Electroreductive Intermolecular Coupling of Coumarins with Benzophenones: Synthesis of 4-(2-Hydroxyphenyl)-5,5-diaryl-γ-butyrolactones, 2-(2,2-Diaryl-2,3-dihydrobenzofuran-3-yl)acetic Acids, and 4-(Diarylmethyl)coumarins

Article abstract of DOI:10.1021/acs.joc.6b02056

The electroreductive coupling of coumarins with benzophenones in the presence of TMSCl gave adducts reacted at the 4-position of coumarins as trimethylsilyl ethers. From 3-methylcoumarin, 3,4-cis-adducts were formed stereoselectively. The de-trimethylsily

Full text of DOI:10.1021/acs.joc.6b02056

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Article
Electroreductive Intermolecular Coupling of Coumarins with Benzophenones:
Synthesis of 4-(2-Hydroxyphenyl)-5,5-diaryl-gamma-butyrolactones, 2-(2,2-
Diaryl-2,3-dihydrobenzofuran-3-yl)acetic acids, and 4-Diarylmethylcoumarins
Naoki Kise, Yusuke Hamada, and Toshihiko Sakurai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02056 • Publication Date (Web): 05 Oct 2016
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Electroreductive Intermolecular Coupling of Coumarins with Benzophenones:
Synthesis of 4-(2-Hydroxyphenyl)-5,5-diaryl-γ-butyrolactones, 2-(2,2-Diaryl-
2,3-dihydrobenzofuran-3-yl)acetic acids, and 4-Diarylmethylcoumarins
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Naoki Kise,* Yusuke Hamada, and Toshihiko Sakurai
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University,
4ꢀ101, Koyamaꢀcho Minami, Tottori 680ꢀ8552, Japan
ABSTRACT
The electroreductive coupling of coumarins with benzophenones in the presence of TMSCl gave
adducts reacted at the 4ꢀposition of coumarins as trimethylsilyl ethers. From 3ꢀmethylcoumarin,
3,4ꢀcisꢀadducts were formed stereoselectively. The detrimethylsilylation of the adducts with 1 M
HCl aq or TBAF in THF at 25 ºC produced 4ꢀ(2ꢀhydroxyphenyl)ꢀ5,5ꢀdiarylꢀγꢀbutyrolactones. The
γꢀbutyrolactones were further transformed to 2ꢀ(2,2ꢀdiarylꢀ2,3ꢀdihydrobenzofuranꢀ3ꢀyl)acetic acids
by treatment with 1 M HCl aq at reflux temperature. The detrimethylsilylation of the adducts with
1 M HCl in MeOH afforded 2ꢀ(2,2ꢀdiarylꢀ2,3ꢀdihydrobenzofuranꢀ3ꢀyl)acetic acid methyl esters.
The detrimethylsiloxylation of the adducts or dehydration of the γꢀbutyrolactones brought about
4ꢀdiarylmethylcoumarins.
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INTRODUCTION
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Recently, 3ꢀ and 4ꢀsubsutituted coumarin derivatives are extensively investigated as
pharmacologically active compounds, such as anticancer, antineurodegenerative, and
antituberculous agents.1 Therefore, the synthesis of 3ꢀ and 4ꢀsubsutituted coumarins attracts much
attention from the synthetic chemists.2,3 On the other hand, electroreduction is one of the useful
method for the reductive coupling of carbonyl compounds4 and we have reported the
electroreductive crossꢀcoupling of heterocycles, such as phthalimides,5 indoles,6 and uracils,7 with
carbonyl compounds. In this context, we attempted the electroreductive crossꢀcoupling of
coumarins with carbonyl compounds, since this type of reaction is previously unknown and
expected to provide a new synthetic route to 4ꢀsubsutituted coumarin derivatives. We have already
reported the electroreductive hydrodimerization of coumarin at its 4ꢀposition.8 In contrast, we
report in this paper that the crossꢀcoupled products reacted at the 4ꢀposition of coumarins were
obtained as trimethylsilyl ethers by the electroreduction of coumarins with benzophenones in the
presence of TMSCl (Scheme 1). From 3ꢀmethylcoumarin (R1 = Me, R2 = H), 3,4ꢀcisꢀadducts were
formed with complete stereoselectivity. At first, we expected that 4ꢀsubstituted coumarins can be
prepared from the adducts by detrimethylsilylation of the trimethylsilyl ethers and subsequent
dehydration of the resultant alcohols. Contrary to our expectation, the adducts were immediately
transformed to 4ꢀ(2ꢀhydroxyphenyl)ꢀ5,5ꢀdiarylꢀγꢀbutyrolactones by desilylation under acidic (1 M
HCl aq) or basic (TBAF in THF) conditions at 25 ºC (Scheme 2). Under acidic conditions with 1
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M
HCl aq at reflux temperature, the γꢀbutyrolactones further transformed to
2ꢀ(2,2ꢀdiarylꢀ2,3ꢀdihydrobenzofuranꢀ3ꢀyl)acetic acids, while their methyl esters were formed by
treatment of the adducts with 1 M HCl in MeOH. Eventually, 4ꢀsubstituted coumarin derivatives
could be obtained by direct dehydrosiloxylation of the adducts or dehydration of the
γꢀbutyrolactones with cat. pꢀTsOH in refluxing toluene or xylene. Reaction mechanisms of the
electroreductive coupling and the transformations of the adducts were also discussed.
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Scheme 1. Electroreductive Hydorodimerization and Cross-Coupling of Coumarins
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Hydrodimerization (Ref. 8)
O
O
7
8
+e
4
9
CH3CN
O
O
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O
O
66% meso:dl = 75:25
Cross-Coupling with Benzophenones (This Work)
Ar Ar
R2
+2e
TMSCl
R2
OTMS
R1
R1
Ar
Ar
4
4
+
3
THF
O
O
O
O
O
R1 = R2 = H
R1 = Me, R2 = H; cis
R1 = Me, R2 = H
R1 = H, R2 = Me
Scheme 2. Transformation of Adducts
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RESULTS AND DISCUSSION
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Electroreductive Coupling of Coumarins with Benzophenones.
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The electroreduction of coumarins 1a-c with benzophenones 2a-f (2 equiv) was carried out in
THF containing TMSCl (5 equiv) according to our already reported method5ꢀ7 and the results are
summarized in Table 1. As a cathode material, Pt, Au, Ag, Cu, Sn, and Pb brought about almost
the same yields (70ꢀ75%) of 4ꢀ(diphenyl((trimethylsilyl)oxy)methyl)chromanꢀ2ꢀone (3a) in the
reaction of 1a with 2a (run 1). In all cases, the adducts coupled at the 4ꢀposition of 1a-c with 2a-f
were obtained as trimethylsilyl ethers 3a-l in moderate to high yields. It is noted that the
electroreductive coupling of 3ꢀmethylcoumarin (1b: R1 = Me, R2 = H) with 2a-d gave the adducts
3g-j as single diastereomers (>99% selectivity by 1H NMR analysis) (runs 7ꢀ10). Of these adducts,
3j was confirmed to be cisꢀisomer by Xꢀray crystallographic analysis. The other adducts 3g-i
could, therefore, be assumed to be cisꢀisomers. We have already observed similar cisꢀselective
additions in the electroreduction of 1ꢀalkoxycarbonylꢀ3ꢀmethyxycarbonylindoles6 and
1,3ꢀdimethyluracils7 with aromatic ketones.
