Tetrahydrothiophene-catalyzed synthesis of benzo[n.1.0] bicycloalkanes

Article abstract of DOI:10.1021/jo062209m

(Chemical Equation Presented) A catalytic intramolecular cyclopropanation for the preparation of benzobicyclic compounds with [n.1.0] units has been developed. In the presence of 20 mol % of tetrahydrothiophene, the reactions of compounds 2a-2h afford ver

Full text of DOI:10.1021/jo062209m

Tetrahydrothiophene-Catalyzed Synthesis of Benzo[n.1.0]
Bicycloalkanes
Long-Wu Ye, Xiu-Li Sun, Chuan-Ying Li, and Yong Tang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. China
tangy@mail.sioc.ac.cn
ReceiVed October 24, 2006
A catalytic intramolecular cyclopropanation for the preparation of benzobicyclic compounds with [n.1.0]
units has been developed. In the presence of 20 mol % of tetrahydrothiophene, the reactions of compounds
2a-2h afford versatile benzo[n.1.0]bicycloalkanes with excellent stereoselectivity in moderate to good
isolated yields.
Introduction
rich alkene substrates. In our recent study on ylide chemistry
in organic synthesis,8 we found that an intramolecular ylide
Michael addition reaction of ester 1a (using K2CO3 as base to
generate ylide) afforded 2H-chromene 3a in 85% yield, and the
desired cyclopropane was not observed. Noticeably, using Cs2-
CO3 instead of K2CO3, 1a gave 4H-chromene 4a as a major
product (Scheme 1). Thus, 2H-chromenes and 4H-chromenes
could be synthesized controllably from the same starting material
just by the choice of a base.9 During the study on the mechanism
of this reaction, we found that when the oxygen atom of the
vinylogous ester 1a was replaced by OCH2 group, an ylide
cyclopropanation10 product 5a was obtained in 76% yield under
similar reaction conditions (Scheme 1), providing easy access
to benzo[n.1.0] bicycloalkanes. In this paper, we wish to report
this reaction in details.
[n.1.0] Bicycloalkanes have received considerable interest
because of their frequent occurrence in biologically active
natural and nonnatural products.1,2 In addition, fused bicyclic
compounds are important intermediates for the synthesis of some
complex molecules because of their latent reactivity and highly
stereoselective transformation.3 Therefore, several strategies
have been reported for the construction of this important
structural motif.4,5 Of the synthetic methods developed, most
are involved in inter- or intramolecular cyclopropanation of
electron-rich alkenes5,3d with metal carbenes. Recently, a tandem
Michael addition-substitution of stabilized sulfur6 and nitrogen7
ylides to R,â-unsaturated compounds has been reported to
produce such compounds, which complement metal-carbenoid
methodologies and are often better suited to relatively electron-
(1) (a) Srikrishna, A.; Anebouselvy, K. J. Org. Chem. 2001, 66, 7102.
(b) Guella, G.; Skropeta, D.; Breuils, S.; Mancini, I.; Pietra, F. Tetrahedron
Lett. 2001, 42, 723. (c) Gant, T. G.; Noe, M. C.; Corey, E. J. Tetrahedron
Lett. 1995, 36, 8745. (d) Lee, E.; Shin, I. J.; Kim, T. S. J. Am. Chem. Soc.
1990, 112, 260.
(2) (a) Anquetin, G.; Rouquayrol, M.; Mahmoudi, N.; Santillana-Hayat,
M.; Gozalbes, R.; Greiner, J.; Farhati, K.; Derouin, F.; Guedj, R.; Vierling,
P. Bioorg. Med. Chem. Lett. 2004, 14, 2773. (b) Lee, W.; Miller, M. J.
J. Org. Chem. 2004, 69, 4516. (c) Wang, T.-Z.; Pinard, E.; Paquette, L. A.
J. Am. Chem. Soc. 1996, 118, 1309.
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ReV. 2003, 103, 977. (b) Sarpong, R.; Su, J. T.; Stoltz, B. M. J. Am. Chem.
Soc. 2003, 125, 13624. (c) Bran˜a, M. F.; Guisado, C.; Alguacil, L. F.;
Garrido, E.; Pe´rez-Garc´ıa, C.; Ruiz-Gayo, M. Bioorg. Med. Chem. Lett.
2002, 12, 3561. (d) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911.
(e) Rogers, D. H.; Yi, E. C.; Poulter, C. D. J. Org. Chem. 1995, 60, 941.
