PPh3-catalyzed ylide cyclization for the controllable synthesis of benzobicyclo[4.3.0] compounds: base effects and scope

Article abstract of DOI:10.1016/j.tet.2007.11.052

A catalytic intramolecular ylide annulation for the controllable construction of benzobicyclo[4.3.0] ring systems with three continuous stereogenic centers is developed in a single manipulation. In the presence of 20 mol % of triphenylphosphine, the react

Full text of DOI:10.1016/j.tet.2007.11.052

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1487e1493
www.elsevier.com/locate/tet
PPh3-catalyzed ylide cyclization for the controllable synthesis
of benzobicyclo[4.3.0] compounds: base effects and scope
Long-Wu Ye a, Xun Han b, Xiu-Li Sun a, Yong Tang a,
*
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
b Department for Intensive Instruction, Nanjing University, Nanjing 210093, China
Received 22 October 2007; received in revised form 9 November 2007; accepted 13 November 2007
Available online 21 November 2007
Abstract
A catalytic intramolecular ylide annulation for the controllable construction of benzobicyclo[4.3.0] ring systems with three continuous
stereogenic centers is developed in a single manipulation. In the presence of 20 mol % of triphenylphosphine, the reactions of compounds
1ae1f afford benzobicyclo[4.3.0] compounds 3 and 4 as major products, respectively, with excellent diastereoselectivities in good to excellent
yields, depending on the base used. In addition, 2-methyl a,b-unsaturated esters 2ae2c also work well to give the corresponding benzobicy-
clo[4.3.0] compounds with one quaternary carbon center with high diastereoselectivities in good yields under the same conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
3 with excellent diastereoselectivities in good to excellent
yields in the presence of 20 mol % of triphenylphosphine.13,14
On the basis of the result, very recently, we observed a strong
base effect and found that using Cs2CO3 instead of Na2CO3 as
a base, the same substrates 1ae1f gave benzobicyclo[4.3.0]
compounds 4 as major products. Thus, both benzobicy-
clo[4.3.0] compounds 3 and 4 could be synthesized controlla-
bly from the same starting material just by a choice of the
base (Scheme 1). In addition, we also found that a-methyl
a,b-unsaturated esters 2 could work well to give the corres-
ponding benzobicyclo[4.3.0] compounds with one quaternary
carbon center (Scheme 1). In this paper, we wish to report these
results in detail.
The occurrence of the benzobicyclo[4.3.0] subunit in many
natural and synthetic biologically active compounds1,2 has
promoted many strategies for its construction.3,4 Of the
synthetic methods developed, most are involved in inter- or in-
tramolecular metal mediated annulation reactions.4 Recently,
ylide cyclizations have been developed for the preparation of
five- or six-membered ring as well as such bicyclic com-
pounds.5e10 Lu demonstrated that phosphines were good
catalysts for the construction of cyclopentene derivatives.5
Zhang, Fu, and Miller independently documented its asymmet-
ric version.6 Krische developed the first intramolecular variant
of the annulation.7 Aggarwal reported a novel asymmetric syn-
thesis of epoxide- and aziridine-fused heterocycles via a sulfur
ylide route.8 In a previous study on ylide chemistry,11 we found
that a,b-unsaturated esters 1ae1f12 underwent readily a formal
[3þ2] cycloaddition to afford benzobicyclo[4.3.0] compounds
2. Result and discussion
In the phosphine-catalyzed intramolecular formal [3þ2]
cycloaddition of compound 1, we observed that the desired
product 3 was contaminated with 4 in all cases investigated.12
In addition, when a,b-unsaturated ketone was used as a
substrate, product 4 was obtained as a major product. These
results suggested that products 4 could be formed probably
* Corresponding author. Tel.: þ0086 21 54925156; fax: þ0086 21
54925078.
E-mail address: tangy@mail.sioc.ac.cn (Y. Tang).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.052

1488
L.-W. Ye et al. / Tetrahedron 64 (2008) 1487e1493
EtO2C
R1
H
CO2R2
Na2CO3
H
EtO2C
H
EtO2C
R1
3
Br
O
R1
95-99% yield (3/4 > 90/10)
CO2R2
R = CH3
R = H
R
H
EtO2C
CO2R2
O
5
O
R1
H
CO2R2
H
4
1: R = H
2: R = CH3
Cs2CO3
O
78-87% yield (dr > 92/8)
82-96% yield (3/4 < 19/81)
Scheme 1. Base effects on phosphine-catalyzed formal [3þ2] cycloaddition.
due to the isomerization of products 3 under basic conditions.
