Synthesis of 1-indanonyl oxepanes

Article abstract of DOI:10.1055/s-0031-1290304

A variety of 1-indanonyl oxepanes with the novel structure of indanonyl oxepanes was prepared from reaction of hydroxybenzaldehydes via a series of reasonable transformations, including the regioselective PhBClmediated allylation (or Claisen rearrangement), one-pot reaction of ring-closing metathesis and the Wittig olefination, hydrogenation, and the Friedel-Crafts intramolecular cyclization. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0031-1290304

LETTER
▌867
LSeyttenr thesis of 1-Indanonyl Oxepanes
1-Indanonyl Oxepanes
Meng-Yang Chang,* Nien-Chia Lee
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
Fax +886(7)3125339; E-Mail: mychang@kmu.edu.tw
Received: 20.12.2011; Accepted after revision: 25.01.2012
lowed by polyphosphoric acid (PPA)-mediated Friedel–
Crafts intramolecular acylation.
Abstract: A variety of 1-indanonyl oxepanes with the novel struc-
ture of indanonyl oxepanes was prepared from reaction of hydroxy-
benzaldehydes via a series of reasonable transformations, including
the regioselective PhBCl2-mediated allylation (or Claisen rear-
rangement), one-pot reaction of ring-closing metathesis and the
Wittig olefination, hydrogenation, and the Friedel–Crafts intramo-
lecular cyclization.
X
X
O
O
hydrogenation
then Friedel–Crafts
O
acylation
Key words: heterocycles, metalation, metathesis, Wittig reaction,
fused ring systems
a X = H
b X = F
c X = OMe
1
CO2Et
X
2
X
ring-closing
metathesis
double
allylation
O
OH
The bicyclic benzofused ring system, along with related
structures, such as benzo[b]oxepane, represents the struc-
tural motifs of benzooxacycloheptanes (Figure 1). Recent
reports on new methods for the preparation of ben-
zo[b]oxepane have reflected the strong interest, in the
synthesis of these useful building blocks.1,2 The cyclic
system incorporates two rings connected by a fused ring
containing a benzene ring adjacent to the ring junction.
This structural motif has been observed in a number of
natural alkaloid products such as radulanin A,3 heliannuol
A, B, C, and D,4 and pterulone.5 The structural framework
of 1-indanone presents a particular challenge, and its for-
mation is the main focus of the research presented in this
area.6 A number of unique approaches in regard to 1-inda-
none have been explored because of its important poten-
tial biological properties.7 However, there is no example
for synthesizing skeleton 1 with a combination of ben-
zo[b]oxepane and 1-indanone.
then Wittig
olefination
CHO
CHO
3
4
Scheme 1 Retrosynthetic route of skeleton 1
Chattopadhyay8 and Wang9 reported that a general syn-
thesis of benzofused oxepane via a sequential Claisen re-
arrangement and ring-closing metathesis was the key
route. Herein, a more convenient route for synthesizing
skeleton 1 was the PhBCl2-mediated double allylation of
4-substituted 3-hydroxybenzaldehyde 4 with LDA, as
shown in Scheme 2.
To initiate our work, the directed ortho metalation of
model substrate 4a was studied.10 The regioselective
PhBCl2-mediated double allylation of compound 4a with
a three equivalents of LDA provided a diallyl compound
3a in 62% yield via the possible boron complex chelated
intermediate A (see Equation 1.).10e The LDA should ini-
tiate the generated intermediate A so that the ortho C2-
metalation can proceed. The C2 allylation was regioselec-
tively formed from intermediate A, and then intermediate
B was further transformed to compound 3a via the O-al-
lylation of C3. Compounds 3b and 3c were also provided
in 70% and 72% yields, respectively, under the above-
mentioned metalation conditions. For preparing 3-allyl-
oxy-2-allylbenzaldehyde 3, a convenient and efficient
one-pot, double-allylation method was developed from 4-
substituted 3-hydroxybenzaldehyde 4 with a moderate
yield.
