Construction of the bicyclo[3.3.1]nonenone core by successive Michael reactions of 2-cyclohexenone derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.08.068

Construction of the bicyclo[3.3.1]nonenone core was achieved by stepwise annulation of 2-cyclohexenone derivatives and acrylates via successive Michael reactions. The process could also be effected by a one-pot procedure.

Full text of DOI:10.1016/j.tetlet.2004.08.068

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7401–7405
Construction of the bicyclo[3.3.1]nonenone core by successive
Michael reactions of 2-cyclohexenone derivatives
Ryukichi Takagi,* Takashi Nerio, Yukiko Miwa, Shuji Matsumura and Katsuo Ohkata*
Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526, Japan
Received 28 July 2004; revised 6 August 2004; accepted 13 August 2004
Abstract—Construction of the bicyclo[3.3.1]nonenone core was achieved by stepwise annulation of 2-cyclohexenone derivatives and
acrylates via successive Michael reactions. The process could also be effected by a one-pot procedure.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The bicyclo[3.3.1]nonane skeleton is often found in bio-
O
O
logically active natural products such as Garsubellin A
(Fig. 1).1 Therefore, many types of synthetic methods
for bicyclo[3.3.1]nonane derivatives have been re-
ported.2,3 They have also found use as synthetic interme-
diates for other ring systems.4 Recently, polycyclic
polyprenylated acylphloroglucinols featuring a highly
oxygenated and densely substituted bicyclo[3.3.1]non-
ane-2,4,9-trione core, have attracted attention as targets
for organic synthesis.5 Herein the construction of the
bicyclo[3.3.1]nonenone core by stepwise and one-pot
annulation of 2-cyclohexenone derivatives with acrylates
via successive Michael reactions is described.
CO2R
º
LDA, THF, -78 C
CO2R
OAc
2a-c
3a-c
1
3a: 50%
3b: 55%
3c: 74%
O
O
4
5
6
3
RO2C
RO2C
1
7
K2CO3, TBAB
solvent
8
2
4a-c
5a-c
O
8
1
5
2
a: R = Et
The stepwise annulation of 2-methyl-2-cyclohexenone 1
with acrylates 2a–c6 via successive Michael reactions
was examined (Scheme 1). Annulation precursors 3a–c
7
b: R = PhCH2CH2
c: R = t-Bu
PhCH2CH2O2C
3
6
4
6b
Scheme 1.
OH
H
O
O
were obtained by the intermolecular Michael reaction
of 1 with acrylates 2a–c, respectively (3a: 50%, 3b:
55%, 3c: 74%). The intramolecular Michael reaction of
3a–c was performed under solid–liquid phase transfer
conditions: a solution of the annulation precursors 3a–
c was stirred in the presence of K2CO3 as the base and
tetrabutylammonium bromide (TBAB) as the phase
transfer catalyst.7 Upon treating annulation precursor
3a with K2CO3 (3.0equiv) and TBAB (1.0equiv) (Table
1, entry 1), annulation proceeded at the a0-position of
the carbonyl group with accompanied migration of the
double bond to give a,a0-annulation products 4a and
5a (4a: 67%, 5a: 4%). The relative stereochemistry of
H
O
O
Garsubellin A
Figure 1.
Keywords: One-pot reaction; Bicyclo[3.3.1]nonenone; Successive Mic-
hael reaction.
*
Corresponding authors. Tel.: +81 82 424 7432; fax: +81 82 424
0747; e-mail addresses: rtakagi@hiroshima-u.ac.jp; ohkata@sci.
hiroshima-u.ac.jp
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.068

7402
R. Takagi et al. / Tetrahedron Letters 45 (2004) 7401–7405
Table 1. Stepwise annulation between 1 and 2a–c
Entry
1
Subst.
K2CO3 (equiv)
3.0
TBAB (equiv)
1.0
Solvent
Toluene
Conditions
Producta
3a
80ꢁC, 30h
4a: 67%
5a: 4%
2
3
4
3a
3b
3b
1.2
2.0
2.0
0.2
0.1
1.0
Toluene
Toluene
THF
70ꢁC, 28h
80ꢁC, 91h
90ꢁC, 115h
4a: 59%
5a: 13%
4b: 36%
5b: 29%
4b: 35%
5b: 23%
6b: 3%
5
6
3b
3c
3.0
2.0
1.0
1.0
EtOH
THF
90ꢁC, 3h
90ꢁC, 31h
4a: 10%
4c: 71%
5c: 8%
a Isolated yield.
