Multicomponent Coupling Reaction Using Arynes: Synthesis of Xanthene Derivatives

Article abstract of DOI:10.1021/acs.joc.5b01452

One-pot synthesis of xanthene derivatives was achieved by a route involving the cascade three-component coupling reaction of arynes with DMF and active methylenes followed by the S_N2′ reaction of three-component coupling products with thiols. T

Full text of DOI:10.1021/acs.joc.5b01452

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Multi-component Coupling Reaction Using Arynes: Synthesis of Xanthene Derivatives
Eito Yoshioka, Masatoshi Nishimura, Takashi Nakazawa, Shigeru Kohtani and Hideto Miyabe*
School of Pharmacy, Hyogo University of Health Sciences, Minatojima, Kobe 650-8530, Japan.
E-mail: miyabe@huhs.ac.jp
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FAX: (+81) 78-304-2794
ABSTRACT
Oneꢀpot synthesis of xanthene derivatives was achieved by a route involving the cascade threeꢀcomponent coupling
reaction of arynes with DMF and active methylenes followed by the SN2’ reaction of threeꢀcomponent coupling
products with thiols. The reactivity of threeꢀcomponent coupling products toward nucleophiles and the further
conversion of oxygen heterocycles allowing facile incorporation of structural variety were studied.
Synthetic strategies involving cascade/domino/tandem process offer the advantage of multiple carbonꢀcarbon
and/or carbonꢀheteroatom bond formations in a single operation.1,2 In recent years, arynes have gained increased
attention as highly reactive species for constructing the multiꢀsubstituted arenes.3 In particular, the multiꢀcomponent
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coupling reactions using arynes continue to attract much interest.4,5 Recently, we reported the insertion of arynes into
the C=O bond of formamides6,7 and its application to the cascade process trapping the transient intermediates with
nucleophiles or dienophiles.8 In this paper, we describe the synthetic application to prepare the oxygen heterocycles
such as xanthene derivatives via a route involving threeꢀcomponent coupling reaction of arynes with
N,Nꢀdimethylformamide (DMF) and active methylenes followed by the SN2’ reaction of threeꢀcomponent coupling
products with thiols. We also report the further conversion of xanthene derivatives allowing facile incorporation of
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structural variety.
O
a)
b)
TBAF
H
NMe2
O
MeO
OH
O
Me
Me
MeO
O
O
rt, 12 h
TMS
OTf
2
O
Me
Me
O
1
4 (69%)
rt, 12 h
O
3
MeO
MeO
-bond
insertion
NMe2
NMe2
F
1
O
O
A
O
MeO
O
MeO
NMe2
O
O
Me2NH
D
4
Me
Me
Me
Me
O
O
O
OH
C
B
5
Scheme 1. Oneꢀpot fourꢀcomponent coupling reaction.8a
In our previous study,8a we reported that fourꢀcomponent coupling reaction using two different 1,3ꢀdiketones
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2 and 3 gave the xanthene derivative 4 by a oneꢀpot procedure (Scheme 1). This transformation involves the insertion
of aryne into the C=O of DMF giving benzoxetene A and orthoꢀquinone methide B,9 which are trapped by anion C.
The xanthene 4 is formed by the SN2’ reaction of threeꢀcomponent coupling product 5 and anion D.
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Scheme 2. Reaction of threeꢀcomponent coupling products 5, 8 and 10 with second nucleophiles.
However, the structural variety of oxygen heterocycles prepared by this fourꢀcomponent coupling reaction is
limited as shown below. For further expansion of this multiꢀstep sequential transformation, we first directed our
attention to the reactivity of threeꢀcomponent coupling products such as 5 and the adaptability of second nucleophiles
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in the SN2’ reaction trapping 5. Our experiments began with the investigation of the reactivity of 5, 8 and 10 (Scheme
2). The SN2’ reaction of 5 with 1,3ꢀdiketones 3 or 6 proceeded effectively to give xanthenes 4 and 7 in good chemical
yields. Similarly, tricyclic substrate 8 has shown the excellent reactivity toward 1,3ꢀdiketone 3. In marked contrast, no
reaction was observed when bicyclic substrate 10 was employed. Next, the adaptability of second nucleophiles was
studied. Under the similar conditions, the acyclic active methylenes such as acetylacetone and diethyl malonate did not
work as a second nucleophile trapping 5. Consequently, the usable nucleophile is limited to cyclic 1,3ꢀdiketones.