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Unfortunately, the electroreductive coupling of 1a with 4,4’ꢀdimethoxybenzophenone (2g)
under the same conditions as above afforded the hydrodimer of 1a (4) as the major product (42%)
and the desired crossꢀcoupled product 3m was obtained in a low yield (28%) with a trace amount
(4%) of 4ꢀ(trimethylsilyl)chromanꢀ2ꢀone (5) as shown in Scheme 3. Since already reported CV
data of coumarins9 and benzophenones10 were recorded under different conditions, we measured the
CV of 1a-c and 2a-g under the same conditions to compare their first reduction peaks (Table 2).
These results revealed that 1a (−1.88 V vs SCE) is slightly less reducible than 2a (−1.85 V) but
more reducible than 2g (−2.08 V). Therefore, the reaction mechanism of the electroreductive
coupling of coumarins with benzophenones can be presumed as illustrated in Scheme 4. Initially,
carbanion A is generated by the twoꢀelectron transfer to 2a and Oꢀsilylation with TMSCl. The
nucleophilic 1,4ꢀaddition of A to 1a and following Oꢀsilylation of the resulting enolate anion B give
silyl ketene acetal C. The labile C is readily desilylated to 3a during workup. When R1 is
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methyl group, protonation at the 3ꢀposition in C occurs predominantly from the less hindered side
(β side) to produce cisꢀisomer of 3g. Incidentally, the electroreduction of 1a in the presence of
TMSCl gave 5 in 39% yield and the hydrodimer 4 in 24% yield (Scheme 5). The electroreductive
trimethylsilylation of 1a to 5 probably proceeds through the trimethylsilylation of carbanion D
generated by the twoꢀelectron transfer to 1a followed by Oꢀsilylation with TMSCl and subsequent
desilylation of the resultant ketene silyl acetal E during workup.
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Table 1. Electroreductive Coupling of Coumarins 1a-c with Benzophenones 2a-fa
run
1
R1
H
R2
H
Ar2C=O
% yieldb
75
1
2
3
Ar = Ph
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
2a
2b
2c
2d
2e
2f
3a
2
H
H
Ar = 4ꢀFC6H4
dibenzosuberone
dibenzosuberenone
9ꢀfluorenone
xanthone
73
3b
3
H
H
86
3c
4
H
H
89
3d
5
H
H
80
3e
6
H
H
78
3f
7
Me
Me
Me
Me
H
H
Ar = Ph
86c
84c
52c
86c
83
2a
2b
2c
2d
2a
2b
cis-3g
cis-3h
cis-3i
cis-3j
3k
8
H
Ar = 4ꢀFC6H4
dibenzosuberone
dibenzosuberenone
Ar = Ph
9
H
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12
H
Me
Me
H
Ar = 4ꢀFC6H4
62
3l
aElectroreduction was carried out in 0.3 M Bu4NClO4/THF using a Pt cathode at a constant current
of 0.2 A (2 F/mol for 2). bIsolated yields. cObtained as cis only.
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CV data of 1a, 2a, and 2g.
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Scheme 4. Presumed Reaction Mechanism of Electroreductive Coupling
of Coumarins with Benzophenones
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Scheme 5. Electroreduction of 1a in the Presence of TMSCl
Desilylation of Adducts 3a-l with 1 M HCl aq/dioxane and 1 M HCl/MeOH.
The adducts 3a-j were stirred in 1 M HCl aq and dioxane (1:1) at 25 ºC until almost all of 3a-j
were consumed (Table 3). From 3a-e, 4ꢀ(2ꢀhydroxyphenyl)ꢀ5,5ꢀdiarylꢀγꢀbutyrolactones 6a-e were
obtained after stirring for 5ꢀ12 h in good to high yields (runs 1, 3, 5, 7, and 9), although a
considerable amount of 3d (23%) remained even after prolonged reaction time of 96 h (run 7). In
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the case of 3f, 2ꢀ(2,3ꢀdihydrobenzofuranꢀ3ꢀyl)acetic acid derivative 7f was formed as the major
product with a small amount of γꢀbutyrolactone 5f after stirring for 3 h (run 11) and as the sole
product after 24 h in 81% yield (run 12). From 3ꢀmethyl substituted 3,4ꢀcisꢀadducts cis-3g-j (R1 =
Me, R2 = H), 3,4ꢀtransꢀγꢀbutyrolactones trans-6g-j were obtained as the sole products in high yields
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(runs 13 and 15ꢀ17).
The stereostructures of trans-6g,h,j were confirmed by Xꢀray
crystallography. On the contrary, 4ꢀmethyl substituted adducts 3k,l (R1 = H, R2 = Me) were
completely inert under the same conditions at 25 ºC. Next, the mixtures of 3a-e in 1 M HCl aq
and dioxane (1:1) were refluxed until almost all of initially formed 6a-e were disappeared. In lieu
of 6a-e, 2ꢀ(2,2ꢀdiarylꢀ2,3ꢀdihydrobenzofuranꢀ3ꢀyl)acetic acids 7a-e were obtained as the sole
products in moderate to good yields (runs 2, 4, 6, 8, and 10). However, the transformation of the
3ꢀmethyl substituted γꢀbutyrolactones trans-6g-j to 7g-j (R1 = Me, R2 = H) was very slow even
under the reflux conditions. As an example, trans-6g was diminished to less than 10% after reflux
for 144 h to give 7g in 42% yield as a single stereoisomer (run 14). The stereoconfiguration of the
obtained 7g was assumed to be threo as described below. In contrast, the 4ꢀmethyl substituted 3k,l
(R1 = H, R2 = Me) were readily transformed to 3ꢀmethyl substituted 7k,l after reflux for 24 h (runs
18 and 19).
Second, the adducts 3a-l were treated with 1 M HCl in MeOH and the results are summarized
in Table 4. In the reactions of 3a,b,e-h, methyl esters of 7a,b,e-h (8a,b,e-h) were effectively
produced through γꢀbutyrolactones 6 at 25 ºC (runs 1,3,7ꢀ9, and 11). From other adducts 3c,d,i,k,l,
the corresponding methyl esters 8c,d,i,k,l were obtained under the same conditions but at reflux
temperature (runs 5,6,12,16, and 17). Although 8j (52%) was given from cis-3j, a considerable
amount of trans-6j (45%) was remained even after reflux for 108 h (run 14). From cis-3g-j (R1 =
Me, R2 = H), methyl esters 8g-j were obtained as single stereoisomers (runs 9ꢀ14). Since the
stereoconfiguration of 8h could be determined to be threo by Xꢀray crystallography, those of 8g,i,j
were assumed to be threo. The esterification of 7g obtained from run 14 in Table 3 certainly
afforded the methyl ester threo-8g.
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The presumed reaction mechanism of the transformation of 3a (cis-3g) to 6a (trans-6g) and 7a
(threo-7g) in 1 M HCl aq/dioxane is depicted in Scheme 6. It is assured that acid catalyzed
desilylation of 3a (cis-3g) generates 9a (cis-9g), although 9a (cis-9g) could not be detected.
Transformation of 9a (cis-9g) to 6a (trans-6g) rapidly proceeds through successive acid catalyzed
processes as follows: ring closure of protonated 9a (F: R1 = H) to G, proton migration from G to H,
sixꢀmembered ring opening of H to I, and finally deprotonation of I produce 6a. Similarly,
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3,4ꢀcisꢀδꢀlactone cis-9g (R1
=
Me) is transformed to stereochemically retained
3,4ꢀtransꢀγꢀbutyrolactone trans-6g. Under reflux conditions, 6a is further converted to 7a via ring
opening of protonated 6a (J) to carbocation K, intramolecular nucleophilic substitution of the
phenoxy group in K, and deprotonation of the resultant L. In the transformation of trans-6g to
threo-7g, the stereoconfiguration is retained.
