Regioselective synthesis of functionalized 4-nitro- and 4-amino-phenols based on formal [3+3] cyclocondensations of 3-ethoxy-2-nitro-2-en-1-ones with 1,3-bis(silyloxy)-1,3-butadienes

Article abstract of DOI:10.1016/j.tetlet.2009.03.190

Functionalized 4-nitro- and 4-aminophenols were regioselectively prepared based on [3+3] cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-ethoxy-2-nitro-2-en-1-ones.

Full text of DOI:10.1016/j.tetlet.2009.03.190

Tetrahedron Letters 50 (2009) 3017–3019
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective synthesis of functionalized 4-nitro- and 4-amino-phenols
based on formal [3+3] cyclocondensations of 3-ethoxy-2-nitro-2-en-1-ones
with 1,3-bis(silyloxy)-1,3-butadienes
Abdolmajid Riahi a,b, Mohanad Shkoor a, Rasheed Ahmad Khera a, Helmut Reinke a, Peter Langer a,b,
*
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Functionalized 4-nitro- and 4-aminophenols were regioselectively prepared based on [3+3] cyclizations
of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-ethoxy-2-nitro-2-en-1-ones.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 7 February 2009
Revised 26 March 2009
Accepted 30 March 2009
Available online 2 April 2009
Keywords:
Aminophenols
arenes
Cyclizations
Regioselectivity
Silyl enol ethers
Functionalized 4-nitro- and 4-aminophenols are of considerable
pharmacological relevance and occur in several natural products.1
4-Nitrophenols show antiandrogenetic,2a vasodilative,2b and estro-
genic activities.2c A wide range of pharmacological activities have
been reported for functionalized 4-aminophenols and related mole-
cules.3–8 The synthesis of 4-nitrophenols by nitration of phenols
suffers from the low o/p-regioselectivity. In addition, several side-
reactions are possible for functionalized substrates, due to the harsh
reaction conditions. Hydroxy- and nitro-substituted biaryls have
been prepared by Ullmann-type reactions, by nucleophilic aromatic
substitutions9 and by nitrationof appropriate biphenyls.10 However,
the scope of these reactions is limited by the harsh reaction condi-
tions and by steric effects. The synthesis of 4-aminophenols and
amino-substituted biaryls by palladium(0)-catalyzed coupling
reactions11 suffers from the fact that electron-rich arenes, in partic-
ular sterically encumbered substrates, sometimes react sluggishly
or not at all. Last but not the least, the synthesis of the required start-
ing materials, highly functionalized or sterically encumbered 4-bro-
mo- or 4-iodophenols or 4-bromo- or 4-iodoanilines, can be a
difficult and tedious task.
based on [4+2] cycloadditions.12 Chan and Brownbridge were the
first to report13 the synthesis of salicylates by formal [3+3] cycliza-
tions of 1,3-bis(silyloxy)-1,3-butadienes14 with 3-silyloxy-2-en-1-
ones. This reaction has been extensively studied in recent years.15
Herein, we report, for the first time, a convenient synthesis of 4-ni-
tro- and 4-aminophenols based on formal [3+3] cyclizations of 1,3-
bis(trimethylsilyloxy)-1,3-butadienes with 3-ethoxy-2-nitro-2-en-
1-ones. The products reported herein are not readily available by
other methods.
Aryl phenolates 2a–c were prepared from aroyl chlorides 1a–c
according to the literature.16 The reaction of 2a–c with nitrometh-
ane, following a known procedure,17 gave the
a-nitroacetophenon-
es 3a–c (Scheme 1, Table 1). The reaction of the latter with triethyl
orthoformate and acetic anhydride afforded the 3-ethoxy-2-nitro-
2-en-1-ones 4a–c. 1,3-Bis(silyloxy)-1,3-butadienes 5a–e were pre-
pared as previously reported.13 The TiCl4-mediated cyclization of
4a with 5a afforded the 4-nitrophenol 6a with excellent regioselec-
tivity (Scheme 2). The best yield was obtained when the reaction
was carried out in a highly concentrated solution.18
The formation of 6a can be explained by reaction of 4a with
TiCl4 to give allylic cation A. The attack of the terminal carbon atom
of 5a onto A resulted in the formation of intermediate B (Scheme
2). The elimination of (methoxy)trimethylsilane (intermediate C)
and subsequent cyclization gave intermediate D. The elimination
of titanium hydroxide and aromatization resulted in the formation
of product 6a.
