Preparation and unequivocal identification of the regioisomers of nitrocatechol monobenzyl ether

Article abstract of DOI:10.1080/00397911.2017.1334919

The four positional isomers of nitrocatechol monobenzyl ether were prepared as intermediates to nitrobenzodioxanes directly from 2-benzyloxyphenol or, through two-four steps, from catechol. These preparations addressed the issue of the certain identificat

Full text of DOI:10.1080/00397911.2017.1334919

Synthetic Communications
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Preparation and Unequivocal Identification of the
Regioisomers of Nitrocatechol Monobenzyl Ether
Cristiano Bolchi, Francesco Bavo & Marco Pallavicini
To cite this article: Cristiano Bolchi, Francesco Bavo & Marco Pallavicini (2017): Preparation
and Unequivocal Identification of the Regioisomers of Nitrocatechol Monobenzyl Ether, Synthetic
Communications, DOI: 10.1080/00397911.2017.1334919
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Date: 17 June 2017, At: 02:46

Preparation and Unequivocal Identification of the Regioisomers of Nitrocatechol
Monobenzyl Ether
Cristiano Bolchi1,, Francesco Bavo1, Marco Pallavicini1
1Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Milano, Italia
Corresponding author Cristiano Bolchi E-mail: cristiano.bolchi@unimi.i
Abstract
The four positional isomers of nitrocatechol monobenzyl ether were prepared as
intermediates to nitrobenzodioxanes directly from 2-benzyloxyphenol or, through two-
four steps, from catechol. These preparations addressed the issue of the certain
identification of the nitration products prescinding from chemical correlation to the
synthetic precursors because the positional isomers are very similar for some properties
and analytical data available from literature are largely incomplete and not conclusive.
The here provided NMR, DSC and acidity data unequivocally distinguish each
nitrocatechol monobenzyl ether from its regioisomers.
Graphical Abstract
KEYWORDS: nitrocatechol, cerium ammonium nitrate (CAN), catechol monobenzyl
ether, 2-benzyloxyphenol, 2-benzyloxy-4,6-dinitrophenol, regioisomer
1

INTRODUCTION
Desymmetrized dihydroxyphenols and, among these, catechol monoethers are very
important starting materials. Their ortho, meta and para substituted derivatives have been
used as key intermediates in the synthesis of the 1,4-benzodioxane substructure of
neuronal nicotinic agonists[1] and of -adrenergic antagonists[2,3] or, more generally, of
the phenoxy portion of these latter compounds.[4,5] Often commercially avalaible,
catechol monoethers are highly reactive substrates to elctrophilic aromatic substitutions,
owing their reactivity to the two electron donating groups. These substitutions, however,
proceed with only moderate regiocontrol because all the four unsubstituted ring carbons
are nucleophilic sites. Furthermore, if electron donating, the incoming substituent makes
the aromatic system even more inclined to undergo further substitutions and therefore it
is difficult to stop the process after a single substitution. Anyway, this drawback does not
affect nitration, which can be easily stopped at mononitration by regulating the reaction
temperature. Besides giving access to a number of reduced derivatives, a further
advantage of catechol monoethers nitration is that the nitro group exerts a specific effect
on the two oxy substituents: it exalts the acidity and thus facilitates the etherification of
the ortho or para positioned OH and, on the other hand, it makes the ortho or para
positioned OR susceptible of nucleophilic substitution by hydroxide ion. Such a dual
effect of the nitro group confers synthetic versatility to the regioisomeric nitro derivatives
of catechol monoethers such as guaiacol and 2-benzyloxyphenol. In the case of these
latter positional isomers (1a-d), an additional advantage is provided by the easy removal,
if necessary, of benzyl by hydrogenolysis.
2

