Heteroaryl radicals. Part 1. Synthesis of linear pyridine-fused ring systems by endo-selective 2-pyridyl radical cyclizations

Article abstract of DOI:10.1039/b204436f

Bu₃SnH-induced 2-pyridyl radicals, derived from the 2-bromopyridinyl-substituted methylenecyclohexane 4 and also the vinyl- and the allyl-cyclohexanols 5 and 6, undergo endo-selective cyclizations to give six-, seven- and eight-membered-ring an

Full text of DOI:10.1039/b204436f

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Heteroaryl radicals. Part 1. Synthesis of linear pyridine-fused ring
systems by endo-selective 2-pyridyl radical cyclizations†
Sarbendu Maiti, Basudeb Achari, Ranjan Mukhopadhyay and Asish Kr. Banerjee*
1
Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata-700 032, India
Received (in Cambridge, UK) 8th May 2002, Accepted 11th June 2002
First published as an Advance Article on the web 26th June 2002
Bu3SnH-induced 2-pyridyl radicals, derived from the 2-bromopyridinyl-substituted methylenecyclohexane 4
and also the vinyl- and the allyl-cyclohexanols 5 and 6, undergo endo-selective cyclizations to give six-, seven- and
eight-membered-ring annulated pyridines 7, 11 and 12.
Organotin-mediated intramolecular aryl-radical cyclizations
have emerged as useful synthetic methods for benzo-fused ring
structures.1 To a very limited extent such reactions involving
heteroaryl radicals have also been successfully used to construct
heteroaromatic-fused systems.1c,d,2 Ring closures in aryl radicals,
as in the case of alkyl radicals, readily proceed via 5-exo and
6-exo pathways, generating five- and six-membered rings.1,3
However, the relatively small steric demand of an aryl radical
coupled with its enhanced reactivity, compared with that of
alkyl radicals,4 allow it to enter into uncommon 6-endo-4 and
higher-order exo- and endo-ring annulated products also.1c,d,5,6
Ghatak and co-workers reported5a,7–11 a potentially useful route
to certain linearly benzannulated six- to nine-membered ring
structures through endo-trig aryl-radical cyclizations in n-
Bu3SnH-induced reactions. For example, radical cyclizations
of methylenecyclohexanes A produced the endo-cyclization
products B exclusively and in excellent yields7 [equation (1)].
Scheme 1 (a) NaI, EtOH, reflux, 5 h, 65%.
and 6 was obtained by alkylation (Scheme 1) of the enamine 1
with 2-bromo-3-(bromomethyl)pyridine (2),12 prepared by a
modified route. Wittig olefination of 3 in THF in the presence
of n-BuLi produced the exo-olefin 4 (Scheme 2).
(1)
Similar regioselective aryl-radical cyclizations in cyclohexanols
C at the terminal olefinic centre, through 7- and 8-endo-trig
pathways, led to the respective seven8- and eight9-membered
ring-fused tricyclic alcohols D [equation (2)]. We report herein
Scheme 2 (a) MePϩPh3IϪ, n-BuLi, THF, 0 ЊC to room temp., 88%,
(b) CH2᎐᎐CHMgBr, THF, reflux, 5 h, 48%; (c) allyl bromide, indium,
MeOH–H2O (4 : 1), room temp., 24 h, 55%.
The crystalline cyclohexanols 5 and 6 were obtained by
condensation of the ketone 3 in THF with vinylmagnesium
bromide and allylmagnesium bromide, respectively; only one
diastereoisomer was formed in each case (Scheme 2). The
indium Barbier procedure13 was also equally effective for the
allylation of 3 and gave the same alcohol 6. The assigned
stereostructures are based upon analogy.8,14
(2)
Radical cyclization of the unsaturated bromopyridine 4
with n-Bu3SnH and a catalytic amount of AIBN in refluxing
benzene under high dilution afforded exclusively the cyclo-
hexane-ring-annulated pyridine 7 (Scheme 3).
that similarly substituted 2-pyridyl radicals are equally effective
in undergoing such cyclization, generating pyridine-fused six-,
seven- and eight-membered-ring annulated derivatives.
Results and discussion
The key starting ketone 3 for the three olefinic precursors 4, 5
† This paper has been dedicated to Professor U. R. Ghatak on the
occasion of his 70th birthday.
Scheme 3 (a) n-Bu3SnH, AIBN, C6H6, reflux, 2 h, 90%.
DOI: 10.1039/b204436f
J. Chem. Soc., Perkin Trans. 1, 2002, 1769–1773
This journal is © The Royal Society of Chemistry 2002
1769

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Table 1 Relative yields (%)a of products from cyclization of 4 in
benzene
(Scheme 4), as suggested4b for the cyclization of some alkenyl-
aryl radicals.