In 1 M HCl/MeOH, the acid catalyzed
transformation of 3a and cis-3g to 6a and trans-6g proceeds rapidly in the same way. As shown in
Scheme 7, methanolysis of 6a takes place rapidly to give methyl ester M. Successive acid
catalyzed dehydration of M to carbocation N, ring closure of N to O, and finally deprotonation of O
afford 8a. From trans-6g (R1 = Me), threo-8g is formed with complete retention of the
stereochemistry.
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Table 3. Desilylation of 3a-l with 1 M HCl aq/dioxane
3
4
5
6
7
8
R1
R2
Ar Ar
OH
R2
R2
R1
COOH
Ar
1 M HCl aq
/dioxane
OTMS
R1
4
3
4
5
3
3
+
2
Ar
Ar
6a-f
9
O
Ar
O
O
O
O
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3a-f R1 = R2 = H
cis-3g-j R1 = Me; R2 = H
3k,l R1 = H; R2 = Me
7a-f
threo-7g
7k.l
trans-6g-j
run
1
temp.
25 ºC
reflux
25 ºC
reflux
25 ºC
reflux
25 ºC
reflux
25 ºC
reflux
25 ºC
25 ºC
25 ºC
reflux
25 ºC
25 ºC
reflux
reflux
reflux
time
6 h
% yielda
85
% yielda
83
6
7
3
6a
3a
2
24 h
12 h
24 h
5 h
7a
7b
7c
7d
3a
3
87
92
68b
83
5
6b
6c
6d
6e
6f
3b
4
61
3b
5
3c
6
24 h
96 h
72 h
12 h
7 h
69
3c
7
3d
8
73
3d
9
3e
10
11
12
13
14
15
16
17
18
19
75
77
81
7e
7f
7f
3e
3 h
3f
24 h
24 h
144 h
24 h
24 h
24 h
24 h
24 h
3f
92c
8c
98c
99c
90c
trans-6g
trans-6g
trans-6h
trans-6i
trans-6j
cis-3g
cis-3g
cis-3h
cis-3i
cis-3j
3k
42
threo-7g
98
72
7k
7l
3l
aIsolated yields. b3d (23%) was recovered. cObtained as trans only.
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Table 4. Desilylation of 3a-l with 1 M HCl/MeOH
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run
1
temp.
25 ºC
reflux
25 ºC
25 ºC
reflux
reflux
25 ºC
25 ºC
25 ºC
reflux
25 ºC
reflux
reflux
reflux
25 ºC
reflux
reflux
time
12 h
2 h
% yielda
% yielda
86
6
8
3
8a
8a
8b
3a
2
82
3a
3
12 h
2 h
87
3b
4
95
6c
3c
5
2 h
73
8c
3c
6
12 h
12 h
2 h
95
8d
3d
7
90
8e
3e
8
84
8f
3f
9
12 h
2 h
96b
89b
92b
86b
12b
52b
47
threo-8g
threo-8g
threo-8h
threo-8i
threo-8j
threo-8j
8k
cis-3g
cis-3g
cis-3h
cis-3i
cis-3j
cis-3j
3k
10
11
12
13
14
15
16
17
12 h
6 h
12 h
108 h
12 h
2 h
85c
45c
48
trans-6j
trans-6j
6k
85
8k
3k
2 h
96
8l
3l
aIsolated yields. bObtained as threo only. cObtained as trans only.
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Scheme 6. Presumed Reaction Mechanism of Acid Catalyzed Transformation
3
4
5
of 3a (cis-3g) to 6a (trans-6g) and 7a (threo-7g)
6
7
8
9
Ph
Ph
Ph
Ph
OTMS
R1
Ph
OH
R1
Ph
OH
R1
+H2O
-TMSOH
+H+
-H+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
O
OH
3a
cis-3g
9a
cis-9g
F
Ph
Ph
Ph
OH
R1
Ph
R1
-H+
R1
O
OH
+H+
Ph
Ph
O
H
H
OH
O
OH
O
OH
I
G
R1
COOH
Ph
OH
OH
R1
+H+
-H+
R1
Ph
Ph
Ph
Ph
Ph
O
O
O
O
OH
H
K
6a
trans-6g
J
R1
R1
COOH
COOH
-H+
Ph
Ph
Ph
Ph
+H+
O
O
H
7a
threo-7g
L
Scheme 7. Presumed Reaction Mechanism of Acid Catalyzed Transformation
of 6a (trans-6g) to 8a (threo-8g) in 1 M HCl/MeOH
Ph
OH
R1
OH
R1
+H+
H2O
COOMe
Ph
Ph
+MeOH
MeOH
R1
Ph
Ph
H+
Ph
COOMe
O
O
OH
OH
H2O
N
6a
trans-6g
M
R1
R1
COOMe
COOMe
H+
Ph
Ph
Ph
Ph
+H+
O
O
H
8a
O
threo-8g
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2
Isomerization of cis-3g and trans-6g to trans-3g and cis-6g
3
4
5
6
7
8
Since the isomerization of cis-3g by treatment with cat. DBU at 25 ºC did not proceed entirely,
the reaction was carried out in refluxing toluene (Scheme 8). Although the desired trans-3g was
given in 38% yield stereoselectively after 12 h, a significant amount of 6g (44%) was also formed
with a trans:cis ratio of 57:43. The obtained trans-3g was selectively transformed to cis-6g and
erythro-8g by treatment with 1 M HCl in MeOH at 25 ºC and reflux temperature, respectively.
This result shows that cis-6g is inert in 1 M HCl/MeOH at 25 ºC in contrast to trans-6g. Actually,
when the diastereomeric mixture of 6g (trans:cis = 57:43) was treated with 1 M HCl in MeOH at 25
ºC, threo-8g was selectively formed from trans-6g whereas cis-6g completely remained. On the
other hand, the treatment of trans-6g with cat. DBU in refluxing toluene for 12 h gave an
equilibrium mixture of 6g (trans:cis = 57:43). This result suggests that trans-6g is slightly stable
than cis-6g under the conditions. The DFT calculations of the both isomers of 6g at the
B3LYP/6ꢀ311+G(2d,p) level using the IEFPCM model in toluene at 383 K also showed that
trans-6g is a little lower in energy than cis-6g (0.41 kcal/mol corresponding to 63:37 dr).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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3
4
Scheme 8. Isomerization of cis-3g and trans-6g
5
6
7
8
9
Ph
Ph
Ph
OTMS
Me
Ph
OTMS
Me
OH
Me
DBU
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
toluene
reflux
12 h
Ph
Ph
O
O
O
O
O
O
cis-3g
trans-3g 38%
6g 44% (trans:cis = 57:43)
Ph
Me
Ph
OTMS
1M HCl
/MeOH
OH
Me
1M HCl
/MeOH
COOMe
Ph
Me
25 °C
12 h
reflux
60 h
Ph
Ph
Ph
O
O
O
O
O
erythro-8g 85%
cis-6g 73%
trans-3g
Me
OH
OH
1M HCl
/MeOH
COOMe
Ph
Me
Me
+
Ph
Ph
Ph
Ph
25 °C
12 h
Ph
O
O
O
O
O
threo-8g 48%
6g (trans:cis = 57:43)
cis-6g 35%
OH
Me
OH
Me
DBU
Ph
Ph
Ph
6g 67% (trans:cis = 57:43)
toluene
reflux
12 h
O
O
O
O
Ph
trans-6g
Desilylation of Adducts 3a-l with TBAF/THF.
The adducts 3a-l were treated with TBAF in THF at 25 ºC for 15 min (Table 5). Except for
the reaction of 3f, the γꢀbutyrolactones 6a-e and 6g-l were obtained in good to excellent yields (runs
1ꢀ5 and 8ꢀ13). The reaction of 3f for 15 min afforded 7f as the major product with a small amount
of 6f (run 6). After 3h, 7f was obtained as the sole product in 60% yield (run 7). Similarly to the
acid catalyzed desilylation described above, trans-6g-j were selectively formed from cis-3g-j (runs
8ꢀ11).
