Effect of calcium reagents on aldol reactions of phenolic enolates with aldehydes in alcohol

Full text of DOI:10.1021/jo961352k

6768
J . Org. Chem. 1996, 61, 6768-6769
Sch em e 1
Effect of Ca lciu m Rea gen ts on Ald ol
Rea ction s of P h en olic En ola tes w ith
Ald eh yd es in Alcoh ol
Hiroyuki Saimoto, Koji Yoshida, Tetsuya Murakami,
Minoru Morimoto, Hitoshi Sashiwa, and
Yoshihiro Shigemasa*
Department of Materials Science, Faculty of Engineering,
Tottori University, Koyama, Tottori 680, J apan
Received J uly 17, 1996
Organic reactions that occur in aqueous media have
received growing attention recently and in general elimi-
nate the constraints of inert atmosphere and anhydrous
conditions.1-4 Many organic compounds, however, ex-
hibit only sparing solubility in water. It has been
reported that divalent and trivalent metal reagents such
as Ca(OH)2, CaCl2/KOH, or SmCl3/KOH play an impor-
tant role in the aldol reaction of unprotected ketoses with
formaldehyde in water or alcohol.5,6 Herein we report
the aldol-type reaction of phenolic enolates derived from
methyl 2,4-dihydroxybenzoate (1) and its analogs with
not only water-soluble aldehydes but also hydrophobic
aldehydes in methanol (Scheme 1). This reaction was
accomplished using alkaline earth metal reagents such
as Ca(OH)2, CaCl2/KOH, or BaCl2/KOH instead of alka-
line metal reagents such as KOH or LiCl/KOH.
Ta ble 1. Rea ction of Meth yl 2,4-Dih yd r oxyben zoa te
w ith F or m a ld eh yd e or Ben za ld eh yd ea
run RCHO solvent
1c HCHO H2O
reagent (mmol)
KOH (0.2)
product yieldb (%)
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
86 (100)
0d
2c HCHO MeOH KOH (0.2)
3
4
5
6
7
8
9
HCHO MeOH CaCl2/KOH (0.4/0.4)
PhCHO H2O KOH (0.4)
PhCHO MeOH KOH (0.4)
PhCHO MeOH Mg(OH)2 (0.4)
PhCHO MeOH Ca(OH)2 (0.4)
PhCHO MeOH Ba(OH)2 (0.4)
PhCHO MeOH LiCl/KOH (0.4/0.4)
84 (94)
6 (100)
0d
0e
63 (94)
65 (100)
0d
10 PhCHO MeOH NaCl/KOH (0.4/0.4)
11 PhCHO MeOH CaCl2/KOH (0.4/0.4)
12 PhCHO MeOH CaCl2/KOH (0.4/0.8)
13 PhCHO MeOH BaCl2/KOH (0.4/0.8)
0d
63 (100)
73 (100)
64 (99)
Table 1 shows the results of several aldol reactions,
referred to as runs 1-13. The reaction of water-soluble
formaldehyde with the phenolic enolate of 1 in aqueous
KOH produced a 3-hydroxymethylated derivative 2a
(Table 1, run 1). In contrast, the reaction of hydrophobic
benzaldehyde in aqueous KOH hardly proceeded (Table
1, run 4). In run 5 (Table 1), methanol was used as the
solvent instead of water in order to dissolve both the
aldehyde and substrate. Nevertheless, the reaction using
KOH in methanol failed to give the desired adduct. We
found that a similar reaction using the reagents CaCl2/
KOH dissolved in methanol produced a 63% yield of the
adduct 2b in run 11 (Table 1, quantitative yield is based
on consumption of 1).7 A comparison of runs 2 and 3
(Table 1) shows a similar effect of CaCl2 on the reaction
of 1 with formaldehyde in methanol. Any other type of
products 3-5 were not obtained. A regioselective C-C
bond formation at the C(3) position of 1 was estimated
a
RCHO, 0.72 mmol; 1, 0.60 mmol; solvent, 2 mL; 0 °C, 24 h.
b
Isolated yield. Yields are based on the consumption of 1 when
d
shown in parentheses. c Reaction time, 18 h. Recovery of 1, 100%.
e Recovery of 1, 91%.
