A Convenient One-Pot Method for the Construction of Tetrasubstituted Phenols through a Michael Addition-Aldol Cyclization Sequence

Article abstract of DOI:10.1021/jo9704669

The sodium salt of dimethyl 1,3-acetonedicarboxylate (1) readily reacts with certain alkynals under mild conditions in THF to give a tetrasubstituted aromatic ring with regiocontrol at the metaposition through a Michael addition-aldol cyclization sequence. Thus the reaction of I with propynal, 2-butynal, 2-pentynal, 2-octynal, 4-(benzoyloxy)-2-butynal, and 4-((tetrahydropyranyl)-oxy)-2-butynal at 25 °C gave the following products: dimethyl 2-hydroxybenzene-1,3-dicarboxylate (11percent), dimethyl 2-hydroxy-4-methylbenzene-1,3-dicarboxylate (45percent), dimethyl 4-ethyl-2-hydroxybenzene-1,3-dicarboxylate (46percent), dimethyl 2-hydroxy-4-pentylbenzene-1,3-dicarboxylate (42percent), dimethyl 2-hydroxy-4-((pivaloyloxy)methyl)benzene-1,3-dicarboxylate (88percent), dimethyl 2-hydroxy-4-((benzoyloxy)methyl)benzene-1,3-dicarboxylate (74percent), and dimethyl 2-hydroxy-4-(((tetrahydropyranyl)oxy)methyl)benzene-1,3-dicarboxylate (70percent).

Full text of DOI:10.1021/jo9704669

5
688
J . Org. Chem. 1997, 62, 5688-5689
A Con ven ien t On e-P ot Meth od for th e Con str u ction of
Tetr a su bstitu ted P h en ols th r ou gh a Mich a el Ad d ition -Ald ol
Cycliza tion Sequ en ce†
Adri a´ n Covarrubias-Z u´ n˜ iga* and Eduardo R ´ı os-Barrios
Instituto de Qu ı´ mica, Universidad Nacional Aut o´ noma de M e´ xico, Circuito Exterior,
Ciudad Universitaria, Coyoac a´ n 04510, M e´ xico
Received March 14, 1997X
The sodium salt of dimethyl 1,3-acetonedicarboxylate (1) readily reacts with certain alkynals under
mild conditions in THF to give a tetrasubstituted aromatic ring with regiocontrol at the meta-
position through a Michael addition-aldol cyclization sequence. Thus the reaction of I with
propynal, 2-butynal, 2-pentynal, 2-octynal, 4-(benzoyloxy)-2-butynal, and 4-((tetrahydropyranyl)-
oxy)-2-butynal at 25 °C gave the following products: dimethyl 2-hydroxybenzene-1,3-dicarboxylate
(11%), dimethyl 2-hydroxy-4-methylbenzene-1,3-dicarboxylate (45%), dimethyl 4-ethyl-2-hydroxy-
benzene-1,3-dicarboxylate (46%), dimethyl 2-hydroxy-4-pentylbenzene-1,3-dicarboxylate (42%),
dimethyl 2-hydroxy-4-((pivaloyloxy)methyl)benzene-1,3-dicarboxylate (88%), dimethyl 2-hydroxy-
4
-((benzoyloxy)methyl)benzene-1,3-dicarboxylate (74%), and dimethyl 2-hydroxy-4-(((tetrahydro-
pyranyl)oxy)methyl)benzene-1,3-dicarboxylate (70%).
In the present work, we describe an easy one-pot
Ta ble 1
t (°C)
synthesis of phenols, employing the dimethyl 1,3-acetone-
dicarboxylate anion (1) (formed with NaH in THF). We
have observed that anion 1 readily reacts with alkynals
under mild conditions to give tetrasubstituted aromatic
ring products (eq 1).
producta (yield, %)
no.
alkynal (R)
2a (H)
2b (Me)
2c (Et)
2d (CH2)4CH3
2e (CH2OPv)
2f (CH2OBz)
2g CH2OTHP)
1
2
3
4
5
6
7
-10
-10
25
25
25
3a (11)
3b (45)
3c (46)
3d (42)
3e (88)
3f (76)
3g (70)
2
25
25
a
Products were characterized by common spectroscopic tech-
niques (IR, 1H NMR, C NMR, MS). In addition, HRMS data
13
(EI) were obtained for products in entries 4-6.