Our strategy to circumvent these problems is based on the
application of a ‘building block strategy’. Ashburn and co-workers
reported the synthesis of 2-nitro-20-alkoxycarbonyl-biphenyls
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.190

3018
A. Riahi et al. / Tetrahedron Letters 50 (2009) 3017–3019
Me3SiO OSiMe3
R2
O
O
i
O
OH
PhO
2a-c
Ar
O
R1
Cl
Ar
5a-e
R2
O
R1
1a-c
i
O
O2N
Ar
Ar
OEt
ii
+
NO2
6a-i
O
ii
O
O2N
iii
4a-c
Ar
OEt
4a-c
O2N
Ar
O
OH
R2
O
R1
3a-c
Ar
Scheme 1. Synthesis of 4a–c; (i) PhOH (1.0 equiv), 1a–c (1.03 equiv), 60 °C; (ii)
CH3NO2 (1.0 equiv), 2a–c (0.33 equiv), KOtBu (1.0 equiv), DMSO, 12 h, 0–10 °C; (iii)
3a–c (1.0 equiv), Ac2O (1.0 equiv), HC(OEt)3 (1.2 equiv), 120 °C, 6 h.
NH2
7a-i
Scheme 3. Synthesis of 6a–i and 7a–i; (i) TiCl4, CH2Cl2, ꢀ78 ? 20 °C, 18 h, (ii) H2,
Pd/C (10 mol %), 20 °C, 48 h.
Table 1
Synthesis of 6a–i and 7a–i
a
a
4
5
6,7
Ar
R1
R2
%
(6)
% (7)
a
a
a
a
a
b
b
c
a
b
c
d
e
a
b
a
b
a
b
c
d
e
f
g
h
i
Ph
Ph
Ph
Ph
Me
Me
Et
Me
Me
Me
Me
Me
Me
H
Me
Et
nBu
nOct
H
Me
H
56
57
65
58
62
68
72
56
70
86
85
95
92
90
91
89
88
90
Ph
2-MeC6H4
2-MeC6H4
2-ClC6H4
2-ClC6H4
c
Me
a
Yields of isolated products.
Me3SiO OSiMe3
O
OH
TiCl4
CH2Cl2
OMe
OMe
5a
EtO
O
_
Ph
78 to 20 °C
18 h
+
NO2
Ph
NO2
6a (56%)
4a
TiCl4
_
H2O
Figure 1. Crystal structure of 6a (50% probability level).
O
O
TiCl4
EtO
O
+
The yields of the products derived from dienes 5b–e, containing
a substituent located at carbon atom C-4, were higher than those
derived from 5a. The hydrogenation of 4-nitrophenols 6a–i, in
the presence of catalytic amounts of Pd/C (10 mol %), afforded 4-
aminophenols 7a–i in excellent yields (Scheme 3, Table 1).19
The structures of all compounds were established by spectro-
scopic methods. The structure of 6a was independently confirmed
by X-ray crystal structure analysis (Fig. 1).20
OMe
OTiCl3
Ph
Ph
NO2
NO2
A
D
5a
Me3SiCl
Me3SiCl
In conclusion, we have reported the regioselective synthesis of
functionalized 4-nitro- and 4-aminophenols based on [3+3] cyclo-
condensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-
ethoxy-2-nitro-2-en-1-ones.
O
O
Me3SiO
EtO
OMe
TiCl3
Me3SiO
OMe
TiCl4
Me3SiCl
O
O
Ph
Ph
Acknowledgment
Me3SiOEt
NO2
NO2
Financial support by the State of Mecklenburg-Vorpommern
(scholarship for M.S.) is gratefully acknowledged.
B
C
Scheme 2. Possible mechanism of the formation of 6a.
References and notes
1. Römpp Lexikon Naturstoffe; Steglich, W., Fugmann, B., Lang-Fugmann, S., Eds.;
Thieme: Stuttgart, 1997.
2. (a) Li, C.; Taneda, S.; Suzuki, A. K.; Furuta, C.; Watanabe, G.; Taya, K. Eur. J.