Cyclization of the vinyl alcohol 5 (Scheme 6) under high
[Bu3SnH], M
7a
12
67
100
16
8a
9a
0.1b, d, f
4
8
84
25
0.01b, d, f
0.002b, e, f
0.1c, d, g
2
1
82
38
0.003b, e, g
61
a Determined by GC and based on the assumption that the total
yield of 7, 8 and 9 was 100%. b Reactions were carried out under
reflux. c Reaction was carried out at room temperature. d n-Bu3SnH was
added in one lot. e n-Bu3SnH in benzene solution was added dropwise.
f AIBN was used as radical initiator. g Triethylborane was used as
radical initiator.
The assigned structure 7 was consistent with 1H and 13C
NMR spectral data. The trans-geometry to the newly generated
ring junction has been derived by analogy.7
To determine whether 7 originates directly by 6-endo-
cyclization of the heteroaryl radical E and/or by an indirect
route involving 5-exo-ring closure followed by neophyl
rearrangement of the resulting radical F to radical H via a
cyclopropyl intermediate G (Scheme 4), analogous to that
Scheme 6 (a) n-Bu3SnH, AIBN, C6H6, reflux, 5 h.
dilution led to a mixture of products from which pure 6- and
7-membered-ring annulated alcohols 10 and 11, respectively,
were isolated in the ratio 1 : 1.6 on chromatography in excellent
total yield. The assigned structures of these alcohols are in
agreement with the 1H and 13C NMR spectra. The stereo-
chemistry shown for the benzylic methyl group in 10 has been
assigned as it resonates at a downfield position (δ 1.48) compar-
able to that reported15,17 in similar benzodecalin derivatives
(δ 1.31–1.32; δ 1.10 for the epimer). Cyclization of the 2-pyridyl
radical from 5 thus affords the 6-membered-ring product 10
in significant amounts besides the major 7-membered-ring
product 11, unlike that of the aryl radical which led only to
7-membered-ring products under comparable conditions.8 This
is not surprising as there are a number of examples in the aryl-
radical cyclizations where subtle variation in the structures of
the substrates lead to mixtures of 6-exo and 7-endo products or
exclusively either of these.5,6,9,16,18
Reaction of the allyl alcohol 6 (Scheme 6) gave the new
product 12 (78%) of the rare6 8-endo type as the only isolable
material. Formation of the 8-endo product in preference to the
7-exo product parallels the earlier observations in alkyl-19 and
aryl-radical6,8,11,20 cyclizations.
Scheme 4
reported4b,15 for a few aryl-radical cyclizations, some additional
experiments were performed. To facilitate identification of
the cyclized products, the 5-exo-ring-closed compound 8 was
prepared by intramolecular Heck reaction of 4 in the presence
of sodium formate16 (Scheme 5). The assigned structure of
Conclusions
In conclusion, the intrinsic preference of intramolecular
n-Bu3SnH-mediated 2-pyridyl-radical cyclization of methylene-
cyclohexane or vinyl/allylcyclohexanols for the terminal olefinic
carbon centre constitutes an efficient method of preparing
pyridine-ring-fused six-, seven- and eight-membered-ring
annulated polycyclic compounds which are not easily accessible
by classical methodology. Further investigations on the general-
ity of this type of endo-selective heteroaryl-radical cyclizations
as a potential synthetic entry to a variety of new ring-fused
heterocyclic structures of general interest are in progress.
Scheme 5 5% Pd(OAc)2, 20% Ph3P, HCOONa (1 eq), DMF, 85–90 ЊC,
24 h.