To understand the different reactivities between tricyclic substrates and bicyclic substrate, we calculated the
stable conformations of 8 and 10 (Figure 1).10 In the optimized structure of 8, the hydroxyl group occupies pseudoꢀaxial
direction which would be crucial for the efficiency of SN2’ process. In contrast, the computational structure
optimization of 10 supported the formation of stable intramolecular hydrogen bond between the hydroxyl group and the
carbonyl group.
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Pseudo-axial conformation
Hydrogen-bonding conformation
Me
Me
Me
O
O
O
O
OH
vs
H
O
O
O
Me
Nu
tricyclic substrate 8
bicyclic substrate 10
Figure 1. Stable conformations of substrates 8 and 10.
With these results in mind, the reactive tricyclic substrate 8 was used in further investigations screening the
usable nucleophiles. We found that thiophenol acted as a second nucleophile in SN2’ reaction of tricyclic substrate 8
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(Table 1). Initially, we allowed tricyclic substrate 8 to react with 2 equivalents of thiophenol in CH3CN at room
temperature (entry 1). The desired xanthene derivative 11a having a phenylthio group at 9 position was obtained in
22% yield, accompanied by 43% yield of the recovered starting material 8. The chemical yield of 11a increased to 51%
when the reaction was carried out under reflux conditions (entry 2). The further improvement in the chemical yield was
observed by employing acetic acid as an additive at room temperature (entry 3), although the use of trifluoroacetic acid
(TFA) was less effective (entry 4). These results indicate that the mild Brønsted acid is suitable for the activation of the
hydroxyl group as a leaving group. In contrast, the reaction of bicyclic substrate 10 with thiophenol did not proceed
effectively (entry 5). For comparison, phenol did not work even under the acidic conditions (entries 6 and 7).
Table 1. Reaction with thiophenol or phenola
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MeO
O
MeO
SPh O
PhSH or PhOH
CH3CN, 12 h
O
O
OH
11a
8
Enrty
Substrate
Nucleophile
(2.0 equiv.)
PhSH
PhSH
PhSH
PhSH
PhSH
PhOH
PhOH
Additive
(0.5 equiv.)
none
none
AcOH
TFA
AcOH
none
AcOH
Temp.
Yield (%)b
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10
8
8
rt
reflux
22 (43)
51 (10)
89
complex mixture
not detected
trace
rt
rt
rt
rt
rt
trace
a Reactions were carried out with 8 or 10 (1.0 equiv.) and nucleophile (2.0 equiv.) in CH3CN.
b Isolated yield. The yield in parentheses is for the recovered substrate 8.
Next, we allowed tricyclic substrate 8 to react with ethanethiol (EtSH) in the presence of acetic acid (Scheme
3). As expected, the xanthene derivative 11b was isolated in 97% yield. Good yield was obtained when tricyclic
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substrate 5 was employed.
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Scheme 3. Reaction of 8 or 5 with thiols.
We were gratified to observe the sufficient nucleophilicity of thiols toward tricyclic substrates under mild
acidic conditions. Therefore, the SN2’ reaction with thiols was next applied to the oneꢀpot fourꢀcomponent coupling
reaction starting from the insertion of arynes to DMF (Scheme 4).11 After a solution of triflate 1 (1.0 equiv.),
1,3ꢀdiketone 3 (1.2 equiv.) and anhydrous TBAF (3.0 equiv.) in DMF was stirred at room temperature for 3 h, a
solution of thiophenol (4.0 equiv.) and acetic acid (6.0 equiv.) in CH3CN was added to the reaction mixture. Although
the desired xanthene 11a was obtained in 16% yield, xanthene 9, generated by the reaction of 8 with 1,3ꢀdiketone 3,
was a major product. Improvement in the chemical yield of xanthene 11a was observed by changing the amounts of
triflate 1 and 1,3ꢀdiketone 3. When triflate 1 (1.2 equiv.) and 1,3ꢀdiketone 3 (1.0 equiv.) were employed, the fromation
of 9 was mostly suppressed to afford 11a in 71% yield. Under the similar reaction conditions, fourꢀcomponent coupling
reactions giving xanthenes 11b, 12 and 14 proceeded effectively by a oneꢀpot procedure. These transformations involve
the formation of two C–C, two C–O and C–S bonds.