In view of the synthesis of the regioisomeric nitrobenzodioxanes 2a-d as bioisosteres of
the pyridodioxanes 3a-d, previously reported nicotinic agonists,[6] we needed the four
regioisomers 1a-d (Scheme 1). An overview of the literature methods shows that most
syntheses of the single positional isomers of 1 are quite laborious (Scheme 2).[7–15] The
reported overall yields are generally very modest (about 20%), apart those of 1a from
catechol monobenzyl ether III (43%)[15] and of 1b from 1,3-benzodioxol I (about
50%).[7,8]
Furthermore, some of these procedures date back to the sixties and the eighties and even
today not all the regioisomers are adequately provided with a number of accurate
physical and spectral data so as to allow an immediate and incontrovertible identification
distinguishing, in particular, between 1a and 1d and between 1b and 1c. Indeed, the
melting point of 1a is unknown and its 1H NMR spectrum has been only roughly
described,[15,16] while, for 1d, the melting point is reported,[14] but not the 1H NMR
spectrum, which should be very similar to that of 1a in the multiplicity pattern and
chemical shifts of the three vicinal hydrogens of the phenol ring. On the other hand, 1b
and 1c, which have almost identical melting points,[8,9,14] are hardly distinguishable from
each other on the basis of the 1H NMR spectrum descriptions reported in literature.[8,17]
RESULTS AND DISCUSSION
We focused on nitration of III and on separation and analytical characterization of the
nitration products. As all the four nitrable positions of III are reactive to electrophilic
3

substitution, we oriented to mild nitration conditions such as treatment of a
dichloromethane solution of III with NaNO3 and diluted sulfuric acid at low temperature
(-10 °C). After three hours under these conditions, III was no more detectable by TLC
and chromatography of the reaction mixture separated three products that, in the order of
elution, were recognized by 1H NMR analysis as resulting from mono-nitration in ortho
to OH or OBn, mono-nitration in para to OH or OBn and dinitration respectively
(Scheme 3).
Assignment of 1a instead of 1d structure to the first eluted ortho-nitrated product (35%
yield) on the only basis of 13C NMR and 1H NMR spectrum was questionable, although
the latter spectrum was consistent with that reported for 1a in a patent,[15,16] as very
similar NMR spectra can be expected for 1d. On the other hand, also the melting point
(98 °C), higher than that reported for 1d,[14] was not resolutory because literature does not
provide the melting point of 1a. The identification of the product as 1a was therefore
supported by NOESY spectrum that showed interaction between the benzylic protons and
the phenol H-3, and definitively confirmed by characterizing 1d. This was synthesized as
illustrated in Scheme 2 according to Augstein et al.[14] The literature low melting point of
1d (44-52 °C),[14] much lower than that we had found for 1a, was confirmed by the
viscous oil consistency of our product. The 1H NMR and the 13C NMR spectra, as
expected, showed patterns of signals and multiplicity very similar to those of 1a with
chemical shift differences which, yes, allow to clearly distinguish 1a and 1d from each
other but only a posteriori, that is by comparing the respectively acquired spectra (Figure
1A, Table I).
4

Once identified 1a, an analogous problem was addressed by the identification of the
second eluted para-nitrated product because the only reported analytical data of 1b and
1c, namely melting points and 1H NMR spectrum descriptions, are virtually identical.
Again, any doubt was removed by unequivocally synthesizing 1b from 4-nitrocatechol
through selective benzylation of the more acidic OH, para positioned to the nitro
substituent (Scheme 2). As shown in Table I and in Figure 1B, the 1H NMR spectra of 1b
and 1c are indeed nearly identical and only the comparison of the 13C NMR spectra and,
in particular, of the chemical shifts of the three unsubstituted carbons of phenol ring
allows 1c to be certainly distinguished from 1b. On the basis of such a comparison, we
could concluded that the second eluted product was 1c (30% yield) and that the o-p
orientation by OH prevails over that by OBn resulting in the formation of 1a and 1c
instead of 1d and 1b.
To validate such an assignment we also verified the expected higher acidity of 1a and 1c
compared to that of 1d and 1b by measuring the pH of equimolar aqueous solutions of
the respective potassium salts. In fact, we found that both the potassium salts of 1a and 1c
are sensibly less basic (8.57 and 8.44 pH) than the potassium salts of 1d and 1b (9.18 and
9.42 pH). Interestingly, the pH values of the solutions of the potassium salts of 1a and 1c
indicated also that, between the two phenols, 1c is little more acidic than 1a and this can
be explained by a strong intramolecular hydrogen bond between the ortho positioned OH
and NO2 in 1a.[18] Furthermore, the basicity ranking we found for the potassium salts of
1a-1d (1b>1d>>1a>1c) corresponds, if overturned, to the acidity order of mono-nitrated
5