product 8 is based upon H and 13C NMR analysis, and the
1
Experimental
stereochemistry was deduced by analogy.16 Cyclization of 4 was
carried out with different concentrations of n-Bu3SnH and the
products analysed by GC (Table 1). This showed the formation
of the exo product 8 (in minor amounts) and the debrominated
olefin 9 besides the endo product 7, the ratio being dependent
on the concentrations employed. The cyclization of 4 with
n-Bu3SnH in higher concentration (0.1 M) in the presence of
AIBN was found to yield 7, 8 and 9 in the proportions ca. 12 : 4
: 84. Repeating the cyclization with Bu3SnH in the presence of
Et3B15 at room temperature gave virtually similar results,
though 7 becomes the major product at high dilution. As the
exo/endo ratio depends on the stannane concentration, it is
conceivable that at least part of the endo product arises via
Mps recorded for the compounds are uncorrected. NMR
spectra of CDCl3 solutions were recorded with Bruker DPX-
300 spectrometers. In all cases, chemical shifts are in δ (ppm)
relative to TMS as internal standard; J-values are given in Hz,
and multiplicity is indicated as follows: s, singlet; d, doublet; t,
triplet; q, quartet; dd, double doublet; br, broad; m, multiplet;
etc. Protonation levels of the carbons indicated in 13C NMR
data were derived from DEPT spectra. Mass spectra were
recorded using a JEOL AX-500 mass spectrometer. IR spectra
were recorded using a JASCO FT/IR-410. All reagents were of
commercial quality and used from freshly opened containers
without purification. Organic solvents were dried by standard
methods and distilled before use. All the reactions were
rearrangement of the initially generated exo-radical
F
1770 J. Chem. Soc., Perkin Trans. 1, 2002, 1769–1773

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performed under N2 atmosphere. Reaction progress was
monitored by thin-layer chromatography (TLC) on precoated
aluminium-backed plates (Merck Kieselgel 60F254) and the
spots were visualized by UV light. Anhydrous Na2SO4 was used
as drying agent during extraction processes. Silica gel (60–120
mesh) was used for column chromatography. Petroleum spirit
used was of boiling range 60–80 ЊC. Bu3SnH (1 M solution
in hexane) was purchased from Aldrich. Ether refers to
diethyl ether. Gas chromatographic analyses were performed
on an HP-6890A machine using an HP-5 column (30 m ×
0.32 mm; film thickness 0.25 µm) with N2 as carrier gas and the
temperature programme was as follows: 150 ЊC–5 min–2 ЊC
minϪ1–200 ЊC–5 min.
trated. The crude material was chromatographed on silica gel
(EtOAc–petroleum spirit, 1–2%) to give bromoalkene 4 (235
mg, 88%) as a white crystalline solid; mp 53–54 ЊC; IR (KBr)
νmax 1639, 1558 cmϪ1; δH (300 MHz) 1.28–1.73 (6H, m),
2.05–2.14 (1H, m), 2.30–2.38 (1H, m), 2.45–2.51 (1H, m), 2.78
(1H, dd, J 13.9 and 8.2 Hz), 3.05 (1H, dd, J 13.9 and 6.4 Hz),
4.54 (1H, s), 4.70 (1H, s), 7.17 (1H, dd, J 7.4 and 4.6 Hz), 7.43
(1H, dd, J 7.5 and 1.6 Hz), 8.21 (1H, dd, J 4.4 and 1.8 Hz);
δC (75 MHz) 24.4 (CH2), 28.5 (CH2), 33.1 (CH2), 35.0 (CH2),
38.0 (CH2), 42.5 (CH), 106.6 (CH2), 122.4 (CH), 137.8 (C),
139.1 (CH), 144.8 (C), 147.5 (CH), 151.3 (C); MS (EI) m/z 267
(Mϩ ϩ 1), 265, 186 (100%), 173, 171, 103; Found: C, 58.54;
H, 6.24; N, 5.04. C13H16BrN requires C, 58.66; H, 6.06; N,
5.26%.
2-Bromo-3-(bromomethyl)pyridine (2)
2-(2-Bromopyridin-3-ylmethyl)-1-vinylcyclohexanol (5)
(2-Bromopyridin-3-yl)methanol (2 g, 10.63 mmol), prepared
through the NaBH4 reduction of 2-bromopyridine-3-carbalde-
hyde,21 was dissolved in CH2Cl2 (100 mL). To this solution was
added carbon tetrabromide (4.23 g, 12.76 mmol) at Ϫ10 ЊC and
the mixture was stirred for 10 minutes. Triphenylphosphine
(3.35 g, 12.75 mmol) was then added to it portionwise during
15 minutes at the same temperature. The reaction mixture was
further stirred for 30 minutes at Ϫ10 ЊC to complete the
reaction (TLC monitor). The reaction mixture was decomposed
with saturated aq. NaCl (60 mL) at 0 ЊC. The organic layer was
separated and the aqueous layer was further extracted with
CH2Cl2 (2 × 20 mL). The combined organic layer was washed
with brine, dried, and the solvent was evaporated under reduced
pressure. The residual product was chromatographed (EtOAc–
petroleum spirit, 4–6%) to give dibromide 2 (2.4 g, 90%) as a
colourless oil, which solidified on refrigeration; mp 33–34 ЊC
[reported12 as an oil, bp 90–91 ЊC (1 mmHg)]; δH 4.56 (2H, s),
7.29 (1H, dd, J 7.5 and 4.7 Hz), 7.78 (1H, dd, J 7.5 and 1.9 Hz),
8.32 (1H, dd, J 4.8 and 1.8 Hz).
