A Concise Synthesis of Asymmetrically 4,5-Disubstituted 9,9-Dimethyl-9 H -xanthenes

Article abstract of DOI:10.1055/s-0034-1379368

A concise synthesis of asymmetrically 4,5-disubstituted 9,9-dimethyl-9H-xanthenes was developed. The monolithiation of 4,5-dibromo-9H-xanthene, subsequent zincation, and the Negishi coupling with diverse electrophiles afforded the corresponding 4-aryl- or 4-vinyl-9H-xanthenes in good yields and with high selectivity. The second substitution reactions were performed under mild reaction conditions, thus providing a convenient synthetic route to functionalized molecules based on the 9H-xanthene skeleton.

Full text of DOI:10.1055/s-0034-1379368

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 187–192
paper
187
R. Matsubara et al.
Paper
Synthesis
A Concise Synthesis of Asymmetrically 4,5-Disubstituted
9,9-Dimethyl-9H-xanthenes
Asymmetrically 4,5-Disubstituted 9H-Xanthenes
Ryosuke Matsubara*
t-Bu
t-Bu
t-Bu
Miki Koide
t-BuLi
ZnCl2
Pd(dba)2 (cat.)
Ph3P (cat.)
electrophile
R1
Br
Br
R1
Br
Yong-Soon Shin
Toshiyuki Shimada
Masahiko Hayashi
O
O
O
R2
THF, 20 °C, 24 h
11 examples
Department of Chemistry, Graduate School of Science,
Kobe University, 1-1 Rokkodai, Nada, Kobe, 657-8501, Japan
matsubara.ryosuke@people.kobe-u.ac.jp
+
8
1
7
(
8
8
)
0
3
5
7
9
9
t-Bu
t-Bu
t-Bu
R2 = aryl, vinyl, alkyl, boryl,
hydroxy, trifluoromethyl
R1 = aryl, vinyl, acyl
Received: 17.09.2014
Swager
Schwalbe
Accepted after revision: 30.09.2014
Published online: 10.11.2014
DOI: 10.1055/s-0034-1379368; Art ID: ss-2014-f0568-op
t-Bu
t-Bu
Mes
S
R
N
N
N
Zn
N
Abstract A concise synthesis of asymmetrically 4,5-disubstituted 9,9-
dimethyl-9H-xanthenes was developed. The monolithiation of 4,5-di-
bromo-9H-xanthene, subsequent zincation, and the Negishi coupling
with diverse electrophiles afforded the corresponding 4-aryl- or 4-vinyl-
9H-xanthenes in good yields and with high selectivity. The second sub-
stitution reactions were performed under mild reaction conditions,
thus providing a convenient synthetic route to functionalized molecules
based on the 9H-xanthene skeleton.
S
O
Mes
O
N
N
S
N
t-Bu
t-Bu
S
Key words xanthenes, metalation, cross-coupling, palladium, zinc
Barloy
t-Bu
Nocera
t-Bu
9,9-Dimethyl-9H-xanthene (9,9-DMX) has a rigid archi-
tecture (Figure 1); the two substituents at the 4- and 5-po-
sitions are located in parallel to each other with a fixed
distance. Therefore, 9,9-DMX can be used as a backbone of
the functionalized molecules with the active sites at the 4-
and 5-positions of 9,9-DMX, as exemplified by Xantphos,1 a
bidentate phosphine ligand with a large bite angle. Several
asymmetrically 4,5-disubstituted 9,9-DMXs (R1 ≠ R2) have
been reported as functionalized materials and catalysts as
shown in Figure 2.2
O
PPh2
OH
R
O
O
Cl
N
Mn
O
N
O
t-Bu
N
t-Bu
t-Bu
t-Bu
R
Figure 2 Asymmetrically 4,5-disubstituted 9H-xanthenes as function-
alized molecules
R1
R2
O
were often further substituted by di-tert-butyl groups at
the 2- and 7-positions.3 The modification of only one bro-
mine atom was implemented by the halogen–lithium ex-
change with alkyllithium reagents followed by nucleophilic
reactions.2 The exception is the synthesis of a chemosensor
dye,4 in which the Mizoroki–Heck reaction of 4,5-dibromo-
9,9-DMX with a vinylarene afforded the monoadduct, albeit
with low selectivity (mono/di = 4:1). To the best of our
knowledge, the selective monoarylation of 4,5-dibromo-
asymmetrically 4,5-disubstituted (R1 ≠ R2)
9,9-dimethyl-9H-xanthenes
Figure 1 9,9-Dimethyl-9H-xanthenes
4,5-Dibromo-9,9-DMX is the common intermediate of
the asymmetrically 4,5-disubstituted 9,9-DMXs, which
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 187–192

