Reinvestigation of acetylation of 3,4-dihydroxybenzaldehyde and reconciliation of previously reported analytical data

Article abstract of DOI:10.1016/j.tetlet.2016.01.075

Acetylation of 3,4-dihydroxybenzaldehyde was reinvestigated. The results in the regiochemical outcome were analyzed in detail by NMR methods and compared with previously published data.

Full text of DOI:10.1016/j.tetlet.2016.01.075

Tetrahedron Letters 57 (2016) 1019–1021
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reinvestigation of acetylation of 3,4-dihydroxybenzaldehyde
and reconciliation of previously reported analytical data
Carlos Berenguer Albiñana , John J. Hayward , Tomas Hudlicky , Ales Machara b,
a,b
a
a,
⇑
⇑
a
Department of Chemistry, Brock University, 500 Glenridge Ave., St Catharines, ON L2S 3A1, Canada
Department of Organic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 2030/8, 128 43 Prague 2, Czech Republic
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Acetylation of 3,4-dihydroxybenzaldehyde was reinvestigated. The results in the regiochemical outcome
were analyzed in detail by NMR methods and compared with previously published data.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 14 December 2015
Revised 18 January 2016
Accepted 20 January 2016
Available online 21 January 2016
Keywords:
Acylation
Regioselectivity
Rearrangement
NMR spectroscopy
Methanolysis
In a recent chemoenzymatic synthesis of ent-hydromorphone1
reported by our group the conversion of 3,4-dihydroxybenzalde-
hyde (1) to its 4-methoxymethyl ether (3) was required, as shown
in Scheme 1. The selective acetylation of the 3-hydroxyl group in 1
spectra appeared to be mixtures of 3- and 4-acetyl isomers, with
the 3-acetyl isomer predominating (the data in Table 1, entries 1,
6, and 7 are listed for the major isomer). We also noticed that
the NMR spectra of a freshly crystallized product with a sharp
melting point showed varying ratios of the 3- and 4-acetyl isomers
depending on the length of time in solution. To clear up the confu-
sion we examined the acylation of 1 and the analysis of products in
greater detail in order to reconcile the widely differing data for
acetate 2. To this end we prepared the compound by the available
2
was performed by a procedure previously reported by Wandless
in his synthesis of ustilotoxin D and derived from the earlier work
3
of the Wightman group.
We have embarked on the second-generation synthesis of
hydromorphone where we wished to replace Pb(OAc)
4
in the
1
,2,6
oxidative dearomatization step with other reagents and possibly
also with electrochemical oxidation. To accomplish this task, large
amounts of the model compound 4 were prepared as shown in
Scheme 2. Repetition of our procedure1 for the synthesis of 2,
resulted in a material whose melting point value (115 °C) as well
literature methods
analyzing the progress of acylation (vide
NMR) and comparing the NMR spectra recorded in several different
deuterated solvents (see Supplementary material).
The discrepancy in the melting point values may be easily
6
explained by different polymorphs obtained on workup and crys-
1
as the H NMR data differed substantially from the data previously
tallization of the product. The variations in NMR data and/or
appearance of additional signals can be explained by the equilibra-
tion of acetyl isomers at 3- and 4-positions as it is well known that
acyl groups undergo 1,2- or 1,3-migrations to adjacent nucleophilic
1
reported by us (mp = 88–91 °C). Examination of older published
data revealed inconsistencies in melting point values as well as
in NMR data, as summarized in Table 1.
The discrepancy in melting point values initially led us to sus-
pect that we may have obtained the regioisomer acylated at the
7
groups. The observed ratios of the 3- and 4-acetyl isomers are
dependent on the solvent and the time the product remains in
solution prior to the NMR experiment (see Supporting information
for the results of monitoring).
4
-position. The melting point of 115 °C we obtained agreed with
4
5
the value reported by Hänsel and Pascu but not with that previ-
ously reported by us and by Wightman.3 In addition, the NMR
1
NMR analysis of 2 in CDCl
- and 4-acetyl isomers that equilibrates to about 80:20 after about
0 min. To investigate the isomerism of 2 in CDCl , spectra were
3
shows an initial 96:4 ratio of the
3
3
3
⇑
Corresponding authors.
E-mail addresses: thudlicky@brocku.ca (T. Hudlicky), macharaa@natur.cuni.cz
obtained every 5 min over the course of an hour. Exchange Spec-
troscopy (EXSY) spectra show a small positive enhancement of
(
A. Machara).
http://dx.doi.org/10.1016/j.tetlet.2016.01.075
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

