Concurrent synthesis of vanillin and isovanillin

Article abstract of DOI:10.1007/s11164-012-0804-6

A method for concurrent synthesis of vanillin and isovanillin has been developed by a nonregioselective Vilsmeier-Haack reaction of O-alkyl guaiacols. O-Alkylation of guaiacol provided the corresponding O-alkyl guaiacol (1), which was then formylated with N-methylformanilide/phosphorus oxychloride to give a mixture of 4-alkoxy-3-methoxy-benzaldehyde (2) and 3-alkoxy-4- methoxybenzaldehyde (3). Finally, the obtained mixture underwent a selective dealkylation by anhydrous aluminium trichloride, while leaving methyl groups intact to simultaneously achieve the significant fine chemicals vanillin and isovanillin.

Full text of DOI:10.1007/s11164-012-0804-6

Res Chem Intermed (2013) 39:2849–2856
DOI 10.1007/s11164-012-0804-6
Concurrent synthesis of vanillin and isovanillin
•
•
•
Wei-Bin Huang Cai-Yan Du Jian-An Jiang
Ya-Fei Ji
Received: 29 May 2012 / Accepted: 3 September 2012 / Published online: 26 September 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A method for concurrent synthesis of vanillin and isovanillin has been
developed by a nonregioselective Vilsmeier–Haack reaction of O-alkyl guaiacols. O-
Alkylation of guaiacol provided the corresponding O-alkyl guaiacol (1), which was
then formylated with N-methylformanilide/phosphorus oxychloride to give a mixture
of 4-alkoxy-3-methoxy-benzaldehyde (2) and 3-alkoxy-4-methoxybenzaldehyde (3).
Finally, the obtained mixture underwent a selective dealkylation by anhydrous alu-
minium trichloride, while leaving methyl groups intact to simultaneously achieve the
significant fine chemicals vanillin and isovanillin.
Keywords Concurrent synthesis Á Vanillin Á Isovanillin Á Vilsmeier–Haack
reaction Á Selective dealkylation
Introduction
Both vanillin and isovanillin are significant and indispensable organic compounds in
the pharmaceutical, perfumery and flavor industry [1]. Most vanillin and isovanillin
are primarily produced via synthetic methods. In particular, the annual production of
vanillin is currently estimated to be over 15,000 t. Therefore, the synthesis of
vanillin and isovanillin has always gained continuous attention in academia and
industry. At the present times, Li et al. [2] reported an enzymatic synthesis of
vanillin from glucose, and Bjørsvik et al. [3] also developed a chemical synthesis of
vanillin by oxidation of lignosulfonates. On the other hand, Wang et al. [4]
described a mild efficient Mitsunobu protocol for the regioselective alkylation of
W.-B. Huang Á C.-Y. Du Á J.-A. Jiang Á Y.-F. Ji (&)
School of Pharmacy, East China University of Science and Technology, Campus P.O. Box 363,
130 Meilong Road, Shanghai 200237, China
e-mail: ji_yafei@yahoo.com.cn
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W.-B. Huang et al.
COOH
CHOH
COOH
CHO
C
O
OHCCOOH
NaOH
Cu2+, O2
OMe
OMe
OH
OMe
OH
OMe
OH
OH
Scheme 1 Industrial process for synthesis of vanillin
3,4-dihydroxybenzaldehyde to prepare isovanillin, and Bao et al. [5] undertook an
efficiently solvent-free debenzylation to obtain isovanillin using magnesium iodide.
Condensation of guaiacol with glyoxylic acid followed by oxidation–decarbox-
ylation is currently the major commercial route to vanillin (Scheme 1). Umemura
[6] described a procedure to prepare vanillin, therein the condensation of guaiacol
with glyoxylic acid in basic medium provided the intermediate 4-hydroxy-3-
methoxymandelic acid, from which subsequent oxidation–decarboxylation was
conducted with air using cupric catalyst. As to isovanillin, the main industrial
process encompassed an inevitable dealkylation of 3-alkoxy-4-methoxybenzalde-
hyde with large amounts of concentrated sulphuric acid (Scheme 2) [7, 8].