Pharmacol. 2006, 543, 194; (b) Yoki, K.; Kamata, K.; Toda, N.; Hayashi, H.;
The TiCl4-mediated cyclization of 3-ethoxy-2-nitro-2-en-1-ones
4a–c with 1,3-bis(trimethylsilyloxy)-1,3-butadienes 5a–e afforded
the 4-nitrophenols 6a–i in 56–72% yield (Scheme 3, Table 1).

A. Riahi et al. / Tetrahedron Letters 50 (2009) 3017–3019
15. Review: Feist, H.; Langer, P. Synthesis 2007, 327.
3019
Seki, K.-i.; Taneda, S.; Yoshino, S.; Sakushima, A.; Sakata, M.; Suzuki, A. K. Biol.
Pharm. Bull. 2003, 26, 394; (c) Bitsch, N.; Dudas, C.; Koerner, W.; Failing, K.; Biselli,
S.; Rimkus, G.; Brunn, H. Arch. Environ. Contam. Toxicol. 2002, 43, 257; (d) Api, A.
M.; Gudi, R. Mutat. Res. 2000, 464, 263; (e) Lehman-McKeeman, L. D.; Caudill, D.;
Vassallo, J. D.; Pearce, R. E.; Madan, A.; Parkinson, A. Toxicol. Lett. 1999, 111, 105.
3. (a) Nadin, L.; Murray, M. Biochem. Pharmacol. 1999, 58, 1201; (b) Fent, K.;
Escher, C.; Caminada, D. Reprod. Toxicol. 2006, 22, 175; (c) Khamdang, S.;
Takeda, M.; Noshiro, R.; Narikawa, S.; Enomoto, A.; Anzai, N.; Piyachaturawat,
P.; Endou, H. J. Pharmacol. Exp. Ther. 2002, 303, 534; (d) Gobec, S.; Brozic, P.;
Rizner, T. L. Bioorg. Med. Chem. Lett. 2005, 15, 5170; (e) Tran, T.; Saheba, E.;
Arcerio, A. V.; Chavez, V.; Li, Q.-y.; Martinez, L. E.; Primm, T. P. Bioorg. Med.
Chem. 2004, 12, 4809.
4. (a) Alvi, K. A.; Nair, B.; Gallo, C.; Baker, D. J. Antibiot. 1997, 50, 264; (b) de
Oliveira, M. F.; Oliveira, J. H. H. L.; Galetti, F. C. S.; de Souza, A. O.; Silva, C. L.;
Hajdu, E.; Peixinho, S.; Berlinck, R. G. S. Planta Med. 2006, 72, 437; (c) Lee, J.;
Chubb, A. J.; Moman, E.; McLoughlin, B. M.; Sharkey, C. T.; Kelly, J. G.; Nolan, K.
B.; Devocelle, M.; Fitzgerald, D. J. Org. Biomol. Chem. 2005, 3, 3678.
5. Alvi, K. A.; Diaz, M. C.; Crews, P.; Slate, D. L.; Lee, R. H.; Moretti, R. J. Org. Chem.
1992, 57, 6604.
16. Nakamatsu, S.; Yoshizawa, K.; Toyota, S.; Toda, F.; Matijasic, I. Org. Biomol.
Chem. 2003, 1, 13.
17. Field, G. F.; Zally, S. Synthesis 1979, 295.
18. General procedure for the synthesis of 4-nitrophenols 6a–i: To a CH2Cl2 solution
(2 mL/1 mmol of 4a–c) of 4a–c were added 5a–e (1.1 mmol) and,
subsequently, TiCl4 (1.1 mmol) at 78 °C. The temperature of the solution was
allowed to warm to 20 °C during 18 h with stirring. To the solution was added
hydrochloric acid (10%, 20 mL) and the organic and the aqueous layer were
separated. The latter was extracted with CH2Cl2 (3 ꢁ 20 mL). The combined
organic layers were dried (Na2SO4), filtered, and the filtrate was concentrated
in vacuo. The residue was purified by chromatography (silica gel, n-heptane /
EtOAc) to give 6a–i. Methyl 3-hydroxy-6-nitrobiphenyl-2-carboxylate (6a):
Reaction starting with 4a (331 mg, 1.5 mmol) and 5a (429 mg, 1.7 mmol), 6a
was isolated after chromatography (silica gel, heptanes/EtOAc) as a yellowish
solid (230 mg, 56%), mp = 137/138 °C. 1H NMR (300 MHz, CDCl3): d 3.35 (S, 3 H,
OCH3), 7.02 (d, 3J = 9.0 HZ, 1 H, CHAr), 7.07–7.10 (m, 2 H, CHPh), 7.27–7.31 (m, 3