guaiacols, that is 2-methoxy-4-nitro- >2-methoxy-6-nitro- >> 2-methoxy-3-nitro- > 2-
methoxy-5-nitrophenol.[19] This indicates that, as expected, nitrocatechol mono benzyl
ethers and monomethyl ethers show parallel acidity rankings. The third eluted product
was identified as 2-benzyloxy-4,6-dinitrophenol (1e) by NMR and HRMS analysis and it
was excluded that dinitration was occurred at 3 and 5 positions on account of the
previous identification of the mono-nitrated products as 1a and 1c. Its yield amounted to
12%.
Interest in having all four regioisomers 1a-1d prompted us to consider the nitration of III
under alternative conditions, such as treatment with ceric ammonium nitrate (CAN) in
acetonitrile, which is reported to give all the four mono-nitrated positional isomers, each
with 10-30% yield, when applied to catechol monomethyl ether.[20] On the contrary,
nitration of III with CAN in acetonitrile and subsequent chromatography exclusively
provided 1a and 1c and in very high yield (Scheme 4). Under such conditions, dinitration
did not occur and 1b and 1d were not formed in an appreciable amount.
CONCLUSIONS
In summary, we prepared the four positional isomers of nitrocatechol monobenzyl ether:
the two isomers o- and p-nitrated to OH by nitration of 2-benzyloxyphenol, preferably
with CAN as a nitrating agent in acetonitrile, and the two isomers o- and p-nitrated to
OBn from catechol through four- and two-steps syntheses respectively. It was soon
realized that the main challenge was the nitrated products unequivocal identification,
which was impossible on the basis of the preparation of a single isomer because of the
6

incomplete and sometimes rough analytical data reported in literature. Therefore, the four
nitrocatechol monobenzyl ethers were accurately characterized for H and 13C NMR
spectral data, DSC traces and acidity properties so as to allow, from then on, their
incontrovertible and independent identification prescinding from any chemical
correlation to the synthetic precursors.
EXPERIMENTAL
Nitration of III with sodium nitrate and sulphuric acid: Sodium nitrate (2.30 g, 27,05
mmol), 3 M sulfuric acid (31 mL) and sodium nitrite (10 mg) were sequentially added to
a stirred solution of 2-benzyloxyphenol (5 g, 25.0 mmol) in DCM (40 mL) cooled at -10
°C. The reaction mixture was stirred for three hours at the same temperature, then diluted
with DCM and washed with water. The organic phase was concentrated and purified on
silica gel (cyclohexane/ethyl acetate 8/2) to give, in sequence, 1a (2.15 g, 35%) and 1c
(1.84 g, 30%) as yellow solids and 1e ( 0.87 g, 12%) as a brown solid. Analytical data for
1a, 1c and 1e are reported in Table I and in the Supporting Information.
Nitration of III with CAN: A solution of (NH4)2Ce(NO3)6 (10 g, 18.2 mmol) in
acetonitrile (60 mL) was added dropwise to a stirred solution of 2-benzyloxyphenol (5 g,
25.0 mmol) in acetonitrile (40 mL) cooled at -5 °C. The reaction mixture was stirred for 3
h at 0 °C and then diluted with water and extracted with ethyl acetate. The organic phase
was concentrated and the resulting residue was purified on silica gel (cyclohexane/ethyl
acetate 8/2) to give, in sequence, 1a (3.56 g, 58.1%) and 1c (2.08 g, 34.0%) as yellow
7

