Synthesis of indenoindene-fused α-methylene-γ-butyrolactones via a tandem intra- and intermolecular Friedel-Crafts reaction

Article abstract of DOI:10.1016/j.tetlet.2011.01.153

An efficient synthesis of indenoindene-fused α-methylene-γ- butyrolactones was carried out via a tandem intra- and intermolecular Friedel-Crafts reaction from the spiro-lactone, which can be easily prepared from ninhydrin by indium-mediated Barbier reaction of cinnamyl bromide.

Full text of DOI:10.1016/j.tetlet.2011.01.153

Tetrahedron Letters 52 (2011) 1700–1704
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of indenoindene-fused
a-methylene-c-butyrolactones via a
tandem intra- and intermolecular Friedel–Crafts reaction
⇑
Bo Ram Park, Se Hee Kim, Yu Mi Kim, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of indenoindene-fused
a-methylene-c-butyrolactones was carried out via a tan-
Received 11 January 2011
Revised 28 January 2011
Accepted 31 January 2011
Available online 19 February 2011
dem intra- and intermolecular Friedel–Crafts reaction from the spiro-lactone, which can be easily pre-
pared from ninhydrin by indium-mediated Barbier reaction of cinnamyl bromide.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
a
-Methylene-
Indenoindene
Friedel–Crafts reaction
c-butyrolactone
a
-Methylene-
c
-butyrolactone derivatives have attracted much
metal reagents and carbonyl compounds to generate homoallyl
alcohols followed by acid-catalyzed lactonization.2b–e,3
attention,1,2 because they are found in a wide range of natural sub-
stances and are pivotal units for the observed biological activities.1,2
Recently, we have been interested in the development of effi-
Furthermore,
a
-methylene-
c
-butyrolactones serve as versatile
cient synthetic methods for various
a-methylene-c-butyrolactones
starting materials for many important compounds.1–4 In addition,
from Baylis–Hillman adducts.3 In continuation of our studies, we
various fused
a-methylene-
c
-butyrolactones4a–d and their double-
decided to synthesize indenoindene-fused a-methylene-c-butyro-
bond isomerized butenolide derivatives4e–j have also attracted
much attention. The most straightforward method for the synthesis
lactones5,6 using the spiro-lactone derivative derived from ninhy-
drin and Baylis–Hillman bromide,3c as shown in Scheme 1. The
indenoindene moiety should fix the target compound 6a as a
of
a-methylene-
c-butyrolactones involves the reaction of allylic
O
O
O
O
O
COOMe
In/aq THF
Ph
O
OH
Ph
p-TsOH
COOMe
+
O
rt, 2 h
CH2Cl2, rt
Br
Ref. 3c
Ph
O
O
1
2a
3a
4a
O
O
O
O
O
O
O
O
O
benzene/H2SO4
benzene
4a
intramolecular
Friedel-Crafts
intermolecular
Friedel-Crafts
HO
HO
6a
5a
Scheme 1.
⇑
Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.153

B. R. Park et al. / Tetrahedron Letters 52 (2011) 1700–1704
1701
butterfly-like conformation, which was known to be essential in
some NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors)
including nevirapine.7
Ph Ph
HO Ph
O
O
O
O
O
O
O
Required starting material 4a was prepared according to our
previous paper.3c The reaction of ninhydrin (1) and cinnamyl bro-
HO
Ph Ph
mide 2a in the presence of indium metal afforded c-hydroxy ester
3a, and subsequent acid-catalyzed lactonization of 3a with p-TsOH
provided the spiro-lactone 4a in good yield (77%).3c,8 With com-
pound 4a in hand, we examined Friedel–Crafts type reactions in
7a
9a
8a
Figure 1.