H, CHPh), 7.82 (d, 3J = 8.9 HZ, 1H, CHAr), 11.07 (S, 1 H, OH). 13C NMR (CDCl3,
75 MHz): d = 52.5 (OCH3), 113.6 (CCOOCH3), 117.7, 127.7, 127.7, 127.7, 127.8,
127.8, 128.5 (CHAr), 133.7, 136.2, 139.0 (CAr), 163.8 (COH), 170.2 (CO). IR (KBr,
6. Ismail, L. D.; Lorenz, P.; Stermitz, F. J. Nat. Prod. 1998, 61, 1174.
7. (a) Davies, J.; Wang, H.; Taylor, T.; Warabi, K.; Huang, X.-H.; Andersen, R. J. Org.
Lett. 2005, 7, 5233; (b) Thale, Z.; Johnson, T.; Tenney, K.; Wenzel, P. J.;
Lobkovsky, E.; Clardy, J.; Media, J.; Pietraszkiewicz, H.; Valeriote, F. A.; Crews, P.
J. Org. Chem. 2002, 67, 9384.
cmꢀ1):
m~ = 3086 (w), 3062 (w), 2954 (w), 1735 (w), 1670 (m), 1599 (w), 1576
(w), 1525 (m), 1501 (w), 1442 (m), 1324 (m), 1220 (m), 1156 (w), 1132 (m),
1095 (w), 1074 (w), 1026 (w), 970 (w), 907 (m), 837 (w), 813 (w), 769 (w), 727
(s), 698 (m), 672 (m), 648 (w), 584 (w), 553. GC–MS (EI, 70 eV): m/z (%) = 273
([M]+, 80), 242 (17), 241 (100), 224 (15), 213 (25), 212 (13), 196 (14), 185 (18),
184 (11), 183 (13), 159 (16), 157 (11), 155 (20), 140 (15), 139 (66), 138 (10),
129 (25), 128 (14), 127 (19), 115 (10), 113 (10), 102 (10), 77 (12), 63 (11).
HRMS (EI): calcd for C14H11O5N ([M]+): 273.06317; found: 273.063020.
19. General procedure for the synthesis of 4-aminophenols 7a–i. To a MeOH
suspension (25 mL) (EtOH in case of 7c) of Pd/C (10 mol %) were added 6a–i
(1.0 equiv). The mixture was set under a hydrogen atmosphere. After stirring
for 48 h at 20 °C, the reaction mixture was filtered (Celite) and the filtrate was
concentrated in vacuo. The residue was purified by chromatography (silica gel,
8. (a) Werbel, L. M.; Cook, P. D.; Elslager, E. F.; Hung, J. H.; Johnson, J. L. J. Med.
Chem. 1986, 29, 924; (b) Take, K.; Okumura, K.; Takimoto, K.; Kato, M.; Ohtsuka,
M.; Shiokawa, Y. Chem. Pharm. Bull. 1991, 39, 2915; (c) Astles, P. C.; Brown, T. J.;
Cox, P.; Halley, F.; Lockey, P. M. Bioorg. Med. Chem. Lett. 1997, 7, 907; (d) Ukita,
T.; Nakamura, Y.; Kubo, A.; Yamamoto, Y.; Takahashi, M. J. Med. Chem. 1999, 42,
1293; (e) Sun, L.; Tran, N.; Liang, C.; Tang, F.; Rice, A.; Schreck, R.; Waltz, K.;
Shawver, L. K.; McMahon, G.; Tang, C. J. Med. Chem. 1999, 42, 5120; (f) Poupart,
M.-A.; Cameron, D. R.; Chabot, C.; Ghiro, E.; Goudreau, N.; Goulet, S.; Poirier,
M.; Tsantrizos, Y. S. J. Org. Chem. 2001, 66, 4743; (g) Parikh, V.; Welch, W. M.;
Schmidt, A. W. Bioorg. Med. Chem. Lett. 2003, 13, 269; (h) Wang, L.; Wang, G. T.;
Wang, X.; Tong, Y.; Sullivan, G.; Park, D.; Leonard, N. M.; Li, Q.; Cohen, J.; Gu,
W.-Z.; Zhang, H. J. Med. Chem. 2004, 47, 612; (i) Sheppard, G. S.; Kawai, M.;
Craig, R. A.; Davidson, D. J.; Majest, S. M.; Bell, R. L.; Henkin, J. Bioorg. Med. Chem.
