Iodocarbocyclization of α-iodocycloalkanones bearing an allenyl side chain: Synthesis of spirocyclic cycloalkanones

Article abstract of DOI:10.1016/j.tetlet.2005.12.015

AlCl₃/ICl-mediated iodocarbocyclizations of α- iodocycloalkanones bearing an allenyl side chain are described. Treatment of iodocycloalkanones 4a-i with AlCl₃/ICl gave spirocyclic cycloalkanones 5a-i and 6a-i as a mixture of products

Full text of DOI:10.1016/j.tetlet.2005.12.015

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1167–1171
Iodocarbocyclization of a-iodocycloalkanones bearing an allenyl
side chain: synthesis of spirocyclic cycloalkanones
Hsien-Hsun Lin, Gen-I Lin, Ying-Ruei Lin, Chien-Fu Liang,
Chao-Hsiang Chen and Chin-Kang Sha*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan, ROC
Received 3 November 2005; revised 1 December 2005; accepted 5 December 2005
Abstract—AlCl3/ICl-mediated iodocarbocyclizations of a-iodocycloalkanones bearing an allenyl side chain are described. Treat-
ment of iodocycloalkanones 4a–i with AlCl3/ICl gave spirocyclic cycloalkanones 5a–i and 6a–i as a mixture of products.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Ionic iodocarbocyclization reactions involving intra-
molecular attack of a carbon nucleophile at a double
bond activated by an electrophilic iodinating reagent
are efficient processes to construct carbocyclic frame-
works. Iodocarbocyclization involving 1,3-dicarbonyl
compounds, such as 4-alkenyl and 4-alkynyl malonates,
was extensively studied by Taguchi and co-workers.1
The related ionic selenocarbocyclization of a-seleno
ketones was investigated by ToruÕs group.2 Free-radical
atom-transfer cyclization of iodo substrates mediated
with hexamethylditin3 or other reagents4 has also been
reported. We have recently described the AlCl3/ICl-
mediated5 and photo-induced6 iodocarbocyclization of
a-iodocycloalkanones. As an extension, we have investi-
gated AlCl3/ICl-mediated iodocarbocyclization of a-
iodocycloalkanones bearing an allenyl side chain. Here,
we report our preliminary results.
1). Deprotonation of hydrazones 1a–c with n-BuLi
followed by alkylation with allenylalkyl iodides 2 and
hydrolysis gave cycloalkanones 3a–c. Treatment of 3a–
c with chlorotrimethylsilane and hexamethyldisilazane
gave the corresponding trimethylsilylenol ethers. Iodin-
ation of these TMS-enol ethers with a mixture of NaI
and m-CPBA7 afforded a-iodocycloalkanones 4a–c.
Preparation of compounds 4d–i in Scheme 2 and Table
1 according to the same method was reported in our pre-
vious paper.6
Treatment of iodocycloalkanones 4a–f with AlCl3/ICl in
CH2Cl2 at 0 ꢁC gave 5a–f as minor products and 6a–f as
major products (Scheme 2 and Table 1).8 When the reac-
tions were performed at À78 ꢁC, compounds 5a–f were
obtained predominantly, and compounds 6a–f were
formed as minor products. For the formation of the
seven-member-ring products, treatment of 4g–i with
AlCl3/ICl in CH2Cl2 at both À78 ꢁC and 0 ꢁC gave com-
pounds 5g–i as major products and compounds 6g–i as
a-Iodocycloalkanones bearing an allenyl side chain were
prepared according to conventional methods (Scheme
N
N
O
O
1. n-BuLi
1. HMDS, TMSI
n
n
2. I
n
2. NaI, m-CPBA
I
m
m
m
2
1a m = 1
1b m = 2
1c m = 3
3a m = 1, n = 2, 87%
3b m = 2, n = 2, 85%
3c m = 3, n = 2, 85%
4a m = 1, n = 2, 82%
4b m = 2, n = 2, 80%
4c m = 3, n = 2, 81%
3. silica gel, CH Cl
2
2
Scheme 1.
Keywords: Iodocarbocyclization; a-Iodocycloalkanones; Spirocyclic cycloalkanones.
*
Corresponding author. Tel.: +886 3 5722427; fax: +886 3 5725870; e-mail: cksha@mx.nthu.edu.tw
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.015

