Highly regioselective construction of spirocycles via phosphine-catalyzed [3 + 2]-cycloaddition

Article abstract of DOI:10.1021/jo026111t

A direct entry to spirocycles with low to moderate regioselectivity was achieved by triphenylphosphine-catalyzed [3 + 2]-cycloaddition of active exo-methylenecycles (1) and ethyl 2,3-butadienoate (2). The regioselectivity of the reaction was greatly impro

Full text of DOI:10.1021/jo026111t

High ly Regioselective Con str u ction of Sp ir ocycles via
P h osp h in e-Ca ta lyzed [3 + 2]-Cycloa d d ition
Yishu Du, Xiyan Lu,* and Yihua Yu
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
xylu@pub.sioc.ac.cn
Received J une 28, 2002
A direct entry to spirocycles with low to moderate regioselectivity was achieved by triphenylphos-
phine-catalyzed [3 + 2]-cycloaddition of active exo-methylenecycles (1) and ethyl 2,3-butadienoate
(2). The regioselectivity of the reaction was greatly improved by using the bulky tert-butyl ester of
the 2,3-butadienoate (5). The regioselectivity of the reaction was further enhanced by using the
tert-butyl 2-butynoate as the substrate. This protocol provided an efficient entry to the skeleton of
spirocarbocycles, especially spiro[4.n]alkanes.
In tr od u ction
phosphine-catalyzed [3 + 2]-cycloaddition reaction.8 Herein,
we wish to report an efficient and practical method of
constructing spirocyclic skeletons with high regioselec-
tivity.
Spirocyclic skeletons widely occur in a large number
of natural products.1 Among many approaches to make
spirocycles, [3 + 2]-cycloaddition is one of the most ef-
ficient methods of synthesizing spiro[4.n]alkanes.2 The
common difficulty lies in the selective construction of the
spirocycles and the control of their stereochemistry. It is
still a challenge for synthetic chemists to develop a simple
method to construct spirocarbocycles.
Recently, some important reactions were discovered in
the phosphine-catalyzed reaction of 2,3-butadienoates or
2-butynoates,3 such as isomerization,4 R-addition,5 γ-ad-
dition,6 and [3 + 2]-cycloaddition.7 We envisioned that an
efficient entry to spirocarbocycles might be achieved by
the application of our recently developed method of the
Resu lts a n d Discu ssion
To initiate our studies, a solution of 2-methylene-3,4-
dihydro-2H-naphthalen-1-one (1a ) (1.0 mmol) and ethyl
2,3-butadienoate (2) (1.2 mmol) in dry toluene (10 mL)
was treated with Ph3P (10 mol %) at room temperature
for 11 h. Two regioisomers were obtained in total yield
of 93% with moderate selectivity (3a :4a ) 79:21) (eq 1).
(1) For reviews of spirocyclic compounds, see: (a) Heathcock, C. H.
In The Total Synthesis of Natural Products; ApSimon, J ., Ed.; Willey:
New York, 1973; Vol. 2, pp 466 and 504. (b) Marshall, J . A.; Brady, S.
F.; Andersen, N. H. Fortschr. Chem. Org. Naturst. 1974, 31, 283. (c)
Martin, J . D. In Studies in Natural Products Chemistry; Rahman, A.
U., Ed.; Elsevier: Amsterdam, 1990; Vol. 6, p 59. (d) Sannigrahi, M.
Tetrahedron 1999, 55, 9007 and references therein.
(2) For some examples of the synthesis of spirocycles via [3 + 2]-
cycloaddition reaction involving three-carbon synthons, see: (a) Dan-
heiser, R. L.; Carini, D. J .; Basak, A. J . Am. Chem. Soc. 1981, 103,
1604. (b) Trost, B. M.; Acemoglu, M. Tetrahedron Lett. 1989, 30, 1495.
(c) Trost, B. M.; King, S. A.; Schmidt, T. J . Am. Chem. Soc. 1989, 111,
5902. (d) Trost, B. M.; Yang, B.; Miller, M. L. J . Am. Chem. Soc. 1989,
111, 6482. (e) Trost, B. M.; Sharma, S.; Schmidt, T. J . Am. Chem. Soc.
1992, 114, 7903. (f) Trost, B. M.; Marrs, C. M. J . Am. Chem. Soc. 1993,
115, 6636. (g) Knolker, H.-J .; J ones, P. G.; Grafe, R. Synlett 1996, 1155.
(h) Akiyama, T.; Hoshi, E.; Fujiyoshi, S. J . Chem. Soc., Perkin Trans.
1 1998, 2121. (i) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.;
Carreira, E. M. Angew. Chem., Int. Ed. 1999, 38, 3186.
(3) For a recent account on phosphine-catalyzed reactions, see: (a)
Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. For recent
reports on phosphine-catalyzed reactions, see: (b) Frank, S. A.;
Mergott, D. J .; Roush, W. R. J . Am. Chem. Soc. 2002, 124, 2404. (c)
Wang, L.-C.; Luis, A. L.; Agapiou, K.; J ang, H.-Y.; Krische, M. J . J .
Am. Chem. Soc. 2002, 124, 2402. (d) Lumbierres, M.; Moreno-Man˜as,
M.; Vallribera, A. Tetrahedron 2002, 58, 4061.
Compounds 3a and 4a have been characterized by
1
1
spectroscopic analysis (IR, H NMR, 13C NMR, H -1H
(6) (a) Trost, B. M.; Li, C.-J . J . Am. Chem. Soc. 1994, 116, 3167. (b)
Trost, B. M.; Li, C.-J . J . Am. Chem. Soc. 1994, 116, 10819. (c) Zhang,
C.; Lu, X. Synlett 1995, 645. (d) Trost, B. M.; Dake, G. R. J . Org. Chem.
1997, 62, 5670.