O
O
O
O
benzo[b]oxepane
1-indanone
skeleton 1
Figure 1 Structures of oxepane, 1-indanone, and skeleton 1
In this article, we report a simple route for synthesizing
the novel skeleton 1 as shown in Scheme 1, which consists
of a PhBCl2-mediated double allylation of 4-substituted 3-
hydroxybenzaldehyde 4 with LDA, an one-pot combina-
tion of the ring-closing metathesis of diallyl compound 3
followed by the Wittig olefination of the resulting ben-
zo[b]oxepane skeleton, the hydrogenation of ester 2, and
basic hydrolysis of the resulting hydrogenated ester fol-
SYNLETT 204012, 236, 0867–0872
Advanced online publication: 28.02.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290304; Art ID: ST-2011-W0792-L
© Georg Thieme Verlag Stuttgart · New York

868
M.-Y. Chang, N.-C. Lee
LETTER
X
X
OH
O
Grubbs II
LDA, PhBCl2
THF, allylBr
CH2Cl2, then
Ph3P=CHCO2Et
CHO
CHO
4a, X = H
4b, X = F
4c, X = OMe
3a, X = H (62%)
3b, X = F (70%)
3c, X = OMe (72%)
X
X
X
O
O
O
H2, Pd/C
EtOAc
1) 6 M NaOH
2) PPA
(2 steps)
O
CO2Et
CO2Et
2a, X = H (88%)
2b, X = F (80%)
2c, X = OMe (85%)
5a, X = H (93%)
5b, X = F (95%)
5c, X = OMe (98%)
1a, X = H (72%)
1b, X = F (65%)
1c, X = OMe (77%)
Scheme 2 Synthesis of 6-oxacyclohepta[e]indan-3-ones 1a–c
by the PPA-mediated Friedel–Crafts intramolecular ring
closure of the resulting acids.12 The structures of com-
pounds 1a and 1c were determined using single-crystal X-
ray analysis (Figure 2).13,14
O
Li
3
O
Li
LDA
PhBCl2
LDA
allylBr
B
Ph
2
2
4a
3a
allylBr
CHO
O
H
A
B
Equation 1 Possible PhBCl2-mediated intermediate
In order to construct the benzo[b]oxepane skeleton, com-
pound 3a with the diallyl group was first subjected to an
intramolecular ring-closing metathesis by using the
Grubbs second-generation catalyst in dichloromethane
according to the reported conditions.11 Next, the Wittig
olefination of the resulting benzaldehyde bearing a seven-
membered ring with Ph3P=CHCO2Et in dichloromethane
afforded the α,β-unsaturated ester 2a. Because dichloro-
methane could be used as the same reaction solvent for
ring-closing metathesis and Wittig olefination, a combi-
nation of the two steps was required. Comparing the two
routes, we found that the one-pot reaction provided a
higher yield (88%) than the two-step reaction process
(75%). From the literature reports on the synthesis of a
benzo[b]oxepane skeleton using the Claisen rearrange-
ment as the key step, it was evident that the present meth-
odology shortened the synthesis steps and increased the
reaction yields. Compounds 2b and 2c were obtained in
80% and 85% yield, respectively, under the one-pot reac-
tion conditions. Then, when skeleton 2 was treated with
hydrogen in the presence of a catalytic amount of 10%
palladium on activated carbon in EtOAc, compounds 5a–
c were isolated in 93–98% yields. Finally, three 1-in-
danonyl oxepanes 1a–c, with a tricyclic skeleton, were
obtained as sole isomers in yields of 65–77% via the
NaOH-promoted hydrolysis of compounds 5a–c followed
Figure 2 X-ray structure of compound 1c
With the successful results in hand, we attempted to pre-
pare other tricyclic skeletons of 1-indanonyl oxepanes.15
Six possible skeletons are shown in Figure 3. Based on the
relative position between the carbonyl group of the inda-
none skeleton and the oxygen atom of the oxepane skele-
ton, the structure of 1-indanonyl oxepane could be
classified into three types: (i) one ortho-substituted skele-
ton A1, (ii) two para-substituted skeletons B1,2, and (iii)
three meta-substituted skeletons C1–3. According to the
above-mentioned analyses, we envisioned that the ana-
logues 1 would be generated from hydroxybenzaldehydes
4a–c via the key Claisen rearrangement.16
Synlett 2012, 23, 867–872
© Georg Thieme Verlag Stuttgart · New York

LETTER
1-Indanonyl Oxepanes
869
rated mixture with the one-pot reaction gave compounds
2a and 2d in 15% and 73% yields, respectively. Further-
more, compound 1d (skeleton B2) was easily yielded by
the hydrogenation of compound 2d and ring closure of
compound 5d. During the regioselective PPA-mediated
Friedel–Crafts acylation, compound 1d was isolated as
the sole product. Attempts to isolate skeleton A1 failed
during the intramolecular cyclization. When the regiose-
lective ring-closure step of acid substrate was treated with
SOCl2 and AlCl3, compound 1e was achieved with a 49%
yield without the formation of compound 1d.
