Synthesis of spiro[4.5]cyclohexadienones with an allene motif via a base-promoted intramolecular ipso-Friedel-Crafts addition of phenols to propargyl bromides

Article abstract of DOI:10.1016/j.tet.2013.02.082

We developed a novel synthetic method for allenyl spiro[4.5] cyclohexadienone derivatives based on a base-promoted intramolecular ipso-Friedel-Crafts addition of phenols to propargyl bromides. The present spirocyclization proceeded in a CH₂Cl₂-tert-BuOH mixed solvent system using potassium tert-butoxide as the base, and produced the corresponding spiro[4.5]cyclohexadienone derivatives with an allene motif in up to 99% yield. This-type allenyl spirocycle was also accessible through Pd-catalyzed intramolecular ipso-Friedel-Crafts alkylation when a propargyl carbonate derivative with a naphthol unit was used as a substrate. Acid-promoted skeletal rearrangement of the reaction adducts was also examined.

Full text of DOI:10.1016/j.tet.2013.02.082

Tetrahedron 69 (2013) 3403e3409
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Tetrahedron
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Synthesis of spiro[4.5]cyclohexadienones with an allene motif via
a base-promoted intramolecular ipso-FriedeleCrafts addition of
phenols to propargyl bromides
*
Tetsuhiro Nemoto, Riliga Wu, Zengduo Zhao, Takuya Yokosaka, Yasumasa Hamada
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 January 2013
Received in revised form 18 February 2013
Accepted 22 February 2013
Available online 26 February 2013
We developed a novel synthetic method for allenyl spiro[4.5]cyclohexadienone derivatives based on
a base-promoted intramolecular ipso-FriedeleCrafts addition of phenols to propargyl bromides. The
present spirocyclization proceeded in a CH2Cl2etert-BuOH mixed solvent system using potassium tert-
butoxide as the base, and produced the corresponding spiro[4.5]cyclohexadienone derivatives with an
allene motif in up to 99% yield. This-type allenyl spirocycle was also accessible through Pd-catalyzed in-
tramolecular ipso-FriedeleCrafts alkylation when a propargyl carbonate derivative with a naphthol unit
was used as a substrate. Acid-promoted skeletal rearrangement of the reaction adducts was also examined.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Alkylation
Dearomatization
ipso-FriedeleCrafts addition
Palladium
Spiro compounds
1. Introduction
derivatives with an allene motif, resulting in characteristic reaction
profiles. To investigate the reactivity, we planned to synthesize the
Efficient construction of spirocyclic frameworks is an important
topic in synthetic organic chemistry because of their broad distri-
bution in biologically active natural products and pharmaceuticals,
as well as their usefulness in complex molecule syntheses. Among
the various spirocycles, spirocyclohexadienones are the most im-
portant class of compounds in organic synthesis.1 Extensive efforts
have been focused on the development of an efficient synthetic
method based on hypervalent iodine reagents,2 ipso-halocycliza-
tion,3 radical cyclization,4 areneeRu complex-mediated dearoma-
allenyl spirocyclohexadienone intermediates B as pure compounds.
They could not be selectively obtained through this Pd catalysis,
however, due to the difficulty in stopping this cascade process along
the way. Therefore, an alternative synthetic method was developed.
In addition, potential synthetic utilities of B-type compounds led us
tization,5 Cu-catalyzed oxygenation of
a
-azido-N-arylamides,6
transition metal-catalyzed ipso-FriedeleCrafts allylic alkylation of
phenols,7,8 and Pd-catalyzed arylative dearomatization.9
We recently reported a novel synthetic method for spirocyc-
lohexadienone derivatives based on a Pd-catalyzed intramolecular
ipso-FriedeleCrafts addition of phenols to h
3-propargylpalladium(II)
complexes (Scheme 1).10 When para-substituted phenol derivatives
with a propargyl carbonate moiety A was reacted with a Pd catalyst
in
a (CH2Cl)2eMeOH mixed solvent system, spiro[5.5]cyclo-
hexadienone derivatives with a diene motif C were obtained in
excellent yield. Mechanistic studies revealed that this reaction
process involved the rearomatization-assisted oxidative addition
of intermediate B, the initially produced spirocyclohexadienone
* Corresponding author. Tel./fax: þ81 43 226 2920; e-mail addresses: y-hamada@
Scheme 1. Pd-catalyzed intramolecular spirocyclization using propargyl carbonate
derivatives.
faculty.chiba-u.jp, hamada@p.chiba-u.ac.jp (Y. Hamada).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.082

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T. Nemoto et al. / Tetrahedron 69 (2013) 3403e3409
to begin synthetic work on this class of compounds. Herein, we
report a novel synthetic method for spiro[4.5]cyclohexadienones
with an allene motif via a base-promoted intramolecular ipso-Frie-
deleCrafts addition of phenols to propargyl bromides.
3def were effective substrates for this reaction system, and
products with a spiro[4.5]cyclohexadienone skeleton 4bef were
obtained in 63e97% yield (entries 2e6). Naphthol derivative 3g
was also applicable to this reaction, affording the corresponding
naphthoquinone derivative 4g in 72% yield (entry 7). Moreover,
spirocyclization of 3h, bearing a bulky di(tert-butyl)malonate
tether, proceeded smoothly to give 4h in excellent yield (entry 8).
In contrast, when phenol derivative 3i, a substrate bearing a CH2
unit-longer tether than 3a, was reacted under the optimized
conditions, the desired spiro[5.5]cyclohexadienone was not ob-
tained, and we detected several products that formed through an
intermolecular O-alkylation.13 This finding indicates that the
tether length between the phenol and propargyl bromide unit is
a crucial factor for this reaction system. Furthermore, N-Ts-teth-
ered substrate 3j was prepared using the synthetic methods
shown in Scheme 3. Tosyl amide derivative 5j was first reacted
with propargyl bromide derivative 6 to give 7j in 89% yield.
Deprotection of the TBS group and the acetyl group was per-
formed under basic conditions, affording compound 8j in 87%
yield. Subsequent bromination of the alcohol moiety provided N-
Ts-tethered substrate 3j in 59% yield. Spirocyclization of 3j pro-
ceeded under the optimized conditions, producing the corre-
sponding products 4j in 74% yield.
As shown in Scheme 1, allenyl spiro[4.5]cyclohexadienones
derived from phenol derivatives were transformed into the corre-
sponding diene-type adducts in the presence of Pd(0) catalyst
through the rearomatization-assisted oxidative addition of C(sp3)e
C(sp2) bond. In contrast, a similar oxidative addition process did not
occur at 40 ꢀC when naphthoquinone derivative 4g was used as the
substrate.14 Pd-catalyzed intramolecular ipso-FriedeleCrafts alkyl-
ation of propargyl carbonate derivative with a naphthol unit 9g
proceeded at 40 ꢀC to provide allenyl spirocycle 4g in 96% yield
(Scheme 4).15
2. Results and discussions
A base-promoted intramolecular ipso-nucleophilic addition of
phenols to alkyl halides or related electrophiles via a SN2 mecha-
nism is a classical method for the synthesis of spirocyclohex-
adienones,11 and has been recently applied to several natural
product syntheses.12 Thus, we first examined intramolecular ipso-
FriedeleCrafts addition of phenols via a SN20 mechanism using
propargyl bromide derivative 3a as a model substrate (Table 1),
which could be easily prepared from the corresponding malonate
derivative 1a and 1,4-dibromo-2-butyne (45% yield for two steps)
(Scheme 2). We investigated the effect of base in CH2Cl2 (0.1 M) and
the corresponding product 4a was obtained in the highest yield
(50% yield) when using 1.5 equiv of sodium tert-butoxide (entry 5).