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Soc. 2006, 128, 2516. (b) Harrak, Y.; Blaszykowski, C.; Bernard, M.; Cariou,
K.; Mainetti, E.; Mourieˇs, V.; Dhimane, A.-L.; Fensterbank, L.; Malacria,
M. J. Am. Chem. Soc. 2004, 126, 8656. (c) Luzung, M. R.; Markham,
J. P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 10858. (d) Porta, E. L.;
Piarulli, U.; Cardullo, F.; Paio, A.; Provera, S.; Seneci, P.; Gennari, C.
Tetrahedron Lett. 2002, 43, 761. (e) Yang, D.; Gao, Q.; Lee, C.-S.; Cheung,
K.-K. Org. Lett. 2002, 4, 3271.
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H.; Umino, A.; Matsumura, T.; Hagihara, T.; Takano, M.; Nakada, M.
J. Am. Chem. Soc. 2003, 125, 2860. (b) Tokunoh, R.; Tomiyama,
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10.1021/jo062209m CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/17/2007
J. Org. Chem. 2007, 72, 1335-1340
1335

Ye et al.
TABLE 1. Effect of Solvent on the Cyclopropanationa
SCHEME 1. Substrate-Dependent Ylide Cyclization
entry
time (h)
solvent
yield (%)b
1
2
3
4
5
6
7
8
32
16
14
14
22
32
18
29
THF
32
<5c
16
ButOH
CH3CN
DMSO
DCE
<5c
56
CH3Ph
DME
CH2Cl2
15
19
49
SCHEME 2. A Plausible Mechanism for the Annulation
Reaction
d
a THT (20 mol %), 2a in solvent (0.25 M), rt, 15 min, then Cs2CO3 (2.0
equiv), 80 °C. b Isolated yield. c Determined by H NMR. d At 45 °C.
1
TABLE 2. Effects of Base and Additivea
entry
time (h)
additive
base
yield (%)b
1
2
3
4
5
6
7
24
58
14
22
34
25
34
/
/
/
/
ButOK
K2CO3
DBU
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
<5c
8
<5c
56
35
44
29
20 uL H2O
5 uL H2O
KI (0.4 equiv)
SCHEME 3. Cross-Experiment
a THT (20 mol %), 2a in DCE (0.25 M), rt, 15 min, then additive, base
1
(2.0 equiv), 80 °C. b Isolated yield. c Determined by H NMR.
TABLE 3. Effects of Reaction Temperature and Substrate
Concentrationa
Results and Discussion
Initial Results. The mechanism for the formation of 2H-
chromene 3a from compound 1a was proposed as follows
(Scheme 2):9 tetrahydrothiophene I reacted with bromide 1a to
form sulfonium salt II, which was deprotonated by K2CO3 to
generate the corresponding sulfonium ylide III in situ. An
intramolecular Michael addition of the ylide to acrylate, followed
by a â-elimination,11 produced intermediate V. An intramo-
lecular SN2′ reaction of intermediate V afforded 2H-chromene
3a and regenerated tetrahydrothiophene to finish a catalytic
cycle. Alternatively, the intermediate II may also decompose
entry
time (h)
c (M)
T (°C)
yield (%)b
1
2
3
48
29
22
12
22
13
15
0.25
0.25
0.25
0.25
0.25
0.10
0.05
25
45
80
80
80
80
80
<10c
49
56
59
45
4d
5e
6
76
61
7
a THT (20 mol %), 2a in DCE, rt, 15 min, then Cs2CO3 (2.0 equiv).
b Isolated yield. c Determined by 1H NMR. d 100 mol % of THT. e 10 mol
% of THT.
(7) (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.
into ylide VI and ynoate in the presence of K2CO3. Michael
addition of the ylide VI into ynoate furnished V, which gave
2H-chromene 3a as shown in Scheme 2. As a cross-experiment
shown in Scheme 3 gave 3b and 4b (3b/4b ) 9/1) in 85% total
yields and 2H-chromene 3a was not observed, we speculated
that the latter pathway is much less possible.
(8) For ylide cyclopropanation, please see: (a) Deng, X.-M.; Cai, P.;
Ye, S.; Sun, X.-L.; Liao, W.-W.; Li, K.; Tang, Y.; Wu, Y.-D.; Dai, L.-X.
J. Am. Chem. Soc. 2006, 128, 9730. (b) Zheng, J.-C.; Liao, W.-W.; Tang,
Y.; Sun, X.-L.; Dai, L.-X. J. Am. Chem. Soc. 2005, 127, 12222. (c) Jiang,
H.; Deng, X.-M.; Sun, X.-L.; Tang, Y.; Dai, L.-X. J. Org. Chem. 2005, 70,
10202. (d) Liao, W.-W.; Li, K.; Tang, Y. J. Am. Chem. Soc. 2003, 125,
13030. (e) Ye, S.; Huang, Z.-Z.; Xia, C.-A.; Tang, Y.; Dai, L.-X. J. Am.