4a and 5a was assigned by the coupling constant
O
3
3JH7,H8exo in 1H NMR: 4a: JH7,H8exo = 6.1Hz; 5a:
CO2R
method A or B
3JH7,H8exo = 12.8Hz.8 The amount of base did not affect
the ratio of 4a and 5a to a large extent (K2CO3:
1.2equiv, TBAB: 0.2equiv, 4a: 59%, 5a: 13%, Table 1,
entry 2). The annulation of phenylethyl ester 3b in some
solvents was next examined (Table 1, entries 3–5). The
annulation of 3b in both toluene and THF gave bicyclic
compounds 4b and 5b with the same tendency (Table 1,
entries 3 and 4, 4b:5b = ca. 3:2). In the annulation of 3b,
a small amount of PhCH2CH2OH was obtained as a
consequence of slight decomposition. Isomerization
studies between 4b and 5b indicated that 5b was the
thermodynamically favored product: the bicyclic com-
pounds 4b and 5b were heated separately under the
stepwise annulation conditions for 9days. Although 5b
did not isomerize to 4b at all (4b:5b = 0:100), 4b isomer-
ized somewhat to 5b (4b:5b = 85:15). When THF was
used as the solvent, bicyclic compound 6b, an a,c-annul-
ation product, was also obtained (3%). The annulation
of 3b in EtOH gave bicyclic compound 4a, generated
by ester exchange, in low yield (10%, Table 1, entry 5).
It is considered that the moderate yields (61–72%, Table
1, entries 1–4) arise from decomposition of the ester
group. Treatment of 3c with K2CO3 (2.0equiv) and
TBAB (1.0equiv) gave the best results (4c: 71%, 5c:
8%, Table 1, entry 6).9
OAc
+
2a-c
a: R = Et
b: R = PhCH2CH2
c: R = t-Bu
1
O
O
O
RO2C
EtO2C
RO2C
RO2C
5a-c
4a-c
CO2Et
O
6b,c
7
Scheme 2.
situ by treatment of 1 with LDA, followed by acrylates
2b and 2c, respectively. To the reaction mixture were
added K2CO3 and TBAB, and the mixture was heated
(method B, Table 2, entries 2–4).10 With method B,
the a,a0-annulation products 4b,c and 5b,c were
obtained in moderate yields along with a small amount
of a,c-annulation products 6b,c. In contrast with the
stepwise annulation, the thermodynamically favored
a,a0-annulation products 5b,c were obtained as the
major isomer in the one-pot annulation. The basic species
(diisopropylamine, AcOLi) generated in situ in the
one-pot reaction may effect to isomerization between
4b,c and 5b,c.
Since the stepwise annulation of 2-methyl-2-cyclohex-
enone 1 with acrylates 2a–c proceeded sufficiently, one-
pot annulation via successive Michael reactions between
2-methyl-2-cyclohexenone 1 and acrylates 2a–c (Scheme
2) was subsequently investigated. First, the one-pot
annulation of 1 with 2a by a one operation process
was examined (method A): a mixture of 1, 2a, K2CO3
and TBAB was heated at 80ꢁC for 42h in toluene. As
a result, three bicyclic compounds 4a, 5a, and 7 were
obtained (4a: 2%, 5a: 2%, 7: 15%, Table 2, entry 1).
The bicyclic compound 7 most likely formed by Michael
reaction of the annulation precursor 3a with another
molecule of acrylate 2a at the a-position, prior to the
intramolecular ring-closing Michael reaction. To avoid
the generation of annulation products such as 7, a
one-pot annulation by two operations was examined:
the annulation precursors 3b and 3c were generated in
Next, the stepwise annulation of some di-substituted 2-
cyclohexenones 8–10 with acrylates 2a–c was examined
(Scheme 3)7 and the results are summarized in Table
3. The annulation precursors 11a–c, 12, and 13 were
obtained by the Michael reaction of 8–10 with acrylates
2a–c. Treatment of 11a–c and 12 with K2CO3 and
TBAB gave a,a0-annulation products 14a–c and 17 as
the major isomer, respectively (Table 3, entries 1–4).