1168
H.-H. Lin et al. / Tetrahedron Letters 47 (2006) 1167–1171
I
minor products. When the reactions were carried out at
O
O
O
30 ꢁC, compounds 5g–i were formed as minor products
and compounds 6g–i were obtained as major products
(Table 2).
I
AlCl , ICl
3
+
n
I
CH Cl
2
2
o
o
m
m
m
4a m = 1, n = 2
4b m = 2, n = 2
4c m = 3, n = 2
4d m = 1, n = 3
4e m = 2, n = 3
4f m = 3, n = 3
4g m = 1, n = 4
4h m = 2, n = 4
4i m = 3, n = 4
5a m = 1, o = 1
5b m = 2, o = 1
5c m = 3, o = 1
5d m = 1, o = 2
5e m = 2, o = 2
5f m = 3, o = 2
5g m = 1, o = 3
5h m = 2, o = 3
5i m = 3, o = 3
6a m = 1, o = 1
6b m = 2, o = 1
6c m = 3, o = 1
6d m = 1, o = 2
6e m = 2, o = 2
6f m = 3, o = 2
6g m = 1, o = 3
6h m = 2, o = 3
6i m = 3, o = 3
To rationalize these results, a plausible reaction mecha-
nism shown in Scheme 3 was proposed. Upon treatment
with AlCl3, the iodoketone moiety in 4d became trans-
formed into dichloroaluminum enolate via intermediate
complex 7. During this reaction, ICl was generated and
reacted with the allenyl group. At this point, addition
of one extra equivalent of ICl increased the yield of
the products. At À78 ꢁC (entries 1–9) and 0 ꢁC (entries
Scheme 2.
Table 1. Iodocarbocyclizations of a-iodocycloalkanones at 0 and À78 ꢁC
Entry
a-Iodo cycloalkanones
Products
Yields at 0 ꢁC (5:6)a,b
Yields at À78 ꢁC (5:6)a,b
I
O
O
O
I
1
83% (1:6)
85% (3:1)
2
I
+
+
4a
5a
6a
6b
I
O
O
O
I
2
3
81% (1:7)
85% (1:9)
84% (4:1)
87% (3:1)
2
I
4b
5b
I
O
O
O
I
2
I
+
4c
5c
6c
I
O
O
O
O
I
4
91% (1:8)
94% (5:1)
3
I
+
4d
5d
6d
I
O
I
O
5
6
91% (1:8)
96% (1:9)
92% (6:1)
93% (6:1)
3
I
+
4e
5e
6e
I
O
I
O
O
3
I
+
4f
5f
6f
I
O
O
O
I
7
72% (2:1)
74% (6:1)
4
I
+
4g
5g
6g
I
I
O
O
O
4
I
8
9
71% (3:1)
75% (2:1)
75% (6:1)
73% (5:1)
+
4h
5h
6h
I
O
O
I
O
4
I
+
4i
5i
6i
a Direct addition of ICl to 4a–i at the double bonds of the allenyl side chains also occurred to give some trace amount (3–5%) of side products.
b Ratio of the products was determined from the 1H NMR spectra of products.

H.-H. Lin et al. / Tetrahedron Letters 47 (2006) 1167–1171
Table 2. Iodocarbocyclizations of a-iodocycloalkanones at 30 ꢁC
1169
Entry
a-Iodo cycloalkanones
Products
Yields at 30 ꢁC (5:6)a,b
I
O
O
O
I
1
67% (1:8)
70% (1:5)
69% (1:7)
4
I
+
4g
5g
6g
I
I
O
O
O
4
I
2
3
+
4h
5h
6h
I
O
I
O
O
4
I
+
4i
5i
6i
a Direct addition of ICl to 4g–i at the double bonds of the allenyl side chains also occurred to give some trace amount (3–5%) of side products.
b Ratio of the products was determined from the 1H NMR spectra of products.
7–9), ICl reacted preferentially at the more electron-rich
inner double bonds of the allenyl side chain to form
intermediate 8 (pathway a). Subsequent cyclization of
8 gave 10. Aqueous workup afforded 5d as the major
product. At the 0 ꢁC (entries 1–6, pathway b), complex
8 equilibrated to the more stable complex 9 with I+
complexing at the terminal double bond. Subsequent
cyclization of 9 gave 11. Aqueous workup afforded 6d
as the major product. Pathway a seems to be a kineti-
cally controlled process, whereas pathway b might be
a thermodynamically controlled reaction. For the for-
mation of the seven-member-ring products (entries 7–
9), reactions at both 0 ꢁC and À78 ꢁC were all kinetically
controlled, and afforded 5g–i as major products. Only
when the temperature of reaction was raised to 30 ꢁC,
the reactions (entries 1–3, Table 2) could become thermo-
dynamically controlled, to give 6g–i as the major
products.
We then tested the reaction with iodocycloalkanones
14a, b6 and 14c9 with a 3-substituted allenyl side chain
(Scheme 4). To our surprise, none of these iodocyclo-
alkanones could cyclize to the desired products. Only
addition of ICl to the allenyl moiety on the side chain
occurred to give compounds 15a–c and 16a–c. Appar-
ently in the reactions of 4a–i (Table 1), cyclization of
dichloroaluminum enolates to iodonium moieties in 8
and 9 (Scheme 3) are faster than the addition of chloride
ion to the iodonium moieties. Only trace amount (3–5%)
of side products formed from the addition of ICl to the
Al
Cl2
O
AlCl3
Cl
.
.
.
.
O
I
AlCl3
ICl
I
7
4d
AlCl3
O+
Cl
I
Cl
Cl
Al
I
path a
H2O
O
5d
10
8
AlCl3
O+
I
Cl
Cl
Cl
path b
Al
I
H2O
6d
O
11
9
Scheme 3.