The yield improved slightly (64% yield) when the reaction was
performed in a CH2Cl2etert-BuOH (4/1) mixed solvent system un-
der diluted conditions (0.04 M) (entry 7). The yield was signifi-
cantly affected by the counter cation of tert-butoxide, as well as by
the solvent ratio. The best result was obtained when the reaction
was performed in a CH2Cl2etert-BuOH (4/1) mixed solvent system
(0.04 M) using potassium tert-butoxide as the base (90% yield)
(entry 9).
Table 1
Optimization of the reaction conditions using 3a
Acid-promoted dienoneephenol rearrangement of spi-
rocyclohexadienones is a useful method for synthesizing func-
tionalized phenol derivatives. Treatment of 4a with several acid
promoters, however, did not produce the rearranged phenol de-
rivative. On the other hand, Luche reduction of 3a, followed by
treatment of the obtained alcohol intermediate with para-tolue-
nesulfonic acid (TsOH) in CH3CN, afforded the corresponding bi-
cyclic adduct 10a in 87% yield in two steps (Scheme 5). Although
skeletal rearrangement could be performed using 10 mol % of TsOH,
the yield was slightly decreased (79% yield for two steps). When 4d
was utilized as the substrate for this ring expansion process,
product 10d was obtained in 89% yield as the sole product.16 This
result clearly indicated that the allenyl group is selectively rear-
ranged to the less hindered vicinal carbon on the six-membered
ring. Halide-substituted spirocycle 4f and naphthoquinone de-
rivative 4g were also applicable to this skeletal rearrangement,
affording the corresponding multi-cyclic adducts 10f and 10g in
62% and 75% yield, respectively.17
Entry Base
Solvent
Concn (M) Time (h) Yielda (%)
1
i-Pr2NEt
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0.1
0.1
0.1
0.1
0.1
0.04
73
46
46
47
22
23
23
18
8
14
2
3
4
K2CO3
Cs2CO3
NaH
No reaction
30
35
50
62
64
35
90
66
76
35
5
6
NaOet-Bu CH2Cl2
NaOet-Bu CH2Cl2
7
8
NaOet-Bu CH2Cl2et-BuOH (4/1) 0.04
LiOet-Bu CH2Cl2et-BuOH (4/1) 0.04
9
KOet-Bu
KOet-Bu
KOet-Bu
KOet-Bu
CH2Cl2et-BuOH (4/1) 0.04
CH2Cl2et-BuOH (9/1) 0.04
CH2Cl2et-BuOH (1/1) 0.04
10
11
12
8
8
t-BuOH
0.04
8
a
Isolated yield.
3. Conclusion
We developed a novel synthetic method for obtaining allenyl
spiro[4.5]cyclohexadienone derivatives using a base-promoted
intramolecular ipso-FriedeleCrafts addition of phenols to prop-
argyl bromides. In addition, when using a propargyl carbonate
derivative with a naphthol unit as a substrate, Pd-catalyzed intra-
molecular ipso-FriedeleCrafts alkylation proceeded smoothly to
afford the corresponding allenyl spirocyclic molecule. Subsequent
acid-catalyzed skeletal rearrangements provided the correspond-
ing ring-expanded adducts in excellent yield, demonstrating the
potential utility of this synthetic method. Further studies are in
progress.
Scheme 2. Synthesis of propargyl bromide derivative 3a.
Having developed efficient conditions, we next examined the
scope and limitations of the different substrates (Table 2). In ad-
dition to model substrate 3a, ortho-disubstituted phenol de-
rivatives 3b and 3c, as well as meta-substituted phenol derivatives

T. Nemoto et al. / Tetrahedron 69 (2013) 3403e3409
3405
Table 2
Scope and limitationsa
Entry
Substrates
Products
Time (h)
Yieldb (%)
MeOOC
COOMe
COOMe
4a
4b
4c
1
2
3a (R1 = H)
3b (R1 = CH3)
8
90
97
COOMe
R1
R1
O
18
HO
Br 3c (R1 = OCH3)
·
R1
R2
3
4
18
16
63
92
R1
MeOOC
R2
3d (R2 = CH3)
3e (R2 = OCH3)
4d
4e
4f
COOMe
COOMe
COOMe
COOMe
5
6
16
14
74
66
HO
·
Br 3f (R2 = Cl)
O
MeOOC
COOMe
COOMe
7
8
4g
1
72
99
3g
3h
HO
HO
·
O
Br
-BuOOC
COO -Bu
COO -Bu
COO -Bu
COOMe
15
4h
Br
·
O
COOMe
COOMe
COOMe
4i
9
18
21
0
3i
HO
Br
O
·
Ts
Ts
N
N
10
74
3j
4j
HO
Br
·
O
a
Reaction conditions. KOet-Bu (1.5 equiv), CH2Cl2et-BuOH (4/1) (0.04 M), rt.
Isolated yield.
b
Scheme 3. Synthesis of 3j.
Scheme 5. Derivatization of the reaction adducts using an acid-catalyzed skeletal
rearrangement.
4. Experimental
4.1. General
Infrared (IR) spectra were recorded on a JASCO FT/IR 230 Fourier
transform infrared spectrophotometer, equipped with ATR (Smiths
Detection, DuraSample IR II). NMR spectra were recorded on a JEOL
Scheme 4. Synthesis of 4g using Pd-catalyzed intramolecular ipso-FriedeleCrafts
alkylation.

3406
T. Nemoto et al. / Tetrahedron 69 (2013) 3403e3409
ecp 400 spectrometer, operating at 400 MHz for 1H NMR and
100 MHz for 13C NMR. Chemical shifts in CDCl3 were reported
downfield from TMS (¼0 ppm) for 1H NMR. For 13C NMR, chemical
shifts were reported in the scale relative to the solvent signal [CHCl3
(77.0 ppm)] as an internal reference. ESI mass spectra were mea-
sured on JEOL AccuTOF LC-plus JMS-T100L. Reactions were carried
out in dry solvent under argon atmosphere. Other reagents were
purified by the usual methods.