188
R. Matsubara et al.
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Synthesis
9,9-DMXs by coupling reactions has not been reported. In
this paper, we report a concise synthesis of asymmetrically
4,5-disubstituted 9,9-DMXs using the selective coupling re-
actions.
treatment of 1 with t-BuLi (1.2 equiv) followed by ZnCl2 (1.4
equiv) underwent the Negishi cross-coupling reaction6
with methyl 4-iodobenzoate (1.4 equiv) in the presence of
the palladium catalyst (10 mol%) to afford monoarylated
product 2a in 68% yield (Table 1, entry 1). Diarylated prod-
uct 3 was obtained in <5% yield. The selectivity in the lithia-
tion was determined to be 5:86:9 (1/Li-1/Li2-1) by the
treatment of the lithiated xanthenes with MeOH. With the
suitable reaction conditions for the selective monoarylation
of 1, the substrate scope of this reaction was investigated
(Table 1). Diverse aryl iodides participated in the Negishi
coupling resulting in moderate to good yields, regardless of
the electronic nature of the substituents on aryl iodides
(entries 2–6). The xanthenes with a formyl group could be
synthesized efficiently (entries 7 and 8). The basic nitrogen
atom did not affect the cross-coupling reaction (entry 9).
Both aryl and vinyl iodides underwent coupling with 1 un-
der the standard reaction conditions; vinyl-9H-xanthene 2j
was obtained in a reasonable yield (52%, entry 10). The in-
termediate organozinc species derived from 1 could be
trapped using an acid chloride without catalyst, affording
monoacylated product 2k (entry 11).
To demonstrate the utility of the developed method for
the synthesis of asymmetrically 4,5-disubstituted 9,9-
DMXs, several functionalizations of product 2a were con-
ducted (Scheme 3).7 The olefination of 2a resulted in high
yields by either Migita–Kosugi–Stille coupling8 (step b) or
Mizoroki–Heck reaction9 (step c). The Suzuki–Miyaura cou-
pling10 of 2a introduced the second aryl substituent into the
9H-xanthene backbone (step d). The Miyaura boration11 of
2a proceeded smoothly to afford borylated 9H-xanthene 7
in a high yield (step e). Pinacol borate 7 served as the inter-
mediate for further transformations to synthesize diverse
asymmetrically 4,5-disubstituted 9,9-DMXs. The Suzuki–
Miyaura coupling of 7 with an aryl iodide afforded the cor-
responding 4,5-diaryl-9,9-DMX 6b (step f). The oxidation of
7 with sodium perborate introduced a hydroxyl group on
the 9H-xanthene scaffold (step g). The installation of the tri-
fluoromethyl group on the 9H-xanthene scaffold could be
achieved by reacting 7 with the CuCF3 reagent (step h).12
The hydrolysis of 713 followed by the rhodium-catalyzed
1,4-conjugate addition14 to cyclohex-2-en-1-one afforded
alkylated product 10 (step i). Thus, diverse asymmetrically
4,5-disubstituted 9,9-DMXs could be synthesized using this
method.
First, the transition-metal-catalyzed cross-coupling re-
action of 1 with arylboronic acid was attempted (Scheme
1). Because monoarylated product 2 may be less reactive
than starting material 1 due to steric hindrance, a selective
monocoupling reaction may be possible. Therefore, the re-
action of equimolar amounts of 1 and arylboronic acid was
carried out in the presence of Pd(PPh3)4 as the catalyst.
