Base-catalyzed condensation of 2-hydroxybenzaldehydes with α,β-unsaturated aldehydes - Scope and limitations

Article abstract of DOI:10.1002/adsc.200404239

The base-catalyzed condensation of α,β-unsaturated carbonyl compounds with 2-hydroxybenzaldehydes yielding tetrahydroxanthones and dihydrobenzopyrans has been investigated. A novel access to highly functionalized dihydrobenzopyrans via a mild generation of the dienol of senecialdehyde and subsequent conjugated aldol reaction has been reported.

Full text of DOI:10.1002/adsc.200404239

FULL PAPERS
Base-Catalyzed Condensation of 2-Hydroxybenzaldehydes with
a,b-Unsaturated Aldehydes -- Scope and Limitations
Bernhard Lesch,a Jakob Torꢀng,a Sylvia Vanderheiden,b Stefan Brꢀseb,*
a
Institut fꢁr Organische Chemie, Universitꢀt Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany
Institut fꢁr Organische Chemie, Universitꢀt Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
b
Fax: (þ49)-721-608-8581, e-mail: braese@ioc.uka.de
Received: July 26, 2004; Accepted: January 3, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The base-catalyzed condensation of a,b-un- subsequent conjugated aldol reaction has been re-
saturated carbonyl compounds with 2-hydroxybenzal- ported.
dehydes yielding tetrahydroxanthones and dihydro-
benzopyrans has been investigated. A novel access
to highly functionalized dihydrobenzopyrans via a Keywords: g-aldol reaction; enols; enones; nucleophil-
mild generation of the dienol of senecialdehyde and ic addition; oxygen heterocycles
Introduction
solvent (t-BuOH, CHCl3/H2O, dioxane, water only) and
base (t-BuOK, K2CO3, DABCO) used.[3] The applica-
Benzopyrans are a common motif found in natural prod- tion of this concept on 2-cyclohexen-1-one (4) to yield
ucts and derived lead structures. Some examples are the tetrahydroxanthenones as seen in 5 has been recently
cyclooxygenase inhibitior cordiachromene (1) and (ꢀ)- and independently reported by us[4] (Scheme 1) and
D9-THC (2).[1] The development of new efficient proc- the Kim group.[5] Most closely related to these protocols
esses for the construction of complex molecules using is the procedure described by Ravichandran.[3e]
metal-free reagents has been receiving increasing atten-
The aforementioned reaction conditions[4] were used
tion over the last couple of years. Recently, carbon-car- to test 2-hydroxybenzaldehyde (3a) in the condensation
bon bond forming reactions using tertiary amines via an reaction with senecialdehyde (6a) as a model system.
addition-aldol reaction mode (Baylis–Hillmanreaction) The condensation product 7a was isolated in 57% yield.
were explored.[2]
Additionally, 22% of tricyclic species 8a were separated
from the reaction mixture (Scheme 2).[6]
By 1H and 13C NMR studies, the tricyclic hemiacetal
structure 8a was assigned to this compound. It was
formed as a single diastereomer. Similar tricyclic hemi-
acetals have been synthesized from citraldienamine, 2-
hydroxybenzaldehyde and 2-hydroxy-1-naphthalde-
hyde, respectively.[7] The latter reaction requires the syn-
thesis and isolation of the dienamine, while the method
presented here is a one-step procedure. In analogy to the
Results and Discussion
The condensation of Michael acceptors with 2-hydroxy-
benzaldehydes, as exemplified by 3a, which in turn
yields benzo[b]pyrans, has proven to be a versatile entry
to this class of compounds. It should be noted that, albeit
simple and high yielding, this reaction is sensitive due to
the ambident nature of the starting materials, as both the
2-hydroxybenzaldehyde and the a,b-unsaturated sys-
tem have an electrophilic and a nucleophilic site. There-
fore different protocols have been described, varying in Scheme 1. Synthesis of 2,3,4,4a–tetrahydroxanthen-1-ones.[4]
Adv. Synth. Catal. 2005, 347, 555–562
DOI: 10.1002/adsc.200404239
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Bernhard Lesch et al.
FULL PAPERS
formed by a Michael addition/aldol condensation se-
quence. In the case presented the Baylis–Hillman path-
way is possible, as DABCO is used as a catalyst, but not
probable, because sodium carbonate turned out to be
the best reagent for the formation of 7a (see below).
Therefore, we postulate that the phenolate 12 undergoes
a 1,4-addition to senecialdehyde. The resulting enolate
13 undergoes an intramolecular aldol addition with sub-
sequent elimination of water from the aldol adduct 14 to
yield 7a.
