# Synthesis of Benzo[b]fluorenone Nuclei of Stealthins

Authors: Sujit Kumar Ghorai; Saroj Ranjan De; Raju Karmakar; Nirmal Kumar Hazra; Dipakranjan Mal
Journal: Research Letters in Organic Chemistry
 (2009)

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## Abstract

Two routes, one based on a Michael-initiated aldol condensation and the other on an intramoleculer carbonyl-ene reaction, have been found to be feasible for an entry to benzo[b]fluorenones. Reaction of 4,9-dimethoxybenz[f]indenone with nitromethane in the presence of DBU gave the corresponding Michael adduct, which afforded 2-methyl-5,10-dimethoxybenzo[b]fluorenone on reaction with methacrolein under a variety of basic conditions. Similarly, 2-methallyl-4,9-dimethoxybenz[f]indenone reacted with nitromethane to give the corresponding Michael adduct, Nef reaction of which furnished 3-formyl-2-methyl-4,9-dimethoxybenz[f]indanone. This underwent ene-cyclization under the influence of SnCl4. 5H2O, and yielded 2-methyl-5,10-dimethoxybenzo[b]fluorenone.


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## Body

## 1. Introduction

Stealthins A (1a) and B (1b), isolated
from Streptomyces viridochromogenes as potent radical scavengers, are the first  known members of natural benzo[b]fluorenones [1]. Interest in this
group of compounds grew considerably due to the identification of structurally
allied natural products, stealthin C (1c)
[2], kinafluorenone (2) [3],
prekinamycin (3) [4], and kinamycin
antibiotics (e.g., kinamycin D, 4)
[5] (Figure 1). Their synthesis became an active area of research since 1996
[6–19]. In line with the Ishikawa approach [19], we intended to explore the
chemistry of benz[f]indenones (e.g., 5b) to establish new synthetic routes
to functionalized benzo[b]fluorenones
[20]. Herein, we report regiospecific construction of the D-ring of benzo[b]fluorenones (e.g., 6) from the corresponding
benz[f]indenones.
Figure 1
Naturally occurring
benzo[b]fluorenones.


## 2. Results and Discussion

Initial studies were focused on the
utilization of the readily accessible
benz[f]indenones 5a and 5b [21]. DBU-promoted Michael addition of nitromethane to the
indenones furnished indenones 7a and 7b, respectively. The intended
annulation of 7b with methacrolein
was then studied with different base-solvent systems (Scheme 1). But, none of
the attempts gave desired product 8.
Instead, most of the methods produced
benzo[b]fluorenone 6 in low yields. The best yield was
25%, which was obtained with DBU in benzene. The presence of singlet at δ 2.23 for
Ar-CH3 in H1 NMR spectrum was indicative of the structure 6. It is probable that the compound 6 was formed from tetracycle 8 through elimination of HNO2.
Considering the fact that even a weak base such as n-Bu3P caused the elimination of NO2 group, we examined the route (Scheme 2), involving an acid-catalyzed
cyclization. The d4 Synthon equivalent 9 was prepared in two steps from methacrolein by adaptation of Miyakoshi
protocol [22] (Scheme 2). Conjugate
addition of the reagent 9 to
benz[f]indenone 5b in the presence of DBU provided 10 in good yield. H1 NMR spectrum of the product
indicated the formation of a 1:1 mixture of diastereomers. When treated with 1 N HCl, the
mixture afforded the expected product 8 in
trace amount, the major product being 6 (25%). Repeated attempts to optimize the transformation of 10 into 8 were of no
avail.
Scheme 1
Michael-aldol sequence.Scheme 2
Michael-aldol sequence.As an alternative avenue, the strategy
(Scheme3) based upon the
intramolecular carbonyl-ene reaction [23] of 11 was undertaken. Preparation of the key precursor 11 is depicted in Scheme 3. LDA-promoted allylation of 12 [21] with allyl bromide 13a furnished 14a. Characteristic multiplets at δ 5.6 and
two doublets at δ 5.1 and δ 4.87 in H1
NMR spectrum were in complete agreement with the structure 14a. The cis-relationship
between the angular allyl group and the methano bridge was inferred by comparing
the NMR signals of C-4a H of an angularly methylated analog [24].   Flash
vacuum pyrolysis (FVP) of the adduct 14a at 475°C/0.01 mm gave enone 5c in sufficiently pure form for the next use. It was then subjected to conjugate
addition with nitromethane in the presence of DBU to produce allylated nitro
adduct 15a as a single isomer in 92%
yield (Scheme 3). Similarly, precursor 15b was obtained in three steps from 12. Methallylation of 12 with methallyl iodide 13b in the presence of LDA gave 14b  (91%), FVP of which furnished 5d. Addition of nitromethane to 5d in the presence of DBU-furnished
intermediate 15b in 80% yield. Nef
reaction [25] of 15b with NaOMe and
TiCl3-buffer provided aldehyde 11 in moderate yield (50%). The singlet at δ 9.94 in H1
NMR spectrum and the band at 1718 cm−1 in IR spectrum confirmed the
presence of CHO functionality in 11.
When a solution of the aldehyde in dichloromethane was treated with SnCl4⋅ 5H2O
[26], D-ring aromatized compound 6 was formed in 45% yield.
Scheme 3
Intramolecular carbonyl-ene approach.