A solution of vinyl bromide (9.8 mL of 1 M solution in THF,
10 mmol) was added dropwise to a suspension of magnesium
(77.6 mg, 3.2 mg-atm) in dry THF (5 mL) at 0–5 ЊC during
10 minutes and the mixture was stirred at room temperature
until all the magnesium was dissolved. To this solution was
added a solution of ketone 3 (280 mg, 1.04 mmol) in dry THF
(5 mL) at 0–5 ЊC during 20 minutes. The reaction mixture was
stirred at room temperature for 1 h and then heated under
reflux for 5 h. Saturated aq. NH4Cl (20 mL) was added and
THF was removed in a rotary evaporator under reduced
pressure. The residual part was extracted with ether (10 mL ×
3). The combined organic part was washed with brine, dried,
and concentrated. The crude product was chromatographed
over silica gel (EtOAc–petroleum sprit, 10–20%) to furnish
alcohol 5 (148 mg, 48%) as a white solid; mp 80–81 ЊC;
IR (KBr) νmax 3389, 1653, 1578, 995, 921 cmϪ1; δH (300 MHz)
1.10–1.18 (1H, m), 1.31–1.41 (2H, m), 1.55–1.79 (7H, m), 2.38
(1H, dd, J 13.5 and 11.1 Hz), 3.02 (1H, dd, J 13.5 and 3.0 Hz),
5.17 (1H, d, J 10.8 Hz), 5.35 (1H, d, J 17.3 Hz), 6.03 (1H,
dd, J 17.3 and 10.8 Hz), 7.16 (1H, dd, J 7.5 and 4.7 Hz), 7.42
(1H, dd, J 4.6 and 1.9 Hz), 8.20 (1H, dd, J 7.5 and 1.8 Hz);
δC (75 MHz) 21.3 (CH2), 25.6 (CH2), 26.1 (CH2), 36.0 (CH2),
39.4 (CH2), 43.5 (CH), 74.4 (C), 112.2 (CH2), 122.4 (CH),
138.1 (C), 139.9 (CH), 144.7 (C), 145.5 (CH), 147.5 (CH);
MS (EI) m/z 297 (Mϩ ϩ 1), 295, 242, 240, 227, 225, 216
(100%), 200, 198, 186, 184, 173, 171, 134, 130, 189; Found:
C, 56.64; H, 5.91; N, 4.86. C14H18BrNO requires C, 56.77; H,
6.13; N, 4.73%.
2-(2-Bromopyridin-3-ylmethyl)cyclohexanone (3)
A mixture of enamine 1 (4.74 g, 31 mmol), bromide 2 (7.16 g,
28 mmol) and NaI (121 mg, 0.8 mmol) in dry ethanol (75 mL)
was heated under reflux for 5 h. Ethanol was removed in a
rotary evaporator under reduced pressure, and the residue was
diluted with water and extracted with CH2Cl2 (50 mL × 3). The
combined organic layer was washed with brine, dried, and
concentrated. The residual product was chromatographed
(EtOAc–petroleum spirit, 5–10%) to give ketone 3 (5 g, 65%);
mp 55–56 ЊC; IR (KBr) νmax 1708 cmϪ1; δH (300 MHz) 1.43–1.49
(1H, m), 1.62–1.73 (2H, m), 1.87–1.90 (1H, m), 2.06–2.13 (2H,
m), 2.32–2.40 (2H, m), 2.54 (1H, dd, J 14.0 and 6.6 Hz),
2.72–2.78 (1H, m), 3.28 (1H, dd, J 13.9 and 6.6 Hz), 7.18 (1H,
dd, J 7.4 and 4.7 Hz), 7.64 (1H, dd, J 7.4 and 1.7 Hz), 8.21 (1H,
dd, J 4.6 and 1.8 Hz); δC (75 MHz) 25.3 (CH2), 28.1 (CH2), 34.2
(CH2), 35.1 (CH2), 42.3 (CH2), 50.2 (CH), 122.6 (CH), 137.2
(C), 140.1 (CH), 144.4 (C), 147.8 (CH), 211.7 (CO); MS (EI)
m/z 268 (Mϩ), 189 (100%), 188, 172, 170, 146, 130, 120, 117,
108; Found: C, 53.94; H, 5.39; N, 4.98. C12H14BrNO requires C,
53.75; H, 5.26; N, 5.22%.
1-Allyl-2-(2-bromopyridin-3-ylmethyl)cyclohexanol (6)
Allyl bromide (0.13 mL, 1.5 mmol) was added to a solution
of ketone 3 (200 mg, 0.74 mmol) and indium powder (103 mg,
0.9 mg-atom) in MeOH–H2O (1 : 4; 10 mL) and the mixture
was stirred at room temperature for 24 h. Again, identical
amounts of allyl bromide and indium powder were added and
the mixture was further stirred for another 24 h at room tem-
perature. The reaction mixture was poured into aq. KH2PO4
(5%; 50 mL) and was then extracted with EtOAc (50 mL × 3).
