Unforeseen formation of 2-bromo-3-hydroxybenzaldehyde by bromination of 3-hydroxybenzaldehyde

Article abstract of DOI:10.1016/j.tetlet.2004.04.174

Contrary to literature reports, bromination of 3-hydroxybenzaldehyde can afford both 2-bromo-5-hydroxybenzaldehyde and 2-bromo-3-hydroxybenzaldehyde, but 4-bromo-3-hydroxybenzaldehyde was not detected. 2-Bromo-3-hydroxybenzaldehyde was converted into 2-(benzyloxy)-1-bromo-5-methoxy-7-methylnaphthalene. X-ray crystallographic analysis supports the identity of 2-bromo-3- hydroxybenzaldehyde.

Full text of DOI:10.1016/j.tetlet.2004.04.174

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5091–5094
Unforeseen formation of 2-bromo-3-hydroxybenzaldehyde by
bromination of 3-hydroxybenzaldehyde
Willem A. L. van Otterlo, Joseph P. Michael, Manuel A. Fernandes
and Charles B. de Koning*
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, 2050 Johannesburg, South Africa
Received 24 March 2004; revised 22 April 2004; accepted 29 April 2004
Abstract—Contrary to literature reports, bromination of 3-hydroxybenzaldehyde can afford both 2-bromo-5-hydroxybenzaldehyde
and 2-bromo-3-hydroxybenzaldehyde, but 4-bromo-3-hydroxybenzaldehyde was not detected. 2-Bromo-3-hydroxybenzaldehyde
was converted into 2-(benzyloxy)-1-bromo-5-methoxy-7-methylnaphthalene. X-ray crystallographic analysis supports the identity of
2-bromo-3-hydroxybenzaldehyde.
ꢀ 2004 Elsevier Ltd. All rights reserved.
As a result of recent debate in the chemistry literature
the outcome of the bromination of 3-hydroxybenzalde-
hyde 1 has been placed in doubt.1;2 In 1912 Pschorr
reported that bromination (Br2, CHCl3) of 3-
hydroxybenzaldehyde 1 afforded 2-bromo-5-hydroxy-
benzaldehyde 2 (Scheme 1).3 On the contrary, in 1925,
Hodgson and Beard reported that bromination of 1
under the same conditions afforded a mixture of 2 and 4-
bromo-3-hydroxybenzaldehyde 3 (Scheme 1), although
only 2 was characterized.4 More than 25 years later,
Pandya et al. also reported that bromination of 1, this
time using acetic acid as solvent, afforded only 3 in a
52% yield.5
More recently, other workers,6 including ourselves,7
have used related reaction conditions (e.g., our condi-
tions: Br2, CCl4) for the bromination of 1 to afford 2. In
our work this product was used for the synthesis of
complex isochromanes and related compounds.7 At
least two other groups of workers8;9 have repeated the
reaction using the conditions published by both Hodg-
son (Br2, CHCl3) and Pandya (Br2, AcOH). These re-
sults, including an X-ray crystal structure,9 indicate that
bromination of 1 affords only the Pschorr product 2 and
not compound 3.
Br
CHO
OH
OH
2
CHO
CHO
However, based on the fact that Hodgson’s bromination
of 1 can also apparently afford 3, Tatsuta and co-
workers have described a synthesis of the natural
product medermycin (also known as lactoquinomycin)10
5 and its enantiomer using the putative 3 as a starting
material.11 As shown in Figure 1 the phenolic sub-
stituent of the starting material is required to be the
phenol in position 9 of medermycin. Subsequently, in
2002, Morin and co-workers cast doubt on the product
of Tatsuta’s synthesis, based on their experimental evi-
dence.1 They reported that bromination of 3-hydroxy-
benzaldehyde 1 using Tatsuta’s bromination conditions
(HBr, AcOH), afforded the Pschorr product 2. This
assignment was supported by an X-ray crystal structure
Br
OH
3
1
CHO
Br
4
OH
Scheme 1. Bromination of 3-hydroxybenzaldehyde.
Keywords: Bromination; Regioisomers; Naphthalenes.