## 3. Conclusion

We have validated two synthetic
routes to benzo[b]fluoren-11-ones from benz[f]indenones 5. The intramolecular carbonyl-ene
reaction of the intermediate 11
(Scheme 3) proved to be better pathway
than the tandem Michael-aldol route (Scheme 2) to benzo[b]fluoren-11-one 6.


## 4. Experimental

The general
experimental is described in [27].Benz(f)inden-1-One 5c
This compound was prepared from14a.
Mp:
80–85°C; yellow; yield 93%; IR (cm−1): 1684; H1 NMR
(200 MHz), 8.20 (d, 1H, J = 8.1),
7.97 (d, 1H, J = 8.1), 7.57–7.41 (m,
3H), 6.01–5.88 (m, 1H), 5.23–5.12 (m, 2H),
4.28 (s, 3H), 4.02 (s, 3H), 3.11–3.07 (m, 2H); C13 NMR
(50 MHz): 193.99, 152.2, 144.6, 141.5, 139.8, 134.5, 132.9, 131.1, 129.4,
127.1, 126.2, 125.7, 123.0, 117.1, 115.5, 62.8, 62.7, 29.5; MS (m/z): 280 (M+,
100%), 265, 250, 223, 178, 165.Benz(f)inden-1-One 5d
This compound was prepared as a yellow oil in 90% yield from14b. IR (cm−1): 1689; H1 NMR (300 MHz): 8.10 (d, 1H, J = 8.1), 7.97 (d,
1H, J = 8.1), 7.60–7.40 (m, 3H), 4.85
(d, 2H, J = 10.8),  4.28 (s, 3H), 4.02 (s, 3H), 3.04 (s, 2H),
1.79 (s, 3H); C13 NMR (75 MHz): 192.9, 152.0, 144.5, 142.6, 140.9,
140.4, 132.7, 131.0, 129.3, 127.0, 126.0, 125.6, 122.9, 115.3, 112.5, 62.9,
62.7, 33.3, 22.5; MS (m/z): 294 (M+, 100%), 279, 263, 236, 165, 152, 139.Benzo(b)fluorenone 6: Method A
To a stirred
solution of the nitro compound7a (100 mg, 0.33 mmol), and methacrolein
(60 mg, 0.86 mmol) in benzene (5 mL) at 0°C was added  DBU (10 mg,
0.066 mmol). Stirring was continued for 24 hours at rt. The reaction mixture was diluted with
diethyl ether (50 mL), washed with saturated sodium bicarbonate solution (10 mL) and then with brine (10 mL). The organic phase was dried (Na2SO4)
and concentrated. The resulting residue was purified by preparative TLC to give
a yellow crystalline solid of 6 (26 mg, 25%).Method B
To a stirred solution of aldehyde11 (50 mg, 0.154 mmol) in
dichloromethane (6 mL) was added  SnCl4⋅5H2O (5 mg) under nitrogen atmosphere. The stirring was
continued for 30 hours. After usual work up of the reaction mixture, the
residue was purified by preparative TLC to provide 6 (21 mg, 45%). Mp:
150-151°C; IR (cm−1): 1695; H1 NMR (200 MHz):
8.29 (d, 1H, J = 7.4), 8.04 (d, 1H, J = 7.4), 7.88 (d, 1H, J = 7.7), 7.65–7.36 (m, 4H), 4.28 (s,
3H), 4.00 (s, 3H), 2.42 (s, 3H); C13 NMR (50 MHz): 190.4,
153.7, 146.4, 140.0, 138.8, 136.4, 135.4, 133.6, 130.8, 129.4, 127.8, 126.7,
125.5, 124.4, 124.1, 122.4, 119.9, 63.1, 61.1, 21.3; MS (m/z): 304 (M+, 100%),
289, 218, 189, 149, 57.Compound7a
This was
prepared from  benzindenone5a and nitromethane in 89% yield according to the procedure described