Vinylogous aldol reactions of dienolates have gained
attention due to their application in the synthesis of nat-
ural products.[8] The problem of regioselectivity, i.e., a-
versus g-substitution, has been a particular field of re-
search.[9] While a-substitution usually occurs under ki-
Scheme 2. Initial result: formation of 2,2-dimethyl-2H-chro-
mene-3-carbaldehyde (7a) and 9-methyl-8,12-dioxatricy-
clo[7.3.1.02,7]trideca-2,4,6-trien-11-ol (8a).
published mechanism,[7] we propose that the formation netic control at low temperatures, the g-substituted
of tricyclic compound 8a involves the vinylogous addi- product as the thermodynamically stable isomer can
tion of the dienolate 9 to the 2-hydroxybenzaldehyde be isolated when the reaction is performed at elevated
3a. The phenolic hydroxy group of the a,b-unsaturated temperatures.[8b] Recently, Katsuki and co-workers re-
aldehyde 10 undergoes a base-promoted intramolecular ported a chromium-salen catalyst for the g-selective al-
stereoselective 1,4-addition to form the aldehyde 11. dol addition of silicon dienol ethers.[10] Dienols were syn-
This aldehyde cyclizes stereoselectively to give the hem- thesized earlier, for example, by a ring opening of alke-
iacetal 8a.
nyloxiranes.[11] But all reported procedures required the
Several mechanisms for the formation of 7a have been use of strong bases like lithium amides or organometal-
proposed. On the one hand, in the presence of DABCO, lic intermediates, most notably the use of toxic reagents
a Baylis–Hillman reaction/Michael addition pathway such as cadmium chloride.[8f] In contrast, our research
has been postulated,[3f] on the other hand, 7a may be suggests that even weak bases are sufficient to foster
Scheme 3. Mechanism rationale for the formation of 7a and 8a.
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Condensation of 2-Hydroxybenzaldehydes with a,b-Unsaturated Aldehydes
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the deprotonation of senecialdehyde, as 8a is probably
formed by a vinylogous aldol reaction.
Although the results cannot explain the selectivities
observed, it can be noted that triethylamine favors the
To optimize the product distribution either towards 7a formation of 8a (yield 7a 15%, 8a 47%, according to
or 8a, the type of catalyst was varied with respect to nu- GC), while sodium carbonate predominantly leads to
cleophilicity and basicity. Triphenylphosphine was ap- the formation of 7a (yield 7a 59%, 8a 18%, according
plied as a very weakly basic, but good nucleophilic cata- to GC). Furthermore, it was possible to increase the ra-
lyst. Potassium hydroxide was chosen as a very basic, but tio of 7a:8a from 2.5 in the initial experiments to 3.3 un-
poorly nucleophilic catalyst. Within these margins, we der optimized conditions and to reverse the selectivity
also investigated several amines, ranging from weakly by choosing triethylamine as catalyst.
basic pyridines to very basic DBU.[12]
Whilethe experiments describedabove were conduct-
The amount of catalyst (0.5–1.5 equivs.) used has in ed using sonication to obtain consistent reaction condi-
essence no influence either on the yield or on the prod- tions, this becomes obsolete in a homogeneous liquid
uct distribution. Since the reaction is efficiently only cat- phase. Therefore, the improved reaction conditions
alyzed by bases with pKb values between 3 (NEt3: pKb ¼ were used with the substrates 3a – j with stirring at
3.25, Na2CO3: pKb ¼3.70) and 5.5 (DABCO: pKb ¼5.18, 558C for two days (Scheme 4). The substrate spectrum
DMAP: pKb ¼4.8)[13] the experimental pKb value of the includes electron-rich (3b–e), electron-poor (3g, h)
phenolate of 2-hydroxybenzaldehyde (pKb ¼5.2)[14] and and sterically hindered (3f, i,[16] j) aldehydes. As can be
the approximated pKb value of dienolate 9 (pKb ¼3.7) seen from Table 1, the product distribution is strongly
are within this range.[15] Stronger bases like KOH dependent on substrate. While it is mostly insensitive
(pKb ¼ ꢀ1.7) or DBU (pKb ¼approx. 2) cause loss of to steric demands on the 3-position (3a, f, i, j), it is strong-
yields, perhaps due to extensive decomposition of the ly influenced by the electronic properties of the arene.