Table 1
Synthesis of pentacyclic lactones
Entry
Substrate
Conditions
Product (%)
O
O
O
O
O
O
O
H2SO4 (5 equiv)
benzene
reflux, 9 h
1
2
O
Ph
6a (95%)
4a
O
O
H2SO4 (20 equiv)
chlorobenzene
reflux, 2 h
4a
6b (87%)a
Cl
O
O
O
H2SO4 (20 equiv)
ethylbenzene
reflux, 6 h
3
4a
6c (53%)a
Et
O
O
O
H2SO4 (20 equiv)
p-xylene
reflux, 20 h
4
4a
Me
6d (58%)
Me
O
O
O
O
O
O
O
H2SO4 (5 equiv)
benzene
reflux, 2 h
5
6e (94%)
Me
4b
Me
O
O
O
H2SO4 (30 equiv)
toluene
6
4b
reflux, 48 h
6f (81%)a
Me
Me
O
O
O
O
O
O
O
PPA
benzene
reflux, 80 h
7
6g (28%)
MeO
4c
OMe
a Single isomer.

1702
B. R. Park et al. / Tetrahedron Letters 52 (2011) 1700–1704
O
O
O
O
allyl bromide
(4.0 equiv)
H2SO4 (0.1 equiv)
benzene
O
O
O
O
O
4a
+
In (2.5 equiv)
DMF, rt, 12 h
reflux, 60 min
Ph
Ph
Ph
HO
11 (72%, 1:1 mixture)
10 (92%)
Scheme 2.
ortho-isomer was not formed presumably due to steric hindrance.
The reaction of 4a and ethylbenzene also produced the p-isomer 6c
in 53% (entry 3). The reaction of 4a in p-xylene required a longer
reaction time (20 h) to obtain moderate yield (58%) of 6d (entry
4). The reason might be due to steric crowding around the carbo-
cation in the second intermolecular Friedel–Crafts reaction with
p-xylene. Product 6d showed atropisomeric restricted rotation
around the C–C bond between the xylyl moiety and indenoindene
ring based on its 1H and 13C NMR spectra.5h,8,11 The reaction of 4b
in benzene or toluene afforded 6e and 6f in good yields, respec-
tively (entries 5 and 6). However, the reaction of methoxy deriva-
tive 4c in benzene did not produce the expected product 6g, which
might be attributed to the loss of nucleophilicity of the p-anisole
moiety by protonation with H2SO4. When we used PPA (polyphos-
phoric acid), compound 6g was obtained (entry 7), albeit in low
yield (28%). The structure of indenoindene-fused
a-methylene-c-
butyrolactone 6 was confirmed unequivocally by its crystal struc-
ture (6e as an example, Fig. 2)10 and the spectroscopic data.8
As a last entry, spiro-lactone 10 was prepared by the reaction of
4a and allylindium reagents (Scheme 2). When we ran the reaction
of 10 in benzene in the presence of H2SO4, we did not obtain the
corresponding pentacyclic lactone via the intramolecular Friedel–
Crafts reaction. Instead, 1,3-diene derivative 11 was isolated as a
cis/trans mixture in 72%.8
Figure 2. ORTEP drawing of compound 6e.
The
a-methylene-c-butyrolactone moiety of 6a could be con-
verted easily to a butenolide moiety of 12 by treatment with DBU
in CH3CN at room temperature, as shown in Scheme 3. Such a fused
butenolide moiety is found in many natural substances,4e–j and our
method could provide an alternative route for numerous fused
butenolides.
O
O
O
DBU (1.0 equiv)
CH3CN, rt, 5 h
6a
In summary, we disclose an efficient synthesis of indenoindene-
fused a-methylene-c-butyrolactones via a tandem intra- and inter-
molecular Friedel–Crafts reaction from the spiro-lactone, which can
be easily obtained from ninhydrin and Baylis–Hillman adduct. Fur-
ther studies on the structure modification and screening of their
antiviral activities are currently underway.