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Table 5. Desilylation of 3a-l with TBAF/THF
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
run
1
time
% yielda
95
% yielda
6
7
3
15 min
15 min
15 min
15 min
15 min
15 min
3 h
6a
6b
6c
6d
6e
6f
3a
2
83
3b
3
98
3c
4
99
3d
5
82
3e
6
18
58
60
7f
7f
3f
7
3f
8
15 min
15 min
15 min
15 min
15 min
15 min
86b
97b
74b
84b
81
trans-6g
trans-6h
trans-6i
trans-6j
6k
cis-3g
cis-3h
cis-3i
cis-3j
3k
9
10
11
12
13
73
6l
3l
aIsolated yields. bObtained as trans only.
The presumed reaction mechanism of the transformation of 3a-l to 6a-l and 7f is exhibited in
Scheme 9. Treatment of 3a-l with TBAF generates alkoxide anion P. Ring closure by
intramolecular nucleophilic addition of P and subsequent ring opening of the sixꢀmembered ring in
the resultant Q to R rapidly occur. While γꢀbutyrolactones 6a-l are produced by protonation of the
phenoxide anion in R, 7f is formed by intramolecular nucleophilic substitution probably due to the
electronic effect of the xanthone ring in R and subsequent protonation of the resultant carboxylate
anion S.
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Scheme 9. Presumed Reaction Mechanism of Transformation of 3a-l to 6a-l and 7f with TBAF
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The rapid conversion from δꢀlactones 3a-l to γꢀbutyrolactones 6a-l under both acidic and
basic conditions described above did not proceed in the case of δꢀlactam 3n which was prepared by
the electroreductive coupling of 1ꢀmethylquinolinꢀ2(1H)ꢀone (1d) with 2a (Scheme 10). The
treatment of 3n with 1 M HCl in MeOH or TBAF in THF at 25 ºC gave desilylated δꢀlactam 9n in a
high yield.
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Scheme 10. Electroreductive Coupling of 1d with 2a and desilylation of adduct 3n
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Detrimethylsiloxylation of 3a-j.
Detrimethylsiloxylation7 of 3a-j was carried out by reflux in xylene or toluene containing a
catalytic amount of pꢀTsOH (Table 6). From 3a-f (R1 = H), 4ꢀdiarylmethylcoumarins 11a-f were
obtained
as
the
sole
products
(runs
1ꢀ6).
On
the
contrary,
4ꢀ(diarylmethylene)ꢀ3ꢀmethylchromanꢀ2ꢀones 10g-i were exclusively produced from cis-3g-i (R1 =
Me) (runs 7ꢀ9). From cis-3j (R1 = Me), 4ꢀdiarylmethylcoumarin 11j (59%) was obtained with 10j
(37%) after reflux in xylene for 24 h (run 10). However, the isomerization of 10j to 11j did not
complete even after 96 h (run 11). Similarly, detrimethylsiloxylation of 3n in toluene for 12 h
gave 4ꢀbenzhydrylꢀ1ꢀmethylquinolinꢀ2(1H)ꢀone (11n) in 85% yield (run 12). Isomerization of
exoꢀalkenes 10g,h to endoꢀalkenes 11g,h could be readily effected by treatment with a catalytic
amount of DBU in THF at 25 ºC (Scheme 11).
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Table 6. Detrimethylsiloxylation of 3a-j
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
run
1
solvent
xylene
xylene
xylene
toluene
xylene
toluene
xylene
xylene
xylene
xylene
xylene
toluene
time
24 h
24 h
48 h
12 h
24 h
24 h
24 h
24 h
24 h
24 h
96 h
12 h
% yielda
% yielda
82b
80c
10
11
3
11a
11b
11c
11d
11e
11f
3a
2
3b
3
79
3c
4
90
3d
5
95
3e
6
65
3f
7
80
85
78
59
34
10g
10h
10i
10j
10j
cis-3g
cis-3h
cis-3i
cis-3j
cis-3j
3n
8
9
10
11
12
37
63
85
11j
11j
11n
aIsolated yields. b7a (8%) was formed as a byꢀproduct. c7b (16%) was formed as a byꢀproduct.
Scheme 11. Isomerization of 10g,h to 11g,h
.
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3
4
5
6
7
8
The presumed reaction mechanism of transformation of 3a and cis-3g to 11a and 10g was
shown in Scheme 12. Acid catalyzed detrimethylsiloxylation of 3a and cis-3g generates
carbocation T and subsequent deprotonation of T affords 10a,g. In the reaction of 3a (R1 = H),
carbocation U is formed by hydride migration of T or protonation to 10a and subsequently
deprotonated to give 11a. Consequently, 11a is obtained as the sole product by the displacement
of equilibrium. In contrast, the result of run 7 in Table 6 shows that the isomerization of 10g (R1 =
Me) to 11g does not proceed entirely under the conditions.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 12. Presumed Reaction Mechanism of Detrimethylsiloxylation of 3a,g to 10g and 11a
On the other hand, the γꢀbutyrolactones 6a-h were also transformed to the
4ꢀdiarylmethylcoumarins 11a-h under the same conditions as above (Table 7). From 6a-f (R1 = H),
11a-f were obtained by reflux in toluene for 12 h (runs 1ꢀ6). It is noted that 11g,h were formed
together with 10g,h from trans-6g,h (R1 = Me) in refluxing xylene (runs 7 and 8). In addition, the
(2,3ꢀdihydrobenzofuranꢀ3ꢀyl)acetic acid 7a was also transformed to 11a by reflux in xylene for only
6 h (Scheme 13). From these results, the reaction mechanism of acid catalyzed transformation of
6a, trans-6g, and 7a to 10g and 11a,g can be proposed as shown in Scheme 14. Carbocation K is
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3
4
5
6
7
8
9
formed by acid catalyzed ring opening of 6a, trans-6g, and 7a as shown in Scheme 6.
Deprotonation of K and following lactonization of the resultant carboxylic acid V give 10a,g.
Alternatively, carbocation W is formed by hydride migration of K or protonation to V and then
undergoes deprotonation to give carboxylic acid X. Finally, lactonization of X produces 11a,g.
In the reactions of 6a and 7a (R1 = H), 10a isomerizes to 11a through U according to the
mechanism shown in Scheme 12.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 7. Dehydration of 6a-h
run
1
solvent
toluene
toluene
toluene
toluene
toluene
toluene
xylene
xylene
time
12 h
12 h
12 h
12 h
12 h
12 h
24 h
12 h
% yielda
% yielda
80
42b
10
11
6
11a
11b
11c
11d
11e
11f
11g
11h
6a
2
6b
3
73
6c
4
63
6d
5
76
6e
6
99
6f
7
46
16
50
10g
10h
trans-6g
trans-6h
8
47
aIsolated yields. b7b (19%) was formed as a byꢀproduct.
Scheme 13. Dehydration of 7a to 11a
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4
5
6
7
Scheme 14. Presumed Reaction Mechanism of Dehydration of 6a, trans-6g and 7a
to 10g and 11a,g
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
These reaction mechanisms shown in Schemes 12 and 14 are supported by the DFT
calculations of 6a-11a at the B3LYP/6ꢀ311+G(2d,p) level in toluene at 383 K. The energy profile
illustrated in Scheme 15 indicates that the energies of 9a, 6a, and 7a decrease in this order.
Dehydrated product 10a is much more stable than 7a (13.4 kcal/mol) and 6a (19.6 kcal/mol). It is
to be anticipated that endoꢀalkene 11a is lower in energy (5.9 kcal/mol) than exoꢀalkene 10a.
