BF3-promoted synthesis of spiroindenyl heterocycles

Article abstract of DOI:10.1016/j.tetlet.2010.04.049

An easy and straightforward synthesis of spiroindenyl heterocycles by the repeated treatment of boron trifluoride etherate (BF₃-OEt₂) is reported. The overall transformation from ketones 1 to spiro-fused indenes 3 proceeds via Wittig olefination, deconjugation, Grignard addition, and intramolecular electrophilic cyclization in moderate yields. It presents a novel rearrangement reaction catalyzed by boron trifluoride etherate and broadens the scope of application.

Full text of DOI:10.1016/j.tetlet.2010.04.049

Tetrahedron Letters 51 (2010) 3154–3158
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
BF3-promoted synthesis of spiroindenyl heterocycles
a
a
b
c
Meng-Yang Chang a, , Chung-Han Lin , Yeh-Long Chen , Ru-Ting Hsu , Ching-Yao Chang
*
a Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
b Department of Nursing, ShuZen College of Medicine and Management, Luju, Kaohsiung 821, Taiwan
c Department of Biotechnology, Asia University, Wufeng, Taichung 413, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
An easy and straightforward synthesis of spiroindenyl heterocycles by the repeated treatment of boron
trifluoride etherate (BF3-OEt2) is reported. The overall transformation from ketones 1 to spiro-fused ind-
enes 3 proceeds via Wittig olefination, deconjugation, Grignard addition, and intramolecular electrophilic
cyclization in moderate yields. It presents a novel rearrangement reaction catalyzed by boron trifluoride
etherate and broadens the scope of application.
Received 5 March 2010
Revised 8 April 2010
Accepted 13 April 2010
Available online 18 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Boron trifluoride etherate
Rearrangement
Spiroindenyl heterocycles
1. Introduction
spiroindenyl piperidines have high affinity for r receptors in the
psychotomimetic effects.3a Herein, an easy and novel methodology
for synthesizing spiroindenyl heterocycles with aryl group at C-3
indene framework is described via a BF3-mediated cascade intra-
molecular electrophilic rearrangement of tertiary diaryl alcohol
as the key step in good yields.
Notably, boron trifluoride etherate (BF3-OEt2) has been re-
viewed for reactions involving carbon–carbon or carbon–hetero-
atom bond formations. Due to the numerous advantages
associated with this eco-friendly compound, recent investigations
have explored its applications as an effective reagent for various
reactions. Some representative examples include cycloaddition,
isomerization, unexpected rearrangement reactions, ring contrac-
tion, and ring expansion.1 In previous studies, we investigated
the interesting rearrangement reactions related to BF3-OEt2 in
the context of synthesizing five-, six-, and seven-membered
structural frameworks (pyrrolidine, piperidine, azepane, and ben-
zoisoquinoline).2 To further investigate the synthetic application
of boron trifluoride etherate, a simple strategy for preparing
spiroindenyl heterocycles was developed. The unique spiro-fused
structural features prompted various strategies from synthetic
chemists.3 Most of them are indane, indoline, or dihydrobenzofu-
ran derivatives and were obtained through a number of different
chemical routes related to carbanionic reactions,3a,b free radical
cyclization,3c Heck reaction,3d and Fischer reaction.3e
2. Results and discussion
As shown in Table 1 and Eq. 1, synthesis of spiroindenyl hetero-
cycles is described as follows. b,c-Unsaturated esters 2a–f were
prepared by the two-step protocol: (i) Wittig olefination of
cyclic ketones 1a–f (a, benzenesulfonylpiperidin-4-one; b,
OH
N
N
4a
3a
good selectivity for vesamicol receptor
O
high affinity for the £mreceptors
Indeed, the molecular framework of spiropiperidine has been
used as a core template to design ligands binding to various molec-
ular targets (Fig. 1).4 Efange et al. had identified some spiropiperid-
inyl heterocycles with the conformationally restricted spiro-fused
4-phenylpiperidine framework which have greater selectivity for
the vesamicol receptor.4a Chambers et al. had found that some
O
N
HO
NH2
HN
N
O
O
NH
N
H
4b
4c
* Corresponding author. Tel.: +886 7 3121101x2220; fax: +886 7 3125339.
E-mail addresses: mychang@kmu.edu.tw, mychang624@yahoo.com.tw (M.-Y.
Chang).
growth hormone secretagogues
selective δ opioid receptor agonists
Figure 1. Biologically active spiropiperidines.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.049