(7) (a) Zhang, C.; Lu, X. J . Org. Chem. 1995, 60, 2906. (b) Xu, Z.;
Lu, X. Tetrahedron Lett. 1997, 38, 3461. (c) Zhu, G.; Chen, Z.; J iang,
Q.; Xiao, D.; Cao, P.; Zhang, X. J . Am. Chem. Soc. 1997, 119, 3836. (d)
Xu, Z.; Lu, X. J . Org. Chem. 1998, 63, 5031. (e) Xu, Z.; Lu, X.
Tetrahedron Lett. 1999, 40, 549.
(8) Very recently, some spiroheterocycles were constructed by Pyne’s
group using our recently developed method of the phosphine-catalyzed
[3 + 2]-cycloaddition reaction. See: (a) Pyne, S. G.; Schafer, K.; Skelton,
B. W.; White, A. H. Chem. Commun. 1997, 2267. (b) Ung, A. T.;
Schafer, K.; Lindsay, K. B.; Pyne, S. G.; Amornraksa, K.; Wouters, R.;
Van der Linden, I.; Biesmans, I.; Lesage, A. S. J .; Skelton, B. W.; White,
A. H. J . Org. Chem. 2002, 67, 227.
(4) (a) Trost, B. M.; Kazmaier, U. J . Am. Chem. Soc. 1992, 114, 7933.
(b) Guo, C.; Lu, X. J . Chem. Soc., Chem. Commun. 1993, 394. (c) Guo,
C.; Lu, X. J . Chem. Soc., Perkin Trans. 1 1993, 1921.
(5) Trost, B. M.; Dake, G. R. J . Am. Chem. Soc. 1997, 119, 7595.
10.1021/jo026111t CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/12/2002
J . Org. Chem. 2002, 67, 8901-8905
8901

Du et al.
TABLE 1. . Tr ip h en ylp h osp h in e-Ca ta lyzed
[3 + 2]-Cycloa d d ition of 1 a n d 2a
SCHEME 1
TABLE 3. Tr ibu tylp h osp h in e-Ca ta lyzed
[3 + 2]-Cycloa d d ition Rea ction of 1 a n d 8a
entry
substrate
time, h
yield, %b (ratio 6:7)c
d
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
-
40
-
-
96 (90:10)
d
-
-
d
-
11
48
4
17
16
21
10d (>97:3)
56 (92:8)
19 (89:11)
96 (>97:3)
30d (>97:3)
94 (>97:3)
a
A solution of 1 (1.0 mmol), 2 (1.2 mmol), and PPh3 (0.10 mmol)
b
in dry toluene (10 mL) was stirred at room temperature. Isolated
yield. c Determined by 1H NMR. The reaction is sluggish.
d
10
1j
TABLE 2. Tr ip h en ylp h osp h in e-Ca ta lyzed
a
A solution of compound 1 (0.20 mmol), 8 (0.24 mmol), and PBu3
[3 + 2]-Cycloa d d ition Rea ction of 1 a n d 5a
(0.04 mmol, 20 mol %) in dry toluene (2 mL) was stirred at room
temperature. b Isolated yield. c Determined by H NMR. Precipi-
1
d
tation of a white solid occurred.
Under similar conditions as shown in eq 1, other exo-
methylenecycles underwent addition of ethyl 2,3-buta-
dienoate to obtain regioisomeric spirocycles in total yields
of 28-98% with low to moderate selectivity (3:4 ) 58:42
to 84:16) (Table 1).
entry
substrate
time, h
yield, %b (ratio 6:7)c
1
2
3
4
5
1a
1b
1c
1d
1e
1f
1g
1h
1i
18
50
3
2
4
72
2
96
7
98 (91:9)
95 (92:8)
99 (95:5)
98 (93:7)
96 (92:8)
78 (80:20)
63 (78:22)
92 (92:8)
93 (91:9)
90 (74:26)
The regioselectivity of the reaction was greatly im-
proved by introducing a bulky group into the 2,3-
butadienoate. When tert-butyl 2,3-butadienoate (5) was
used as a three-carbon synthon instead of ethyl 2,3-
butadienoate, the reaction proceeded smoothly to afford
spirocycles 6 and 7 in high yields (63-99%) with moder-
ate to high selectivities (6:7 ) 74:26 to 95:5) (Table 2).
The great enhancement of the regioselectivity by
introducing a bulky group into the 2,3-butadienoate
might be rationalized by comparing the transition states
A and B of the reaction. The higher energy will occur in
B due to the steric influence of the bulky group (E) with
the skeleton of C2 components, making the product 3 or
6 more preferable (Scheme 1).
6d
7d
8
9
10
1j
12
a
A solution of 1 (0.20 mmol), 5 (0.24 mmol), and PPh3 (0.02
mmol, 10 mol %) in dry benzene (2 mL) was stirred at reflux.
Isolated yield. c Determined by 1H NMR. Reaction was per-
b
d
formed in toluene.
COSY, DEPT 135°, HMQC, and MS) and elemental
analysis. The characteristic feature of the spectra of 3a
was that the olefinic hydrogen C3-H, which appeared
as a multiplet, showed two strong vicinal couplings with
It was also shown in Table 2 that the regioselectivities
of R-methylenecycloalkanones 1f,g (entries 6 and 7) and
compound 1j (entry 10) were still not good enough.
According to our previous study, nucleophilic addition of
phosphines to 2-butynoates can form the similar 1,3-
dipole intermediates as those derived from 2,3-butadi-
enoates with phosphines,3,7a and the regioselectivities of
2-butynoate were generally better than that of 2,3-
butadienoate in the [3 + 2]-cycloaddition.7a
1
C4-H and two weak allylic couplings with C1-H in H-
1H COSY experiments. The spectra of 4a showed that
the olefinic hydrogen C2-H exhibited only one vicinal
coupling with C3-H as a triplet. Another important
1
difference between 3a and 4a in the H NMR spectra is
that the chemical shift of the olefinic hydrogen of 3a lies
in a higher field than that of 4a due to the effect of the
carbonyl group.
8902 J . Org. Chem., Vol. 67, No. 25, 2002

Construction of Spirocycles via [3 + 2]-Cycloaddition
(br s, 1H), 3.75 (br s, 2H); MS (m/z) 222 (M+, 79Br). Anal. Calcd
for C10H7BrO: C, 53.84; H, 3.16. Found: C, 53.81; H, 3.19.