Annulation of 11c and 12 gave rise to single products.
When 3-ethoxy-6-ethoxycarbonyl derivative 13 was used

R. Takagi et al. / Tetrahedron Letters 45 (2004) 7401–7405
Table 2. One-pot annulation between 1 and 2a–c
7403
Entry
1
Acrylate
Methoda
K2CO3 (equiv)
3.0
TBAB (equiv)
1.0
Conditions
Productb
2a
A
80ꢁC, 42h
4a: 2%
5a: 2%
7: 15%
4b: 6%
5b: 12%
4b: 9%
5b: 20%
6b: 2%
4c: 16%
5c: 28%
6c: 7%
2
3
2b
2b
B
B
1.6
2.0
0.02
1.0
80ꢁC, 24h
80ꢁC, 40h
4
2c
B
3.0
1.0
90ꢁC, 18h
a Method A: 1, 2a, K2CO3, TBAB, toluene. Method B: (1) 1, LDA, THF, ꢀ78ꢁC then 2, ꢀ78ꢁC to rt. (2) K2CO3, TBAB.
b Isolated yield.
as the substrate, a,c-annulation product 20 was
obtained as the major product (Table 3, entry 5).
O
O
O
CO2Et
CO2R
Table 4 summarizes the one-pot annulation between the
cyclohexenone derivatives 8–10 and acrylates 2a–c
(Scheme 4). One-pot annulation of 8 in a one operation
process (method A) proceeded in low yield to give ann-
ulation products 14a and 21, via successive Michael
reactions (Table 4, entry 1). The one-pot annulation of
8 in two operations (method B)10 gave annulation prod-
ucts with a higher ratio of the thermodynamically more
stable 15b and 15c compared with the stepwise protocol
(Table 4, entries 2 and 3). In the case of the reaction of
10 with 2c, the ratios were similar with those of stepwise
reactions (Table 4, entry 5).
EtO
EtO
O
8
9
10
R3
R2
R1
LDA, THF, -78 ºC
8-10
CO2R
OAc
11a-c, 12, 13
11a: 50%
11b: 56%
11c: 83%
2a-c
12: 41%
13: 66%
O
O
R3
R3
In summary, the construction of the bicyclo[3.3.1]non-
enone core was achieved by the stepwise annulation of
2-cyclohexenones 1, 8, 9 and 10 with acrylates 2a–c via
successive Michael reactions. The annulation precursors
3a–c, 11a–c, 12, and 13 reacted via the thermodynami-
cally more stable enolate to furnish the bicyclo[3.3.1]-
nonenone core by a0-annulation of the enolate. The
annulation could also be carried out in a one-pot reac-
tion to give the bicyclo[3.3.1]nonenone derivatives with
the same tendency. Although bicyclic compounds are
usually constructed via enamine derivatives of cyclic
ketone, this reported procedure affords the
bicyclo[3.3.1]nonenone derivatives directly from the
cyclohexenone derivatives.
RO2C
R2
RO2C
R2
15a-c, 19
R1
R1
K2CO3, TBAB
14a-c, 17, 18
solvent
1O
R
a: R = Et
b: R = PhCH2CH2
c: R = t-Bu
R3
RO2C
R2
16a,b , 20
11a-c, 14a-c, 15a-c, 16a,b: R1 = H, R2 = Me, R3 = Me
12, 17: R = PhCH2CH2, R1 = OEt, R2 = Me, R3 = H
13, 18, 19, 20: R = t-Bu, R1= OEt, R2 = H, R3 = CO2Et
Scheme 3.
Table 3. Stepwise annulation between 8–10 and 2a–c
Entry
1
Subst.
K2CO3 (equiv)
3.0
TBAB (equiv)
1.0
Solvent
Toluene
Conditions
Producta
11a
80ꢁC, 6h
14a: 65%
15a: 13%
16a: 4%
2
11b
2.0
1.0
Toluene
90ꢁC, 9h
14b: 49%
15b: 13%
16b: 6%
3
4
5
11c
12
3.0
2.0
3.0
1.0
1.0
1.0
THF
Toluene
THF
90ꢁC, 23h
80ꢁC, 54h
80ꢁC, 24h
14c: 91%
17: 41%
18, 19: 17%b,c
20: 48%
13
a Isolated yield.
b Purification by preparative TLC gave a mixture of diastereomers.
c The ratio of 18 and 19 was 10:7 according to the 1H NMR.