However, a mixture of monoarylated product 2 and di-
arylated product 3 was obtained in a nonselective manner
(2/3 = 2:1 to 1:1). A change in the solvent, base, or the tran-
sition metal catalyst did not improve the selectivity of the
reaction.5 To our surprise, even when two equivalents of 1
to arylboronic acid were used, the selectivity did not im-
prove; a considerable amount of 3 was still obtained. This is
probably because the π-electrons of the newly substituted
aryl group of 2 may coordinate to the palladium catalyst
and promote its oxidative addition to the second C–Br
bond, resulting in more amounts of diarylated product 3
than that expected only because of the steric factor
(Scheme 2).
t-Bu
t-Bu
t-Bu
Br
Br
Ar
Ar
Ar
[Pd], [Ni]
ArB(OH)2
O
O
O
+
Br
t-Bu
t-Bu
t-Bu
1
2
3
Scheme 1 Attempted reaction of 4,5-dibromo-9,9-dimethyl-9H-xan-
thene (1) with arylboronic acid
t-Bu
t-Bu
fast
O
Pd
O
3
Br
Pd Br
t-Bu
t-Bu
2-Pd
In conclusion, we have developed a concise synthesis of
asymmetrically 4,5-disubstituted 9,9-DMXs. The selective
metal–halogen exchange of 4,5-dibromo-9,9-DMX afforded
a monolithiated species, which was transmetalated to zinc
organometallics and coupled with diverse reagents afford-
ing the corresponding monofunctionalized 9H-xanthenes.
The 9H-xanthenes were then transformed to the corre-
sponding asymmetrically 4,5-disubstituted 9,9-DMXs,
which are potentially useful functionalized molecules.
Scheme 2 Facilitated second oxidative addition due to the neighbor-
ing aryl group
Finding that the C–Br bonds of 1 and 2 have similar sus-
ceptibility to oxidative addition by palladium, another
strategy was considered, in which 1 would be subjected to
halogen–metal exchange resulting in monometalation, fol-
lowed by treatment with a haloarene. Under the optimized
reaction conditions, the organozinc species prepared by the
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Table 1 Monofunctionalization of 4,5-Dibromo-2,7-di-tert-butyl-9,9-
dimethyl-9H-xanthenea
corded using JEOL JNM-LA 400 and Bruker Avance 500 instruments
using Me4Si (δ = 0 ppm) and CDCl3 (δ = 77.0 ppm) as the internal stan-
dard, respectively. Standard abbreviations are used to report NMR
spectra. Due to the machine feature, inevitable noises were observed
at 96 and 74 ppm in 13C NMR spectra taken by the JEOL JNM-LA 400
spectrometer. Mass spectra were measured using a JEOL JMS-T100LP
mass spectrometer. Elemental analyses were carried out using a
Yanako CHN Corder MT-5 instrument. Preparative column chroma-
tography was carried out using Fuji Silysia BW-4:10MH silica gel or
YMC_GEL Silica (6 nm, I-40-63 μm). TLC was carried out using Merck
25 TLC aluminum sheets, silica gel 60 F254. 4,5-Dibromo-2,7-di-tert-
butyl-9,9-DMX (1) was synthesized according to the reported meth-
od.3
t-Bu
t-Bu
t-BuLi (1.2 equiv)
ZnCl2 (1.4 equiv)
Pd(dba)2 (10 mol%)
Ph3P (20 mol%)
Br
Br
R
O
O
electrophile (1.4 equiv)
THF, 20 °C, 24 h
Br
t-Bu
t-Bu
1
2
4-Aryl-5-bromo-2,7-di-tert-butyl-9,9-dimethyl-9H-xanthenes 2a–i and
4-Bromo-2,7-di-tert-butyl-9,9-dimethyl-5-[(1E)-oct-1-en-1-yl]-9H-xan-
thene (2j); General Procedure
Entry
Electrophile
Product
Yield (%)b
68
A THF solution of t-BuLi (0.25 M, 0.25 mmol) was added to a stirred
solution of 4,5-dibromo-2,7-di-tert-butyl-9,9-DMX (1; 100 mg, 0.21
mmol) in THF (3 mL) over 30 min using a syringe pump at –78 °C. The
stirring was continued for 1 h at –78 °C. Then, a THF solution of ZnCl2
(1 M, 0.29 mL, 0.29 mmol) was added to the solution, and the result-
ing mixture was warmed to r.t. The stirring was continued for 30 min
at r.t., and then Pd(dba)2 (12 mg, 0.021 mmol), Ph3P (11 mg, 0.042
mmol) and the appropriate aryl iodide or trans-1-iodooct-1-ene (0.29
mmol) were added to the solution in this order. The mixture was
stirred for 24 h at r.t. The reaction was quenched by adding sat. aq
NH4Cl (5 mL), and the mixture was extracted with CH2Cl2 (3 × 10 mL).