oil. IR (ATR)
(CDCl3):
n
2953,1735,1660, 1594,1263, 1224, 853 cmꢁ1; 1H NMR
2.73 (d, J¼14.4 Hz, 1H), 2.80 (d, J¼14.4 Hz, 1H), 3.09e3.14
d
(m, 1H), 3.39e3.46 (m, 1H), 3.71 (s, 3H), 3.78 (s, 3H), 3.80 (s, 3H),
4.75e4.87 (m, 2H), 5.50 (d, J¼1.2 Hz, 1H), 6.07 (dd, J¼1.2, 10.0 Hz,
1H), 6.62 (d, J¼10.0 Hz,1H); 13C NMR (CDCl3):
d 39.1, 42.5, 51.8, 53.0,
53.2, 55.8, 60.1, 80.2, 101.1, 104.3, 125.3, 147.2, 170.3,þ171.8, 176.5,
188.1, 201.8; (þ)-ESI-HRMS. Calcd for C17H18NaO6 (MþNaþ):
341.0996. Found: 341.0959.
4.2. Experimental procedure of the intramolecular ipso-
FriedeleCrafts addition of phenols to propargyl bromides and
compound characterization
4.2.6. Dimethyl 6-chloro-8-oxo-4-vinylidenespiro[4.5]deca-6,9-
diene-2,2-dicarboxylate (4f). Compound 4f was prepared from 3f
according to the typical procedure shown in Section 4.2.1. Colorless
oil. IR (ATR)
NMR (CDCl3):
n
2954, 1734, 1659, 1435, 1263, 1216, 975, 869 cmꢁ1; 1H
4.2.1. Typical experimental procedure for the intramolecular ipso-
FriedeleCrafts addition of phenols to propargyl bromides (Table 1,
entry 9). Compound 3a (36.9 mg, 0.10 mmol) and KOet-Bu (16.8 mg,
0.15 mmol) were dissolved in CH2Cl2 (2.0 mL) and t-BuOH (0.5 mL),
and the resulting solution was stirred at room temperature. After 8 h,
the reaction was quenched with satd aq NH4Cl solution, and the
mixture was extracted with AcOEt. The combined organic layers were
washed with brine, dried over Na2SO4, and then concentrated in
vacuo. The obtained residue was purified by flash column chroma-
tography (SiO2, hexane/acetone¼7:1) to give dimethyl 8-oxo-4-
vinylidenespiro[4.5]deca-6,9-diene-2,2-dicarboxylate 4a (26.0 mg,
d
2.76 (dd, J¼1.6, 14.4 Hz, 1H), 2.97 (d, J¼14.4 Hz, 1H),
3.22e3.28 (m, 1H), 3.35e3.42 (m, 1H), 3.78 (s, 3H), 3.82 (s, 3H),
4.86e4.90 (m, 2H), 6.13 (dd, J¼2.0, 10.0 Hz, 1H), 6.39 (d, J¼2.0 Hz,
1H), 6.91 (d, J¼10.0 Hz, 1H); 13C NMR (CDCl3):
d 39.0, 42.6, 53.3,
53.4, 55.1, 59.8, 80.9, 103.4, 124.3, 128.5, 150.5, 158.1,þ170.3, 171.7,
184.7, 202.4; (þ)-ESI-HRMS. Calcd for C16H15ClNaO5 (MþNaþ):
345.0500. Found: 345.0469.
4.2.7. Dimethyl 40-oxo-2-vinylidene-40H-spiro[cyclopentane-1,10-naph-
thalene]-4,4-dicarboxylate (4g). Compound 4g was prepared from 3g
according to the typical procedure shown in Section 4.2.1. Colorless
90%yield)ascolorlessoil.IR(ATR)
n
2954,1729,1662,1624,1434,1253,
2.65 (s, 2H), 3.27
oil. IR (ATR)
NMR (CDCl3):
n
1725, 1659, 1596, 1432, 1264, 1156, 870, 767 cmꢁ1; 1H
1201, 1159, 1111, 1080, 853 cmꢁ1; 1H NMR (CDCl3):
d
d
2.95 (d, J¼16.8 Hz, 1H), 3.04 (d, J¼16.8 Hz, 1H),
(t, J¼4.0 Hz, 2H), 3.80 (s, 6H), 4.82 (m, 2H), 6.15 (d, J¼9.6 Hz, 2H), 6.80
3.40e3.53 (m, 2H), 3.81 (s, 3H), 3.84 (s, 3H), 4.56e4.71 (m, 2H), 6.31
(d, J¼10.4 Hz, 1H), 6.94 (d, J¼10.4 Hz, 1H), 7.35e7.40 (m, 1H), 7.47 (d,
J¼8.0 Hz, 1H), 7.56e7.60 (m, 1H), 8.11 (dd, J¼1.6, 8.0 Hz, 1H); 13C NMR
(d, J¼9.6 Hz, 2H); 13C NMR (CDCl3):
d 37.9, 43.5, 50.0, 53.3 (2C), 59.6,
80.0, 102.5, 126.8 (2C), 150.9 (2C), 171.2 (2C), 185.8, 202.3; (þ)-ESI-
HRMS. Calcd for C16H16NaO5þ (MþNaþ): 311.0890. Found: 311.0902.
(CDCl3):
d 39.1, 48.2, 50.9, 53.3, 53.3, 59.4, 80.0, 106.9, 125.0, 126.2,
127.0, 127.5, 131.0, 132.9, 147.4, 150.9, 171.3, 171.9, 184.6, 202.9;
(þ)-ESI-HRMS. Calcd for C20H18NaO5 (MþNaþ): 361.1046. Found:
þ
4.2.2. Dimethyl 7,9-dimethyl-8-oxo-4-vinylidenespiro[4.5]deca-6,9-
diene-2,2-dicarboxylate (4b). Compound 4b was prepared from 3b
according to the typical procedure shown in Section 4.2.1. Colorless
361.1023.
solids. IR (ATR)
1074, 907, 867, 839, 781, 763, 728 cmꢁ1; 1H NMR (CDCl3):
2.59 (s, 2H), 3.24 (t, J¼4.0 Hz, 2H), 3.87 (s, 6H), 4.75 (t, J¼4.0 Hz, 2H),
6.55 (s, 2H); 13C NMR (CDCl3):
15.9 (2C), 38.0, 43.9, 49.6, 53.2 (2C),
n
2954, 1733, 1584, 1461, 1434, 1391, 1275, 1249, 1151,
4.2.8. Di-tert-butyl 6-methoxy-8-oxo-4-vinylidenespiro[4.5]deca-6,
9-diene-2,2-dicarboxylate (4h). Compound 4h was prepared from
3h according to the typical procedure shown in Section 4.2.1. Col-
d
1.86 (s, 6H),
d
orless oil. IR (ATR)
n
2978, 1724, 1666, 1369, 1286, 1168, 1141,
1.48 (s, 18H), 2.54 (s, 2H), 3.17 (t,
59.5, 79.5,103.3,132.8(2C),146.3(2C),171.5(2C),187.0, 202.0;(þ)-ESI-
855 cmꢁ1 1H NMR (CDCl3):
;
d
HRMS. Calcd for C18H20NaO5þ (MþNaþ): 339.1203. Found: 339.1155.
J¼4.4 Hz, 2H), 4.79 (t, J¼4.4 Hz, 2H), 6.14 (dd, J¼1.6, 10.4 Hz, 2H),
6.85 (dd, J¼1.6, 10.4 Hz, 2H); 13C NMR (CDCl3):
d 27.8 (6C), 37.7, 43.4,
50.2, 61.1, 79.6, 82.3 (2C), 102.9, 126.7 (2C), 151.4 (2C), 170.6, 186.0,
4.2.3. Dimethyl 7,9-dimethoxy-8-oxo-4-vinylidenespiro[4.5]deca-6,9-
diene-2,2-dicarboxylate (4c). Compound 4c was prepared from 3c
according to the typical procedure shown in Section 4.2.1. Colorless
þ
202.3; (þ)-ESI-HRMS. Calcd for C22H28NaO5 (MþNaþ): 395.1829.