2b was obtained using alkaline earth metal salts com-
bined with KOH (Table 1, runs 12 and 13) and alkaline
earth metal hydroxides (Table 1, runs 7 and 8) with the
exception of Mg(OH)2 (Table 1, run 6), which hardly
dissolved in methanol. Among the various reagents
investigated in Table 1, CaCl2/KOH (run 12) gave the
best result. The effectiveness of the divalent metal
reagents mentioned above is attributed to their ability
as Lewis acids to activate the carbonyl group of the
aldehyde. Coordination of the carbonyl group of the
aldehyde to the metal cation of the phenolic enolate
possibly brought both molecules close enough to react.
A comparison of run 12 in Table 1 with runs 1 and 2
in Table 2 demonstrated that this reaction was not
affected by the character of carbonyl substituents of
resorcinol derivatives, while resorcinol itself failed to give
the corresponding adduct. Interestingly, treatment of a
mixture of 2,4-dihydroxybenzaldehyde (8) and benzalde-
hyde with CaCl2/KOH did not afford the homocoupling
product of 8 but afforded the cross-coupling product 9.
The electrophilic reactivity of the carbonyl group in 8
might be decreased by the anionic charge of the aromatic
part of the compound. On the analogy of the regioselec-
tive C-C bond formation at the C(3) position of benzoate
1
by H NMR analysis of 2a and 2b, which showed two
doublet signals corresponding to the aromatic protons
having an o-coupling constant.8
Runs 5, 9, and 10 in Table 1 show that the reaction of
1 with benzaldehyde in methanol did not proceed when
various alkaline metal reagents were used. The adduct
(1) For reviews, see: (a) Grieco, P. A. Aldrichim. Acta 1991, 24, 59.
(b) Li, C. J . Chem. Rev. 1993, 93, 2023. (c) Lubineau, A.; Auge, J .;
Queneau, Y. Synthesis 1994, 741.
(2) Patil, V. J . Tetrahedron Lett. 1996, 37, 1481.
(3) (a) Schmid, W.; Whitesides, G. M. J . Am. Chem. Soc. 1991, 113,
6674. (b) Kobayashi, S.; Nagayama, S. J . Org. Chem. 1996, 61, 2256.
(4) Denis, C.; Laignel, B.; Plusquellec, D.; Le Marouille, J .-Y.; Botrel,
A. Tetrahedron Lett. 1996, 37, 53.
(5) Shigemasa, Y.; Yokoyama, K.; Sashiwa, H.; Saimoto, H. Tetra-
hedron Lett. 1994, 35, 1263.
(6) Saimoto, H.; Yatani, S.; Sashiwa, H.; Shigemasa, Y. Tetrahedron
Lett. 1995, 36, 937.
(8) Different regioselectivity in the reaction of resorcinols with
aldehydes and formation of resins: (a) Ho¨gberg, A. G. S. J . Am. Chem.
Soc. 1980, 102, 6046. (b) Tunstad, L. M.; Tucker, J . A.; Dalcanale, E.;
Weiser, J .; Bryant, J . A.; Sherman, J . C.; Helgeson, R. C.; Knobler, C.
B.; Cram, D. J . J . Org. Chem. 1989, 54, 1305. (c) Konishi, H.; Ohata,
K.; Morikawa, O.; Kobayashi, K. J . Chem. Soc., Chem. Commun. 1995,
309. (d) Gutsche, C. D. Calixarenes; The Royal Society of Chemistry:
Cambridge, Great Britain, 1989; and references cited therein.
(7) A typical procedure is as follows: benzaldehyde (76 mg, 0.72
mmol) and 1 (101 mg, 0.60 mmol) were treated with CaCl2‚2H2O (59
mg, 0.4 mmol) in 0.4 M KOH methanol solution (2 mL) for 24 h at 0
°C. After acidification with 1 M HCl, extractive workup followed by
purification by preparative TLC (benzene-EtOAc 10:1, developed
twice) afforded 2b (131 mg) along with 1 (27 mg).
S0022-3263(96)01352-7 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 20, 1996 6769
Ta ble 2. Rea ction of Resor cin ol Der iva tives w ith
Va r iou s Ald eh yd es in Meth a n ola
hydroxyl group by an intramolecular hydrogen bonding
with the neighboring carbonyl group.
This sequence was successfully applied to the one-pot
synthesis of methyl cannabichromevarinate 18 (Table 2,
run 9).10,11 Similar to the transformation of 1 into 17,
the C-C bond formation between 10 and citral was
supposed to be performed at the C(3) position of 10.