The combined organic layers were dried (MgSO4), and the residue ob-
tained after evaporation was purified by chromatography on silica gel
(EtOAc–hexane) to afford the product.
1
2
3
4
5
6
7
I
CO2Me
2a
2b
2c
2d
2e
2f
73
52
57
54
58
50
I
I
I
I
I
I
OMe
NO2
Ac
CN
4-Bromo-2,7-di-tert-butyl-5-[4-(methoxycarbonyl)phenyl]-9,9-di-
methyl-9H-xanthene (2a)
Yield: 74.9 mg (68%); white solid; mp 174.9–176.1 °C; Rf = 0.50
(hexane–EtOAc, 10:1).
2g
CHO
IR (neat, ATR): 2962, 2903, 2867, 1719, 1612, 1568, 1477, 1445, 1417,
1398 cm–1
.
CHO
O
8
2h
70
1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 8.4 Hz, 2 H), 7.81 (d, J = 8.4
Hz, 2 H), 7.46 (d, J = 2.4 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.36 (d, J = 2.4
Hz, 1 H), 7.31 (d, J = 2.4 Hz, 1 H), 3.97 (s, 3 H), 1.68 (s, 6 H), 1.37 (s, 9
H), 1.31 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 167.3, 146.9, 146.1, 145.2, 142.8,
131.2, 130.3, 130.0, 129.1, 128.6, 128.4, 128.1, 126.1, 122.5, 121.6,
115.6, 110.1, 52.1, 35.3, 34.6, 34.6, 32.1, 31.5, 31.4
I
I
9
2i
2j
69
52
N
I
10
n-C6H13
HRMS (ESI): m/z [M + Na]+ calcd for C31H35BrO3 + Na: 557.1667;
O
found: 557.1651.
11c
2k
34
OMe
Cl
Anal. Calcd for C31H35BrO3: C, 69.53; H, 6.59. Found: C, 69.90; H, 6.64.
O
a See the experimental section for details.
b Isolated yield.
4-Bromo-2,7-di-tert-butyl-9,9-dimethyl-5-phenyl-9H-xanthene (2b)
Yield: 70 mg (73%); white solid; mp 151.5–153.8 °C; Rf = 0.30
(hexane).
c Pd(dba)2 and Ph3P were not added.
IR (neat, ATR): 2962, 2866, 1602, 1568, 1475, 1456, 1434, 1403, 1362,
1325 cm–1
.
All reactions were carried out in well-cleaned and oven-dried glass-
ware under magnetic stirring. The operations were performed under
an atmosphere of dry argon using Schlenk and vacuum techniques.
All the starting materials were obtained from commercial sources or
synthesized following standard procedures. Melting points were mea-
sured using a Yanaco MP-500D instrument and are not corrected. IR
spectra were recorded as films on a Thermo Scientific Nicolet iS5 FT-
IR spectrophotometer in ATR mode. 1H and 13C NMR spectra were re-
1H NMR (400 MHz, CDCl3): δ = 7.73 (dd, J = 8.0, 1.6 Hz, 2 H), 7.48–7.44
(m, 2 H), 7.42–7.40 (m, 2 H), 7.38–7.36 (m, 1 H), 7.35 (d, J = 2.4 Hz, 1
H), 7.31 (d, J = 2.4 Hz, 1 H), 1.68 (s, 6 H), 1.37 (s, 9 H), 1.31 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 146.7, 145.9, 145.6, 145.3, 138.0,
131.4, 130.3, 129.8, 129.3, 128.3, 127.9, 127.1, 126.3, 121.7, 121.6,
110.2, 35.3, 34.5, 34.5, 32.0, 31.5, 31.3.
