An efficient synthesis of flavans from salicylaldehyde and acetophenone derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.09.147

An efficient total synthesis of flavans from the reactions of salicylaldehyde and acetophenone derivatives is reported. The synthesis involves preparation of chalcones through an aldol reaction followed by reduction of both the double bond and the ketone using NaBH₄ and an acetic acid mediated cyclization. Methoxy groups on the aromatic rings did not affect significantly the yields of the procedure.

Full text of DOI:10.1016/j.tetlet.2011.09.147

Tetrahedron Letters 52 (2011) 6716–6718
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An efficient synthesis of flavans from salicylaldehyde and acetophenone
derivatives
⇑
Ofentse Mazimba, Ishmael B. Masesane , Runner R. Majinda
Department of Chemistry, University of Botswana, P/Bag UB 00704, Gaborone, Botswana
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2011
Revised 16 September 2011
Accepted 30 September 2011
Available online 6 October 2011
An efficient total synthesis of flavans from the reactions of salicylaldehyde and acetophenone derivatives
is reported. The synthesis involves preparation of chalcones through an aldol reaction followed by reduc-
tion of both the double bond and the ketone using NaBH4 and an acetic acid mediated cyclization. Meth-
oxy groups on the aromatic rings did not affect significantly the yields of the procedure.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Flavan
Acetophenone
Salicylaldehyde
Aldol condensation
Reduction
Flavans are a group of flavanoids possessing a 2-phenylchroman
nucleus. They exist widely in the plant kingdom and exhibit many
important biological and pharmacological activities.1–3 Flavans
have attracted the attention of many synthetic chemists and a
number of general procedures have been developed for their syn-
thesis. These include intramolecular Mitsunobu reaction,4 cycliza-
tion of chalcones and the reduction of flavanones,5 flav-2-enes6
and flavones.7 Most of these procedures suffer from long reactions
times, poor yields and harsh conditions.
Herein, we report a short and efficient procedure for the total
synthesis of flavans which involves the reduction of 2-hydroxy-
chalcones with NaBH4 and subsequent cyclization using acetic
acid. 2-Hydroxychalcones are commonly synthesized via Claisen
or aldol condensation between 2-hydroxyacetophenone and benz-
aldehyde.8,9 This reaction suffers from long reaction times and low
yields for polyhydroxylated benzaldehydes or acetophenones con-
trary to our method which used salicyladehyde and acetophenone
for the synthesis of 2-hydroxychalcone. The general strategy for
the construction of flavan 1 was based on the retrosynthetic anal-
ysis shown in Scheme 1. Disconnection of flavan 1 at the ether
bond furnished advanced intermediate 2. Functional group inter-
conversions gave chalcone 3 and further disconnection identified
commercially available salicylaldehyde (5) and acetophenone (4)
as the starting materials. For most of the reported procedures for
the synthesis of the 2-phenylchroman nucleus, the oxygen which
forms the ether is introduced as 2-hydroxyacetophenone, while
in our procedure it is introduced as salicylaldehyde.
In the event, efficient access to intermediate chalcone 3 was
achieved through an aldol condensation between acetophenone
(4) and salicylaldehyde (5) in a mixture of 40% NaOH(aq) and etha-
nol at 60 °C for 2 h. This reaction afforded chalcone 3 in 85% yield
(Scheme 2). The successful preparation of chalcone 3 set the stage
for the crucial cyclization reaction. Consequently, treatment of a
solution of chalcone 3 in methanol with NaBH4 gave derivative 2
in 88% yield. It is noteworthy that the carbon–carbon double bond
was also reduced under these conditions and there is literature
precedence to such a reduction.10 Subsequent dissolution of 2 in
OH
O
OH
1
2
OH
CHO
OH
+
O
O
5
4
3
⇑
Corresponding author.
E-mail address: masesane@mopipi.ub.bw (I.B. Masesane).
Scheme 1. Reterosynthetic analysis of flavan 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.147

