Efficient preparation method of 4-hydroxybenzoic esters – Oxidation of substituted Hagemman's ester

Article abstract of DOI:10.1016/j.tetlet.2017.04.090

A practical two-step synthetic method of diversely R-substituted 4-hydroxybenzoic esters, which may have wide applications in household chemicals and polymeric materials, was developed by 2:1 coupling between ethyl acetoacetate and aldehydes (RCHO) in t-BuOK/t-BuOH, followed by oxidative aromatization of the resulting Hagemman's esters. Application of the condition using stoichiometric NBS and catalytic TMS·OTf efficiently induced oxidation of the Hagemman's esters to produce 4-hydroxybenzoic esters.

Full text of DOI:10.1016/j.tetlet.2017.04.090

Accepted Manuscript
Efficient preparation method of 4-hydroxybenzoic esters – oxidation of substi-
tuted Hagemman’s ester
Sein Kang, Dahye Kim, Ik Joon In, Sangho Koo
PII:
S0040-4039(17)30544-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.090
TETL 48882
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
11 March 2017
25 April 2017
Please cite this article as: Kang, S., Kim, D., Joon In, I., Koo, S., Efficient preparation method of 4-hydroxybenzoic
esters – oxidation of substituted Hagemman’s ester, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/
j.tetlet.2017.04.090
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Efficient preparation method of 4-
hydroxybenzoic esters – oxidation of
substituted Hagemman’s ester
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Sein Kang, Dahye Kim, Ik Joon In, Sangho Koo*

1
Tetrahedron Letters
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Efficient preparation method of 4-hydroxybenzoic esters – oxidation of substituted
Hagemman’s ester
Sein Kanga , Dahye Kima , Ik Joon Ina and Sangho Kooa,b,
∗
aDepartment of Energy Science and Technology, Myongji University, Myongji-Ro 116, Cheoin-Gu, Yongin, Gyeonggi-Do 17058, Korea
bDepartment of Chemistry, Myongji University, Myongji-Ro 116, Cheoin-Gu, Yongin, Gyeonggi-Do 17058, Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
A practical two-step synthetic method of diversely R-substituted 4-hydroxybenzoic esters, which
may have wide applications in household chemicals and polymeric materials, was developed by
2:1 coupling between ethyl acetoacetate and aldehydes (RCHO) in t-BuOK/t-BuOH, followed
by oxidative aromatization of the resulting Hagemman’s esters. Application of the condition
using stoichiometric NBS and catalytic TMS·OTf efficiently induced oxidation of the
Hagemman’s esters to produce 4-hydroxybenzoic esters.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
4-hydroxybenzoic acids
Hagemman’s ester
oxidation
aromatization
bromination
Being found as natural products showing antimicrobial
activity1 as well as major components of lignin,2 4-
hydroxybenzoic acids and their esters (parabens) have been
widely used as food preservatives,3 monomers for poly(phenylene
oxide)s (PPO),4 and intermediates of pesticides and antiseptics.5
The electron donating and withdrawing substituents at para-
position do not allow easy preparation of the parent compound
either from phenols or from benzoic acids. Instead, aromatization
or oxidation of properly substituted precursors would lead to the
desired compounds.6 It was thus envisioned that the ester of 4-
hydroxybenzoic acids could be synthesized by oxidation of the
corresponding Hagemman’s esters, which might be obtained by
the 2:1 coupling and annulation of acetoacetate and various
aldehydes (Scheme 1).
repertoire for the synthesis of 4-hydroxybenzoic esters. We
herein report the details of the two-step protocol for the efficient
synthesis of R-substituted 4-hydroxybenzoic esters from readily
available simple acyclic compounds.