Consequently, the product of the dehydration of 6a and 7a converges with 11a.
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Scheme 15. Energy Profile from 9a to 6a, 7a, 10a, and 11a Calculated by the
B3LYP/6-311+G(2d,p)/IEFPCM(toluene) Method at 383K
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSION
The electroreductive intermolecular coupling of coumarins 1a-c with benzophenones 2a-f in
the presence of TMSCl in THF gave the adducts reacted at the 4ꢀposition of 1a-c as TMS ethers
3a-l. From 3ꢀmethylcoumarin (1b), only 3,4ꢀcisꢀadducts cis-3g-j were selectively obtained. The
treatment of 3a-l with 1 M HCl/dioxane aq or TBAF in THF at 25 ºC gave
4ꢀ(2ꢀhydroxyphenyl)ꢀ5,5ꢀdiarylꢀγꢀbutyrolactones 6a-l. The desilylation of cis-3g-j under the both
conditions selectively produced 3,4ꢀtransꢀγꢀbutyrolactones trans-6g-j. At reflux temperature in 1
M
HCl
aq/dioxane,
6a-g,k,l
were
further
transformed
to
(2,2ꢀdiarylꢀ2,3ꢀdihydrobenzofuranꢀ3ꢀyl)acetic acids 7a-g,k,l. On the other hand, methyl esters of
7a-l (8a-l) were formed from 3a-l by treatment with 1 M HCl in MeOH. From cis-3g-j,
threoꢀisomers of 8g-j (threo-8g-j) were selectively obtained with completely retaining the
stereochemistry. Detrimethylsiloxylation of 3a-f or dehydration of 6a-f with refluxing cat.
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3
4
5
6
7
8
9
pꢀTsOH/toluene or xylene afforded 4ꢀdiarylmethyl substituted coumarins 11a-f. Although the
detrimethylsiloxylation of cis-3g,h under the same conditions produced 4ꢀdiarylmethyleneꢀ3ꢀmethyl
substituted coumarins 10g,h, these exoꢀalkenes 10g,h were readily isomerized to endoꢀalkenes
11g,h by treatment with cat. DBU in THF at 25 ºC.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General Methods. Column chromatography was performed on silica gel 60. THF was freshly
distilled from sodium benzophenone ketyl radical. DMF, TMSCl, and TEA were distilled from
CaH2.
Typical Procedure of Electroreductive Coupling. A 0.3 M solution of Bu4NClO4 in THF (15
mL) was placed in the cathodic chamber of a divided cell (40 mL beaker, 3 cm diameter, 6 cm
height) equipped with a platinum cathode (5 X 5 cm2), a platinum anode (2 X 1 cm2), and a ceramic
cylindrical diaphragm (1.5 cm diameter). A 0.3 M solution of Et4NOTs in DMF (4 mL) was placed
in the anodic chamber (inside the diaphragm). Coumarin (1a) (146 mg, 1.0 mmol), benzophenone
(2a) (368 mg, 2.0 mmol), TMSCl (0.64 mL, 5.0 mmol), and TEA (0.70 mL, 5.0 mmol) were added
to the cathodic chamber. After 400 C (2 F/mol for 2a) of electricity was passed at a constant current
of 200 mA at 25 ºC under nitrogen atmosphere, the catholyte was evaporated in vacuo. The residue
was dissolved in diethyl ether (20 mL) and insoluble solid was filtered off. After removal of the
solvent in vacuo, the residue was purified by column chromatography on silica gel (hexanesꢀEtOAc,
10:1) to give 3a (286 mg) in 71% yield.
4-(Diphenyl((trimethylsilyl)oxy)methyl)chroman-2-one (3a): colorless paste (301 mg, 75%); Rf
0.2 (hexanesꢀethyl acetate, 10:1); IR (ATR) 1763 cmꢀ1; 1H NMR (CDCl3) δ −0.16 (s, 9H), 2.27 (dd,
1H, J = 8.1, 17.2 Hz), 3.19 (d, 1H, J = 17.2 Hz), 4.07 (d, 1H, J = 8.1 Hz), 6.76ꢀ6.80 (m, 1H),
6.90ꢀ6.94 (m, 1H), 6.98ꢀ7.01 (m, 1H), 7.11ꢀ7.36 (m, 11H); 13C NMR (CDCl3) δ 1.5 (q), 31.0 (t),
45.3 (d), 84.0 (s), 116.2 (d), 120.9 (s), 122.7 (d), 127.31 (d), 127.34 (d), 127.8 (d), 128.4 (d), 128.6
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(d), 128.7 (d), 131.3 (d), 140.8 (s), 141.1 (s), 152.5 (s), 167.2 (s); HRMS (ESI, ion trap) calcd for
C25H27O3Si (M + H+) 403.1729; found 403.1726.
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73%); Rf 0.4 (hexanesꢀethyl acetate, 5:1); IR (ATR) 1761 cmꢀ1; H NMR (CDCl3) δ −0.16 (s, 9H),
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2.78 (dd, 1H, J = 8.0, 17.2 Hz), 3.15 (d, 1H, J = 17.2 Hz), 4.04 (d, 1H, J = 8.0 Hz), 6.78ꢀ6.81 (m,
1H), 6.93ꢀ7.04 (m, 6H), 7.06ꢀ7.11 (m, 2H), 7.19ꢀ7.28 (m, 3H); 13C NMR (CDCl3) δ 1.5 (q), 30.9 (t),
45.4 (d), 83.1 (s), 114.3 (d, JCCF = 21.6 Hz), 114.4 (d, JCCF = 20.4 Hz), 116.4 (d), 120.5 (s), 123.0 (d),
128.8 (d), 130.4 (d, JCCCF = 8.4 Hz), 130.6 (d, JCCCF = 8.4 Hz), 131.2 (d), 136.4 (s), 136.8 (s), 152.4
(s), 162.19 (s, JCF = 248.3 Hz), 162.23 (s, JCF = 249.8 Hz), 167.1 (s); HRMS (ESI, ion trap) calcd
for C25H25F2O3Si (M + H+) 439.1541; found 439.1538.
4-(5-((Trimethylsilyl)oxy)-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)chroman-2-one (3c):
colorless paste (369 mg, 86%); Rf 0.3 (hexanesꢀethyl acetate, 10:1); IR (ATR) 1767 cmꢀ1; 1H NMR
(CDCl3) δ −0.12 (s, 9H), 2.27 (dd, 1H, J = 9.6, 15.3 Hz), 2.51 (dd, 1H, J = 7.7, 17.0 Hz), 2.64 (dd,
1H, J = 9.6, 15.3 Hz), 2.87 (dd, 1H, J = 9.6, 15.3 Hz), 3.04ꢀ3.11 (m, 2H), 3.73 (d, 1H, J = 7.7 Hz),
6.34ꢀ6.40 (m, 1H), 6.74ꢀ6.80 (m, 1H), 6.96ꢀ7.01 (m, 1H), 7.02ꢀ7.11 (m, 2H), 7.14ꢀ7.20 (m, 2H),
7.22ꢀ7.32 (m, 2H), 7.42ꢀ7.47 (m, 1H), 7.78ꢀ7.84 (m, 1H); 13C NMR (CDCl3) δ 1.8 (q), 30.3 (t), 35.5
(t), 36.1 (t), 51.2 (d), 86.6 (s), 116.3 (d), 121.7 (s), 122.8 (d), 125.2 (d), 125.4 (d), 127.7 (d), 127.8
(d), 128.5 (d), 129.6 (d), 129.9 (d), 130.7 (d), 131.4 (d), 131.8 (d), 139.2 (s), 140.68 (s), 140.73 (s),
141.2 (s), 152.5 (s), 167.8 (s); HRMS (ESI, ion trap) calcd for C27H29O3Si (M + H+) 429.1886;
found 429.1882.
