Synthesis of novel tetracyclic chromenes through carbanion chemistry of 4-methyl coumarins

Article abstract of DOI:10.1016/j.tetlet.2006.06.047

Various substituents were introduced onto the methyl group in 4-methyl coumarins through lithiation, followed by reactions with a wide range of electrophiles. The presence of an alkoxy group on 6′-phenyl ring was found to be pivotal for the success of thi

Full text of DOI:10.1016/j.tetlet.2006.06.047

Tetrahedron Letters 47 (2006) 5909–5913
Synthesis of novel tetracyclic chromenes through
carbanion chemistry of 4-methyl coumarins
Ningyi Chen, Nareshkumar Jain,* Jiayi Xu, Michael Reuman, Xun Li,
Ronald K. Russell and Zhihua Sui
Johnson & Johnson Pharmaceutical Research and Development, LLC 1000 Route 202, Raritan, NJ 08869, USA
Received 21 May 2006; revised 5 June 2006; accepted 8 June 2006
Available online 30 June 2006
Dedicated to Professor K. C. Nicolaou on the occasion of his 60th birthday
Abstract—Various substituents were introduced onto the methyl group in 4-methyl coumarins through lithiation, followed by reac-
tions with a wide range of electrophiles. The presence of an alkoxy group on 60-phenyl ring was found to be pivotal for the success of
this reaction. This procedure provided a convenient synthetic pathway to elaborate the methyl group of 4-methylcoumarins. Appli-
cation of this methodology was showcased with the synthesis of biologically important novel tetracyclic chromene ring systems
(n = 1–3).
Ó 2006 Elsevier Ltd. All rights reserved.
Coumarin derivatives are widespread in nature.1 Many
of them exhibit a broad spectrum of biological activity
such as antiinfective, anticancer, antimyotoxic, phyto-
estrogenic and phytotoxic activities. Among the numer-
ous naturally occurring coumarins, the 4-substituted
coumarins are especially interesting, exhibiting antican-
cer and HIV-1-reverse transcriptase inhibitory proper-
ties.2 In addition, several coumarin derivatives have
been identified as nuclear hormone receptor modulators
including SERMs, PRMs and SARMs.3 Although the
biological benefits of the 4-substituted coumarins are
widespread, there are very few general methods known
to prepare these compounds. Besides the classic synthe-
sis by the Perkin and Pechmann condensations,4,5 sev-
eral groups6,7 have recently reported a palladium-
catalyzed carbonylative annulation of internal alkynes
for the synthesis of coumarin derivatives.
estrogen receptor modulators. Our approach to such a
complex tetracyclic system is described in Scheme 1.
We envisioned that this complex tetracyclic ring system
could be constructed by intramolecular displacement
reaction of 4-substituted coumarins 2 bearing a leaving
group. Since coumarins 3 are easily synthesized from
Perkin and Pechmann condensations between 4 and 5,9
the key step for our synthesis is to establish a general
method to synthesize 4-substituted coumarins 2 from 3.
To the best of our knowledge, only two general methods
are known to functionalize 4-methyl coumarins. The first
one is bromination of 4-methyl group using radical
chemistry and the second is allylic oxidation of 4-methyl
group to alcohols or aldehydes by selenium oxide.10
Unfortunately, both methods failed when applied to
our electron rich coumarin 3. In this letter, we wish to re-
port a general method to synthesize 4-substituted couma-
rins 3 using a carbanion approach. Use of these highly
functionalized coumarins in construction of biologically
important, novel chromene-derived tetracyclic ring
systems 1(a–c) is also described.
In conjunction with our work on SERMs (Selective
estrogen receptor modulators),8 we needed to develop a
general method to prepare substituted tetracyclic ring
system 1 such as benzopyranobenzopyran 1a (n = 1),
benzopyranobenzoxapane 1b (n = 2) and benzo-
pyranobenzoxocane 1c (n = 3). These tetracyclic ring
systems are excellent at mimicking natural ligands as
We envisioned that the 4-methyl group of 3 is acidic
enough to be deprotonated by a strong base, such as
LDA and LiHMDS, to provide the corresponding lith-
ium homoenolate 6. We were pleased to observe that
the deprotonation of the 4-methyl group of 3 went
smoothly upon treatment with LiHMDS (1.5 equiv) at
ꢀ30 °C in THF. This was evidenced by quenching the
*
Corresponding author. Tel.: +1 610 458 4135; fax: +1 610 458
8249; e-mail: njain@prdus.jnj.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.047