O. Mazimba et al. / Tetrahedron Letters 52 (2011) 6716–6718
6717
OH
O
O
O
ii
i
+
OH
OH
OH
5
4
3
2
iii
O
1
Scheme 2. Reagents and conditions: (i) 40% NaOH(aq), EtOH, 60 °C, 2 h, 85%; (ii) NaBH4, MeOH, 25 °C, 10 min, 88%; (iii) AcOH, reflux, 30 min, 71%.
OMe
O
OH
OH
O
ii, iii
OMe
i
+
OMe
O
O
5
6
9
12
= o-OMe
= o-OMe
= o-OMe
7 = m-OMe
8 = p-OMe
10 = m-OMe
11 = p-OMe
13 = m-OMe
14 = p-OMe
Scheme 3. Reagents and conditions: (i) 40% NaOH(aq), EtOH, 60 °C, 2 h, 83% [9], 66% [10], 78% [11]; (ii) NaBH4, MeOH, 25 °C, 10 min; (iii) AcOH, reflux, 30 min, 70% [12], 38%
[13], 78% [14].
OMe
OMe
OMe
R
O
OH
OH
O
ii, iii
i
+
R
R
O
O
15
4 (R = H)
16 (R = H)
20 (R = H)
6 (R = o-OMe)
7 (R = m-OMe)
8 (R = p-OMe)
17 (R = o-OMe)
18 (R = m-OMe)
19 (R = p-OMe)
21 (R = o-OMe)
22 (R = m-OMe)
23 (R = p-OMe)
Scheme 4. Reagents and conditions: (i) 40% NaOH(aq), EtOH, 60 °C, 2 h, 76% [16], 72% [17], 56% [18], 87% [19]; (ii) NaBH4, MeOH, 25 °C, 10 min; (iii) AcOH, reflux, 30 min, 64%
[20], 58% [21], 63% [22], 85% [23].
acetic acid and refluxing for 30 min gave flavan 111,12 in 71% yield.
It was found that the synthesis of 1 proceeded without having to
purify intermediate 2.
To test the generality of this synthetic route, a variety of meth-
oxyacetophenones 6–8 and salicylaldehyde (5) were reacted under
the conditions described above to give the corresponding chal-
cones 9–11 in 66–83% yields. The carbon–carbon double bonds
and ketones of these chalcones were reduced using NaBH4 and al-
lowed to undergo the acetic acid mediated cyclization to give the
corresponding flavans 12–14 in 38–78% yields from the chalcones,
Scheme 3.
In summary, we have reported a general method for the synthe-
sis of flavans which involved reduction of both the ketone and dou-
ble bond of chalcones using NaBH4 and subsequent cyclization. The
reaction is not affected by the presence of methoxy group substit-
uents on either of the aromatic rings.
Acknowledgements
We wish to thank the Department of Chemistry, University of
Botswana for studentship funding (to O.M.), Mr. Disang Mosima-
neathebe for MS experiments and Mr. Marape for NMR experiments.
Next we decided to study the effects of a methoxy group at-
tached to the salicyladehyde on our procedure. To this end, salicyl-
Supplementary data
aldehyde derivative 15 was treated with
a
solution of
acetophenone (4) in a mixture of 40% NaOH(aq) and ethanol to give
chalcone 16 in 76% yield. Subsequent reduction of the alkene and
ketone groups of 16 followed by cyclization gave flavan 20 in
88% yield from chalcone 16. Further reactions of acetophenone
methoxy derivatives 6–8 afforded the corresponding chalcones
17–19 in 56–87% yields. Reduction and cyclization of chalcones
17–19 gave the corresponding flavans 21–23 in overall yields of
58–85%, Scheme 4.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.147.
References and notes
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11. Typical experimental procedure: To a solution of acetophenone (40 mmol) and
salicylaldehyde (40 mmol) in EtOH (50 mL) was added 40% NaOH (10 mL)
aqueous solution dropwise and the reaction was refluxed at 60 °C for 2 h. The
solution/suspension was poured onto cold H2O and the mixture neutralized
with 2 M HCl until the solution was acidic. The resulting yellow precipitate was
collected, washed with H2O and recrystallized from EtOH to yield a yellow
solid (4.2 g, 85% yield of 3). NaBH4 powder (5 equiv, 33.5 mmol) was added
slowly to a stirred methanolic solution of 3 (6.7 mmol) at 25 °C. The resulting
suspension was stirred for 10 min and after cooling the mixture was quenched
with 2 M HCl. The organic layer was separated and the aqueous phase
extracted with EtOAc (3 ꢀ 15 mL). The combined organic phase was dried
(MgSO4) and concentrated to a brown gum (1.3 g, 88% yield of 2). Glacial AcOH
(10 ml) was added to 2 (4.4 mmol). The solution was heated at reflux for
30 min, then cold H2O (15 mL) followed by saturated NaHCO3 (30 mL) were
added, and the solution extracted with EtOAc (2 ꢀ 20 mL). The combined
organic layer was washed with H2O (20 ml) and brine (20 ml), dried over
anhydrous MgSO4. After filtration, the solvent was evaporated under reduced
pressure and the residue was purified by silica gel column chromatography
eluting with petroleum ether–EtOAc (v/v, 4:1) to give flavan 1 (710 mg, 71%).
12. Spectral data for 1. Yellow gum; tmax (neat): 2985, 2924, 1619, 1511, 1457,
1371, 1152, 1110, 839, 771 cmꢁ1; dH (300 MHz, acetone-d6): 2.03 (1H, m, H-
3a), 2.20 (1H, m, H-3b), 2.77 (1H, m, H-4a), 2.98 (1H, m, H-4b), 5.08 (1H, dd,
J = 2.4, 10.2 Hz, H-2), 6.79 (1H, ddd, J = 0.9, 7.2, 8.1 Hz, H-6), 6.87 (1H, dd,
J = 0.9, 8.1 Hz, H-8), 7.05 (1H, ddd, J = 1.5, 7.5 Hz, H-40), 7.13 (1H, dd, J = 1.5,
7.2 Hz, H-5), 7.24 (1H, dt, J = 1.5, 8.1 Hz, H-7), 7.33 (2H, dt, J = 1.5, 7.5 Hz, H-30
and 50), 7.40 (2H, dd, J = 1.5, 7.5 Hz, H-20 and 60); dC (75 MHz, acetone-d6):
26.4 (C-4), 39.7 (C-3), 73.0 (C-2), 115.1 (C-8), 119.5 (C-6), 125.9 (C-20 and 60),
128.4 (C-4a), 128.8 (C-40), 126.9 (C-7), 128.0 (C-30 and 50), 130.1 (C-5), 145.9
(C-10), 155.1 (C-8a); HRMS (EI) found M+, 210.1049. C15H14
210.1045.
O requires