4-(5-((Trimethylsilyl)oxy)-5H-dibenzo[a,d][7]annulen-5-yl)chroman-2-one (3d): white solid
(380 mg, 89%); Rf 0.5 (hexanesꢀethyl acetate, 5:1); mp 201ꢀ203 ºC; IR (ATR) 1759 cmꢀ1; 1H NMR
(CDCl3) δ 0.30 (s, 9H), 2.11 (d, 1H, J = 16.5 Hz), 2.26 (dd, 1H, J = 7.5, 16.5 Hz), 3.83 (d, 1H, J =
7.5 Hz), 5.71ꢀ5.76 (m, 1H), 6.53ꢀ6.58 (m, 1H), 6.95ꢀ7.16 (m, 5H), 7.17ꢀ7.20 (m, 1H), 7.27ꢀ7.32 (m,
1H), 7.35ꢀ7.44 (m, 3H), 7,48ꢀ7.53 (m, 1H), 7.88ꢀ7.91 (m, 1H); 13C NMR (CDCl3) δ 3.0 (q), 29.9 (t),
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38.7 (d), 88.7 (s), 115.8 (d), 121.7 (s), 122.2 (d), 126.96 (d), 126.98 (d), 127.04 (d), 127.1 (d), 127.2
(d), 128.2 (d), 129.3 (d), 130.27 (d), 130.34 (d), 131.6 (d), 131.9 (d), 132.1 (s), 132.4 (s), 139.5 (s),
140.5 (s), 152.6 (s), 168.0 (s). Anal. Calcd for C27H26O3Si: C, 76.02; H, 6.14. Found: C, 76.07; H,
6.13.
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4-(9-((Trimethylsilyl)oxy)-9H-fluoren-9-yl)chroman-2-one (3e): colorless paste (320 mg, 80%);
Rf 0.45 (hexanesꢀethyl acetate, 5:1); IR (ATR) 1769 cmꢀ1; 1H NMR (CDCl3) δ −0.37 (s, 9H), 2.40 (d,
1H, J = 7.5 Hz), 2.50 (dd, 1H, J = 7.5, 16.8 Hz), 3.49 (d, 1H, J = 7.5 Hz), 6.80ꢀ6.85 (m, 1H),
6.98ꢀ7.02 (m, 1H), 7.10ꢀ7.17 (m, 2H), 7.25ꢀ7.30 (m, 2H), 7.32ꢀ7.42 (m, 4H), 7.60ꢀ7.66 (m, 2H); 13C
NMR (CDCl3) δ 0.9 (q), 29.8 (t), 45.9 (d), 85.0 (s), 116.2 (d), 119.96 (d), 120.00 (d), 121.1 (s),
122.8 (d), 124.1 (d), 125.2 (d), 127.1 (d), 127.3 (d), 128.7 (d), 129.1 (d), 129.6 (d), 132.0 (d), 139.6
(s), 139.7 (s), 144.8 (s), 146.6 (s), 152.2 (s), 166.7 (s); HRMS (ESI, ion trap) calcd for C25H24O3Si
(M + H+) 401.1573; found 401.1571.
4-(9-((Trimethylsilyl)oxy)-9H-xanthen-9-yl)chroman-2-one (3f): colorless paste (325 mg, 78%);
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Rf 0.3 (hexanesꢀethyl acetate, 10:1); IR (ATR) 1767 cmꢀ1; H NMR (CDCl3) δ −0.16 (s, 9H), 2.52
(dd, 1H, J = 7.5, 16.6 Hz), 2.79 (d, 1H, J = 16.6 Hz), 3.18 (d, 1H, J = 7.5 Hz), 6.71ꢀ6.77 (m, 1H),
6.87ꢀ6.91 (m, 1H), 6.94ꢀ6.98 (m, 1H), 7.00ꢀ7.14 (m, 5H), 7.24ꢀ7.36 (m, 4H); 13C NMR (CDCl3)
δ 1.5 (q), 29.8 (t), 50.5 (d), 74.0 (s), 115.9 (d), 116.05 (d), 116.12 (d), 120.6 (s), 122.4 (d), 122.5 (d),
122.8 (d), 124.6 (s), 127.4 (d), 127.5 (d), 128.8 (d), 129.1 (d), 129.5 (d), 131.4 (d), 150.0 (s), 150.1
(s), 152.4 (s), 167.2 (s); HRMS (ESI, ion trap) calcd for C25H25O4Si (M + H+) 417.1522; found
417.1519.
(3R*,4S*)-4-(Diphenyl((trimethylsilyl)oxy)methyl)-3-methylchroman-2-one (cis-3g): colorless
paste (358 mg, 86%); Rf 0.3 (hexanesꢀethyl acetate, 10:1); IR (ATR) 1763 cmꢀ1; 1H NMR (CDCl3)
δ −0.14 (s, 9H), 1.25 (d, 3H, J = 6.9 Hz), 2.92ꢀ3.01 (m, 1H), 4.13 (d, 1H, J = 5.8 Hz), 6.75ꢀ6.87 (m,
3H), 6.98ꢀ7.04 (m, 2H), 7.13ꢀ7.21 (m, 3H), 7.24ꢀ7.28 (m, 1H), 7.33ꢀ7.38 (m, 3H), 7.44ꢀ7.50 (m,
2H); 13C NMR (CDCl3) δ 1.7 (q), 14.7 (q), 38.0 (d), 51.4 (d), 84.8 (s), 116.1 (d), 122.5 (d), 124.6 (s),
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126.7 (d), 127.3 (d), 127.6 (d), 128.3 (d), 128.4 (d), 128.7 (d), 130.8 (d), 140.3 (s), 142.0 (s), 152.1
(s), 170.6 (s); HRMS (ESI, ion trap) calcd for C26H29O3Si (M + H+) 417.1886; found 417.1884.
(3R*,4S*)-4-(Bis(4-fluorophenyl)((trimethylsilyl)oxy)methyl)-3-methylchroman-2-one (cis-3h):
colorless paste (380 mg, 84%); Rf 0.25 (hexanesꢀethyl acetate, 10:1); IR (ATR) 1763 cmꢀ1;1H NMR
(CDCl3) δ −0.15 (s, 9H), 1.25 (d, 3H, J = 7.3 Hz), 2.94ꢀ3.02 (m, 1H), 4.07 (d, 1H, J = 5.9 Hz),
6.75ꢀ6.80 (m, 1H), 6.83ꢀ6.89 (m, 4H), 6.93ꢀ6.99 (m, 2H), 7.02ꢀ7.08 (m, 2H), 7.18ꢀ7.23 (m, 2H),
7.38ꢀ7.44 (m, 2H); 13C NMR (CDCl3) δ 1.8 (q), 15.0 (q), 38.1 (d), 51.7 (d), 84.2 (s), 113.9 (d, JCCF
= 20.4 Hz), 114.5 (d, JCCF = 21.6 Hz), 116.6 (d), 122.9 (d), 124.4 (s), 130.4 (d, JCCCF = 8.4 Hz),
130.6 (d, JCCCF = 8.4 Hz), 130.8 (d), 136.1 (s), 137.8 (s), 152.3 (s), 162.3 (s, JCF = 248.0 Hz), 162.4
(s, JCF = 248.0 Hz); HRMS (ESI, ion trap) calcd for C26H27F2O3Si (M + H+) 453.1698; found
453.1694.