1170
H.-H. Lin et al. / Tetrahedron Letters 47 (2006) 1167–1171
OTMS
O
1.
I
R1
R1
R2
2. t-BuLi
NaI
m-CPBA
3. CuCN, HMPA
4. TMSCl, Et3N
R2
12a R = H, R = H
13a-c
1
2
12b R = H, R = CH
1
2
3
12c R = CH , R = H
1
3
2
I
O
O
I
O
I
I
R1
R1
R1
AlCl3, ICl
Cl
Cl
+
I
CH2Cl2, 0oC
R2
R2
R2
15a-c
16a-c
14a, 64% (two steps)
14b, 59% (two steps)
14c, 32% (two steps)
15a + 16a, 87% (1 : 1)a
15b + 16b, 86% (1.8 : 1)a
15c + 16c, 81% (2.2 : 1)a
aRatio of the products was determined from the 1H NMR spectra of products.
Scheme 4.
T. Tetrahedron Lett. 1998, 39, 7357; (i) Kitagawa, O.;
Suzuki, T.; Inoue, T.; Watanabe, Y.; Taguchi, T. J. Org.
Chem. 1998, 63, 9470; (j) Kitagawa, O.; Suzuki, T.;
Fujiwara, H.; Taguchi, T. Tetrahedron Lett. 1999, 40,
2549; (k) Kitagawa, O.; Suzuki, T.; Fujiwara, H.; Fujita,
M.; Taguchi, T. Tetrahedron Lett. 1999, 40, 4585; (l)
Kitagawa, O.; Fujiwara, H.; Suzuki, T.; Taguchi, T.; Shiro,
M. J. Org. Chem. 2000, 65, 6819.
allenyl groups was detected (Table 1, entries 1–9). In
the cases of 14a–c, addition of chloride ion to the iodo-
nium moieties became much faster than cyclization and
afforded 15a–c and 16a–c as a mixture of products.
In summary, we have developed a convenient iodocar-
bocyclization reaction of a-iodocycloalkanones bearing
an allenyl side chain. This reaction provides a new
method to prepare spirocyclic ketones 5 and 6 bearing
allylic iodide moieties. Selective formation of either 5
or 6 as the major product is achieved through control-
ling the reaction temperature. Furthermore, this ionic
iodocarbocyclization reaction is complementary to our
photo-cyclization method6 reported earlier. This ionic
cyclization occurred at the central carbon of the allene
group whereas the photo-induced cyclization reacted
at the proximal carbon of the allene group.
2. Toru, T.; Kawai, S.; Ueno, Y. Synlett 1996, 539.
3. (a) Curran, D. P.; Chen, M.-H.; Kim, D. J. Am. Chem. Soc.
1986, 108, 2489; (b) Curran, D. P.; Kim, D. Tetrahedron
Lett. 1986, 27, 5821; (c) Curran, D. P.; Chang, C.-T.
Tetrahedron Lett. 1987, 28, 2477; (d) Curran, D. P.; Chang,
C.-T. J. Org. Chem. 1989, 54, 3140; (e) Curran, D. P.
Synthesis 1988, 417, 489; (f) Jasperse, C. P.; Curran, D. P.;
Fevig, T. L. Chem. Rev. 1991, 91, 1237.
4. (a) Marek, I.; Chakraborty, A. Chem. Commun. 1999, 2375;
(b) Marek, I. J. Chem. Soc., Perkin Trans. 1 1999, 535;
(c) Oshima, K.; Yorimitsu, H.; Nakamura, T.; Shinokubo,
H. J. Org. Chem. 1998, 63, 8604; (d) Curran, D. P.; Chang,
C.-T. Tetrahedron Lett. 1990, 31, 933.
Acknowledgements
5. Sha, C.-K.; Lee, F.-C.; Lin, H.-H. Chem. Commun. 2001,
39.
6. Sha, C.-K.; Lin, H.-H.; Chang, W.-S.; Luo, S.-Y. Org. Lett.
2004, 6, 3289.
7. Sha, C.-K.; Young, J.-J.; Jean, T.-S. J. Org. Chem. 1987, 52,
3919.
We thank the National Science Council for financial
support of this research through the grant NSC93-
2113-M-007-025.
8. A representative procedure for iodocarbocyclization: To a
solution of compound 4a (100 mg, 0.36 mmol) in CH2Cl2
(4.0 mL) was added AlCl3 (70 mg, 0.54 mmol) at À78 ꢁC, or
0 ꢁC, or 30 ꢁC. The mixture was stirred at À78 ꢁC, or 0 ꢁC,
or 30 ꢁC for 15 min. A solution of ICl in CH2Cl2 (1 M,
0.43 mL, 0.43 mmol) was added dropwise at À78 ꢁC, or
0 ꢁC, or 30 ꢁC. The reaction mixture was stirred at À78 ꢁC,
or 0 ꢁC, or 30 ꢁC for 5 min and then quenched with H2O
(20 mL), saturated Na2S2O3 solution (13 mL) and saturated
NaHCO3 solution (13 mL). The mixture was extracted with
EtOAc (15 mL · 3). The combined organic layers were
washed with brine and dried (MgSO4). Concentration and
silica gel column chromatography (EtOAc/hexane = 1:150)
gave products 5a and 6a (80 mg, 83%) as a pale yellow
liquid.
References and notes
1. (a) Kitagawa, O.; Inoue, T.; Taguchi, T. Tetrahedron Lett.
1992, 33, 2167; (b) Kitagawa, O.; Inoue, T.; Hirano, K.;
Taguchi, T. J. Org. Chem. 1993, 58, 3106; (c) Kitagawa, O.;
Inoue, T.; Taguchi, T. Tetrahedron Lett. 1994, 35, 1059; (d)
Inoue, T.; Kitagawa, O.; Kurumizawa, S.; Ochiai, O.;
Taguchi, T. Tetrahedron Lett. 1995, 36, 1479; (e) Inoue, T.;
Kitagawa, O.; Ochiai, O.; Shiro, M.; Taguchi, T. Tetrahe-
dron Lett. 1995, 36, 9333; (f) Inoue, T.; Kitagawa, O.; Oda,
Y.; Taguchi, T. J. Org. Chem. 1996, 61, 8256; (g) Inoue, T.;
Kitagawa, O.; Saito, A.; Taguchi, T. J. Org. Chem. 1997,
62, 7384; (h) Kitagawa, O.; Suzuki, T.; Inoue, T.; Taguchi,