Sch em e 1
We have found that this transformation is a general
one, and several â-substituted propynals can be converted
to the corresponding aromatic products (Table 1). The
reactions were carried out using 3 mmol of the dimethyl
1
,3-acetonedicarboxylate, 3.6 mmol of NaH, and 3 mmol
of the corresponding alkynal in THF (4 mL).
This reaction can be explained by a sequence of steps
1
2
involving Michael addition followed by aldol cyclization
3
through the enolate intermediates (Scheme 1). The
analogous reaction with alkynones has been described.4
The reactions afford phenols in moderate to high yields,
and only in the case of propynal as Michael acceptor, is
5
the yield low, probably due to anionic polymerization.
Exp er im en ta l Section
The supply of phenols is of significant importance in
synthetic chemistry, because numerous biologically ac-
All reactions were carried out under an argon atmosphere.
6
Tetrahydrofuran was freshly distilled over benzophenone-
sodium. Propynal, 2-butynal, and 2-pentynal were synthesized
from the commercially available alcohols by oxidation with the
tive and naturally occurring compounds have this moiety
in their framework.7 The simple, general, one-pot method
described here for the construction of the phenolic system
should be useful in the synthesis of these natural
products.
8
J ones reagent; 4-(benzoyloxy)-2-butynal and 4-(pivaloyloxy)-
2-butynal were synthesized from 2-butyn-1,4-diol by mono-
3
protection with BzCl and PvCl, respectively, and Et N in
9
,10
8
CH
2
Cl
2
followed by oxidation with the J ones reagent.
1
0
4
-((Tetrahydropyranyl)oxy)-2-butynal was obtained by oxida-
†
Contribution No. 1574 of the Instituto de Qu ´ı mica, UNAM.
Abstract published in Advance ACS Abstracts, J uly 1, 1997.
X
(
1) Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. React. 1959, 10,
(7) (a) Ghera, E.; Ben-David, Y. J . Org. Chem. 1988, 53, 2972-2979.
1
79-555.
(b) Itoh, Y.; Brossi, A.; Hame, E.; Lin, C. M. Helv. Chim. Acta 1988,
71, 1199-1209. (c) Ozaki, Y.; Mochida, K.; Kim, S. Chem. Pharm. Bull.
1987, 35, 1790-1795. (d) Ozaki, Y.; Kim, S. Ibid. 1989, 37, 304-307.
(e) Ozaki, Y.; Mochida, K.; Kim, S. J . Chem. Soc., Perkin Trans. 1 1989,
1219-1224.
(
(
(
2) Schaefer, J . P.; Bloomfield, J . J . Org. React. 1967, 15, 1-203.
3) Mukaiyama T. Org. React. 1982, 28, 203-331.
4) (a) Deuschel, W. Helv. Chim. Acta 1951, 34, 168-185. (b) Ried,
W.; K o¨ nig, E. Liebigs. Ann. 1972, 757, 153-169.
(
5) Morton, M. Anionic Polymerization, Principles and Practice;
Academic Press: New York, 1973.
6) Bamfield, P.; Gordon, P. F. Chem. Soc. Rev. 1984, 13, 441-488.
(8) Veliev, M. G.; Guseinov, M. M. Synthesis 1980, 461.
(9) Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 453-461.
(10) Frazer, M. M.; Raphael, R. A. J . Chem. Soc. 1955, 4280-4283.
(
S0022-3263(97)00466-0 CCC: $14.00 © 1997 American Chemical Society

One-Pot Construction of Tetrasubstituted Phenols
tion with MnO 11
J . Org. Chem., Vol. 62, No. 17, 1997 5689
+
2
in CH
2
Cl
2
; 2-octynal and dimethyl 1,3-
intensity) 224 (M , 36), 192 (100), 161 (96), 134 (93). Anal.
acetonedicarboxylate were purchased from Aldrich Inc.
Melting points are uncorrected. Thin-layer chromatography
was performed on silica gel 60 F254 plates and visualized by
Calcd for C11
5.41.
12 5
H O : C, 58.92; H, 5.35. Found: C, 59.03; H,
Dim eth yl 4-eth yl-2-h yd r oxyben zen e-1,3-d ica r boxyla te
1
UV irradation. H NMR spectra were recorded either at 200
-1 1
(
3c): yield 46%; oil; IR (neat) 3151, 1732, 1677, 1621 cm ; H
or 300 MHz, while 1 C NMR spectra were run at 75 MHz. Low-
and high-resolution mass spectra were measured at 70 eV (EI).
