ortho-Formylation of oxygenated phenols

Article abstract of DOI:10.1016/j.tetlet.2009.08.101

Oxygenated phenols are mono-formylated using a mixture of paraformaldehyde, MgCl₂, and Et₃N in THF. In all cases but one, only one regioisomer of the salicylaldehyde is obtained in good to high yield.

Full text of DOI:10.1016/j.tetlet.2009.08.101

Tetrahedron Letters 50 (2009) 6339–6341
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Tetrahedron Letters
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ortho-Formylation of oxygenated phenols
Øyvind W. Akselsen a, Lars Skattebøl b, Trond Vidar Hansen a,
*
a School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway
b Department of Chemistry, University of Oslo, PO Box 1033 Blindern, N-0315 Oslo, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2009
Revised 14 August 2009
Accepted 28 August 2009
Available online 2 September 2009
Oxygenated phenols are mono-formylated using a mixture of paraformaldehyde, MgCl2, and Et3N in THF.
In all cases but one, only one regioisomer of the salicylaldehyde is obtained in good to high yield.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Resorcinols
Phenols
ortho-Formylation
Salicylaldehydes
Regioselectivity
Formylation of aromatic compounds is an important reaction in
synthetic organic chemistry, and numerous methods are avail-
able.1 By directed ortho-metallation of an activated phenol, a for-
myl group can be introduced selectively,2 but this methodology
requires the introduction and removal of the activating group for
the synthesis of salicylaldehydes. On the other hand, salicylaldehy-
des are accessible from the corresponding phenols by several clas-
sical formylation reactions. However, the yields are often only
moderate and the lack of regioselectivity is problematic.3 More-
over, the reaction conditions are quite harsh employing environ-
mentally disagreeable reagents. The regioselectivity is even more
of a problem for 1,3-dihydroxylated phenols (resorcinols). The re-
cently reported regioselective ortho-formylation of substituted
phenols using the MgCl2–Et3N base system and paraformaldehyde
affords salicylaldehydes in excellent yields.4 The salicylaldehydes
obtained by this method have been employed by us and others
for the preparation of useful products and intermediates.5 We
wanted to extend this methodology to substituted mono-protected
resorcinols, a structural feature found in many natural products
and biologically active substances.6
protecting groups; salicylaldehydes 3 and 4 were obtained in 80%
and 88% yields, respectively. Further substitution with either chlo-
rine or bromine atoms at the 4-position afforded the mono-formy-
lated salicylaldehydes 5–11 in good to high yields (Table 1).
Formylation of 3-(tert-butyldimethylsilyloxy)-4-chlorophenol and
3-(tert-butyldimethylsilyloxy)-4-bromophenol was accompanied
by minor unidentified byproducts. The structural assignments of
the salicylaldehydes were based on spectral data and by compari-
son with authentic samples.7,8
Resorcinols mono-protected as acetate, pivalate, or tert-butoxy-
carbonyl derivatives were subjected to the same reaction condi-
tions, but only low yields of the corresponding salicylaldehydes
were obtained in all three cases. Furthermore, subjecting 2,3-dime-
thoxyphenol to the formylating reagents gave the corresponding
salicylaldehyde 12 in only 11% yield. On the other hand, 2,3-(meth-
ylenedioxy)-phenol, a structural entity found in several highly oxy-
genated natural products9 was cleanly converted into the desired
salicylaldehyde 13 in almost quantitative yield using our formyla-
tion protocol. When 3,4-(methylenedioxy)-phenol was reacted
Reacting paraformaldehyde and 3-methoxyphenol in the pres-
ence of the MgCl2–Et3N base system yielded 4-methoxysalicylalde-
hyde (1) and 6-methoxysalicylaldehyde in 92% and 5% yield,
respectively (Scheme 1).7,8 Replacing the methoxy group with the
larger benzyloxy group, afforded exclusively 4-benzyloxysalicylal-
dehyde (2) in 88% yield. The same encouraging results were ob-
tained with either tert-butyldimethylsilyl or thexyldimethylsilyl
OH
O
OH
MgCl2, Et3N, (CH2O)n
OR
OR
R'
R'
THF,
Δ
R = H, Me, Bn, TBS, TDS
R' = H, Cl, Br
* Corresponding author. Tel.: +47 22857450; fax: +47 22855947.