* Corresponding author. Tel.: +27-11-717-6724; fax: +27-11-717-6749;
e-mail: dekoning@aurum.chem.wits.ac.za
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.174

5092
W. A. L. van Otterlo et al. / Tetrahedron Letters 45 (2004) 5091–5094
OH
nOe
CHO
Br
Br
N
CHO
CHO
OH
OH
O
O
i, ii
nOe
Ph
9
Br
1
H
O
OBn
OH
CHO
O
6
7
8
O
O
3
1
5
O
Br
BnO
CO2Me
CO2H
OH
O
iii
OH
O
9
CHO
H
O
O
Scheme 2. Reagents and conditions: (i) Br2, CCl4, rt, add H2O, crys-
tallized at 0 ꢁC; (ii) BnBr, K2CO3, DMF, 60 ꢁC (45% over two steps);
(iii) NaOMe, dimethyl succinate, MeOH, 50 ꢁC (77%).
Br
O
O
2
N
6
OH
synthesized by Nicolaou et al.16 using an alternative
route indicated that 7 was the product obtained and not
8. The 13C NMRspectrum of 7 proved to be substan-
tially different to that of 8.15
Figure 1. Synthesis of medermycin 5 from the putative 4-bromo-3-
hydroxybenzaldehyde 3 or the isomer 6 from 2.
of a derivative, 2-bromo-5-(p-nitrobenzoyl)benzalde-
hyde.1 Based on this experimental finding, Morin pro-
posed a structural revision to natural medermycin in
which the carbohydrate moiety is now attached to po-
sition 6 of the naphthoquinone that is 6. However, there
seems to be little doubt that the natural product itself
has structure 5: Williamson et al. has recently provided
extensive NMRspectral evidence to support the original
structure assigned to the natural product.2
Further investigation of this reaction showed in fact that
a mixture of the regioisomers 2 and 4 (ratio 1:2) was
obtained in the bromination of 1 and we were able to
obtain predominantly 2-bromo-3-hydroxybenzaldehyde
4 by crystallization at 0 ꢁC from CCl4.17 Most impor-
tantly, a single crystal X-ray structure (Fig. 2) confirmed
that the bromine atom of intermediate 4 was placed
between the aldehyde and the phenol substituents as
suggested by the NOE NMRspectroscopic studies and
comparison of spectral data.18
In this paper we wish to report that the bromination
of 3-hydroxybenzaldehyde 1 can also afford an alterna-
tive regioisomer, 2-bromo-3-hydroxybenzaldehyde 4
(Scheme 1), indicating that another possible regioisomer
of medermycin may have been synthesized by Tatsuta
and co-workers.11
Pursuing our interests in the synthesis of substituted
naphthalenes, we converted the aldehyde 7 into the
conjugated half-ester 9 (77% yield) by using modified
Stobbe conditions.19 We used sodium methoxide gen-
erated in situ as base instead of the usual potassium tert-
butoxide because the benzyl-protecting group of 7
proved to be unstable when using the latter. Subsequent
cyclization of 9 with sodium acetate in acetic anhydride
afforded naphthalene derivative 10 in acceptable yields
(Scheme 3).
As part of our ongoing programme on the synthesis of
substituted naphthalenes,12 we had previously bromi-
nated 3-hydroxybenzaldehyde 1 (Br2, CCl4) to afford 2-
bromo-5-hydroxybenzaldehyde 2 under rather specific
conditions.13;14 Recently, we isolated the product of this
reaction in a different manner. The reaction mixture was
stirred for 2 h at room temperature, water was added
and the resulting solution placed in a refrigerator. After
16 h an off-white solid had crystallized from the reaction
mixture. This was isolated by filtration and subjected to
a normal O-benzylation protocol (BnBr, Me2CO,
K2CO3). However, we were surprised to isolate the 2-
bromo-3-benzyloxy regioisomer 7 as the major product
(45%, two steps) after column chromatography,15 rather
than the 2-bromo-5-benzyloxy isomer 8 (yield 1%) iso-
lated previously as the major component in our work
(Scheme 2).7;15 Repeating the reaction a number of times
in this manner again gave 7 as the major product.
The structure of the O-benzylated product 7 was sup-
ported by NOE NMRspectroscopic studies in which
distinctive interactions were evident between the benzyl
methylene and 4-H protons, and also between the
aldehyde and 6-H protons. In addition, comparison of
the spectroscopic data of 7 with the same compound
Figure 2. X-ray crystal structure of 2-bromo-3-hydroxybenzaldehyde 4.