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Scheme 4. Oneꢀpot fourꢀcomponent coupling reactions.
To synthesize xanthene derivatives with structural variety, we finally investigated the further conversion of
the fourꢀcomponent coupling products 14 and 11a having a phenylthio group at 9 position (Scheme 5). To introduce the
alkyl group, the nucleophilic substitution of 14 with organometallic reagents was evaluated. Among several reagents,12
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the use of diethylzinc led to the formation of the ethylated xanthene 15 in 96% yield. Similarly, the ethylated xanthene
16 was formed form 11a. This conversion was successfully applied to the reaction using diethyl malonate 17 and Et2Zn
via the formation of zinc complex E.12 As expected, the desired product 18 was obtained in 95% yield, allowing facile
incorporation of structural variety. It is important to note that the obtained xanthene derivatives 15, 16 and 18 could not
be synthesized by the direct SN2’reaction of threeꢀcomponent coupling products such as 8 with Et2Zn or diethyl
malonate 17.
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Scheme 5. Further conversion of 14 and 11a using dialkylzincs.
In conclusion, we have developed the multiꢀcomponent coupling reaction for the synthesis of xanthene
derivatives. Most of the synthetic approaches to the benzoꢀfused oxygen heterocycles have involved the use of phenol
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derivatives.13 Therefore, new approaches using transition metalꢀcatalyzed aromatic C–O bond formation continues to
attract much interest.14 This cascade reaction is important as an alternative approach involving the aromatic C–O
bondꢀforming process using arynes and DMF.
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Experimental Section
General. Melting points are uncorrected. 1H NMR spectra were measured at 400 or 600 MHz with CDCl3 or C6D6 as
an internal standard (7.26 or 7.15 ppm, respectively). 13C NMR spectra were measured at 101 or 151 MHz with CDCl3
or C6D6 as an internal standard (77.0 or 128.0 ppm, respectively). HRMS measurements using electrospray ionization
(ESI) were performed with a timeꢀofꢀflight (TOF) mass analyzer.
We reported the experimental procedure for preparing of 2Hꢀchromenes 8 and 10 in our previous paper.8a According
to this procedure, 2Hꢀchromene 5 was prepared.8e
2,3,4,4a-Tetrahydro-4a-hydroxy-8-methoxy-3,3-dimethyl-1H-xanthen-1-one (5). Colorless crystals. Sublimated
decomposition Mp 118ꢀ120 °C (CH2Cl2–iꢀPrOH). IR (KBr) 3417, 2957, 1671, 1603, 1566, 1467 cmꢀ1. 1H NMR (C6D6)
δ 8.21 (1H, s), 6.94 (1H, br t, J = 8.0 Hz), 6.73 (1H, br d, J = 8.0 Hz), 6.03 (1H, br d, J = 8.0 Hz), 3.20 (3H, s), 2.39
(1H, br s), 2.32 (1H, dd, J = 16.0, 1.5 Hz), 2.13 (1H, dd, J = 14.0, 1.0 Hz), 2.03 (1H, br d, J = 14.0 Hz), 1.91 (1H, br d,
J = 16.0 Hz), 0.94 (3H, s), 0.69 (3H, s). 13C NMR (C6D6) δ 196.1, 158.2, 153.9, 132.2, 128.7, 124.7, 111.0, 110.3,
103.4, 96.7, 55.2, 52.6, 48.7, 31.4, 30.3, 27.8. HRMS (ESI+) calcd for C16H18O4Na (M+Na+): 297.1097, Found:
297.1095.