solids. Analytical data for 1a and 1c are reported in Table I and in the Supporting
Information.
2-Benzyloxy-5-nitrophenol (1b): A solution of 4-nitrocatechol (5 g, 32.2 mmol) in DMF
(25 mL) was added dropwise to a suspension of NaH (774 mg, 32.2 mmol) in DMF (50
mL) cooled at -10 °C. The reaction mixture was stirred for 1 h at room temperature. After
cooling at -10 °C, a solution of benzyl bromide (3.8 mL, 32.2 mmol) in DMF (20 mL)
was slowly added over a period of 30 min. After 16 h at room temperature, the mixture
was diluted with ethyl ether and washed with 1 N HCl. The organic phase was
concentrated and the resultant residue purified on silica gel (cyclohexane/DCM 8/2) to
give 1b (6.32 g, 80%) as a light yellow solid. The analytical data are reported in Table I
and in the Supplementary material.
REFERENCES
1.
Bolchi, C.; Gotti, C.; Binda, M.; Fumagalli, L.; Pucci, L.; Pistillo, F.; Vistoli, G.;
Valoti, E.; Pallavicini, M. J. Med. Chem. 2011, 54, 7588-7601.
2.
Valoti, E.; Pallavicini, M,; Villa, L.; Pezzetta, D. J. Org. Chem. 2001, 66, 1018-
1025.
3.
Pallavicini, M.; Budriesi, R.; Fumagalli, L.; Ioan, P.; Chiarini, A.; Bolchi, C.;
Ugenti, M. P.; Colleoni, S.; Gobbi, M.; Valoti, E. J. Med. Chem. 2006, 49, 7140-7149.
4. Pallavicini, M.; Fumagalli, L.; Gobbi, M.; Bolchi, C.; Colleoni, S.; Moroni, B.;
Pedretti, A.; Rusconi, C.; Vistoli, G.; Valoti, E. Eur. J. Med. Chem. 2006, 41, 1025-1040.
8

5.
Fumagalli, L.; Pallavicini, M.; Budriesi, R.; Gobbi, M.; Straniero, V.; Zagami,
M.; Chiodini, G.; Bolchi, C.; Chiarini, A.; Micucci, M.; Valoti, E. Eur. J. Med. Chem.
2012, 58, 184-191.
6.
Bolchi, C.; Bavo, F.; Gotti, C.; Fumagalli, L.; Fasoli, F.; Binda, M.; Mucchietto,
V.; Sciaccaluga, M.; Plutino, S.; Fucile, S.; Pallavicini, M. Eur. J. Med. Chem. 2017, 125,
1132-1144.
7.
Alam, M. I.; Alam, M. A.; Alam, O.; Nargotra, A.; Taneja, S. C.; Koul, S. Eur. J.
Med. Chem. 2016, 114, 209-219.
8.
Kobayashi, S.; Okimoto, K.; Imakura, Y. Chem. Pharm. Bull. 1982, 30, 1567-
1573.
9.
Page, D. F.; Clinton, R. O. J. Org. Chem. 1962, 27, 218-226.
10.
Cambie, R. C.; Clark, G. R.; Coombe, S. L.; Coulson, S. A.; Rutledge, P. S.;
Woodgate, P. D. J. Organomet. Chem. 1996, 507, 1-21.
11. Astles, P. C.; Brown, T. J.; Cox, P.; Halley, F.; Lockey, P. M.; McCarthy, C.;
McLay, I. M.; Majid, T. N.; Morley, A. D.; Porter, B.; Ratcliffe, A. J.; Walsh, R. J. A.
Bioorg. Med. Chem. Lett. 1997, 7, 907-912.
12.
13.
Bredereck, H.; Heck, H. Chem. Ber. 1958, 91, 1314-1318.
Barton, D. H. R.; Linnell, W. H.; Senior, N. Quart. J. Pharm. Pharmacol. 1945,
18, 41-47.
14.
Augstein, J.; Green, S. M.; Monro, A. M.; Potter, G. W. H.; Worthing, C. R.;
Wrigley, T. I. J. Med. Chem. 1965, 8, 446-456.
15.
Widdowson, K. L.; Veber, D. F.; Jurewicz, A. J.; Hertzberg, R. P.; Rutledge, M.
C. Jr. US6262113 B1, 2001.
9

