Synthesis of novel piperidyl spirofused benzofurans/benzopyrans by radical cyclization

Article abstract of DOI:10.1002/jhet.630

Several new piperidyl spirofused benzofurans and piperidyl spirofused benzopyrans were synthesized via an intramolecular radical cyclization as the key step. It was found that the yield of the formation of five-member ring was much higher than that of six

Full text of DOI:10.1002/jhet.630

1238
Synthesis of Novel Piperidyl Spirofused Benzofurans/
Benzopyrans by Radical Cyclization
Vol 48
Zilong Tang,a,b* Joelle Mayrargue,b and Mouad Alamib
aSchool of Chemistry and Chemical Engineering, Hunan University of Science and Technology,
Xiangtan 411201, People’s Republic of China
bDepartment of Chemistry, Faculty of Pharmacy, University of Paris-Sud, Chatenay-Malabry,
Cedex, France
*E-mail: zltang67@yahoo.com.cn
Received March 31, 2010
DOI 10.1002/jhet.630
Published online 19 July 2011 in Wiley Online Library (wileyonlinelibrary.com).
Several new piperidyl spirofused benzofurans and piperidyl spirofused benzopyrans were synthesized
via an intramolecular radical cyclization as the key step. It was found that the yield of the formation of
five-member ring was much higher than that of six-member ring. In addition, the substituent attached to
the benzene ring had almost no effect on the cyclization.
J. Heterocyclic Chem., 48, 1238 (2011).
INTRODUCTION
RESULTS AND DISCUSSION
In 1994, the fourth opioid receptor, opioid receptor-like
1 (ORL1), was discovered by homology cloning [1]. Sub-
sequently, nociceptin, also named orphanin FQ (NC/OFQ),
is a peptide consisting of 17-amino acids and was identified
as an endogenous ligand for ORL1 in 1995 [2]. Pharmaco-
logical studies using NC/OFQ and ORL1-deficient mice
showed that the NC/OFQ-ORL1 system might play impor-
tant roles in pain regulation [3], learning and memory [4],
food intake [5], anxiety [6], cardiovascular system [7], and
locomotor activity [8]. These results prompted many indus-
trial and academic researches to identify small molecules
as potent and selective ORL1 agonists and antagonists [9].
Various structural classes of nonpeptide ligands for
ORL1 have been reported [9c–9f], such as morphinan-
based ligands, benzimidazopiperidines, spiropiperidines,
aryl piperidines, and aminoquinolines. However, the de-
velopment of new ORL1 ligands with high selectivity
and bioavailability still remains an important challenge,
especially for the extensive elucidation and control of
the physiological role of the ORL1. Herein, we present
the synthesis of new piperidyl spirofused benzofurans
and piperidyl spirofused benzopyrans (Fig. 1) aiming at
the development of new ORL1 ligands.
The synthetic sequence for the new piperidyl spiro-
fused benzofurans (benzopyrans) is outlined in Scheme
1. The preparation of the important intermediates 8 and
12 from substituted phenol 4 and pyridylalkyl alcohols 5
or 9 via three steps was previously reported from our
laboratory [10]. Initially, Mitsunobu reaction of 4 and 5
or 9 gave pyridine derivatives 6 and 10, respectively.
Subsequent alkylation of compounds 6 and 10 followed
by reduction with sodium borohydride afforded inter-
mediates 8 and 12. But, during the reduction of pyridin-
ium salt 7a (n ¼ 1), a decoupling reaction encountered
and the reaction gave 8a in only 10% yield with substi-
tuted phenol 4a as the major product. Fortunately,
reduction of salts 8b and 12 gave the desired products
in moderate to good yields. Hence, to avoid the above
mentioned decoupling reaction, in this text, we describe
a new sequence for the preparation of intermediates 8a
and 12 as shown in Scheme 2. Compounds 15 and 16
were obtained smoothly in 83% and 90% yields by
reduction of the corresponding pyridinium salts 13 and
14 resulted from alkylation of pyridylalkyl alcohols 5
and 9, respectively [10]. Subsequent Mitsunobu reac-
tions of 15, 16 with substituted phenol 4 were effected
C
V
2011 HeteroCorporation

November 2011
Synthesis of Novel Piperidyl Spirofused Benzofurans/Benzopyrans by
Radical Cyclization
1239
Figure 1. New piperidyl spirofused benzofurans/benzopyrans.
in the presence of PPh3 and diethyl azodicarboxlate
(DEAD) in dichloromethane at room temperature giving
8a and 12 in 37–70% yields.