7404
R. Takagi et al. / Tetrahedron Letters 45 (2004) 7401–7405
Table 4. One-pot annulation between 8–10 and 2a–c
Entry
1
Subst.
Acrylate
Methoda
A
K2CO3 (equiv)
3.0
TBAB (equiv)
1.0
Conditions
Productb
8
2a
80ꢁC, 42h
14a: 5%
21: 12%
2
3
8
8
2b
2c
B
B
3.0
3.0
1.0
1.0
80ꢁC, 47h
14b: 29%
15b: 16%
16b: 15%
14c: 34%
15c: 32%
16c: 4%
90ꢁC, 18h
4
5
9
10
2b
2c
B
B
3.0
3.0
1.0
1.0
80ꢁC, 13h
80ꢁC, 25h
17: 17%
18, 19: 31%c,d
20: 35%
a Method A: 8, 2a, K2CO3, TBAB, toluene. Method B: (1) substrate (8, 9, or 10), LDA, THF, ꢀ78ꢁC then 2, ꢀ78ꢁC to rt. (2) K2CO3, TBAB.
b Isolated yield.
c Purification by preparative TLC gave a mixture of diastereomers.
d The ratio of 18 and 19 was 25:6 according to the 1H NMR.
Okamura, M.; Iwagawa, T.; Doe, M. J. Nat. Prod. 2001,
64, 1261; (d) Weng, J.-R.; Lin, C.-N.; Tsao, L.-T.; Wang,
O
R3
+
R2
R1
CO2R
OAc
method A or B
ˇ
J.-P. Chem. Eur. J. 2003, 9, 1958; (e) Savikin-Fodulovic,
´
K.; Aljancic, I.; Vajs, V.; Menkovic, N.; Macura, S.;
ˇ ´
´
2a-c
´
´
Gojgic, G.; Milosavljevic, S. J. Nat. Prod. 2003, 66, 1236;
(f) Hua, Y.; Liu, H.-Y.; Ni, W.; Chen, C.-X.; Lu, Y.;
Wang, C.; Zheng, Q.-T. J. Nat. Prod. 2003, 66, 898; (g)
Lin, Y.-L.; Wu, Y.-S. Helv. Chim. Acta 2003, 86, 2156; (h)
Wu, J.; Zhang, S.; Xiao, Q.; Li, Q.; Huang, J.; Long, L.;
Huang, L. Tetrahedron Lett. 2004, 45, 591; (i) Stierle, D.
B.; Stierle, A. A.; Hobbs, J. D.; Stokken, J.; Clardy J. Org.
Lett. 2004, 6, 1049.
8-10
a: R = Et
b: R = PhCH2CH2
c: R = t-Bu
O
O
R3
R3
RO2C
RO2C
2. For reviews: (a) Peters, J. A. Synthesis 1979, 321; (b)
Butkus, E. Synlett 2001, 1827.
R2
R2
R1
R1
14a-c, 17, 18
15a-c, 19
O
´
3. (a) Barluenga, J.; Ballesteros, A.; Santamarıa, J.; de la
Ru´a, R. B.; Rubio, E.; Tomas, M. J. Am. Chem. Soc.
´
1O
R
2000, 122, 12874; (b) Byeon, C.-H.; Hart, D. J.; Lai, C.-S.;
´
EtO2C
R3
Unch, J. Synlett 2000, 119; (c) Camps, P.; Gonzalez, A.;
RO2C
EtO2C
Mun˜oz-Torrero, D.; Simon, M.; Zu´n˜iga, A.; Martins, M.
A.; Font-Bardia, M.; Solans, X. Tetrahedron 2000, 56,
8141; (d) Yang, J.-D.; Kim, M.-S.; Lee, M.; Baik, W.;
Koo, S. Synthesis 2000, 801; (e) Klaic, L.; Velkovic, J.;
Mlinaric-Majerski, K. Synth. Commun. 2002, 32, 89; (f)
Simon, C.; Peyronel, J.-F.; Clerc, F.; Rodriguez. J. Eur. J.
