Synthesis of a new class of spirophenanthrones

Article abstract of DOI:10.1055/s-0029-1217174

Using 5 mol% of proline as a recoverable catalyst, 9-phenanthrols react with formaldehyde at room temperature, through Mannich bases and 10-methylene-9-phenanthrone intermediates, to form a new class of spirophenanthrones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217174

LETTER
1501
Synthesis of a New Class of Spirophenanthrones
Synthesis of
a
N
ew
u
Class of
S
p
e
irophenanth
-
rone
s
song Wu, Shuang-zheng Lin, Ming-zong Li, Tian-pa You*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, P. R. of China
E-mail: ytp@ustc.edu.cn
Received 2 January 2009
O
S
Abstract: Using 5 mol% of proline as a recoverable catalyst, 9-
phenanthrols react with formaldehyde at room temperature, through
Mannich bases and 10-methylene-9-phenanthrone intermediates, to
form a new class of spirophenanthrones.
O
S
R
S
R
S
N
N
O
Key words: polymethoxyaromatics, Mannich bases, hetero Diels–
Alder reaction, 10-methylene-9-phenanthrone, dimerization
2a
+
O
Ar
Ar
O
O
Several groups of natural products with polymethoxyaro-
matic structure are known to have important biological ac-
tivities.1–4 Recently, we are interested in a new class of
polymethoxyaromatics 1 (Figure 1) with a spiro structure.
Herein we wish to report a new synthesis of these
spirophenanthrones in combination with an efficient one-
pot phenanthrol synthesis.
2b
2
O
O
3
4
O
OH
R
O
CH2X
X = NMe2 or OMe
R
O
R = (OMe)n, n = 1–3; OCH2O
R
Scheme 1
R
1
R
CHO
Br
(Ph3P)2NiCl2
OH
OH
Figure 1
R
Zn, DMF, 60 °C
R
Recently, Bilgic and Mohinder found that o-quinone me-
thide precursor reacted with 1,3-thiazine or substituted
styrenes via the Diels–Alder reaction to give chroman
derivatives 2a and 2b,5 On the other hand, 1,2-naphtho-
quinone-1-methide dimerized to form a spirodimer 3.6 We
also found that o-quinone methide 4 could be prepared
from o-dimethylaminomethylphenol or o-methoxymeth-
ylphenol (Scheme 1).7
– H2O
R
R
OH
Based on these previous reports, we present here a conve-
nient and efficient synthetic approach of spirophenan-
throne 1. In this approach, 9-phenanthrol 5 was used as a
precursor. Compound 5 was prepared from o-bromo-
benzaldehyde using the method developed by our group
(Scheme 2).8
5
Scheme 2 Synthesis of 9-phenanthrols
Mannich base 6, which proved to be very unstable. Elim-
ination of proline then produced the 10-methylene-9-
phenanthrone intermediate 7 which was highly reactive
and readily dimerized via a hetero Diels–Alder reaction
(Scheme 3).
Condensation of 5 with formaldehyde catalyzed by pro-
line at room temperature gave directly the target product
spirophenanthrone 1. The substrate 9-phenanthrol 5 first
underwent a Mannich reaction affording the expected
The Mannich reaction and the subsequent decomposition
of the Mannich base were both promoted by acids and the
Mannich reaction also required the participation of a sec-
ondary amine, thus a catalytic quantity of proline was
SYNLETT 2009, No. 9, pp 1501–1505
Advanced online publication: 13.05.2009
DOI: 10.1055/s-0029-1217174; Art ID: W00209ST
x
x.
x
x.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

1502
X.-s. Wu et al.
LETTER
used as the promoter which served both as a secondary
amine and an acidic catalysis. With this promoter, the en-
tire reaction could be completed within 2–4 hours at room
temperature and reasonable yields (60–85%) were ob-
tained. Moreover, the proline could be recovered expedi-
ently.