The chemical introduction of an aldehyde group on aromatic nucleus can be
delivered by many means, including direct methods (e.g., Gattermann reaction,
Reimer–Tiemann reaction, Duff reaction, and Vilsmeier–Haack reaction) and
indirect methods (whereby the group on aromatic nucleus converted into aldehyde
group mainly by oxidation or reduction) [9]. It should be noted that Vilsmeier–
Haack reaction for attachment of formyl group is superior to other direct methods
in terms of yield, simplicity, and practicality. For example, by formylation
with N-methylformanilide/phosphorus oxychloride, the availability of recyclable
N-methylaniline generated from N-methylformanilide enables economical prepara-
tion of veratraldehyde from veratrole [10].
In this study, we developed a method for concurrent synthesis of vanillin and
isovanillin by a nonregioselective Vilsmeier–Haack reaction of O-alkyl guaiacols
(Scheme 3). O-Alkylation of guaiacol provided the corresponding O-alkyl guaiacol (1),
which was formylated with N-methylformanilide/phosphorus oxychloride to give
a mixture of regioisomeric 4-alkoxy-3-methoxybenzaldehyde (2) and 3-alkoxy-
4-methoxybenzaldehyde (3). Accordingly, the resulting mixture underwent an efficient
selectivedealkylationbyanhydrousaluminium trichloride, whileleavingmethylgroups
intact to simultaneously achieve the desired fine chemicals vanillin and isovanillin.
Results and discussion
According to generally reported methods [11, 12], compounds 1 were synthesized
by alkylation of guaiacol with alkyl bromide in excellent yields of 88.0–95.3 %.
Individually, in the presence of potassium carbonate, guaiacol was alkylated with
n-propyl bromide for 10 h to give the corresponding 1a in 95.3 % yield, or with
n-butyl bromide for 15 h to give the corresponding 1c in 94.4 % yield. While the
123

Concurrent synthesis of vanillin and isovanillin
2851
CHO
CHO
OMe
CHO
Me2SO4
Conc. H2SO4
NaOH
OR
OH
OR
OH
OMe
Scheme 2 Industrial process for synthesis of isovanillin. R = Me, Et
CHO
CHO
N-methylformanilide
RBr
+
OH K2CO3
OR
POCl3
OMe
OR
OMe
OMe
OR
OMe
2a-c
3a-c
1a-c
81.8-84.4%
88.0-95.3%
CHO
CHO
AlCl3
+
OMe
OH
OH
OMe
vanillin
isovanillin
50.7-68.4%
27.6-41.4%
Scheme 3 Concurrent synthesis of vanillin and isovanillin. a: R = n-Pr; b: R = i-Pr; c: R = n-Bu
treatment of guaiacol with i-propyl bromide in similar conditions for 24 h provided
1b in relatively low yield of 88.0 % due to slightly greater steric hindrance of
i-propyl group.
In the investigation of Vilsmeier–Haack reaction of O-alkyl guaiacols 1 with
N-methylformanilide/phosphorus oxychloride, the gained products accounted for
good yields of 81.8–84.4 %. Although the resultant 2 and 3 were not visibly
1
distinguished by GC analysis, H NMR, 13C NMR and HPLC tests unambiguously
demonstrated that the formylation reaction simultaneously achieved the two
regioisomers, resulting from nonregioselective attack of electrophilic formyl group
1
on para-position to either of the two alkoxy groups. H NMR analysis further
proved that each para-product 2 (to OR) possesses more quantity than the
corresponding concomitant 3, and the ratios of 2/3 are consistent with that of
methoxy/alkoxy group of the Taft’s substituent electric parameter r* values [13, 14]
albeit the correlation is a little poor. The Taft’s parameter r* was revised to solve
the shortcoming of the Hammett constant r. Here, i-propoxy group has the strongest
electron-donating ability with the lowest Taft’s r* value, but methoxy group was
the opposite. The results of the formylation of aryl diethers 1 are summarized in
Table 1. Indeed, the determined ratios of 2 and 3 met the final results of vanillin and
isovanillin well (Table 2). Thus, the nonregioselective formylation of 1 accom-
plished a synchronous synthesis of two regioisomeric aldehydes 2 and 3, and
accordingly led to the desired vanillin and isovanillin.
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W.-B. Huang et al.
