Synthesis of ortho-hydroxyacetophenone derivatives from Baylis-Hillman acetates

Article abstract of DOI:10.1016/S0040-4039(02)01441-7

Synthesis of ortho-hydroxyacetophenone derivatives 5 was carried out from the reaction of Baylis-Hillman acetates 1 and active methylene compounds 2 in N,N-dimethylformamide in the presence of K₂CO₃.

Full text of DOI:10.1016/S0040-4039(02)01441-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6597–6600
Synthesis of ortho-hydroxyacetophenone derivatives from
Baylis–Hillman acetates
Jae Nyoung Kim,* Yang Jin Im and Jeong Mi Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Kwangju 500-757, South Korea
Received 10 June 2002; revised 8 July 2002; accepted 12 July 2002
Abstract—Synthesis of ortho-hydroxyacetophenone derivatives 5 was carried out from the reaction of Baylis–Hillman acetates 1
and active methylene compounds 2 in N,N-dimethylformamide in the presence of K2CO3. © 2002 Elsevier Science Ltd. All rights
reserved.
ortho-Hydroxyacetophenones are important synthetic
intermediates for the synthesis of various useful com-
pounds such as flavonols,1a lamellarin alkaloids,1b
fluorescence 3-hydroxychromones1c and many other
compounds.1 ortho-Hydroxyacetophenones and related
compounds can be prepared by the Fries type rear-
rangement most often2a–c or by other methods.2d,e
effectively in the presence of nucleophilic species and a
proton source.4 We thought that deacetylation could be
minimized in an aprotic and polar solvent such as
N,N-dimethylformamide (DMF).4 As expected the
desired ortho-hydroxyacetophenone derivative 5a was
obtained in reasonable yield. Among the examined
conditions the use of DMF and K2CO3 gave the best
results. Similar systems such as KF/DMF, Cs2CO3/
DMF or K2CO3/CH3CN were found to be less
effective.
Recently, Chamakh and Amri have reported on the
novel one-pot synthesis of (E)-4-alkylidene-2-cyclo-
hexen-1-ones via a cross coupling of the Baylis–Hillman
acetates 1 and aliphatic 1,3-diketones in the presence of
potassium carbonate in absolute ethanol at reflux tem-
perature (Scheme 1).3 In the paper, they reported the
mechanism as the tandem three-step reaction: SN2% sub-
stitution–deacetylation–cyclization reactions.
As shown in Scheme 2, the reaction of the Baylis–Hill-
man acetate 1a and 2,4-pentanedione (2a) in DMF gave
the corresponding 2-hydroxy-4-methyl-5-benzylace-
tophenone (5a) in 71% isolated yield.5,6 The plausible
reaction mechanism is shown in Scheme 2. Initial SN2%
reaction between 1a and 2a gave the allylic substitution
product 3. This compound existed as a tautomeric
keto–enol mixture (keto-form/enol-form, 5:2) in CDCl3,
whereas keto-form of 3 was observed as a sole tautomer
in DMSO-d6. Subsequent aldol condensation of 3
We presumed that we could prepare the ortho-hydroxy-
acetophenone derivative 5a if we protect the deacetyla-
tion step before the last intramolecular aldol
condensation (Scheme 2). Deacetylation might occur
O
OAc O
O
O
K2CO3
1. deacetylation
R
2. aldol
Ac
R
+
R
EtOH
SN2'
O
Ac
Scheme 1.
Keywords: ortho-hydroxyacetophenones; Baylis–Hillman acetates; deacetylation; N,N-dimethylformamide.
* Corresponding author. Fax: +82-62-5303389; e-mail: kimjn@chonnam.chonnam.ac.kr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01441-7