E-mail address: t.v.hansen@farmasi.uio.no (T.V. Hansen).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.101

6340
Ø. W. Akselsen et al. / Tetrahedron Letters 50 (2009) 6339–6341
Table 1
ortho-Formylation of oxygenated phenols
Phenol
Aldehyde (yield %)
Phenol
Aldehyde (yield %)
Phenol
Aldehyde (yield %)
O
OH
OTBS
O
OH
OH
OTBS
OH
O
OBn
OH
Br
OMe
OBn
OH
Cl
OMe
OBn
Cl
Br
1 (92)a
6 (85)
11 (85)
O
OH
O
OH
OH O
MeO
OH
OH
OH
OH
OH
MeO
MeO
OTBS
OBn
MeO
OTBS
Cl
Cl
2 (88)
12 (11)
7 (60)
OTBS
O
OH
OH O
O
OTBS
OH
O
O
O
OH
O
OTBS
OH
Cl
OTBS
Cl
13 (97)
3 (80)
8 (73)
O
O
OH
Br
O
O
OH
OH
O
O
OH
OH
O
O
O
OMe
OTDS
OMe
OTDS
OMe
Br
14 (45)
4 (88)
9 (90)
OH
OH
OH O
OH
Cl
OH
OH
O
O
O
O
OMe
OTBS
OTBS
Cl
Br
Br
15 (82)
5 (94)
10 (73)
a
5% of 6-methoxysalicylaldehyde was also obtained.
Skattebøl, L. Tetrahedron Lett. 2005, 46, 3829; (d) Hansen, T. V.; Skattebøl, L.
Tetrahedron Lett. 2005, 46, 3357; (e) Odlo, K.; Klaveness, J.; Rongved, P.; Hansen,
T. V. Tetrahedron Lett. 2006, 47, 1101; (f) Anwar, H. F.; Skattebøl, L.; Skramstad,
J.; Hansen, T. V. Tetrahedron Lett. 2005, 46, 5285; (g) Wright, B. J. D.; Hartung, J.;
Peng, F.; Van de Water, R.; Liu, H.; Tan, Q.-H.; Chou, T.-C.; Danishefsky, S. J. J.
Am. Chem. Soc. 2008, 130, 16786; (h) Byun, J. H.; Kim, H. Y.; Kim, Y. S.; Mook-
Jung, I.; Kim, D. J.; Lee, W. K.; Yoo, K. H. Bioorg. Med. Chem. Lett. 2008, 18, 5591;
(i) Nichols, D. E.; Frescas, S. P.; Chemel, B. R.; Rehder, K. S.; Zhong, D.; Lewin, A.
H. Bioorg. Med. Chem. 2008, 16, 6116; (j) Chen, Y.; Steinmetz, M. G. Org. Lett.
2005, 7, 3729; (k) Ueno, T.; Koshiyama, T.; Ohashi, M.; Kondo, K.; Kono, M.;
Suzuki, A.; Yamane, T.; Watanabe, Y. J. Am. Chem. Soc. 2005, 127, 6556.
under the same conditions, 2-hydroxy-4,5-(methylenedioxy)-
benzaldehyde 14 was formed in 45% yield. Furthermore, salicylal-
dehyde 15 was obtained in 82% yield as the sole product when
2,3-(isopropylidenedioxy)-phenol was subjected to the ortho-
formylation conditions. Again, complete regioselectivity was
observed in all three cases.7,8
In conclusion, we have extended our simple and regioselective
ortho-formylation protocol to mono-protected resorcinols and
methylenedioxy- substituted phenols. The formylations occurred
with high to excellent yields.