Table 1 Results of the
formylation of O-alkyl
guaiacols 1
OR
r* [14]
Yield (%)a
Ratio (2/3)b
OMe
1.77
1.57
1.51
1.55
–
1/1 (2 = 3)
1.24/1
a
n-PrO (1a)
i-PrO (1b)
n-BuO (1c)
81.8
84.4
83.1
Combined isolated yield of 2
and 3
b
2.45/1
Determined by 1H NMR
1.34/1
analysis
Table 2 Combined yields and individual yields of vanillin and isovanillin
R
Yield (%)a
Yield (%)b
Ratio (vanillin/isovanillin)
Vanillin
Isovanillin
n-Pr (2a ? 3a)
i-Pr (2b ? 3b)
n-Bu (2c ? 3c)
a
95.3
96.0
88.2
53.9
68.4
50.7
41.4
27.6
37.5
1.30/1
2.48/1
1.35/1
Combined isolated yield of vanillin and isovanillin
b
Individual isolated yield
Previously, the i-propyl group has properlyserved as aprotecting group for hydroxy
group of phenolic compounds, and its selective removal easily occurs under acidic
conditions such as HBr–HOAc as well as Lewis acid [12, 15–17]. In the case of
substrates 2c and 3c containing more difficult deblocking of n-butoxy group, we
examined HBr–HOAc system, as well as Lewis acid TiCl4 and AlCl3, to remove the n-
butyl group. The experimental results revealed that the pleasing aluminium trichloride
is absolutely able to cleave n-butoxy group under ambient temperature with the
methoxyl groups maintained intact. In the optimized reaction conditions, with 2.1
equiv. anhydrous aluminium trichloride for 18 h, the cleavage of the n-butoxy group
for 2c and 3c brought about vanillin and isovanillin in 88.2 % combined yield. In
contrast, the cleavage of the n-propoxy group for 2a and 3a, and i-propoxy group for
2b and 3b completely resulted in vanillin and isovanillin in more than 95 % combined
yields needing only 5 h (Table 2). Furthermore, for the i-propoxy group-containing
aromatic aldehydes 2b and 3b, 1.8 equiv. anhydrous aluminium trichloride is
sufficient to remove the i-propyl groups. Consequently, the ease of removing the alkyl
groups with anhydrous aluminium trichloride give a sequence of i-Pr [ n-Pr [ n-Bu.
A few methods for de-n-propylation and de-n-butylation have been reported; however,
either harsh reaction conditions or lower yields gave rise to poorer accessibility [18–
21]. Distinctively, our procedure of dealkylation by anhydrous aluminium trichloride
is a mild convenient and efficient process, as well as having outstanding selectivity for
fully retaining the methyl group.
Conclusions
In conclusion, we have developed a novel method for concurrent synthesis of
two significant fine chemicals, vanillin and isovanillin, by a nonregioselective
123

Concurrent synthesis of vanillin and isovanillin
2853
Vilsmeier–Haack formylation of O-alkyl guaiacols with N-methylformanilide/
phosphorus oxychloride in good yields. By means of chemical nonregioselectivity,
the methodology of simultaneous synthesis of two great organic compounds is a
rewarding attempt in synthetic chemistry. In addition, compared to a sterically
hindered i-propyl group containing the relatively active methenyl (CH) group,
efficient adoption and selective removal of the inert n-propyl and n-butyl groups are
of potential and special applications in the strategy of protecting groups.
Experimental
The NMR spectra were recorded on Bruker AV400 spectrometer at 400 and
1
100 MHz, for H and 13C, respectively, and the chemical shifts were expressed in
d ppm relative to tetramethylsilane as an internal standard. MS and HRMS were
carried out on a Micromass GCTTM gas chromatograph-mass spectrometer and a
QSTAR Pulsar I LC/TOF MS mass spectrometer, respectively. The melting points
were recorded on open capillaries and are uncorrected. All solvents and reagents
were obtained from commercial sources and used without further purification. Thin-
layer chromatography (TLC) was performed on silica gel HF254 and TLC
visualizations were performed with ultraviolet (UV) light.
General procedure for preparation of 1-alkoxy-2-methoxybenzene (1)
To ethanol (80 mL) were added guaiacol (6.2 g, 0.05 mol), potassium carbonate
(13.8 g, 0.10 mol), alkyl bromide (0.10 mol), and potassium iodide (1.7 g,
0.01 mmol), and the mixture was heated to reflux. The progress of the reaction
was monitored by TLC (typically within 10–24 h). After the reaction had finished,
the mixture was filtered, concentrated, and passed through a short column of silica
gel (eluent: dichloromethane) to get the 1-alkoxy-2-methoxybenzene (1) as a pale
yellow liquid with 88.0–95.3 % yields.