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J. N. Kim et al. / Tetrahedron Letters 43 (2002) 6597–6600
OAc O
O
O
K2CO3
O
O
+
DMF
O
O
70 oC, 5 h
2a
1a
OH
O
3
aldol
- H2O
1. keto-enol tautomerization
2. 1,3-proton transfer
O
OH
O
O
4
5a
Scheme 2.
afforded 4. Rapid keto–enol tautomerization and pro-
ton transfer gave 5a. Trace amount of deacetylated
compound 6 was observed on TLC (see Scheme 3). It
is noteworthy to compare the results in ethanol with
those of in DMF (Scheme 3). Under the reported
Amri’s conditions, small amount of 5a (6%) and
appreciable amounts of (E)-4-benzylidene-3-methyl-2-
cyclohexen-1-one (6, 40%)5 were isolated. In this case,
unusual ethoxy compound 7 was isolated.5 Similar
results were observed in methanol solvent.5
nones were isolated together with 2-hydroxyacetophe-
nones (entries 4 and 5). The 4-hydroxy compounds
5d% and 5e% were generated as shown in Scheme 4.
Similarly, the reaction with ethyl acetoacetate (2b)
gave similar results (entries 6 and 7). However, in
these cases 5f% and 5g% were isolated, which were
formed via decarbethoxylation. It is interesting to
note that (E)-4-benzylidene-2-cyclohexen-1-one deriva-
tives, 5f% and 5g%, were isolated in appreciable
amounts in the case of ethyl acetoacetate. These
results imply decarbethoxylation is easier than the
corresponding deacetylation. Besides 2a and 2b, other
activated methylene compounds such as methanesul-
fonylacetone (2c) and 1-benzoylacetone (2d) gave sim-
ilar results (entries 8 and 9).
The reaction must be conducted under nitrogen atmo-
sphere. Otherwise, severe decomposition of the gener-
ated product to intractable mixtures was observed.
The major decomposition process could be thought as
the air oxidation of the benzylic position followed by
further oxidation toward quinone system.
General procedure for the preparation of
5 is
With the optimized conditions (DMF, K2CO3, heat-
ing) for the synthesis of ortho-hydroxyacetophenone
derivative 5a in hand, we examined the reaction of
some Baylis–Hillman acetates7 with 2,4-pentanedione
(2a), ethyl acetoacetate (2b), methanesulfonylacetone
(2c) and 1-benzoylacetone (2d). The representative
results are summarized in Table 1. Baylis–Hillman
acetates 1b and 1c gave the corresponding ortho-
hydroxyacetophenones 5b and 5c, respectively. From
the Baylis–Hillman acetates 1d and 1e, which were
derived from ethyl vinyl ketone, 4-hydroxyacetophe-
straightforward as follows: A stirred solution of 1
and active methylene compounds 2 (1.1 equiv.) in
DMF in the presence of K2CO3 (1.1 equiv.) was
heated to 70–90°C under N2 for the time given in
Table 1. After the usual work-up process and column
chromatography (hexane/ether, 15:1) desired 5 was
isolated in good to moderate yields.5
In conclusion, we have disclosed the facile synthesis
of ortho-hydroxyacetophenones and related com-
pounds. By changing the reaction conditions slightly,
OEt
K2CO3
1a + 2a
EtOH
OH
OH
OH
O
reflux, 6 h
6 (40%)
K2CO3
O
O
7 (7%)
5a (6%)
OMe
MeOH
reflux, 8 h
+
6 (26%)
5a (5%)
+
7' (18%)
O
Scheme 3.

J. N. Kim et al. / Tetrahedron Letters 43 (2002) 6597–6600
Table 1. Synthesis of o-hydroxyacetophenone derivatives
6599
entry
1
1,3-diketone
B-H acetate
OAc O
conditions
product (% yield)
O
O
K2CO3, DMF
70 oC, 5 h
OH
2a
2a
1a
O
5a (71%, mp 60-61 oC)
OAc O
K2CO3, DMF
70 oC, 5 h
2
OH
1b
O
5b (76%, mp 73-74 oC)
OAc O
K2CO3, DMF
70 oC, 5 h
2a
2a
3
OH
Cl
Cl
1c
O
5c (71%, mp 107-108 oC)
OH
OAc O
K2CO3, DMF
80 oC, 5 h
4
OH
O
1d
O
5d' (23%, oil)
5d (45%, oil)
OH
OAc O
1e
K2CO3, DMF
80 oC, 5 h
5
2a
Cl
OH
OH
Cl
Cl
O
O
5e'(32%, mp 87-88 oC)
5e (31%, oil)
O
O
K2CO3, DMF
90 oC, 7 h
6
1a
1c
1a
OEt
O
2b
5f' (26%, oil)
EtO
O
5f (41%, mp 64-65 oC)
K2CO3, DMF
90 oC, 7 h
7
2b
O
Cl
OH
Cl
5g' (21%, mp 68-69 oC)
EtO
O
5g (41%, mp 73-74 oC)
OH
O
O
K2CO3, DMF
90 oC, 7 h
8
9
SO2Me
OH
SO2Me
SO2Me
2c
2d
5h (52%, mp 130-131 oC)
5h' (16%, oil)
O
K2CO3, DMF
80 oC, 8 h
1a
OH
O
Ph
Ph
5i (61%, mp 97-98 oC)
selective synthesis of different compounds could be
achieved. By adopting the Amri’s condition (use of
ethanol solvent) 4-alkylidene-2-cyclohexen-1-ones could
be synthesized. Whereas, when the solvent was replaced
with DMF ortho-hydroxyacetophenone derivatives
could be obtained.
Acknowledgements
This work was supported by grant (No. R05-2000-000-
00074-0) from the Basic Research Program of the
Korea Science & Engineering Foundation.