16.
The 1H NMR spectrum of 1a in ref. 15 is registered in CD3COCD3, but we found
the there reported chemical shifts when we registered the spectrum of 1a in CDCl3 and
not in CD3COCD3.
17.
Wang, Z. Q.; Staab, A. J.; Seekamp, C. K.; Luke, G. P. WO2008118935 A1,
2008.
18.
Baitinger, W. F.; Schleyer, R. P.; Murty, T. S. S. R.; Robinson, L. Tetrahedron
1964, 20, 1635-1647.
19.
20.
Sunkel, J.; Staude, H. Ber. Bunsenges. Phys. Chem. 1968, 72, 567-573.
Chaudhuri, K.; Chawla, H. M. Indian J. Chem. 1985, 24B, 1277-1279.
10

Table I. Melting points and 1H and 13C NMR chemical shifts of the four mono-nitrated
regioisomers of 2-benzyloxyphenol (1a-1d) and of 2-benzyloxy-4,6-dinitrophenol (1e)
and pH of the aqueous solutions of the potassium salts of 1a-1d.
Compd Mp a
(°C)
1H NMR: chemical shifts of protons of phenol ring 13C NMR:
pH of K salt
(3.5 mM in
water) at
b
chemical
shifts of
H-C3
H-C4
H-C5
H-C6
unsubstituted 25°C
carbons of
phenol ring b
97.77
7.16
6.85
7.72
116.72,
118.81,
120.67
116.87,
120.89,
124.52
107.67,
114.20,
118.85
110.34,
110.89,
116.81
106.57,
119.38
8.57
9.18
8.44
9.42
nd
1a
1d
1c
1b
1e
(dd, 8.2,
1.2)
(t, 8.2)
(dd, 8.2,
1.2)
viscous
oil
7.49
7.12
7.19
(dd,
(t, 8.2)
(dd, 8.2,
1.8)
8.2,1.8)
83.07
83.76
7.87
7.90
7.01
(d, 2.4)
(dd, 8.8,
2.4)
(d, 8.8)
6.97 (d,
9.9)
7.81 (m)
7.81 (m)
c
-
7.29 (d,
2.9)
8.43 (d, 2.9)
11

a The melting points were determined by DSC analysis and the melting peak maximum is
reported for each compound.
b The spectra were registered in CDCl3 excepting those of 1e, which were registered in
DMSO-d6.
c Decomposition > 200 °C.
12

Scheme 1. Regioisomeric mononitrated 2-benzyloxyphenols 1a-d as precursors of
nitrobenzodioxanes 2a-d, conceived as bioisosteres of pyridodioxanes 3a-d.
13

Scheme 2. Mononitrated 2-benzyloxyphenols from 1,3-benzodioxol, catechol and 2-
benzyloxyphenol: (a) HNO3, H2SO4, AcOH, -5 °C; 7 (b) BnONa, BnOH, DMSO, 155 °C;
8 (c) BnCl, Na2CO3, KI, EtOH, H2O, reflux; 9 (d) HNO3, AcOH, rt; 9 (e) KOH, H2O, 2-
methoxyethanol, reflux; 9 (f) HNO3, Et2O, rt; 10 (g) BnBr, NaH (2 eq), DMF, rt; 11 (h)
BnBr, NaH (1 eq), DMF, rt; 11 (i) BzCl, KOH, H2O, rt; 12 (j) HNO3, AcOH, rt; 13 (k)
BnBr, MgSO4, K2CO3, acetone, reflux; 14 (l) KOH, EtOH, reflux; 14 (m) NaNO3, NaNO2,
H2SO4, DCM, rt. 15
14

Scheme 3. Nitration products from catechol monobenzyl ether treated with NaNO3 and
diluted H2SO4 at low temperature.
15

Scheme 4. Nitration products from catechol monobenzyl ether treated with CAN in
acetonitrile.
16

Figure 1. Aromatic region of the 1H NMR spectra of 1a-1d. (A) The three adjacent
hydrogens of the phenol ring of 1a and 1d give analogous sequence of signals: dd, dd and
t (from low field to high field). (B) In the aromatic region, the spectra of 1b and 1c are
nearly identical.
17