Elemental analyses were performed by Galbraith Laboratories,
Inc.; column chromatography was carried out using silica gel
3
NMR δ ppm 1.21 (t, J ) 7.6 Hz, 3H), 2.63 (q, J ) 7.6 Hz, 2H),
3
1
1
.94 (s, 6H), 6.78 (d, J ) 8.2 Hz, 1H), 7.80 (d, J ) 8.2 Hz, 1H),
13
1.12 (s, 1H); C NMR δ ppm 14.9, 27.1, 29.6, 52.24, 52.29,
10.4, 119.4, 130.9, 150.0, 158.6, 167.6, 170.1; MS (EI) m/ z
(70-230 mesh).
+
(relative intensity) 238 (M , 25), 206 (100), 175 (75), 148 (52).
Gen er a l P r oced u r e for th e P r ep a r a tion of Dim eth yl
Anal. Calcd for C12
H, 5.99.
Dim et h yl 2-h yd r oxy-4-p en t ylb en zen e-1,3-d ica r b ox-
14 5
H O : C, 60.50; H, 5.88. Found: C, 60.65;
2
-H yd r oxy 1,3-Dica r b oxyla t e Der iva t ives 3a -g. Di-
m eth yl 2-Hyd r oxy-4-((p iva loyloxy)m eth yl)ben zen e-1,3-
d ica r boxyla te (3e). Dimethyl 1,3-acetonedicarboxylate (97%;
yla te (3d ): yield 42%; oil; IR (neat) 3151, 1735, 1677, 1261
0
.4 g, 2.23 mmol) was added dropwise to a mixture of NaH
-1 1
cm ; H NMR δ ppm 0.86 (m, 3H), 1.28 (m, 4H), 1.6 (m, 2H),
(60%; 0.107 g, 2.67 mmol) in dry THF (4 mL) with magnetic
2
.58 (t, J ) 7.6, 1H), 3.91 (s, 3H), 3.92 (s, 3H), 6.74 (d, J ) 8.2
stirring. 4-(Pivaloyloxy)-2-butynal (0.38 g 2.26 mmol) was
added to the resulting solution. After 2 h, the mixture was
poured into dilute HCL (15 mL), the organic phase was
separated, and the aqueous phase was extracted with ethyl
acetate. The combined organic phase was washed with brine
13
Hz, 1H), 7.76 (d, J ) 8.2 Hz, 1H), 11.10 (s, 1H); C NMR δ
ppm 170.0, 167.6, 158.6, 148.8, 130.6, 122.9, 120.0, 110.3,
5
2.24, 52.13, 33.8, 31.5, 30.3, 22.2, 13.7; MS (EI) m/ z (relative
+
intensity) 280 (M , 26), 248 (100), 205 (99); HRMS calcd for
C
C
15
H
H
28
O
5
280.1311, found 280.1314. Anal. Calcd for
: C, 64.28; H, 7.14. Found: C, 64.59; H, 7.47.
(
15 mL), dried over anhydrous Na
residue was subjected to column chromatography. The phenol
e (88%, 0.63g) was eluted using 3% ethyl acetate in hexane:
2 4
SO , and concentrated. The
15
28
O
5
Dim eth yl 2-h yd r oxy-4-((ben zoyloxy)m eth yl)ben zen e-
,3-d ica r boxyla te (3f): yield 76%; oil; IR (neat) 3075, 1725,
678, 1266 cm ; H NMR δ ppm 3.87 (s, 3H), 4.97 (s, 3H),
.42 (s, 2H), 7.02 (d, J ) 8.1 Hz, 1H), 7.92 (d, J ) 8.1 Hz, 1
3
1
1
5
-1 1
mp 54-56 °C; IR (neat) 3147, 1730, 1683, 1156 cm ; H NMR
-
1
1
δ ppm 1.21 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H), 5.16 (s, 2H), 6.95
(
d, J ) 8.2 Hz, 1H), 7.90 (d, J ) 8.2, 1H), 11.29 (s, 1H); 13
C
1
3
H), 7.8-8.3 (m, 3H), 8.1-8.3 (m, 2H), 11.31 (s, 1H); C NMR
δ ppm 3.87 (s, 3H), 3.97 (s, 3H), 5.42 (s, 2H), 7.02 (d, J ) 4
Hz, 1H), 7.92 (d, J ) 4 Hz, 1H), 7.92 (d, J ) 4 Hz, 1H), 7.8-
NMR δ ppm 27.1, 38.8, 52.5, 52.6, 63.6, 112.3, 112.8, 118.69,
1
31.7, 142.3, 151.6, 159.1, 166.5, 169.7; MS (EI) m/ z (relative
+
intensity) 324 (M , 14), 292 (23), 208 (100), 207 (72); HRMS
calcd for C16 324.1209, found 324.1199. Anal. Calcd for
: C, 59.25; H, 6.17. Found: C, 58.87; H, 6.22.