Selective incorporation of the p-hydroxyl group of 10 into
1
the newly formed pyran ring was estimated by the H
NMR analysis as mentioned above. The regioselectivity
of these processes was also confirmed since the spectral
data of synthetic 18 was identical to those reported.12,13
Hydrolysis of 18 by 1.5 M NaOH in a 1:1 mixture of water
and methanol at 45 °C for 2 days produced a naturally
occurring cannabinoid, dl-cannabichromevarinic acid
(19),12,14 in a 42% yield.
In conclusion, the aldol-type reaction of phenolic eno-
lates of 2,4-dihydroxybenzoate derivatives with aldehydes
in methanol is achieved using divalent metal reagents
such as Ca(OH)2 and CaCl2/KOH. This sequence is
successfully applied to the synthesis of dl-cannabichrom-
evarinic acid.
a
RCHO, 0.72 mmol; substrate, 0.60 mmol; MeOH, 2mL; 0 °C.
b
Isolated yield. Yields are based on the consumption of the
substrate when shown in parentheses. c Recovery of 12, 98%.
Ack n ow led gm en t. The authors would like to ex-
press their appreciation for the partial financial support
of a Grant-in-Aid for Scientific Research (C) (No.
08651034) and that of a Grant-in-Aid for Exploratory
Research (No. 08875179) from the Ministry of Educa-
tion, Science, Sports and Culture of J apan.
d
Recovery of 13, 91%. e Citral, 0.29 mmol; 10, 0.24 mmol; EtOH,
1 mL; 20 °C.
1, the aldol-type reaction of phenolic enolate of benzoate
109 having a substituent at the C(6) position might be
performed at the C(3) position (Table 2, run 3). However,
benzoates 12 and 13, having only one hydroxyl group,
did not produce any addition products as shown in runs
4 and 5 (Table 2). Therefore, activation of the C(3)
position requires the presence of both o- and p-hydroxyl
groups.
Runs 6-8 in Table 2 demonstrated the reaction with
various aldehydes. An aliphatic aldehyde, acetaldehyde,
was transformed into the corresponding adduct 15 rela-
tively slowly. In the case of an R,â-unsaturated aldehyde,
citral (Table 2, run 8), the aldol-type reaction with the
phenolic enolate of 1 followed by cyclization of the
intermediate 16 led to benzopyran 17.10 TLC analysis
revealed that the successive cyclization partly proceeded
after an acidic workup. The regioselectivity of the
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data (5 pages).
J O961352K
(11) Leading references of the synthesis of naturally occurring
2H-chromenes: (a) Cardillo, G.; Cricchio, R.; Merlini, L. Tetrahedron
1968, 24, 4825. (b) Crombie, L.; Crombie, W. M. L.; Forbes, R.;
Whitaker, A. J . Chem. Res., Miniprint 1977, 1301. (c) Mohamed, S.
E. N.; Thomas, P.; Whiting, D. A. J . Chem. Soc., Perkin Trans. 1 1987,
431. (d) Iyer, M. R.; Trivedi, G. K. J . Nat. Prod. 1993, 56, 268. (e)
Yamaguchi, S.; Shouji, N.; Kuroda, K. Bull. Chem. Soc. J pn. 1995, 68,
305.
(12) Shoyama, Y.; Hirano, H.; Makino, H.; Umekita, N.; Nishioka,
I. Chem. Pharm. Bull. 1977, 25, 2306.
(13) Different regioselectivity was reported on the reaction of
5-methylresorcinol with cinnamaldehyde: Sartori, G.; Casiraghi, G.;
Bolzoni, L.; Casnati, G. J . Org. Chem. 1979, 44, 803.
1
cyclization was confirmed by the H NMR analysis of 17,
(14) Previously 19 was prepared from 20: Shoyama, Y.; Hirano, H.;
Nishioka, I. J . Labelled Compd. Radiopharm. 1978, 14, 835.
in which a singlet peak corresponding to the remaining
o-hydroxyl proton was observed at 11.14 ppm. This
selectivity is explained by the deactivation of the o-
(9) Mori, K.; Kamada, A.; Mori, H. Liebigs Ann. Chem. 1989, 303.
(10) In the case of R,â-unsaturated aldehydes, small amounts of side
products of type 4 were formed.