Org. Chem. 2002, 3359; (g) Barluenga, J.; Ballesteros, A.;
R2
16b,c, 20
21
8, 14a-c, 15a-c, 16b,c: R1 = H, R2 = Me, R3 = Me
9, 17: R = PhCH2CH2, R1 = OEt, R2 = Me, R3 = H
10, 18, 19, 20: R = t-Bu, R1 = OEt, R2 = H, R3 = CO2Et
Scheme 4.
´
de la Ru´a, R. B.; Santamarıa, J.; Rubio, E.; Tomas, M.
J. Am. Chem. Soc. 2003, 125, 1869.
´
4. (a) Miesch, M.; Mislin, G.; Franck-Neumann, M. Synlett
1996, 385; (b) Momose, T.; Toshima, M.; Seki, S.; Koike,
Y.; Toyooka, N.; Hirai, Y. J. Chem. Soc., Perkin Trans. 1
1997, 1315; (c) Geirsson, J. K. F.; Eiriksdottir, E. G.
Synlett 2001, 664; (d) Gambacorta, A.; Tofani, D.;
Lupattelli, P.; Tafi, A. Tetrahedron Lett. 2002, 43, 2195.
5. (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Kim, S.; Wei, H. X.
J. Am. Chem. Soc. 1999, 121, 4724; (b) Nicolaou, K. C.;
Pfefferkorn, J. A.; Cao, G.-Q.; Kim, S.; Kessabi, J. Org.
Lett. 1999, 1, 807; (c) Young, D. G. J.; Zeng, D. J. Org.
Chem. 2002, 67, 3134; (d) Spessard, S. J.; Stoltz, B. M.
Org. Lett. 2002, 4, 1943; (e) Usuda, H.; Kanai, M.;
Shibasaki, M. Org. Lett. 2002, 4, 859; (f) Usuda, H.;
Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2002, 43,
3621; (g) Ciochina, R.; Grossman, R. B. Org. Lett. 2003,
5, 4619; (h) Kras, G. A.; Nguyen, T.; Jeon, I. Tetrahederon
Lett. 2003, 44, 659; (i) Klein, A.; Miesch, M. Tetrahederon
Lett. 2003, 44, 4483; (j) Mehta, G.; Bera, M. K. Tetrahe-
dron Lett. 2004, 45, 1113.
Acknowledgements
NMR and MS measurements were made using JEOL
JMN-LA500 and JEOL SX-102A, respectively, at the
Natural Science Center for Basic Research and Develop-
ment (N-BARD), Hiroshima University. We thank Dr.
Yoshikazu Hiraga for NMR measurements (JEOL
JMN-LA500) at the Hiroshima Prefectural Institute of
Science and Technology. We thank Dr. Satoshi Kojima
for prereading the manuscript.
References and notes
1. For some recent reports on natural products bearing
a bicyclo[3.3.1]nonanone core: (a) Cuesta-Rubio, O.;
Padron, A.; Castro, H. V.; Pizza, C.; Rastrelli, L. J. Nat.
Prod. 2001, 64, 973; (b) Winkelmann, K.; Heilmann, J.;
Zerbe, O.; Rali, T.; Sticher, O. J. Nat. Prod. 2001, 64, 701;
(c) Nakatani, M.; Abdelgaleil, S. A. M.; Kurawaki, J.;
6. Villie´ras, J.; Rambaud, M. Synthesis 1982, 9, 924.
7. Typical procedure for the stepwise annulation: To a
solution of 3c (93.6mg, 0.37mmol) in THF (2.0mL) were

R. Takagi et al. / Tetrahedron Letters 45 (2004) 7401–7405
7405
added K2CO3 (103.5mg, 0.75mmol) and TBAB (120.9mg,
0.38mmol). The mixture was stirred at 90ꢁC for 31h.
After complete consumption of 3c by GC monitoring, the
mixture was cooled to rt and quenched with 1N HCl. The
resulting mixture was extracted with ether. The combined
organic layer was washed with H2O, brine, dried over
MgSO4, filtered, and evaporated. The resulting residue
was purified by preparative TLC (silica gel, hexane/
EtOAc = 10/1) to give annulation products 4c and 5c
(4c: 71%, 5c: 8%, Table 1, entry 6).