The combined organic layer was washed with brine, dried, and
concentrated. The residue was chromatographed over silica gel
(EtOAc–petroleum spirit, 10–12%) to give alcohol 6 (127 mg,
55%) as a white solid; mp 74–75 ЊC; IR (KBr) νmax 3350, 1639,
1560, 984, 906 cmϪ1; δH (300 MHz) 1.10–1.13 (1H, m),
1.22–1.31 (2H, m), 1.43–1.69 (6H, m), 1.75–1.83 (1H, m),
2.39–2.60 (3H, m), 3.18 (1H, dd, J 13.5 and 3.5 Hz), 5.17 (2H,
m), 5.87–6.01 (1H, m), 7.18 (1H, dd, J 7.4 and 4.6 Hz),
7.46 (1H, dd, J 7.4 and 1.8 Hz), 8.20 (1H, dd, J 4.6 and 1.8 Hz);
δC (75 MHz) 21.9 (CH2), 25.5 (CH2), 26.8 (CH2), 35.2 (CH2),
37.4 (CH2), 43.5 (CH), 45.4 (CH2), 73.2 (C), 119.3 (CH2), 122.9
(CH), 134.0 (CH), 138.6 (C), 140.3 (CH), 145.2 (C), 148.0 (CH);
MS (EI) m/z 311 (Mϩ ϩ 1), 309, 268, 270 (100%), 188, 172, 170,
95, 88, 55; Found: C, 57.92; H, 6.21; N, 4.67. C15H20BrNO
requires C, 58.07; H, 6.50; N, 4.51%.
2-Bromo-3-(2-methylenecyclohexylmethyl)pyridine (4)
n-BuLi (1.5 mL of 1.6 M solution in hexane, 3 mmol) was added
to a solution of methyltriphenylphosphonium iodide (1.4 g,
3.5 mmol) in dry THF (10 mL) at 0 ЊC, and the mixture was
stirred at the same temperature for 2.5 h. To this solution was
added a solution of ketone 3 (268 mg, 1 mmol) in dry THF
(10 mL), and the mixture was stirred at 0 ЊC for 30 minutes and
at room temperature for 2 h. Saturated aq. ammonium chloride
(20 mL) was added to the reaction mixture and THF was
removed in a rotary evaporator under reduced pressure. The
residue was extracted with CH2Cl2 (20 mL × 3) and the com-
bined organic layer was washed with brine, dried, and concen-
J. Chem. Soc., Perkin Trans. 1, 2002, 1769–1773
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General procedure for radical cyclization of the olefins 4–6
(63 mg, 0.203 mmol) was treated with Bu3SnH (0.3 mL of 1 M
solution in hexane, 0.304 mmol) in the presence of AIBN (6 mg,
0.037 mmol). After work-up, the crude product was chromato-
graphed (EtOAc–petroleum spirit, 25–30%) to give alcohol 12
(42 mg, 78%) as white crystals; mp 129 ЊC; IR (KBr) νmax 3250,
2923, 2852, 1582, 1453, 1272, 1218, 962, 789 cmϪ1; δH (300
MHz) 1.10–1.19 (2H, m), 1.25–1.59 (8H, m), 1.68–1.74 (3H, m),
2.02–2.13 (1H, m), 2.32 (1H, d, J 14.3 Hz), 2.82–2.89 (1H, m),
2.98 (1H, dd, J 13.5 and 10.4 Hz), 3.21–3.31 (1H, m), 7.05 (1H,
dd, J 7.5 and 4.8 Hz), 7.42 (1H, dd, J 7.6 and 1.2 Hz), 8.38 (1H,
dd, J 4.7 and 1.4 Hz); δC (75 MHz) 21.7 (CH2), 25.3 (CH2), 26.1
(CH2), 31.3 (CH2), 34.2 (CH2), 37.4 (CH2), 38.1 (CH2), 43.5
(CH2), 51.1 (CH), 72.9 (C), 121.3 (CH), 136.7 (C), 136.9 (CH),
147.3 (CH), 160.2 (C); MS (FAB) m/z 232 (Mϩ ϩ 1, 100%), 154,
107; Found: C, 78.03; H, 9.24; N, 5.81. C15H21NO requires C,
77.88; H, 9.15; N, 6.05%.
To a gently stirred refluxing solution of the appropriate olefin
4–6 (0.203 mmol) in degassed dry benzene (80 mL) was added a
solution of Bu3SnH (1.5 eq) and AIBN (6 mg, 0.037 mmol) in
degassed dry benzene (20 mL) slowly over a period of ca. 3.5 h.