12 (81%)
Scheme 3.
benzene in the presence of H2SO4.9 The reactions proceeded via an
initial intramolecular Friedel–Crafts type reaction to form interme-
diate 5a via the corresponding oxonium intermediate, and the sub-
sequent intermolecular Friedel–Crafts reaction with benzene
generates the final pentacyclic lactone 6a in good yield (95%).8
We did not observe the formation of 5a or 7a-9a (Fig. 1), which
could be formed if the intermolecular Friedel–Crafts reaction was
more facile than the intramolecular reaction.5g,h Based on these re-
sults, the reaction sequence presumably involves sequential intra-
molecular cyclization followed by an intermolecular Friedel–Crafts
reaction. When we used AcOH as the acid catalyst, compound 6a
was not formed even after refluxing for a long time. When TfOH
was used, the amounts of intractable side products were increased.
Thus H2SO4 was chosen as the acid catalyst.
Acknowledgments
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (2010-
0015675). Spectroscopic data were obtained from the Korea Basic
Science Institute, Gwangju branch.
References and notes
1. For the leading reviews on the synthesis and biological activity of
a-
methylene- -butyrolactones, see: (a) Kitson, R. R. A.; Millemaggi, A.; Taylor,
c
R. J. K. Angew. Chem., Int. Ed. 2009, 48, 9426–9451; (b) Hoffmann, H. M. R.; Rabe,
J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94–110; (c) Lepoittevin, J.-P.; Berl, V.;
Gimenez-Arnau, E. Chem. Record 2009, 9, 258–270; (d) Elford, T. G.; Hall, D. G.
Synthesis 2010, 893–907.
Encouraged by the results, we carried out the synthesis of sim-
ilar pentacyclic lactones, as shown in Table 1. The reaction of 4a in
chlorobenzene required larger excess amounts of H2SO4 (20 equiv),
and compound 6b was obtained in 87% (entry 2). It is interesting to
note that only the p-isomer was formed. The corresponding
2. For the synthesis of a-methylene-c-butyrolactones, see: (a) Lee, A. S.-Y.; Chang,
Y.-T.; Wang, S.-H.; Chu, S.-F. Tetrahedron Lett. 2002, 43, 8489–8492; (b)
Paquette, L. A.; Mendez-Andino, J. Tetrahedron Lett. 1999, 40, 4301–4304; (c)
Ramachandran, P. V.; Garner, G.; Pratihar, D. Org. Lett. 2007, 9, 4753–4756; (d)
Le Lamer, A.-C.; Gouault, N.; David, M.; Boustie, J.; Uriac, P. J. Comb. Chem. 2006,

B. R. Park et al. / Tetrahedron Letters 52 (2011) 1700–1704
1703
8, 643–645; (e) Kabalka, G. W.; Venkataiah, B. Tetrahedron Lett. 2005, 46, 7325–
7328.
3. For our recent synthesis of lactone derivatives, see: (a) Park, B. R.; Kim, K. H.;
Kim, J. N. Tetrahedron Lett. 2010, 51, 6568–6571; (b) Kim, K. H.; Lee, H. S.; Kim,
S. H.; Lee, K. Y.; Lee, J.-E.; Kim, J. N. Bull. Korean Chem. Soc. 2009, 30, 1012–1020;
(c) Lee, K. Y.; Park, D. Y.; Kim, J. N. Bull. Korean Chem. Soc. 2006, 27, 1489–1492.
J = 8.7 Hz, 2H), 7.34–7.42 (m, 4H), 7.54 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H),
7.76 (t, J = 7.8 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d
51.18, 66.78, 95.06, 124.37, 124.50, 124.90, 125.70, 126.46, 128.43, 129.43,
129.68, 129.71, 130.49, 133.09, 133.90, 135.58, 137.35, 138.69, 140.23, 144.56,
155.38, 168.40, 198.79; ESIMS (positive ion) m/z 399 (M++H), 401 (M++H+2).
Anal. Calcd for C25H15ClO3: C, 75.29; H, 3.79. Found: C, 75.03; H, 4.05.
Compound 6c: 53%; white solid, mp 188–191 °C; IR (KBr) 1778, 1728,
4. For the synthesis of fused a-methylene-c-butyrolactones and butenolides, see:
(a) Chen, V. X.; Boyer, F.-D.; Rameau, C.; Retailleau, P.; Vors, J.-P.; Beau, J.-M.