O
p
O
p
o
O
O
O
O
A1
B1
B2
O
O
m
m
m
O
O
O
After the starting material was changed as 4-hydroxy-
benzaldehyde (4d), attempts to synthesize skeleton C2 or
C3 were further studied (Scheme 4). First, compound 3e
provided a 69% yield by the three-step protocol. Next,
treatment of compound 3e with the one-pot reaction of the
ring-closing metathesis and the Wittig olefination afford-
ed compound 2e in an 80% yield. After the hydrogenation
of compound 2e and the Friedel–Crafts ring closure of
compound 5e, compounds 1f (skeleton C3) and 1g (skel-
eton C2) were isolated in 60% and 19% yields, respective-
ly. The preference for a linear formation was ascribed to
the steric effect. The structures of linear compound 1f and
O
C1
C2
C3
Figure 3 Six skeletons of 1-indanonyl oxepanes
As shown in Scheme 3, the unseparated mixture of com-
pounds 3a and 3d was provided in 52% yields of three
steps via the reaction sequence of O-allylation, Claisen re-
arrangement, and O-allylation. From the phenomenon, we
found that the present route could not provide a regiose-
lective Claisen rearrangement.17 Treatment of the unsepa-
OH
O
O
1) allylBr, K2CO3
+
2) decalin, reflux
3) allylBr, K2CO3
CHO
(52% over 3 steps)
CHO
CHO
Grubbs II
4a
3a
3d
CH2Cl2, then
Ph3P=CHCO2Et
(2a, 15%; 2d, 73%)
O
1) 6 M NaOH
H2, Pd/C
O
O
2) PPA
or SOCl2, AlCl3
(2 steps)
EtOAc (96%)
O
X
(B2)
1d, X = H (66%)
1e, X = Cl (49%)
CO2Et
CO2Et
5d
2d
Scheme 3 Synthesis of 5-oxacyclohepta[f]indan-1-ones 1d–e
O
OH
Grubbs II
CH2Cl2, then
1) allylBr, K2CO3
Ph3P=CHCO2Et
(80%)
2) decalin, reflux
3) allylBr, K2CO3
(69% over 3 steps)
CHO
CHO
4d
3e
O
O
O
O
1) 6 M NaOH
H2, Pd/C
EtOAc (93%)
+
2) PPA
O
O
(two-steps)
(C3)
(C2)
1g (19%)
CO2Et
CO2Et
2e
5e
1f (60%)
Scheme 4 Synthesis of 5-oxacyclohepta[f]indan-3-one 1f and 6-oxacyclohepta[e]indan-1-one 1g
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 867–872

870
M.-Y. Chang, N.-C. Lee
LETTER
angular compound 1g were constructed using single-crys-
OMe
OMe
CHO
OMe
O
tal X-ray analysis.13
Grubbs II
CH2Cl2, then
Grubbs cat,
Pd/C, CH2Cl2
O
O
Furthermore, 2-hydroxybenzaldehyde (4e) was chosen as
the reasonable starting material for constructing com-
pound 1h (skeleton C1). The sole compound 1h was
formed via the above-mentioned synthesis sequence
(Scheme 5): (i) three-step double allylation of compound
4e (40%); (ii) one-pot combination of compound 3f in a
one-pot reaction with ring-closing metathesis and the
Wittig olefination reaction (72%); (iii) hydrogenation of
compound 5f (96%); and (iv) intramolecular ring closure
of compound 5f (74%, two steps). Based on the above re-
sults, although the isolation of skeleton A1 could not been
achieved, a variety of novel skeletons 1 with the structure
of indanonyl oxepane was prepared from the reaction of
hydroxybenzaldehydes.