Finally, the cyclization of intermediates 8, 12 to the
title products would be achieved by free radical reaction
with tributyltin hydide (Bu3SnH) [11]. The reaction was
ignited by azodiisobutyronitrile (AIBN, initiator) to pro-
duce the target compounds 1a, 2a, 3a–b [12] in 39–85%
yields (Scheme 1; Table 1). It can be clearly seen from
the table, the reaction gave the five-member ring (n ¼ 1)
product in much higher yield than that of the six-member
ring (n ¼ 2) (entry 1 vs entry 2). Moreover, we observed
that the free radical reaction of 8b (n ¼ 2) was slower
than 8a (n ¼ 1), and not completed at the same condition.
In addition, the R group attached to the benzene ring had
almost no effect on the cyclization (entry 3 vs entry 4).
It should be further noted that the final products were
usually contaminated by tin derivative, which made the
Scheme 1. Synthesis of piperidyl spirofused benzofurans (benzopyrans) 1, 2, and 3.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1240
Z. Tang, J. Mayrargue, and M. Alami
Vol 48
Scheme 2. Synthesis of 8a and 12.
purification very difficult. We found an effective work-up
process for the purification by initially eliminating the tin
derivative. This needed to form the corresponding salts of
the spirofused piperidines by adding HCl to ethyl acetate
solution of the crude products. Afterwards, the separated
aqueous layer was neutralized with saturated Na2CO3 so-
lution and extracted with dichloromethane.
ring. In addition, the R group attached to the benzene ring
had almost no effect on the cyclization.
EXPERIMENTAL
All solvents were dried by standard procedure. Infrared
1
spectra were recorded on a PE-2000 FT-IR. H and 13C NMR
As pointed out in the literature, within the group of
opioid ligands with a morphinan structure the phenolic
group in the 3-position was historically regarded as a
requirement for high affinity interaction with a respec-
tive H-bond accepting site of the opioid receptor [13].
We thus decided to convert the methoxyl group con-
nected with the benzene ring in compounds 1a, 2a into
hydroxyl group. The goal was accomplished by deme-
thylation of the methoxyl group with BBr3 or HCl.
Reaction of compound 1a with BBr3 in dichloromethane
at room temperature gave the desired product 1b in 60%
yield (entry 5), while to our surprised, very low yield
was obtained for compound 2a. We then used HCl as
demethylation reagent, the desired product 2a was
obtained in 77% yield (entry 6) when the reaction was
performed at 100ꢀC.
spectra were recorded on Bruker ARX 200-MHz sonde QNP
(H, C, F, P) and Bruker Avance 400-MHz sonde H-BB with
gradient Z spectrometer. Chemical shifts (d) are given in ppm
relative to Me4Si (0, 1H) or CDCl3 (77.0, 13C). Mass spectra
were obtained with Thermo Finnigan LCQ Advantage spec-
trometer. Elemental analysis was measured on PE 2400 II
CHNS instrument. Thin-layer chromatography (TLC) was run
on precoated silica gel phates (Merck 60F254). Column chro-
matography was carried out using flash silica gel.
General procedure for the preparation of 8 and 12.
Method A (for preparation 8b, 12a,b) See ref. 10 for the prep-
aration of 8b, 12a,b.
Method B (for preparation 8a, 12a,b). To a 100-mL, three-
neck flask with a stirring bar, 3.61 g of 2-iodo-6-methoxyphe-
nol 4a (14.4 mmol, 1 eq), 4.17 g of PPh3 (16 mmol, 1.1 eq),
alcohol 15 (24 mmol, 1.7 eq), and 50 mL of dry CH2Cl2 were
added under argon. Then, a solution of DEAD (16 mmol, 2.9
mL, 1.1 eq) in 10 mL CH2Cl2 was added dropwise at room
temperature. After the addition was completed, the mixture
was stirred for an additional 8 h at the same temperature. The
solvent was removed under reduced pressure, and the residue
was subjected to chromatography to afford 8a in 37% yield
(2.0 g).12a: Yield: 67% (Method B). 12b: Yield: 70% (Method
In summary, we have synthesized several new piperidyl
spirofused benzofurans and piperidyl spirofused benzo-
pyrans via an important intramolecular radical cycliza-
tion. It was found that the yield of the formation of five-
member ring was much higher than that of six-member
1
B). H NMR and 13C NMR of 8a–b, 12a–b see ref. 10.