R
R
R
R
O
O
OH
R
R
L-proline
HCHO
1
5
For a better understanding of the scope and efficiency of
above reactions, various substituted 9-phenanthrols were
tested (Table 1).10 As shown in Table 1, when the substit-
uent was electron donating, moderate to good yield was
obtained (entries 1–5). Among these substrates,
2,3,4,5,6,7-hexamethoxyl-9-phenanthrol gave the highest
yield (85%, entry 1).When the substituent was electron
withdrawing, the yield decreased (entry 7). This was due
to the fact that the Mannich reaction occurred more readi-
ly with electron-rich aromatic rings. An unexpected result
was found from picen-13-ol substrate (entry 8), from
which no expected product was obtained. This might be
due to its highly steric hindrance.
R
R
R
R
OH
O
N
COOH
6
7
Scheme 3 Synthesis of spirophenanthrones
Table 1 Results of the Synthesis of the Dimers of 10-Methylene-9-phenanthrones9,10
Entry
Substrate
Product
Isolated yield (%)
OMe
OMe
OMe
OMe
MeO
MeO
O
O
OMe
OMe
OH
MeO
MeO
MeO
MeO
1
85
OMe
OMe
OMe
MeO
MeO
OMe
OMe
OMe
OMe
OMe
OMe
5a
1a
MeO
MeO
O
O
OH
2
82
MeO
MeO
OMe
OMe
OMe
OMe
OMe
5b
1b
OMe
O
O
O
O
O
O
OH
O
O
O
O
O
3
79
O
O
O
OMe
OMe
OMe
5c
1c
Synlett 2009, No. 9, 1501–1505 © Thieme Stuttgart · New York

LETTER
Synthesis of a New Class of Spirophenanthrones
1503
Table 1 Results of the Synthesis of the Dimers of 10-Methylene-9-phenanthrones9,10 (continued)
Entry
Substrate
Product
Isolated yield (%)
O
O
O
O
O
O
O
O
O
O
OH
4
65
O
O
O
O
5d
1d
Me
Me
Me
Me
O
O
OH
5
6
7
67
60
31
Me
Me
5e
1e
O
O
OH
5f
1f
F
F
F
F
O
O
OH
F
F
5g
1g
OH
8
no reaction
–
5h
10-Methylene-9-phenanthrone may react in either a dipo- Although the catalyst proline used in the reaction was
1
lar form (8) or a diradical form (9).6 In the H NMR sig- levorotatory, all products formed were racemic. A
nals of compound 1a–g, the methylene protons in the byproduct 10 could also been isolated, and its structure
dihydropyran ring appear as four trebles of doublets at d = was identified (Scheme 4). Presumably, this compound
2.1–3.2 ppm. This can support the [4+2] cycloaddition was formed by Michael addition of 9-phenanthrol to10-
process as the mode A and indicates a diradical methylene-9-phenanthrone.
mechanism6 (Figure 2).
Synlett 2009, No. 9, 1501–1505 © Thieme Stuttgart · New York

1504
X.-s. Wu et al.
LETTER
(2) (a) Xia, Y.; Yang, Z.-Y.; Xia, P.; Bastow, K. F.; Kuo, S.-C.;
Li, K.-H. J. Med. Chem. 1998, 41, 1155. (b) Freyer, A. J.;
Abu Zarga, M. H.; Firdous, S.; Shamma, M. J. Nat. Prod.
1987, 50, 684.
(3) (a) Gupta, S.; Das, L.; Datta, A. B.; Poddar, A.; Janik, M. E.;
Bhattacharrya, B. Biochemistry 2006, 45, 6467.
R
R
R
R
R
O–
O
O
+
CH2
CH2
CH2
R
(b) Charlton, J. L. J. Nat. Prod. 1998, 61, 1447.
8
9
7
(4) (a) Damu, A. G.; Kuo, P.-C.; Shi, L.-S.; Li, C.-Y.; Kuoh,
C.-S.; Wu, P.-L.; Wu, T.-S. J. Nat. Prod. 2005, 68, 1071.
(b) Wei, L.; Shi, Q.; Bastow, K. F.; Brossi, A.; Morris-
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Teng, C.-M.; Lee, K.-H. J. Med. Chem. 2007, 50, 3674.