6. (a) Winssinger, N.; Barluenga, S. Chem. Commun. 2007, 22; (b) Kozubek, A.;
Tyman, J. H. P. Chem. Rev. 1999, 99, 1; (c) Pandey, J.; Jha, A. K.; Hajela, K. Bioorg.
Med. Chem. 2004, 12, 2239; (d) Shi, Y.-L.; Shi, M. Org. Biomol. Chem. 2007, 5,
1499; (e) Anwar, H. F.; Hansen, T. V. Org. Lett. 2009, 11, 587; (f) Kamat, V. S.;
Chuo, F. Y.; Kubo, I.; Nakanishi, K. Heterocycles 1981, 15, 1163; (g) Shinonaga,
H.; Kawamura, Y.; Ikeda, A.; Aoki, M.; Sakai, N.; Fujimoto, N.; Kawashima, N.
Tetrahedron 2009, 65, 3446.
Acknowledgment
Financial support to Ø.W.A. from the University of Oslo is grate-
fully acknowledged.
7. Typical experimental procedure: To a dry THF solution (10 ml) of the phenol
(1 mmol), anhydrous magnesium chloride (0.19 g, 2 mmol), triethylamine
(0.20 g, 2 mmol) and paraformaldehyde (90 mg, 3 mmol) were added. The
reaction mixture was heated to reflux under an argon atmosphere for 1–4 h,
and monitored by TLC (hexane:ethyl acetate = 8:2). After complete
consumption of the phenol, the reaction mixture was cooled and diluted
with diethyl ether (20 ml). The organic layer was washed successively with HCl
(1 M, 2 Â 10 ml) and water (2 Â 10 ml), and then dried (MgSO4). In most
cases the product was sufficiently pure for further use, or the product was
purified by column chromatography using hexane:ethyl acetate (95:5 to
70:30). Spectral and physical data of new products: 4-(t-Butyldimethylsilyloxy)-
References and notes
1. Olah, G. A.; Ohannasian, L.; Arvanaghi, M. Chem. Rev. 1987, 87, 671.
2. (a) Gilman, H.; Bebb, R. L. J. Am. Chem. Soc. 1939, 61, 109; (b) Wittig, G.;
Fuhrman, G. Chem. Ber. 1940, 73, 1197; (c) Hartung, C. G.; Snieckus, V.. In
Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim, 2002; Vol. 1,
pp 330–363.
3. For a review, see: Laird, T. In Comprehensive Organic Chemistry; Stoddart, J. F.,
Ed.; Pergamon: Oxford, 1979; Vol. 1, pp 1105–1160.
4. (a) Hofsløkken, N. U.; Skattebøl, L. Acta Chem. Scand. 1999, 53, 258; (b) Hansen,
T. V.; Skattebøl, L. Org. Synth. 2005, 82, 64.
2-hydroxybenzaldehyde (3)10
:
pale brown oil (80% yield); Rf = 0.39 (9:1
hexane:EtOAc); IR (KBr, cmÀ1
)
m
: 3567, 1646; 1H NMR (200 MHz, CDCl3):
d = 11.31 (s, 1H), 9.70 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 6.45 (dd, J = 8.5, 2.2 Hz,
1H), 6.37 (d, J = 2.2 Hz, 1H), 0.96 (s, 9H), 0.23 (s, 6H); 13C NMR (75 MHz, CDCl3):
d = 194.50, 164.06, 135.41, 115.80, 113.07, 107.62, 25.48, 18.21, À4.37. 4-[(2,3-
5. (a) Anwar, H. F.; Hansen, T. V. Tetrahedron Lett. 2008, 49, 4443; (b) Anwar, H. F.;
Skattebøl, L.; Hansen, T. V. Tetrahedron 2007, 63, 9997; (c) Hansen, T. V.;

Ø. W. Akselsen et al. / Tetrahedron Letters 50 (2009) 6339–6341
6341
Dimethylbutan-2-yl)-dimethylsilyloxy]-2-hydroxybenzaldehyde (4)11