And it is envisioned that strong base will promote the forma-
tion of product 4. As expected, under a similar reaction condi-
tion using Cs2CO3 instead of Na2CO3 as a base, substrate 1a
gave benzobicyclo[4.3.0] compound 4a as a major product
instead of 3a in good yield. Thus, benzobicyclo[4.3.0] com-
pounds 3a and 4a could be synthesized controllably just by
a choice of the base.
To optimize this protocol, several reaction conditions were
investigated using compound 1a as a model substrate. Initially,
we examined first the effects of the reaction temperature on
this annulation reaction. As shown in Table 1, lowering the re-
action temperature increased the selectivity for the formation
of 3a slightly but decreased the yield when using Na2CO3 as
a base (entries 1e3, Table 1). Base proved to strongly influ-
ence the product distribution. For instance, Na2CO3 gave com-
pound 3a as a major product. Using Cs2CO3 instead of
Na2CO3, the reaction selectivity was reversed and benzobicy-
clo[4.3.0] compound 4a was obtained as a major product (4a/
3a¼82:18) in almost quantitative yield (entry 5, Table 1).
K2CO3 gave a mixture of 3a and 4a with a ratio of 41:59.
At 90 ꢀC, the desired product could be furnished in 90% yield
even if the catalyst loading was reduced to 10 mol % (entry 6,
Table 1). In the absence of PPh3, the desired product was not
observed. In addition, increasing the reaction temperature or
prolonging the reaction time could not improve the selectivity
for the formation of 3a and 4a (entry 7, Table 1).
The generality of the intramolecular annulation reaction
was investigated by employing a variety of a,b-unsaturated
carbonyl compounds. Substrates 1ae1f are readily accessible
from the corresponding salicylaldehydes, as shown in Scheme
2.15 2-Chloroethanol reacted with the salicylaldehydes, fol-
lowed by the Wittig reaction, bromination with NBS,
DesseMartin oxidation, and then Wittig reaction, affording
the desired cyclization precursor bromides 1ae1f. In addition,
substrate 1 could also be readily available from the corres-
ponding salicylaldehydes in three steps, i.e., a substitution
reaction with g-bromocrotonate and then a BayliseHillman
reaction, followed by bromination with NBS.
Under the optimal conditions, as shown in Table 2, a,b-
unsaturated esters could furnish selectively benzobicy-
clo[4.3.0] compounds 3 and 4 with excellent stereoselectivity
in good to excellent yields, just by a simple choice of the base.
Using Na2CO3 as a base, compound 3 was obtained as a major
product while Cs2CO3 gave product 4 instead. The substitu-
ents on the benzene ring had slight effects on the yields and
Table 1
Effect of reaction conditions on the formal [3þ2] cycloadditiona
EtO2C
EtO2C
H
H
CO2Et
20 mol % PPh3
CO2Et
CO2Et
Br
+
H
CH3Ph,
H
O
1a
CO2Et
O
O
3a
4a
Entry
T (ꢀC)
Base
3a/4ab
Yieldc (%)
1
70
80
90
90
90
90
110
90
90
90
Na2CO3
Na2CO3
Na2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
tBuOK
DBU
94:6
91:9
88:12
41:59
18:82
18:82
18:82
d
85
95
2
3
99
94
4
5
96
90
6d
7
94
8
<10
<5
<5
9
d
d
10
a
DABCO
Reagents and conditions: PPh3 (26 mg, 20 mol %), 1a (199 mg, 0.5 mmol) in CH3Ph base (1.5 equiv), 70e110 ꢀC, 5e11 h.
Determined by 300 MHz 1H NMR.
Isolated yield.