M.-Y. Chang et al. / Tetrahedron Letters 51 (2010) 3154–3158
3155
Table 1
Synthesis of spiroindenyl heterocycles 3a,b
Y
CO2Et
Y
O
1) Ph P=CHCO Et, CHCl
1) ArMgBr, THF
3
2
3
(
)
( )
n
(
)
n
n
(Eq. 1)
2) DBU, THF
2) BF -OEt , DCM
3
2
X
X
X
n = 1
X = CH
n = 1
X = CH
3a-3l
2
2
1a, X = NBs 1d, n = 0
2a, X = NBs (70%) 2d, n = 0 (40%)
1b, X = O
1c, X = CH 1f, n = 3
1e, n = 2
2b, X = O (62%)
2c, X = CH (52%) 2f, n = 3 (52%)
2e, n = 2 (48%)
2
2
Entry
Reactant
Grignard reagent
Yield (%)/product
81/3a
1
2a
2a
2a
PhMgBr
N
Bs
OMe
MeO
87/3b
2
3
2-MeOPhMgBr
3-MeOPhMgBr
N
Bs
MeO
5
3
85/3c
7
OMe
N
Bs
MeO
91/3d
4
2a
4-MeOPhMgBr
OMe
N
Bs
75/3e
5
6
2b
2b
PhMgBr
O
MeO
89/3f
4-MeOPhMgBr
OMe
O
63/3g
63/3h
7
8
2c
2c
PhMgBr
OMe
MeO
2-MeOPhMgBr
(continued on next page)

3156
M.-Y. Chang et al. / Tetrahedron Letters 51 (2010) 3154–3158
Table 1 (continued)
Entry
Reactant
Grignard reagent
Yield (%)/product
MeO
82/3i
9
2c
4-MeOPhMgBr
4-MeOPhMgBr
4-MeOPhMgBr
OMe
MeO
52/3j
10
11
2d
2e
OMe
OMe
MeO
43/3k
MeO
40/3l
12
2f
4-MeOPhMgBr
OMe
a
The yields of isolated products 3a–l based on the b,
Each product showed satisfactory NMR and HRMS data.
c
-unsaturated esters 2a–f.
b
tetrahydropyran-4-one; c, cyclohexanone; d, cyclopentanone; e,
cycloheptanone; f, cyclooctanone) with ethyl triphenylphosphor-
anylidene acetate (Ph3P@CHCO2Et) in chloroform at reflux temper-
isomer was not isolated (entry 3). Regarding intermediate C, a pos-
sible reason might be that 7-methoxy group could chelate second-
ary carbocation to generate a five-membered stable conformation
insofar as the chance of a regiospecific ring closure was increased.
In view of the experimental simplicity, the preparation of com-
pound 3a was also conducted in a multigram scale (10 mmol) with
72% overall yield in two steps. With the result in hand, treatment of
compounds 2b–f with the two-step protocol was also afforded un-
der the rearrangement process (entries 5–12). Twelve spiro-fused
ature for 10 h, (ii) deconjugation of the resulting
a,b-unsaturated
esters with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in tetrahy-
drofuran at reflux temperature for 10 h.5 After careful repeated
purification, six compounds 2a–f were isolated from the crude
products with a mixture of nonconjugated and conjugated isomer
in 40–70% yields. For both compounds 2a and 2b, the ratios of non-
conjugated to conjugated isomer were nearly 3/1. For four com-
pounds 2c–f with
a cycloalkane ring, the relative ratios of
nonconjugated to conjugated isomer were from 2/1 to 1/1. Under
various reaction conditions, attempts at a complete deconjugation
of a
,b-unsaturated esters 2 were unsuccessful.5a
Initially, we employed compound 2a as the model substrate to
examine the reaction via Grignard addition with arylmagnesium
bromide reagents (Ar = Ph, 2-MeOPh, 3-MeOPh, 4-MeOPh) in tetra-
hydrofuran in ice bath for 5 h and followed by subsequent BF3-
mediated reaction in dichloromethane at rt for 45 min.6 Notably,
four spiroindenyl piperidines 3a–d were isolated in good yields
by a two-step method (entries 1–4) without the formation of the
expected 4-diarylethylenyl-1,2,3,6-tetrahydropyridine. The char-
acteristic structural framework of compounds 3b and 3d was
determined by single-crystal X-ray analysis.7 The X-ray structure
of compound 3d is shown in Figure 2.
How is skeleton 3 produced? The possible mechanism is de-
scribed as follows (Scheme 1): (a) the initial event may be consid-
ered as the formation of the intermediate A with a stable benzylic
cation, (b) carbocation migration from the resonance form of struc-
ture A and B is generated, (c) a 5-endo-trig cyclization, according to
Baldwin’s rules8 for the ring closure, yields intermediates C, (d)
skeleton 3 is afforded from intermediate D via an intramolecular
1,3-proton shift9 of intermediate C, and followed by aromatization.
Based on the results, we found that the sole compound 3c with 7-
methoxy isomer was obtained in 85% yield and another 5-methoxy
Figure 2. X-ray structure of compound 3d. The unit cell contains solvent (EtOAc),
which is omitted.