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Synthesis
CO2Me
Br
Br
Ar
Ar
O
O
O
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
4
1
b
5
c
R
a
68%
Br
89%
80%
Ar
Ar
CF3
Ar
O
d
88%
O
O
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
2a
9
Ar = 4-MeO2CC6H4
6a R = H
6b R = OMe
f
h
O
49%
i
e
82%
B(pin)2
49%
Ar
OH
Ar
Ar
O
g
O
O
89%
90%
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
8
10
7
Scheme 3 Synthesis of asymmetrically 4,5-disubstituted 9,9-DMXs. Reagents and conditions: (a) t-BuLi (1.2 equiv), THF, –78 °C, 1 h; ZnCl2 (1.4 equiv),
–78 °C, 1 h; Pd(dba)2 (10 mol%), Ph3P (20 mol%), 4-MeO2CC6H4I (1.4 equiv), 20 °C, 24 h, 68%; (b) Pd2(dba)3 (5 mol%), P(t-Bu)3 (11 mol%), Bu3Sn(vinyl)
(1.05 equiv), toluene, 25 °C, 17 h, 89%; (c) Pd(dba)2 (20 mol%), P(o-Tol)3 (40 mol%), Et3N (1 equiv), methyl acrylate (4 equiv), THF, 80 °C, 44 h, 80%;
(d) Pd(PPh3)4 (20 mol%), K2CO3 (2 equiv), PhB(OH)2 (3 equiv), DMF, 80 °C, 50 h, 88% (6a); (e) PdCl2(dppf) (13 mol%), KOAc (3 equiv), B2(pin)2 (3.3
equiv), DMSO, 100 °C, 46 h, 82%; (f) Pd(PPh3)4 (10 mol%), K2CO3 (2 equiv), 4-MeOC6H4I (1.2 equiv), 80 °C, 26 h, 49% (6b); (g) NaBO3·4H2O (3 equiv),
THF–H2O (1:1, v/v), 25 °C, 4 h, 90%; (h) [(phen)CuCF3] (1.2 equiv), KF (1 equiv), DMF, 50 °C, air, 14 h, 49%; (i) 1. aq 1 M HCl (0.6 equiv), NaIO4 (3 equiv),
H2O–THF (1:4, v/v), 25 °C, 1 h, 95%, 2. [Rh(cod)2]BF4 (10 mol%), cyclohex-2-en-1-one (1.2 equiv), KOH (0.1 equiv), H2O–1,4-dioxane (1:2, v/v), 25 °C,
23 h, 94%.
HRMS (ESI): m/z [M + Na]+ calcd for C29H33BrO + Na: 499.1613; found:
499.1607.
IR (neat, ATR): 2961, 2902, 2864, 1597, 1515, 1442, 1394, 1344, 1264,
1244 cm–1
.
Anal. Calcd for C29H33BrO: C, 72.95; H, 6.97. Found: C, 72.69; H, 6.98.
1H NMR (400 MHz, CDCl3): δ = 8.33 (d, J = 6.8 Hz, 2 H), 7.90 (d, J = 8.8
Hz, 2 H), 7.51 (d, J = 2.4 Hz, 1 H), 7.43 (d, J = 2.0 Hz, 1 H), 7.37 (d, J = 2.4
Hz, 1 H), 7.30 (d, J = 2.0 Hz, 1 H), 1.69 (s, 6 H), 1.38 (s, 9 H), 1.31 (s, 9
H).
4-Bromo-2,7-di-tert-butyl-5-(4-methoxyphenyl)-9,9-dimethyl-9H-
xanthene (2c)
Yield: 54.7 mg (52%); white solid; mp 150.3–152.2 °C; Rf = 0.50
(hexane–benzene, 2:1).
13C NMR (100 MHz, CDCl3): δ = 147.2, 146.9, 146.4, 145.3, 145.1,
145.0, 131.2, 131.1, 130.3, 128.5, 126.9, 126.0, 123.4, 123.2, 121.8,
110.1, 35.3, 34.6, 34.5, 32.1, 31.4, 31.3.
IR (neat, ATR): 2961, 1609, 1514, 1464, 1440, 1422, 1400, 1361 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 8.0 Hz, 2 H), 7.41 (d, J = 2.0
Hz, 1 H), 7.38 (d, J = 2.8 Hz, 1 H), 7.35 (d, J = 2.4 Hz, 1 H), 7.29 (d, J = 2.0
Hz, 1 H), 7.02 (d, J = 8.8 Hz, 2 H), 3.88 (s, 3 H), 1.67 (s, 6 H), 1.36 (s, 9
H), 1.31 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 158.8, 146.7, 145.9, 145.6, 145.3,
131.4, 131.4, 130.4, 129.7, 128.9, 128.3, 126.1, 121.6, 121.3, 113.3,
110.1, 55.3, 35.3, 34.5, 32.0, 31.5, 31.3.
