A new entry to 9-azabicyclo[3.3.1]nonanes using radical translocation/cyclisation reactions of 2-(but-3-ynyl)-1-(o-iodobenzoyl)piperidines

Article abstract of DOI:10.1039/b203243k

The 2-[4-(trimethylsilyl) but-3-ynyl]piperidines 16a-c, upon treatment with tributyltin hydride in the presence of azoisobutyronitrile in refluxing toluene, gave the 9-azabicyclo[3.3.1]nonanes 17a-c in high yields, respectively. Compound 17c was subjected to desilylation, ozonolysis, and subsequent 1,2-transposition of the resulting carbonyl group to give 9-benzoyl-1-methyl-9-azabicyclo[3.3.1]nonan-3-one, a potential precursor for the synthesis of (±)-euphococcinine.

Full text of DOI:10.1039/b203243k

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A new entry to 9-azabicyclo[3.3.1]nonanes using radical
translocation/cyclisation reactions of 2-(but-3-ynyl)-1-
(o-iodobenzoyl)piperidines†
1
Tatsunori Sato, Taro Yamazaki, Yumi Nakanishi, Jun-ichi Uenishi and Masazumi Ikeda*
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
Received (in Cambridge, UK) 2nd April 2002, Accepted 22nd April 2002
First published as an Advance Article on the web 13th May 2002
The 2-[4-(trimethylsilyl)but-3-ynyl]piperidines 16a–c, upon treatment with tributyltin hydride in the presence of
azoisobutyronitrile in refluxing toluene, gave the 9-azabicyclo[3.3.1]nonanes 17a–c in high yields, respectively.
Compound 17c was subjected to desilylation, ozonolysis, and subsequent 1,2-transposition of the resulting carbonyl
group to give 9-benzoyl-1-methyl-9-azabicyclo[3.3.1]nonan-3-one, a potential precursor for the synthesis of
( )-euphococcinine.
Introduction
Results and discussion
Bridged azabicyclic rings are widely found as the basic struc-
tural elements in biologically active alkaloids such as cocaine,
atropine, and epibatidine. Recently we have developed a new
synthetic method for the 7-azabicyclo[2.2.1]heptane and 8-
azabicyclo[3.2.1]octane ring systems 4 which involves treatment
of 1-(o-iodobenzoyl)-2-(prop-2-ynyl)-pyrrolidines and -piper-
idines 1 with tributyltin hydride (Bu3SnH) in the presence of
azoisobutyronitrile (AIBN) in boiling toluene.1 The formation
of 4 can be formulated as proceeding via the α-acylamino
radicals 3 which are generated by a 1,5-hydrogen transfer
(a radical translocation)2 of the initially formed aryl radicals 2.
The radicals 3 then undergo a 5-exo-dig cyclisation to lead
to 4 (Scheme 1). As a further extension of this reaction, we
The radical precursor 16a was prepared starting from methyl
N-Boc-pipecolinate 55 according to the procedures previously
described for the synthesis of the pyrrolidine congener1d
(Scheme 2). Thus, 5 was subjected to allylation, and hydrobor-
ation of the resulting allylated ester 6 with bis(3-methylbutan-2-
yl)borane (disiamylborane) followed by oxidation afforded the
alcohol 7a. Swern oxidation of 7a gave the aldehyde 13a, which
was then allowed to react with bromoform and triphenylphos-
phine in the presence of potassium tert-butoxide to give the
dibromoalkene 14a. Treatment of 14a with butyllithium and
quenching with trimethylsilyl chloride gave the N-Boc-2-[4-
(trimethylsilyl)but-3-ynyl]piperidine 15a. Replacement of the
N-Boc group by an o-iodobenzoyl group gave the radical pre-
cursor 16a. The radical precursor 16b was also prepared from
5, which was subjected successively to LiAlH4 reduction (9b),
Swern oxidation (10b), the Horner–Emmons reaction with tri-
ethyl phosphonoacetate (11b), catalytic hydrogenation over
Pd–C (12b), and LiAlH4 reduction to afford the alcohol 7b.
This alcohol 7b was converted into 16b (via 13b, 14b and 15b)
in a similar manner to the reaction sequences used for the
preparation of 16a.
A toluene solution of Bu3SnH (2.7 mol equiv.) and a small
amount of AIBN (0.32 mol equiv.) was added by syringe pump
to a refluxing solution of 16a in toluene over a period of 1 h and
the mixture was further refluxed for 2 h. The crude material was
chromatographed on silica gel to give a ca. 1 : 1 diastereomeric
mixture of the 9-azabicyclo[3.3.1]nonane 17a in 98% combined
yield. No simple reduction product was obtained. The structure
of 17a was confirmed by the following chemical trans-
formation. Treatment of 17a with trifluoroacetic acid in DCM
gave the methylene derivative 18a which was then oxidised with
ozone to afford the ketone 19a in 45% overall yield (Scheme 3).
The ketone 19a showed a strong carbonyl absorption at 1732
cmϪ1 (a ketone and an ester) in addition to an absorption due
to the N-benzoyl group at 1646 cmϪ1 in the IR spectrum. The
1H NMR spectrum revealed a doublet of doublets due to a
bridgehead proton (5-H) at δ 4.32 (J 6.2 and 3.7 Hz).
Scheme 1
have now investigated the Bu3SnH-mediated radical reaction
of the 2-(but-3-ynyl)piperidines 16a–c and found that the
translocation and 6-exo-dig cyclisation reactions proceed in a
regioselective manner to afford the expected 9-azabicyclo-
[3.3.1]nonane ring system.3 In this paper we also describe a
transformation of the cyclised product 17c into 9-benzoyl-1-
methyl-9-azabicyclo[3.3.1]nonan-3-one 28, a protected form
of ( )-euphococcinine 29.4
Similar treatment of 16b with Bu3SnH–AIBN gave the
expected 9-azabicyclo[3.3.1]nonane 17b in 67% yield as a ca.
1 : 1 diastereomeric mixture, along with the hexahydropyrido-
[2,1-a]isoindolone 20 in 22% yield. The compound 17b was
again converted into the ketone 19b via the methylene derivative
18b in 55% overall yield, which showed a ketonic absorption at
† Electronic supplementary information (ESI) available: Experimental
details for 5–16. See http://www.rsc.org/suppdata/p1/b2/b203243k/
1438
J. Chem. Soc., Perkin Trans. 1, 2002, 1438–1443
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b203243k