After complete addition, the mixture was further refluxed for
an additional 2 h. Benzene was removed in a rotary evaporator
under reduced pressure. The residual product was taken up in
ether (50 mL) – saturated aq. KF (50 mL) and the reaction
mixture was stirred vigorously at room temperature for 10 h.
The organic phase was separated and the aqueous phase was
further extracted with ether. The combined organic phase was
washed with brine, dried, and concentrated to give the crude
product, which on chromatography (EtOAc–petroleum spirit)
yielded pure cyclized product 7; 10 and 11; or 12, respectively.
5,5a,6,7,8,9,9a,10-Octahydrobenzo[g]quinoline (7). Following
the general procedure, olefin 4 (54 mg, 0.203 mmol) was treated
with Bu3SnH (0.3 mL of 1 M solution in hexane, 0.30 mmol)
in the presence of AIBN (6 mg, 0.037 mmol). After work-up,
the crude product was chromatographed (EtOAc–petroleum
spirit, 3–4%) to give tricycle 7 (34 mg, 90%) as white crystals;
mp 44–45 ЊC; IR (KBr) νmax 2924, 2847, 1572, 1443, 1414, 785
cmϪ1; δH (300 MHz) 1.05–1.25 (2H, m), 1.26–1.57 (4H, m), 1.78
(2H, d, J 6.6 Hz), 1.89 (2H, t, J 12.4 Hz), 2.41–2.59 (2H, m),
2.75 (1H, dd, J 16.7 and 4.6 Hz), 2.98 (1H, dd, J 17.3 and 4.6
Hz), 7.01 (1H, dd, J 7.5 and 4.6 Hz), 7.31 (1H, d, J 7.5 Hz), 8.33
(1H, d, J 4.5 Hz); δC (75 MHz) 26.0 (CH2), 26.2 (CH2), 33.5
(CH2), 33.7 (CH2), 36.6 (CH2), 38.2 (CH), 38.6 (CH), 40.2
(CH2), 120.8 (CH), 131.8 (C), 136.1 (CH), 146.7 (CH), 157.1
(C); MS (EI) m/z 187 (Mϩ, 100%), 172, 158, 144, 130, 118, 107,
91; Found: C, 83.49; H, 9.08; N, 7.52. C13H17N requires C,
83.37; H, 9.15; N, 7.48%.
9a-Methyl-5a,6,7,8,9,9a-hexahydro-5H-indeno[1,2-b]pyridine
(8) and 3-(2-methylenecyclohexylmethyl)pyridine (9)
A stirred mixture of the olefin 4 (200 mg, 0.752 mmol),
Pd(OAc)2 (8.4 mg, 0.039 mmol), PPh3 (394 mg, 0.15 mmol) and
HCOONa (51 mg, 0.752 mmol) in dry DMF (12 mL), was
heated at 85–90 ЊC for 24 h. The cooled reaction mixture was
diluted with water (30 mL) and extracted with ether (30 ×
3 mL). The combined organic layer was washed with brine,
dried, and evaporated. GC of the crude product showed 8 and
9 to be present in the ratio 1 : 3. The crude product was chrom-
atographed on silica gel. The first fraction (EtOAc–petroleum
spirit, 2–4%) gave tricycle 8 (28 mg, 20%) as a colourless oil; IR
(neat) νmax 2925, 2853, 1576, 1420, 1371, 1157, 1092, 785 cmϪ1
;
δH (300 MHz) 1.29 (3H, s), 1.32–1.56 (6H, m), 1.72–1.79 (2H,
m), 2.05–2.17 (1H, m), 2.65 (1H, dd, J 15.6 and 7.1 Hz), 2.87
(1H, dd, J 15.6 and 7.1 Hz), 7.01 (1H, t, J 6.0 Hz), 7.49 (1H, d,
J 7.4 Hz), 8.36 (1H, d, J 4.7 Hz); δC (75 MHz) 22.5 (CH2), 23.1
(CH2), 24.6 (CH3), 27.4 (CH2), 33.6 (CH2), 34.2 (CH2), 45.2
(CH), 46.0 (C), 121.4 (CH), 133.4 (CH), 136.0 (C), 147.6 (CH),
171.9 (C); MS (EI) m/z 187 (Mϩ), 172 (100%), 144, 132, 130;
Found: C, 83.65; H, 8.94; N, 7.23. C13H17N requires C, 83.37;
H, 9.15; N, 7.48%.