5910
N. Chen et al. / Tetrahedron Letters 47 (2006) 5909–5913
X
O
R2
n(H2C)
HO
m
R2
Cyclization
R1
O
O
R1
O
O
1a (n=1, R1=R2=OH)
1b (n=2, R1=R2=OH)
1c (n=3, R1=R2=OH)
m
2 ( = 0 to 2)
Substituion
Reaction
COOH
OP
O
PO
CH3
4
P
R2
Li
R2
4
R2
O
3
OH
R1
Perkin
R1
O
O
R1
O
O
Pechmann
condensations
6
5
3
Scheme 1. Synthesis of tetracyclic chromene: retro synthesis.
reaction mixture with D2O. Mono deuterated product
3a-d1 was obtained almost exclusively (Table 1, entry
1). Having established a deprotonation condition for
4-methyl coumarins 3, we then focused our attention
to the bromination of 3a. Again, the deprotonation
was carried out using LiHMDS to yield the correspond-
ing homoenolate 6a (structure not shown). The resulting
homoenolate was reacted with several brominating
reagents. The reaction with CBr4 at ꢀ78 °C then warmed
up to ꢀ10 °C over 5 h afforded 33% of brominated
product 7a and about 55% of starting material 3a was
recovered. Several reaction conditions such as increasing
the reaction time and adjusting temperature did not
improve the yield of these reactions. Reaction of homo-
enolate 6a with molecular bromine at ꢀ78 °C afforded
88% of 7a along with 7% of unidentified aromatic bro-
mination products. The best results were obtained when
freshly purified NBS was used to react with homoenol-
ate 6a at ꢀ78 °C for 6 h. With the use of NBS, no aro-
matic bromination was observed. This bromination
reaction was used in a large scale preparation of benzo-
pyranobenzopyran 1a (Scheme 2). Demethylation of 7a
was conveniently accomplished with BBr3 in dichloro-
methane at room temperature. In situ treatment of the
corresponding tris-phenol with aqueous NaOH solution
directly resulted in the formation of benzopyranobenzo-
pyran which was isolated from the alkaline aqueous
solution by acid precipitation in more than 89% overall
yield for two steps.
was drawn to SEMCl as an electrophile to carry out
one carbon homologation of 3. To our satisfaction,
when the Li-homoenolate of 3a–c was reacted with
SEMCl, it provided SEM homologated product 7f–i in
high yields ranging from 67–81%. As expected, the reac-
tion with MOMCl, MOMBr and CH3I also produced
substituted coumarins 7j–n in high yields. Compounds
7f and 7j were successfully used in the synthesis of ben-
zopyranobenzoxapane 1b (n = 2). The global deprotec-
tion of protecting groups was carried out using BBr3
in CH2Cl2, followed by cyclization under Mitsunobu
protocol to give 1b in 73% overall yield for two steps
(Scheme 3).
It is interesting to note that, the homoenolate formed
from 3e (OP is absent, Table 1, entry 12), it produced
no desired product 7i with SEMCl under all attempted
conditions. Instead, we isolated an undesired product
10 (ca. 12%). We believe that the majority of intermedi-
ate 9 may have formed preferentially upon reaction with
SEMCl but decomposed during work-up to give back
starting material 3e (Scheme 4). The possibility that
the homoenolates failed to form was ruled out with
D2O experiment (Table 1, entry 13). The results suggest
that the ortho alkoxy group might be playing a key role
in directing the electrophilic addition reaction with
homoenolate 6.
For two-carbon and three-carbon elongation reactions,
homoenolates of 3c and 3b were reacted with a-chloro-
acetyl chloride to yield products 7o and 7p in good yields.
(Table 1, entries 20 and 21). To our delight, when homo-
enolates of 3b and 3d were treated with allyl bromide,
homo allyic coumarins 7q and 7u were obtained in
excellent yields. Compound 7o was converted to benzo-
pyranone 1c (X@O) in a one-pot reaction. The global
deprotection of SEM groups was achieved by 1 N HCl,
followed by treatment with 2 N NaOH to give 1c
(X@O) in 96% yield. The synthesis of benzopyranobenz-
oxacane 1d (X@H2) was achieved in four steps starting
from homo allylic coumarin 7q. The first step is the oxi-
dation of double bond using catalytic amount of OsO4
For the synthesis of benzopyranobenzoxapane 1b
(n = 2), we needed one carbon homologation of 3. When
the solution of the homoenolate of 3a or 3b was treated
with benzaldehyde at ꢀ78 °C, it resulted in an aldol like
product 7b in 78% and 7c in 83%, respectively. Encour-
aged by these results, we carried out similar reactions
with freshly prepared formaldehyde. All attempts to
react with formaldehyde and para-formaldehyde failed
to give any product 7d or 7e. Reactions of homoenolate
with freshly prepared formaldehyde (as gas or solution
in THF) at various conditions resulted in no reaction
(Table 1, entries 7 and 8). At this point, our attention