Chem. Soc. 2002, 124, 2432. For ylide aziridination and epoxidation, see:
(f) Zheng, J.-C.; Liao, W.-W.; Sun, X.-X.; Sun, X.-L.; Tang, Y.; Dai,
L.-X.; Deng, J. G. Org. Lett. 2005, 7, 5789. (g) Liao, W.-W.; Deng,
X.-M.; Tang, Y. Chem. Commun. 2004, 1516. (h) Li, K.; Deng, X.-M.;
Tang, Y. Chem. Commun. 2003, 2074.
On the basis of this mechanism, the C-O cleavage involving
â-elimination is one of the key steps to form 2H-chromene 3.
It is envisioned that the annulation described above would be
terminated when the oxygen atom is replaced by OCH2 group.
(9) Ye, L.-W.; Sun, X.-L.; Zhu, C.-Y.; Tang, Y. Org. Lett. 2006, 8, 3853.
1336 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesis of Benzo[n.1.0] Bicycloalkanes
SCHEME 4. Synthesis of Substrates 2a, 2b, and 2b′
SCHEME 5. Synthesis of Substrate 2c
TABLE 4. Synthesis of Substrates 2d-2ha
SCHEME 6. A Possible Mechanism for THT-Catalyzed
Cyclopropanation Reaction
entry
EWG
t (h)
yield(%)b
1
2
3
4
5
CO2Et (2d)
CO2 Bu (2e)
CHO (2f)
COPh (2g)
COCH3 (2h)
12
12
12
32
19
98
98
74
89
98
t
a Reactions were carried out with 1.5 equiv of alkene and 2.5 mol % of
the second-generation Grubbs catalyst. b Isolated yield.
better in halogenated solvents than in nonhalogenated solvents.
Of the conditions screened, 1,2-dichloroethane (DCE) was the
optimal solvent. Under this condition, 56% yield of 5a was
obtained (entry 5, Table 1).
As expected, under a similar reaction condition using Cs2CO3
as a base, substrate 2a (X ) OCH2) gave cyclopropane product
5a in good yield.
Effects of Reaction Conditions on the Cyclopropanation
Reaction. To optimize this intramolecular process, several
reaction conditions were investigated using compound 2a as a
substrate. Initially, we examined the effect of solvents using
20 mol % of tetrahydrothiophene (THT) as catalyst and 2.0
equiv of cesium carbonate as a base. As shown in Table 1, the
intramolecular cyclopropanation reaction usually proceeded
We also investigated the base effects on this reaction.
Although KOBut, K2CO3, and DBU gave the desired product,
cesium carbonate was found to be the best one (entry 4, Table
2) under our screened conditions. As water could accelerate
some ylide reactions,12 a trace amount of water was added to
further improve this reaction but resulted in a decrease of the
yield (entries 5 and 6, Table 2). The addition of 40 mol % of
KI was also found to decrease the yield (entry 7, Table 2).
Reaction temperature and concentration of the substrate
proved to influence the yield of this reaction strongly. For
(10) For reviews on ylide cyclopropanation, please see: (a) Ye, S.; Tang,
Y.; Sun, X.-L. Synlett 2005, 2720. (b) Lebel, H.; Marcoux, J.-F.; Molinaro,
C.; Charette, A. B. Chem. ReV. 2003, 103, 977. (c) Mu¨ller, P.; Fruit, C.
Chem. ReV. 2003, 103, 2905. (d) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K.
Chem. ReV. 1997, 97, 2341. For recent examples, see: (e) Aggarwal,
V. K.; Grange, E. Chem. Eur. J. 2006, 12, 568. (f) Kunz, R. K.; Macmillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 3240. (g) Huang, K.; Huang, Z.-Z.
Synlett 2005, 1621. (h) Mikołajczyk, M.; Midura, W. H.; Michedkina, E.;
Filipczak, A. D.; Wieczorek, M. W. HelV. Chim. Acta 2005, 88, 1769.
(11) Tamura, Y.; Taniguchi, H.; Miyamoto, T.; Tsunekawa, M.; Ikeda,
M. J. Org. Chem. 1974, 39, 3518.
(12) Huang, Y.-Z.; Tang, Y.; Zhou, Z.-L.; Xia, W.; Shi, L.-P. J. Chem.
Soc., Perkin Trans. 1 1994, 7, 893.
J. Org. Chem, Vol. 72, No. 4, 2007 1337

Ye et al.