starting materials, while weaker bases like pyridine When the electrophilicity of the aldehyde is lowered
(pKb ¼8.79) or N,N-dimethylaniline (pKb ¼8.8) fail to by donor substituents, the selectivity as well as the over-
catalyze the reaction efficiently. Triphenylphosphine is all yield are diminished. As both products were obtained
not an active catalyst, making a nucleophilic role of in mediocre yields for 4-methoxysalicylaldehyde (3c),
the catalyst improbable. The best results for the forma- only tricyclic product 8e was isolated in very poor yields
tion of 7a were obtained using sodium carbonate, while when 4-diethylaminosalicylaldehyde (3e) was used. The
triethylamine favors the formation of 8a. The benzopyr- poor results of 3h using sodium carbonate as base are
an 7a is most likely formed via an oxa-Michael addition, due to the poor solubility of the sodium salt of the alde-
because non-nucleophilic bases like sodium carbonate hyde: After addition of the base, a yellowprecipitate was
are efficient catalysts for its generation.
formed, presumably the sodium salt of anion 12. After
As the reaction mixture contains two phases, the na- work-up and column chromatography, 90% of the start-
ture of the base exerts an important effect on the distri- ing material was recovered. Therefore, the catalyst was
bution of the postulated anionic species in the reaction changed to the second best, DABCO, which was expect-
mixture. To gain further insight into the problem of ed to be more soluble. Indeed, after an initial precipita-
the solubility, we varied the solvent content for the tion, the solution became clear within 16 h, leading to
two most successful catalysts, namely sodium carbonate 27% of 7h and 37% of 8h. The involvement of a nucleo-
for 7a and triethylamine for 8a, from pure water over philic attack of the phenolate accounts for the low yields
mixtures of water and dioxane to pure dioxane. In the
absence of water, no efficient turnover occurred, either
with Na2CO3 or with NEt3. In all other cases, the reac-
tions proceeded to the desired products, with the best
yields in a monophasic solution with a ratio of 3/1 diox-
ane/water (v/v). While the influence of the solvent on
the product distribution was small when sodium carbo-
nate was used, a distinctive effect could be observed
for triethylamine. In the mixtures containing higher
amounts of water, the yield of 7a as well as the ratio
7a:8a was diminished. Very small yields in pure dioxane
are explained by the lack of stabilization of the anions,
thus lowering the acidity of the 2-hydroxybenzaldehyde
as well as that of the dienol. This is also in accordance
with the observation that the color of the aqueous sol-
vents turned to intense yellow after the addition of the
catalyst, while the pure dioxane solution was much less
colored after addition of triethylamine and remained
colorless when sodium carbonate was used.
Scheme 4. Synthesis of 2,2-dimethyl-2H-chromene-3-carbal-
dehydes 7a – j and 9-methyl-8,12-dioxatricyclo[7.3.1.02,7]tri-
deca-2,4,6-trien-11-ols 8a–j.
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Bernhard Lesch et al.
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Table 1. Yields of 2,2-dimethyl-2H-chromene-3-carbaldehydes 7 and 9-methyl-8,12-dioxatricyclo[7.3.1.02,7]trideca-2,4,6-trien-
11-ols 8.
R1
R2
R3
pKb
Conditions[d]
Yield of 7 [%][a]
Yield of 8 [%][a]
[b]
2-Hydroxybenzaldehyde
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
H
H
OMe
OMe
H
H
H
H
H
H
H
H
H
OMe
OMe
H
H
H
H
H
H
H
OMe
OMe
H
5.83 [5.2][c]
5.83 [5.2][c]
6.21
6.21
5.34
5.34
6.21
6.21
5.71
5.71
6.38
6.38
7.80
7.80
8.92
8.92
8.92
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
C
A
B
A
B
65
19
58
13
36
4
81
36
0
19
46
23
36
15
44
10
46
6.1
3.5
27
57
17
51
8.9
47
37
23
61
24e)
44e)
H
NEt2
NEt2
H
H
H
H
H
H
H
H
H
H
H
H
H
0
OMe
OMe
Br
Br
H
H
H
Allyl
Allyl
Ph
Br
Br
Cl
44
10
58
17
0
3f
3g
3g
3h
3h
3h
3i
3i
3j
3j
Cl
NO2
NO2
NO2
H
H
H
0
27
52
19
65
23
5.50
5.50
5.80
5.80
Ph
H
[a]
Isolated yields.
[b]
pKb of the phenolate in water. Calculated using Advanced Chemistry Development (ACD) Software Solaris V4.76.
Experimental value.
Conditions: A: 0.5 equivs. Na2CO3, stirring, 558C, 2.5 d. B: 0.5 equivs. NEt3, stirring, 558C, 2.5 d. C: 0.5 equivs. DABCO,
stirring, 558C, 2.5 d.
While all other compounds were single diastereomers, 8j was obtained as a 1/1 mixture, probably differing in the relative
stereochemistry of the lactol hydroxy group.