W. A. L. van Otterlo et al. / Tetrahedron Letters 45 (2004) 5091–5094
5093
Tatsuta and co-workers11 and Pandya et al.,5 for the
formation of the alternative regioisomer 3 from 1.
Therefore, in addition to the regioisomer of medermycin
suggested by Morin and co-workers1 it is also possible
that Tatsuta may have synthesized regiosiomer 13 from 2-
bromo-3-hydroxybenzaldehyde 4 as depicted in Figure 3.
Br
Br
BnO
CO2Me
CO2H
BnO
CO2Me
i
OR
9
10 R = Ac,
11 R = Me
ii, iii
Br
BnO
Me
iv, v, vi
Acknowledgements
nOe
OMe
12
This work was supported by the National Research
Foundation (NRF, GUN 2053652), Pretoria, and the
University of the Witwatersrand (University Research
nOe
Scheme 3. Reagents and conditions: (i) NaOAc, Ac2O, reflux, 61%; (ii)
KOH, MeOH, rt, 100%; (iii) (MeO)2SO2, K2CO3, acetone, reflux, 98%;
(iv) LiAlH4, THF, 0 ꢁC, 99%; (v) (Cl2BrC)2, PPh3, CH2Cl2, rt, 81%;
(vi) L-Selectride, CH2Cl2, 0 ꢁC, 93%.
ꢀ
Council). Mrs. C. F. Kellock (nee Broli) and Dr. A. L.
Rousseau are thanked for conducting some of the initial
investigations.
Acetate 10 was successfully hydrolyzed with sodium or
potassium hydroxide to give the crystalline naphthol in
quantitative yield. The intermediate was methylated
under standard conditions to afford the substituted
naphthalene 11 in excellent yield. The ester substituent
of 11 was then converted into a methyl group using
conditions optimized by Bringmann et al.20 to afford 12,
characterized by rigorous NMRspectroscopy, which
References and notes
ꢀ
1. Leo, P.-M.; Morin, C.; Philouze, C. Org. Lett. 2002, 4,
2711–2714.
2. Williamson, R. T.; McDonald, L. A.; Barbieri, L. R.;
Carter, G. T. Org. Lett. 2002, 4, 4659–4662.
3. Pschorr, R. Justus Liebig’s Ann. Chem. 1912, 391, 23–39.
4. Hodgson, H. H.; Beard, H. G. J. Chem. Soc. 1925, 875–
881.
1
included NOE and a three bond HMBC H–13C NMR
5. Pandya, K. C.; Pandya, R. B. K.; Singh, R. N. J. Indian
Chem. Soc. 1952, 29, 363–367.
spectroscopy experiment. Comparison of the spectro-
scopic data of 12 with those obtained by using 8 as a
starting material by other researchers, which led to
4-(benzyloxy)-1-bromo-5-methoxy-7-methyl-naphthalene
proved to be substantially different.21
6. (a) Qiao, L.; Zhao, L.-Y.; Rong, S.-B.; Wu, X.-W.; Wang,
S.; Fujii, T.; Kazanietz, M. G.; Rauser, L.; Savage, J.;
Roth, B. L.; Flippen-Anderson, J.; Kozikowski, A. P.
Bioorg. Med. Chem. Lett. 2001, 11, 955–959; (b) Harmata,
M.; Barnes, C. L.; Rao Karra, S. R.; Elahmad, S. J. Am.
Chem. Soc. 1994, 116, 8392–8393.
7. (a) de Koning, C. B.; Michael, J. P.; van Otterlo, W. A. L.
Tetrahedron Lett. 1999, 40, 3037–3040; (b) de Koning, C.
B.; Michael, J. P.; van Otterlo, W. A. L. J. Chem. Soc.,
Perkin Trans. 1 2000, 799–811.
In conclusion, it is clear that the bromination of 1 gives
mixtures of monobrominated products. In our case we
were able to detect both the 2-bromo-5-hydroxybenz-
aldehyde and 2-bromo-3-hydroxybenzaldehyde isomers
2 and 4 in the reaction mixture, but not 3. We were also
successful in synthesizing the substituted naphthalene 12
from isomer 4. It is unlikely that the structure of the
natural medermycin is incorrect, as extensive spectro-
scopic data have been produced to verify the structure.2
On the basis of the bromination experiments conducted
in our laboratories, 2-bromo-5-hydroxybenzaldehyde 2
and 2-bromo-3-hydroxy-benzaldehyde 4 were the only
isomers that we were able to isolate in appreciable
quantities. An extensive literature search shows no
claims, apart from the work of Hodgson and Beard,4
8. Barfknecht, C. F.; Nichols, D. E. J. Med. Chem. 1971, 14,
370–372.