HRMS (ESI): m/z [M + Na]+ calcd for C29H32BrNO3 + Na: 544.1463;
found: 544.1450.
Anal. Calcd for C29H32BrNO3: C, 66.67; H, 6.17; N, 2.68. Found: C,
66.58; H, 6.24; N, 2.59.
4-(4-Acetylphenyl)-5-bromo-2,7-di-tert-butyl-9,9-dimethyl-9H-xan-
thene (2e)
Yield: 59.2 mg (54%); white solid; mp 187.4–189.8 °C; Rf = 0.35
(hexane–EtOAc, 10:1).
HRMS (ESI): m/z [M + Na]+ calcd for C30H35BrO2 + Na: 529.1718;
found: 529.1714.
IR (neat, ATR): 2960, 2865, 1681, 1605, 1478, 1440, 1395, 1361, 1261,
Anal. Calcd for C30H35BrO2: C, 71.00; H, 6.95. Found: C, 70.79; H, 7.00.
1243 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 8.4 Hz, 2 H), 7.85 (d, J = 8.8
Hz, 2 H), 7.47 (d, J = 2.8 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.36 (d, J = 2.4
Hz, 1 H), 7.31 (d, J = 2.4 Hz, 1 H), 2.67 (s, 3 H), 1.69 (s, 6 H), 1.38 (s, 9
H), 1.31 (s, 9 H).
4-Bromo-2,7-di-tert-butyl-9,9-dimethyl-5-(4-nitrophenyl)-9H-xan-
thene (2d)
Yield: 62.3 mg (57%); yellow solid; mp 236.3–237.9 °C; Rf = 0.20
(hexane–benzene, 10:1).
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13C NMR (100 MHz, CDCl3): δ = 198.3, 147.0, 146.2, 145.3, 145.3,
143.1, 137.9, 135.6, 131.2, 130.5, 130.1, 129.8, 128.4, 128.0, 126.1,
122.7, 121.7, 107.8, 35.3, 34.5, 34.5, 32.1, 31.4, 31.3.
HRMS (ESI): m/z [M + Na]+ calcd for C31H35BrO2 + Na: 541.1718;
found: 541.1753.
4-Bromo-2,7-di-tert-butyl-9,9-dimethyl-5-(pyridin-2-yl)-9H-xanthene
(2i)
Yield: 68.6 mg (69%); white solid; mp 172.2–173.7 °C; Rf = 0.30
(hexane–EtOAc, 10:1).
IR (neat, ATR): 2960, 2867, 1588, 1566, 1467, 1441, 1434, 1405, 1363,
1288 cm–1
.
Anal. Calcd for C31H35BrO2: C, 71.67; H, 6.79. Found: C, 71.60; H, 6.89.
1H NMR (400 MHz, CDCl3): δ = 8.75 (d, J = 10.4 Hz, 1 H), 8.15 (d, J = 8.0
Hz, 1 H), 7.77 (td, J = 8.0, 2.0 Hz, 1 H), 7.73 (d, J = 2.4 Hz, 1 H), 7.48 (d,
J = 2.8 Hz, 1 H), 7.42 (d, J = 2.4 Hz, 1 H), 7.37 (d, J = 2.0 Hz, 1 H), 7.27–
7.24 (m, 1 H), 1.68 (s, 6 H), 1.39 (s, 9 H), 1.32 (s, 9 H).
4-Bromo-2,7-di-tert-butyl-5-(4-cyanophenyl)-9,9-dimethyl-9H-xan-
thene (2f)
Yield: 60.3 mg (58%); white solid; mp 204.3–206.5 °C; Rf = 0.80 (ben-
13C NMR (100 MHz, CDCl3): δ = 155.6, 149.4, 146.9, 146.1, 145.7,
145.3, 135.5, 131.4, 129.8, 128.4, 127.8, 126.6, 126.4, 123.3, 121.9,
121.8, 110.0, 35.2, 34.6, 34.5, 32.2, 31.5, 31.3.
HRMS (DART): m/z [M + H]+ calcd for C28H33BrNO: 478.1746; found:
478.1714.
zene).