Found: 395.1823.
oil. IR (ATR)
1107, 860, 747, 665 cmꢁ1
J¼4.0 Hz, 2H), 3.65 (s, 6H), 3.81 (s, 6H), 4.79 (t, J¼4.0 Hz, 2H), 5.83 (s,
2H); 13C NMR (CDCl3):
37.6, 46.0, 48.6, 53.3 (2C), 55.2 (2C), 59.1,
n
3012, 2954, 1730, 1669, 1617, 1434, 1249, 1229, 1202,
;
1H NMR (CDCl3):
d
2.69 (s, 2H), 3.33 (t,
4.2.9. 2-Tosyl-4-vinylidene-2-azaspiro[4.5]deca-6,9-dien-8-one
(4j). Compound 4j was prepared from 3j according to the typical
d
procedure shown in Section 4.2.1. White solids. IR (ATR)
1627, 1401, 1348, 1165, 1091, 1033, 856, 817, 665 cmꢁ1 1H NMR
(CDCl3):
2.48 (s, 3H), 3.36 (s, 2H), 4.05 (t, J¼4.4 Hz, 2H), 4.92 (t,
n 1665,
77.2, 79.9, 104.5, 119.2 (2C), 149.6 (2C), 171.7, 176.4, 201.5; (þ)-ESI-
;
HRMS. Calcd for C18H20NaO7 (MþNaþ): 371.1101. Found: 371.1082.
d
þ
J¼4.4 Hz, 2H), 6.22 (d, J¼10.0 Hz, 2H), 6.75 (d, J¼10.0 Hz, 2H), 7.39
4.2.4. Dimethyl 6-methyl-8-oxo-4-vinylidenespiro[4.5]deca-6,9-
diene-2,2-dicarboxylate (4d). Compound 4d was prepared from
3d according to the typical procedure shown in Section 4.2.1. White
(d, J¼8.4 Hz, 2H), 7.73 (d, J¼8.4 Hz, 2H); 13C NMR (CDCl3):
d 21.6,
48.7, 49.8, 56.3, 82.3, 100.2, 127.9 (2C), 128.6 (2C), 129.8, 129.9 (2C),
132.0 (2C), 144.4, 147.4, 185.4; (þ)-ESI-HRMS. Calcd for
C18H17NNaO5Sþ (MþNaþ): 350.0821. Found: 350.0852.
solids. IR (ATR)
n
2954, 1731, 1663, 1626, 1434, 1259, 1223, 1201,
1162, 1110, 1084, 859, 750 cmꢁ1
;
1H NMR (CDCl3):
d
2.00 (s, 3H),
2.61 (d, J¼14.8 Hz, 1H), 2.77 (d, J¼14.8 Hz, 1H), 3.16e3.23 (m, 1H),
3.37e3.42 (m, 1H), 3.79 (s, 3H), 3.83 (s, 3H), 4.80 (dd, J¼4.0, 5.2 Hz,
2H), 6.07 (d, J¼2.0 Hz, 1H), 6.10 (s, 1H), 6.81 (d, J¼10.0 Hz, 1H); 13C
4.3. Experimental procedure for the preparation of propargyl
bromide derivatives and compound characterization
NMR (CDCl3):
d
19.8, 39.2, 42.5, 53.1, 53.3, 53.3, 59.7, 79.8, 103.6,
4.3.1. Typical experimental procedure for the preparation of
malonate-tethered propargyl bromide derivatives (Scheme 2). To
a stirred solution of 1a7a (1.76 g, 5.00 mmol) in THF (20 mL) at 0 ꢀC
was added NaH (60% oil, 240 mg, 6.00 mmol), and the resulting
mixture was kept stirring at the same temperature. After 30 min,
a THF solution of 1,4-dibromo-2-butyne (1.27 g, 6 mmol in 5 mL of
THF) was added to the reaction mixture, and the reaction mixture
124.6, 127.9, 151.4, 159.5, 170.9, 171.6, 186.3, 201.9; (þ)-ESI-HRMS.
þ
Calcd for C17H18NaO5 (MþNaþ): 325.1046. Found: 325.1000.
4.2.5. Dimethyl 6-methoxy-8-oxo-4-vinylidenespiro[4.5]deca-6,9-
diene-2,2-dicarboxylate (4e). Compound 4e was prepared from 3e
according to the typical procedure shown in Section 4.2.1. Colorless

T. Nemoto et al. / Tetrahedron 69 (2013) 3403e3409
3407
was stirred for 3 h at room temperature. After dilution with AcOEt,
the reaction was quenched with satd aq NH4Cl solution, washed
with brine, dried over Na2SO4, and then evaporated in vacuo. The
obtained crude residue was purified by flash column chromatog-
raphy (SiO2, hexane/AcOEt¼20:1) to give 2a as colorless oil (1.30 g,
54% yield). To a stirred solution of 2a (1.30 g, 2.70 mmol) in THF
(13.5 mL) at 0 ꢀC was added a THF solution of TBAF (1 M solution,
3.2 mL, 3.20 mmol), and the resulting mixture was stirred for
30 min at the same temperature. After dilution with AcOEt, the
reaction was quenched with satd aq NH4Cl solution, washed with
brine, dried over Na2SO4, and then evaporated in vacuo. The ob-
tained crude residue was purified by flash column chromatography
(SiO2, hexane/acetone¼6:1) to give dimethyl 2-(4-bromobut-2-yn-
1-yl)-2-(4-hydroxybenzyl)malonate 3a as white solids (837 mg,
23.1, 31.6, 52.6 (2C), 55.2, 57.7, 78.2, 83.4, 98.7, 106.8, 115.8, 132.5,
þ
156.2, 159.1, 170.6 (2C); (þ)-ESI-HRMS. Calcd for C17H19BrNaO6
(MþNaþ): 422.0257. Found: 422.0244.
4.3.6. Dimethyl 2-(4-bromobut-2-yn-1-yl)-2-(2-chloro-4-hydroxy-
benzyl)malonate (3f). Compound 3f was prepared from the corre-
sponding malonate derivative7a and 1,4-dibromo-2-butyne
according to the typical procedure shown in Section 4.2.1. Color-
less oil. IR (ATR)
n 3418, 2952, 1734, 1609, 1500, 1437, 1211, 1051,
772 cmꢁ1 1H NMR (CDCl3):
;
d
2.79 (t, J¼2.4 Hz, 2H), 3.49 (s, 2H),
3.76 (s, 6H), 3.92 (t, J¼2.4 Hz, 2H), 5.10 (br s, 1H), 6.68 (dd, J¼2.8,
8.4 Hz, 1H), 6.82 (d, J¼2.8 Hz, 1H), 7.21 (d, J¼8.4 Hz, 1H); 13C NMR
(CDCl3):
d 14.7, 23.3, 33.9, 53.1 (2C), 57.7, 79.2, 82.7, 114.2, 116.6,
124.7, 132.8, 135.2, 155.7, 170.5 (2C); (þ)-ESI-HRMS. Calcd for
þ
84% yield). IR (ATR)
n
3439, 1718, 1614, 1514, 1436, 1288, 1198, 1106,
2.73 (t, J¼1.6 Hz, 2H), 3.31
C16H16BrClNaO5 (MþNaþ): 424.9762. Found: 424.9777.
1064, 840, 752 cmꢁ1; 1H NMR (CDCl3):
d
(s, 2H), 3.76 (s, 6H), 3.93 (t, J¼1.6 Hz, 2H), 4.93 (br s, 1H), 6.72 (d,
4.3.7. Dimethyl 2-(4-bromobut-2-yn-1-yl)-2-((4-hydroxynaph-
thalen-1-yl)methyl)malonate (3g). Compound 3g was prepared
from the corresponding malonate derivative7a and 1,4-dibromo-2-
butyne according to the typical procedure shown in Section 4.2.1.
