JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
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3.33 (septet, 1H, CHMe2, J ¼ 7.0 Hz); 2.88–2.78 (m, A2B2 system, 4H,
2xH-9 and 2xH-10); 1.24 (d, 6H, CHMe2, J ¼ 7.0 Hz).
HRMS m/z (by using APCI-ESI ion source) 237.1272
[M þ H] þ (calcd. for C17H16O 237.1274).
13C NMR of 2-isopropyl-3-methoxy-9,10-dihydrophenanthrene
(9) (100 MHz, CDCl3) d 156.0 (C-5); 137.3 (s); 136.5 (s); 134.7 (s);
132.5 (s); 129.5 (s); 128.1 (d); 127.0 (d); 126.8 (d); 125.9 (d); 123.3
(d); 106.0 (d); 55.7 (OMe); 29.5 (C-9a); 28.3 (C-10a); 26.7 (CHMe2);
22.8 (CHMe2).
2-Isopropylphenanthren-3,4-dione (12)
To a solution of 11 (100 mg, 0.42 mmol) in CH2Cl2 (20 ml),
Dess–Martin periodinane (269 mg, 0.63 mmol) was added dropwise
at 0 ꢀC. The reaction mixture was stirred at rt for 12 h. After moni-
toring by TLC, the reaction mixture was washed with 1 M NaOH
solution (20 ml). The organic layer was separated and dried with
Na2SO4, and the solvent was removed under reduced pressure to
afford 2-isopropylphenanthren-3,4-dione (12) (64.1 mg, 61%) as a
red liquid. Rf ¼ 0.40 (1:4 EtOAc-hexanes).
1H NMR of 4-isopropyl-3-methoxy-9,10-dihydrophenanthrene
(9a) (400 MHz, CDCl3) d 7.49 (bd, 1H, H-5, J ¼ 7.7 Hz); 7.29–7.19 (m,
3H, H-6, H-7, H-8); 7.06 (d, 1H, H-1, J ¼ 8.2 Hz); 6.77 (d, 1H, H-2,
J ¼ 8.2 Hz); 3.85 (s, 3H, OMe); 3.70 (septet, 1H, CHMe2, J ¼ 7.0 Hz);
2.73–2.63 (m, A2B2 system, 4H, 2xH-9 and 2xH-10); 1.41 (d, 6H,
CHMe2, J ¼ 7.0 Hz).
1H NMR (400 MHz, CDCl3) d 9.37 (d, 1H, H-5, J ¼ 8.6 Hz); 8.08 (d,
1H, H-8, J ¼ 8.6 Hz); 7.80 (bd, 1H, H-10, J ¼ 8.2 Hz); 7.69 (ddd, quasi
bt, 1H, H-6 b, J ¼ 8.6 Hz, J ¼ 6.9 Hz, J ¼ 1.4 Hz); 7.52 (ddd, quasi bt,
1H, H-7 b, J ¼ 8.6 Hz, J ¼ 6.9 Hz, J ¼ 0.9 Hz); 7.35 (d,1H, H-9,
J ¼ 8.2 Hz); 7.18 (d, 1H, H-1, J ¼ 0.9 Hz); 3.07 (septet, 1H, CH(CH3)2,
J ¼ 6.9 Hz); 1.21 (d, 6H, CH(CH3)2, J ¼ 6.9 Hz).
2-isopropyl-3-methoxyphenanthrene (10)
To a solution of 9 (50 mg, 0.20 mmol) in toluene (2 ml), a solution
of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (49.5 mg,
0.22 mmol) in toluene (5 ml) was added. The reaction mixture was
refluxed for 24 h. After monitoring by TLC, the mixture was
allowed to reach rt and then the solvent was removed under
reduced pressure. The crude product was purified by TLC eluting
with hexane to yield 2-isopropyl-3-methoxyphenanthrene (10)
(21 mg, 42%) as a colourless liquid and 3-methoxy-2-(prop-1-en-2-
yl)phenanthrene (10a) (14 mg, 28%) as a colourless liquid.
13C NMR (100 MHz, CDCl3) d 182.3 (s); 181.5 (s); 146.9 (s); 139.7
(d); 137.5 (d); 134.3 (s); 132.5 (s); 131.3 (d); 129.1 (d); 127.7 (d);
127.1 (d); 126.9 (d); 125.0 (s); 27.4 (d); 21.7 (q).
HRMS m/z (by using APCI-ESI ion source) 251.1066
[M þ H] þ (calcd. for C17H14O2 251.1067).
1H NMR of 2-isopropyl-3-methoxyphenanthrene (10) (400 MHz,
CDCl3) d 8.60 (bd, 1H, H-5, J ¼ 8.1 Hz); 7.98 (s, 1H, H-1); 7.87 (d, 1H,
H-8, J ¼ 7.7 Hz); 7.69 (s, 1H, H-4); 7.68 (d, 1H, H-9a, J ¼ 8.8 Hz); 7.62
(bt, 1H, H-6 overlapped with H-10); 7.61 (d, 1H, H-10a, J ¼ 8.8 Hz);
7.56 (dt, 1H, H-7, J ¼ 7.7 Hz, J ¼ 1.1 Hz); 4.08 (s, 3H, OMe); 3.48 (sep-
tet, 1H, CHMe2, J ¼ 6.6 Hz); 1.35 (d, 6H, CHMe2, J ¼ 6.6 Hz).
Results and discussion
Synthesis
2-Isopropylphenol (17) was used as the starting material for the
preparation of 13. The synthesis of 19 with a sequence of 17 !