5-Met h oxy-2-m et h ylen ein d a n -1-on e (1e): white solid;
mp 83-85 °C (ethyl acetate-petroleum ether); IR (KBr) ν
When tert-butyl 2-butynoate (8) was used instead of
tert-butyl 2,3-butadienoate (5) in the tributylphosphine-
catalyzed [3 + 2]-cycloaddition reaction, the regioselec-
tivity was further improved in some cases (>97:3).
Especially, improved high regioselectivities were ob-
served for the simple R-methylenecycloalkanones (entries
6 and 7, 6:7 ) 89:11 to 92:8), which were of consider-
able interest as a synthetic route to naturally occurring
spiro[4.5]decane sesquiterpenes and spiro[4.4]nonanes
(Table 3).
1
1691, 1647 cm-1; H NMR (300 MHz, CDCl3) δ 7.81 (d, J )
8.2 Hz, 1H), 6.94 (d, J ) 8.2 Hz, 1H), 6.92 (s, 1H), 6.30 (m,
1H), 5.57 (m, 1H), 3.90 (s, 3H), 3.71(s, 2H); MS (m/z) 175 (M+
+ 1), 174 (M+, 100), 146, 131, 115, 103, 102, 77. Anal. Calcd
for C11H10O2: C, 75.84; H, 5.79. Found: C, 75.99; H, 5.84.
2-Meth ylen ecycloh exa n on e (1f):10 1H NMR (300 MHz,
CDCl3) δ 5.83 (m, 1H), 5.14 (m, 1H), 2.61-2.56 (m, 2H), 2.47-
2.43 (m, 2H), 1.92-1.88 (m, 2H), 1.79-1.75 (m, 2H).
2-Meth ylen e-cyclop en ta n on e (1 g).10 1H NMR (300 MHz,
CDCl3) δ 5.98 (m, 1H), 5.32 (m, 1H), 2.72-2.65 (m, 2H), 2.35
(t, J ) 8.2 Hz, 2H), 1.99-1.92 (m, 2H).
1-ter t-Bu t oxyca r b on yl-3-m et h ylen ep yr r olid in -2-on e
(1h ): white solid; mp 73-75 °C (ethyl acetate-petroleum
ether); IR (KBr) ν 1778, 1742, 1716 cm-1; 1H NMR (300 MHz,
CDCl3) δ 6.11 (t, J ) 2.8 Hz, 1H), 5.40 (t, J ) 2.5 Hz, 1H),
3.66 (t, J ) 7.0 Hz, 2H), 2.67 (m, 2H), 1.49 (s, 9H); MS (m/z)
198 (M+ + 1), 197 (M+), 142, 124, 98, 96, 57 (100), 56, 43, 41.
Anal. Calcd for C10H15NO3: C, 60.90; H, 7.67; N, 7.10. Found:
C, 60.54; H, 7.63; N, 7.47.
Con clu sion
An efficient approach with high regioselectivity to
prepare spiro[4.n]alkanes, especially the skeleton of
spiro[4.5]decanes, via phosphine-catalyzed [3 + 2]-cy-
cloaddition reaction was developed, which features a
rapid and efficient construction of the spirocarbocyclic
skeleton.
Exp er im en ta l Section
3-Meth ylen e-1-tosylp yr r olid in -2-on e (1i): white solid;
mp 104-106 °C (ethyl acetate-petroleum ether); IR (KBr) ν
1718, 1660, 1596 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.97 (dd,
J ) 7.6, 0.5 Hz, 2 H), 7.35 (dd, J ) 7.6, 0.5 Hz, 2 H), 6.11 (t,
J ) 2.8 Hz, 1H), 5.47 (t, J ) 2.5 Hz, 1H), 3.89 (t, J ) 6.9 Hz,
2H), 2.85-2.78 (m, 2H), 2.44 (s, 3H); MS (m/z) 252 (M+ + 1),
Gen er a l. For 13C NMR, chemical shifts were reported
relative to CHCl3 (77.00 ppm for 13C NMR) as an internal
reference. 2-Methylene-3,4-dihydro-2H-naphthalen-1-one (1a ),9
2-methylenecyclohexanone (1f),10 2-methylenecyclopentanone
(1g),10 1,3-bibenzyl-5-methylenehydantoin (1j),11 ethyl 2,3-
butadienoate (2),12 tert-butyl 2,3-butadienoate (5),12 and tert-
butyl 2-butynoate (8)13 were prepared by the reported methods.
Syn th esis of r-Meth ylen ecycloa lk a n on es or -cycloa l-
k a n a m id es (1). Compounds 1b,9 1c,9 1d ,14 and 1e14 were
synthesized by a method similar to that of the literature.
Compounds 1h and 1i were prepared from the 3-methyl-
enepyrrolidin-2-one by the usual methods.15
187 (100), 186, 119, 91, 89, 68, 65. Anal. Calcd for C12H13
-
NO3S: C, 57.35; H, 5.21; N, 5.57. Found: C, 57.21; H, 5.41;
N, 5.50.
1,3-Biben zyl-5-m eth ylen eh yd a n toin (1j):11 white solid;
1
mp 84-85 °C (ethyl acetate-petroleum ether); H NMR (300
MHz, CDCl3) δ 7.27 (m, 10H), 6.30 (d, J ) 2 Hz, 1H), 4.72 (s,
4H), 4.63 (d, J ) 2 Hz, 1H).
Tr ip h en ylp h osp h in e-Ca ta lyzed [3 + 2]-Cycloa d d ition
of 1 w ith Eth yl 2,3-Bu ta d ien oa te (2) (Ta ble 1). A solution
of 1 (1.0 mmol), ethyl 2,3-butadienoate (2) (1.2 mmol), and
PPh3 (0.10 mmol) in dry toluene (10 mL) was stirred at room
temperature. The mixture was then stirred for the indicated
time at room temperature. The reaction mixture was concen-
trated under reduced pressure and the residue was purified
by column chromatography on silica gel (petroleum ether-
ethyl acetate) to give 3 and 4.