1-Methoxy-2-n-propoxybenzene (1a)
7.9 g (95.3 %, 10 h); 1H NMR (400 MHz, CDCl3), d (ppm): 6.87–6.93 (m, 4H, Ar),
3.99(t, J = 6.8 Hz, 2H, CH2), 3.87(s, 3H, CH3), 1.88(sext, J = 7.2 Hz, 2H, CH2), 1.05
(t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3), d (ppm): 149.43, 148.57,
120.83, 120.81, 113.06, 111.82, 70.42, 55.94, 22.50, 10.45; MS-EI (m/z): 166.1 (M?);
HRMS (ESI): m/z (M ? Na?) calcd. for C10H14O2Na: 189.0891; found: 189.0886.
1-Methoxy-2-i-propoxybenzene (1b)
7.3 g (88.0 %, 24 h); 1H NMR (400 MHz, CDCl3), d (ppm): 6.88–6.98 (m, 4H, Ar),
4.53 (heptet, J = 6.0 Hz, 1H, CH), 3.86 (s, 3H, CH3), 1.37 (d, J = 6.0 Hz, 6H,
CH3); 13C NMR (100 MHz, CDCl3), d (ppm): 150.52, 147.35, 121.30, 120.79,
116.12, 112.14, 71.41, 55.92, 22.14 (2C); MS-EI (m/z): 166.1 (M?); HRMS (ESI):
m/z (M ? Na?) calcd. for C10H14O2Na: 189.0891; found: 189.0886.
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1-n-Butoxy-2-methoxybenzene (1c)
8.5 g (94.4 %, 15 h); 1H NMR (400 MHz, CDCl3), d (ppm): 6.96–6.85 (m, 4H, Ar),
4.03 (t, J = 6.8 Hz, 2H, CH2), 3.87 (s, 3H, CH3), 1.84 (quint, J = 7.2 Hz, 2H,
CH2), 1.51 (sext, J = 7.2 Hz, 2H, CH2), 0.99 (t, J = 7.2 Hz, 3H, CH3); 13C NMR
(100 MHz, CDCl3), d (ppm): 149.43, 148.61, 120.83, 120.78, 113.02, 111.81,
68.64, 55.95, 31.26, 19.23, 13.90; MS-EI (m/z): 180.1 (M?); HRMS (ESI):
m/z (M ? Na?) calcd. for C11H16O2Na: 203.1048; found: 203.1050.
General procedure for preparation of 4-alkoxy-3-methoxybenzaldehyde (2)
and 3-alkoxy-4-methoxybenzaldehyde (3)
Phosphorus oxychloride (9.2 g, 0.06 mol) was added dropwise to a stirred mixture
of cold (ice bath) N-methylformanilide (8.1 g, 0.06 mol) and the compound 1
(0.04 mol). The mixture was heated at 115 °C for 1 h, and then at 100 °C for 18 h.
After the reaction had finished, the mixture was cooled, and then basified with an
aqueous solution of sodium hydroxide (2 mol/L, 100 mL) and extracted with
dichloromethane (150 mL 9 3). The separated organic phase was concentrated, and
then distilled in vacuo to provide the mixture of 2 and 3 as yellow liquid with
81.8–84.4 %.
3-Methoxy-4-n-propoxybenzaldehyde (2a) and 4-methoxy-3-n-
propoxybenzaldehyde (3a)
1
6.3 g (81.8 %); bp 123–126 °C/2 mmHg; H NMR (400 MHz, CDCl3, 2a and 3a),
d (ppm): 9.82 (s, 2H, CHO), 7.46–7.40 (m, 2H, Ar), 7.39–7.37 (m, 2H, Ar), 6.96 (d,
J = 8.4 Hz, 1H, Ar), 6.95 (d, J = 8.0 Hz, 1H, Ar), 4.05 (t, J = 6.8 Hz, 2H, CH2),
4.02 (t, J = 6.8 Hz, 2H, CH2), 3.93 (s, 3H, CH3), 3.91 (s, 3H, CH3), 1.95–1.80
(m, 4H, CH2), 1.043 (t, J = 7.6 Hz, 3H, CH3), 1.035 (t, J = 7.2 Hz, 3H, CH3); 13
C
NMR (100 MHz, CDCl3, 2a and 3a), d (ppm): 190.97, 190.91, 154.84, 154.18,
149.84, 149.13, 130.08, 129.87, 126.80, 126.59, 110.39, 110.61, 110.29, 109.27,
70.57, 70.49, 56.17, 56.03, 22.32, 22.27, 10.39, 10.37; MS-EI (m/z): 194.1 (M?);
HRMS (ESI): m/z (M ? H?) calcd. for C11H15O3: 195.1021; found: 195.1019.