(c) Stark, D.; Lykkeberg, A. K.; Christensen, J.; Budnik, B.
A.; Abe, F.; Jaroszewski, J. W. J. Nat. Prod. 2002, 65, 1299.
(5) Bilgic, S.; Bilgic, O.; Bueyuekkidan, B.; Guenduez, M.
J. Chem. Res. 2007, 2, 76.
R
R
O
O
O
R
R
CH2
R
R
C
R
H2
O
R
CH2
C
H2
B
A
(6) Chauhan, M. S.; Mckinon, D. M. Can. J. Chem. 1981, 59,
2223.
Figure 2
(7) (a) Weinert, E.; Dondi, R.; Colloredo-Melz, S.;
Frankenfield, K. N.; Mitchell, C. H.; Freccero, M.; Rokita,
S. E. J. Am. Chem. Soc. 2006, 128, 11940. (b) Gardner, P.
D.; Sarrafizadeh, H. R.; Brandon, R. L. J. Am. Chem. Soc.
1959, 81, 5515.
B–
R
OH
R
(8) (a) Lin, S.-Z.; Chen, Q.-A.; You, T.-P. Synlett 2007, 2101.
(b) Lin, S.-Z.; You, T.-P. Tetrahedron 2008, 64, 9906.
(9) Synthesis of the Dimer of 10-Methylene-9-
phenanthrones 1a–g – General Procedure
HO+
R
To a stirred suspension of the 9-phenanthrol (1 mmol) in
MeOH (10mL, 9d was in THF–MeOH = 4:1), L-proline (6
mg, 0.05 mmol) and 36% aq formaldehyde (0.1 mL, 1.2
mmol) were added. The mixture was stirred at r.t. for 2–4 h.
The reaction product was evaporated under vacuum. The
residue was purified by flash column chromatography on
SiO2, eluting with PE–EtOAc, to produce the dimer of 10-
methylene-9-phenanthrones.
R
R
O
R
R
OH
R
HO
HO
R
R
(10) Selective Spectroscopic Data of the Dimer of
10-Methylene-9-phenanthrones
R
R
10
Compound 1a: 1H NMR (300 MHz, CDCl3): d = 2.29 (m, 1
H), 2.54–2.60 (m, 2 H), 2.92 (m, 1 H), 3.72 (s, 3 H), 3.74 (s,
3 H), 3.77 (s, 3 H), 3.87 (s, 3 H), 3.89 (s, 3 H), 3.91 (s, 3 H),
3.96 (s, 6 H), 4.00 (s, 3 H), 4.02 (s, 3 H), 4.03 (s, 3 H), 4.06
(s, 3 H), 6.83 (s, 1 H), 7.11 (s, 1 H), 7.26 (s, 1 H), 7.68 (s, 1
H). 13C NMR (75 MHz, CDCl3): d = 20.6, 32.8, 55.9, 55.9,
56.1, 56.3, 61.0, 61.1, 61.1, 61.2, 61.2, 61.3, 61.4, 61.5, 83.1,
97.4, 98.0, 103.6, 105.2, 107.7, 113.1, 116.3, 117.7, 121.5,
123.1, 124.9, 132.4, 140.3, 142.3, 142.5, 146.7, 151.7,
151.8, 152.0, 152.2, 152.3, 152.4, 153.2, 153.6, 197.6.
HRMS–FAB: m/z [M + H]+ calcd for C42H44O14: 773.2809;
found: 773.2810. Anal. Calcd for C42H44O14: C, 65.28; H,
5.74; O, 28.98. Found: C, 65.41; H, 5.72; O, 28.92.