[c]
[d]
[e]
in 7h, as the nitro group in the para position lowers the and acceptor-substituted resorcins. In contrast to the re-
nucleophilicity of the oxygen. actions of senecialdehyde with 2-hydroxybenzalde-
In spite of these drawbacks, this method remains a hydes as above, all cases formed dihydrobenzopyrans
convenient, one-step procedure for the synthesis of with a high degree of chemoselection due to an aldol-
these heterocycles. It is applicable over a wide range of type condensation of the phenolate and a subsequent
substrates, from modestly electron-rich to modestly ring closure.[18a] While unsubstituted resorcin failed to
electron-poor 2-hydroxybenzaldehydes, although the give any of the desired product, resorcin-carbaldehydes
reaction conditions must be adjusted in some difficult and other acceptor-substituted resorcin derivatives con-
cases.
densed with senecialdehyde and several a,b-unsaturat-
When the arene becomes even more electron-rich, as ed aldehydes. We reasoned that the higher acidity of
it is the case with 2,4-dihydroxybenzaldehyde (14), none the phenol hence increases the nucleophilicity at the car-
of the described reactions is observed and the formation bon of the phenolate. Crotonaldehyde and cinnamalde-
of the dihydrobenzopyran 15 becomes predominant. hyde react with the resorcin-aldehyde 14a to give dihy-
This reaction has been reported as giving access to the drobenzopyrans 15c and 15d, respectively, in low yields.
dihydrobenzopyran moiety[17] from senecialdehyde, cro-
As our results in Scheme 5 indicate, all desired prod-
tonaldehyde, cinnamaldehyde and citral and was exten- ucts 15a–h could be obtained, albeit in moderate to
sively studied by Crombie et al. during their work on a low yields. In order to optimize the reaction, resorcin al-
synthesis of cannabinoids.[18] Although the reaction has dehyde (14a) was chosen as the model compound and
proven to be very useful, the harsh reaction conditions screening of bases was performed (DABCO, DMAP,
required (typically refluxing pyridine)[19] and unsatisfac- NEt3, i-Pr2EtN, KOH, NaOH, K2CO3, Na2CO3, Cs2CO3).
tory yields in certain cases are drawbacks for this route DABCO was found to be superior to all bases tested.
to chromenes. We decided to investigate the scope and Potassium hydroxide was the second and cesium carbo-
limitations of the mild catalytic method described which nate was the third best yielding 24% and 20% of prod-
allows reaction temperatures below 608C, by applying uct, respectively. During the reactions, a considerable
these conditions to several a,b-unsaturated aldehydes amount of insoluble substance was formed. In order to
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Condensation of 2-Hydroxybenzaldehydes with a,b-Unsaturated Aldehydes
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Experimental Section
GC (gas chromatography) analytical: Hewlett-Packard HP
5890 Series II 12 mꢁ0.25 mm capillary column HP I (carrier
gas N2). TLC (thin layer chromatography): silica gel coated
aluminium plates (Merck, silica gel 60, F254). Detection under
UV light at 254 nm, displayed with molybdatophosphate (5%
phosphomolybdic acid in ethanol, dipping solution) and potas-
sium permanganate (0.45 g potassium permanganate and
2.35 g of sodium carbonate in 90 mL of water, dipping solu-
tion). Solvent mixtures are understood as volume/volume. Ab-
breviations: cyc¼cyclohexane, EtOAc¼ethyl acetate, Pen¼
pentane, and PE¼light petroleum ether. Descriptions without
a nominated temperature were done by room temperature (rt).
Solid materials were powdered. Solvents, reagents and chemi-
cals were purchased from Aldrich, Fluka, Janssen, and Merck.
Ethyl acetate, light petroleum ether and dichloromethane
were distilled prior to use. All other solvents, reagents and
chemicals were used as purchased.
Scheme 5. Reaction of resorcin derivatives 14 with a,b-unsa-
turated aldehydes 6.
Table 2. Reaction of resorcin derivatives 14 with a,b-unsatu-
rated aldehydes 6a–d.
Entry
6
R1
R2 14 R3 R4
Product Yield [%]
General Procedure for the Optimization by GC
Analysis
1
2
3
4
5
6
7
8
6a Me Me 14a
H
H
H
H
H
H
H
H
H
H
15a
15b
15c
15d
15e
53
35
34
10
18
24
40
21
6b Me
6c n-Pr
6d Ph
H
H
H
14a
14a
14a
The solvent was treated with ultrasound for 15 min. while a
stream of argon was passed through it. In 1 mL, the given
amount of catalyst, 0.20 mL (0.18 g, 2.1 mmol) of senecialde-
hyde (6a) and 0.22 mL (0.23 g, 2.1 mmol) of 2-hydroxybenzal-
dehyde (3a) were suspended. The mixture was subjected to ul-
trasound for 36 hours, diluted with a saturated solution of so-
dium carbonate and extracted three times with ethyl acetate.