J¼8.4 Hz, 2H), 6.99 (d, J¼8.4 Hz, 2H); 13C NMR (CDCl3):
d 14.8, 22.6,
36.8, 52.8 (2C), 58.4, 79.1, 82.7, 115.4 (2C), 127.3, 130.8 (2C), 154.8,
170.5 (2C); (þ)-ESI-HRMS. Calcd for C16H17BrNaO5 (MþNaþ):
þ
391.0152. Found: 391.0124.
White solids. IR (ATR)
n 3432, 1742, 1708, 1281, 1210, 1064, 834,
753 cmꢁ1 1H NMR (CDCl3):
;
d
2.77 (t, J¼2.4 Hz, 2H), 3.67 (s, 6H),
4.3.2. Dimethyl 2-(4-bromobut-2-yn-1-yl)-2-(4-hydroxy-3,5-dime-
thylbenzyl)malonate (3b). Compound3b was prepared from the
corresponding malonate derivative10 and 1,4-dibromo-2-butyne
according to the typical procedure shown in Section 4.3.1. White
3.81 (s, 2H), 3.97 (t, J¼2.4 Hz, 2H), 5.79 (s,1H), 6.67 (d, J¼8.0 Hz,1H),
7.20 (d, J¼8.4 Hz, 1H), 7.43e7.43 (m, 2H), 8.05 (d, J¼8.4 Hz, 1H), 8.20
(dd, J¼2.0, 8.0 Hz, 1H); 13C NMR (CDCl3):
d 14.7, 23.3, 32.7, 52.8 (2C),
58.6, 79.1, 83.2, 107.9, 122.4, 123.6, 123.7, 124.7, 124.8, 126.4, 128.3,
þ
solids. IR (ATR)
1202, 1147, 1062 cmꢁ1
J¼2.0 Hz, 2H), 3.24 (s, 2H), 3.75 (s, 6H), 3.94 (t, J¼2.0 Hz, 2H), 4.78
(br s, 1H), 6.72 (s, 2H); 13C NMR (CDCl3):
14.8, 15.9 (2C), 22.6, 36.8,
n
3420, 2917, 1752, 1725, 1489, 1432, 1270, 1248,
133.7, 151.2, 170.5 (2C); (þ)-ESI-HRMS. Calcd for C20H19BrNaO5
;
1H NMR (CDCl3):
d
2.17 (s, 6H), 2.74 (t,
(MþNaþ): 441.0308. Found: 441.0324.
d
4.3.8. Di-tert-butyl 2-(4-bromobut-2-yn-1-yl)-2-(4-hydroxybenzyl)
malonate (3h). Compound 3h was prepared from the corresponding
malonate derivative10 and 1,4-dibromo-2-butyne according to the
52.6 (2C), 58.4, 77.2, 78.9, 82.9, 122.9, 126.5, 129.9 (2C), 151.4, 170.4
(2C); (þ)-ESI-HRMS. Calcd for C18H21BrNaO5þ (MþNaþ): 419.0465.
Found: 419.0449.
typical procedure shown in Section 4.2.1. Colorless oil. IR (ATR)
3430, 2978,1712,1516,1368,1294,1218,1139,1105, 841, 755cmꢁ1; 1H
NMR (CDCl3):
1.47 (s,18H), 2.64 (t, J¼2.0 Hz, 2H), 3.21 (s, 2H), 3.94 (t,
J¼2.0 Hz, 2H), 5.10 (br s,1H), 6.71 (d, J¼8.4 Hz, 2H), 7.06 (d, J¼8.4 Hz,
2H); 13C NMR (CDCl3):
14.9, 22.7, 27.9(6C), 36.3, 59.0, 78.6, 82.1 (2C),
n
4.3.3. Dimethyl 2-(4-bromobut-2-yn-1-yl)-2-(4-hydroxy-3,5-dime-
thoxylbenzyl)malonate (3c). Compound 3c was prepared from the
corresponding malonate derivative10 and 1,4-dibromo-2-butyne
according to the typical procedure shown in Section 4.3.1. Color-
d
d
83.4, 115.1 (2C), 127.8, 131.3 (2C), 154.7, 169.0 (2C); (þ)-ESI-HRMS.
þ
less oil. IR (ATR)
1204, 1108 cmꢁ1; 1H NMR (CDCl3):
2H), 3.77 (s, 6H), 3.86 (s, 6H), 3.95 (t, J¼2.4 Hz, 2H), 5.44 (br s, 1H),
6.40 (s, 2H); 13C NMR (CDCl3):
14.8, 22.7, 37.8, 52.8 (2C), 56.3 (2C),
n
1732, 1613, 1517, 1458, 1428, 1338, 1292, 1246,
Calcd for C22H29BrNaO5 (MþNaþ): 475.1091. Found: 475.1095.
d
2.76 (t, J¼2.4 Hz, 2H), 3.33 (s,
4.3.9. Dimethyl 2-(4-bromobut-2-yn-1-yl)-2-(4-hydroxyphenethyl)
malonate (3i). Compound 3i was prepared from the corresponding
malonate derivative7a and 1,4-dibromo-2-butyne according to the
d
58.4, 79.2, 82.8, 106.5 (2C), 126.1, 133.9,þ146.8 (2C), 170.2 (2C);
(þ)-ESI-HRMS. Calcd for C18H21BrNaO7 (MþNaþ): 451.0363.
Found: 451.0357.
typical procedure shown in Section 4.2.1. Colorless oil. IR (ATR)
3454, 2953, 1725, 1514, 1436, 1201, 1061, 822, 754 cmꢁ1 1H NMR
(CDCl3):
2.29e2.33 (m, 2H), 2.44e2.48 (m, 2H), 2.96 (t, J¼2.4 Hz,
n
;
d
4.3.4. Dimethyl 2-(4-bromobut-2-yn-1-yl)-2-(4-hydroxy-2-methyl-
benzyl)malonate (3d). Compound 3d was prepared from the cor-
responding malonate derivative7a and 1,4-dibromo-2-butyne
according to the typical procedure shown in Section 4.3.1. Color-
2H), 3.74 (s, 6H), 3.88 (t, J¼2.4 Hz, 2H), 4.64 (s,1H), 6.75 (d, J¼8.4 Hz,
2H), 7.07 (d, J¼8.4 Hz, 2H); 13C NMR (CDCl3):
d 14.7, 23.5, 29.5, 34.3,
52.9 (2C), 56.8, 78.5, 82.0, 115.2 (2C), 129.5 (2C), 132.8, 154.0, 170.6
(2C); (þ)-ESI-HRMS. Calcd for C17H19BrNaO5þ (MþNaþ): 405.0308.