2-Meth ylen e-3,4-d ih yd r o-2H-n a p h th a len -1-on e (1a ):9
white solid; mp 46-47 °C (ethyl acetate-hexane); 1H NMR
(300 MHz, CDCl3) δ 8.02 (dd, J ) 7.8, 1.0 Hz, 1 H), 7.38 (td,
J ) 7.5, 1.4 Hz, 2H), 7.24 (bt, J ) 7.9 Hz, 1H), 7.15 (dd, J )
7.5, 0.5 Hz, 1H), 6.14 (br s, 1H), 5.35 (q, J ) 1.6 Hz, 1H), 2.90
(t, J ) 6.0 Hz, 2H), 2.76 (br t, J ) 6.0 Hz, 2H).
6-Meth oxy-2-m eth ylen e-3,4-d ih yd r o-2H-n a p h th a len -1-
on e (1b):16 white solid; mp 44-45.5 °C (ethyl acetate-
1
petroleum ether); IR (KBr) ν 1664, 1597 cm-1; H NMR (300
E t h yl 1′-oxo-3′,4′-d ih yd r osp ir o[cyclop en t -3-en e-1,2′-
n a p h th a len e]-3-ca r boxyla te (3a ): oil; IR (neat) ν 1713,
MHz, CDCl3) δ 7.99 (d, J ) 8.7 Hz, 1 H), 6.76 (dd, J ) 8.7, 2.4
Hz, 1H), 6.61 (d, J ) 2.1 Hz, 1H), 6.10 (br s, 1H), 5.31 (br s,
1H), 3.76 (s, 3H), 2.87 (t, J ) 5.9 Hz, 2H), 2.74 (m, 2H); MS
(m/z) 188 (M+, 100), 160, 148, 145, 120, 115, 91. Anal. Calcd
for C12H12O2: C, 76.57; H, 6.43. Found: C, 76.38; H, 6.39.
2-Meth ylen ein d a n -1-on e (1c):17 oil;1H NMR (400 MHz,
CDCl3) δ 7.91 (d, J ) 7.7 Hz, 1 H), 7.65 (td, J ) 7.7, 1.0 Hz,
1H), 7.53 (d, J ) 7.7 Hz, 1H), 7.45 (t, J ) 7.7 Hz, 1H), 6.41 (s,
1H), 5.68 (s, 1H), 5.07 (s, 2H).
1
1683, 1639 cm-1; H NMR (300 MHz, CDCl3) δ 7.98 (d, J )
7.9 Hz, 1H), 7.40 (td, J ) 7.5, 1.2 Hz, 1H), 7.24 (t, J ) 7.5 Hz,
1H), 7.16 (d, J ) 7.6 Hz, 1H), 6.64 (m, 1H), 4.11 (q, J ) 7.2
Hz, 2H), 3.09 (ddd, J ) 18.7, 4.5, 2.2 Hz, 1H), 3.04-2.87 (m,
3H), 2.63 (br d, J ) 15.3 Hz, 1H), 2.39 (ddd, J ) 18.6, 4.4, 1.9
Hz, 1H), 2.12 (t, J ) 6.9 Hz, 2H) 1.21 (t, J ) 7.2 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 200.1, 164.8, 143.3, 140.9, 133.6,
133.4, 131.2, 128.8, 128.4, 126.9, 60.4, 52.1, 42.2, 40.2, 34.7,
25.9, 14.4; MS (m/z) 270 (M+). Anal. Calcd for C17H18O3: C,
75.53; H, 6.71. Found: C, 75.50; H, 6.94.
5-Br om o-2-m eth ylen ein d a n -1-on e (1d ): white solid; mp
95-97 °C (ethyl acetate-petroleum ether); IR (KBr) ν 1697,
1
1642 cm-1; H NMR (300 MHz, CDCl3) δ 7.73 (d, J ) 8.2 Hz,
E t h yl 1′-oxo-3′,4′-d ih yd r osp ir o[cyclop en t -2-en e-1,2′-
n a p h th a len e]-2-ca r boxyla te (4a ): white solid; mp 52-54
°C (ethyl acetate-petroleum ether); IR (KBr) ν 1710, 1677,
1625 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.00 (dd, J ) 7.7, 1.3
Hz, 1H), 7.39 (td, J ) 7.5, 1.4 Hz, 1H), 7.24 (t, J ) 7.6 Hz,
1H), 7.16 (d, J ) 7.6 Hz, 1H), 6.94 (t, J ) 2.6 Hz, 1H), 4.05 (q,
J ) 7.1 Hz, 2H), 3.05 (ddd, J ) 16.7, 13.2, 4.5 Hz, 1H), 2.86
(ddd, J ) 16.7, 4.5, 2.9 Hz, 1H), 2.70 (tdd, J ) 13.2, 4.5, 0.5
Hz, 1 H), 2.51 (td, J ) 7.6, 2.5 Hz, 2H), 2.17 (dt, J ) 13.1, 6.5
Hz, 1H), 2.04 (dtd, J ) 13.1, 7.6, 0.6 Hz, 1H) 1.86 (ddd, J )
13.1, 4.5, 2.8 Hz, 1 H), 1.11 (t, J ) 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 199.8, 164.0, 145.8, 143.5, 140.2, 133.3, 131.9,
128.5, 128.2, 126.8, 60.3, 59.5, 33.5, 32.0, 30.9, 26.4, 14.2; MS
(m/z) 270 (M+). Anal. Calcd for C17H18O3: C, 75.53; H, 6.71.
Found: C, 75.34; H, 6.60.
1H), 7.68 (s, 1H), 7.55 (d, J ) 8.2 Hz, 1H), 6.39 (br s, 1H), 5.67
(9) Gras, J .-L. Org. Synth. 1981, 60, 88.
(10) Tsuji, J .; Nisar, M.; Minami, I. Tetrahedron Lett. 1986, 27, 2483.