Chem. Eur. J. 2010, 16, 13941–13945; (b) Rodriguez, C. M.; Martin, T.; Martin, V.
S. J. Org. Chem. 1996, 61, 8448–8452; (c) Barrero, A. F.; Oltra, J. E.; Alvarez, M.;
Rosales, A. J. Org. Chem. 2002, 67, 5461–5469; (d) Marshall, J. A.; Griot, C. A.;
Chobanian, H. R.; Myers, W. H. Org. Lett. 2010, 12, 4328–4331; (e) Matsuo, K.;
Shindo, M. Org. Lett. 2010, 12, 5346–5349; (f) Krawczyk, E.; Koprowski, M.;
Luczak, J. Tetrahedron: Asymmetry 2007, 18, 1780–1787; (g) Delaunay, J.;
Orliac-Le Moing, A.; Simonet, J. Tetrahedron 1988, 44, 7089–7094; (h) Demir, A.
S.; Gercek, Z.; Duygu, N.; Igdir, A. C.; Reis, O. Can. J. Chem. 1999, 77, 1336–1339;
(i) Wu, Q.-H.; Wang, C.-M.; Cheng, S.-G.; Gao, K. Tetrahedron Lett. 2004, 45,
8855–8858; (j) Wu, Q.-H.; Liu, C.-M.; Chen, Y.-J.; Gao, K. Helv. Chim. Acta 2006,
89, 915–922.
1275 cmÀ1 1H NMR (CDCl3, 300 MHz)
; d 1.19 (t, J = 7.5 Hz, 3H), 2.59 (q,
J = 7.5 Hz, 2H), 4.50 (s, 1H), 6.01 (s, 1H), 6.37 (s, 1H), 6.64 (d, J = 7.8 Hz, 2H), 7.05
(d, J = 7.8 Hz, 2H), 7.36–7.48 (m, 4H), 7.51 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 7.5 Hz,
1H), 7.74 (t, J = 7.5 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d
15.10, 28.26, 51.18, 67.04, 95.25, 123.99, 124.30, 124.67, 125.88, 126.64,
127.69, 129.07, 129.10, 129.39, 129.42, 133.12, 135.90, 137.09, 137.25, 140.19,
143.63, 145.21, 156.08, 168.62, 199.26; ESIMS (positive ion) m/z 393 (M++H).
Anal. Calcd for C27H20O3: C, 82.63; H, 5.14. Found: C, 82.71; H, 5.02.
Compound 6d: 58% (major/minor, 3:2); white solid, mp 226–229 °C; IR (KBr)
1778, 1727, 1219 cmÀ1 1H NMR (major, CDCl3, 300 MHz) d 1.52 (s, 3H), 2.08 (s,
;
3H), 4.47 (dd, J = 2.7 and 2.4 Hz, 1H), 6.09 (d, J = 2.7 Hz, 1H), 6.14 (br s, 1H), 6.45
(d, J = 2.4 Hz, 1H), 6.99 (br s, 2H), 7.33–7.91 (m, 8H); 1H NMR (minor, CDCl3,
300 MHz) d 1.55 (s, 3H), 2.10 (s, 3H), 4.59 (dd, J = 3.3 and 3.0 Hz, 1H), 5.85 (d,
J = 3.3 Hz, 1H), 6.24 (d, J = 3.0 Hz, 1H), 6.52 (br s, 1H), 6.96 (br s, 2H), 7.33–7.91
(m, 8H); 13C NMR (major + minor, CDCl3, 75 MHz) d 20.97 (2C), 22.03, 22.66,
51.32, 51.53, 67.47, 67.50, 93.36, 96.22, 123.59, 124.38, 124.43, 124.72, 124.76,
125.11, 125.34, 127.29, 127.57, 128.55, 128.81, 128.86, 129.04, 129.09 (2C),
129.46, 131.09, 132.06, 132.68, 133.50, 134.83, 135.17, 135.40, 135.57, 136.00,
136.58 (2C), 136.61, 136.82, 137.30, 138.75, 139.17, 145.84, 146.30, 156.06,
159.86, 168.53, 169.01, 199.03, 200.56 (four carbons are overlapped); ESIMS
(positive ion) m/z 393 (M++H). Anal. Calcd for C27H20O3: C, 82.63; H, 5.14.