PPh3: 10 mol %.
b
c
d

L.-W. Ye et al. / Tetrahedron 64 (2008) 1487e1493
1489
O
R
R
R
1a, R = H, R1 = OEt
CO2Et
a, b, c
d, e
H
Br
OH
1b, R = 4-Cl, R1 = OEt
1c, R = 4-Br, R1 = OEt
1d, R = 4-MeO, R1 = OEt
1e, R = 4-MeO, R1 = OMe
1f, R = H, R1 = C6H4(p-Cl)
O
OH
O
CO2Et
Br
R
O
COR1
OH
1
R
CO2Et
COR1
f, g
h
H
O
OH
Scheme 2. Synthesis of substrates 1ae1f. Reagents and conditions: (a) 2-chloroethanol, NaOH/H2O, 98 ꢀC, 68e77%; (b) Ph3P]C(CH3)CO2Et, CH2Cl2, rt,
81e88%; (c) NBS, AIBN, CCl4, reflux, 98e100%; (d) DesseMartin oxidant, CH2Cl2, rt, 74e85%; (e) Ph3P]CHCOR1, CH2Cl2, rt, 85e95%; (f)
BrCH2CH¼CHCOR1, NaH, DMF, rt, 56e88%; (g) CH2]CO2Et, DABCO, rt, 52e56%; (h) Me2S, NBS, CH2Cl2, rt, 75e85%.
Table 2
Controllable synthesis of benzobicyclo[4.3.0] compoundsa
EtO2C
H
EtO2C
H
R
CO2Et
Br
R
R
20 mol % PPh3, base
CH3Ph, 80-90 °C
EWG
EWG
H
+
H
O
EWG
O
O
4
1
3
Entry
1
R
EWG
Base
4 or 3 (4/3)b
Yieldc (%)
1
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
H
H
CO2Et
CO2Et
Na2CO3
Cs2CO3
Na2CO3
Cs2CO3
Na2CO3
Cs2CO3
Na2CO3
Cs2CO3
Na2CO3
Cs2CO3
Na2CO3
Cs2CO3
3a (9:91)
4a (82:18)
3b (6:94)
4b (83:17)
3c (10:90)
4c (82:18)
3d (9:91)
4d (81:19)
3e (10:90)
4e (81:19)
4f (81:19)
4f (86:14)
95
96
99
82
96
89
96
83
99
85
81
78
2
3
4-Cl
4-Cl
CO2Et
CO2Et
4
5
4-Br
4-Br
CO2Et
CO2Et
6
7
4-MeO
4-MeO
4-MeO
4-MeO
H
CO2Et
CO2Et
8
9
CO2Me
CO2Me
COC6H4( p-Cl)
COC6H4( p-Cl)
10
11
12
a
1f
H
PPh3 (26 mg, 20 mol %), 1 (0.5 mmol) in CH3Ph (0.10 M), rt, 15 min, base (1.5 equiv), 80e90 ꢀC, 5e11 h.
Determined by 300 MHz 1H NMR.
b
c
Isolated yield for 3þ4.
diastereoselectivities (entries 1e10, Table 2). In addition, a,b-
Figure 1, 43 mol % of 1b was converted into benzobicy-
clo[4.3.0] compound 3b after 2 h and 4b was not observed.
Four hours later, 73 mol % of 1b was converted into 3b and
4b remained undetectable. However, more than 80 mol % of
4b was detected after further 2 h, which should be isomerized
from 3b. Prolonging the reaction time to 9 h, the ratio of 4a/3a
was almost no change, suggesting that there be a balance
between 3b and 4b under the reaction conditions. To further
confirm this isomerization mechanism, we designed a-methyl
a,b-unsaturated ester 2 as a substrate and it is expected that, in
this case, the desired product would be 5 or 50 with a quater-
nary carbon that could block the isomerization (Eq. 2).
unsaturated ketone 1f could only give 4f dominantly whatever
Na2CO3 or Cs2CO3 was used (entries 11 and 12, Table 2). No-
ticeably, the diastereoselectivity of this reaction is excellent
and only one diastereomer was observed in all cases described
in Table 2.