(11) Ravindranathan, T.; Hiremath, S. V.; Gosavi, K.; Reddy, D. R.
Synthesis 1989, 38.
(12) Lang, R. W.; Hansen, H.-J . Org. Synth. 1984, 62, 202.
(13) Otaka, A.; Mitsuyama, E.; Kinoshita, T.; Tamamura, H.; Fujii,
N. J . Org. Chem. 2000, 65, 4888.
(14) Depreux, P.; Moussavi, E.; Lesieur, D. Synth. Commun. 1992,
22, 1541.
(15) Fotiadu, F.; Pardigon, O.; Buono, G. Tetrahedron Lett. 1999,
40, 867.
(16) Collins, D. J .; Fallon, G. D.; Skene, C. E. Aust. J . Chem. 1994,
47, 623.
(17) Newsoroff, G. P.; Sternhell, S. Aust. J . Chem. 1972, 25, 1669.
J . Org. Chem, Vol. 67, No. 25, 2002 8903

Du et al.
Eth yl 6′-Meth oxy-1′-oxo-3′,4′-d ih yd r osp ir o[cyclop en t-
3-en e-1,2′-n a p h th a len e]-3-ca r boxyla te (3b): oil; IR (neat)
°C (ethyl acetate-petroleum ether); IR (KBr) ν 1784, 1752,
1718, 1628 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.99 (t, J ) 2.5
Hz, 1H), 4.17 (q, J ) 7.2 Hz, 2H), 3.91 (m, 1H), 3.63 (m, 1H),
2.67-2.36 (m, 4H), 2.03-1.9 (m, 2H), 1.54 (s, 9H), 1.26 (t, J )
1
ν 1712, 1673, 1638 cm-1; H NMR (300 MHz, CDCl3) δ 7.93
(d, J ) 8.8 Hz, 1H), 6.74 (dd, J ) 8.8, 2.5 Hz, 1H), 6.62 (m,
1H), 6.59 (d, J ) 2.5 Hz, 1H), 4.09 (q, J ) 7.1 Hz, 2H), 3.76 (s,
3H), 3.09-2.82 (m, 4H), 2.59 (br d, J ) 18.3 Hz, 1H), 2.36 (br
d, J ) 18.5 Hz, 1H), 2.07 (t, J ) 5.9 Hz, 2H) 1.19 (t, J ) 7.1
Hz, 3H); MS (m/z) 300 (M+); EI-HRMS calcd for C18H20O4
300.1361, found 300.1330.
7.2 Hz, 3H); MS (m/z) 236 (M+ - OtBu). Anal. Calcd for C16H23
-
NO5: C, 62.12; H, 7.49; N, 4.53. Found: C, 62.28; H, 7.53; N,
4.48.
Eth yl 2-tosyl-1-oxo-2-a za sp ir o[4.4]n on -7-en e-7-ca r box-
yla te a n d eth yl 2-tosyl-1-oxo-2-a za sp ir o[4.4]n on -6-en e-
Eth yl 6′-Meth oxy-1′-oxo-3′,4′-d ih yd r osp ir o[cyclop en t-
2-en e-1,2′-n a p h th a len e]-2-ca r boxyla te (4b): oil; IR (neat)
6-ca r boxyla te (3i a n d 4i): oil; IR (neat) ν 1731, 1712 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.92 (d, J ) 8.3 Hz, 2 H), 7.34
(dd, J ) 8.5, 0.5 Hz, 2 H), 6.91 (t, J ) 2.5 Hz, 0.18H), 6.57 (m,
0.82H), 4.16 (q, J ) 7.1 Hz, 1.64H), 4.01(q, J ) 7.1 Hz, 0.36H),
3.89-3.75 (m, 2H), 2.91-2.74 (m, 2H), 2.52-2.35 (m, 2H), 2.45
(s, 3H), 2.10-2.01 (m, 2H), 1.26 (t, J ) 7.1 Hz, 2.46H), 1.13 (t,
J ) 7.1 Hz, 0.54H); MS (m/z) 363 (M+); EI-HRMS calcd for
C18H21NO5S 363.1140, found 363.1143.
1
ν 1708, 1666 cm-1; H NMR (300 MHz, CDCl3) δ 8.05 (d, J )
8.7 Hz, 1H), 7.00 (t, J ) 2.5 Hz, 1H), 6.84 (dd, J ) 8.7, 2.5 Hz,
1H), 6.69 (br d, J ) 2.2 Hz, 1H), 4.13 (q, J ) 7.1 Hz, 2H), 3.86
(s, 3H), 3.11-3.05 (m, 1H), 2.90-2.75 (m, 2H), 2.58 (m, 2H),
2.25-2.07 (m, 2H), 1.93-1.86 (m, 1H) 1.20 (t, J ) 7.1 Hz, 3H);
MS (m/z) 300 (M+). Anal. Calcd for C18H20O4: C, 71.98; H, 6.71.
Found: C, 71.90; H, 6.72.
Eth yl 1,3-d iben zyl-2,4-d ioxo-1,3-d ia za sp ir o[4.4]n on -7-
en e-7-ca r boxyla te a n d eth yl 1,3-d iben zyl-2,4-d ioxo-1,3-
d ia za sp ir o[4.4]n on -6-en e-6-ca r boxyla te (3j a n d 4j): oil; IR
Eth yl 1′,3′-Dih yd r o-1′-oxosp ir o[cyclop en t-3-en e-1,2′-in -
d a n e]-3-ca r boxyla te (3c): oil; IR (neat) ν 1712, 1636, 1608
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.79 (dd, J ) 7.6, 0.4 Hz,
(neat) ν 1771, 1712, 1637, 1606 cm-1 1H NMR (300 MHz,
;
1H), 7.62 (td, J ) 7.3, 1.1 Hz, 1H), 7.47-7.40 (m, 2H), 6.77
(m, 1H), 4.21 (q, J ) 7.1 Hz, 2H), 3.22-3.03 (m, 4H), 2.64-
2.47 (m, 2H), 1.30 (t, J ) 7.1 Hz, 3H); MS (m/z) 256 (M+). Anal.
Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 75.02; H,
6.41.
CDCl3) δ 7.50-7.23 (m, 10H), 7.14 (m, 0.35H), 6.61 (m, 0.65H),
4.74 (d, J ) 5.0 Hz, 2H), 4.56-4.15 (m, 3.30H), 3.89-3.86 (m,
0.35H), 3.72 (m, 0.35H), 3.03-2.99 (m, 1.30H), 2.57-2.41 (m,
2.35H), 2.0-1.85 (m, 0.35H), 1.26 (t, J ) 7.2 Hz, 1.95H) 0.99
(t, J ) 7.1 Hz, 1.05H); MS (m/z) 404 (M+); EI-HRMS calcd for
C
24H24N2O4 404.1736, found 404.1711.
Eth yl 1′,3′-Dih yd r o-1′-oxosp ir o[cyclop en t-2-en e-1,2′-in -
d a n e]-2-ca r boxyla te (4c): oil; IR (neat) ν 1712, 1629, 1609
Tr ip h en ylp h osp h in e-Ca t a lyzed Cycloa d d it ion of 1
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.80 (d, J ) 7.6 Hz, 1H),
w ith ter t-Bu tyl 2,3-Bu ta d ien oa te (5). Gen er a l P r oced u r e
for th e P r ep a r a tion of Sp ir ocycles 6 a n d 7 (Ta ble 2). A
solution of 1 (0.20 mmol), 5 (0.24 mmol), and PPh3 (0.02 mmol,
10 mol %) in dry benzene (2 mL) was stirred at reflux. After
the reaction was completed, the reaction mixture was concen-
trated under reduced pressure and the residue was purified
by column chromatography on silica gel (petroleum ether-
ethyl acetate) to give 6 and 7.
Tr ibu tylp h osp h in e-Ca ta lyzed Cycloa d d ition of 1 w ith
ter t-Bu tyl 2-Bu tyn oa te (8). Gen er a l P r oced u r e for th e
P r ep a r a tion of Sp ir ocycles 6 a n d 7 (Ta ble 3). A solution
of compound 1 (0.20 mmol), 8 (0.24 mmol), and PBu3 (0.04
mmol, 20 mol %) in dry toluene (2 mL) was stirred at room
temperature. After the reaction was completed, the reaction
mixture was concentrated under reduced pressure and the
residue was purified by column chromatography on silica gel
(petroleum ether-ethyl acetate) to give 6 and 7.
7.60 (td, J ) 7.6, 1.2 Hz, 1H), 7.43 (dt, J ) 7.7, 0.8 Hz, 1H),
7.36 (td, J ) 7.7, 0.8 Hz, 1H), 7.08 (t, J ) 2.6 Hz, 1H), 4.01 (q,
J ) 7.1 Hz, 2H), 3.44 (d, J ) 17.1 Hz, 1H), 3.15 (d, J ) 17.1
Hz, 1H), 2.74-2.64 (m, 2H), 2.48-2.38 (m, 1H), 2.03-1.95 (m,
1H), 1.01 (t, J ) 7.1 Hz, 3H); MS (m/z) 256 (M+). Anal. Calcd
for C16H16O3: C, 74.98; H, 6.29. Found: C, 74.73; H, 6.43.
Eth yl 5′-br om o-1′,3′-d ih yd r o-1′-oxosp ir o[cyclop en t-3-
en e-1,2′-in d a n e]ca r boxyla te a n d eth yl 5′-br om o-1′,3′-d i-
h yd r o-1′-oxo-sp ir o[cyclop en t -2-en e-1,2′-in d a n e]-2-ca r -
1
boxyla te (3d a n d 4d ): oil; IR (neat) ν 1716, 1635 cm-1; H
NMR (300 MHz, CDCl3) δ 7.66-7.54 (m, 3H), 7.07 (br s,
0.22H), 6.74 (br s, 0.78H), 4.25-4.02 (m, 2H), 3.36-3.03 (m,
4H), 2.70-2.45 (m, 2H), 1.32-1.00 (m, 3H); MS (m/z) 334 (M+,
79Br). Anal. Calcd for C16H15BrO3: C, 57.33; H, 4.51. Found:
C, 57.32; H, 4.66.
Eth yl 5′-m eth oxy-1′,3′-d ih yd r o-1′-oxo-sp ir o[cyclop en t-
3-en e-1,2′-in d a n e]-3-ca r boxyla te a n d eth yl 5′-m eth oxy-
1′,3′-d ih yd r o-1′-oxo-sp ir o[cyclop en t-2-en e-1,2′-in d a n e]-2-
ter t-Bu tyl 1′-oxo-3′,4′-d ih yd r osp ir o[cyclop en t -3-en e-
1,2′-n a p h th a len e]-3-ca r boxyla te (6a ): oil; IR (neat) ν 1705,
ca r boxyla te (3e a n d 4e): oil; IR (neat) ν 1702, 1634 cm-1
;
1
1684, 1636 cm-1; H NMR (300 MHz, CDCl3) δ 8.06 (dd, J )
1H NMR (300 MHz, CDCl3) δ 7.72 (d, J ) 8.5 Hz, 1H), 7.06
(m, 0.18H), 6.59 (br d, J ) 8.5 Hz, 1H), 6.87 (br s, 1H), 6.75
(m, 0.82H), 4.20 (q, J ) 7.1 Hz, 1.64H), 4.03 (q, J ) 7.1 Hz,
0.36H), 3.88 (s, 3H), 3.40 (d, J ) 17.2 Hz, 0.18H), 3.18-3.01
(m, 3.82H), 2.61-2.41 (m, 2H), 1.28 (t, J ) 7.1 Hz, 2.46H),
1.05 (t, J ) 7.1 Hz, 0.54H); MS (m/z) 286 (M+); EI-HRMS calcd
for C17H18O4 286.1205, found 286.1177.