Lett. 2004, 14, 965; (j) Mor, M.; Rivara, S.; Lodola, A.; Plazzi, P. V.; Tarzia, G.;
Duranti, A.; Tontini, A.; Piersanti, G.; Kathuria, S.; Piomelli, D. J. Med. Chem.
2004, 47, 4998; (k) Hayakawa, I.; Shioya, R.; Agatsuma, T.; Furukawa, H.;
Naruto, S.; Sugano, Y. Bioorg. Med. Chem. Lett. 2004, 14, 4383.
9. (a) Poesche, W. H. J. Chem. Soc. C 1966, 890; (b) Forrest, J. J. Chem. Soc. 1960,
589; (c) Helmchen, G.; Prelog, V. Helv. Chim. Acta 1972, 55, 2599; (d) Suzuki, H.;
Enya, T.; Hisamatsu, Y. Synthesis 1997, 1273; (e) Bell, A. J.; Read, R. W. Aust. J.
Chem. 1987, 40, 1813.
10. (a) Kleppinger, R.; Lillya, C. P.; Yang, C. J. Am. Chem. Soc. 1997, 119, 4097; (b)
Mohanakrishnan, A. K.; Srinivasan, P. C. J. Org. Chem. 1995, 60, 1939.
11. Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004.
heptanes
heptanes/EtOAc = 2:1).
Methyl
6-amino-3-hydroxybiphenyl-2-
carboxylate (7a): Starting with 6a (130 mg, 0.475 mmol), 7a was isolated
(99 mg, 86%) by column chromatography (silica gel, heptanes/
EtOAc = 30:1 ? 20:1) as a yellowish solid, mp = 95–97 °C. 1H NMR (300 MHz,
CDCl3): d 3.02 (br, 2 H, NH2), 3.30 (s, 3 H, OCH3), 6.82–6.84 (m, 2 H, CHAr), 7.08–
7.11 (m, 2 H, CHPh), 7.22–7.35 (m, 3 H, CHPh), 10.07 (br, 1 H, OH). 13C NMR
(CDCl3, 75 MHz): d = 51.6 (OCH3), 112.5 (CCOOCH3), 117.7, 123.1, 127.0, (CHAr),
127.5 (CAr), 128.5 (2 ꢁ CHAr), 128.9 (2 ꢁ CHAr), 136.9, 139.1 (CAr), 154.7 (COH),
~
171.3 (CO). IR (KBr, cmꢀ1):
m = 3742 (w), 3060 (w), 2922 (w), 2788 (w), 2671
(w), 1721 (s), 1586 (m), 1488 (m), 1455 (m), 1433 (m), 1348 (m), 1302 (m),
1277 (s), 1239 (m), 1217 (s), 1158 (m), 1110 (m), 1087 (m), 1029 (w), 982 (m),
949 (m), 911 (m), 871 (m), 807 (m), 776 (m), 750 (m), 730 (m), 719 (s), 698 (s),
646 (m), 613 (m), 549 (m). GC–MS (EI, 70 eV): m/z (%) = 243 ([M]+, 32), 212
(16), 211 (100), 183 (24), 155 (15), 154 (67), 128 (16), 127 (10), 77 (10). HRMS
(EI): calcd for C14H13O3N ([M]+): 243.08899; found: 243.089209.
20. CCDC-720054 contains all crystallographic details of this publication and is
available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge Crystallographic Data Centre,
12 Union Road, GB-Cambridge CB21EZ; Fax: (+44)1223-336-033; or
deposit@ccdc.cam.ac.uk.
12. Ashburn, B. O.; Carter, R. G.; Zakharov, L. N. J. Am. Chem. Soc. 2007, 129, 9109.
13. Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102, 3534.
14. For a review of 1,3-bis(silyloxy)-1,3-butadienes, see: Langer, P. Synthesis 2002,
441.