
II
Scheme 2. Synthesis of tricyclic (4e–g) and tetracyclic pyran core system (4h).

6578
T. Narender et al. / Tetrahedron Letters 51 (2010) 6576–6579
O
O
O
Ph-CH=CH-CH2Br
AlCl3
R1
R2
R1
R2
3i: R1,R2=CH3; 61%
R1
R2
O
NaH in DMF
at - 20ºC
1b: R1,R2=CH3
Dry Dioxane, R.T;. 3h
O
O
4i: R1,R2=CH3; 55%
OH
OH
HO
O
III
Scheme 3. Synthesis of natural products like molecules (4i).
the pyran core (4l), might be due to formation of O-alkenylated
O
O
intermediate (VIII) via 3,3-retro-Claisen rearrangement, (Scheme
6). It appears to be that breakage of C–O bond in 8 generates pri-
mary carbocation on the alkenyl group might not be feasible,
where as in the intermediate VI and VII breakage of C–O bond
leads to the formation of tertiary and secondary carbocation,
respectively. Further studies however are required to confirm the
exact reaction mechanism.
To determine the role of the solvents in the reaction time and
yields various solvents such as DMF, DMSO, H2O, THF, dioxane,
benzene, AcCN, EtOH, AcOH were used. Best results were obtained
only in presence of dioxane, EtOH and AcOH.
R1
R2
AlCl3
Dry Dioxane, R1
O
R2
O
R.T;. 3h
4a: R1,R2=H; 61%
4b: R1,R2=CH3; 90%
O
3j: R1,R2=H; 51%
3k: R1,R2=CH3; 63%
AlCl3
O
R1
Dry Dioxane,
R.T;. 3h
O
R2
R1
R2
O
4a: R1,R2=H; 61%
3l: R1,R2=H; 48%
4b: R1,R2=CH3; 90%
3m: R1,R2=CH3; 55%
In conclusion a new chemical access has been developed for the
synthesis of pyrans and pyran core embedded derivatives from 1,3-
diketone derivatives such as bisalkenyl cyclohexa-1,3-diketone,
4,4-dimethyl-1,3-diketone, 5,5-dimethyl-1,3-diketone (dimedone),
cyclopenta-1,3-diketone and also 1,3-diketoesters in one step for
the first time using AlCl3. During this process we have prepared
several natural products like building blocks such as tricyclic
(4e–g), tetracyclic (4h) and flavonoid like intermediates (4i), which
can be utilized for the total synthesis of natural products I–III of
biological importance (Fig. 1; Schemes 1–3). Further work is in pro-
gress in our laboratory in this direction.
Scheme 4. Synthesis of pyrans 4a and 4b from mixed alkenylated 1,3-diketones.
droxyl provides the desired pyran 4a and isoprene (7). The forma-
tion of 7 was confirmed by authentic sample of isoperene on TLC
and GC (Fig. 2).
The reaction with 8 did not provide the pyran 4c under similar
conditions, The attempts to synthesize 3,4-dihydro-2H-pyran
derivatives from bisallylated 1,3-diones (3p) also failed to provide
O
O
AlCl3
O
O
O
Dry Dioxane
Prenylbromide
O
O
R.T;. 3h
4j: 52%
NaH in DMF
at -20ºC
1e
3n; 42%
O
O
O
O
O
O
6a
6b
O
O
O
O
AlCl3
Geranylbromide
O
DryDioxane,
R.T;. 3h
O
NaH in DMF at-20ºC
O
1e
4k: 48%
3o; 58%
O
O
O
or
O
O
O
6d
6c
Scheme 5. Synthesis of pyran derivatives (4j and 4k) from 1,3-dikentoester (1e).

T. Narender et al. / Tetrahedron Letters 51 (2010) 6576–6579
6579
3. Moumou, Y.; Vasseur, J.; Trotin, F.; Dubois, J. Phytochemistry 1992, 31, 1239.
4. Soria-Mercado, I. E.; Prieto-Davo, A.; Jensen, P. R.; Fenical, W. J. Nat. Prod. 2005,
68, 904.
O
O
O
AlCl3
5. (a) Chakraborty, D. P.; Das, K. C.; Islam, A. J. Indian Chem. Soc. 1970, 47, 1197; (b)
Chakraborty, D. P.; Das, K. C.; Islam, A. J. Indian Chem. Soc. 1985, 62, 600.
6. (a) Kurdyumov, A. V.; Lin, N.; Hsung, R. P.; Gullickson, G. C.; Cole, K. P.;
Sydorenko, N.; Swidorski, J. J. Org. Lett. 2006, 8, 191; (b) Lee, Y. R.; Kim, D. H.;
Shim, J. J.; Kim, S. K.; Park, J. H.; Cha, J. S.; Lee, C. S. Bull. Korean Chem. Soc. 2002,
23, 998.