N. Chen et al. / Tetrahedron Letters 47 (2006) 5909–5913
5911
Table 1. 4-Substituted coumarins
E
R2
P
Li
R2
3
R2
E+
5
CH3
O
O
4'
LiHMDS
1
OP
OP
R1
O
O
R1
1'
O
R1
O
O
6
3
7
Entry
SMa
OP
R1
R2
E+
Product, E
Conditionsb,c,d
Yield (%)
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3b
3a
3c
3a
3b
3d
3e
3e
3a
3b
3b
3d
3c
3b
3c
3b
3a
3d
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OSEM
OMe
OMe
OMe
Absent
Absent
OMe
OMe
OMe
OMe
OSEM
OMe
OSEM
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OSEM
OMe
OMe
F
OMe
OMe
OMe
OMe
OMe
F
OMe
OMe
OMe
OMe
OMe
H
OMe
OSEM
OMe
H
H
H
H
OMe
H
D2O
CBr4
Br2
3a-d1, D–
ꢀ30 °C/10 min.f
ꢀ10 °C, 5 hf
ꢀ78 °C, 15 mine
ꢀ78 °C, 8 he
ꢀ78 °C, 8 he
ꢀ78 °C, 8 he
ꢀ78 °C, 8 he
ꢀ78 °C, 8 he
ꢀ10 °C, 28 hf
ꢀ10 °C, 28 hf
ꢀ10 °C, 28 hf
ꢀ10 °C, 28 hf
ꢀ30 °C/10 min.f
ꢀ20 °C, 28 hf
ꢀ20 °C, 28 hf
ꢀ10 °C, 28 hf
ꢀ20 °C, 28 hf
ꢀ20 °C, 28 hf
ꢀ30 °C, 28 hf
ꢀ78 °C, 2 he
ꢀ78 °C, 2 he
ꢀ30 °C, 16 hf
ꢀ30 °C, 18 hf
>90
33
88
82
78
83
0
7a, Br–
7a
7a
NBS
PhCHO
PhCHO
H2CO
7b, PhCH(OH)–
7c, PhCH(OH)–
7d, HOCH2–
7e, HOCH2–
7f, SEM–
7g, SEM–
7h, SEM–
7i, SEM–
3e-d1, D–
7j, MOM–
7k, MOM–
7j, MOM–
7l, MOM–
7m, MOM–
7n, CH3–
7o, ClCH2CO–
7p, ClCH2CO–
7q, CH2@CHCH2–
7u, CH2@CHCH2–
H2CO
0
9
SEMCl
SEMCl
SEMCl
SEMCl
SEMCl
MOMBr
MOMBr
MOMCl
MOMBr
MOMBr
CH3I
81
77
67
Trace
>90
77
81
67
83
76
97
66
82
77
86
10
11
12
13
14
15
16
17
18
19
20
21
22
23
OMe
H
OSEM
OMe
OSEM
OMe
OMe
F
OSEM
OMe
OSEM
OMe
OMe
H
ClCH2COCl
ClCH2COCl
CH2@CHCH2Br
CH2@CHCH2Br
a Compounds 3(a–e) were prepared by a modified protocol of Perkin and Pechmann condensation (see Ref. 4).
b Anhydrous THF was used as solvent.
c 1 M LiHMDS in THF (Aldrich) was used in all reactions.
d Enolization was carried out at ꢀ30 °C.
e The enolization was carried out at ꢀ30 °C and then cooled down to ꢀ78 °C and electrophile was added.
f The electrophile was added at ꢀ30 °C and then warmed to the respective temperature. General experimental procedure for the formation of
homoenolates of 4-methyl coumarins and reactions with electrophiles illustrated with preparation of 7f: A 200 mL single neck flask was charged
with lithium bis(trimethylsilyl)amide ((TMS)2NLi, 16 mL 1 M solution in THF, 16 mmol). 3-(2,4-Dimethoxy-phenyl)-7-methoxy-4-methyl-chro-
men-2-one (3.45 g, 10.6 mmol, 1.51 equiv) in anhydrous THF (105 mL) was added to the reaction mixture over a 10-min period stirred at ꢀ30 °C
for 45 min. (2-Chloromethoxy-ethyl)-trimethyl-silane (1.95 g, 11.7 mmol) was added to the reaction mixture over a 10-min period at ꢀ30 °C and
stirring was 11.7 mmol continued at ꢀ10 °C for 12 h. The reaction mixture was quenched with saturated aqueous solution of NH4Cl (250 mL) and
extracted with EtOAc (250 mL). The organic phase was condensed in vacuo at 60 °C to yield a crude product which was purified by flash
chromatography to yield the title compound 7f as a white solid. MS (Cl) m/z 456 (M+), 457 (M+H, loop positive). HRMS, m/z calcd for (M+)
456.1968; found 456.1979. 1H NMR (400 MHz, CDCl3): d 7.70 (1H, d, J = 8.8 Hz), 7.11 (1H, d, J = 8.8 Hz), 6.93–6.89 (2H, m), 6.62–6.59 (2H, m),
3.92 (3H, s), 3.88 (3H, s), 3.79 (3H, s), 3.51 (2H, t, J = 7.6 Hz), 3.42–3.35 (m, 2H), 3.03–2.83 (m, 2H), 0.89 (3H, t, J = 7.8 Hz), 0.01 (9H, s). 13C
NMR (400 MHz, CDCl3): 163.57, 162.70, 162.62, 159.66, 156.31, 151.03, 133.11, 127.82, 123.50, 117.37, 114.93, 113.58, 106.22, 102.25, 100.52,
69.90, 69.48, 57.19, 56.97, 56.82, 31.87, 19.49, 0.01.
and NaIO4 with 2,6-lutidine protocol,11 followed by
NaBH4 reduction12 to yield primary alcohol 2b. The
primary alcohol was converted to bromide using CBr4/
PPh3 in 85% yield.13 The global deprotection of all three
methyl groups was effected by BBr3, followed by sponta-
neous cyclization in 20% w/v NaOH to afford benzo-
pyranobenzoxacane 1d in 65% yield (Scheme 5).
R
O
O
OMe
i
ii
OH
Br
OMe
O
OH
OMe
i
MeO
O
O
HO
O
O
1b
OMe
7f (R=CH2CH2TMS)
7j (R=Me)
O
O
MeO
O
HO
O
7a
1a
Scheme 3. Synthesis of benzopyranobenzoxapane. Reagents and
conditions: (i) BBr3, CH2Cl2, rt, 14 h, followed by workup with 20%
NaOH (aq) and 2 N HCl (aq). (ii) DIAD, PPh3, THF, 26 h. Overall
yield 73% (for 7f), 77% (for 7j).
Scheme 2. Synthesis of benzopyranobenzopyran. Reagents and con-
ditions: BBr3, CH2Cl2, rt, 14 h, followed by workup with 20% NaOH
(aq) and 2 N HCl (aq). Yield, 89%.