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General procedure for the reaction of 5, 8 and 10 with 1,3-diketones 3 or 6. To a solution of 5, 8 or 10 (0.10
mmol) and 1,3ꢀdiketones 3 or 6 (0.10 mmol) in DMF (1.0 mL) was added a solution of anhydrous TBAF (63 mg, 0.20
mmol) in DMF (0.10 mL) under argon atmosphere at room temperature. After being stirred at room temperature for 12
h, silica gel (0.50 g) was added to the reaction mixture, which was concentrated under reduced pressure. Purification of
the residue by flash silica gel column chromatography (AcOEt:hexane = 1:10–1:0 with 2% CH2Cl2) afforded the
products 4 (31 mg, 84%), 7 (32 mg, 81%) and 9 (27 mg, 79%). We reported the characterization data of 4 in our
previous paper.8a
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2,3,4,9-Tetrahydro-9-(2-hydroxy-5,5-dimethyl-6-oxo-1-cyclohexen-1-yl)-8-methoxy-3,3-dimethyl-1H-xanthen-
1-one (7). Brown solid. IR (KBr) 3179, 2960, 1713, 1618, 1588, 1469, 1381 cmꢀ1. 1H NMR (CDCl3) δ 10.49 (1H, s),
7.11 (1H, br dt, J = 8.2, 1.4 Hz), 6.68 (1H, br dd, J = 8.2, 1.0 Hz), 6.54 (1H, br d, J = 8.2 Hz), 4.69 (1H, s), 3.72 (3H, s),
2.78ꢀ2.44 (2H, m), 2.34 (1H, d, J = 17.9 Hz), 2.31 (1H, d, J = 17.9 Hz), 2.00 (1H, d, J = 17.4 Hz), 1.91 (1H, d, J = 17.4
Hz), 1.90ꢀ1.75 (2H, m), 1.12 (3H, s), 1.11 (3H, s), 0.97 (3H, s), 0.93 (3H, s). 13C NMR (CDCl3) δ 205.9, 196.8, 170.9,
168.4, 156.3, 151.9, 127.5, 116.8, 112.5, 110.4, 108.2, 105.7, 55.3, 50.7, 43.1, 40.1, 33.5, 30.6, 30.0, 25.4, 25.1, 24.9,
24.3, 23.9. HRMS (ESI+) calcd for C24H29O5 (M+H+): 397.2010, Found: 397.2005.
2,3,4,9-Tetrahydro-9-(2-hydroxy-6-oxo-1-cyclohexen-1-yl)-8-methoxy-1H-xanthen-1-one (9). Colorless crystals.
Mp 182.5ꢀ184 °C (CH2Cl2–iꢀPrOH). IR (KBr) 3072, 2945, 1646, 1617, 1588, 1469 cmꢀ1. 1H NMR (CDCl3) δ 10.55 (1H,
s), 7.13 (1H, t, J = 8.0 Hz), 6.69 (1H, dd, J = 8.0, 1.0 Hz), 6.57 (1H, dd, J = 8.0, 1.0 Hz), 4.73 (1H, s), 3.75 (3H, s), 2.74
(1H, dt, J = 18.0, 5.0 Hz), 2.60ꢀ2.50 (3H, m), 2.43ꢀ2.36 (2H, m), 2.13 (1H, m), 2.06ꢀ1.99 (3H, m), 1.82 (1H, m), 1.72
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(1H, m). C NMR (CDCl3) δ 201.2, 197.2, 172.7, 170.7, 156.8, 151.9, 127.6, 118.2, 112.9, 112.6, 108.3, 106.4, 55.7,
37.2, 36.0, 29.6, 27.8, 23.7, 20.0, 19.9. HRMS (ESI+) calcd for C20H21O5 (M+H+): 341.1384, Found: 341.1383.
General procedure for the reaction of 5 and 8 with thiols. To a solution of 5 or 8 (0.10 mmol) in CH3CN (0.85
mL) were added thiophenol or ethanethiol (0.20 mmol) and acetic acid (3.0 µL, 0.050 mmol) under argon atmosphere
at room temperature. After being stirred at room temperature for 12 h, the reaction mixture was concentrated under
reduced pressure. Purification of the residue by flash silica gel column chromatography (AcOEt:hexane = 1:20–1:0
with 2% CH2Cl2) afforded the products 11a (30 mg, 89%), 11b (28 mg, 97%) and 12 (34 mg, 93%).