In a previous communication,12 we proposed a mechanism
involved in a double Michael addition to explain the formal
[3þ2] cycloaddition reactions for the formation of product
3. In the aforementioned reaction, we observed a strong base
effect: stronger base gave product 4 more. In particularly,
a,b-unsaturated ketone 1f only produced 4f as the major prod-
uct even if Na2CO3 was used. On the basis of these results, it is
easy to speculate that compound 4 was formed by an isomeri-
zation of product 3 under basic conditions (Eq. 1). To demon-
strate the hypothesis, we monitored the annulation reaction of
1b using Cs2CO3 as the base by 1H NMR. As shown in
EtO2C
H
EtO2C
H
R
R
EWG
EWG
Cs2CO3
ð1Þ
ð2Þ
H
H
O
O
4
3
EtO2C
H
EtO2C
CO2Et
CO2Et
H
20 mol % PPh3, Na2CO3
Br
CO2Et
H
H
CH3Ph, 90 °C
+
O
CO2Et
R
O
O
2
R
R
5
5'

1490
L.-W. Ye et al. / Tetrahedron 64 (2008) 1487e1493
4b
4b
4b
4b
4b
3b
3b
3b
99%
conv
9 h
6 h
4b
4b
4b
4b
3b
4b
3b
3b
96% conv
3b
3b
3b
1b
1b
73% conv
43% conv
4.5
4 h
2 h
3b
3b
3b
4.0
3.5
3.0
EtO2C
H
EtO2C
H
Cl
CO2Et
Cl
CO2Et
Cl
CO2Et
Br
H
H
O
CO2Et
O
O
1b
3b
4b
Figure 1. 1H NMR monitoring on the annulation of 1b using Cs2CO3.
supporting the proposed mechanism. As summarized in Table 3,
the substituents on the benzene ring had almost no effect on the
diastereoselectivities (entries 1e4, Table 3). Noticeably,
diastereoisomers 5 and 50 could be easily separated by flash
chromatography. These results, together with the 1H NMR trace
in Figure 1, demonstrated clearly that the product 4 was formed
by the isomerization of compound 3.
R
CO2Et
Br
R
CO2Et
Ph3P=C(CH3)CO2Et
CH2Cl2, rt
Br
O
O
CO2Et
O
2
2a: R = H; yield: 81%
2b: R = Cl; yield: 71%
2c: R = OMe; yield: 80%
Scheme 3. Synthesis of substrates 2aec.
The structures of compounds 4ae4f and 5ae5c were char-
1
The synthesis of a-methyl a,b-unsaturated esters 2aec was
shown in Scheme 3. The synthetic method is similar to that of
substrate 1 except that different phosphorus ylides were used
in the final step (Scheme 3). As expected, substrates 2 gave
only benzobicyclo[4.3.0] compounds with a quaternary carbon
5 and 50 as the products in good yields using Na2CO3 as a base.
The isomerized products were not observed at all, further
acterized by H, 13C NMR, and HRMS or elemental analysis.
Compounds 4f12 and 5b were further confirmed by single-
crystal X-ray diffraction analysis (Fig. 2).
A possible mechanism is proposed as shown in Scheme 4 to
explain the aforementioned reactions. Triphenylphosphine I
reacts with bromide 1 to form phosphonium salt II, which is
deprotonated by Cs2CO3 to generate the corresponding
Table 3
Intramolecular phosphine-catalyzed annulation reactiona
EtO2C
H
EtO2C
H
R
R
CO2Et
CO2Et
R
20 mol % PPh3, Na2CO3
Br
CO2Et
H
H
CH3Ph, 90 °C
+
O
CO2Et
O
O
5'
2
5
Entry
2
R
5 (5/50)b
Yield (%)c
1
2
3d
4
a
2a
2b
2b
2c
H
5a (93:7)
5b (95:5)
5b (96:4)
5c (92:8)
82
78
90
87
4-Cl
4-Cl
4-MeO
PPh3 (26 mg, 20 mol %), 5 (0.5 mmol) in CH3Ph (0.10 M), rt, 15 min, then Na2CO3 (80 mg, 1.5 equiv), 90 ꢀC, 8e12 h.
b
c
d
Determined by 300 MHz 1H NMR.
Isolated yield.
Using 50 mol % PPh3.

L.-W. Ye et al. / Tetrahedron 64 (2008) 1487e1493
4. Experimental
1491
4.1. General
All reactions were carried out under N2 unless otherwise
noted. All solvents were purified according to standard
1
methods prior to use. H NMR and 13C NMR spectra were
recorded in chloroform-d3 on a VARIAN Mercury 300.
4.2. Representative procedure for the controllable
synthesis of benzobicyclo[4.3.0] compounds
4.2.1. Preparation of 1,3a,4,9b-tetrahydro-cyclopenta-
[c]chromene-1,3-dicarboxylic acid diethyl ester 4a
To a solution of substrate 1a (0.50 mmol, 199 mg) in CH3Ph
(5.0 mL) was added triphenylphosphine (0.10 mmol, 26 mg).