General procedure for the synthesis of 1a–3a, 3b. Argon
was bubbled into a solution of 8a (1.0 g, 28 mmol, 1 eq) in
dry toluene (75 mL) in a round bottle with a stirring bar and a
condenser for 15 min. Then, tributyl hydride (1.13 mL, 42
mmol, 1.5 eq), and AIBN (260 mg) were added. The mixture
was heated at 95ꢀC for 20 h. The resulting mixture was evapo-
rated under reduced pressure to give crude product. The crude
was diluted with AcOEt and added HCl to form the corre-
sponding salt of the spirofused piperidine, and separated. The
aqueous layer was neutralized with saturated Na2CO3 solution,
and extracted with dichloromethane (3 ꢁ 25 mL). The com-
bined organic phases were dried over Na2SO4, evaporated to
Table 1
The results of the synthesis of compounds 1, 2, and 3.
Entry
R
n
Product
Yield/%
1
2
3
4
5
6
OMe
OMe
OMe
H
OH
OH
1
2
–
–
1
2
1a
2a
3a
3b
1b
2b
85
40
41
39
60
77
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DOI 10.1002/jhet

November 2011
Synthesis of Novel Piperidyl Spirofused Benzofurans/Benzopyrans by
Radical Cyclization
1241
give the crude, which was then subjected to flash chromatogra-
phy on silica gel giving product 1a (0.55 g, 85%).
organic layers were dried over Na2SO4 and evaporated. The
crude was then subjected to flash chromatography on silica gel
giving product 1b (0.14 g, 60%).
IR (KBr): 3403, 3020, 2940, 2856, 1711, 1606, 1476, 1420,
;
1363, 1215, 1085, 1062, 758, 669 cmꢂ1 1H NMR (CDCl3,
0
0
1 -Methylspiro[7-methoxybenzofuran-2(3H),3 -piperidine] 1a. Yield:
85%, viscous oil; IR (film): 3020, 2940, 2854, 1711, 1621,
1593, 1492, 1466, 1289. 1270, 1216, 1101, 1064, 755, 668
1
cmꢂ1; H NMR (CDCl3, 200 MHz): d 1.55–1.80 (m, 4H), 1.98
200 MHz): d 1.57–1.81 (m, 4H), 1.99 (td, 1H, J ¼ 11.1 Hz, J
¼ 3.8 Hz), 2.11 (dd, 1H, J ¼ 11.5 Hz, J ¼ 1.0 Hz), 2.27 (s,
3H, NCH3), 2.76 (d, 1H, J ¼ 11.0 Hz), 2.81–2.86 (m, 1H),
4.40 (dd, 1H, J ¼ 8.8 Hz, J ¼ 1.3 Hz), 4.70 (d, 1H, J ¼ 8.8
Hz), 6.46–6.78 (m, 3H, ArH); 13C NMR (CDCl3, 50 MHz): d
22.67, 33.75, 45.83, 46.76, 55.05, 64.51, 80.87, 114.07,
115.61, 120.64, 134.68, 141.49, 147.10; MS(EI, 70ev) m/z (%)
¼ 219 (5) [Mþ], 161 (5), 147 (6), 105 (4), 91 (8), 71 (20), 58
(100); Anal. Calcd. for C13H17NO2: C 71.21; H 7.81; N 6.39.
Found: C 71.60; H 7.77; N 6.36.
Synthesis of 10-Methylspiro[8-hydroxybenzopyran-3(4H),30-
piperidine] 2b. Compound 2a (0.11 g, 0.44 mmol) and HCl
(10 N, 15 mL) were mixed together, sealed, and heated at
100ꢀC for 12 h. After cooling, the solution was neutralized
with Na2CO3 solution, and extracted with CH2Cl2 (3 ꢁ 15
mL). The combined organic layers were dried over Na2SO4
and evaporated under reduced pressure. The crude was sub-
jected to flash chromatography on silica gel giving product 2b
(80 mg, 77%).
(td, 1H, J ¼ 11.0 Hz, J ¼ 3.9 Hz), 2.10 (dd, 1H, J ¼ 11.0 Hz,
J ¼ 1.0 Hz), 2.25 (s, 3H, NCH3), 2.70 (d, 1H, J ¼ 11.0 Hz),
2.75–2.85 (m, 1H), 3.86 (s, 3H, OCH3), 4.38 (dd, 1H, J ¼ 9.0
Hz, J ¼ 1.3 Hz), 4.69 (d, 1H, J ¼ 9.0 Hz), 6.71–6.86 (m, 3H,
ArH); 13C NMR (CDCl3, 50 MHz): d 22.94, 34.00, 46.57,
46.83, 55.40, 55.84, 64.82, 81.72, 111.60, 115.33, 120.77,
134.44, 144.57, 147.92; MS(EI, 70ev) m/z (%) ¼ 233 (10)
[Mþ], 161 (7), 117 (5), 91 (10), 71(60), 58 (100); Anal. Calcd.
for C14H19NO2: C 72.07; H 8.21; N 6.00. Found: C 71.94; H
8.26; N 5.96.