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2,3,4,9-Tetrahydro-8-methoxy-9-(phenylthio)-1H-xanthen-1-one (11a). Colorless crystals. Mp 130ꢀ133 °C
(CH2Cl2–hexanes). IR (KBr) 2943, 2892, 1641, 1585, 1482, 1470, 1382 cmꢀ1. 1H NMR (CDCl3) δ 7.30 (1H, br t, J =
7.8 Hz), 7.14 (3H, br t, J = 7.8 Hz), 7.00 (2H, br dd, J = 7.8, 1.0 Hz), 6.68 (1H, d, J = 8.2 Hz), 6.41 (1H, d, J = 8.2 Hz),
5.49 (1H, s), 3.89 (3H, s), 2.52 (1H, dt, J = 17.6, 1.0 Hz), 2.41ꢀ2.32 (2H, m), 2.22 (1H, dt, J = 17.6, 1.0 Hz), 2.02ꢀ1.89
(2H, m). 13C NMR (CDCl3) δ 195.8, 167.7, 156.9, 151.3, 137.1, 131.9, 128.8, 128.1, 127.8, 111.8, 110.7, 108.2, 106.5,
55.9, 36.9, 35.6, 27.4, 20.2. HRMS (ESI+) calcd for C20H18O3SNa (M+Na+): 361.0869, Found: 361.0872.
2,3,4,9-Tetrahydro-8-methoxy-9-(ethylthio)-1H-xanthen-1-one (11b). Colorless oil. IR (KBr) 2959, 1643, 1589,
1483, 1379 cmꢀ1. 1H NMR (CDCl3) δ 7.18 (1H, br t, J = 8.2 Hz), 6.68 (1H, br d, J = 8.2 Hz), 6.67 (1H, br d, J = 8.2 Hz),
5.20 (1H, s), 3.89 (3H, s), 2.72 (1H, dt, J = 17.9, 5.0 Hz), 2.62ꢀ2.34 (5H, m), 2.34ꢀ2.05 (2H, m), 1.12 (3H, t, J = 7.6 Hz).
13C NMR (CDCl3) δ 196.4, 167.5, 156.9, 151.5, 128.0, 112.6, 112.3, 108.5, 106.8, 55.9, 37.0, 30.2, 27.7, 24.3, 20.4,
14.0. HRMS (ESI+) calcd for C16H18O3SNa (M+Na+): 313.0869, Found: 313.0868.
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2,3,4,9-Tetrahydro-8-methoxy-3,3-dimethyl-9-(phenylthio)-1H-xanthen-1-one (12). Colorless crystals. Mp
147ꢀ148 °C (CH2Cl2–hexanes). IR (KBr) 2958, 1664, 1647, 1585, 1469, 1382 cmꢀ1. 1H NMR (CDCl3) δ 7.29ꢀ7.25 (1H,
m), 7.17ꢀ7.12 (3H, m), 7.05 (2H, br dt, J = 8.2, 1.6 Hz), 6.66 (1H, br d, J = 8.2 Hz), 6.45 (1H, br d, J = 8.2 Hz), 5.50
(1H, s), 3.83 (3H, s), 2.32 (1H, d, J = 16.0 Hz), 2.31 (1H, d, J = 16.0 Hz), 2.25 (1H, d, J = 17.4 Hz), 2.19 (1H, d, J =
17.4 Hz), 1.12 (3H, s), 1.03 (3H, s). 13C NMR (CDCl3) δ 195.8, 166.0, 156.9, 151.5, 136.5, 132.5, 128.5, 128.2, 127.9,
111.8, 110.2, 108.4, 106.4, 55.8, 50.9, 41.3, 35.9, 32.1, 28.9, 28.1. HRMS (ESI+) calcd for C22H22O3SNa (M+Na+):
389.1182, Found: 389.1184.