A weighed amount of n-decane was added and the combined
organic phases were dried over anhydrous magnesium sulfate.
The mixture was analyzed by GC.
6a Me Me 14b
6a Me Me 14c
Me
OMe 15f
H
H
6a Me Me 14d Me
6b Me 14d Me
15g
15h
H
Conditions: DABCO, H2O, sonication, 4 d.
circumvent the polymerization of senecialdehyde, the
reaction was performed without sonication at 458C
with intense stirring. This procedure provided the prod-
uct in 44% yield but did not prevent the formation of the
insoluble side product. A last attempt was made by add-
General Procedure for Base-Catalyzed Condensation
of Senecialdehyde with 2-Hydroxybenzaldehydes on a
Preparative Scale
ing senecialdehyde at a very slow rate and in large ex- The solvent was subjected to ultrasound for 15 min. while a
stream of argon was passed through it. In an amount of solvent
needed for a two molar solution of the reactants, 0.5 equivs. of
catalyst, 1.0 equiv. of senecialdehyde and 1.0 equiv. 2-hydroxy-
benzaldehyde were suspended. The mixture was stirred at
558C for 2.5 days, diluted with a saturated solution of sodium
carbonate, and extracted three times with ethyl acetate. The
combined organic phases were dried over anhydrous magnesi-
um sulfate and purified as described below.
cess. In this experiment, six equivalents of senecialde-
hyde were added to the reaction mixture under intense
stirring over a period of 18 hours. The yield, however,
was determined to be 45%. Finally, various solvents
and mixtures of solvents were investigated, but none
provided the desired increase in yield. Even though
our method does not provide chromenes in high yields,
it should be considered as an alternative to the establish-
ed methods and applied when temperature sensitive
compounds are involved.
2,2-Dimethyl-2H-chromene-3-carbaldehyde (7a) and 9-
Methyl-8,12-dioxatricyclo[7.3.1.02,7]trideca-2,4,6-trien-11-
ol (8a): Synthesized from 1.00 mL (875 mg, 10.4 mmol) of sen-
ecialdehyde (6a), 1.11 mL (1.27 g, 10.4 mmol) of 2-hydroxy-
benzaldehyde (3a) and 551 mg (5.22 mmol) of sodium carbo-
nate in 5 mL dioxane/water, 3/1. The crude product was puri-
fied by column chromatography (eluent EtOAc/PE for 7a,
then 1/1 for 8a) to yield 1.27 g (65%) of 7a as a yellow oil and
397 mg (19%) of 8a as colorless crystals. Compound 7a: Rf
(EtOAc/PE, 1/5)¼0.68; compound 8a: mp 153–1558C, Rf
(EtOAc/PE, 1/1)¼0.38.
Conclusion
In conclusion, we have demonstrated that the reaction
of substituted 2-hydroxybenzaldehydes with a,b-unsa-
turated aldehydes gives rise to dihydrobenzopyrans de-
pending on the catalyst used. In future studies, we will
explore asymmetric variants of these reactions and their
use in the synthesis of complex natural products.
8-Methoxy-2,2-dimethyl-2H-chromene-3-carbaldehyde
(7b) and 6-Methoxy-9-methyl-8,12-dioxatricyclo[7.3.1.02,7]-
trideca-2,4,6-trien-11-ol (8b): Synthesized from 1.58 g
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Bernhard Lesch et al.
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(10.4 mmol) of 2-hydroxy-3-methoxybenzaldehyde (3b),
1.00 mL (0.875 g, 10.4 mmol) of senecialdehyde (6a) and
551 mg (5.20 mmol) of sodium carbonate in 5 mL of dioxane/
water, 3/1. The crude product was purified by column chroma-
tography (eluent EtOAc/PE for 7b, then 1/1 for 8b) to yield
1.31 g (58%) of 7b as a yellow solid and 566 mg (23%) of 8b
as colorless crystals. Compound 7b: mp 53–568C, Rf (EtOAc/
PE, 1/5)¼0.36; compound 8b: mp 173–1758C, Rf (EtOAc/
PE, 1/1)¼0.26.
Rf (Et2O/Pen, 1/5)¼0.51 ; compound 8g: mp 148–1518C, Rf
(Et2O)¼0.70.