1
020
C. B. Albiñana et al. / Tetrahedron Letters 57 (2016) 1019–1021
Scheme 1. Catechol protection strategy used in the synthesis of ent-hydromorphone.
Scheme 2. Model study for second-generation oxidative dearomatization.
Table 1
Comparison of literature data (NMR and melting point) published for acetate 2
Report (Ref.)
Mp
NMR dataa
Yield
Solvent
-methanolb
Ar-CHO
Ar-H1
Ar-H2
Ar-H3
2 3
ArO CCH
1
2
3
4
Hudlicky (1)
Wandless (2)
Wightman (3)
Hänsel (4)
88–91 °C (Et
NR
2
O)
d
4
9.78
9.64
7.69
7.47
7.58
7.39
7.07
6.94
2.33
2.17
2.00
2.33
84%
50%
86%
40% over
c
c
c
c
c
CDCl
-methanold
CDCl
3
87–89 °C (Et
2
O/pet. ether)
d
4
9.67
9.97
7.30 (2H, m)
7.68
6.90
7.08
112–113 °C (MeOH)
3
7.67
2
steps
5
6
7
Pacsu (5)
Carreira (6)
This work
109–110 °C (benzene)
NR
None
-acetone
CDCl
—
9.85
9.85
—
7.70
—
7.61
—
7.14
7.11
—
2.29
2.40
35%
66%
65%
d
6
113–114 °C (Et
11–114 °C (CH
2
O)
Cl
3
7.70–7.68 (2H, m)
1
2
2
/pentane)
a
b
c
Spectral data reported in entries 1, 6, and 7 correspond to the major 3-acetyl isomer.
Spectral data were acquired in d -methanol, not in CDCl as originally reported.
4
3
Chemical shifts are approximate, obtained from a PDF of NMR spectrum.
Reported chemical shifts match those of 3,4-dihydroxybenzaldehyde and CH
d
3
CO
2
CD
3
.
the 3-acetoxy isomer when the 4-acetoxy peaks are irradiated; this
enhancement is larger with a longer evolution time and higher
temperatures, confirming that the isomers are in a dynamic equi-
isomers is unfounded as any such mixture will equilibrate to the
thermodynamically more stable 4-phenoxide. We hope that our
study clarifies the contradictions that result from the comparisons
of the previously published data.
librium. When the CDCl
ted with K CO in D O the equilibrium moves to a 96:4 ratio
favoring 2 (see Supplementary material).
In d -methanol the initial ratio is 89:11, favoring the 3-isomer.
3
solution of the 3- and 4-acetates is trea-
2
3
2
Experimental
4
Both acetates undergo methanolysis over time. The NMR data
3
-Acetoxy-4-hydroxybenzaldehyde (2): To a suspension of 3,4-
dihydroxybenzaldehyde (0.39 g, 2.83 mmol) and sodium acetate
0.58 g, 7.06 mmol) in EtOAc (5 mL) was added Ac O (0.35 g,
.43 mmol) dropwise. The reaction mixture was stirred overnight
eventually correspond to 3,4-dihydroxybenzaldehyde (1) and
3
3
d -methyl acetate, as demonstrated by the analysis of Wightman’s
(
3
2
data and by our repetition (the methanolysis of 2 is complete in 16
hours, see the Supplementary material).
and then was quenched with water (10 mL). The water layer was
extracted with EtOAc (2 Â 5 mL) and the combined organic layers
were washed with water, brine, and dried over magnesium sulfate.
After ten minutes the mixture was filtered and the solvent
The next step in the synthesis involves the alkylation of 2 with
MOM chloride in DMF. The initial ratio of 3- to 4-acetates is 87:13
in DMF. This ratio changes to ꢀ96:4 upon the addition of base (see
Supplementary material). After deprotection the MOM ether 3 is
obtained as essentially a single compound (ꢀ96:4 ratio).
removed under reduced pressure. Column chromatography (SiO
CH Cl :MeOH, 50:1) of the residue afforded 0.33 g (65%) of the title
compound, which equilibrates in CDCl to a 80:20 mixture of the
- and 4-acetates. The rest of the mass corresponds to 3,4-diacetoxy-
2
;
2
2
In conclusion, while the equilibration of acetyl isomers in 2 is a
well-known process the interpretation of NMR data is confusing
and time-sensitive. Anyone repeating this work should check the
results, especially the NMR data, against those reported here with
special attention paid to the conditions and time under which the
spectra are obtained. Finally, if the next reaction of acetate 2 is car-
ried out under basic conditions then the concern over mixture of
3
3
benzaldehyde (0.10 g, 17%) and starting material (0.04 g, 10%). The
desired product was crystallized in one of the two ways: (a) the
product was dissolved in Et O at room temperature until the solu-
2
tion was saturated and then cooled to À17 °C in a freezer and
allowed to crystallize overnight; or (b) a saturated solution of the