0
1 -Methylspiro[8-methoxybenzopyran-3(4H),30-piperidine] 2a. Yield
40% (0.11 g), viscous oil; IR [(film): 3020, 2940, 1711, 1600,
1419, 1363, 1216, 1089, 767, 669 cmꢂ1 1H NMR (CDCl3,
;
200 MHz]: d 1.54–1.69 (m, 2H), 1.75–2.03 (m, 4H), 2.16 (d,
1H, J ¼ 11.5 Hz), 2.22(s, 3H, NCH3), 2.37 (dq, 1H, J ¼ 14.0
Hz, J ¼ 3.2 Hz), 2.67 (dt, 1H, J ¼ 11.6 Hz, J ¼ 1.3 Hz),
2.81–2.89 (m, 1H), 3.85 (s, 3H, OCH3), 4.12–4.32 (m, 2H),
6.72 (dd, 1H, ArH, J ¼ 7.9 Hz, J ¼ 1.6 Hz), 6.83 (t, 1H, ArH,
J ¼ 7.9 Hz), 6.98 (dd, 1H, ArH, J ¼ 7.9 Hz, J ¼ 1.6 Hz); 13C
NMR (CDCl3, 50 MHz): d 21.66, 30.97, 34.24, 35.92, 46.66,
55.70, 56.09, 63.25, 66.29, 108.91, 118.88, 119.36, 129.77,
144.25, 148.27; MS(EI, 70ev) m/z (%) ¼ 247 (15) [Mþ], 176
(12), 161 (8), 105 (7), 91 (10), 71 (80), 58 (100); Anal. Calcd.
for C15H21NO2: C 72.84; H 8.56; N 5.66. Found: C 72.60; H
8.52; N 5.63.
IR (KBr): 3330, 3019, 2942, 1711, 1600, 1475, 1428, 1362,
1216, 1084, 760, 665 cmꢂ1 1H NMR (CDCl3, 200 MHz): d
;
1.51–170 (m, 2H), 1.75–2.02 (m, 4H), 2.16 (d, 1H, J ¼ 11.7
Hz), 2.24 (s, 3H, NCH3), 2.39 (dq, 1H, J ¼ 14.0 Hz, J ¼ 3.3
Hz), 2.69 (dt, 1H, J ¼ 11.6 Hz, J ¼ 1.4 Hz), 2.85–2.90 (m,
1H), 4.11–4.31 (m, 2H), 6.72–6.91 (m, 3H, ArH); 13C NMR
(CDCl3, 50 MHz): d 21.57, 31.08, 34.18, 35.68, 46.62, 56.06,
63.45, 66.05, 112.19, 117.78, 120.07, 129.26, 141.80, 144.87;
MS(EI, 70 ev) m/z (%) ¼ 233 (7) [Mþ], 161 (8), 105 (15), 91
(15), 71 (30), 58 (100); Anal. Calcd. for C14H19NO2: C 72.07;
H 8.21; N 6.00. Found: C 71.62; H 8.17; 5.97.
10-Benzylspiro[7-methoxybenzofuran-2(3H),40-piperidine] 3a
[12]. Yield: 41% (0.25 g), colorless oil; IR (film): 3023, 2950,
1
2860, 1712, 1598, 1486, 1365, 1214, 1088, 764, 664 cmꢂ1; H
NMR (CDCl3, 200 MHz): d 1.66–1.77 (m, 2H), 1.92–2.08 (m,
4H), 2.97–3.85 (m, 2H), 3.54 (s, 2H), 3.87 (s, 3H, OCH3),
4.43 (s, 2H), 6.72–6.89 (m, 3H, ArH), 7.23–7.38 (m, 5H,
ArH); 13C NMR (CDCl3, 50 MHz): d 36.44 (2C), 45.11, 50.90
(2C), 55.85, 63.38, 80.94, 111.31, 115.14, 121.13, 127.01,
128.17 (2C), 129.08 (2C), 136.21, 138.13, 144.54, 147.50;
Anal. Calcd. for C20H23NO2: C 77.64; H 7.49; N 4.53. Found:
C 77.22; H 7.53; N 4.51.
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1
1711, 1599, 1480, 1421, 1364, 1215, 1098, 766, 669 cmꢂ1; H
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