Found: 405.0299.
less oil. IR (ATR)
n 3451, 2952, 1729, 1608, 1205, 1435, 1293, 1269,
1206, 1063 cmꢁ1; 1H NMR (CDCl3):
d
2.26 (s, 3H), 2.76 (t, J¼2.0 Hz,
2H), 3.36 (s, 2H), 3.74 (s, 6H), 3.91 (t, J¼2.0 Hz, 2H), 4.67 (br s, 1H),
6.56 (dd, J¼2.8, 8.4 Hz, 1H), 6.62 (d, J¼2.8 Hz, 1H), 6.95 (d, J¼8.4 Hz,
4.3.10. Synthesis of compound 7j. To a stirred solution of 5j7a (3.86 g,
9.86 mmol) in THF (30 mL) at 0 ꢀC was added NaH (60% oil. 473 mg,
11.8 mmol). After being stirred for 30 min at room temperature,
a solution of freshly prepared alkynyl bromide 6 (2.83 g, 14.8 mmol)
in THF (19 mL) was added to the mixture. After being stirred for 12 h
at room temperature, the reaction was quenched with water, and the
mixture was extracted with AcOEt. The combined organic layers
were washed with water and brine, dried over NaSO4, and then
concentrated in vacuo. The obtained residue was purified by flash
column chromatography (SiO2, hexane/AcOEt¼10:1) to give 4-(N-(4-
((tert-butyldimethylsilyl)oxy)benzyl)-4-methylphenylsulfonamido)
but-2-yn-1-yl acetate 7j (4.44 g, 90% yield) as white solids. IR (ATR)
1H); 13C NMR (CDCl3):
d 14.7, 19.8, 22.9, 33.4, 52.8 (2C), 58.4, 78.8,
83.1,112.8,117.3,125.9, 131.6,139.1,154.4,170.5 (2C); (þ)-ESI-HRMS.
Calcd for C17H19BrNaO5 (MþNaþ): 405.0308. Found: 405.0306.
þ
4.3.5. Dimethyl 2-(4-bromobut-2-yn-1-yl)-2-(4-hydroxy-2-metho-
xylbenzyl)malonate (3e). Compound 3e was prepared from the
corresponding malonate derivative10 and 1,4-dibromo-2-butyne
according to the typical procedure shown in Section 4.3.1. Color-
less oil. IR (ATR)
n
3444, 2952, 1732, 1616, 1510, 1434, 1295, 1208,
1158, 1125 cmꢁ1
;
1H NMR (CDCl3):
d
2.70 (t, J¼2.4 Hz, 2H), 3.34 (s,
2H), 3.72 (s, 3H), 3.74 (s, 6H), 3.93 (t, J¼2.4 Hz, 2H), 4.91 (br s, 1H),
n
2929, 2857, 1748, 1509, 1348, 1254, 1221, 1159, 1091, 903, 752,
6.31e6.34 (m, 2H), 7.04 (d, J¼8.0 Hz, 1H); 13C NMR (CDCl3):
d
15.0,
657 cmꢁ1; 1H NMR (CDCl3):
d
0.19 (s, 6H), 0.98 (s, 9H), 2.07 (s, 3H),

3408
T. Nemoto et al. / Tetrahedron 69 (2013) 3403e3409
2.45 (s, 3H), 3.95 (s, 2H), 4.24 (s, 2H), 4.38 (s, 2H), 6.80 (d, J¼8.0 Hz,
2H), 7.19 (d, J¼8.0 Hz, 2H), 7.32 (d, J¼8.0 Hz, 2H), 7.78 (d, J¼8.0 Hz,
the reaction was stirred for 1 h, and then quenched with water. After
a half of solvent was evaporated in vacuo, the mixture was diluted
with AcOEt, washed with brine, and then dried over Na2SO4. After
concentration in vacuo, the obtained alcohol adduct was directly
utilized for the next reaction. To a stirred solution of the crude
product in CH3CN (2.4 mL) at room temperature was added
TsOH$H2O (23.0 mg, 0.12 mmol). After being stirred for 1 h at room
temperature, the reaction mixture was quenched with satd aq
NaHCO3 solution. Aqueous layer was extracted with AcOEt, and
the combined organic layers were washed with brine. After con-
centration in vacuo, the obtained residue was purified by flash
column chromatography (SiO2, hexane/acetone¼30:1) to give di-
methyl 4-vinylidene-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate
2H); 13C NMR (CDCl3):
d
ꢁ4.5 (2C), 18.2, 20.6, 21.5, 25.6 (3C),
35.6, 49.5, 51.8, 79.4, 79.8, 120.2 (2C), 127.3, 127.9 (2C), 129.4 (2C),
130.0 (2C), 136.0, 143.5, 155.6, 169.9; (þ)-ESI-HRMS. Calcd for
C26H35NNaO5SSiþ (MþNaþ): 524.1897. Found: 524.1907.
4.3.11. Synthesis of compound 8j. To a stirred solution of 7j (100 mg,
0.2 mmol) in MeOH (2 mL) was added K2CO3 (82.8 mg, 0.6 mmol).
After being stirred for 12 h at room temperature, the reaction was
quenched with satd aq NH4Cl solution, and the mixture was
extracted with AcOEt. The combined organic layers were washed
with water and brine, dried over Na2SO4, and then concentrated in
vacuo. The obtained residue was purified by flash column chroma-
tography (SiO2, hexane/AcOEt¼2:1) to give N-(4-hydroxybenzyl)-N-
(4-hydroxybut-2-yn-1-yl)-4-methylbenzenesulfonamide 8j (60 mg,
10a (28.5 mg, 87% yield) as colorless solids. IR (ATR)
1435,1272,1238,1075, 763 cmꢁ1; 1H NMR (CDCl3):
3.08 (t, J¼3.2 Hz,
2H), 3.31 (s, 2H), 3.71 (s, 6H), 5.13 (t, J¼3.2 Hz, 2H), 7.12e7.18 (m, 3H),
7.40e7.43 (m,1H); 13C NMR (CDCl3):
33.4, 35.3, 52.8 (2C), 53.5, 78.9,
n 2953, 1735,
d
87% yield) as white solids. IR (ATR)
n
3353, 2920, 1509, 1349, 1155,
2.41 (s, 3H), 3.79
d
1090, 988, 899, 754 cmꢁ1 1H NMR (CDCl3):
;
d
97.9, 126.4, 126.6, 127.1, 129.0, 129.6, 132.4, 171.0 (2C), 207.3; (þ)-ESI-
(s, 2H), 3.85 (s, 2H), 4.14 (s, 2H), 6.73 (d, J¼8.4 Hz, 2H), 7.08
HRMS. Calcd for C16H16NaO4þ (MþNaþ): 295.0941. Found: 295.0911.
(d, J¼8.4 Hz, 2H), 7.42 (d, J¼8.4 Hz, 2H), 7.75 (d, J¼8.4 Hz, 2H); 13C
NMR (DMSO-d6):
d
21.0, 35.7, 48.7, 49.1, 76.3, 85.7, 115.3 (2C), 125.1,
4.5.2. Dimethyl 8-methyl-4-vinylidene-3,4-dihydronaphthalene-2,
2(1H)-dicarboxylate (10d). Compound 10d was prepared from 4d
according to the typical experimental procedure shown in Section
127.5 (2C), 129.6 (2C), 129.8 (2C), 135.6, 143.4, 157.1; (þ)-ESI-HRMS.
Calcd for C18H29NNaO4Sþ (MþNaþ): 368.0927. Found: 368.0918.