A similar procedure was followed for the other substrates
Table 1). The physical constants and spectral data obtained
8
5
1
.3 (m, 3H), 8.1-8.3 (m, 2H), 11.31 (s, 1H); 13C NMR δ ppm
20 7
H O
2.6, 52.7, 113.0, 118.8, 121.6, 128.4, 129.5, 129.8, 130.1, 131.8,
16 20 7
C H O
33.3, 142.0, 159.2, 165.9, 166.9, 169.8; MS (EI) m/ z (relative
+
intensity) 344 (M , 7), 312 (13), 207 (27), 105 (100), HRMS
(
calcd for C18
: C, 62.79, H, 4.65. Found: C, 62.90; H, 4.27.
Dim et h yl 2-h yd r oxy-4-[((t et r a h yd r op yr a n -2-yl)oxy)-
m eth yl]ben zen e-1,3-d ica r boxyla te (3g): yield 70%; oil; IR
16 7
H O 344.0896, found 344.0907. Anal. Calcd for
for other phenols (entries 1-4 and 6-8) are summarized
below.
18 16 7
C H O
Dim eth yl 2-h yd r oxyben zen e-1,3-d ica r boxyla te (3a ):
1
2
yield 11%; mp 72 °C (lit. mp 70-71 °C); IR (KBr) 3441, 1728,
-1 1
-
1
13
(neat) 3138, 1733, 1678, 1263 cm ; H NMR δ ppm 1.45-1.98
1
1
614, 1262 cm
;
C NMR δ 20.1, 52.2, 52.3, 110.6, 121.0,
(
m, 6H), 3.45-3.60 (m, 1H), 3.80-3.95 (m, 1H), 3.93 (s, 3H),
30.9, 144.2, 158.8, 167.6, 170.1; MS (EI) m/ z (relative
+
3.95 (s, 3H), 4.57 and 4.82 (AB sys, J ) 13.6 Hz, 2H), 4.64 (t,
J ) 3.4 Hz, 1H), 7.01 (d, J ) 8.2 Hz), 7.87 (d, J ) 8.2 Hz),
1
6
intensity) 210 (M , 76), 178 (56), 147 (94), 120 (100). Anal.
Calcd for C10 : C, 57.56; H, 4.76. Found: C, 57.56; H,
.04.
Dim et h yl 2-h yd r oxy-4-m et h ylb en zen e-1,3-d ica r b ox-
10 5
H O
1.22 (s, 1H); 13C NMR δ ppm 19.1, 25.3, 30.2, 52.2, 52.4, 62.0,
6.4, 98.1, 112.1, 118.4, 121.3, 131.4, 144.8, 158.9, 166.9, 169.9;
5
+
MS (EI) m/ z (relative intensity) 324 (M , 2), 208 (69), 191
(100). Anal. Calcd for C16
C, 58.88; H, 6.24.
yla te (3b): yield 45%; mp 44-46 °C; IR (neat) 3138, 1735,
-
1
1
20 7
H O : C, 59.25; H, 6.17. Found:
1
3
1
1
676, 1265 cm ; H NMR δ ppm 2.31 (s, 3H), 3.90 (s, 3H),
.91 (s, 3H), 6.70 (d, J ) 8.7 Hz,1H), 7.73 (d, J ) 8.7 Hz, 1H),
1
3
1.11 (s, 1H); C NMR δ ppm 20.1, 52.2, 52.3, 110.6, 121.0,
23.0, 130.9, 144.2, 158.8, 167.6, 170.1; MS (EI) m/ z (relative
Ack n ow led gm en t. This research was supported by
a Grant-in-aid for scientific research No. 40361-5-3352E
from CONACYT, M e´ xico.
(
11) Goldman, I. M. J . Org. Chem. 1969, 34, 1979-1981.
(12) Barton, D. H. R.; Dressaire, G.; Willis, B. J .; Barrett, G. M.;
Pfeffer, M. J . Chem. Soc. Perkin Trans. 1 1982, 665-669.
J O9704669