Scheme 1. Practical disconnection to the R-substituted 4-
hydroxybenzoic esters
We have reported the synthesis of ethyl 2,6-dimethyl-4-
oxocyclohex-2-ene-1-carboxylate (2a) by 2:1 coupling of ethyl
acetoacetate and acetaldehyde with catalytic t-BuOK in t-BuOH
(Scheme 2, R = CH3).12 The initial 1:1 coupling produces the
condensation product 4 (R = CH3), with which the second
coupling of ethyl acetoacetate gives symmetrical diketo-diester A
(R = CH3). Aldol reaction between the two carbonyl groups,
followed by intramolecular esterification of the resulting
hydroxyl group with the opposite ester generates bicyclic lactone
B (R = CH3), which may undergo decarboxylation to provide 2a.
The use of t-BuOH (playing with higher pKa) is important in
controlling the reaction pathway towards B, instead of aldol
condensation leading to the isomeric ester at lower pKa (e.g.
EtOH).12
In principle, diversely R-substituted hindered Hagemman’s
esters can be prepared by the selection of the group R in
aldehydes.7 There are a couple of oxidation methods of
Hagemman’s esters reported in the literature so far, one by air
oxidation using expensive metal catalysts like Pt and Pd or base
at high temperature,8 and the other by troublesome Br2 in CS2.9 In
an effort to synthesize carotenoids with improved biological
activity, we need to develop a practical synthetic method of
diversely R-substituted 4-hydroxybenzoic esters as the terminal
ring structure.10 Because a condition using N-bromosuccinimide
(NBS) with catalytic trimethylsilyl trifloromethanesulfonate
(TMS·OTf) has been a superior procedure to that of α-
bromination of carbonyl compounds using Br2,11 oxidation of
Hagemman’s ester using this condition would be a perfect
———
∗ Corresponding author. Tel.: +82-31-330-6185; fax: +82-31-335-7248; e-mail: sangkoo@mju.ac.kr

2
Tetrahedron
The utility of this reaction sequence was demonstrated for
(lactonization of the side chain bromination). The yield of 1d was
increased to 62% at 80 ºC at the expense of 9 and some of the
unreacted starting material. The formation of lactone 10 was also
increased at this temperature (17%).
the synthesis of diversely R-substituted Hagemman’s esters 2
(Table 1). Two equivalents of ethyl acetoacetate were coupled
with various aliphatic aldehydes 3 in t-BuOK/t-BuOH at 80 °C
for 12 h to give the corresponding Hagemman’s esters in 73–95%
yields (Entries 1–5).13 Steric hindrance of R seemed to prevent
easy formation of bicyclic lactone B. No product 2 was obtained
from 2,2-dimethylpropanal (R = t-Bu, entry 6). It is interesting to
note that ethyl 2-oxoacetate also produced 3-methylcyclohex-2-
en-1-one with 4,5-diester substitutions in 65% yield (Entry 7).
Aromatic aldehydes required higher temperature (110 °C) and
longer reaction time (24 h) to produce reasonable yields (43–
80%) of Hagemman’s esters 2, presumably as the same reason of
steric hindrance (Entries 8–17). 2-Furfural gave the higher yield
and naphthalene-2-carbaldehyde gave the lower. There seemed to
be some correlations between the electronic nature of R and the
yield of 2: the withdrawer to higher yield.
Scheme 3. Investigation of the oxidation of cyclohex-2-en-1-
ones by NBS/TMS·OTf according to the substituent (electronic
and steric) effect.
Scheme 2. Mechanism for the synthesis of Hagemman’s ester 2
by 2:1 coupling between ethyl acetoacetate and aldehyde 3.
Table 1. The yield of Hagemman’s esters 2 according to the
reaction in Scheme 2.a
Entry
R
Yield 2 (%) Entry
R
Yield 2 (%)
1
2
3
4
5
6
7
8
9
Me
95
88
74
93
73
0
10
11
12
13
14
15
16
17
p-MeC6H4
p-MeSC6H4
p-MeOC6H4
p-NCC6H4
p-NO2C6H4
p-BrC6H4
p-ClC6H4
2-naphtyl
55
43
40
57
63
58
68
46
Et
n-Pr
i-Pr
s-Bu
t-Bu
CO2Et
2-furanyl
Ph
Scheme 4. The mechanism of the oxidation using
NBS/TMS·OTf was elucidated for hindered Hagemman’s ester
2d.