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(3R*,4S*)-3-Methyl-4-(5-((trimethylsilyl)oxy)-10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)c
hroman-2-one (cis-3i): colorless paste (230 mg, 52%); Rf 0.4 (hexanesꢀethyl acetate, 10:1); IR
(ATR) 1765 cmꢀ1; 1H NMR (CDCl3) δ −0.12 (s, 9H), 1.55 (d, 3H, J = 7.2 Hz), 2.29ꢀ2.37 (m, 1H),
2.70ꢀ2.77 (m, 1H), 2.83ꢀ2.96 (m, 2H), 4.04 (d, 1H, J = 5.9 Hz), 6.22 (brs, 1H), 6.68ꢀ6.77 (m, 2H),
6.89ꢀ6.93 (m, 1H), 6.95ꢀ7.00 (m, 1H), 7.09ꢀ7.34 (m, 5H), 7.79ꢀ7.83 (m, 1H), 7.93 (brs, 1H); 13C
NMR (CDCl3) δ 1.8 (q), 14.7 (q), 34.8 (t), 36.2 (t), 38.7 (d), 57.0 (d), 87.7 (s), 116.7 (d), 122.9 (d),
125.2 (s), 125.6 (d), 125.7 (d), 127.8 (d), 128.3 (d), 128.6 (d), 129.6 (d), 129.7 (d), 130.0 (d), 131.4
(d), 132.5 (d), 140.8 (s), 141.1 (s), 152.5 (s), 170.7 (s); HRMS (ESI, ion trap) calcd for C28H31O3Si
(M + H+) 443.2042; found 443.2038.
(3R*,4S*)-3-Methyl-4-(5-((trimethylsilyl)oxy)-5H-dibenzo[a,d][7]annulen-5-yl)chroman-2-one
(cis-3j): white solid (378 mg, 86%); Rf 0.3 (hexanesꢀethyl acetate, 10:1); mp 201ꢀ203 ºC; IR (ATR)
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1767 cmꢀ1; H NMR (CDCl3) δ 0.37 (s, 9H), 0.44 (d, 3H, J = 7.5 Hz), 2.69ꢀ2.76 (m, 1H), 4.01 (d,
1H, J = 5.7 Hz), 5.73ꢀ5.76 (m, 1H), 6.47ꢀ6.50 (m, 1H), 6.92ꢀ6.95 (m, 1H), 7.02ꢀ7.06 (m, 1H),
7.08ꢀ7.10 (m, 2H), 7.11 (s, 2H), 7.22ꢀ7.27 (m, 1H), 7.34ꢀ7.43 (m, 3H), 7.44ꢀ7.48 (m, 1H), 7.86ꢀ7.89
(m, 1H); 13C NMR (CDCl3) δ 3.4 (q), 12.3 (q), 37.3 (d), 43.0 (d), 88.1 (s), 116.0 (d), 121.9 (d),
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125.8 (s), 126.5 (d), 126.7 (d), 127.0 (d), 127.27 (d), 127.34 (d), 127.6 (d), 128.4 (d), 128.8 (d),
129.7 (d), 130.2 (d), 132.2 (d), 132.3 (d), 132.6 (s), 133.3 (s), 140.5 (s), 141.7 (s), 152.3 (s), 171.9
(s). Anal. Calcd for C28H28O3Si: C, 76.33; H, 6.41. Found: C, 76.41; H, 6.42.
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4-(Diphenyl((trimethylsilyl)oxy)methyl)-4-methylchroman-2-one (3k): white solid (345 mg,
83%); Rf 0.3 (hexanesꢀethyl acetate, 10:1); mp 173ꢀ175 ºC; IR (ATR) 1761, 1749 cmꢀ1; 1H NMR
(CDCl3) δ −0.26 (s, 9H), 1.52 (s, 3H), 2.42 (d, 1H, J = 16.2 Hz), 3.10 (d, 1H, J = 16.2 Hz),
6.63ꢀ6.69 (m, 1H), 6.83ꢀ6.88 (m, 1H), 7.02ꢀ7.05 (m, 1H), 7.10ꢀ7.18 (m, 4H), 7.20ꢀ7.25 (m, 2H),
7.34ꢀ7.42 (m, 3H), 7.64ꢀ7.69 (m, 2H); 13C NMR (CDCl3) δ 1.3 (q), 24.0 (q), 40.2 (t), 48.2 (s), 88.4
(s), 116.4 (d), 122.5 (d), 126.5 (d), 127.2 (d), 127.4 (d), 127.6 (d), 128.28 (s), 128.31 (d), 129.4 (d),
129.7 (d), 130.1 (d), 141.2 (s), 141.5 (s), 152.2 (s), 168.1 (s). Anal. Calcd for C26H28O3Si: C, 74.96;
H, 6.77. Found: C, 74.97; H, 6.75.
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4-(Bis(4-fluorophenyl)((trimethylsilyl)oxy)methyl)-4-methylchroman-2-one (3l): white solid
(280 mg, 62%); Rf 0.3 (hexanesꢀethyl acetate, 10:1); mp 139ꢀ141 ºC; IR (ATR) 1757 cmꢀ1; 1H NMR
(CDCl3) δ −0.25 (q, 9H), 1.47 (s, 3H), 2.42 (d, 1H, J = 16.0 Hz), 2.98 (d, 1H, J = 16.0 Hz),
6.67ꢀ6.72 (m, 1H), 6.81ꢀ6.87 (m, 2H), 6.89ꢀ6.94 (m, 1H), 7.03ꢀ7.15 (m, 5H), 7.24ꢀ7.29 (m, 1H),
7.60ꢀ7.67 (m, 2H); 13C NMR (CDCl3) δ 1.2 (q), 23.8 (q), 40.1 (t), 48.3 (s), 87.7 (s), 113.4 (d, JCCF
=
21.6 Hz), 114.2 (d, JCCF = 20.4 Hz), 116.6 (d), 122.7 (d), 127.9 (s), 128.7 (d), 129.3 (d), 131.5 (d,
JCCCF = 8.4 Hz), 131.8 (d, JCCCF = 7.2 Hz), 136.9 (s, JCCCCF = 3.6 Hz), 137.2 (s, JCCCCF = 3.3 Hz),
152.2 (s), 161.9 (s, JCF = 248.3 Hz), 162.0 (s, JCF = 249.5 Hz), 167.9 (s). Anal. Calcd for
C26H26F2O3Si: C, 69.00; H, 5.79. Found: C, 69.04; H, 5.80.
4-(Bis(4-methoxyphenyl)((trimethylsilyl)oxy)methyl)chroman-2-one (3m): colorless paste as a
mixture with 2g containing 129 mg of 3m (28%). Although 3m could not be purified, 6m and 8m
were isolated after desilylation with 1 M HCl aq/dioxane and 1 M HCl/MeOH described below; Rf
0.6 (hexanesꢀethyl acetate, 5:1); 1H NMR (CDCl3) δ −0.17 (s, 9H), 2.73 (dd, 1H, J = 8.0, 17.2 Hz),
3.16 (d, 1 H, J = 17.2 Hz), 3.812 (s, 3 H), 3.814 (s, 3H), 4.01 (d, 1 H, J = 8.0 Hz), 6.74ꢀ6.81 (m, 5
H), 6.92ꢀ6.96 (m, 1 H), 6.99ꢀ7.05 (m, 3H), 7.16ꢀ7.21 (m, 3 H); 13C NMR (CDCl3) δ 1.6 (q), 31.0 (t),
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45.7 (d), 55.0 (q), 112.50 (d), 112.54 (d), 116.3 (d), 121.2 (s), 122.8 (d), 128.4 (d), 129.9 (d), 130.1
(d), 134.4 (d), 132.8 (s), 133.3 (s), 152.5 (s), 158.96 (s), 159.04 (s), 167.5 (s); HRMS (ESI, ion trap)
calcd for C27H31O5Si (M + H+) 463.1941; found 463.1939.