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Scheme 3 Reagents and conditions: i, Bu3SnH, AIBN, toluene, reflux;
ii, CF3CO2H, CH2Cl2; iii, O3, CH2Cl2, Ϫ78 ЊC, then PPh3.
fact that the side chain at the 2-position mainly occupies an
axial position in order to minimise allylic 1,3-strain1c,6 with the
N᎐C double bond in the amide.
᎐
Encouraged by the success of the synthesis of the 9-aza-
bicyclo[3.3.1]nonane ring system, we then applied the present
method to the synthesis of ( )-euphococcinine 29, which is an
alkaloid isolated from a small sea-coast plant, Euphorbia atoto7
and also found in the defence secretion of the ladybugs
Cryptolaenus montrouzieri8a and Epilachna varivesti.8b The
radical precursor 16c was prepared from methyl N-Boc-
2-methylpiperidine-2-carboxylate 8 (via 9c–15c) by the same
reaction sequences as those used for the preparation of 16b.
The Bu3SnH-mediated radical reaction of 16c proceeded
efficiently to give the 9-azabicyclo[3.3.1]nonane 17c in 95%
yield as a ca. 1 : 1 diastereomeric mixture, which was converted
into the ketone 19c via the methylene derivative 18c in 63%
overall yield (see Scheme 3).
The 1,2-transposition9 of the carbonyl group of 19c was then
investigated. Considerable difficulty, however, was encountered
in finding a route to the intermediate alkene 23. Sodium
borohydride reduction of 19c gave the alcohol 22 in 81% yield.
A variety of procedures for the dehydration of the alcohol 22,
employing the mesyl derivative in refluxing lutidine or collidine,
the Burgess reagent,10 and the xanthate in refluxing xylene
were examined without success. In general, either unchanged
material or uncharacterised products were obtained. Only when
the alcohol 22 was treated with the Martin sulfurane de-
hydrating agent at 80 ЊC in benzene11 the desired alkene 23 was
obtained but in 5% yield; the major product (57% yield) was
the bis(trifluoromethyl)phenylmethyl ether 24, probably with
inversion of configuration. The difficulty of attaining dehydra-
tion under the E2 elimination conditions may be ascribed to
the rigidly fixed equatorial configuration of the hydroxy group
of 22. The syn elimination is also unfavourable because the
location of the 7-methylene group blocks formation of the
cyclic transition state involving the axial hydrogen at the 3-
position‡ which is required for this elimination to take place.
Scheme 2 Reagents and conditions: i, LiN(SiMe3)2, THF, Ϫ78 ЊC; then
CH2᎐᎐CHCH2Br; ii, Sia2BH, THF; then aq. NaOH, 30% H2O2; iii,
LiN(SiMe3)2, THF, Ϫ78 ЊC; then MeI; iv, LiAlH4, Et2O; v, (COCl)2,
DMSO, Et3N, CH2Cl2; vi, (EtO)2P(O)CH2CO2Et, BuLi, THF; vii,
H2 (5 kg cmϪ2), 10% Pd–C, AcOEt; viii, CHBr3, PPh3, ButOK, toluene;
ix, BuLi, TMEDA, THF, Ϫ78 ЊC; then Me3SiCl; x, Me3SiI, MeCN;
then MeOH; xi, o-iodobenzoyl chloride, DMAP, Et3N, benzene.
1729 cmϪ1 in the IR spectrum. The structure of the minor
product 20 was assigned by a comparison of the spectroscopic
data with those of the closely related compound 21.1c The
product distribution of 17b (65%) and 20 (23%) probably
reflects the population of two conformers A and B of 16b,
which generate the α-acylamino radicals at the 6- (leading to
17b) and 2-position of the piperidine ring (leading to 20),
respectively, through the corresponding short-lived aryl radicals.
Conformer A is favoured over conformer B because the steric
repulsion between the bulky o-iodophenyl and 2-[4-(trimethyl-
silyl)but-3-ynyl] groups may occur in the latter, in spite of the
‡ The numbering system of the 9-azabicyclo[3.3.1]nonane ring system
may change depending upon the substituents. To avoid confusion in
this discussion, we used the numbering system for compounds 22–28
as shown in formula 22.
J. Chem. Soc., Perkin Trans. 1, 2002, 1438–1443
1439