3-Methoxy-4-i-propoxybenzaldehyde (2b) and 4-methoxy-3-i-propoxybenzaldehyde
(3b)
6.5 g (84.4 %); bp 115–119 °C/2 mmHg; 1H NMR (400 MHz, CDCl3, 2b and 3b),
d (ppm): 9.80 (s, 2H, CHO), 7.43–7.35 (m, 4H, Ar), 6.94 (d, J = 8.0 Hz, 2H, Ar),
4.70–4.55 (m, 2H, CH), 3.90 (s, 3H, CH3), 3.87 (s, 3H, CH3), 1.39 (d, J = 6.4 Hz,
6H, CH3), 1.36 (d, J = 6.4 Hz, 6H, CH3); 13C NMR (100 MHz, CDCl3, 2b and 3b),
d (ppm): 190.98, 190.88, 155.61, 153.09, 150.33, 147.82, 130.00, 129.70, 126.63,
126.50, 112.82, 112.57, 110.90, 109.53, 71.30, 71.27, 56.13, 55.99, 21.89 (2C),
21.85 (2C); MS-EI (m/z): 194.1 (M?); HRMS (ESI): m/z (M ? H?) calcd. for
C11H15O3: 195.1021; found: 195.1013.
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Concurrent synthesis of vanillin and isovanillin
2855
4-n-Butoxy-3-methoxybenzaldehyde (2c) and 3-n-butoxy-4-methoxybenzaldehyde
(3c)
1
6.8 g (83.1 %); bp 140–144 °C/2 mmHg; H NMR (400 MHz, CDCl3, 2c and 3c), d
(ppm): 9.80 (s, 2H, CHO), 7.42–7.37 (m, 2H, Ar), 7.364 (s, 1H, Ar), 7.360 (s, 1H, Ar),
6.931 (d, J = 8.4 Hz, 1H, Ar), 6.927 (d, J = 8.4 Hz, 1H, Ar), 4.06 (t, J = 6.8 Hz, 2H,
CH2), 4.04 (t, J = 6.8 Hz, 2H, CH2), 3.90 (s, 3H, CH3), 3.88 (s, 3H, CH3), 1.86–1.76 (m,
4H, CH2),1.54–1.40(m,4H,CH2), 0.949 (t, J = 7.6 Hz, 3H, CH3), 0.945(t, J = 7.6 Hz,
3H, CH3); 13C NMR (100 MHz, CDCl3, 2c and 3c), d (ppm): 190.95, 190.88, 154.82,
154.19, 149.82, 149.14, 130.05, 129.83, 126.78, 126.57, 111.35, 110.58, 110.20, 109.23,
68.82, 68.70, 56.13, 55.99, 31.03, 30.94, 19.16, 19.13, 13.82, 13.80; MS-EI (m/z): 208.1
(M?); HRMS (ESI): m/z (M ? H?) calcd. for C12H17O3: 209.1178; found: 209.1178.
General procedure for preparation of vanillin [22] and isovanillin [5]
A solution of the mixture of 2 and 3 (10 mmol) in dichloromethane (30 mL) was stirred
at room temperature for 10 min. To the mixture was added in one portion anhydrous
aluminium trichloride (21 mmol to the mixture of 2a and 3a as well as the mixture of 2c
and 3c, 18 mmol to the mixture of 2b and 3b). The resulting solution was stirred at room
temperature for a corresponding time (5 h for the mixture of 2a and 3a as well as the
mixture of 2b and 3b, and 18 h for the mixture of 2c and 3c). The reaction solution was
quenched with aqueous ammonium chloride (2 mol/L, 50 mL) and extracted with
dichloromethane (50 mL 93). The separated organic phase was washed with saturated
brines (60 mL 92) and concentrated to provide the crude products, which were isolated
by column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to yield
vanillin and isovanillin.
Vanillin from 2a: 0.82 g (53.9 %), off-white solid; mp 80–82 °C ([22]:
1
81–84 °C); H NMR (400 MHz, CDCl3), d (ppm): 9.81 (s, 1H, CHO), 7.44–7.39
(m, 2H, Ar), 7.03 (d, J = 8.4 Hz, 1H, Ar), 6.43 (s, 1H, OH), 3.94 (s, 3H, CH3); 13
C
NMR (100 MHz, CDCl3), d (ppm): 191.02, 151.78, 147.21, 129.83, 127.58, 114.45,
108.83, 56.12; MS-EI (m/z): 152.0 (M?); HRMS (ESI): m/z (M ? H?) calcd. for
C8H9O3: 153.0552; found: 153.0559.