The resulting mixture was stirred at room temperature for
15 min. Then Cs2CO3 (0.75 mmol, 245 mg) was added. The
mixture was stirred at 90 ꢀC for 8 h. After the reaction was
complete, the mixture was filtered rapidly through a funnel
with a thin layer of silica gel and eluted with ethyl acetate.
The filtrate was concentrated and the residue was purified by
chromatography on silica gel to afford the desired product 4a
as colorless oil. Yield: 96%; 1H NMR (300 MHz, CDCl3,
TMS): d 7.29 (d, J¼7.5 Hz, 1H), 7.18e7.13 (m, 1H),
6.97e6.90 (m, 2H), 6.82 (t, J¼1.5 Hz, 1H), 4.46 (dd, J¼10.8
and 4.5 Hz, 1H), 4.34e4.23 (m, 4H), 3.97 (t, J¼7.8 Hz, 1H),
3.76e3.65 (m, 2H), 3.52e3.47 (m, 1H), 1.38e1.32 (m, 6H);
13C NMR (75 MHz, CDCl3): d 172.1, 163.7, 154.8, 141.7,
137.9, 129.7, 127.7, 124.4, 121.5, 117.1, 66.6, 61.6, 60.8,
58.8, 42.8, 39.5, 14.1(9), 14.1(7); IR n/cmꢁ1 2982 (m), 2933
(m), 1734 (s), 1716 (s), 1631 (m), 1581 (m), 1490 (m), 1246
(m), 758 (m); MS (ESI, positive mode, m/z) 371
(MþMeOHþNaþ), 339 (MþNaþ), 317 (MþHþ); HRMS
(EI) calcd for C18H20O5 (Mþ): 316.1311, found: 316.1304.
Figure 2. X-ray crystal structure of compound 5b.
EtO2C
EtO2C
H
Cs2CO
3R
EWG
R
H
CO2Et
Br
R
EWG
H
H
O
EWG
PPh3
I
O
1
O
4
3
+
P Ph3
EtO2C
H
R
CO2Et
P Ph3
R
EWG
Br
H
O
EWG
O
II
V
Cs2CO3
+
EtO2C
R
P Ph3
CO2Et
P Ph3
R
EWG
O
EWG
III
IV
O
Scheme 4. A possible mechanism for the annulation reaction.
4.2.2. 8-Chloro-1,3a,4,9b-tetrahydro-cyclopenta[c]-
chromene-1,3-dicarboxylic acid diethyl ester 4b
phosphonium ylide III in situ. An intramolecular Michael ad-
dition of the ylide, followed by a Michael addition of phospho-
nium salt IV and then b-elimination of triphenylphosphine,
completes the catalytic cycle.
1
Yield 82% (oil, 10 h); H NMR (300 MHz, CDCl3, TMS):
d 7.31 (d, J¼2.7 Hz, 1H), 7.09 (dd, J¼9.0 and 2.4 Hz, 1H),
6.85e6.82 (m, 2H), 4.44 (dd, J¼11.1 and 4.8 Hz, 1H),
4.36e4.22 (m, 4H), 3.91 (t, J¼8.1 Hz, 1H), 3.71 (dt, J¼8.1
and 2.4 Hz, 1H), 3.64 (t, J¼10.2 Hz, 1H), 3.49e3.42 (m,
1H), 1.37 (t, J¼7.2 Hz, 3H), 1.32 (t, J¼7.2 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d 171.8, 163.6, 153.5, 141.6, 137.7,
129.4, 127.8, 126.2, 125.9, 118.5, 66.8, 61.8, 60.9, 58.6,
42.5, 39.3, 14.2; IR n/cmꢁ1 2983 (m), 2937 (m), 1733 (s),
1716 (s), 1632 (m), 1580 (m), 1485 (m), 1247 (m), 818 (m),
748 (m), 640 (m); MS (ESI, positive mode, m/z) 407
(MþMeOHþNaþ), 405 (MþMeOHþNaþ), 375 (MþNaþ),
373 (MþNaþ); HRMS (EI) calcd for C18H19O5Cl (Mþ):
350.0921, found: 350.0923.
3. Conclusion
In summary, the controllable synthesis of benzobicy-
clo[4.3.0] compounds 3 and 4 with three continuous stereo-
genic centers has been developed. The mechanistic insight
1
of the base effect was investigated by H NMR monitoring
and chemical experiments in detail. In addition, benzobicy-
clo[4.3.0] compounds with one quaternary carbon center could
also be prepared with high diastereoselectivities in good
yields. The high diastereoselectivity, cheap and readily avail-
able catalyst, the simple procedure, and the mild conditions
make these methods potentially useful in organic synthesis.