:
colorless
d = 193.70, 162.83, 160.01, 137.66, 116.56, 107.56, 106.06, 25.49, 18.32; HRMS
m/z calcd for
13H19BrO3Si (M+): 330.0287; found; 330.0284. 6-(t-
Butyldimethylsilyloxy)-3-bromo-2-hydroxybenzaldehyde (11): yellow solid (85%
yield); mp 94–97 °C; Rf = 0.60 (8:2 hexane:EtOAc); IR (KBr, cmÀ1
: 3418,
oil (88% yield); Rf = 0.38 (9:1 hexane:EtOAc); IR (KBr, cmÀ1
)
m: 3524, 1646,
C
1626; 1H NMR (300 MHz, CDCl3): d = 11.31 (s, 1H), 9.69 (s, 1H), 7.37 (d,
J = 8.5 Hz, 1H), 6.44 (dd, J = 2.2, 8.5 Hz, 1H), 6.36 (d, J = 2.1 Hz, 1H), 1.75–1.62
(m, 1H), 0.91 (m, 12H), 0.27 (s, 6H); 13C NMR (75 MHz, CDCl3): d = 194.46,
164.05, 163.60, 135.37, 115.75, 113.10, 107.65, 34.00, 25.12, 19.97, 18.46,
)
m
1645; 1H NMR (200 MHz, CDCl3): d = 12.40 (s, 1H), 10.23 (s, 1H), 7.53 (dd,
J = 0.3, 8.8 Hz, 1H), 6.25 (d, J = 8.8 Hz, 1H), 0.98 (s, 9H), 0.27 (s, 6H); 13C NMR
(50 MHz, CDCl3): d = 194.23, 159.57, 158.86, 140.71, 113.91, 110.52, 101.76,
25.56, 18.30, À4.39; HRMS m/z calcd for C12H19BrO3Si (M+): 330.0287; found;
330.0281. 2-Hydroxy-3,4-(methylenedioxy)-benzaldehyde: (13): white solid (97%
yield); mp 113–115 °C (lit.14 115–116 °C); Rf = 0.62 (7:3 hexane:EtOAc); 1H
NMR (200 MHz, CDCl3): d = 10.97 (s, 1H), 9.71 (s, 1H), 7.14 (d, J = 8.2 Hz, 1H),
6.56 (d, J = 8.2 Hz, 1H), 6.08 (s, 1H); 13C NMR (75 MHz, CDCl3): d = 195.06,
155.13, 145.49, 134.10, 130.43, 118.25, 102.80, 101.95. 2-Hydroxy-3,4-
(isopropylidene-dioxy)benzaldehyde (15): pale yellow solid (82% yield); mp
À2.42. 5-Chloro-2-hydroxy-4-methoxybenzaldehyde (5)12
:
white solid (94%
: 3281,
yield); mp 106–107 °C; Rf = 0.37 (8:2 hexane:EtOAc); IR (KBr, cmÀ1
) m
1643, 1623; 1H NMR (200 MHz, CDCl3): d = 11.38 (s, 1H), 9.64 (s, 1H), 7.46 (s,
1H), 6.45 (s, 1H), 3.91 (s, 3H); 13C NMR (75 MHz, CDCl3): d = 193.61, 162.91,
161.64, 133.75, 114.75, 114.10, 100.32, 56.52. 4-(Benzyloxy)-5-chloro-2-
hydroxybenzaldehyde (6)13: white solid (85% yield); mp 105–106 °C; Rf = 0.59
(6:4 hexane:EtOAc); IR (KBr, cmÀ1 : 3408, 1645, 1622; 1H NMR (300 MHz,
) m
CDCl3): d = 11.42 (s, 1H), 9.69 (s, 1H), 7.53 (s, 1H), 7.50–7.31 (m, 5H), 6.56 (s,
1H), 5.20 (s, 2H); 13C NMR (75 MHz, CDCl3): d = 193.68, 162.81, 160.77, 135.01,
133.92, 128.71, 128.37, 127.05, 114.96, 114.67, 101.63, 70.99. 4-(t-
Butyldimethylsilyloxy)-5-chloro-2-hydroxybenzaldehyde (7): white solid (60%
68–69 °C; IR (KBr, cmÀ1 : 3382, 1663; Rf = 0.34 (8:2 hexane:EtOAc); 1H NMR
) m
(200 MHz, CDCl3): d = 10.93 (s, 1H), 9.67 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.46 (d,
J = 8.2 Hz, 1H), 1.71 (s, 6H); 13C NMR (75 MHz, CDCl3): d = 194.94, 154.73,
145.31, 133.82, 129.84, 120.92, 117.81, 101.96, 25.87; HRMS m/z calcd for
C10H10O4 (M+): 194.0579; found: 194.0579.