C. B. Albiñana et al. / Tetrahedron Letters 57 (2016) 1019–1021
1021
acetate in CH
2
Cl
2
was prepared and a layer of pentane was added
Supplementary data
gently, yielding a biphasic system. Diffusion-controlled mixing of
the solvents at room temperature yielded a crystalline product.
Supplementary data (included are NMR spectra of products
obtained by Wandless as well as those from our previous report
and this work. Assignment of NMR signals is provided for the
minor 4-acetoxy isomer. Data is also provided for equilibration
(in CDCl ) and hydrolysis (in d -methanol) experiments) associated
2 2 2
O); 111–114 °C (CH Cl
/pentane); 1H
2
: mp = 113–114 °C (Et
NMR (600 MHz, CDCl ) d = 9.85 (1H, s), 7.70–7.68 (2H, m), 7.11
1H, d, J = 8.4 Hz), 2.40 (3H, s);
3
13
(
C NMR (150 MHz, CDCl
3
)
d = 191.2, 169.1, 155.2, 139.0, 129.5, 129.0, 124.2, 117.4, 19.2.
3
4
1
H NMR data for the 4-acetoxy isomer (600 MHz, CDCl
3
)
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2016.01.075.
d = 9.91 (1H, s), 7.51 (1H, d, J = 1.8 Hz) 7.46 (1H, dd, J = 8.2,
.8 Hz), 7.29 (1H, d, J = 8.2 Hz), 2.40 (3H, s).
1
References and notes
Acknowledgments
1.
.
Varghese, V.; Hudlicky, T. Angew. Chem., Int. Ed. 2014, 53, 4355.
2
(a) Sawayama, A. M.; Tanaka, H.; Wandless, T. J. J. Am. Chem. Soc. 2003, 125,
The authors are grateful to the following agencies for the
financial support of this work: Noramco, Inc.; Natural Science
and Engineering Council of Canada (NSERC) (Idea to Innovation
and Discovery Grants); Canada Research Chair Program, Canada
Foundation for Innovation (CFI); TDC Research, Inc.; TDC Research
Foundation; Ontario Partnership for Innovation and Commercial-
ization (OPIC); and the Advanced Biomanufacturing Centre (Brock
University). One of us (A.M.) is grateful to the University Centre of
Excellence of Charles University, Prague, Czech Republic for
support of part of this work. We thank Razvan Simionescu (Brock
University) for his expert assistance with NMR experiments.
6
864; (b) Sawayama, A. M.; Tanaka, H.; Wandless, T. J. J. Org. Chem. 2004, 69,
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194.