TABLE 5. Intramolecular Cyclopropanationa
a Reagents and conditions: 20 mol % of THT, 2.0 equiv of Cs2CO3, 2 in DCE (0.1 M), room temperature, 15 min, then 80 °C, 12-72 h. b Method A:
O3 was bubled into the crude product for a few minutes before chromatography; method B: purification by column chromatography. c Isolated yield. d At
1
45 °C. e 6% of 5c′ was isolated. f Conversion by H NMR.
example, the conversion was very low at room temperature
(entry 1, Table 3). However, when the temperature was increased
from room temperature to 80 °C, 56% yield was obtained. At
this temperature, even if 10% mol of THT was used, the desired
product was given in 45% yield. Without THT, cyclopropanation
product was not detected. We also investigated the concentration
effect of the substrate and found that the yield was increased to
76% yield when 0.10 M of 2a was used.
unsaturated carbonyl compounds with different structures.
Substrates 2a, 2b, and 2b′ are readily accessible from salicyl-
aldehyde, as shown in Scheme 4.13 Substrate 2c was prepared
from dialdehyde 8 by a selective Wittig reaction, followed
bytreatment with NaBH4 and PBr3 as described in Scheme 5.
(15) In all cases except for substrates 2e and 2f, some byproducts were
observed. The byproducts could not be separated by flash chromatography
from the desired [n.1.0] bicyclic compounds in most cases, so they were
not well characterized except for 5c′ isolated from the cyclopropanation
reaction mixture of 2c (eq 1). Fortunately, they could be readily removed
by bubbling O3 for a few minutes and, thus, the pure desired products could
be obtained easily.
Reaction Scope. The generality of the intramolecular cyclo-
propanation was evaluated by employing a variety of R,â-
(13) (a) Aurrecoechea, J. M.; Lo´pez, B.; Ferna´ndez, A.; Arrieta, A.;
Coss´ıo, F. P. J. Org. Chem. 1997, 62,1125. (b) Mori, K.; Tanaka, T. I.;
Honda, H.; Yamamoto, I. Tetrahedron 1983, 39, 2303.
(14) (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360. (b) Chatterjee, A. K.; Morgan, J. P.;
Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783.
1338 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesis of Benzo[n.1.0] Bicycloalkanes
SCHEME 7. A Rationale for the High Diastereoselectivity
Substrates 2d-2h were synthesized by a cross-metathesis
reaction between the benzyl bromide 10 and an electron-
deficient alkene using 2.5 mol % of the second-generation
Grubbs catalyst in good to excellent yields (Table 4).14
The cheap and readily available catalyst, the simple procedure,
and the mild reaction condition make this method potentially
useful in organic synthesis. Further investigation of the mech-
anism of the reaction and development of its asymmetric version
are in progress in our laboratory.
As shown in Table 5, R,â-unsaturated esters, ketones, and
aldehydes were good substrates for the intramolecular cyclo-
propanation to afford versatile benzo[n.1.0]bicycloalkanes with
excellent stereoselectivity in moderate to good isolated yields.15
Both Z- and E-R, â-unsaturated esters 2b and 2b′ afforded the
same product 5b, and E-R,â-unsaturated esters 2b gave higher
yield than that of Z-R,â-unsaturated esters 2b′ (entries 2-3,
Table 5). Noticeably, the diastereoselectivity of this reaction is
excellent and only one diastereomer was observed in all cases
as described in Table 5.
Experimental Section
Representative Procedure of Method A: Preparation of 1,-
1a,2,7b-Tetrahydrocyclopropa[c]chromene-1-carboxylic Acid,
Methyl Ester (5a). Tetrahydrothiophene (8.8 µL, 0.1 mmol) was
added to a stirred solution of substrate 2a (0.5 mmol) in DCE (5
mL), and the resulting mixture was stirred at room temperature for
15 min. Cs2CO3 (1.0 mmol, 326 mg) was added and the reaction
mixture was stirred at 80 °C for 13 h. After the reaction was
complete, the resulting mixture was filtered rapidly through a funnel
with a thin layer of silica gel and was eluted with ethyl acetate.
The filtrate was concentrated and the residue was dissolved in CH2-
Cl2. To this solution was bubbled O3 at -78 °C for 10 min. The
resulting mixture was concentrated and the residue was purified
by chromatography on silica gel to afford the product 5a (oil, 76%
The products obtained here are synthetically useful. For
example, product 5f is a key intermediate for the synthesis of
a potential antidepressant.16 The structures of compounds 5a-
5h were determined by 1H, 13C NMR, and HRMS or elemental
analysis. Compound 5g was further confirmed by an X-ray
crystallographic analysis.