yield); mp 42–43 °C; Rf = 0.57 (8:2 hexane:EtOAc); IR (KBr, cmÀ1
) m: 3425,
1651; 1H NMR (300 MHz, CDCl3): d = 11.18 (s, 1H), 9.56 (s, 1H), 7.47 (s, 1H),
6.42 (s, 1H), 1.00 (s, 9H), 0.27 (s, 6H); 13C NMR (75 MHz, CDCl3): d = 193.77,
162.18, 159.12, 134.32, 117.60, 115.89, 108.08, 25.42, 18.29, -4.46; HRMS m/z
calcd for C13H19ClO3Si (M+): 286.0792; found: 286.0790. 6-(t-
Butyldimethylsilyloxy)-3-chloro-2-hydroxybenzaldehyde (8): yellow solid; (73%
8. The regioisomeric ratio of salicylaldehydes was determined by 1H NMR
analyzes of the crude reaction mixtures and by comparison with authentic
samples.
9. (a) Jin, Z. Nat. Prod. Rep. 2007, 24, 886; (b) Chapleur, Y.; Chretien, F.; Ahmed, S.
I.; Khaldi, M. Curr. Org. Synth. 2006, 3, 341; (c) Rinner, U.; Hudlicky, T. Synlett
2005, 365; (d) Hudlicky, T. J. Heterocycl. Chem. 2000, 37, 535; (e) Anwar, H. F.;
Hansen, T. V. Synlett 2008, 2681.
10. Seidel, J. L.; Epstein, W. W.; Davidson, D. W. J. Chem. Ecol. 1990, 16,
1791.
11. Lay, L. Synth. Commun. 2006, 36, 2203.
12. Farkas, L.; Varady, J.; Gottsegen, A. Tetrahedron 1964, 20, 351.
13. Imoto, H. PCT Int. Appl. WO 2008093639, 2008.
yield); mp 107–110 °C; Rf = 0.53 (8:2 hexane:EtOAc); IR (KBr, cmÀ1
) m: 3373,
1645; 1H NMR (300 MHz, CDCl3): d = 12.27 (s, 1H), 10.26 (s, 1H), 7.38 (d,
J = 8.8 Hz, 1H), 6.28 (d, J = 8.8 Hz, 1H), 0.98 (s, 9H), 0.27 (s, 6H); 13C NMR
(75 MHz, CDCl3): d = 194.42, 158.60, 158.13, 137.73, 113.84, 113.55, 109.77,
25.56, 18.30, À4.40; HRMS m/z calcd for C13H19ClO3Si (M+): 286.0792, found:
286.0793. 5-Bromo-4-(t-butyldimethylsilyloxy)-2-hydroxybenzaldehyde (10):
yellow oil (73% yield); Rf = 0.58 (8:2 hexane:EtOAc); IR (KBr, cmÀ1
)
m
: 3406,
1651, 1618; 1H NMR (300 MHz, CDCl3): d = 11.19 (s, 1H), 9.65 (d, J = 0.4 Hz, 1H),
7.64 (s, 1H), 6.41 (s, 1H), 1.02 (s, 9H), 0.29 (s, 6H); 13C NMR (75 MHz, CDCl3):
14. Loriot, M.; Robin, P.; Brown, E. Tetrahedron 1984, 40, 2529.