earlier [25]. Mp: 124°C; IR (cm−1): 1711; H1
NMR (200 MHz): 8.37 (s, 1H, ArH) 8.03 (d, 1H, J = 8.1), 7.89–7.87 (m, 2H), 7.68–7.54 (m, 2H), 4.91–4.82 (ABq,
1H, J = 12.8, 5.8), 4.64–4.53 (ABq,
1H, J = 12.8, 5.8), 4.42–4.34 (m,
1H), 3.21–3.07 (ABq, 1H, J = 19.2,
8.2), 2.74–2.63 (ABq, 1H, J = 19.2, 3.9).Compound7b
This was prepared from5b,
following the procedure described for compound 7a. Mp: 179-180°C; white solid; yield: 89%;
IR (cm−1): 1715; H1 NMR (200 MHz): 8.40 (d, 1H, J = 8.2), 8.10 (d, 1H, J = 8.5), 7.74–7.55 (m, 2H), 5.34–5.29
(m, 1H), 4.43–4.38 (m, 2H), 4.18 (s, 3H), 4.03 (s, 3H) 3.17–3.04 (m, 1H),
2.76–2.65 (m, 1H); C13 NMR (50 MHz):
200.4, 152.9, 148.6, 134.1, 132.7, 129.7, 126.9, 125.3, 122.7, 121.8, 77.8,
77.2, 63.4, 61.8, 42.3, 34.4; MS (m/z): 301 (M+), 254, 239, 197, 141, 115.Compound8
To a mixture of enone5b (0.178 g,
0.740 mmol) and 1,1-ethanediyldioxy-2-methyl-4-nitrobutane 9 (0.389 g,  2.22 mmol) in CH2Cl2 (4 mL) was added  DBU (12 mg, 0.078 mmol)
and the mixture was stirred at rt for 6 hours. It was then
concentrated and purified by column chromatography to
afford 10 as an oil (0.2 g, 65%). H1
NMR spectrum revealed the presence of two isomers as indicated by three signals
δ 4.15, 4.08, and 4.05, corresponding to the methoxy groups. The peak at δ 4.15
was not resolved.
The methine hydrogens of CHNO2 appeared at δ 5.19. To a stirred
solution of above nitro acetal 10 (100 mg, 0.24 mmol) in THF (8 mL) was
added 10% HCl (1 mL) solution. Stirring was continued for 20 hours. After usual
work up of the reaction mixture, the
residue was chromatographed to
afford 6 (18 mg, 25%) and 8 (2.5 mg, 3%).Compound9
Yield:
50%; colorless oil; IR (cm−1):
1541; H1 NMR (200 MHz): 4.66 (d, 1H, J = 4), 4.46 (t, 2H, J = 6), 3.98–3.79 (m, 4H), 2.30–1.77
(m, 3H), 1.00 (d, 3H, J = 6.7); C13 NMR (50 MHz): 106.8, 74.1, 65.1, 65.0, 34.3, 29.0, 14.7.Compound11
This was
prepared from compound15b by Nef reaction [25]. Yield: 50%; purity > 80%; H1
NMR (500 MHz): 9.94 (s, 1H), 8.40 (d, 1H, J = 8.4), 8.10 (d, 1H, J = 8.4), 7.69
(t, 1H, J = 8.2), 7.52 (t, 1H, J = 8.2), 4.87 (s, 1H), 4.78 (s, 2H),
4.21 (s, 3H), 4.16 (brs, 1H), 4.02 (s, 3H) 3.31–3.27 (m, 1H); 2.78–2.75 (ABq,
1H, J = 14.0, 4.3) 1.75 (s, 3H).Compound12
H1 NMR (200 MHz): 8.37
(d, 1H, J = 8.0, 1H), 8.05 (d, 1H, J = 8.0, 1H), 7.68–7.51 (m, 2H), 6.85
(brs, 1 H), 4.80–4.60 (m, 1H), 4.32 (s, 3H), 3.70 (s, 3H), 2.85 (brs, 1H),
2.22–2.15 (m, 1H), 1.5-1.4 (m, 2H), 1.25–1.21 (m, 3H).Compound14a
This
was prepared as thick brownish oil in 88% yield from pentacycle12, following an earlier method [24]. IR (cm−1): 1705; H1