7.8, 1.3 Hz, 1H), 7.47 (td, J ) 7.5, 1.5 Hz, 1H), 7.31 (br t, J )
7.8 Hz, 1H), 7.23 (br d, J ) 7.7 Hz, 1H), 6.60 (m, 1H), 3.17-
2.94 (m, 4H), 2.65 (ddt, J ) 18.5, 2.9, 1.8 Hz, 1H), 2.42 (ddt, J
) 18.5, 2.9, 1.8 Hz, 1H), 2.18 (t, J ) 5.8 Hz, 2H), 1.47 (s, 9H);
13C NMR (75 MHz, CDCl3) 200.1, 164.0, 143.2, 139.6, 134.9,
133.2, 128.6, 128.2, 126.7, 80.2, 51.8, 42.0, 40.1, 34.6, 28.0 (2C),
25.7; MS (m/z) 399 (M+ + 1), 243, 224 (100), 197, 196, 118, 57,
41. Anal. Calcd for C19H22O3: C, 76.48; H, 7.43. Found: C,
76.10; H, 7.43.
Eth yl 6-oxosp ir o[4.4]n on -2-en e-2-ca r boxyla te a n d eth -
yl 6-oxosp ir o[4.4]n on -1-en e-1-ca r boxyla te (3g a n d 4g): oil;
IR (neat) ν 1739, 1710, 1625 cm-1; 1H NMR (300 MHz, CDCl3)
δ 6.94 (t, J ) 2.5 Hz, 0.42H), 6.65 (m, 0.58H), 4.2-4.1 (m, 2H),
2.86-2.81 (m, 1.16H), 2.60-1.70 (m, 8.84H), 1.3-1.1 (m, 3H);
MS (m/z) 208 (M+). Anal. Calcd for C12H16O3: C, 69.21; H, 7.74.
Found: C, 68.85; H, 7.94.
ter t-Bu tyl 6′-m eth oxy-1′-oxo-3′,4′-d ih yd r osp ir o[cyclo-
p en t-3-en e-1,2′-n a p h th a len e]-3-ca r boxyla te (6b): oil; IR
1
(neat) ν 1699, 1688, 1638 cm-1; H NMR (300 MHz, CDCl3) δ
8.04 (d, J ) 8.8 Hz, 1H), 6.84 (dd, J ) 8.8, 2.5 Hz, 1H), 6.68
(d, J ) 2.5 Hz, 1H), 6.60 (m, 1H), 3.86 (s, 3H), 3.18-2.94 (m,
4H), 2.63 (br d, J ) 16.6 Hz, 1H), 2.41 (br d, J ) 16.6 Hz, 1H),
2.15 (m, 2H), 1.47 (s, 9H); MS (m/z) 329 (M+ + 1), 273, 272,
254, 227, 226 (100), 198. Anal. Calcd for C20H24O4: C, 73.15;
H, 7.37. Found: C, 73.01; H, 7.42.
E t h yl 2-(ter t-b u t oxyca r b on yl)-1-oxo-2-a za sp ir o[4.4]-
n on -7-en e-7-ca r boxyla te (3h ): oil; IR (neat) ν 1785, 1751,
1
1716, 1638 cm-1; H NMR (300 MHz, CDCl3) δ 6.67 (m, 1H),
4.19 (q, J ) 7.1 Hz, 2H), 3.70 (td, J ) 6.8, 0.7 Hz, 2H), 3.11-
3.02 (m, 2H), 2.64-2.43 (m, 2H), 2.07-1.95 (m, 2H), 1.54 (s,
9H), 1.29 (t, J ) 7.1 Hz, 3H); MS (m/z) 236 (M+ - OtBu). Anal.
Calcd for C16H23NO5: C, 62.12; H, 7.49; N, 4.53. Found: C,
62.53; H, 7.76; N, 4.33.
ter t-Bu t yl 1′,3′-d ih yd r o-1′-oxosp ir o[cyclop en t -3-en e-
1,2′-in d a n e]-3-ca r boxyla te (6c): oil; IR (neat) ν 1710, 1635
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.79 (d, J ) 7.6 Hz, 1H),
7.63 (td, J ) 7.5, 1.2 Hz, 1H), 7.44 (dt, J ) 7.6, 0.8 Hz, 1H),
7.40 (td, J ) 7.6, 1.2 Hz, 1H), 6.65 (m, 1H), 3.25 (d, J ) 17.1
Hz, 1H), 3.17 (d, J ) 17.1 Hz, 1H), 3.11-3.00 (m, 2H), 2.64-
E t h yl 2-(ter t-b u t oxyca r b on yl)-1-oxo-2-a za sp ir o[4.4]-
n on -6-en e-6-ca r boxyla te (4h ): white solid; mp 107-110.5
8904 J . Org. Chem., Vol. 67, No. 25, 2002

Construction of Spirocycles via [3 + 2]-Cycloaddition
1
2.40 (m, 2H), 1.49 (s, 9H); MS (m/z) 228, 211, 210 (100), 183,
182, 181, 165, 57. Anal. Calcd for C18H20O3: C, 76.03; H, 7.09.
Found: C, 75.73; H, 7.25.
1710, 1637 cm-1; H NMR (300 MHz, CDCl3) δ 6.56 (m, 1H),
3.69 (deformed t, J ) 6.8 Hz, 2H), 3.07-2.99 (m, 2H), 2.57-
2.40 (m, 2H), 2.04-1.94 (m, 2H), 1.54 (s, 9H), 1.48 (s, 9H); 13
C
ter t-Bu tyl 5′-br om o-1′,3′-dih ydr o-1′-oxospir o[cyclopen t-
3-en e-1,2′-in d a n e]-3-ca r boxyla te (6d ): white solid; mp
146.5-147.5 °C (ethyl acetate-petroleum ether); IR (KBr) ν
NMR (75 MHz, CDCl3) δ 177.5, 163.7, 150.3, 139.0, 135.4, 81.0,
80.5, 51.6, 43.3, 43.2, 42.1, 33.8, 28.0; MS (m/z) 282, 264 (M+
- OtBu), 226, 225, 181, 180, 163, 57, 41. Anal. Calcd for C18H27
-
1
1703, 1638 cm-1; H NMR (300 MHz, CDCl3) δ 7.64 (d, J )
NO5: C, 64.07; H, 8.07; N, 4.15. Found: C, 64.08; H, 7.94; N,
3.81.