Found: C, 82.86; H, 5.43.
5. For the synthesis of indenoindene and its derivatives, see: (a) Paisdor, B.; Kuck,
D. J. Org. Chem. 1991, 56, 4753–4759; (b) Harig, M.; Neumann, B.; Stammler, H.-
G.; Kuck, D. Eur. J. Org. Chem. 2004, 2381–2397; (c) Harig, M.; Kuck, D. Eur. J.
Org. Chem. 2006, 1647–1655; (d) Kuck, D.; Schuster, A.; Fusco, C.; Fiorentino,
M.; Curci, R. J. Am. Chem. Soc. 1994, 116, 2375–2381; (e) Ramaiah, D.; Kumar, S.
A.; Asokan, C. V.; Mathew, T.; Das, S.; Rath, N. P.; George, M. V. J. Org. Chem.
1996, 61, 5468–5473; (f) Slemon, C.; Macel, B.; Trifonov, L.; Vaugeois, J. WO 03/
064501 A1, 2003; Chem. Abstr. 2003, 139, 165073.; (g) Kuck, D. Chem. Rev. 2006,
106, 4885–4925; (h) Kuck, D.; Seifert, M. Chem. Ber. 1992, 125, 1461–1469.
6. For our contribution to the synthesis of indenoindene derivatives, see: (a) Kim,
K. H.; Lee, H. S.; Kim, S. H.; Kim, S. H.; Kim, J. N. Chem. Eur. J. 2010, 16, 2375–
2380; (b) Lee, C. G.; Lee, K. Y.; Lee, S.; Kim, J. N. Tetrahedron 2005, 61, 1493–
1499.
7. For the examples of butterfly conformation NNRTIs, see: (a) Mertens, A.; Zilch,
H.; Konig, B.; Schafer, W.; Poll, T.; Kampe, W.; Seidel, H.; Leser, U.; Leinert, H. J.
Med. Chem. 1993, 36, 2526–2535; (b) Wang, J.; Kang, X.; Kuntz, I. D.; Kollman, P.
A. J. Med. Chem. 2005, 48, 2432–2444. Further references were cited in Ref. 6a.
8. Typical procedure for the synthesis of 4a:3c To a stirred solution of ninhydrin
(231 mg, 1.3 mmol) and cinnamyl bromide 2a (255 mg, 1.0 mmol) in aqueous
THF (1:1, 3.0 mL) was added indium powder (148 mg, 1.3 mmol), and the
reaction mixture was stirred at room temperature for 2 h under N2
atmosphere. After the usual aqueous extractive workup and removal of
Compound 6e: 94%; white solid, mp 260–262 °C; IR (KBr) 1778, 1727,
1263 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.37 (s, 3H), 4.47 (dd, J = 2.4 and
;
2.1 Hz, 1H), 5.98 (d, J = 2.1 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.73–6.77 (m, 2H),
7.18–7.24 (m, 6H), 7.52 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.76 (t,
J = 7.8 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 21.47, 50.89,
67.20, 95.43, 123.85, 124.03, 124.72, 126.12, 126.65, 127.71, 128.20, 129.12,
129.20, 130.49, 133.24, 136.12, 137.11, 137.39, 139.59, 140.16, 145.14, 156.05,
168.62, 199.31; ESIMS (positive ion) m/z 379 (M++H). Anal. Calcd for C26H18O3:
C, 82.52; H, 4.79. Found: C, 82.33; H, 4.58.