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4-(Diphenyl((trimethylsilyl)oxy)methyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one
(3n):
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colorless paste (187 mg, 45%); Rf 0.6 (hexanesꢀethyl acetate, 2:1); IR (ATR) 1672 cmꢀ1; 1H NMR
(CDCl3) δ −0.24 (s, 9H), 2.54 (s, 3H), 2.78 (dd, 1H, J = 8.7, 17.7 Hz), 3.06 (d, 1H, J = 17.7 Hz),
4.06 (d, 1H, J = 8.7 Hz), 6.60ꢀ6.62 (m, 1H), 6.95ꢀ6.98 (m, 1H), 7.09ꢀ7.22 (m, 6H), 7.30ꢀ7.37 (6H);
13C NMR (CDCl3) δ 1.4 (q), 28.6 (q), 33.0 (t), 44.7 (d), 83.1 (s), 113.6 (d), 121.2 (d), 123.5 (s),
126.3 (d), 127.2 (d), 127.6 (d), 127.7 (d), 128.7 (d), 129.2 (d), 130.2 (d), 141.0 (s), 141.05 (s),
141.10 (s), 167.9 (s); HRMS (ESI, ion trap) calcd for C26H30NO2Si (M + H+) 416.2046; found
416.2043.
4-(Trimethylsilyl)chroman-2-one (5): colorless paste (132 mg, 60%); Rf 0.35 (hexanesꢀethyl
acetate, 10:1); IR (ATR) 1761 cmꢀ1; 1H NMR (CDCl3) δ 0.04 (s, 9H), 2.46 (dd, 1H, J = 2.6, 7.5 Hz),
2.86 (dd, 1H, J = 2.6, 16.2 Hz), 2.91 (dd, 1H, J = 7.5, 16.2 Hz), 7.02ꢀ7.09 (m, 3H), 7.15ꢀ7.19 (m,
1H); 13C NMR (CDCl3) δ −3.4 (q), 26.2 (d), 30.3 (t), 117.0 (d), 124.1 (d), 125.7 (s), 126.5 (d), 127.4
(d), 150.9 (s), 168.9 (s); HRMS (ESI) calcd for C12H17O2Si (M + H+) 221.0998; found 221.0997.
Typical Procedure of Desilylation of 3a-l with 1 M HCl aq and dioxane. To a solution of 3a
(101 mg, 0.25 mmol) in dioxane (5 mL) was added 1 M HCl aq (5 mL) at 25 ºC, and then the
solution was stirred at this temperature for 6 h. The mixture was neutralized with sat. NaHCO3 aq
and extracted with ethyl acetate (10 mL X 3). After removal of the solvent in vacuo, the residue was
purified by column chromatography on silica gel (hexanesꢀEtOAc, 3:1) to give 6a (70 mg) in 85%
yield.
Typical Procedure of Desilylation of 3a-l with TBAF in THF. To a solution of 3a (101 mg,
0.25 mmol) in THF (5 mL) was added 1 M TBAF in THF (0.25 mL, 0.25 mmol) at 25 ˚C and the
mixture was stirred for 15 min. After addition of AcOH (15 mg, 0.25 mmol), the solvent was
removed in vacuo. The residue was purified by column chromatography on silica gel
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(hexanesꢀEtOAc, 3:1) to give 6a (78 mg) in 95% yield.
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0.4 (hexanesꢀethyl acetate, 2:1); mp 176ꢀ178 ºC; IR (ATR) 3348, 1746 cmꢀ1; H NMR (CDCl3)
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δ 2.77 (dd, 1H, J = 2.0, 17.5 Hz), 2.98 (dd, 1H, J = 8.7, 17.5 Hz), 5.00 (brs, 1H), 5.02 (dd, 1H, J =
2.0, 8.7 Hz), 6.51ꢀ6.55 (m, 1H), 6.71ꢀ6.76 (m, 1H), 6.92ꢀ7.04 (m, 5H), 7.17ꢀ7.22 (m, 2H), 7.30ꢀ7.35
(m, 1H), 7.38ꢀ7.44 (m, 2H), 7.71ꢀ7.76 (m, 2H); 13C NMR (CDCl3) δ 37.0 (t), 43.6 (d), 94.0 (s),
115.3 (d), 120.4 (d), 125.77 (d), 125.84 (d), 126.1 (s), 126.8 (d), 127.2 (d), 128.0 (d), 128.3 (d),
128.6 (d), 128.8 (d), 140.3 (s), 143.5 (s), 153.3 (s), 177.9 (s). Anal. Calcd for C22H18O3: C, 79.98; H,
5.49. Found: C, 79.93; H, 5.50.
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5,5-Bis(4-fluorophenyl)-4-(2-hydroxyphenyl)dihydrofuran-2(3H)-one (6b): colorless paste (80
1
mg, 87%); Rf 0.45 (hexanesꢀethyl acetate, 2:1); IR (ATR) 3341, 1749 cmꢀ1; H NMR (CDCl3)
δ 2.82 (dd, 1H, J = 2.2, 17.9 Hz), 2.98 (dd, 1H, J = 8.5, 17.9 Hz), 4.95 (dd, 1H, J = 2.2, 8.5 Hz),
5.81 (brs, 1H), 6.56ꢀ6.60 (m, 1H), 6.65ꢀ6.71 (m, 2H), 6.72ꢀ6.77 (m, 1H), 6.88ꢀ6.93 (m, 1H),
6.95ꢀ7.00 (m, 1H), 7.06ꢀ7.13 (m, 4H), 7.66ꢀ7.71 (m, 2H); 13C NMR (CDCl3) δ 36.7 (t), 43.8 (d),
93.3 (s), 114.0 (d, JCCF = 21.6 Hz), 115.3 (d), 115.6 (d, JCCF = 21.6 Hz), 120.5 (d), 125.5 (s), 127.6
(d, JCCCF = 8.4 Hz), 127.8 (d, JCCCF = 8.4 Hz), 128.56 (d), 128.62 (d), 135.9 (s, JCCCCF = 3.0 Hz),
139.0 (s, JCCCCF = 3.0 Hz), 153.3 (s), 161.5 (s, JCF = 247.1 Hz), 162.3 (s, JCF = 247.7 Hz), 177.6 (s);
HRMS (ESI, ion trap) calcd for C22H17F2O3 (M + H+) 367.1146; found 367.1144.
3'-(2-Hydroxyphenyl)-3',4',10,11-tetrahydro-5'H-spiro[dibenzo[a,d][7]annulene-5,2'-furan]-5'
-one (6c): white solid (82 mg, 92%); Rf 0.45 (hexanesꢀethyl acetate, 2:1); mp 211ꢀ213 ºC; IR (ATR)
1
3310, 1744 cmꢀ1; H NMR (CDCl3, 60 °C) δ 2.57 (d, 1H, J = 17.2 Hz), ), 2.64ꢀ2.74 (m, 1H),
2.90ꢀ3.03 (m, 2H), 3.32ꢀ3.43 (m, 1H), 3.77ꢀ3.87 (m, 1H), 4.70ꢀ4.80 (m, 1H), 6.10 (brs, 1H),
6.54ꢀ6.66 (m, 2H), 6.75ꢀ6.83 (m, 1H), 6.74ꢀ7.02 (m, 4H), 7.09ꢀ7.23 (m, 3H), 7.53ꢀ7.59 (m, 1H),
7.68ꢀ7.76 (m, 1H); 13C NMR (CDCl3, 60 °C) δ 32.3 (t), 32.5 (t), 36.9 (t), 47.2 (d), 93.1 (s), 115.7
(d), 120.4 (d), 123.9 (d), 125.6 (d), 125.8 (d), 126.3 (d), 126.4 (s), 127.6 (d), 128.2 (d), 128.3 (d),
ꢀ 29 ꢀ
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