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General procedure for the one-pot four-component coupling reaction. To a solution of triflates 1 or 13 (0.24
mmol) and 1,3ꢀdiketones 2 or 3 (0.20 mmol) in DMF (2.0 mL) was added a solution of anhydrous TBAF (227 mg, 0.72
mmol) in DMF (0.36 mL) under argon atmosphere at room temperature. After being stirred at room temperature for 3 h,
a solution of thiophenol or ethanethiol (0.60 mmol) and acetic acid (114 µL, 2.0 mmol) in CH3CN (2.0 mL) was added
to the reaction mixture. After being stirred at room temperature for 16 h, silica gel (2.0 g) was added to the reaction
mixture, which was concentrated under reduced pressure. Purification of the residue by flash silica gel column
chromatography (AcOEt:hexane = 1:20–1:0 with 2% CH2Cl2) afforded the products 11a (48 mg, 71%), 11b (42 mg,
72%), 12 (57 mg, 78%) and 14 (36 mg, 58%).
2,3,4,9-Tetrahydro-9-(phenylthio)-1H-xanthen-1-one (14).13a Colorless crystals. Mp 86ꢀ87 °C (CH2Cl2–hexanes).
IR (KBr) 3058, 2950, 1663, 1640, 1579, 1483, 1458, 1382 cmꢀ1. 1H NMR (CDCl3) δ 7.36ꢀ7.34 (1H, m), 7.31 (1H, br t,
J = 7.8 Hz), 7.19ꢀ7.13 (4H, m), 6.99 (2H, br d, J = 7.8 Hz), 6.78ꢀ6.73 (1H, m), 5.32 (1H, s), 2.57 (1H, dt, J = 17.0, 5.0
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Hz), 2.48ꢀ2.31 (3H, m), 2.08ꢀ1.99 (2H, m). 13C NMR (CDCl3) δ 196.1, 168.0, 150.5, 137.0, 131.1, 129.6, 129.0, 128.1
(2C), 125.1, 122.5, 115.8, 110.5, 40.4, 36.8, 27.5, 20.2. HRMS (ESI+) calcd for C19H16O2SNa (M+Na+): 331.0763,
Found: 331.0764.
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General procedure for the reaction of 11a and 14 with Et2Zn. To a solution of xanthenes 11a or 14 (0.10 mmol)
in diethyl ether (2.0 mL) was added Et2Zn (1.05 M in hexane, 0.19 mL, 0.20 mmol) under argon atmosphere at 0 °C.
After being stirred at room temperature for 4 h, the reaction mixture was diluted with diethyl ether and 0.1 M HCl, and
then extracted with diethyl ether. The organic phase was dried over MgSO4 and concentrated under reduced pressure.
Purification of the residue by flash silica gel column chromatography (AcOEt:hexane = 1:6–1:0 with 2% CH2Cl2)
afforded the products 15 (22 mg, 96%) and 16 (24 mg, 93%).
2,3,4,9-Tetrahydro-9-ethyl-1H-xanthen-1-one (15). Colorless crystals. Mp 73ꢀ74 °C (hexanes). IR (KBr) 2959,
2871, 1643, 1581, 1486, 1456, 1388 cmꢀ1. 1H NMR (CDCl3) δ 7.20ꢀ7.08 (3H, m), 6.99 (1H, br d, J = 8.3 Hz), 3.94 (1H,
t, J = 5.0 Hz), 2.65 (1H, dt, J = 17.4, 5.0 Hz), 2.60ꢀ2.33 (2H, m), 2.37 (1H, m), 2.11ꢀ2.00 (2H, m), 1.74ꢀ1.55 (2H, m),
0.67 (3H, t, J = 7.3 Hz). 13C NMR (CDCl3) δ 197.6, 167.8, 150.7, 129.0, 127.2, 125.4, 124.6, 115.9, 113.6, 37.1, 32.2,
29.9, 27.8, 20.6, 9.1. HRMS (ESI+) calcd for C15H16O2Na (M+Na+): 251.1043, Found: 251.1048.