The development of its asymmetric version is in progress in
our laboratory.
4.2.3. 8-Bromo-1,3a,4,9b-tetrahydro-cyclopenta[c]-
chromene-1,3-dicarboxylic acid diethyl ester 4c
1
Yield 89% (oil, 11 h); H NMR (300 MHz, CDCl3, TMS):
d 7.45 (d, J¼2.4 Hz, 1H), 7.23 (dd, J¼9.0 and 2.4 Hz, 1H),

1492
L.-W. Ye et al. / Tetrahedron 64 (2008) 1487e1493
6.83e6.77 (m, 2H), 4.43 (dd, J¼10.8 and 4.2 Hz, 1H), 4.36e
4.20 (m, 4H), 3.91 (t, J¼7.8 Hz, 1H), 3.71 (dt, J¼7.8 and
2.4 Hz, 1H), 3.64 (t, J¼10.2 Hz, 1H), 3.49e3.41 (m, 1H),
1.37 (t, J¼7.2 Hz, 3H), 1.32 (t, J¼7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 171.8, 163.6, 154.0, 141.6, 137.6,
132.4, 130.7, 126.5, 119.0, 113.5, 66.7, 61.8, 60.9, 58.6,
42.5, 39.3, 14.2 (0), 14.1 (8); IR n/cmꢁ1 2982 (m), 2929
(m), 1734 (s), 1716 (s), 1632 (m), 1581 (m), 1483 (m), 1247
(m), 817 (m), 748 (m); MS (ESI, positive mode, m/z) 451
(MþMeOHþNaþ), 449 (MþMeOHþNaþ), 419 (MþNaþ),
417 (MþNaþ); HRMS (EI) calcd for C18H19O5Br (Mþ):
394.0416, found: 394.0419.
positive mode, m/z) 437 (MþMeOHþNaþ), 405 (MþNaþ),
383 (MþHþ); HRMS (EI) calcd for C22H19O4Cl (Mþ):
382.0972, found: 382.0968.
4.3. Representative procedure for the phosphine-catalyzed
synthesis of benzobicyclo[4.3.0] compounds with one
quaternary carbon center
4.3.1. Preparation of 3-methyl-3,3a,4,9b-tetrahydro-cyclo-
penta[c]chromene-1,3-dicarboxylic acid diethyl ester 5a
To a solution of substrate 2a (0.50 mmol, 206 mg) in
CH3Ph (5.0 mL) was added triphenylphosphine (0.10 mmol,
26 mg). The resulting mixture was stirred at room temperature
for 15 min. Then Na2CO3 (0.75 mmol, 80 mg) was added. The
mixture was stirred at 90 ꢀC for 12 h. After the reaction was
complete, the mixture was filtered rapidly through a funnel
with a thin layer of silica gel and eluted with ethyl acetate.
The filtrate was concentrated and the residue was purified by
flash chromatography on silica gel to afford the desired prod-
uct 5a as colorless oil. Yield: 82%; 1H NMR (300 MHz,
CDCl3, TMS): d 7.60 (d, J¼7.8 Hz, 1H), 7.12e7.07 (m,
1H), 6.90e6.79 (m, 2H), 6.74 (s, 1H), 4.47e4.41 (m, 2H),
4.30e4.15 (m, 5H), 3.10 (dt, J¼9.0 and 3.0 Hz, 1H), 1.44
(s, 3H), 1.34 (t, J¼6.9 Hz, 3H), 1.29 (t, J¼6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d 175.1, 165.3, 154.1, 145.5, 138.3,
129.9, 127.6, 123.0, 121.1, 117.3, 64.7, 61.2, 60.8, 56.9,
43.1, 41.2, 20.3, 14.2, 14.1; IR n/cmꢁ1 2980 (m), 2933 (m),
1734 (s), 1716 (s), 1631 (m), 1580 (m), 1489 (m), 1238
(m), 759 (m); MS (ESI, positive mode, m/z) 385
(MþMeOHþNaþ), 353 (MþNaþ), 331 (MþHþ); HRMS
(EI) calcd for C19H22O5 (Mþ): 330.1467, found: 330.1467.