7. Shen, H. C.; Wang, J.; Cole, K. P.; McLaughlin, M. J.; Morgan, C. D.; Douglas, C. J.;
Hsung, R. P.; Coverdale, H. A.; Gerasyuto, A. I.; Hahn, J. M.; Liu, J.; Sklenicka, H.
M.; Wei, L. L.; Zehnder, L. R.; Zificsak, C. A. J. Org. Chem. 2003, 68, 1729.
8. Tambar, U. K.; Kano, T.; Zepernick, J. F.; Stoltz, B. M. Tetrahedron Lett. 2007, 48,
345.
O
1
3
4a
+
2
3
3,3 sigmatropic
rearrangement
1
O
O
2
3a
7
H
VI
O
O
O
9. (a) Li, C.; Lobkovsky, E.; Porco, J. A. J. Am. Chem. Soc. 2000, 122, 10484; (b) Li, C.;
Johnson, R. P.; Porco, J. A. J. Am. Chem. Soc. 2003, 125, 5095.
10. Shoji, M.; Yamaguchi, J.; Kakeya, H.; Osada, H.; Hayashi, Y. Angew. Chem. 2002,
41, 3192.
11. (a) Malerich, J. P.; Trauner, D. J. Am. Chem. Soc. 2003, 125, 9554; (b) Malerich,
J. P.; Maimone, T. J.; Elliott, G. I.; Trauner, D. J. Am. Chem. Soc. 2005, 127,
6276.
12. Moreau, J.; Hubert, C.; Batany, J.; Hurvois, J. P.; Toupet, L.; Roisnel, T.; Renaudz,
J. L. J. Org. Chem. 2009, 74, 8963.
AlCl3
3,3 sigmatropic
rearrangement
O
O
H
O
3i
4i
VII
Figure 2. Possible reaction mechanisms in the formation of pyran core.
13. (a) Baumstark, A. L.; Choudhary, A.; Vasquez, P. C.; Dotrong, M. J. Heterocycl.
Chem. 1990, 27, 291; (b) West, A. P., Jr.; Engen, D. V.; Pascal, R. A., Jr. J. Org.
Chem. 1992, 57, 784; (c) Felix, C. P.; Khatimi, N.; Laurent, A. J. J. Org. Chem. 1995,
60, 3907; (d) Martins, M. A. P.; Brondani, S.; Leidens, V. L.; Flores, D. C.; Moura,
S.; Zanatta, N.; Horner, M.; Flores, A. F. C. Can. J. Chem. 2005, 83, 1171.
14. (a) Heller, S. T.; Natarajan, S. R. Org. Lett. 2006, 8, 2675; (b) Gosselin, F.; O’Shea,
P. D.; Webster, R. A.; Reamer, R. D.; Tillyer, R. D.; Grabowski, E. J. J. Synth. Lett.
2006, 19, 3267.
15. (a) Bode, J. W.; Hachisu, Y.; Matsuura, T.; Suzuki, K. Tetrahedron Lett. 2003, 44,
3555; (b) Valizadeh, H.; Amiri, M.; Gholipur, H. J. Heterocycl. Chem. 2009, 46,
108; (c) Chauhan, S. S.; Joshi, Y. C. Rasayan. J. Chem. 2008, 1, 475.
16. Aggarwal, R.; Sumran, G.; Kumar, R.; Singh, S. P. Arkivoc 2007, 15, 292.
17. (a) Costantino, L.; Del Corsob, A.; Rastellia, G.; Petrashc, J. M.; Murab, U. Eur. J.
Med. Chem. 2001, 36, 697; (b) Costantino, L.; Rastelli, G.; Gamberini, M. C.;
Vinson, J. A.; Bose, P.; Iannone, A.; Staffieri, M.; Antolini, L.; Del Corso, A.; Mura,
U.; Albasini, A. J. Med. Chem. 1999, 42, 1881.
O
O
8
AlCl3
+
X
O
4c
Dry Dioxane,
R.T;. 3h
O
7
O
O
O
AlCl3
O
Dry Dioxane,
R.T;. 3h
18. Shavaleev, N. M.; Scopelliti, R.; Gumy, F.; Bünzli, J. C. G. Eur. J. Inorg. Chem. 2008,
9, 1523.
O
O
VIII
4l
3,3-retro-Claisen
rearrangement
product
19. (a) Gates, M. D.; Misani, F. J. Am. Chem. Soc. 1942, 64, 1979; (b) Butenschoen, I.;
Moeller, K.; Haensel, W. J. Med. Chem. 2001, 44, 1249; (c) David, D. L.
Phytochemistry 1980, 19, 941; (d) Karl, S. S.; Karl, H. S-R.; Walter, W.; Alfred, R.