H.-H. Lin et al. / Tetrahedron Letters 47 (2006) 1167–1171
1171
Data for 5a: 1H NMR (600 MHz, CDCl3): 6.46–6.45
(m, 1H), 5.89 (d, J = 1.9 Hz, 1H), 4.08 (t, J = 6.8 Hz,
1H), 2.45–2.02 (m, 3H), 2.02–1.51 (m, 5H), 1.51–1.23 (m,
2H); IR(CHCl3): 2930, 2861, 1703, 1630 cmÀ1; MS (EI)
m/z: 276 (M+, <1), 149 (32), 84 (100), 79 (16), 53 (16);
HRMS (EI) m/z: calcd for C10H13IO: 276.0011, found:
CDCl3): d 220.8 (C), 130.5 (C), 130.3 (CH), 54.3 (C), 48.6
(CH2), 38.0 (CH2), 34.1 (CH2), 29.6 (CH2), 27.8 (CH2), 20.6
(CH2); IR(CHCl3): 2932, 2855, 1705, 1652 cmÀ1; MS (EI)
m/z: 276 (M+, <1), 149 (32), 84 (100), 79 (16), 53 (16);
HRMS (EI) m/z: calcd for C10H13IO: 276.0011, found:
276.0006.
1
276.0022. Data for 6a: H NMR (600 MHz, CDCl3): 5.87
9. Compound 14c was prepared according to the procedure
for the preparation of 14a,b, which was reported in Ref.
6.
(t, J = 6.4 Hz, 1H), 4.16 (s, 2H), 2.58–2.22 (m, 4H), 2.16–
1.74 (m, 4H), 1.74–1.23 (m, 2H); 13C NMR (150 MHz,