H4exo); 2.66–2.70 (m, 1H, H5), 2.72–2.80 (m, 1H, H4endo),
3.02 (tt, J = 4.6, 12.8Hz, 1H, H7), 5.35 (ddd, J = 1.4, 2.4,
9.4Hz, 1H, H2), 5.90 (dt, J = 3.6, 9.4Hz, 1H, H3); 13C
NMR (125MHz, CDCl3) d 21.1 (1-CH3), 28.0 (·3,
C(CH3)3), 36.9 (C7), 37.7 (C4), 38.5 (C6), 43.1 (C8), 44.3
(C5), 46.0 (C1), 80.6 (C(CH3)3), 129.1 (C3), 133.3 (C2),
173.9 (CO2), 215.4 (CO); HRMS (EI) Calcd for C15H22O3
[M+] 250.1569. Found 250.1570; Anal. Calcd for
C15H22O3: C, 71.97; H, 8.86. Found: C, 72.02; H,
8.88.
8. The coupling constants (2.1–2.5Hz) between H6exo and
H4exo were observed in the H NMR of 14a–c and 15a–c.
10. Typical procedure for one-pot annulation (method B): To
a
1
solution of LDA [diisopropylamine (0.08mL,
The long range couplings indicate the preferred conformer
of six-membered ring in the bicyclo[3.3.1]nonenone core.
9. (a) Spectral data of 4c: 1H NMR (500MHz, CDCl3) d 1.08
(s, 3H, 1-CH3), 1.47 (s, 9H, C(CH3)3), 1.81 (dd, J = 6.4,
14.0Hz, 1H, H8exo), 1.99–2.08 (m, 1H, H6exo), 2.52 (tt,
J = 1.7, 7.0Hz, 1H, H4exo), 2.59–2.65 (m, 3H, H5, H7,
H8endo), 2.74–2.81 (m, 2H, H4endo, H6endo), 5.30 (ddd,
J = 1.1, 1.7, 9.4Hz, 1H, H2), 5.59–5.64 (m, 1H, H3); 13C
NMR (125MHz, CDCl3) d 21.3 (1-CH3), 28.0 (·3,
C(CH3)3), 34.8 (C6), 36.3 (C4), 37.7 (C7), 41.5 (C8), 44.9
(C5), 46.3 (C1), 80.7 (C(CH3)3), 128.6 (C3), 133.5 (C2),
173.0 (CO2), 216.3 (CO); HRMS (EI) calcd for C15H22O3
[M+] 250.1569. Found 250.1577; Anal. Calcd for
C15H22O3: C, 71.97; H, 8.86. Found: C, 72.16; H, 8.65.
(b) Spectral data of 5c: 1H NMR (500MHz, CDCl3) d 1.10
(s, 3H, 1-CH3), 1.43 (s, 9H, C(CH3)3), 1.73 (t, J = 12.8Hz,
1H, H8exo), 1.96–2.04 (m, 2H, H8endo, H6exo), 2.09–2.15
(m, 1H, H6endo), 2.47 (ddd, J = 1.4, 3.6, 18.6Hz, 1H,
0.58mmol), n-BuLi (1.56M in THF, 0.31mL, 0.48mmol),
THF, 0ꢁC, 30min] was added a solution of 8 (50.2mg,
0.40mmol) in THF (0.5mL) at ꢀ78ꢁC. The reaction
mixture was stirred at ꢀ78ꢁC for 30min. Then, a solution
of acrylate 2c (81.2mg, 0.48mmol) in THF (0.5mL) was
added to the mixture at ꢀ78ꢁC. After the reaction mixture
was allowed to warm to rt over 6h, to the reaction mixture
was added K2CO3 (167.7mg, 1.21mmol) and TBAB
(130.9mg, 0.41mmol). The mixture was stirred at 90ꢁC
for 18h. After complete consumption of 3c by GC
monitoring, the mixture was cooled to rt and quenched
with 1N HCl. The resulting mixture was extracted with
ether. The combined organic layer was washed with H2O,
brine, dried over MgSO4, filtered, and evaporated. The
resulting residue was purified by preparative TLC (silica
gel, hexane/EtOAc = 10/1) to give annulation products
14c, 15c and 16c (14c: 34%, 15c: 32%, 16c: 4%, Table 4,
entry 3).