65
80
53
The mechanism of the oxidation using NBS and catalytic
TMS·OTf was proposed for the hindered Hagemman’s ester 2d
based on the above experimental results (Scheme 4). Presence of
the 4-carbethoxy group allows the major formation of silyl dienol
ether C1 with TMS·OTf. Bromination with NBS at α-position
produces D1, which may undergo dehydrobromination and
tautomerization to give the desired phenol 1d. Bromination at γ-
position initially produces D2, which provides either 9 at room
temperature upon hydrolysis or 1d at 80 °C upon
dehydrobromination and tautomerization. Steric hindrance
between the substituent groups may allow the formation of the
silyl dienol ether C2 from the side chain (as minor). Bromination
at α-position would eventually lead to the desired phenol 1d (not
illustrated), on the other hand, the formation of phenol 10 can be
ascribed to γ-bromination, followed by lactonization with the
ethyl ester and oxidation of cyclohexenone. The yield of lactone
10 was increased at higher temperature. TMS·OTf was used as a
catalyst for bromination because it could be regenerated during
the bromination step, as was illustrated for C1 (Scheme 4).
a Reaction conditions: heated at 80 °C for 12 h (aliphatic aldehyde: Entries 1–
7) or heated at 110 °C for 24 h (aromatic aldehyde: Entries 8–17) with 0.15
equiv. of t-BuOK in t-BuOH.
Oxidation of Hagemman’s ester 2a with NBS and a catalytic
(10 mol%) TMS·OTf worked very well in MeCN as expected.
Ethyl 2,6-dimethyl-4-hydroxybenzoate (1a) was obtained in 91%
yield at 25 °C for 12 h (Scheme 3).14 It was speculated that the
presence of an ester group at 4-position was crucial for facile
oxidation to phenol through the ring bromination as the initial
step. 3,5-Dimethylcyclohex-2-en-1-one (5) produced the
corresponding phenol 6 only in 27% yield under the above
condition (Scheme 3). The side chain bromination became the
major pathway to yield compounds 7 (20%) and 8 (24%). In the
case of sterically hindered Hagemman’s ester 2d, the desired
phenol 1d was obtained in 49% yield at room temperature along
with 28% of 2d (unreacted starting material), 9% of 9 (hydrolysis
of the ring bromination at 4-position), and 10% of 10

3
Generality of the above oxidation using NBS/TMS·OTf was
demonstrated in Table 2 for the Hagemman’s esters, synthesized
in Table 1. The oxidation of hindered Hagemman’s ester 2
requires higher temperature (80 °C) for acceptable yields of 4-
hydroxybenzoic esters 1 except the case of simple 4-carbethoxy-
3,5-dimethylcyclohex-2-en-1-one (2a), in which ambient
temperature is enough to give 91% of the desired product 1a.
Catalyst TMS·OTf was used in 10 mol% with a stoichiometric
amount of NBS.
References and notes
1. (a) Cho, J.-Y.; Moon, J.-H.; Seong, K.-Y.; Park, K.-H. Biosci.
Biotechnol. Biochem. 1998, 62, 2273–2276; (b) Eklund, T. Int. J.
Food Microbiol. 1985, 2, 159–167.
2. (a) Partenheimer, W. Adv. Synth. Catal. 2009, 351, 456–466; (b)
Parr, A. J.; Ng, A.; Waldron, K. W. J. Agric. Food Chem. 1997,
45, 2468–2471.
3. Soni, M. G.; Carabin, I. G.; Burdock, G. A. Food Chem. Toxicol.
2005, 43, 985–1015.
4. Ikeda, R.; Sugihara, J.; Uyama, H.; Kobayashi, S. Polymer Int.
1998, 47, 295–301.