4.2.4. 8-Methoxy-1,3a,4,9b-tetrahydro-cyclopenta[c]-
chromene-1,3-dicarboxylic acid diethyl ester 4d
1
Yield 83% (oil, 11 h); H NMR (300 MHz, CDCl3, TMS):
d 6.86e6.81 (m, 3H), 6.72 (dd, J¼9.0 and 3.0 Hz, 1H), 4.40
(dd, J¼10.5 and 4.5 Hz, 1H), 4.32e4.23 (m, 4H), 3.93 (t,
J¼8.1 Hz, 1H), 3.75e3.71 (m, 4H), 3.63 (t, J¼10.2 Hz, 1H),
3.48e3.45 (m, 1H), 1.37e1.30 (m, 6H); 13C NMR (75 MHz,
CDCl3): d 172.1, 163.8, 154.1, 148.8, 141.6, 137.9, 125.1,
117.8, 113.9 (1), 113.8 (7), 66.9, 61.6, 60.8, 58.9, 55.6,
42.9, 39.8, 14.2(2), 14.1(8); IR n/cmꢁ1 2982 (m), 1734 (s),
1717 (s), 1629 (m), 1499 (m), 1246 (m), 1033 (m), 862 (m),
817 (m), 749 (m); MS (ESI, positive mode, m/z) 401
(MþMeOHþNaþ), 369 (MþNaþ), 347 (MþHþ); HRMS
(EI) calcd for C19H22O6 (Mþ): 346.1416, found: 346.1417.
4.2.5. 8-Methoxy-1,3a,4,9b-tetrahydro-cyclopenta[c]-
chromene-1,3-dicarboxylic acid 1-ethyl ester
3-methyl ester 4e
1
Yield 85% (oil, 11 h); H NMR (300 MHz, CDCl3, TMS):
d 6.87e6.82 (m, 3H), 6.72 (dd, J¼9.0 and 3.0 Hz, 1H), 4.38
(dd, J¼10.8 and 4.5 Hz, 1H), 4.28 (q, J¼7.2 Hz, 2H), 3.93
(t, J¼8.1 Hz, 1H), 3.80 (s, 3H), 3.78e3.71 (m, 4H), 3.65 (t,
J¼10.2 Hz, 1H), 3.48e3.45 (m, 1H), 1.34 (t, J¼7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3): d 172.0, 164.2, 154.1, 148.8,
142.0, 137.5, 125.1, 117.8, 113.9 (1), 113.8 (8), 66.8, 61.6,
58.9, 55.6, 51.8, 43.0, 39.8, 14.2; IR n/cmꢁ1 2984 (m), 1732
(s), 1616 (m), 1499 (m), 1249 (m), 1031 (m), 864 (m), 817
(m), 748 (m); MS (ESI, positive mode, m/z) 387
(MþMeOHþNaþ), 355 (MþNaþ), 333 (MþHþ); HRMS
(EI) calcd for C18H20O6 (Mþ): 332.1260, found: 332.1266.
4.3.2. 8-Chloro-3-methyl-3,3a,4,9b-tetrahydro-cyclo-
penta[c]chromene-1,3-dicarboxylic acid diethyl ester 5b
Yield 78% (solid, 10 h); 1H NMR (300 MHz, CDCl3,
TMS): d 7.63 (d, J¼2.7 Hz, 1H), 7.04 (dd, J¼9.0 and
2.4 Hz, 1H), 6.75 (t, J¼9.0 Hz, 2H), 4.46e4.13 (m, 7H),
3.09 (dt, J¼9.0 and 3.0 Hz, 1H), 1.42 (s, 3H), 1.37
(t, J¼7.2 Hz, 3H), 1.30 (t, J¼7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 174.9, 165.0, 152.8, 146.2, 137.8,
129.6, 127.7, 125.8, 124.5, 118.7, 64.9, 61.4, 61.0, 56.9,
42.8, 41.2, 20.3, 14.2, 14.1; IR n/cmꢁ1 2981 (m), 2936 (m),
1733 (s), 1716 (s), 1630 (m), 1486 (m), 1240 (m), 820 (m),
640 (m); MS (ESI, positive mode, m/z) 421
(MþMeOHþNaþ), 419 (MþMeOHþNaþ), 389 (MþNaþ),
387 (MþNaþ); HRMS (EI) calcd for C19H21O5Cl (Mþ):
364.1078, found: 364.1075.