Compound 6f: 81%; white solid, mp 266–268 °C; IR (KBr) 1768, 1730,
1262 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.29 (s, 3H), 2.36 (s, 3H), 4.45 (s,
;
1H), 5.97 (s, 1H), 6.35 (s, 1H), 6.62 (d, J = 6.0 Hz, 2H), 7.03 (d, J = 6.0 Hz, 2H),
7.16–7.26 (m, 3H), 7.51 (t, J = 6.3 Hz, 1H), 7.60 (d, J = 6.3 Hz, 1H), 7.74 (t,
J = 6.3 Hz, 1H), 7.88 (d, J = 6.3 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 20.97, 21.46,
50.84, 66.94, 95.43, 123.80, 123.98, 124.68, 126.11, 126.62, 128.95, 129.07 (2C),
130.42, 133.19, 136.19, 137.07, 137.20, 137.35, 137.44, 139.53, 145.26, 156.19,
168.70, 199.41; ESIMS (positive ion) m/z 393 (M++H). Anal. Calcd for C27H20O3:
C, 82.63; H, 5.14. Found: C, 82.60; H, 5.45.
solvent afforded crude
c-hydroxy ester 3a. To the crude 3a in CH2Cl2
(2.0 mL) was added p-TsOH (19 mg, 0.1 mmol), and the reaction mixture was
stirred at room temperature for 12 h. After the usual aqueous extractive
workup and column chromatographic purification process (hexanes/EtOAc/
CH2Cl2, 5:1:1) compound 4a was obtained as a white solid, 234 mg (77%).3c
Other compounds were synthesized similarly, and the spectroscopic data of
unknown compounds 4b and 4c are as follows.
Compound 6g: 28%; white solid, mp 232–234 °C; IR (KBr) 1777, 1727,
Compound 4b: 75%; white solid, mp 146–148 °C; IR (KBr) 1789, 1755, 1724,
1263 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.79 (s, 3H), 4.44 (dd, J = 2.4 and
;
1226 cmÀ1
;
1H NMR (CDCl3, 300 MHz) d 2.19 (s, 3H), 4.60 (dd, J = 3.6 and
2.1 Hz, 1H), 5.97 (d, J = 2.1 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 6.72–6.78 (m, 2H),
6.91–6.96 (m, 2H), 7.20–7.29 (m, 4H), 7.54 (t, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz,
1H), 7.76 (t, J = 7.8 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d
50.56, 55.62, 67.32, 95.73, 110.74, 115.77, 123.77, 124.79, 125.13, 126.60,
127.81, 128.26, 129.21 (2C), 132.27, 133.31, 136.27, 137.10, 139.89, 146.46,
155.77, 160.90, 168.64, 199.20; ESIMS (positive ion) m/z 395 (M++H). Anal. Calcd
for C26H18O4: C, 79.17; H, 4.60. Found: C, 79.44; H, 4.56.
3.3 Hz, 1H), 5.63 (d, J = 3.3 Hz, 1H), 6.59 (d, J = 3.6 Hz, 1H), 6.88 (d, J = 8.4 Hz,
2H), 6.93 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 7.5 Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H), 7.84
(t, J = 7.5 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 20.95,
52.86, 84.11, 123.63, 123.71, 124.64, 128.68, 129.22, 129.48, 135.41, 136.67,
137.09, 138.51, 140.74, 141.04, 168.49, 194.13, 194.30; ESIMS (positive ion) m/
z 319 (M++H). Anal. Calcd for C20H14O4: C, 75.46; H, 4.43. Found: C, 75.75; H,
4.54.
Compound 10: 92%; white solid, mp 140–142 °C; IR (KBr) 3464, 1780, 1764,
Compound 4c: 71%; white solid, mp 123–125 °C; IR (KBr) 1788, 1755, 1725,
1729, 1287 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.49 (dd, J = 13.8 and 7.2 Hz, 1H),
;
1514, 1255 cmÀ1
;
1H NMR (CDCl3, 300 MHz) d 3.68 (s, 3H), 4.59 (dd, J = 3.6 and
2.83 (dd, J = 13.8 and 7.8 Hz, 1H), 3.39 (s, OH), 5.07 (dd, J = 3.6 and 3.3 Hz, 1H),
5.16 (d, J = 17.4 Hz, 1H), 5.23 (d, J = 10.2 Hz, 1H), 5.53 (d, J = 3.3 Hz, 1H), 5.76–
5.90 (m, 1H), 6.53 (d, J = 3.6 Hz, 1H), 6.72–7.00 (m, 5H), 7.11–7.21 (m, 2H), 7.51–
7.57 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 46.29, 50.17, 77.18, 96.09, 122.08,
122.71, 123.96, 127.46, 127.95 (2C), 129.15, 129.72, 131.40, 133.01, 134.34,
135.38, 137.37, 153.05, 169.48, 197.51; ESIMS (positive ion) m/z 347 (M++H).