M.-Y. Chang et al. / Tetrahedron Letters 51 (2010) 3154–3158
3157
compound 3m and dienyl compound 7 with E- and Z-isomers
(1:1) were yielded. The ratio was determined by 1H NMR analysis.
We thought that the 4-methoxyphenyl group may induce the reg-
ioselective cyclization in the formation of spiro compound 3m.
Although the synthetic application is decreased, this present work
is complementary to existing methodology.
Y
Y
OH
2) BF -OEt
1) ArMgBr
3
2
Y
Y
2
(
)
(
)
n
n
X
X
A
Ar = Ph, 2-MeOPh, 3-MeOPh, 4-MeOPh
3. Conclusion
Y
Y
Y
Y
Y
In summary, we have successfully presented a synthetic meth-
odology for a novel series of spiroindenyl heterocycles 3 which in-
volved BF3-promoted intramolecular electrophilic cyclization. The
novel strategy showed that boron trifluoride etherate is an excel-
lent Lewis acid to promote the formation of a spiroindene system
with.
3
Y
H
H
(
)
n
(
)
( )
n
n
X
X
X
B
C
D
Scheme 1. The possible rearrangement mechanism.
Acknowledgments
spiroindenyl products 3a–l were provided after separation in 40–
91% yield from compounds 2a–f.
The authors would like to thank the National Science Council of
the Republic of China for its financial support. The project is also
supported by a grant from the Kaohsiung Medical Research Foun-
dation (KMU-Q099003).
Under similar reaction conditions, attempts at two-step cycliza-
tion reaction of
a,b-unsaturated ester 4a were unsuccessful and
the structure of 4-diarylethylenyl-1,2,3,6-tetrahydropyridine was
generated. This is an interesting result. Treatment of compound
4a with electron-donating group (Ar = 4-MeOPh) or electron-with-
drawing group (Ar = 4-FPh) and then followed by subsequent bor-
on trifluoride etherate yielded diene 5a or 5b in 52% or 61% yield,
respectively. The possible mechanism is described in Scheme 2.
The initial event may be considered to be the formation of the
intermediate I. After double bond migration and proton abstrac-
tion, diene 5 is generated. It is worth noting that skeleton 2 was
more appropriate for this role in preference to spiro skeleton 3
than skeleton 4 due to its endo olefin group, which would ulti-
mately facilitate the possibility of intramolecular cyclization under
the reaction condition.
During the further investigation, the temperature of BF3-pro-
moted reaction was examined (Scheme 3). Under reflux tempera-
ture, reaction of the tertiary alcohol (from Grignard reaction of
ketone 6) with boron trifluoride etherate produced the rearranged
and dehydrated products. When Ar was a 4-methoxyphenyl group,
products 3d and 5a were isolated in 85% yield as the inseparated
mixture. When Ar was a phenyl group, a mixture of a sole
References and notes
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Y
Y
CO2Et
1) ArMgBr
H
2) BF -OEt
3
2
Y
Y
N
N
N
Bs
Bs
Bs
I
4a
5a, Y = MeO (52%)
5b, Y = F (61%)
Ar = 4-MeOPh, 4-FPh
Scheme 2. The possible dehydration mechanism.
Y
Y
O
OMe
+
1) ArMgBr
5. (a) Wu, J.; Li, D.; Wu, H.; Sun, L.; Dai, W.-M. Tetrahedron 2006, 62, 4643; (b) Dai,
W.-M.; Lau, C. W. Tetrahedron Lett. 2001, 42, 2541.
OMe
OMe
2) BF -OEt ,
reflux
Ar = 4-MeOPh, Ph
3
2
N
Bs
N
Bs
N
Bs
6.
A
representative procedure of skeleton
arylmagnesium bromide (3.0 mmol) in tetrahydrofuran (10 mL) was added to
a stirred solution of b,
-unsaturated esters 2a–f (1.0 mmol) in tetrahydrofuran
3 is as follows: A solution of
c
6
3d, Y = MeO
3m, Y = H
5a, Y = MeO
7, Y= H (E/Z = 1/1)
(20 mL) in an ice bath. The reaction mixture was stirred at rt for 5 h. Water
(5 mL) was added to the reaction mixture and the mixture was filtered through
a short plug of Celite. The filtrate was concentrated under reduced pressure. The
Scheme 3. BF3-promoted rearrangement/dehydration reaction.