NMR (300 MHz): 8.33 (d, 1H, J = 8.7),
8.06 (d, 1H, J = 8.4), 7.61 (m, 1H),
7.49 (m, 1H), 6.05–6.02 (m, 1H), 5.65–5.50 (m, 2H), 5.07 (d, 1H, J = 16.8), 4.85 (d, 1H, J = 10.2), 4.08 (s, 3H), 4.03 (s, 3H),
3.78 (d, 1H, J = 4.2), 3.45 (brs,
1H), 2.89–2.91 (m, 2H), 2.45–2.38 (m, 1H), 2.0 (ABd, 1H, J = 8.7), 1.80 (ABd, 1H, J = 8.7); C13 NMR (75 MHz): 207.1, 151.2, 147.6, 138.0, 135.2, 135.1, 134.3, 132.4,
128.9, 126.6, 125.8, 125.0, 121.8, 117.5, 63.0, 62.4, 62.1, 50.8, 50.9, 47.0,
46.6, 41.6.Compound14b
This was prepared from pentacycle12, following the
procedure adopted for compound 14a. Yield: 89%; thick
oil; IR (cm−1): 1705; H1
NMR (400 MHz): 8.32 (d, 1H, J = 8.1),
8.07 (d, 1H, J = 8.1), 7.62 (br t,
1H), 7.49 (br t, 1H), 6.00 (dd, 1H, J = 2.8, 5.6), 5.49 (dd, 1H, J = 2.8,
5.6), 4.70 (brs, 1H), 4.66 (brs, 1H), 4.08 (s, 3H), 4.03 (s, 3H), 3.93 (d, 1H, J = 4), 3.44 (brs, 1H), 3.05 (ABd, 1H, J = 13.8), 2.94 (brs, 1H), 2.41 (ABd,
1H, J = 13.8), 1.98 (ABd, 1H, J = 8.8), 1.79 (ABd, 1H, J = 8.8), 1.46 (s, 3H); C13
NMR (50 MHz): 207.4, 151.0, 147.6, 143.1, 138.3, 135.5, 135.3, 134.6, 132.3,
128.8, 126.7, 125.8, 125.0, 121.8, 114.3, 62.8, 61.8, 61.6, 52.5, 50.8, 46.8,
46.1, 45.7, 23.8.Compound15a
This
was prepared from5c,
following the procedure described for compound 7a. Mp:
98-99°C; white solid; yield:
92%; IR (cm−1): 1712; H1 NMR (300 MHz): 8.40 (d, 1H, J = 8.7), 8.10 (d,
1H, J = 8.4), 7.72–7.66 (m, 1H), 7.58
(m, 1H), 5.75–5.61 (m, 1H),  5.23–5.04 (m, 3H), 4.54–4.47 (m, 1H), 4.20 (s, 3H), 4.10 4.05 (m, 1H), 4.01 (s,
3H), 2.83–2.78 (m, 1H); 2.65–2.51 (m, 2H); C13 NMR
(75 MHz): 202.7, 153.1, 148.7, 133.8, 133.3, 133.0, 129.8, 127.0, 125.4, 122.3,
121.9, 118.8, 77.7, 77.3, 63.4, 61.8, 52.2, 39.4, 36.1; MS (m/z): 341 (M+),
307, 290, 280 (100%), 265, 165.Compound15b
This
was prepared from5d,
following the procedure adopted for compound 7a. Mp: 122-123°C; white solid; yield: 90%; IR
(cm−1): 1707; H1 NMR (300 MHz): 8.41 (d, 1H, J = 8.4), 8.10 (d, 1H, J = 8.4), 7.72–7.60 (m, 1H), 7.61–7.55
(m, 1H), 5.07 (dd, 1H, J = 12.8,
4.2), 4.88 (s, 1H), 4.76 (s, 1H), 4.59 (dd, 1H, J = 12.8, 8.7), 4.20 (s, 3H), 4.15–3.90 (m, 1H), 4.00 (s, 3H),
2.95–2.88 (m, 1H); 2.63 (dd, 1H, J = 13.8, 5.1), 2.34 (dd, 1H, J =
13.8, 9.0), 1.73 (s, 3H); C13 NMR (75 MHz):
202.8, 153.3, 148.8, 142.5, 133.3, 132.9, 129.9, 129.8, 126.9, 125.3, 122.0,
114.2, 77.8, 63.3, 61.9, 50.8, 40.5, 39.9, 21.9. MS (m/z): 355 (M+), 319, 304, 294 (100%), 279, 265, 253, 236,
223, 165, 152, 139; anal.
calcd for C20H21NO5: C, 67.59; H, 5.96; N,
3.94, found C, 67.51; H, 5.93; N, 3.93.



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*Source: 528081-2009-03-24.xml*