Anal. Calcd for C22H18O4: C, 76.29; H, 5.24. Found: C, 76.47; H, 5.42.
3.0 Hz, 1H), 5.63 (d, J = 3.0 Hz, 1H), 6.58 (d, J = 3.6 Hz, 1H), 6.65 (d, J = 8.7 Hz,
2H), 6.92 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 7.5 Hz, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.85
(t, J = 7.5 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 52.58,
55.11, 84.17, 114.14, 123.44, 123.60, 123.69, 124.55, 130.54, 135.59, 136.67,
137.15, 140.68, 141.04, 159.51, 168.46, 194.14, 194.44; ESIMS (positive ion) m/
z 335 (M++H). Anal. Calcd for C20H14O5: C, 71.85; H, 4.22. Found: C, 71.79; H,
4.52.
Compound 11: 72% (cis/trans, 1:1); white solid, mp 248–250 °C (decomp.); IR
Typical procedure for the synthesis of 6a: A mixture of compound 4a (152 mg,
0.5 mmol) and H2SO4 (245 mg, 2.5 mmol) in benzene (2.0 mL) was heated to
reflux for 9 h under nitrogen atmosphere. After the usual aqueous extractive
workup and column chromatographic purification process (hexanes/EtOAc/
CH2Cl2, 17:1:4) compound 6a was obtained as a white solid, 173 mg (95%).
Other compounds were synthesized similarly, and the spectroscopic data of 6a-
g are as follows. Compounds 10–12 were prepared as shown in Scheme 2 and
Scheme 3, and the spectroscopic data of 10–12 are also noted herewith.
Compound 6a: 95%; white solid, mp 227–229 °C; IR (KBr) 1778, 1727,
(KBr) 1779, 1726, 1228 cmÀ1 1H NMR (CDCl3, 300 MHz) d 4.47 (t, J = 0.6 Hz,
;
0.5H), 4.69 (t, J = 0.6 Hz, 0.5H), 5.52–5.70 (m, 2H), 5.59 (d, J = 3.3 Hz, 0.5H), 5.64
(d, J = 3.3 Hz, 0.5H), 6.57 (d, J = 3.9 Hz, 0.5H), 6.62 (d, J = 3.9 Hz, 0.5H), 6.70 (d,
J = 11.7 Hz, 0.5H), 6.88–7.57 (m, 9.5H), 7.62 (d, J = 7.8 Hz, 0.5H), 7.78 (d,
J = 7.8 Hz, 0.5H); 13C NMR (CDCl3, 75 MHz) d 55.23, 57.18, 88.36, 89.42, 120.11,
123.23, 123.58, 123.73, 123.89, 123.96, 124.24, 124.79, 125.94, 127.49, 128.15,
128.21, 128.31 (2C), 129.05, 129.18, 129.23, 129.37, 130.80, 131.45, 132.16,
132.27, 132.37, 132.75, 133.72, 133.88, 136.01, 136.03, 136.58, 146.63, 148.52,
169.43 (2C), 198.04, 198.42 (one carbon is overlapped); ESIMS (positive ion) m/z
329 (M++H). Anal. Calcd for C22H16O3: C, 80.47; H, 4.91. Found: C, 80.61; H, 5.03.