4.5.1. Colorless solids. IR (ATR)
n
2924, 1732, 1434, 1313, 1254, 1191,
2.28 (s, 3H), 3.04 (t,
4.3.12. N-(4-Bromobut-2-yn-1-yl)-N-(4-hydroxybenzyl)-4-
methylbenzenesulfonamide (3j). To a stirred solution of 8j (60.0 mg,
0.17 mmol) in CH2Cl2 (0.58 mL) at 0 ꢀC was added PPh3 (57.7 mg,
0.22 mmol) and CBr4 (73.0 mg, 0.22 mmol). After being stirred for 2 h
at room temperature, the reaction mixture was concentrated in
vacuo, and then passed through a short pad of silica to remove tri-
phenylphosphine oxide. The filtrate was concentrated and the ob-
tained residue was purified by flash column chromatography (SiO2,
hexane/AcOEt¼5:1) to give 3j (41.7 mg, 59% yield) as colorless oil. IR
1175, 1065, 862, 785 cmꢁ1; 1H NMR (CDCl3):
d
J¼3.2 Hz, 2H), 3.18 (s, 2H), 3.72 (s, 6H), 5.10 (t, J¼3.2 Hz, 2H),
6.98e7.07 (m, 2H), 7.28 (d, J¼7.6 Hz, 1H); 13C NMR (CDCl3):
d 19.7,
32.4, 33.1, 52.8 (2C), 53.7, 78.4, 98.2, 124.3, 126.0, 128.6, 129.6, 131.1,
þ
136.3, 171.1 (2C), 207.5; (þ)-ESI-HRMS. Calcd for C17H18NaO4
(MþNaþ): 309.1097. Found: 309.1067.
4.5.3. Dimethyl 8-chloro-4-vinylidene-3,4-dihydronaphthalene-2,
2(1H)-dicarboxylate (10f). Compound 10f was prepared from 4f
according to the typical experimental procedure shown in Section
(ATR)
n 3430, 1613, 1596, 1514, 1324, 1208, 1152, 1089, 900, 813, 746,
657 cmꢁ1; 1H NMR (CDCl3):
d
2.46 (s, 3H), 3.60 (t, J¼2.0 Hz, 2H), 3.95
4.5.1. Colorless solids. IR (ATR)
n
2924, 1737, 1446, 1254, 1197, 1057,
(t, J¼2.0 Hz, 2H), 4.25 (s, 2H), 5.07 (s, 1H), 6.80 (d, J¼8.4 Hz, 2H), 7.21
787 cmꢁ1 1H NMR (CDCl3):
;
d
3.04 (t, J¼3.2 Hz, 2H), 3.34 (s, 2H),
(d, J¼8.4 Hz, 2H), 7.35 (d, J¼8.4 Hz, 2H), 7.78 (d, J¼8.4 Hz, 2H); 13C
3.74 (s, 6H), 5.14 (t, J¼3.2 Hz, 2H), 7.08 (dd, J¼8.0, 8.0 Hz, 1H), 7.21
NMR (CDCl3):
d
13.6, 21.6, 35.7, 49.5, 79.6, 80.9,115.6 (2C),126.7,127.8
(d, J¼8.0 Hz, 1H), 7.34 (d, J¼8.0 Hz, 1H); 13C NMR (CDCl3):
d 32.8,
(2C), 129.6 (2C), 130.4 (2C), 135.8, 143.7, 155.6; (þ)-ESI-HRMS. Calcd
33.1, 52.9 (2C), 53.4, 79.0, 97.7, 125.0, 127.0, 127.7, 130.5, 132.2,
þ
for C18H18BrNNaO3Sþ (MþNaþ): 430.0083. Found: 430.0091.
134.3, 170.8 (2C), 207.6; (þ)-ESI-HRMS. Calcd for C16H15ClNaO4
(MþNaþ): 329.0551. Found: 329.0533.
4.4. Pd-catalyzed ipso-FriedeleCrafts alkylation using 9g
4.5.4. Dimethyl 1-vinylidene-1,2-dihydrophenanthrene-3,3(4H)-di-
carboxylate (10g). Compound 10g was prepared from 4g according
to the typical experimental procedure shown in Section 4.5.1. White
Compound 9g (82.8 mg, 0.20 mmol), Pd(dba)2 (5.8 mg,
0.01 mmol), and PPh3 (6.3 mg, 0.024 mmol) were dissolved in
CH2Cl2 (3.2 mL) and MeOH (0.8 mL), and the resulting solution was
stirred at 40 ꢀC. After 5 h, the reaction was concentrated in vacuo,
and the obtained residue was purified by flash column chroma-
tography (SiO2, hexane/AcOEt¼4:1) to give 4g (64.8 mg, 96% yield)
solids. IR (ATR)
n ;
2952, 1732, 1434, 1257, 1196, 858, 817, 746 cmꢁ1
1H NMR (CDCl3):
d
3.14 (t, J¼2.4 Hz, 2H), 3.69 (s, 2H), 3.72 (s, 6H),
5.20 (t, J¼2.4 Hz, 2H), 7.42e7.54 (m, 3H), 7.61 (d, J¼7.6 Hz, 1H), 7.77
(d, J¼8.0 Hz, 1H), 8.01 (d, J¼8.4 Hz, 1H); 13C NMR (CDCl3):
d 31.4,
as colorless oil. Compound 9g: White solids. IR (ATR)
n
3430, 1734,
2.70
33.1, 52.9 (2C), 53.6, 79.0, 98.8, 123.0, 124.4, 125.6, 126.4, 126.8,
1438, 1376, 1267, 1208, 1062, 950, 760 cmꢁ1; 1H NMR (CDCl3):
d
127.0, 127.6, 128.5, 132.0, 132.7, 171.1 (2C), 208.2; (þ)-ESI-HRMS.
þ
(t, J¼2.0 Hz, 2H), 3.34 (s, 2H), 3.70 (s, 3H), 3.72 (s, 6H), 3.93 (t,
Calcd for C20H18NaO4 (MþNaþ): 345.1097. Found: 345.1082.
J¼2.0 Hz, 2H), 4.82 (br s, 1H), 6.32e6.34 (m, 2H), 7.05 (d, J¼8.0 Hz,
1H); 13C NMR (CDCl3):
d 23.1, 32.9, 52.8 (2C), 55.2, 55.9, 58.5, 77.4,
Acknowledgements
83.6, 107.9, 122.4, 123.6, 123.7, 124.7, 124.8, 126.3, 128.4,þ133.7, 151.3,
155.3, 170.5 (2C); (þ)-ESI-HRMS. Calcd for C22H22NaO8 (MþNaþ):
437.1207. Found: 437.1186.
This work was supported by a Grant-in Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science, and Tech-
nology, Japan, the Research Foundation For Pharmaceutical Sciences,
Chiba University, and the Inohana Foundation (Chiba University).
4.5. Experimental procedure for the skeletal rearrangement
of the spirocyclic adducts and compound characterization
4.5.1. Typical experimental procedure for the skeletal rearrangement
of the spirocyclic adducts. To a stirred solution of 4a (34.6 mg,
0.12 mmol) in MeOH (2.4 mL) at 0 ꢀC was added CeCl3$7H2O
(48.0 mg, 0.12 mmol), and the resulting suspension was stirred for
10 min. NaBH4 (9.0 mg, 0.24 mmol) was added to the reaction, and
References and notes
1. For reviews, see: (a) Sannigrahi, M. Tetrahedron 1999, 55, 9007; (b) Kotha, S.;
Deb, A. C.; Lahiri, K.; Manivannan, E. Synthesis 2009, 165; (c) Roche, S. T.; Porco,
J. A., Jr. Angew. Chem., Int. Ed. 2011, 50, 4068; (d) Zhuo, C.-X.; Zhang, W.;
You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662.