6-Nitro-2,2-dimethyl-2H-chromene-3-carbaldehyde (7h)
and 4-Nitro-9-methyl-8,12-dioxatricyclo[7.3.1.02,7]trideca-
2,4,6-trien-11-ol (8h): Synthesized from 871 mg (5.22 mmol)
of 5-nitro-2-hydroxybenzaldehyde (3h), 0.500 mL (439 mg,
5.22 mmol) of senecialdehyde (6a) and 292 mg (2.61 mmol)
of DABCO in 4 mL of dioxane/water, 3/1. The crude product
was purified by column chromatography (eluent Et2O/Pen,
1/1) to yield 331 mg (27%) of 7h as a pale yellow solid and
490 mg (37%) of 8h as colorless crystals. Compound 7h: mp
111–1158C, Rf (Et2O/Pen, 1/1)¼0.64; compound 8h: mp¼
127–1318C, Rf (Et2O/Pen, 1/1)¼0.13.
7-Methoxy-2,2-dimethyl-2H-chromene-3-carbaldehyde
(7c) and 5-Methoxy-9-methyl-8,12-dioxatricyclo[7.3.1.02,7]-
trideca-2,4,6-trien-11-ol (8c): Synthesized from 576 mg
(3.79 mmol) of 2-hydroxy-4-methoxybenzaldehyde (3c),
319 mg (3.79 mmol) of senecialdehyde (6a) and 201 mg
(1.90 mmol) of sodium carbonate in 2 mL of dioxane/water 3/
1. The crude product was purified by column chromatography
(eluent EtOAc/PE for 7c, then 1/1 for 8d) to yield 445 mg
(36%) of 7c as a yellow oil and 134 mg (15%) of 8c as colorless
crystals. Compound 7c: Rf (cyc/EtOAc, 5/1)¼0.32; compound
8c: mp 128–1308C, Rf (cyc/EtOAc, 5/1)¼0.05.
8-Allyl-2,2-dimethyl-2H-chromene-3-carbaldehyde (7i)
and 6-Allyl-9-methyl-8,12-dioxatricyclo[7.3.1.02,7]trideca-
2,4,6-trien-11-ol (8i): Synthesized from 846 mg (5.22 mmol)
of 3-allyl-2-hydroxy-benzaldehyde (3i), 0.500 mL (439 mg,
5.22 mmol) of senecialdehyde (6a) and 277 mg (2.61 mmol)
of sodium carbonate in 4 mL of dioxane/water, 3/1. The crude
product was purified by column chromatography (eluent Et2O/
Pen, 1/10, for 7i, then Et2O for 8i) to yield 616 mg (52%) of 7i as
a yellow oil and 296 mg (23%) of 8i as colorless crystals. Com-
pound 7i: Rf (Et2O/Pen, 1/10)¼0.36; compound 8i: mp 102–
1048C, Rf (Et2O)¼0.71.
6-Methoxy-2,2-dimethyl-2H-chromene-3-carbaldehyde
(7d) and 4-Methoxy-9-methyl-8,12-dioxatricyclo[7.3.1.02,7]-
trideca-2,4,6-trien-11-ol (8d): Synthesized from 1.30 mL
(1.58 g, 10.4 mmol) of 2-hydroxy-5-methoxybenzaldehyde
(3d), 1.00 mL (0.875 g, 10.4 mmol) of senecialdehyde (6a)
and 584 mg (5.20 mmol) of sodium carbonate in 6 mL of diox-
ane/water 1/2. The crude product was purified by column chro-
matography. First, EtOAc/PE (1/5) was used as eluent to yield
1.67 g (74%) 7d as a yellow solid, then eluent was changed to
EtOAc/PE (1/1) to obtain 343 mg (14%) 8d as a colorless solid.
Compound 7d: mp 50–548C, Rf (EtOAc/PE, 1/5)¼0.31; com-
pound 8d: mp 118–1198C, Rf (EtOAc/PE, 1/1)¼0.33.
8-Phenyl-2,2-dimethyl-2H-chromene-3-carbaldehyde (7j)
and 9-Methyl-6-phenyl-8,12-dioxatricyclo[7.3.1.02,7]tride-
ca-2,4,6-trien-11-ol
(8j):
Synthesized
from
1.03 g
(5.22 mmol) of 2-hydroxy-3-phenylbenzaldehyde (3j),
0.500 mL (439 mg, 5.22 mmol) of senecialdehyde (6a) and
277 mg (2.61 mmol) of sodium carbonate in 4 mL of dioxane/
water, 3/1. The crude product was purified by column chroma-
tography (eluent Et2O/Pen, 1/5, for 7j, then Et2O for 8j) to yield
900 mg (65%) of 7j as a yellow oil and 251 mg (24%) of 8j as col-
orless crystals. Compound 7j: mp 71–758C; Rf (Et2O/Pen, 1/
5)¼0.46; compound 8j (both isomers): mp 160–1628C, Rf
(Et2O)¼0.70.