1
A possible mechanism for the cyclopropanation is proposed
as shown in Scheme 6 (substrate 2c was used as an example).
The reaction of tetrahydrothiophene with bromide 2c produced
sulfonium salt II. Deprotonation of salt II, followed by an
intramolecular conjugate addition of ylide III and a 1,3-
elimination, furnished bicycloalkane 5c and regenerated tet-
rahydrothiophene to complete a catalytic cycle. Byproduct 5c′15
was probably formed from the intermediate IV, as shown in
Scheme 6. A clear mechanism waits for further investigation.
yield). H NMR (300 MHz, CDCl3, TMS): δ 7.24 (dd, J ) 1.8,
7.8 Hz, 1H), 7.10 (dt, J ) 1.8, 7.8 Hz, 1H), 6.93 (dt, J ) 0.9, 6.9
Hz, 1H), 6.80 (dd, J ) 0.9, 7.8 Hz, 1H), 4.37 (ABd, J ) 10.8 Hz,
1H), 3.92 (ABd, J ) 10.8 Hz, 1H), 3.72 (s, 3H), 2.57-2.61 (m,
1H), 2.31-2.34 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 172.6,
152.6, 128.7, 127.3, 123.9, 121.8, 117.3, 61.5, 51.9, 26.9, 24.1,
22.8. IR (V/cm-1) 2952 (w), 1722 (s), 1582 (m), 1491 (m), 1439
(m), 757 (m); MS (EI, m/z, rel. intensity) 204 (86.07, M+), 115
(100). Anal. calcd for C12H12O3: C, 70.57; H, 5.92. Found: C,
70.48; H, 6.04.
The diastereoselectivity of the present reaction is excellent
and only one diastereoisomer was observed in all cases we
studied. As shown in Scheme 7, the origin of the selectivity,
we proposed, is that transition-state TS-1 might be anticipated
to be more stable than transition-state TS-2 because of the steric
effects between tetrahydrothiophene group and ester group in
TS-2. Thus, the formation of intermediate IV is favored over
that of intermediate IV′, leading to compound 5c as the major
product.
Representative Procedure of Method B (for 1,1a,6,6a-Tet-
rahydro-cyclopropa[a]indene-1-carboxylic Acid, Ethyl Ester,
5c).17 Tetrahydrothiophene (8.8 µL, 0.1 mmol) was added to a
stirred solution of substrate 2c (0.5 mmol) in DCE (5 mL), and the
resulting mixture was stirred at room temperature for 15 min. Cs2-
CO3 (1.0 mmol, 326 mg) was added and the reaction mixture was
stirred at 80 °C for 62 h. After the reaction was complete, the
resulting mixture was filtered rapidly through a funnel with a thin
layer of silica gel and was eluted with ethyl acetate. The filtrate
was concentrated and the residue was purified by chromatography
1
on silica gel to afford the product 5c (oil, 49% yield); H NMR
(300 MHz, CDCl3, TMS): δ 7.33-7.35 (m, 1H), 7.12-7.15 (m,
3H), 3.70 (s, 3H), 3.24-3.32 (m, 1H), 2.95-3.07 (m, 2H), 2.42-
Conclusions
In summary, we have developed a tandem ylide Michael
addition-elimination- substitution reaction for the controllable
synthesis of 2H-chromenes and 4H-chromenes, and we also
reported a catalytic intramolecular cyclopropanation reaction for
the preparation of benzobicyclic compounds with [n.1.0] units.
(16) Cordi, A. A.; Berque-Bestel, I.; Persigand, T.; Lacoste, J. M.;
Newman-Tancredi, A.; Audinot, V.; Millan, M. J. J. Med. Chem. 2001,
44, 787.
(17) Lo¨ffler, F.; Hagen, M.; Lu¨ning, U. Synlett 1999, 1826.
J. Org. Chem, Vol. 72, No. 4, 2007 1339

Ye et al.
2.48 (m, 1H), 1.22-1.25 (m, 1H); 13C NMR (75 MHz, CDCl3): δ
173.2, 143.5, 141.7, 126.4, 126.3, 125.2, 123.9, 51.8, 35.3, 34.4,
30.5, 26.5.
and the Science and Technology Commission of Shanghai
Municipality.
Supporting Information Available: General synthetic proce-
dures and characterization and spectral data for key compounds,
CIF for compound 5g. This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful for the financial support
from the Natural Sciences Foundation of China, the Major State
BasicResearchDevelopmentProgram(GrantNo.2006CB806105)
JO062209M
1340 J. Org. Chem., Vol. 72, No. 4, 2007