18 ! 19 was described in our previous study in two steps18.
Following our previous procedure, compound 17 was converted
to 19 by O-methylation followed by selective bromination with
CAN/LiBr. Preparation of benzyl bromide 23 from compound 19
was as described by Burnell and Caron24. Following this procedure
with a slight modification, we prepared compound 23. For this
purpose, treatment of compound 19 with CuCN provided benzoni-
trile 20 in 90% yield, which was then esterified with EtOH to give
ester 21 in the presence of H2SO4 (94% yield). Reduction of ester
21 using LiAlH4 gave alcohol 22 (81% yield). Treatment of this
alcohol with PBr3 afforded benzyl bromide 23 in 92% yield.
Phosphonium salt 16 was prepared from benzyl bromide 23 by
reaction with PPh3 and used in the next step without further puri-
fication. The Wittig reaction of 16 with 2-nitrobenzaldehyde (15)
resulted in an (E/Z) mixture of stilbene 14, which was then hydro-
genated on Pd-C to give aniline 13 in 86% overall yield in three
steps from 23 (Scheme 2).
The most important step in our synthetic strategy was the con-
version of amine 13 to tricyclic compound 9 via an intramolecular
Pschorr coupling reaction. The Pschorr reaction has been known
for over a century and proceeds through aryldiazonium salt of
biaryl to give tricyclic arenes25. In this context, Caronna et al. syn-
thesised 4-methoxy-9,10-dihydrophenanthrene via Pschorr cou-
pling26. By a similar approach, the intramolecular Pschorr reaction
of 13 gave the desirable compound 9 along with side product 9a
in a yield of 24% (9:9a ¼ 3:1). Thus, after diazotisation of 13, two
different ring closure reactions occurred at position a and position
b (Scheme 3). In this work, we suppose that amine 13 should give
a phenanthrene ring by a similar approach. Assignment of the
13C
NMR
of
2-isopropyl-3-methoxyphenanthrene
(10)
(100 MHz, CDCl3) d 156.6 (C-3); 138.3 (s); 132.1 (s); 129.8 (s); 129.5
(s); 128.6 (d); 126.7 (s); 126.6 (d); 126.1 (d); 125.9 (d); 125.7 (d);
124.4 (d); 122.4 (d); 101.8 (d); 55.5 (OMe); 27.1 (isopropyl CH);
22.8 (2xCH3).
1H NMR of 3-methoxy-2-(prop-1-en-2-yl)phenanthrene (10a)
(400 MHz, CDCl3) d 8.60 (d, 1H, H-5, J ¼ 8.4 Hz); 8.00 (s, 1H, H-1);
7.87 (d, 1H, H-8, J ¼ 7.7 Hz); 7.70 (s, 1H, H-4); 7.67 (d, 1H, H-9,
J ¼ 9.2 Hz); 7.63 (t, 1H, H-6 overlapped with H-10); 7.62 (d, 1H, H-
10, J ¼ 9.2 Hz); 7.58 (t, 1H, H-7, J ¼ 7.7 Hz); 5.26 (bs, 1H, C ¼ CH2);
5.22 (bs, 1H, C ¼ CH2); 4.07 (s, 3H, OMe); 2.22 (bs, 3H, ¼C-CH3).
2-Isopropylphenanthren-3-ol (11)
To a solution of 10 (100 mg, 0.40 mmol) in CH2Cl2 (30 ml), BBr3
(110 mg, 0.04 ml, 0.44 mmol) was added dropwise under N2 at
0 ꢀC. The reaction mixture was stirred at rt for 12 h; then MeOH
(10 ml) was added to the mixture and the solvent was removed
under reduced pressure. The crude product was dissolved in
EtOAc (30 ml) and washed with H2O (2 ꢁ 30 ml). The organic layer
was dried with Na2SO4 and removed under reduced pressure to
afford 2-isopropylphenanthren-3-ol (11) (88 mg, 93%) as a yellow
solid. Rf ¼ 0.70 (1:4 EtOAc-hexanes), Mp ¼141–143 ꢀC.
1H NMR (400 MHz, CDCl3) d 8.48 (d, 1H, H-5, J ¼ 7.6 Hz); 7.94 (s,
1H, H-1); 7.85 (bd, 1H, H-8, J ¼ 8.0 Hz); 7.70 (s, 1H, H-4); 7.67 (A
part of AB system, d, 1H, H-9, J ¼ 9.3 Hz); 7.59 (B part of AB system,
d, 1H, H-10, J ¼ 9.3 Hz); 7.59–7.52 (m, 2H, H-6 and H-7); 5.19 (s, 1H,
OH); 3.40 (septet, 1H, CH(CH3)2, J ¼ 7.0 Hz); 1.40 (d, 3H, CH3,
J ¼ 7.0 Hz); 1.39 (d, 3H, CH3, J ¼ 7.0 Hz).
1
13C NMR (100 MHz, CDCl3) d 152.5 (C-3); 136.0 (s); 132.0 (s);
129.7 (s); 129.4 (s); 128.5 (d); 127.0 (s); 126.6 (d); 126.2 (d); 126.2
structures of the two isomers was performed via H NMR analysis.
The 1H NMR spectrum of 9 displayed two singlets for the H-1
(d); 126.0 (d); 124.4 (d); 122.5 (d); 106.9 (d); 27.5 (CHMe2); 22.6 (d 7.23 ppm) and H-4 (d 7.01 ppm) protons. On the other hand, the
(2xCHMe2).
1H NMR spectrum of 9a displayed an AB system for H-1 and H-2