T. Nemoto et al. / Tetrahedron 69 (2013) 3403e3409
3409
ꢀ
2. For recent representative examples, see: (a) Canesi, S.; Bouchu, D.; Ciufolini, M. A.
Angew. Chem., Int. Ed. 2004, 43, 4336; (b) Dohi, T.; Maruyama, A.; Yoshimura, M.;
Morimoto, K.; Tohma, H.; Kita, Y. Angew. Chem., Int. Ed. 2005, 44, 6193; (c) Dohi, T.;
Maruyama, A.; Minamitsuji, Y.; Takenaga, N.; Kita, Y. Chem. Commun. 2007, 1224;
(d) Dohi, Y.; Minamitsuji, Y.; Maruyama, A.; Hirose, S.; Kita, Y. Org. Lett. 2008, 10,
3559; (e) Liang, J.; Chen, J.; Du, F.; Zeng, X.; Li, L.; Zhang, H. Org. Lett. 2009, 11,
Kocovsky, P. J. Org. Chem. 1999, 64, 2751; (b) Fernandez, I.; Hermatschweiler, R.;
Breher, F.; Pregosin, P. S.; Veiros, L. F.; Calhorda, M. J. Angew. Chem., Int. Ed. 2006,
45, 6386; (c) Suzuki, Y.; Nemoto, T.; Kakugawa, K.; Hamajima, A.; Hamada, Y.
Org. Lett. 2012, 14, 2350; (d) Xu, Q.-L.; Dai, L.-X.; You, S.-L. Org. Lett. 2012, 14,
2579.
9. (a) Rousseaux, S.; García-Fortanet, J.; Del Aguila Sanchez, M. A.; Buchwald, S. L.
J. Am. Chem. Soc. 2011, 133, 9282 See also; (b) Wu, K.-J.; Dai, L.-X.; You, S.-L. Org.
Lett. 2012, 14, 3772.
10. Nemoto, T.; Zhao, Z.; Yokosaka, T.; Suzuki, Y.; Wu, R.; Hamada, Y. Angew. Chem.,
Int. Ed. 2013, 52, 2217.
ꢀ
2820; (f) Mendelsohn, B. A.; Ciufolini, M. A. Org. Lett. 2009, 11, 4739; (g) Traore,
M.; Maynadier, M.; Souard, F.; Choisnard, L.; Vial, H.; Wong, Y.-S. J. Org. Chem.
2011, 76, 1409 Reviews; (h) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299;
(i) Dohi, T. Chem. Pharm. Bull. 2010, 58, 135.
€
3. (a) Appel, T. R.; Yehia, N. A. M.; Baumeister, U.; Hartung, H.; Kluge, R.; Strohl, D.;
11. (a) Winstein, S.; Baird, R. J. Am. Chem. Soc. 1957, 79, 756; (b) Masamune, S. J. Am.
Chem. Soc. 1961, 83, 1009; (c) Baird, R.; Winstein, S. J. Am. Chem. Soc. 1962, 84, 788.
12. (a) Lalic, G.; Corey, E. J. Org. Lett. 2007, 9, 4921; (b) Dai, M.; Danishefsky, S. J. Tetra-
hedron Lett. 2008, 49, 6610; (c) Magnus, P.; Sane, N.; Fauber, B. P.; Lynch, V. J. Am.
Chem. Soc. 2009, 131, 16045; (d) Eey, S. T.-C.; Lear, M. J. Org. Lett. 2010, 12, 5510.
13. Cyclic dimer was produced as the major by-product.
14. When 4g was treated with Pd catalyst in (CH2Cl)2eMeOH mixed solvent at
a refluxed temperature, the corresponding diene-type adduct was gradually
produced, accompanied by the formation of several by-products.
15. Synthesis of allene derivatives via a similar Pd-catalyzed reaction process,
see: (a) Kimura, M.; Wakamiya, Y.; Horino, Y.; Tamaru, Y. Tetrahedron Lett.
1997, 38, 3963; (b) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2001, 42, 4869; (c)
Kozawa, Y.; Mori, M. J. Org. Chem. 2003, 68, 8068; (d) Bi, H.-P.; Liu, X.-Y.;
Gou, F.-R.; Guo, L.-N.; Duan, X.-H.; Shu, X.-Z.; Liang, Y.-M. Angew. Chem., Int.
Ed. 2007, 46, 7068; (e) Bi, H.-P.; Liu, X.-Y.; Gou, F.-R.; Guo, L.-N.; Duan, X.-
H.; Liang, Y.-M. Org. Lett. 2007, 9, 3527; (f) Shi, Y.; Huang, J.; Yang, Y.-F.; Wu,
L.-Y.; Niu, Y.-N.; Huo, P.-F.; Liu, X.-Y.; Liang, Y.-M. Adv. Synth. Catal. 2009,
351, 141.
€
Fanghanel, E. Eur. J. Org. Chem. 2003, 47; (b) Zhang, X.; Larock, R. C. J. Am. Chem.
Soc. 2005, 127, 12230; (c) Tang, B.-X.; Yin, Q.; Tang, R.-Y.; Li, J.-H. J. Org. Chem.
2008, 73, 9008; (d) Yin, Q.; You, S.-L. Org. Lett. 2012, 14, 3526.
ꢀ
ꢀ
4. (a) Gonzalez-Lopez de Turiso, F.; Curran, D. P. Org. Lett. 2005, 7, 151; (b) Lanza,
T.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.; Zanardi, G. Angew. Chem.,
Int. Ed. 2008, 47, 9439.
5. (a) Pigge, F. C.; Coniglio, J. J.; Rath, N. P. Org. Lett. 2003, 5, 2011; (b) Pigge, F. C.;
Dhanya, R.; Hoefgen, E. R. Angew. Chem., Int. Ed. 2007, 46, 2887.
6. Chiba, S.; Zhang, L.; Lee, J.-Y. J. Am. Chem. Soc. 2010, 132, 7266.
7. (a) Nemoto, T.; Ishige, Y.; Yoshida, M.; Kohno, Y.; Kanematsu, M.; Hamada, Y.
Org. Lett. 2010, 12, 5020; (b) Wu, Q.-F.; Liu, W.-B.; Zhuo, C.-X.; Rong, Z.-Q.;
Ye, K.-Y.; You, S.-L. Angew. Chem., Int. Ed. 2011, 50, 4455; (c) Yoshida, M.;
Nemoto, T.; Zhao, Z.; Ishige, Y.; Hamada, Y. Tetrahedron: Asymmetry 2012, 23,
859 Similar catalytic dearomatization processes using indoles and pyrroles as
nucleophiles, see: (d) Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L. J. Am. Chem. Soc.
2010, 132, 11418; (e) Zhuo, C.-X.; Liu, W.-B.; Wu, Q.-F.; You, S.-L. Chem. Sci. 2012,
3, 205; (f) Wu, Q.-F.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 1680.
8. For examples of transition metal-catalyzed FriedeleCrafts allylic alkylation of
phenols, see: (a) Malkov, A. V.; Davis, S. L.; Baxendale, I. R.; Mitchell, W. L.;
16. The product structure was determined by NOE experiments.
17. For other derivatizations of 4a, see Ref. 10.