2,3,4,9-Tetrahydro-9-ethyl-8-methoxy-1H-xanthen-1-one (16). Colorless crystals. Mp 132ꢀ133 °C (hexanes). IR
(KBr) 2959, 4647, 1586, 1482, 1466, 1388 cmꢀ1. 1H NMR (CDCl3) δ 7.12 (1H, br t, J = 8.2 Hz), 6.62 (2H, br d, J = 8.2
Hz), 4.24 (1H, t, J = 4.6 Hz), 3.81 (3H, s), 2.63 (1H, dt, J = 17.4, 5.0 Hz), 2.57ꢀ2.47 (2H, m), 2.35 (1H, m), 2.08ꢀ2.00
(2H, m), 1.75ꢀ1.58 (2H, m), 0.60 (3H, t, J = 7.6 Hz). 13C NMR (CDCl3) δ 197.5, 167.8, 157.3, 151.7, 127.2, 114.2,
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113.7, 108.4, 106.1, 55.5, 37.1, 27.7, 27.2, 26.9, 20.6, 8.9. HRMS (ESI+) calcd for C16H18O3Na (M+Na+): 281.1148,
Found: 281.1142.
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Procedure for the reaction of 14 with diethyl malonate 17 and Et2Zn. To a solution of diethyl malonate 17 (76 µL,
0.50 mmol) in diethyl ether (2.0 mL) was added Et2Zn (1.05 M in hexane, 0.19 mL, 0.20 mmol) under argon
atmosphere at 0 °C. After being stirred at 0 °C for 30 min, a solution of xanthene 14 (31 mg, 0.10 mmol) in diethyl
ether (2.0 mL) was added to the reaction mixture at 0 °C. After being stirred at 30 °C for 48 h, the reaction mixture was
diluted with diethyl ether and 0.1 M HCl, and then extracted with diethyl ether. The organic phase was dried over
MgSO4 and concentrated under reduced pressure. Purification of the residue by flash silica gel column chromatography
(AcOEt:hexane = 1:6–1:0 with 2% CH2Cl2) afforded the product 18 (34 mg, 95%).
2-(2,3,4,9-Tetrahydro-1-oxo-1H-xanthen-9-yl)-propanedioic acid, 1,3-diethyl ester (18). Colorless crystals. Mp
57ꢀ58 °C (hexanes). IR (KBr) 2981, 2939, 1730, 1644, 1458, 1386 cmꢀ1. 1H NMR (CDCl3) δ 7.48 (1H, dd, J = 7.8, 1.4
Hz), 7.21 (1H, m), 7.08 (1H, m), 7.00 (1H, dd, J = 8.2, 0.9 Hz), 4.74 (1H, d, J = 3.7 Hz), 4.19 (2H, q, J = 7.1 Hz), 3.92
(2H, br d, J = 7.1 Hz), 3.68 (1H, d, J = 3.7 Hz), 2.71ꢀ2.48 (3H, m), 2.38 (1H, m), 2.10ꢀ2.03 (2H, m), 1.25 (3H, t, J = 7.1
Hz), 1.06 (3H, t, J = 7.1 Hz). 13C NMR (CDCl3) δ 197.1, 169.0, 168.2, 167.8, 151.0, 129.9, 128.3, 124.7, 121.5, 116.1,
111.5, 61.4, 61.0, 57.6, 36.9, 31.4, 28.0, 20.4, 14.0, 13.7. HRMS (ESI+) calcd for C20H22O6Na (M+Na+): 381.1309,
Found: 381.1295.
Procedure for the reaction of 14 with EtMgBr. To a solution of xanthenes 14 (62 mg, 0.20 mmol) in diethyl ether
(4.0 mL) was added EtMgBr (1.0 M in THF, 0.80 mL, 0.80 mmol) under argon atmosphere at 0 °C. After being stirred
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at room temperature for 14 h, the reaction mixture was diluted with AcOEt and 0.1 M HCl, and then extracted with
AcOEt. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification of the residue
by preparative TLC (AcOEt:hexane = 1:6) afforded the product 19 (21 mg, 44%).