Compound 1b: 1H NMR (300 MHz, CDCl3): d = 2.27 (m, 1
H), 2.51 (m, 1 H), 2.82 (m, 1 H), 3.04 (m, 1 H), 3.83 (s, 3 H),
3.93 (s, 3 H), 3.96 (s, 3 H), 3.99 (s, 3 H), 4.00 (s, 3 H), 4.04
(s, 3 H), 4.10 (s, 3 H), 4.11 (s, 3 H), 4.14 (s, 3 H), 7.14 (s, 1
H), 7.24 (s, 1 H), 7.29 (s, 1 H), 7.36 (s, 1 H), 7.42 (s, 1 H),
7.52 (s, 1 H), 7.83 (m, 3 H). 13C NMR (75 MHz, CDCl3):
d = 19.6, 34.1, 55.8, 55.8, 56.0, 56.1, 56.2, 56.2, 56.3, 56.5,
82.3, 102.5, 103.1, 103.3, 103.9, 104.7, 106.9, 107.4, 108.7,
109.2, 119.7, 119.9, 121.5, 122.5, 124.6, 126.1, 131.6,
133.8, 146.6, 147.1, 148.7, 148.9, 149.0, 149.1, 149.2,
149.9, 154.5, 198.1. HRMS–FAB: m/z [M + H]+ calcd for
C38H36O10: 653.2387; found: 653.2389. Anal. Calcd for
C38H36O10: C, 69.93; H, 5.56; O, 24.51. Found: C, 69.77; H,
5.50; O, 24.60.
Scheme 4 Michael addition of 9-phenanthrol to10-methylene-9-
phenanthrone
In conclusion, using proline as a recoverable catalyst, we
have conveniently synthesized
a
new class of
spirophenanthrones from 9-phenanthrols. Further biolog-
ical activity testing of these compounds is in progress.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Project was supported by the National Natural Science Foundation
of China (No. 20472077). In addition, we thank the referees for very
valuable advice.
References and Notes
(1) (a) Choi, Y.-W.; Takamatsu, S.; Khan, S. I.; Srinivas, P. V.;
Ferreira, D.; Zhao, J. J. Nat. Prod. 2006, 69, 356. (b) Chen,
M.; Kilgore, N.; Lee, K.-H.; Chen, D.-F. J. Nat. Prod. 2006,
69, 1697.
Compound 1c: 1H NMR (300 MHz, CDCl3): d = 2.27 (m, 1
H), 2.54 (m, 1 H), 2.60 (m, 1 H), 2.91 (m, 1 H), 3.89 (s, 3 H),
3.94 (s, 3 H), 3.99 (s, 3 H), 4.02 (s, 3 H), 6.03 (d, 2 H), 6.14
Synlett 2009, No. 9, 1501–1505 © Thieme Stuttgart · New York

LETTER
(d, 2 H), 6.17 (d, 2 H), 6.21 (d, 2 H), 6.80 (s, 1 H), 7.12 (s, 1
Synthesis of a New Class of Spirophenanthrones
1505
22.3, 34.0, 83.2, 108.5, 122.2, 122.4, 122.8, 123.6, 124.0,
125.0, 126.0, 126.3, 126.8, 127.9, 128.1, 128.3, 129.4,
129.9, 130.1, 133.0, 136.0, 136.8, 137.2, 137.7, 138.2,
145.3, 198.1. HRMS–FAB: m/z [M + H]+ calcd for
C34H28O2: 469.2168; found: 469.2165. Anal. Calcd for
C34H28O2: C, 87.15; H, 6.02; O, 6.83. Found: C, 87.06; H,
5.98; O, 6.79.
H), 7.17 (s, 1 H), 7.70 (s, 1 H). 13C NMR (75 MHz, CDCl3):
d = 20.9, 33.9, 56.2, 56.3, 56.6, 56.7, 83.3, 97.4, 98.0, 101.2,
101.3, 101.8, 102.4, 102.8, 103.8, 106.1, 108.1, 115.1,
116.2, 117.9, 122.1, 123.4, 125.2, 132.6, 141.3, 142.3,
142.6, 145.0, 151.6, 151.8, 152.0, 152.2, 152.4, 152.5,
153.6, 154.2, 197.0. HRMS–FAB: m/z [M + H]+ calcd for
C38H28O14: 709.1557; found: 709.1554. Anal. Calcd for
C38H28O14: C, 64.41; H, 3.98; O, 31.61. Found: C, 64.19; H,
3.41; O, 31.55.