MCPBA
(58%)
then H2
(70%)
OH
7
3c
6
Scheme 6 One-pot combination reaction of compound 3c
We have successfully presented the ortho-metalative-
mediated double allylation reaction of 4-substituted 3-hy-
droxybenzaldehydes 4a–c with PhBCl2 for producing
three 4-substituted 1-indanonyl oxepanes 1a–c (skeleton
B1). The Claisen rearrangement and one-pot combination
reaction of compound 3a with the ring-closing metathesis
and the Wittig olefination were applied to synthesize dif-
ferent 1-indanonyl oxepanes 1d–h, including several skel-
etons para-B2, meta-C1, meta-C2, and meta-C3. Several
structures of the products were confirmed by X-ray crystal
analysis.
Grubbs II
1) allylBr, K2CO3
CH2Cl2, then
2) decalin, reflux
3) allylBr, K2CO3
(40% over 3 steps) CHO
Ph3P=CHCO2Et
(72%)
OH
O
CHO
Acknowledgment
4e
3f
The authors would like to thank the National Science Council of the
Republic of China for its financial support (NSC 99-2113-M-037-
006-MY3).
O
O
H2, Pd/C
EtOAc (96%)
1) 6 M NaOH
2) PPA
(2 steps)
O
References and Notes
O
CO2Et
CO2Et
(1) For reviews on the synthesis of oxacycloheptanes, see:
(a) Yet, L. Chem. Rev. 2000, 100, 2963. (b) Snyder, N. L.;
Haines, H. M.; Peczuh, M. W. Tetrahedron 2006, 62, 9301.
(c) Hoberg, J. O. Tetrahedron 1998, 54, 12631.
2f
5f
(C1)
1h (74%)
Scheme 5 Synthesis of 10-oxacyclohepta[e]indan-3-one 1h
(2) (a) Chirapu, S. R.; Pachaiyappan, B.; Nural, H. F.; Cheng,
X.; Yuan, H.; Lankin, D. C.; Abdul-Hay, S. O.; Thatcher, G.
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Panda, G. Eur. J. Org. Chem. 2009, 204. (c) Nguyen, V. T.
H.; Bellur, E.; Langer, P. Tetrahedron Lett. 2006, 47, 113.
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(3) (a) Asakawa, Y.; Toyota, M.; Takemoto, T. Phytochemistry
1978, 17, 2005. (b) Stefinovic, M.; Snieckus, V. J. Org.
Chem. 1998, 63, 2808.
(4) (a) Macias, F. A.; Molinillo, J. M. G.; Varela, R. M.; Torres,
A.; Fronczek, F. R. J. Org. Chem. 1994, 59, 8261. (b) Sabui,
S. K.; Venkateswaran, R. V. Tetrahedron Lett. 2004, 45,
983. (c) Kishuku, H.; Shindo, M.; Shishido, K. Chem.
Commun. 2003, 350.
(5) (a) Huang, S.; Kuo, H.; Chen, C. Tetrahedron Lett. 2001, 42,
7473. (b) Kahnberg, P.; Lee, C. W.; Grubbs, R. H.; Sterner,
O. Tetrahedron 2002, 58, 5203.
(6) (a) Aono, T.; Kishimoto, S.; Araki, Y.; Noguchi, S. Chem.
Pharm Bull. 1978, 26, 1776. (b) Schuler, G.; Gorls, H.;
Boland, W. Eur. J. Org. Chem. 2001, 1663. (c) Girijia, T.;
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Trans. 1 1991, 1467. (d) Lauchli, R.; Schuler, G.; Boland,
W. Phytochemistry 2002, 61, 807.
With the previous experience of the one-pot combination
reaction of compound 3c, including the ring-closing me-
tathesis and the Wittig olefination reaction, two one-pot
combinations with ring-closing metathesis were explored,
as shown in Scheme 6. The reaction of compound 3c was
first treated with Grubbs second-generation catalyst in the
presence of a catalytic amount of 10% palladium on acti-
vated carbon in dichloromethane, and hydrogen was then
added into the mixture. By this addition sequence, com-
pound 6 was isolated in a 70% yield via the one-pot com-
bination reaction of ring-closing metathesis and
hydrogenation. Then, compound 7 was synthesized in a
58% yield via (i) the ring-closing metathesis of compound
3c with Grubbs second-generation catalyst in dichloro-
methane, and then (ii) the Baeyer–Villiger reaction of the
resulting aldehyde with K2CO3 and MCPBA. Using the
same reaction solvent, the two one-pot combinations en-
hanced the synthesis efficiency and shortened the required
purification time. The structural framework of compound
7 was constructed using single-crystal X-ray analysis.13
Therefore, a domino reaction for establishing the ben-
zo[b]oxepane skeletons 6 and 7 was provided.18
(7) (a) Aono, T.; Kishimoto, S.; Araki, Y.; Noguchi, S. Chem.