Isovanillin from 3a: 0.63 g (41.4 % yield), off-white solid; mp: 115–117 °C ([23:
113–116 °C); 1H NMR (400 MHz, CDCl3), d (ppm): 9.82 (s, 1H, CHO), 7.45–7.38
(m, 2H, Ar), 6.95 (d, J = 8.0 Hz, 1H, Ar), 5.97 (s, 1H, OH), 3.96 (s, 3H, CH3); 13
C
NMR (100 MHz, CDCl3), d (ppm): 191.12, 151.94, 146.21, 130.64, 124.63, 114.09,
110.26, 56.20; MS-EI (m/z): 152.1 (M?) HRMS (ESI): m/z (M ? H?) calcd. for
C8H9O3: 153.0552; found: 153.0553.
Vanillin from 2b: 1.04 g (68.4 %).
Isovanillin from 3b: 0.42 g (27.6 %).
Vanillin from 2c: 0.77 g (50.7 %).
Isovanillin from 3c: 0.57 g (37.5 %).
Acknowledgment We thank the National Natural Science Foundation of China (Project No. 21176074)
for financial support.
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References
1. H.R. Bjørsvik, L. Liguori, F. Minisci, Org. Process Res. Dev. 4, 534 (2000)
2. K. Li, J.W. Frost, J. Am. Chem. Soc. 120, 10545 (1998)
3. H.R. Bjørsvik, F. Minisci, Org. Process Res. Dev. 3, 330 (1999)
4. X. Wang, T. Ju, X. Li, X. Cao, Synlett. 21, 2947 (2010)
5. K. Bao, A. Fan, Y. Dai, L. Zhang, W. Zhang, M. Cheng, X. Yao, Org. Biomol. Chem. 7, 5084 (2009)
6. S. Umemura, N. Takamitsu, T. Enomiya, H. Shiraishi, T. Nakamura, U.S. Patent 4,165,341 (July 28,
1979)
7. K. Nobuyuki, EP 758639 (February 19, 1997)
8. C. Maliverney, U.S. Patent 5,786,516 (July 28, 1998)
9. L.N. Ferguson, Chem. Rev. 38, 227 (1946)
10. J. Szilagyi, J. Halmos, S. Szabo, F. Szileczky, J. Mezei, T. Szabolcsi, G. Kortvelyessi, J. Nyitrai,
I. Miskolczi, K. Szatmari, HU 55741 (June 28, 1991)
11. J.A. Mitchell, J. Chem. Soc. 1792 (1937)
12. R.J. Bushby, Z. Lu, Synthesis 33, 763 (2001)
13. R.W. Taft, in Steric Effects in Organic Chemistry, ed. by M.S. Newman (Wiley, New York, 1956)
14. C. Hansch, A. Leo, D. Hoekman, Exploring QSAR: Volume 2: Hydrophobic Electronic and Steric
Constants (American Chemical Society, Washington, DC, 1995)
15. J.P. Gillespie, L.G. Amoros, F.R. Stermitz, J. Org. Chem. 39, 3239 (1974)
16. T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edn. (Wiley, New York,
1999)
17. M.G. Banwell, B.L. Flynn, S.G. Stewart, J. Org. Chem. 63, 9139 (1998)
18. L. Tong, B.J. Lavey, B.B. Shankar, S.H. Kim, W. Yu, J.A. Zlowski, K.C. Michael, L. Chen, G. Zhou,
WO 054278 (May 14, 2010)
19. A. Palmeira, M.H. Vasconcelos, A. Paiva, M.X. Fernandes, M. Pinto, E. Sousa, Biochem. Pharmacol.
83, 57 (2012)
20. F. Rombouts, D. Franken, M. Braeken, C. Zavattaro, J. Chen, A.A. Trabanco, Tetrahedron Lett. 51,
4815 (2010)
21. A. Vass, J. Dudas, F. Haasz, P. Jekkel, WO 061066 (June 15, 2006)
22. P. Gogoi, P. Hazarika, D. Konwar, J. Org. Chem. 70, 1934 (2005)
23. M.L. Scarpati, A. Bianco, L. Mascitelli, P. Passacantilli, Synth. Commun. 20, 2565 (1990)
123