The second fraction (EtOAc–petroleum spirit, 6–10%) gave
alkene 9 (90 mg, 64%) as a colourless oil; IR (neat) νmax 2927,
2854, 1643, 1575, 1477, 1424, 1026, 886, 792, 713 cmϪ1; δH (300
MHz) 1.17–1.77 (5H, m), 1.97–2.43 (4H, m), 2.55 (1H, dd
J 13.7 and 6.2 Hz), 2.99 (1H, dd, J 13.7 and 6.2 Hz), 4.56 (1H,
s), 4.69 (1H, s), 7.20–7.26 (1H, m), 7.49 (1H, d, J 7.8 Hz), 8.44
(2H, d, J 4.5 Hz); δC (75 MHz) 24.4 (CH2), 28.5 (CH2), 32.9
(CH2), 35.1 (CH2), 35.9 (CH2), 44.3 (CH), 106.2 (CH2), 123.1
(CH), 136.3 (CH), 136.5 (C), 147.2 (CH), 150.4 (CH), 151.8 (C);
MS (EI) m/z 187 (Mϩ), 103, 101 (100%); Found: C, 83.21; H,
9.63; N, 7.16. C13H17N requires C, 83.37; H, 9.15; N, 7.48%.
10-Methyl-5,6,7,8,9,10-hexahydro-5aH-benzo[g]quinolin-9a-
ol (10) and 5,5a,6,7,8,9,10,11-octahydrobenzo[4,5]cyclohepta-
[1,2-b]pyridin-9a-ol (11). Following the general procedure,
olefin 5 (60 mg, 0.203 mmol) was treated with Bu3SnH (0.3 mL
of 1 M solution in hexane, 0.304 mmol) in the presence of
AIBN (6 mg, 0.037 mmol). After work-up, the crude product
was chromatographed on silica gel. First fraction (EtOAc–
petroleum spirit, 20–30%) gave alcohol 10 (15 mg, 34%) as a
white solid; mp 144–145 ЊC; IR (KBr) νmax 3328, 2930, 2863,
1579, 1443, 1387, 1195, 951, 786 cmϪ1; δH (300 MHz) 1.18 (1H,
br s), 1.25–1.45 (3H, m), 1.48 (3H, d, J 7.0 Hz), 1.52–1.80 (5H,
m), 2.13 (1H, br d, J 13.6 Hz), 2.57 (1H, dd, J 16.8 and 5.3 Hz),
2.71–2.81 (2H, m), 7.03 (1H, dd, J 7.5 and 4.7 Hz), 7.33 (1H, d,
J 7.8 Hz), 8.42 (1H, d, J 4.6 Hz); δC (75 MHz) 11.1 (CH3), 21.6
(CH2), 25.6 (CH2), 28.8 (CH2), 32.4 (CH2), 36.8 (CH2), 40.1
(CH), 46.7 (CH), 71.2 (C), 120.9 (CH), 131.0 (C), 135.9 (CH),
147.1 (CH), 158.5 (C); MS (FAB) m/z 218 (Mϩ ϩ 1, 100%), 200,
154, 137, 121, 107; Found: C, 77.19; H, 8.96; N, 6.17. C14H19NO
requires C, 77.38; H, 8.81; N, 6.45%.
Second fraction (EtOAc–petroleum spirit, 40%) yielded
alcohol 11 (24 mg, 55%) as a white solid; mp 169–170 ЊC; IR
(KBr) νmax 3242, 2922, 2852, 1580, 1439, 1100, 919, 794, 762,
710 cmϪ1; δH (300 MHz) 1.20–1.42 (4H, m), 1.49–1.63 (6H, m),
1.69–1.86 (2H, m), 2.02 (1H, d, J 14.3 Hz), 2.78 (1H, dd, J 14.3
and 6.7 Hz), 3.28 (1H, dd, J 14.2 and 10.7 Hz), 3.52 (1H, t,
J 13.2 Hz), 7.00 (1H, dd, J 7.4 and 4.9 Hz), 7.35 (1H, d, J 7.1
Hz), 8.26 (1H, d, J 4.9 Hz); δC (75 MHz) 21.6 (CH2), 26.5
(CH2), 30.9 (CH2), 32.7 (CH2), 37.3 (CH2), 41.2 (CH2), 41.6
(CH2), 45.8 (CH), 72.5 (C), 121.7 (CH), 136.5 (CH), 137.6 (C),
146.6 (CH), 163.3 (C); MS (FAB) m/z 218 (Mϩ ϩ 1, 100%), 200,
154, 137, 107; Found: C, 77.52; H, 8.61; N, 6.41. C14H19NO
requires C, 77.38; H, 8.81; N, 6.45%.
Radical cyclization of 4 with Bu3SnH at 0.1 M concentration
To a solution of 4 (50 mg, 0.188 mmol) in degassed dry benzene
(2 mL) were added Bu3SnH (60 mg, 0.207 mmol) and AIBN
(5 mg, 0.02 mmol) and the mixture was heated under reflux for
9 h. After evaporation of the solvent in a rotary evaporator
under reduced pressure, ether (20 mL) and saturated aq. KF (20
mL) were added to the residue, and the whole mixture was
stirred at room temperature for 24 h. The organic phase was
separated, washed with brine, dried, and concentrated. GC
analysis of the crude product showed it to be a mixture of 7
(tR 10.48), 8 (tR 6.28) and 9 (tR 8.47) in the proportions 12 : 4 : 84.