Pharm. Bull. 1978, 26, 1776. (b) Aono, T.; Araki, Y.;
Tanaka, K.; Imanishi, M.; Noguchi, S. Chem. Pharm. Bull.
1978, 26, 1511. (c) Schuler, G.; Gorls, H.; Boland, W. Eur.
J. Org. Chem. 2001, 1663. (d) Zhang, Z.-P.; Krumm, T.;
Baldwin, I. T. J. Chem. Ecol. 1997, 23, 2777.
(e) Akritopoulou-Zanze, I.; Albert, D. H.; Bousquet, P. F.;
Synlett 2012, 23, 867–872
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cunha, G. A.; Harris, C. M.; Moskey, M.; Dinges, J.;
Stewart, K. D.; Sowin, T. J. Bioorg. Med. Chem. Lett. 2007,
17, 3136.
(8) Chattopadhyay, S. K.; Biswas, T.; Maity, S. Synlett 2006,
2211.
1-Indanonyl Oxepanes
871
hexanes and EtOAc). ESI-HRMS: m/z ] calcd for C13H15O2
203.1072 [M+ + 1; found: 203.1073. 1H NMR (400 MHz,
CDCl3): δ = 7.54 (d, J = 8.0 Hz, 1 H), 6.98 (d, J = 8.0 Hz, 1
H), 4.10 (dd, J = 5.2, 5.6 Hz, 2 H), 3.02 (t, J = 5.6 Hz, 2 H),
2.85–2.82 (m, 2 H), 2.69–2.66 (m, 2 H), 2.05–1.99 (m, 2 H),
1.82–1.76 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ =
205.94, 166.03, 155.93, 132.40, 131.52, 122.75, 121.61,
77.31, 73.29, 36.48, 31.60, 27.83, 24.88. Anal. Calcd for
C13H14O2: C, 77.20; H, 6.98. Found: C, 77.51; H, 7.34.
Single-crystal X-ray diagram shows that the crystal of
compound 1a was grown by slow diffusion of EtOAc into a
solution of compound 1a in CH2Cl2 to yield colorless prism.
The compound crystallizes in the triclinic crystal system,
space group P-1, a = 8.4928(2) Å, b = 10.5935(2) Å,
c = 12.4192(2) Å, V = 1032.67(4) Å3, Z = 4, dcalcd = 1.301
g/cm3, F(000) = 432, 2θ range 1.69–26.40°; R indices (all
data): R1 = 0.0938, wR2 = 0.1850.
(9) Tsai, J.-C.; Li, S.-R.; Chen, L.-Y.; Chen, P. Y.; Jhong, J. Y.;
Shu, C.-J.; Lo, Y.-F.; Lin, C.-N.; Wang, E.-C. J. Chin. Chem.
Soc. 2008, 55, 1317.
(10) (a) De Silva, S. O.; Watanabe, M.; Snieckus, V. J. Org.
Chem. 1979, 44, 4802. (b) Shih, T. L.; Wyvratt, M. J.;
Mrozik, H. J. Org. Chem. 1987, 52, 2029. (c) Snieckus, V.
Chem. Rev. 1990, 90, 879. (d) Rauer, W.; Schleyer, P. V. R.
J. Am. Chem. Soc. 1989, 111, 7191. (e) Lamas, C.; Castedo,
L.; Dominguez, D. Tetrahedron Lett. 1988, 29, 3865.
(11) For reviews on the ring-closing metathesis reaction, see:
(a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.
1995, 28, 446. (b) Schmalz, H. G. Angew. Chem. Int. Ed.
1995, 34, 1833. (c) Schuster, M.; Blechert, S. Angew. Chem.