Similar yields (57–65%) of 4-hydroxybenzoic esters 1 were
obtained for alkyl substituent of R, irrespective of the degree of
substitution (entries 2–5). It is also noteworthy that the phenol
with 3,4-diester group can be obtained in 39% yield by this way
(entry 6). 4-Hydroxybenzoic esters 1 with an aryl substituent of
R were also obtained in reasonable yields (45–73%, entries 7–
16). It is advantageous to have an electron-withdrawing
substituent in the aromatic group of R (e.g. CN, entry 12) in
producing higher yields of 4-hydroxybenzoic esters 1 presumably
due to competing bromination on the electron-rich aromatic ring
(e.g. MeO, entry 11).11
5. Khadem, S.; Marles, R. J. Molecules 2010, 15, 7985–8005.
6. (a) Marshall, L. J.; Cable, K. M.; Botting, N. P. Tetrahedron 2009,
65, 8165–8170; (b) Ramachary, D. B.; Ramakumar, K.; Kishor,
M. Tetrahedron Lett. 2005, 46, 7037–7042; (c) Sharma, A.;
Pandey, J.; Tripathi, R. P. Tetrahedron Lett. 2009, 50, 1812–1816;
(d) Ramachary, D. B.; Narayana, V. V.; Prasad, M. S.;
Ramakumar, K. Org. Biomol. Chem. 2009, 7, 3372–3378.
7.
(a) McCurry, Jr. P. M.; Singh, R. K. Synth. Commun. 1976, 6, 75-
79; (b) Ramachary, D. B.; Ramakumar, K.; Narayana, V. V. J.
Org. Chem. 2007, 72, 1458-1463.
8. (a) Otsuka, Y.; Nasaka, N. Japanese Patent 063488, 2015; (b)
Muller, W. H.; Berthold, R. Eur. Patent 0 049 848, 1982; (c) Kim,
S. H.; Lee, H. S.; Park, B. R.; Kim, J. N. Bull. Korean Chem. Soc.
2011, 32, 1725–1728.
Table 2. Oxidation of Hagemman’s esters
NBS/TMS·OTf to 4-hydroxybenzoic esters 1.a
2
by
9. Bhattacharya, K. K.; Pal, P.; Ghosh, K.; Sen, P. K. Indian J.
Chem. B 1980, 19B, 191–194.
10. Martin, H.-D.; Kock, S.; Scherrers, R.; Lutter, K.; Wagener, T.;
Hundsdorfer, C.; Frixel, S.; Schaper, K.; Ernst, H.; Schrader, W.;
Gorner, H.; Stahl, W. Angew. Chem. Int. Ed. 2009, 48, 400–403.
11. Guha, S. K.; Wu, B.; Kim, B. S.; Baik, W.; Koo, S. Tetrahedron
Lett. 2006, 47, 291–293.
12. Chong, B.-D.; Ji, Y.-I.; Oh, S.-S.; Yang, J.-D.; Baik, W.; Koo, S.
J. Org. Chem. 1997, 62, 9323–9325.
Entry
R
Yield 1 (%) Entry
R
Yield 1 (%)
13. Representative experimental procedure for 2a: To a stirred
solution of ethyl acetoacetate (10.40 g, 79.91 mmol) and
acetaldehyde (1.76 g, 39.95 mmol) in t-BuOH (50 mL) was added
t-BuOK (0.67 g, 5.99 mmol). The mixture was heated at 80 °C for
12 h. Most of solvent was removed under reduced pressure, and
the crude product was dissolved in EtOAc, which was washed
with 1 M HCl and with brine, dried over anhydrous Na2SO4,
filtered, and concentrated to give cyclohexenone 2a (7.45 g, 37.96
mmol) in 95% yield as yellow liquid (a 2.4:1 mixture of
stereoisomers). Data for 2a: Rf = 0.26 (1:4 EtOAc/hexane); 1H
NMR (major, CDCl3) δ 1.08 (d, J = 6.4 Hz, 3H), 1.31 (t, J = 7.2
Hz, 3H), 2.98 (s, 3H), 2.04–2.64 (m, 3H), 3.02 (d, J = 7.6 Hz, 1H),
4.24 (q, J = 7.2 Hz, 2H), 5.97 (br s, 1H) ppm; 13C-NMR (CDCl3) δ
14.2, 19.8, 22.7, 32.8, 43.1, 54.5, 61.3, 128.0, 156.0, 171.9, 198.2
ppm.