~
9. Matos Beja, A.; Paixao, J. A.; Ramos Silva, M.; Alte da
Veiga, L.; Rocha Gonsalves, A. M. d’A.; Serra, A. C. Acta
Cryst. 2000, C56, 354–355.
10. For the history of the isolation of medermycin see: (a)
Takano, S.; Hasuda, K.; Ito, A.; Koide, Y.; Ishii, F.;
Haneda, I.; Chihara, S.; Koyama, Y. J. Antibiot. 1976, 29,
765–768; (b) Fukushima, K.; Arai, T. Mass Spectrosc.
1979, 27, 97–105; (c) Tanaka, N.; Okabe, T.; Isono, F.;
Kashowagi, M.; Nomoto, K.; Takahashi, M.; Shimazu,
A.; Nishimura, T. J. Antibiot. 1985, 38, 1327–1332; (d)
Okabe, T.; Nomoto, K.; Funabashi, H.; Okuda, S.;
Suzuki, H.; Tanaka, N. J. Antibiot. 1985, 38, 1333–1336.
11. Synthesis of medermycin: (a) Tatsuta, K.; Ozeki, H.;
Yamaguchi, M.; Tanaka, M.; Okui, T. Tetrahedron Lett.
1990, 31, 5495–5498; (b) Tatsuta, K.; Ozeki, H.; Yama-
guchi, M.; Tanaka, M.; Okui, T.; Nakata, M. J. Antibiot.
1991, 44, 901–902.
12. (a) de Koning, C. B.; Michael, J. P.; Rousseau, A. L. J.
Chem. Soc., Perkin Trans. 1 2000, 787–797; (b) van
Otterlo, W. A. L.; Ngidi, E. L.; Coyanis, E. M.; de
Koning, C. B. Tetrahedron Lett. 2003, 44, 311–313; For a
recent review on the synthesis of naphthalenes see: (c) de
Koning, C. B.; Rousseau, A. L.; van Otterlo, W. A. L.
Tetrahedron 2003, 59, 7–36.
O
O
HO
N
HO
CHO
H
O
O
Br
O
4
O
13
OH
Figure 3. Regioisomer 13 of medermycin, which could be synthesized
from 2-bromo-3-hydroxybenzaldehyde 4.

5094
W. A. L. van Otterlo et al. / Tetrahedron Letters 45 (2004) 5091–5094
13. Br2 (2.1 cm3, 6.5 g, 41 mmol) was added dropwise over
15 min under N2 to a solution of 3-hydroxybenzaldehyde 1
(5.0 g, 41 mmol) in CCl4 (150 cm3) kept at 25 ꢁC. The
reaction mixture was stirred under N2 for 2 h at rt, after
which H2O (250 cm3) and CH2Cl2 (250 cm3) were added.
The organic layer was separated, dried and removed in
vacuo to afford compound 2 as a white solid (4.2 g, 51%).
14. Most of this work is taken from the PhD thesis of W.A.L.
van Otterlo, University of the Witwatersrand, 1999.
18. Crystal data for 4: C7H5BrO2, crystal size
0.50 · 0.09 · 0.06 mm, crystal system monoclinic, space
ꢁ
group P21, Z ¼ 2, unit cell dimensions: a ¼ 4:8625ð8Þ A,
ꢁ
ꢁ
ꢁ
b ¼ 12:987ð2Þ A,
c ¼ 5:6842ð9Þ A,
b ¼ 101:873ð3Þꢁ,
3
3
V ¼ 351:28ð10Þ A , Dc ¼ 1:900 Mg/m , intensity data were
collected on a Bruker SMART 1K CCD area detector
diffractometer with graphite monochromated Mo Ka
ꢁ
radiation (50 kV, 30 mA), wavelength 0.71073 A, collec-
tion temperature 293(2) K; hmax ¼ 26:48; 2113 reflections
15. Compound 7: Pale pale yellow solid (mp 131.5–132.5 ꢁC,
collected with 1167 independent reflections ðRint ¼
sublimes above 120 ꢁC, recrystallized from EtOH/H2O).