4.2.6. 3-(4-Chloro-benzoyl)-1,3a,4,9b-tetrahydro-
cyclopenta[c]chromene-1-carboxylic acid ethyl ester 4f
1
Yield 78% (oil, 5 h); H NMR (300 MHz, CDCl3, TMS):
d 7.72 (d, J¼8.7 Hz, 2H), 7.44 (d, J¼8.7 Hz, 2H), 7.30 (d,
J¼7.5 Hz, 1H), 7.19e7.13 (m, 1H), 6.99e6.89 (m, 2H), 6.46
(dd, J¼2.1 and 0.9 Hz, 1H), 4.47 (dd, J¼11.4 and 4.2 Hz,
1H), 4.31e4.25 (m, 2H), 4.02 (t, J¼6.9 Hz, 1H), 3.94e3.88
(m, 1H), 3.82 (dt, J¼6.9 and 2.1 Hz, 1H), 3.76e3.69 (m, 1H),
1.33 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 192.0,
171.8, 155.0, 144.7, 143.0, 139.1, 136.1, 130.5, 129.8, 128.7,
127.8, 124.4, 121.6, 117.3, 66.1, 61.7, 59.9, 44.2, 39.5, 14.2;
IR n/cmꢁ1 2982 (m), 1731 (s), 1646 (m), 1585 (m), 1489 (m),
1248 (m), 1014 (m), 832 (m), 760 (m), 579 (m); MS (ESI,
4.3.3. 8-Methoxy-3-methyl-3,3a,4,9b-tetrahydro-cyclo-
penta[c]chromene-1,3-dicarboxylic acid diethyl ester 5c
1
Yield 87% (oil, 8 h); H NMR (300 MHz, CDCl3, TMS):
d 7.22 (d, J¼3.0 Hz, 1H), 6.76e6.66 (m, 3H), 4.46e4.39
(m, 2H), 4.31e4.12 (m, 5H), 3.72 (s, 3H), 3.07 (dt, J¼9.0
and 3.0 Hz, 1H), 1.45 (s, 3H), 1.34 (t, J¼6.9 Hz, 3H), 1.30
(t, J¼6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 175.2,
165.4, 153.7, 148.0, 145.9, 138.0, 123.6, 118.0, 114.3,
113.6, 64.9, 61.2, 60.8, 57.0, 55.5, 43.1, 41.6, 20.4, 14.2,

L.-W. Ye et al. / Tetrahedron 64 (2008) 1487e1493
1493
14.1; IR n/cmꢁ1 2980 (m), 1732 (s), 1713 (s), 1628 (m), 1498
(m), 1238 (m), 1067 (m), 947 (m), 818 (m); MS (ESI, positive
mode, m/z) 415 (MþMeOHþNaþ), 383 (MþNaþ), 360
(MþHþ); HRMS (EI) calcd for C20H24O6 (Mþ): 360.1573,
found: 360.1577.
Tetrahedron Lett. 2004, 45, 7599; (d) Hagiwara, H.; Katsumi, T.; Endou,
S.; Hoshib, T.; Suzuki, T. Tetrahedron 2002, 58, 6651.
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Acknowledgements
We are grateful for the financial support from the Natural
Sciences Foundation of China, the Major State Basic Research
Development Program (Grant no. 2006CB806105), The Chi-
nese Academy of Sciences, and The Science and Technology
Commission of Shanghai Municipality.
8. (a) Unthank, M. G.; Hussain, N.; Aggarwal, V. K. Angew. Chem., Int. Ed.
2006, 45, 7066; (b) Kokotos, C. G.; Aggarwal, V. K. Chem. Commun.
2006, 2156.
Supplementary data
9. (a) Ye, L.-W.; Sun, X.-L.; Li, C.-Y.; Tang, Y. J. Org. Chem. 2007, 72,
1335; (b) Ye, L.-W.; Sun, X.-L.; Zhu, C.-Y.; Tang, Y. Org. Lett. 2006,
8, 3853.
General synthetic procedures and characterization and
spectral data for key compounds, CIF for compound 5b. Sup-
plementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2007.11.052.
10. (a) Johansson, C. C. C.; Bremeyer, N.; Ley, S. V.; Owen, D. R.; Smith, S. C.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2006, 45, 6024; (b) Bremeyer, N.;
Smith, S. C.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2004, 43, 2681.
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