1
2
3
4
5
6
7
8
Me
91
65
59
62
57
39
45
50
9
p-MeC6H4
p-MeSC6H4
p-MeOC6H4
p-NCC6H4
p-NO2C6H4
p-BrC6H4
p-ClC6H4
2-naphtyl
65
61
51
73
66
53
56
50
Et
10
11
12
13
14
15
16
n-Pr
i-Pr
s-Bu
CO2Et
2-furanyl
Ph
14. Representative experimental procedure for 1a: To a stirred
solution of cyclohexenone 2a (11.30 g, 57.60 mmol) in MeCN (50
mL) were added N-bromosuccinimide (10.25 g, 57.60 mmol) and
TMS·OTf (1.28 g, 5.76 mmol, 10 mol%). The mixture was stirred
at room temperature for 12 h under argon atmosphere, diluted with
EtOAc, washed with 1 M HCl, dried over anhydrous Na2SO4,
filtered and concentrated to give the crude product (16.02 g) as
reddish yellow oil. The crude product was purified by SiO2 flash
column chromatography (eluent 25–45% EtOAc/hexane gradient)
to give pure phenol 1a (10.18 g, 52.42 mmol) in 91% yield as
a Reaction conditions: stirred at 25 °C for 12 h (Entry 1) or heated at 80 °C
for 6 h (Entry 2–16) with 0.10 equiv. of TMS·OTf and 1 equiv. of NBS.
In summary, a practical two-step synthetic procedure for 4-
hydroxybenzoic esters 1 was developed by 2:1 coupling between
ethyl acetoacetate and various aldehyde (RCHO), followed by
efficient oxidation of the resulting Hagemman’s esters 2. We
extended the facile 2:1 coupling of ethyl acetoacetate and various
aldehydes (R-CHO) including aromatic ones under t-BuOK/t-
BuOH condition to produce hindered Hagemman’s esters with
various substitution patterns. The condition utilizing
stoichiometric NBS and catalytic TMS·OTf was successfully
applied to the oxidation of the above Hagemman’s esters for
efficient construction of medicinally and industrially useful 4-
hydroxybenzoic esters 1.
1
yellow oil. Data for 1a: Rf = 0.23 (1:4 EtOAc/hexane); H-NMR
(CDCl3) δ 1.36 (t, J = 7.2 Hz, 3H), 2.25 (s, 6H), 4.35 (q, J = 7.2
Hz, 2H), 6.45 (s, 2H) ppm; 13C-NMR (CDCl3) δ 13.9, 19.8, 61.0,
114.5, 125.2, 137.4, 156.8, 171.0 ppm; IR (KBr) 3381, 2978,
2933, 1715, 1655, 1610, 1592, 1461, 1446, 1368, 1256, 1159,
1088, 1029, 854, 783, 716, 637, 604 cm-1; HRMS (EI) calcd for
C11H14O3 194.0943, found 194.0947.
Acknowledgments
This research was supported by Basic Science Research
Programs through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education (NRF-
2015R1D1A1A01057473 and NRF-2016R1A2B4007684).

4
Tetrahedron
Highlights.
ꢀ Hagemman’s esters were prepared by coupling between acetoacetate and aldehydes.
ꢀ Coupling, cyclization, and decarboxylation proceeded in one opt using t-BuOK/t-BuOH.
ꢀ 4-Hydroxybenzoic esters were synthesized by oxidation of Hagemman’s esters.
ꢀ Bromination condition using NBS/TMS·OTf induced oxidation of Hagemman’s esters.