0:0365Þ; 91 parameters; maximum residual electron den-
Spectroscopic data for 7: 1H NMR(400 MHz; CDCl ) dH
sity 0.278 and )0.209 e Aꢀ3; data reduction was carried out
ꢁ
3
10.44 (1H, s, CHO), 7.55–7.29 (7H, m, 5-H, 6-H and
5 · PhH), 7.15 (1H, dd, J 8.1 and 1.6, 4-H), 5.20 (2H, s,
OCH2); 13C NMR(100 MHz; CDCl 3) dC 192.2 (CHO),
155.4, 135.9, 134.9, 128.7, 128.2, 128.2, 127.0, 121.8, 118.8,
using the program SAINT+ [Bruker, 1999, SAINT+. Ver-
sion 6.02 (includes XPREP and SADABS). Bruker AXS
Inc., Madison, Wisconsin, USA] and face indexed absorp-
tion corrections were made using the program XPREP
final R indices: R1 ¼ 0:0275, wR2 ¼ 0:0522. The crystal
structure was solved by direct methods using SHELXTL
,
117.9, 71.3 (OCH2); IR(KBr pellet)
m
max/cmꢀ1 1682s
(C@O st), 1567m (ArC@C st), 698s (C–Br st); CHN C,
57.48; H, 3.68; (C14H11O2Br requires C, 57.75; H, 3.80%).
Compound 8: Pale yellow solid (mp 43–45 ꢁC, recrystal-
.
Nonhydrogen atoms were first refined isotropically fol-
lowed by anisotropic refinement by full matrix least-
squares calculation based on F 2 using SHELXTL [Bruker,
}
lized from CH2Cl2/hexane; lit. 52–54 ꢁC); Keseru, G. M.;
ꢀ
Mezey-Vandor, G.; Nogradi, M.; Vermes, B.; Katjar-
Peredy, M. Tetrahedron 1992, 48, 913–922. Spectroscopic
ꢀ
ꢀ
ꢀ
1999, SHELXTL. Version 5.1. (includes XS, XL, XP,
XSHELL) Bruker AXS Inc., Madison, Wisconsin, USA].
Hydrogen atoms were first located in the difference map,
positioned geometrically and allowed to ride on their
respective parent atoms. Diagrams and publication mate-
rial were generated using SHELXTL and PLATON (Spek, A.
L. Acta Cryst. 1990, A46, C34). Crystallographic data
(excluding structure factors) have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 234067. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax:
+44-(0)-1223-336033 or email: deposit@ccdc.cam.ac.uk).
19. Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron 1998, 54,
1585–1588.
1
data for 8: H NMR(200 MHz; CDCl ) dH 10.28 (1H, s,
3
CHO), 7.51–7.31 (7H, m, 5 · PhH, 3- and 6-H), 7.07 (1H,
dd, J 8.8 and 3.2, 4-H), 5.06 (2H, s, OCH2); 13C NMR
(50 MHz; CDCl3) dC 191.5 (CHO), 158.3, 135.8, 134.6,
133.9, 128.6, 128.2, 127.5, 123.6, 118.1, 113.8, 70.4
(OCH2); IR(KBr)
(ArC@C st).
m
max/cmꢀ1 1694vs (C@O st), 1590m
16. Nicolaou, K. C.; Koide, K.; Bunnage, M. E. Chem. Eur. J.
1995, 1, 454–466.
17. The synthesis of 4 by alternative routes. (i) From 2-
mercuriacetato-3-hydroxybenzaldehyde: (a) Hodgson, H.
H.; Smith, E. W. J. Chem. Soc. 1931, 1500–1508 (ii) From
2-nitro-3-hydroxybenzaldehyde: see Ref. 4; (b) Hodgson,
H. H.; Beard, H. G. J. Chem. Soc. 1926, 147–155. This
paper reports on the chlorination of 1 and finds that the
major product obtained is 2-chloro-3-hydroxybenzalde-
hyde.
€
20. Bringmann, G.; Gotz, R.; Harmsen, S.; Holenz, J.; Walter,
R. Liebigs Ann. Chem. 1996, 2045–2058.
21. Hobbs, P. D.; Upender, V.; Dawson, M. I. Synlett 1997,
965–967.