Compound 1f: 1H NMR (300 MHz, CDCl3): d = 2.28 (td, 1
H), 2.55 (d, 1 H), 2.80 (td, 1 H), 3.09 (d, 1 H), 7.25–7.89 (m,
13 H), 8.52 (d, 1 H), 8.68 (t, 2 H). 13C NMR (75 MHz,
CDCl3): d = 19.5, 33.8, 83.2, 108.5, 122.4, 122.5, 123.0,
123.3, 124.0, 124.6, 126.0, 126.7, 128.8, 129.6, 130.1,
130.7, 132.0, 134.8, 136.9, 140.1, 148.0, 198.6. HRMS–
FAB: m/z [M + H]+ calcd for C30H20O2: 413.1542; found:
413.1544. Anal. Calcd for C30H20O2: C, 87.36; H, 4.89; O,
7.76. Found: C, 86.92; H, 4.88; O, 7.73.
Compound 1d: 1H NMR (300 MHz, DMSO-d6): d = 2.24 (m,
1 H), 2.33 (m, 1 H), 2.68 (m, 1 H), 3.42 (m, 1 H), 5.92 (s, 1
H), 6.06 (s, 2 H), 6.08 (s, 1 H), 6.09 (s, 1 H), 6.10 (s, 1 H),
6.19 (s, 1 H), 6.24 (s, 1 H), 7.02 (d, 1 H), 7.12 (d, 1 H), 7.26
(d, 1 H), 7.28 (d, 1 H), 7.55 (d, 1 H), 7.58 (d, 1 H), 8.16 (s, 1
H), 8.19 (s, 1 H). 13C NMR (75 MHz, DMSO-d6): d = 20.0,
28.9, 80.2, 100.6, 101.1, 101.6, 108.8, 109.4, 111.8, 113.8,
116.4, 117.1, 117.4, 118.1, 120.0, 122.1, 124.1, 126.2,
129.7, 141.9, 144.9, 145.3, 145.7, 146.6, 147.9, 148.2,
193.7. HRMS–FAB: m/z [M + H]+ calcd for C34H20O10:
589.1135; found: 589.1136. Anal. Calcd for C34H20O10: C,
69.39; H, 3.43; O, 27.19. Found: C, 69.54; H, 3.52; O, 27.05.
Compound 1e: 1H NMR (300 MHz, CDCl3): d = 2.22 (m, 1
H), 2.46 (s, 3 H), 2.49 (m, 1 H), 2.52 (s, 3 H), 2.58 (s, 3 H),
2.63 (s, 3 H), 2.76 (m, 1 H), 3.01 (m, 1 H), 7.22 (m, 2 H),
7.38 (d, 1 H), 7.45 (d, 1 H), 7.65–7.83 (m, 5 H), 8.38 (m, 3
H). 13C NMR (75 MHz, CDCl3): d = 19.3, 21.4, 22.1, 22.2,
Compound 1g: 1H NMR (300 MHz, CDCl3): d = 2.26 (m, 1
H), 2.50 (m, 1 H), 2.76 (m, 1 H), 3.01 (m, 1 H), 7.17 (m, 2
H), 7.37 (m, 2 H), 7.55 (m, 2 H), 7.74–7.85 (m, 2 H), 7.97
(m, 1 H), 8.15 (m, 2 H), 8.44 (m, 1 H). 13C NMR (75 MHz,
CDCl3): d = 19.4, 33.9, 82.6, 102.2, 107.4, 107.9, 108.3,
108.6, 110.3, 110.6, 110.7, 111.5, 111.8, 115.8, 116.0,
116.2, 116.4, 116.7, 117.1, 117.4, 124.5, 124.6, 125.0,
125.1, 128.2, 128.3, 131.0, 131.1, 196.3. HRMS–FAB: m/z
[M + H]+ calcd for C30H16F4O2: 485.1165; found: 485.1169.
Anal. Calcd for C30H16F4O2: C, 74.38; H, 3.33; F, 15.69; O,
6.61. Found: C, 74.55; H, 3.39; F, 15.58; O, 6.66.
Synlett 2009, No. 9, 1501–1505 © Thieme Stuttgart · New York

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