Int. Ed. 1997, 36, 2036. (d) Armstrong, S. K. J. Chem. Soc.,
Perkin Trans. 1 1998, 371. (e) Philips, A. J.; Abell, A. D.
Aldrichimica Acta 1999, 32, 75. (f) Pandit, U. K.;
Overkleeft, H. S.; Borer, B. C.; Bieraugel, H. Eur. J. Org.
Chem. 1999, 959. (g) Wright, D. L. Curr. Org. Chem. 1999,
3, 75. (h) Maier, M. E. Angew. Chem. Int. Ed. 2000, 39,
2073. (i) Felpin, F. X.; Lebreton, J. Eur. J. Org. Chem. 2003,
3693. (j) Cossy, J. Chem. Rec. 2005, 5, 70.
Compound 1c
Colorless solid; mp 126–127 °C (recrystallized from
hexanes and EtOAc). ESI-HRMS: calcd for C14H17O3 [M+ +
1]: 233.1178; found: 233.1182. 1H NMR (400 MHz,
CDCl3): δ = 7.06 (s, 1 H), 4.11 (dd, J = 5.2, 5.6 Hz, 2 H),
3.83 (s, 3 H), 2.94–2.92 (m, 2 H), 2.82–2.79 (m, 2 H), 2.63–
2.60 (m, 2 H), 2.04–1.98 (m, 2 H), 1.79–1.73 (m, 2 H). 13
C
NMR (100 MHz, CDCl3): δ = 206.28, 155.54, 151.99,
147.87, 132.36, 131.62, 102.86, 73.48, 55.94, 36.12, 31.50,
27.90, 24.54, 24.32; Anal. Calcd for C14H16O3: C, 72.39; H,
6.94. Found: C, 72.68; H, 7.23. Single-crystal X-ray diagram
shows that the crystal of compound 1c was grown by slow
diffusion of EtOAc into a solution of compound 1c in
CH2Cl2 to yield colorless prism. The compound crystallizes
in the triclinic crystal system, space group P-1,
(12) For Friedel–Crafts acylation reaction, see: (a) Heaney, H. In
Comprehensive Organic Synthesis, Vol. 2; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991, 733.
(b) Olah, G. A. Friedel–Crafts Chemistry; John Wiley and
Sons: New York, 1973. (c) For reviews on the
intramolecular Friedel–Crafts acylation reaction, see:
Heaney, H. In Comprehensive Organic Synthesis, Vol. 2;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991, 753. (d) Sethna, S. In Friedel–Crafts and Related
Reactions, Vol. 3; Olah, G. A., Ed.; Interscience: New York,
1964, 911.
a = 8.4193(10) Å, b = 8.6260(10) Å, c = 9.7658(12) Å,
V = 593.29(12) Å3, Z = 2, dcalcd = 1.300 g/cm3,
F(000) = 248, 2θ range 2.25–26.38°; R indices (all data):
R1 = 0.0978, wR2 = 0.1994.
Compound 1f
(13) CCDC 846976 (1a), 845967 (1c), 853005 (1f), 853004 (1g),
and 845966 (7) contain the supplementary crystallographic
data for this paper. This data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
(14) Representative Synthetic Transformation of Skeleton 1
from 5
Colorless solid; mp 75–76 °C (recrystallized from hexanes
and EtOAc). ESI-HRMS: m/z calcd for C13H15O2 [M+ + 1]:
203.1072; found: 203.1074. 1H NMR (400 MHz, CDCl3):
δ = 7.32 (s, 1 H), 7.24 (s, 1 H), 4.02–3.98 (m, 2 H), 3.05–
3.02 (m, 2 H), 2.89–2.86 (m, 2 H), 2.68–2.65 (m, 2 H), 2.00–
1.95 (m, 2 H), 1.77–1.72 (m, 2 H). 13C NMR (100 MHz,
CDCl3): δ = 206.36, 160.07, 150.58, 144.26, 136.50, 127.76,
115.29, 73.93, 36.89, 34.82, 32.07, 25.98, 25.10. Anal.
Calcd for C13H14O2: C, 77.20; H, 6.98. Found: C, 77.39; H,
7.14. Single-crystal X-ray diagram shows that the crystal of
compound 1f was grown by slow diffusion of EtOAc into a
solution of compound 1f in CH2Cl2 to yield colorless prism.