Radical cyclization of 4 with Bu3SnH at 0.01 M concentration
To a solution of 4 (50 mg, 0.188 mmol) in degassed dry benzene
(20 mL) were added Bu3SnH (60 mg, 0.207 mmol) and AIBN
(5 mg, 0.02 mmol) and the mixture was heated under reflux for
9 h. After usual work-up, GC analysis of the crude product
showed the presence of 7, 8 and 9 in the proportions 67 : 8 : 25.
6,7,8,9,10,11,11a,12-Octahydro-5H-benzo[4,5]cycloocta[1,2-
b]pyridin-7a-ol (12). Following the general procedure, olefin 6
1772
J. Chem. Soc., Perkin Trans. 1, 2002, 1769–1773

View Article Online
4 (a) A. N. Abeywickrema and A. L. J. Beckwith, J. Chem. Soc., Chem.
Radical cyclization of 4 with Bu3SnH–Et3B at room temperature
Commun., 1986, 464; (b) A. N. Abeywickrema, A. L. J. Beckwith
and S. J. Gerba, J. Org. Chem., 1987, 52, 4072 and references cited
therein; (c) P. Rigollier, J. R. Young, L. A. Fowley and J. R. Stille,
J. Am. Chem. Soc., 1990, 112, 9441.
5 (a) A. K. Ghosh, J. K. Mukhopadhyay and U. R. Ghatak, J. Chem.
Soc., Perkin Trans. 1, 1997, 2747 and references cited therein; (b)
C. Andres, J. P. Duque-Soladana, J. M. Iglesias and R. Pedrosa,
Synlett, 1997, 1391.
To a solution of 4 (50 mg, 0.188 mmol) and Bu3SnH (71 mg,
0.24 mmol) in degassed dry benzene (2.8 mL) was added Et3B
(0.75 ml of 1 M solution in THF, 0.752 mmol) at room
temperature. The reaction mixture was stirred at the same
temperature for 48 h. After usual work-up, GC analysis of
the crude product showed the presence of 7, 8 and 9 in the
proportions 16 : 2 : 82.
6 For a review of medium-sized-ring-formation methods, see L. Yet,
Tetrahedron, 1999, 55, 9349.
7 (a) S. Pal, M. Mukherjee, D. Podder, A. K. Mukherjee and
U. R. Ghatak, J. Chem. Soc., Chem. Commun., 1991, 1591; (b) S. Pal,
J. K. Mukhopadhyay and U. R. Ghatak, J. Org. Chem., 1994, 59,
2687.
8 A. K. Ghosh, K. Ghosh, S. Pal and U. R. Ghatak, J. Chem. Soc.,
Chem. Commun., 1993, 809.
9 K. Ghosh, A. K. Ghosh and U. R. Ghatak, J. Chem. Soc., Chem.
Commun., 1994, 629.
10 K. Ghosh and U. R. Ghatak, Tetrahedron Lett., 1995, 36, 4897.
11 J. K. Mukhopadhyay, S. Pal and U. R. Ghatak, Indian J. Chem.,
Sect. B, 1999, 38, 264.
Radical cyclization of 4 with Bu3SnH–Et3B at reflux
To a gently stirred refluxing solution of the olefin 4 (25 mg,
0.094 mmol) in degassed dry benzene (30 mL) was added a
solution of a mixture of Bu3SnH (0.125 mL of 1 M solution in
hexane) and Et3B (0.38 mL of 1 M solution in THF) in
degassed dry benzene (17 mL) slowly over a period of ca 3 h.
After complete addition, the mixture was further refluxed
for an additional 3 h. After usual work-up, GC analysis of
the crude product showed the presence of 7, 8 and 9 in the
proportions 61 : 1 : 38.
12 J. Rebek, Jr., T. Costello and R. Wattley, J. Am. Chem. Soc., 1985,
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13 L. A. Paquette, G. D. Bennett, M. B. Isaac and A. Chhatriwalla,
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16 J. K. Mukhopadhyay, S. Pal and U. R. Ghatak, Synth. Commun.,
1995, 25, 1641.
Acknowledgements
We are grateful to Prof. U. R. Ghatak of our institute for his
valuable suggestions and criticism, and CSIR for the award of a
Research Fellowship to S.M.
17 S. Hagishita and K. Kuriyama, Bull. Chem. Soc. Jpn., 1982, 55,
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