S.; Wasley, J. W. F. J. Med. Chem. 1984, 27, 990; (e) Song, S.; Song, L.; Dai, B.; Yi,
H.; Jin, G.; Zhu, S.; Shao, M. Tetrahedron 2008, 64, 5728; (f) Appendino, G.;
Cravotto, G.; Giovenzana, G. B.; Palmisano, G. J. Nat. Prod. 1999, 62, 1627.
20. Representative procedure for the preparation of 3a: 1,3-diketone 1a (0.5 g,
5 mmol, 1.0 equiv) was added drop wise by syringe to a stirred solution of
sodium hydride (0.3 g, 13.4 mmol, 3 equiv) in dimethyl formamide (10 mL) at
À20 °C. The resulting pale-yellow solution was stirred for 20 min at À20 °C,
then prenyl bromide (1.6 mL, 13.4 mmol, 3 equiv) was added drop wise by
syringe. The reaction mixture was stirred for 20 min at this temperature, then
the reaction flask was removed from the cooling bath and was allowed to reach
to room temperature. The reaction mixture was stirred for 1 h at room
temperature. Then reaction was quenched by adding ice-cold water and
extracted three times with ether. Ether part was concentrated by rotary
evaporation. The pale-yellow oily residue was purified by flash-column
chromatography (hexanes) to provide a colorless oil of 3a Yield: 64%; TLC
(10% ethyl acetate–hexanes) Rf = 0.60%; IR (Neat) 3441, 2932, 2365, 1720,
3p
Scheme 6. Cyclization attempt on C and O-prenylated dione (8) and bisallylated
1,3-diketone (3p).
Acknowledgements
Authors are thankful to Dr. T. K. Chakrobarty, Director, CDRI for
his constant encouragement of the program on natural products’
synthesis, SAIF for spectral data and CSIR, New Delhi for the finan-
cial support.
Supplementary data
1609, 1455, 1391, 1220, 1131, 925, 840, 753, 666 cmÀ1 1H NMR (CDCl3,
;
300 MHz) d 4.83–4.77 (m, 2H), 2.46–2.41 (m, 8H), 1.88–1.79 (m, 2H), 1.57 (s,
6H), 1.50 (s, 6H); 13C NMR (75 MHz): 212.1 (2C), 135.7 (2C), 118.9 (2C), 68.1,
40.7 (2C), 36.6 (2C), 26.2 (2C), 18.1 (2c), 16.9; MS (ESI) m/z 181.1 (M+H)+.
21. Representative procedure for 4a: To a stirred solution of 3a (0.5 g) in dry dioxane
(5 mL) was added catalytic amount of AlCl3 at room temperature and stirred
for 3–4 h. After dilution with moist ether (100 mL), the solution was washed
with water (3 Â 50 mL) to discharge the color. The combined ethereal solution
obtained after extraction was dried over anhydrous Na2SO4 and evaporated
under reduced pressure. The crude mixture was isolated on column-
chromatography to afford desired compound 4a; yield: 75%; TLC (10% ethyl
acetate–hexanes) Rf = 0.35; IR (Neat) 3753, 3679, 3493, 3020, 2928, 2856,
2401, 1719, 1611, 1523, 1393, 1216, 1156, 1115, 1014, 928, 761, 670,
Supplementary data(Spectroscopic characterization of all new
compounds along with their 1H and 13C spectra and 2D NMR spec-
tra, mass) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2010.10.030.
References and notes
1. (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G. Q. Angew. Chem. 2000, 39, 734; (b)
Philip, C. B.; Appleby, L. F.; Day, D.; Chan, Y.; Buckley, B. R.; Allin, S. M.;
McKenzie, M. J. Org. Lett. 2009, 11, 1991.
2. (a) Alvarez-Manzaneda, E. J.; Chahboun, R.; Perez, I. B.; Cabrera, E.; Alvarez, E.;
Alvarez-Manzaneda, R. Org. Lett. 2005, 7, 1477; (b) Alvarez-Manzaneda, E. J.;
Chahboun, R.; Cabrera, E.; Alvarez, E.; Haidour, A.; Ramos, J. M.; Alvarez-
Manzaneda, R.; Hmamouchi, M.; Bouanou, H. J. Org. Chem. 2007, 72, 3332.
532 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.36–2.30 (m, 2H), 2.26–2.21 (m, 2H),
;
1.97–1.88 (m, 2H), 1.65 (t, J = 6.60 Hz, 2H), 1.57(t, J = 7.66 Hz, 2H), 1.26 (s, 6H);
13C NMR (75 MHz): 198.8, 171.1, 110.2, 83.1, 36.9, 32.4, 29.4, 26.8 (2C), 21.2,
15.8; MS (ESI) m/z 181.1 (M+H)+.