8.1 Hz, 1H), 7.63 (s, 1H), 7.54 (d, J ) 8.1 Hz, 1H), 6.63 (m,
1H), 3.18 (d, J ) 8.5 Hz, 2H), 3.09-2.99 (m, 2H), 2.58-2.42
(m, 2H), 1.48 (s, 9H); 13C NMR (75 MHz, CDCl3) 207.9, 163.8,
154.0, 139.5, 136.1, 134.6, 131.3, 130.4, 129.7, 125.5, 80.6, 55.5,
45.1, 44.7, 44.1, 28.1; MS (m/z) 308, 306, 290, 288 (100), 262,
261, 260, 182, 181, 57. Anal. Calcd for C18H19BrO3: C, 59.52;
H, 5.27. Found: C, 59.38; H, 5.43.
ter t-Bu tyl 2-tosyl-1-oxo-2-a za sp ir o[4.4]n on -7-en e-7-ca r -
boxyla te (6i): white solid; mp 95-97 °C (ethyl acetate-
petroleum ether); IR (KBr) ν 1724, 1714, 1640 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.93 (d, J ) 8.3 Hz, 2 H), 7.35 (d, J ) 8.1
Hz, 2 H), 6.48 (m, 1H), 3.87-3.78 (m, 2H), 2.89-2.72 (m, 2H),
2.48-2.33 (m, 5H), 2.11-2.02 (m, 2H), 1.46(s, 9H); MS (m/z)
335, 317, 290, 162 (100), 91, 65, 57. Anal. Calcd for C20H25
NO5S: C, 61.36; H, 6.44; N, 3.58. Found: C, 61.11; H, 6.53;
N, 3.44.
ter t-Bu tyl 5′-m eth oxy-1′,3′-d ih yd r o-1′-oxosp ir o[cyclo-
p en t-3-en e-1,2′-in d a n e]-3-ca r boxyla te (6e): oil; IR (neat)
-
1
ν 1702, 1633 cm-1; H NMR (300 MHz, CDCl3) δ 7.72 (d, J )
8.5 Hz, 1H), 6.93 (d, J ) 8.5 Hz, 1H), 6.87 (s, 1H), 6.30 (br s,
1H), 3.89 (s, 3H), 3.16-3.00 (m, 4H), 2.56-2.41 (m, 2H), 1.49
(s, 9H); MS (m/z) 315 (M+ + 1), 259, 258, 241, 240, 213, 212,
211. Anal. Calcd for C19H22O4: C, 72.59; H, 7.05. Found: C,
72.26; H, 7.04.
ter t-Bu tyl 6-oxosp ir o[4.5]d ec-2-en e-2-ca r boxyla te (6f):
oil; IR (neat) ν 1708, 1637 cm-1; 1H NMR (300 MHz, CDCl3) δ
6.50 (m, 1H), 3.16 (d, J ) 16.7 Hz, 2 H), 2.93 (br d, J ) 16.7
Hz, 2 H), 2.55-2.25 (m, 3H), 2.21 (d, J ) 12.0 Hz, 2H), 2.05-
1.25 (m, 15H); MS (m/z) 177 (M+ - OtBu), 176 (100), 150, 149,
148, 124, 57, 41. Anal. Calcd for C15H22O3: C, 71.97; H, 8.86.
Found: C, 72.32; H, 9.07.
ter t-Bu tyl 6-oxosp ir o[4.4]n on -2-en e-2-ca r boxyla te a n d
ter t-bu tyl 6-oxospir o[4.4]n on -1-en e-1-car boxylate (6g an d
7g): oil; IR (neat) ν 1739, 1706, 1637 cm-1; 1H NMR (300 MHz,
CDCl3) δ 6.85 (t, J ) 2.5 Hz, 0.11H), 6.53 (m, 0.89H), 2.81-
2.75 (m, 1.78H), 2.50-1.80 (m, 8.22H), 1.45 (s, 9H); MS (m/z)
237 (M+ + 1), 181, 180, 163, 162 (100), 135, 134, 124, 57. Anal.
Calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 70.99; H,
8.50.
ter t-Bu t yl 1,3-d ib en zyl-2,4-d ioxo-1,3-d ia za sp ir o[4.4]-
n on -7-en e-7-ca r boxyla te (6j): white solid; mp 91-93 °C
(ethyl acetate-petroleum ether); IR (KBr) ν 1770, 1712, 1637
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.44-7.23 (m, 10H), 6.53
(m, 1H), 4.74 (s, 2H), 4.54 (d, J ) 15.5 Hz, 1H), 4.32 (d, J )
15.6 Hz, 1H), 3.02 (br d, J ) 15.6 Hz, 2H), 2.52-2.45 (m, 2H),
1.46 (s, 9H); MS (m/z) 432 (M+), 376, 358, 331, 330, 91 (100),
84, 57. Anal. Calcd for C26H28N2O4: C, 72.20; H, 6.53; N, 6.48.
Found: C, 72.17; H, 6.87; N, 6.34.
Ack n ow led gm en t. This work was funded by the
Major State Basic Research Program (Grant
G2000077502-A). We also thank the National Natural
Science Foundation of China and the Chinese Academy
of Sciences for financial support.
Su p p or tin g In for m a tion Ava ila ble: 1H-1H COSY data
of 3a and 4a ,1H NMR spectra of compounds 3b, 3e, 4e, 3i, 4i,
3j, and 4j. This material is available free of charge via the
Internet at http://pubs.acs.org.
ter t-Bu t yl 2-(ter t-b u t oxyca r b on yl)-1-oxo-2-a za sp ir o-
[4.4]n on -7-en e-7-ca r boxyla te (6h ): white solid; mp 56-57.5
°C (ethyl acetate-petroleum ether); IR (KBr) ν 1787, 1753,
J O026111T
J . Org. Chem, Vol. 67, No. 25, 2002 8905