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J. N. Kim et al. / Tetrahedron Letters 43 (2002) 6597–6600
5d
(45%)
O
O
O
OAc O
a
a
2a
b
O
b
O
1d
O
5d'
(23%)
O
Scheme 4.
References
129.76, 131.58, 139.94, 147.20, 161.03, 203.94; Mass (70
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presence of K2CO3. As expected, however, 3-benzyl-2,4-
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Selected data for 6: oil; IR (KBr) 1646 cm−1 1H NMR
;
(CDCl3) l 2.19 (s, 3H), 2.47 (t, J=6.9 Hz, 2H), 2.99 (t,
J=6.9 Hz, 2H), 5.99 (s, 1H), 6.94 (s, 1H), 7.28–7.42 (m,
5H); 13C NMR (CDCl3) l 20.85, 26.78, 37.10, 127.63,
127.73, 128.43, 129.18, 131.27, 135.80, 136.51, 155.69,
199.25; Mass (70 eV) m/z (rel. intensity) 91 (24), 115 (31),
141 (38), 155 (72), 183 (27), 198 (M+, 100).
Selected data for 7: oil; IR (KBr) 3445, 1640 cm−1 1H
;
NMR (CDCl3) l 1.28 (t, J=6.9 Hz, 3H), 2.26 (s, 3H), 2.53
(s, 3H), 3.54 (qd, J=7.2 and 1.5 Hz, 2H), 5.45 (s, 1H),
6.77 (s, 1H), 7.27–7.37 (m, 5H), 7.67 (s, 1H), 12.19 (s, 1H);
13C NMR (CDCl3) l 15.40 (CH3), 19.92 (CH3), 26.46
(CH3), 64.79 (CH2), 80.24 (CH), 117.66 (C), 119.82 (CH),
127.46 (CH), 127.69 (CH), 128.44 (CH), 129.36 (CH),
131.21 (C), 140.76 (C), 146.46 (C), 161.51 (C), 204.20 (C);
Mass (70 eV) m/z (rel. intensity) 43 (17), 105 (22), 179 (44),
207 (85), 239 (100), 284 (M+, 84).
Selected data for 7%: oil; IR (KBr) 3464, 1643, 1089 cm−1
;
1H NMR (CDCl3) l 2.24 (s, 3H), 2.57 (s, 3H), 3.39 (s,
3H), 5.33 (s, 1H), 6.77 (s, 1H), 7.25–7.47 (m, 5H), 7.72 (s,
1H), 12.22 (s, 1H); 13C NMR (CDCl3) l 19.93, 26.52,
57.04, 82.04, 117.70, 119.85, 127.50, 127.79, 128.45, 129.08,
130.84, 140.34, 146.26, 161.52, 204.22; Mass (70 eV) m/z
(rel. intensity) 43 (13), 105 (14), 193 (100), 239 (100), 270
(M+, 90).
6. The structure of 5a was confirmed further by NOE exper-
iment. Irradiation of the benzylic proton (l=3.95 ppm)
showed NOE increment (0.9%) of methyl proton at 4-posi-
tion (l=2.21 ppm) and two aromatic protons (0.9 and
0.7%, respectively). From the NOE experiment we can
exclude the regioisomeric structure, 2-methyl-4-hydroxy-5-
benzylacetophenone.
7. We examined the reaction of Baylis–Hillman acetate
derived from hexanal as an example of aliphatic aldehydes.
However, intractable mixtures were formed due to many
side reactions. Elimination of acetic acid and subsequent
Diels–Alder reaction was one of the side reactions as
reported in our previous paper, see: Kim, J. N.; Lee, H. J.;
Lee, K. Y.; Gong, J. H. Synlett 2002, 173.
5. Selected data for 5a: white solid, mp 60–61°C; IR (KBr)
1
2917, 1638, 1491, 1450 cm−1; H NMR (CDCl3) l 2.21 (s,
3H), 2.54 (s, 3H), 3.95 (s, 2H), 6.80 (s, 1H), 7.09–7.29 (m,
5H), 7.42 (s, 1H), 12.17 (s, 1H); 13C NMR (CDCl3) l
20.35, 26.49, 38.65, 117.82, 119.63, 126.22, 128.45, 128.54,