IR (neat, ATR): 2959, 2229, 1607, 1567, 1441, 1394, 1362, 1264, 1247
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.0 Hz, 2 H), 7.76 (d, J = 8.4
Hz, 2 H), 7.48 (d, J = 2.4 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.36 (d, J = 2.4
Hz, 1 H), 7.26 (d, J = 2.0 Hz, 1 H), 1.68 (s, 6 H), 1.37 (s, 9 H), 1.31 (s, 9
H).
13C NMR (100 MHz, CDCl3): δ = 206.4, 147.2, 146.4, 145.2, 145.1,
142.9, 131.7, 131.2, 131.0, 130.2, 128.5, 127.4, 125.9, 123.1, 121.7,
110.6, 110.1, 35.3, 34.5, 34.5, 32.1, 31.4, 31.3.
4-Bromo-2,7-di-tert-butyl-9,9-dimethyl-5-[(1E)-oct-1-en-1-yl]-9H-xan-
thene (2j)
Yield: 37.0 mg (52%); colorless liquid; Rf = 0.70 (hexane–EtOAc,
100:1).
IR (neat, ATR): 2957, 2924, 2855, 1479, 1442, 1362, 1270, 1250, 1208,
HRMS (ESI): m/z [M + Na]+ calcd for C30H32BrNO + Na: 524.1565;
found: 524.1538.
1197, 1112, 969, 872, 815 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.45 (d, J = 2.4 Hz, 1 H), 7.39 (d, J = 2.4
Hz, 1 H), 7.34 (d, J = 2.4 Hz, 1 H), 7.27 (d, J = 2.8 Hz, 1 H), 7.05 (d, J =
15.6 Hz, 1 H), 6.41 (dt, J = 16.4, 6.8 Hz, 1 H), 2.31 (q, J = 7.2 Hz, 2 H),
1.61 (s, 6 H), 1.54–1.50 (m, 8 H), 1.34 (s, 9 H), 1.32 (s, 9 H), 0.92–0.89
(m, 3 H).
4-Bromo-2,7-di-tert-butyl-5-(4-formylphenyl)-9,9-dimethyl-9H-xan-
thene (2g)
Yield: 51.6 mg (50%); white solid; mp 197.4–199.1 °C; Rf = 0.45
(hexane–EtOAc, 10:1).
13C NMR (100 MHz, CDCl3): δ = 146.7, 145.7, 145.6, 145.4, 132.5,
131.7, 129.7, 128.1, 125.4, 124.2, 121.6, 121.2, 120.8, 110.3, 35.3, 34.5,
34.5, 33.5, 31.8, 31.6, 31.5, 31.4, 29.2, 28.9, 22.6, 14.1.
HRMS (DART): m/z [M + H]+ calcd for C31H44BrO: 511.2576; found:
511.2531.
IR (neat, ATR): 2958, 1695, 1605, 1564, 1466, 1443, 1423, 1404, 1391,
1362 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 10.10 (s, 1 H), 7.99 (d, J = 8.0 Hz, 2 H),
7.91 (d, J = 8.0 Hz, 2 H), 7.48 (d, J = 2.4 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H),
7.36 (d, J = 2.0 Hz, 1 H), 7.31 (d, J = 2.4 Hz, 1 H), 1.69 (s, 6 H), 1.38 (s, 9
H), 1.31 (s, 9 H).
Anal. Calcd for C31H43BrO: C, 72.78; H, 8.47. Found: C, 72.96; H, 8.76.
13C NMR (100 MHz, CDCl3): δ = 192.5, 147.1, 146.3, 145.3, 145.2,
144.6, 135.0, 131.2, 131.0, 130.2, 129.4, 128.4, 127.9, 126.1, 122.9,
121.7, 35.3, 34.6, 34.5, 32.1, 32.1, 31.4, 31.3.
HRMS (DART): m/z [M + H]+ calcd for C30H34BrO2: 505.1742; found:
505.1739.
Methyl (5-Bromo-2,7-di-tert-butyl-9,9-dimethyl-9H-xanthen-4-yl)oxo-
acetate (2k)
A THF solution of t-BuLi (0.25 M, 0.25 mmol) was added to a stirred
solution of 1 (100 mg, 0.21 mmol) in THF (3 mL) over 30 min using a
syringe pump at –78 °C. The stirring was continued for 1 h at –78 °C.