5912
N. Chen et al. / Tetrahedron Letters 47 (2006) 5909–5913
References and notes
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In summary, we have developed a highly efficient and
divergent methodology to elaborate the 4-methyl group
in 4-methyl coumarins through anion chemistry. The
homoenolates are reactive enough to undergo reactions
with a wide range of electrophiles, including carbon
electrophiles. This procedure offered easy access to the
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cased with the synthesis of biologically important tetra-
cyclic ring systems 1.8
Supplementary data
Supplementary data (1H and 13C NMRs) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2006.06.047.
Cl
X
O
OSEM
i (for 1c)
O
OH
OSEM
HO
O
O
SEMO
O
O
1c, X=O
1d X=H2
7o
iv (for 1d)
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7q
14
Scheme 5. Synthesis of benzopyranobenzoxacane. Reagents and conditions: (i) 1 N HCl (aq)–THF–CH3CN (1:1:1), 3 h, followed by 2 N NaOH.
Yield, 96%. (ii) OsO4 (0.02 equiv), NaIO4 (4.0 equiv), 2,6-lutidine (2.0 equiv), dioxane–water (3:1) followed by NaBH4 (0.5 equiv). Yield 88%. (iii)
CBr4 (3.0 equiv), PPh3 (3.0 equiv), CH2Cl2, 12 h, rt. Yield, 85%. (iv) BBr3, CH2Cl2, 0 °C, rt, followed by work-up with 20% NaOH. Yield 65%.

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