5-N,N-Dimethylamino-9-methyl-8,12-dioxatricy-
clo[7.3.1.02,7]trideca-2,4,6-trien-11-ol (8e): Synthesized
from 1.01 g (5.22 mmol) of 2-hydroxy-4-N,N-dimethylamino
benzaldehyde (3e), 0.500 mL (439 mg, 5.22 mmol) of senecial-
dehyde and 277 mg of sodium carbonate. The crude product
was purified by column chromatography (eluent Et2O/Pen,
2/1) to afford 8e as a colorless solid; yield: 87.7 g (6.4%), mp
149–1498C, Rf (Et2O/Pen, 2/1)¼0.27.
5-Hydroxy-2,2-dimethyl-2H-chromene-6-carbaldehyde
(15a)
6-Bromo-8-methoxy-2,2-dimethyl-2H-chromene-3-car-
baldehyde (7f) and 4-Bromo-6-methoxy-9-methyl-8,12-di-
oxatricyclo[7.3.1.02,7]trideca-2,4,6-trien-11-ol (8f): Synthe-
sized from 1.21 g (5.22 mmol) of 5-bromo-2-hydroxy-3-me-
thoxybenzaldehyde (3f), 0.500 mL (439 mg, 5.22 mmol) of sen-
ecialdehyde (6a) and 277 mg (5.20 mmol) of sodium carbonate
in 4 mL of dioxane/water, 3/1. The crude product was purified
by column chromatography (eluent Et2O/Pen, 1/5, for 7f, then
Et2O for 8f) to yield 689 mg (44%) of 7f as a yellow solid and
447 mg (27%) of 8f as colorless crystals. Compound 7f: mp
101–1048C, Rf (Et2O/Pen, 1/5)¼0.36; compound 8f: mp
155–1588C; Rf (Et2O)¼0.60.
Under an argon atmosphere, 5.00 g (36.2 mmol) of 2,4-dihy-
droxybenzaldehyde (14a) and 2.03 g (18.1 mmol) of DABCO
were dissolved in 20 ml of water/dioxane, 1/3. Senecialdehyde
(6a; 3.05 g, 36.2 mmol), was added and the mixture was placed
in a sonication bath for 2.5 days. The product was extracted
with 3ꢁ75 mL of Et2O. The combined organic phases were
dried over MgSO4. The solvent was removed by evaporation
under reduced pressure. The crude product was purified by col-
umn chromatography (EtOAc/PE, 1/5) providing 15a as a yel-
low solid; yield: 3.95 g (53%). Recrystallization from heptane
yielded light yellow needles, mp 70–718C, Rf (heptane/EtOAc,
5/1)¼0.31.
6-Bromo-8-chloro-2,2-dimethyl-2H-chromene-3-carbal-
dehyde (7 g) and 4-Bromo-6-chloro-9-methyl-8,12-dioxatri-
cyclo[7.3.1.02,7]trideca-2,4,6-trien-11-ol (8g): Synthesized
from 1.23 g (5.22 mmol) of 5-bromo-3-chloro-2-hydroxyben-
zaldehyde (3g), 0.500 mL (439 mg, 5.22 mmol) of senecialde-
hyde (6a) and 277 mg (2.61 mmol) of sodium carbonate in
4 mL of dioxane/water, 3/1. The crude product was purified
by column chromatography (eluent Et2O/Pen, 1/5, for 7 g,
then Et2O for 8g) to yield 934 mg (58%) of 7g as a yellow oil
and 123 mg (7.4%) of 8g as colorless crystals. Compound 7g:
5-Hydroxy-2-methyl-2H-chromene-6-carbaldehyde
(15b)
Under an argon atmosphere, 500 mg (3.62 mmol) of 2,4-dihy-
droxybenzaldehyde (14a) and 203 mg (1.81 mmol) of DABCO
were dissolved in 2 mL of dioxane/water, 1/3. Crotonaldehyde
(6b; 252 mg, 3.62 mmol), was added and the mixture was
560
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Condensation of 2-Hydroxybenzaldehydes with a,b-Unsaturated Aldehydes
FULL PAPERS
placed in a sonication bath for 60 h. The crude product was ex-
tracted with 3ꢁ15 mL of Et2O and the combined organic phas-
es were dried over MgSO4. Purification by column chromatog-
raphy (EtOAc/PE, 1/5) gave 15b as a yellow oil; yield: 242 mg
(35%). Rf (cyc/EtOAc, 5/1)¼0.43.