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(1E)-9-Ethyl-1-ethylidene-2,3,4,9-tetrahydro-1H-xanthene (19). Colorless oil. IR (KBr) 2965, 2931, 1712, 1604,
1577, 1475, 1452 cmꢀ1. 1H NMR (CDCl3) δ 7.14 (1H, dd, J = 8.1, 0.9 Hz), 7.11 (1H, m), 7.01 (1H, td, J = 8.1, 0.9 Hz),
6.94 (1H, br d, J = 7.8 Hz), 5.47 (1H, q, J = 6.9 Hz), 3.69 (1H, t, J = 4.8 Hz), 2.53 (1H, dt, J = 15.1, 4.8 Hz), 2.44 (1H,
dt, J = 16.5, 5.0 Hz), 2.34 (1H, ddd, J = 16.5, 9.2, 5.0 Hz), 2.15 (1H, br m), 1.85 (1H, m), 1.79ꢀ1.54 (3H, m), 1.74 (3H,
d, J = 6.9 Hz), 0.70 (3H, t, J = 7.6 Hz). 13C NMR (CDCl3) δ 151.8, 148.8, 133.4, 128.6, 126.7, 125.5, 122.8, 115.4,
113.5, 110.6, 35.1, 29.5, 27.8, 25.4, 21.9, 13.6, 9.5. HRMS (ESI) calcd for C17H20ONa (M+Na+): 263.1406, Found:
263.1420. HRMS (ESI) calcd for C17H22O2Na (M+H2O+Na+): 281.1512, Found: 281.1530.
Procedure for the reaction of 14 with diethyl α-bromomalonate 20 and Et2Zn. To a solution of diethyl
αꢀbromomalonate 20 (165 µL, 1.0 mmol) in diethyl ether (2.0 mL) was added Et2Zn (1.0 M in hexane, 0.50 mL, 0.50
mmol) under argon atmosphere at 0 °C. After being stirred at 0 °C for 30 min, a solution of xanthene 14 (31 mg, 0.10
mmol) in diethyl ether (2.0 mL) was added to the reaction mixture at 0 °C. After being stirred at room temperature for
24 h, the reaction mixture was diluted with diethyl ether and 0.1 M HCl, and then extracted with diethyl ether. The
organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification of the residue by
preparative TLC (AcOEt:hexane = 1:2 with 2% CH2Cl2) afforded the products 18 (7.2 mg, 20%) and 21 (15 mg, 34%).
2-Bromo-2-(2,3,4,9-tetrahydro-1-oxo-1H-xanthen-9-yl)-propanedioic acid, 1,3-diethyl ester (21). Colorless
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crystals. Mp 73ꢀ74 °C (hexanes). IR (KBr) 2981, 2938, 1738, 1663, 1642, 1457, 1380 cmꢀ1. H NMR (CDCl3) δ 7.56
(1H, dd, J = 8.2, 1.4 Hz), 7.26 (1H, td, J = 8.2, 1.4 Hz), 7.14ꢀ7.07 (2H, m), 5.35 (1H, s), 4.25ꢀ4.11 (4H, m), 2.81 (1H, dt,
J = 17.9, 3.9 Hz), 2.60ꢀ2.52 (2H, m), 2.32ꢀ2.11 (2H, m), 2.05 (1H, m), 1.29 (3H, t, J = 7.1 Hz), 1.25 (3H, t, J = 7.1 Hz).
13C NMR (CDCl3) δ 196.8, 170.1, 165.8, 165.6, 152.5, 130.5, 128.7, 124.7, 121.0, 116.3, 110.1, 71.2, 63.5, 63.0, 37.7,
36.8, 28.3, 19.7, 13.7; One carbon peak was missing due to overlapping. HRMS (ESI+) calcd for C20H2279BrO6
(M+H+): 437.0594, Found: 437.0597. HRMS (ESI+) calcd for C20H2281BrO6 (M+H+): 439.0577, Found: 439.0577.
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Acknowledgements
This work was partially supported by JSPS KAKENHI GrantꢀinꢀAid for Scientific Research (C) Grant Numbers
25460028 and 15K07879.
Supporting Information
The computationally optimized structures, tables of atom coordinates and absolute energies of 8 and 10, the reaction of
14 with organometallic reagents and 1H and 13C NMR spectra of newly obtained products are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
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of diethyl malonate 17, the competitive formation of the αꢀbrominated product 21 was observed (See: Supporting
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