The compound crystallizes in the monoclinic crystal system,
space group P1 21/c 1, a = 20.6470(13) Å, b = 6.1783(4) Å,
c = 17.7204(10) Å, V = 2093.3(2) Å3, Z = 8, dcalcd = 1.283
g/cm3, F(000) = 864, 2θ range 1.06–26.71°; R indices (all
data): R1 = 0.0883, wR2 = 0.1083.
A solution of 5 (0.4 mmol) and aq NaOH (6 M, 5 mL) in
THF (10 mL) was refluxed for 6 h. The reaction was traced
by TLC until 5 was completely consumed. The reaction
solution was cooled to r.t. and concentrated until one third of
the solution remained. The remained solution was extracted
with EtOAc (3 × 10 mL). The aqueous phase was cooled in
an ice-bath and acidified by adding concentrated aq HCl to
pH 2. The aqueous solution was extracted with EtOAc
(3 × 20 mL), and the extracts were washed with brine. The
combined organic layers were washed with brine, dried,
filtered, and evaporated to afford a crude acid product under
reduced pressure. Without purification, PPA (3 mL) was
added to a solution of the crude acid product in CH2Cl2 (5
mL) at r.t. The reaction mixture was stirred at r.t. for 4 h.
Saturated aq NaHCO3 (10 mL) was added to the reaction
mixture, and the residue was extracted with CH2Cl2 (3 × 30
mL). The combined organic layers were washed with brine,
dried, filtered, and evaporated to afford the crude product
under reduced pressure. Purification on silica gel (hexanes–
EtOAc = 3:1) afforded skeleton 1.
Compound 1g
Colorless solid; mp 107–108 °C (recrystallized from
hexanes and EtOAc). ESI-HRMS: m/z calcd for C13H15O2
[M+ + 1]: 203.1072; found: 203.1076. 1H NMR (400 MHz,
CDCl3): δ = 7.17 (s, 2 H), 4.00–3.98 (m, 2 H), 3.46–3.43 (m,
2 H), 2.99–2.96 (m, 2 H), 2.68–2.65 (m, 2 H), 2.00–1.95 (m,
2 H), 1.74–1.67 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ =
207.91, 160.25, 150.89, 135.42, 134.41, 127.42, 124.38,
73.42, 37.69, 32.17, 24.90, 24.55, 24.20. Anal. Calcd for
C13H14O2: C, 77.20; H, 6.98. Found: C, 77.41; H, 6.76.
Single-crystal X-ray diagram shows that the crystal of
compound 1g was grown by slow diffusion of EtOAc into a
solution of compound 1g in CH2Cl2 to yield colorless prism.
Representative Data for Compound 1a
Colorless solid; mp 135–136 °C (recrystallized from
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 867–872

872
M.-Y. Chang, N.-C. Lee
LETTER
The compound crystallizes in the monoclinic crystal system,
space group P1 21/n 1, a = 9.0400(9) Å, b = 8.6174(9) Å,
c = 13.6389(14) Å, V = 1044.01(18) Å3, Z = 4, dcalcd = 1.287
g/cm3, F(000) = 432, 2θ range 2.50–26.37°; R indices (all
data): R1 = 0.0630, wR2 = 0.1108.
Synthesis 2003, 961. (c) Hiersemann, M.; Abraham, L. Eur.
J. Org. Chem. 2002, 1461. (d) Chai, Y.; Hong, S.; Lindsay,
H. A.; MaFarland, C.; McIntosh, M. C. Tetrahedron 2002,
58, 2905.
(17) Han, X.; Armstrong, D. W. Org. Lett. 2005, 7, 4205.
(18) (a) Kato, H.; Ishigame, T.; Oshima, N.; Hoshiya, N.;
Shimawaki, K.; Arisawa, M.; Shuto, S. Adv. Synth. Catal.
2011, 353, 2676. (b) Tietze, L. F. Chem. Rev. 1996, 96, 195.
(15) Isabelle, M. E.; Wightman, R. H.; Avdovich, H. W.;
Laycock, D. E. Can. J. Chem. 1980, 58, 1344.
(16) For reviews on the Claisen rearrangement, see: (a) Castro,
A. M. Chem. Rev. 2004, 104, 2939. (b) Nubbemeyer, U.
Synlett 2012, 23, 867–872
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