3158
M.-Y. Chang et al. / Tetrahedron Letters 51 (2010) 3154–3158
residue was extracted with ethyl acetate (3 Â 50 mL). The combined organic
J = 4.4, 14.0 Hz, 2H), 1.51 (d, J = 14.0 Hz, 2H); 13C NMR (100 MHz): d 152.00,
143.83, 141.74, 136.36, 135.58, 135.31, 132.85, 129.15 (2Â), 128.56 (2Â),
127.95, 127.64 (2Â), 127.57 (2Â), 127.20, 125.95, 121.96, 120.97, 49.82, 44.98
(2Â), 33.33 (2Â); Anal. Calcd for C25H23NO2S: C, 74.78; H, 5.77; N, 3.49. Found:
C, 74.94; H, 5.89; N, 3.61.
layers were washed with brine, dried, filtered, and evaporated to afford crude
product under reduced pressure. Without further purification, a solution of
boron trifluoride etherate (1 mL) in dichloromethane (5 mL) was added to a
stirred solution of the crude product in dichloromethane (50 mL) at 0 °C. The
reaction mixture was stirred at rt for 45 min. Saturated sodium bicarbonate
solution (10 mL) was added to the reaction mixture and the solvent was
concentrated under reduced pressure. The residue was extracted with ethyl
acetate (3 Â 30 mL). The combined organic layers were washed with brine,
dried, filtered, and evaporated to afford crude product under reduced pressure.
Purification on silica gel (hexane/ethyl acetate = 8/1:4/1) afforded compounds
3a–l. Representative data for compound 3a: mp = 190–191 °C; HRMS (ESI,
M++1) calcd for C25H24NO2S 402.5295, found 402.5298; 1H NMR (400 MHz): d
7.87–7.84 (m, 2H), 7.69–7.57 (m, 3H), 7.51–7.47 (m, 3H), 7.43–7.27 (m, 6H),
6.52 (s, 1H), 3.97 (dt, J = 2.8, 12.4 Hz, 2H), 2.72 (dt, J = 2.8, 12.4 Hz, 2H), 2.30 (dt,
7. CCDC 772318 (3b) and 762275 (3d) contain the supplementary crystallographic
data for this paper. This data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033; e-mail: deposit@ccdc.
cam.ac.uk).
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