Compound 12: 81%; white solid, mp 207–209 °C; IR (KBr) 1767, 1726,
1219 cmÀ1 1H NMR (CDCl3, 300 MHz) d 4.51 (dd, J = 2.7 and 2.1 Hz, 1H), 6.01
;
(d, J = 2.1 Hz, 1H), 6.38 (d, J = 2.7 Hz, 1H), 6.70–6.77 (m, 2H), 7.19–7.28 (m, 3H),
7.34–7.46 (m, 4H), 7.53 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.75 (t,
J = 7.5 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 51.19, 67.29,
95.18, 124.08, 124.37, 124.74, 125.88, 126.61, 127.76, 128.21, 129.14, 129.19,
129.48, 129.49, 133.20, 135.84, 137.16, 140.05, 140.25, 145.03, 155.96, 168.53,
199.18; ESIMS (positive ion) m/z 365 (M++H). Anal. Calcd for C25H16O3: C,
82.40; H, 4.43. Found: C, 82.65; H, 4.71.
1286 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.14 (s, 3H), 6.85–6.88 (m, 2H), 7.25–
;
7.26 (m, 3H), 7.33–7.36 (m, 1H), 7.43–7.52 (m, 3H), 7.58–7.66 (m, 2H), 7.75 (d,
J = 8.1 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 9.79, 63.78,
96.73, 121.84, 124.59, 125.34, 125.43, 127.31, 127.93, 128.44, 128.88, 129.13,
129.27, 130.97, 131.77, 133.45, 136.71, 137.06, 150.87, 158.06, 158.24, 174.96,
197.17; ESIMS (positive ion) m/z 365 (M++H). Anal. Calcd for C25H16O3: C, 82.40;
H, 4.43. Found: C, 82.59; H, 4.56.
Compound 6b: 87%; white solid, mp 260–262 °C; IR (KBr) 1779, 1728,
1218 cmÀ1
;
1H NMR (CDCl3, 300 MHz) d 4.51 (dd, J = 2.4 and 2.1 Hz, 1H), 6.03
9. For the similar Friedel–Crafts type reaction of ketone and arenes under strong
acid conditions, see: (a) Sai, K. K. S.; Esteves, P. M.; da Penha, E. T.; Klumpp, D. A.
(d, J = 2.1 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 6.68 (d, J = 8.7 Hz, 2H), 7.19 (d,

1704
B. R. Park et al. / Tetrahedron Letters 52 (2011) 1700–1704
J. Org. Chem. 2008, 73, 6506–6512; (b) O’Connor, M. J.; Boblak, K. N.; Topinka,
b = 21.5910(5) Å, c = 10.0847(3) Å,
V = 1910.45(8) Z = 4,
(k = 0.71073 Å), R1 = 0.0453, wR2 = 0.1118 (I > 2
deposited in CCDC with number 802634.
a
= 90°, b = 105.9510(10)°,
F000 = 792,
(I)). The X-ray data has been
c
= 90°,
M. J.; Kindelin, P. J.; Briski, J. M.; Zheng, C.; Klumpp, D. A. J. Am. Chem. Soc. 2010,
132, 3266–3267; (c) Klumpp, D. A.; Rendy, R.; Zhang, Y.; Gomez, A.; McElrea, A.
Org. Lett. 2004, 6, 1789–1792; (d) Olah, G. A.; Klumpp, D. A. Acc. Chem. Res.
2004, 37, 211–220; (e) Song, H. N.; Lee, H. J.; Seong, M. R.; Jung, K. S.; Kim, J. N.
Synth. Commun. 2000, 30, 1057–1066.
Å3, Dcalcd = 1.316 mg/m3,
MoK
a
r
11. For the examples of atropisomerism, see: (a) Boiadjiev, S. E.; Lightner, D. A.
Tetrahedron: Asymmetry 2002, 13, 1721–1732; (b) Casarini, D.; Foresti, E.;
Gasparrini, F.; Lunazzi, L.; Macciantelli, D.; Misiti, D.; Villani, C. J. Org. Chem.
1993, 58, 5674–5682.
10. Crystal data of compound 6e: solvent of crystal growth (EtOH/CH2Cl2);
empirical
formula
C26H18O3,
Fw = 378.40,
crystal
dimensions
0.38 Â 0.35 Â 0.23 mm3, monoclinic, space group P2(1)/n, a = 9.1254(2) Å,