5-Hydroxy-2,2,7-trimethyl-2H-chromene-6-
carbaldehyde (15g)
Under an argon atmosphere, 750 mg (4.93 mmol) of 2,4-dihy-
droxy-6-methyl-benzaldehyde (14d) and 276 mg (2.46 mmol)
of DABCO were dissolved in 3 mL of water/dioxane, 1/3. After
adding 415 mg (4.93 mmol) of senecialdehyde (6a) the mixture
was placed in a sonication bath for 2.5 days. The crude product
was extracted with 3ꢁ15 mL of Et2O and the combined organ-
ic phases were dried over MgSO4. Purification by column chro-
matography (EtOAc/PE, 1/5) gave 15g as yellow needle-shap-
ed crystals; yield: 434 mg (40%), mp 56–588C, Rf (cyc/EtOAc,
5/1)¼0.55.
5-Hydroxy-2-propyl-2H-chromene-6-carbaldehyde
(15c)
Under an argon atmosphere, 500 mg (3.62 mmol) of 2,4-dihy-
droxybenzaldehyde (14a) and 203 mg (1.81 mmol) of DABCO
were dissolved 2 mL of water/dioxane, 1/3. 355 mg(3.62 mmol)
of trans-hex-2-enal (6c) were added and the mixture was placed
in a sonication bath for 2.5 days. The crude product was extract-
ed with 3ꢁ15 mL of Et2O and the combined organic phases
were dried over MgSO4. Purification by column chromatogra-
phy (EtOAc/PE, 1/5) afforded 15c as an yellow oil; yield:
0.270 g (34%). Rf (heptane/EtOAc, 5/1)¼0.47.
5-Hydroxy-2,7-dimethyl-2H-chromene-6-carbaldehyde
(15h)
Under an argon atmosphere, 750 mg (4.93 mmol) of 2,4-dihy-
droxy-6-methylbenzaldehyde (14d) and 276 mg (2.46 mmol)
of DABCO were dissolved in 3 ml of water/dioxane, 1/3. Cro-
tonaldehyde (6b; 346 mg, 4.93 mmol) was added and the mix-
ture was placed in a sonication bath for 2.5 days. The crude
product was extracted with 3ꢁ15 mL of Et2O and the com-
bined organic phases were dried over MgSO4. Purification by
column chromatography (EtOAc/PE, 1/5) provided 15h as a
yellow oil; yield: 215 mg (21%), Rf (cyc/EtOAc, 5/1)¼0.48.
5-Hydroxy-2-phenyl-2H-chromene-6-carbaldehyde
(15d)
Under an argon atmosphere, 500 mg (3.62 mmol) of 2,4-dihy-
droxybenzaldehyde (14a) and 203 mg (1.81 mmol) of DABCO
were dissolved in 2 mL of water/dioxane, 1/3. trans-Cinnamal-
dehyde (6d; 476 mg, 3.62 mmol), was added and the mixture
was placed in a sonication bath for 2.5 days. The crude product
was extracted with 3ꢁ15 mL of Et2O and the combined organ-
ic phases were dried over MgSO4. Purification by column chro-
matography (EtOAc/PE, 1/9) gave 15d as a light yellow solid;
yield: 91 mg (10%); mp 65–678C, Rf (heptane/EtOAc, 5/1)¼
0.28.
Supporting Information
Characterization data for the compounds made and the results
of the optimization studies are contained in the Supporting In-
formation.
Acknowledgements
1-(5-Hydroxy-2,2-dimethyl-2H-chromen-6-yl)-
ethanone (15e)
We would like to honour the fruitfulcooperationand many stim-
ulating discussions in the field of cannabinoid chemistry with
Professor Andreas Zimmer and Professor Christa E. Mꢀller.
Furthermore, we would like to express our gratitude towards
the DFG (Graduiertenkolleg 804 “Analyse von Zellfunktionen
durch kombinatorische Chemie und Biochemie”) for financial
support.
Under an argon atmosphere, 500 mg (3.29 mmol) of 2,4-dihy-
droxyacetophenone (14b) and 185 mg (1.65 mmol) of DABCO
were dissolved in 2 mL of water/dioxane, 1/3. Senecialdehyde
(6a; 276 mg, 3.29 mmol) was added and the mixture was placed
in a sonication bath for 2.5 days. The crude product was extract-
ed with 3ꢁ15 mL of Et2O and the combined organic phases
were dried over MgSO4. Purification by column chromatogra-
phy (EtOAc/PE, 1/5) gave 15e as a yellow solid; yield: 131 mg
(18%), mp 93–96 8C, Rf (cyc/EtOAc, 5/1)¼0.48.
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Adv. Synth. Catal. 2005, 347, 555–562
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561

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