Then, a THF solution of ZnCl2 (1 M, 0.29 mL, 0.29 mmol) was added to
the solution, and the mixture was warmed to r.t. The stirring was
continued for 30 min at r.t., and then methyl chlorooxoacetate (36 mg,
0.29 mmol) was added to the solution. The mixture was stirred for 24
h at r.t. The reaction was quenched by adding H2O (5 mL), and the
mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried (MgSO4), and the residue obtained after evaporation
was purified by chromatography on silica gel (EtOAc–hexane); yield:
34.6 mg (34%); white solid; mp 208.0–210.0 °C; Rf = 0.50 (hexane–
EtOAc, 10:1).
4-Bromo-2,7-di-tert-butyl-5-(5-formylfuran-2-yl)-9,9-dimethyl-9H-
xanthene (2h)
Yield: 73.2 mg (70%); orange solid; mp 162.3–164.0 °C; Rf = 0.35
(hexane–EtOAc, 10:1).
IR (neat, ATR): 2961, 1674, 1569, 1511, 1445, 1407, 1363, 1268, 1239,
1220 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.71 (s, 1 H), 8.02 (d, J = 4.0 Hz, 1 H),
7.96 (d, J = 2.4 Hz, 1 H), 7.50 (d, J = 2.8 Hz, 1 H), 7.48 (d, J = 2.4 Hz, 1 H),
7.43 (d, J = 4.0 Hz, 1 H), 7.40 (d, J = 2.4 Hz, 1 H), 1.68 (s, 6 H), 1.39 (s, 9
H), 1.33 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 177.5, 155.7, 151.2, 147.5, 146.3,
145.5, 145.1, 131.2, 130.0, 128.8, 124.2, 122.8, 122.1, 116.9, 114.2,
109.6, 35.0, 34.6, 34.5, 32.5, 31.4, 31.3.
IR (neat, ATR): 2961, 1756, 1740, 1680, 1602, 1568, 1446, 1403, 1363,
1323 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.65 (d, J = 2.0 Hz, 1 H), 7.60 (d, J = 2.0
Hz, 1 H), 7.45 (d, J = 2.0 Hz, 1 H), 7.35 (d, J = 2.0 Hz, 1 H), 3.99 (s, 3 H),
1.66 (s, 6 H), 1.35 (s, 9 H), 1.32 (s, 9 H).
HRMS (ESI): m/z [M + Na]+ calcd for C28H31BrO3 + Na: 517.1354;
13C NMR (125 MHz, CDCl3): δ = 187.0, 162.8, 147.7, 147.6, 146.3,
144.1, 130.6, 129.9, 128.8, 128.5, 126.1, 123.3, 122.0, 109.7, 53.2, 34.9,
34.7, 34.6, 32.6, 31.3, 31.3.
found: 517.1370.
Anal. Calcd for C28H31BrO3: C, 67.88; H, 6.31. Found: C, 67.59; H, 6.35.
HRMS (DART): m/z [M + H]+ calcd for C26H32BrO4: 487.1484; found:
487.1474.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 187–192

192
R. Matsubara et al.
Paper
Synthesis
(5) The different reaction conditions were as follows: catalyst:
Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd/C, NiCl2(dppp); base:
CsF, Cs2CO3, K2CO3, K3PO4; solvent: DME, DMF with or without
H2O, toluene, THF, Et2O; temp: 40–100 °C.
(6) King, A. O.; Okukado, N.; Negishi, E. J. Chem. Soc., Chem.
Commun. 1977, 683.
(7) Compound 2a bearing a methyl ester group was selected as the
substrate for the purpose of demonstrating that the transforma-
tions shown in Scheme 1 can be applied to the substrates
bearing electrophilic substituents. Lithiation and subsequent
derivatizations such as alkylation and phosphorylation would
be possible if the substrates have no functional groups that
would react with the alkyllithium reagent in the bromine–
lithium exchange reaction.
Acknowledgment
Financial support from a Grant-in-Aid for Scientific Research on Inno-
vative Areas ‘Advanced Molecular Transformations by Organocata-
lysts’ from MEXT, Japan, The UBE Foundation, The Japan Prize
Foundation, and Chugai Pharmaceutical Co., Ltd. Award in Synthetic
Organic Chemistry, Japan is appreciated.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379368.
S
u
p
p
ortioInfgrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 187–192