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This view was supported later by isolation of the isomeric axial
alcohol 26, which underwent smooth dehydration with Martin
sulfurane to give back the alkene 23. An alternative synthesis
of the alkene 23 was achieved by palladium-catalysed hydro-
genolysis12 of the alkenyl triflate 2513 in 61% overall yield in
two steps from ketone 19c (Scheme 4).
100.5 MHz) spectra were measured on a JEOL-JNM-PMX 60,
a Varian XL-300 or a Varian UNITY INOVA 400NB spectro-
meter for solutions in CDCl3. δ-Values quoted are relative to
1
tetramethylsilane (δH 0) and CDCl3 (δC 77.02) for H and 13C
NMR, respectively, and J-values are given in Hz. Exact mass
determinations (EI and FAB mass spectra) were obtained on a
JEOL-GCmate or a JEOL-SX 102A instrument (3-NOBA as
matrix), respectively. Column chromatography was performed
on silica gel 60 PF254 (Nacalai Tesque) under pressure. The
experimental details for the preparation of the radical pre-
cursors 16a–c are described in the ESI.†
Radical cyclisation of compound 16a
General procedure. To a stirred, refluxing solution of 16a (493
mg, 0.99 mmol) in toluene (100 cm3) was added a solution of
Bu3SnH (780 mg, 2.68 mmol) and AIBN (53 mg, 0.32 mmol) in
toluene (100 cm3) via a syringe during 1 h, and the mixture was
further refluxed for 2 h. After removal of the solvent in vacuo,
diethyl ether (30 cm3) and 8% aq. KF (50 cm3) were added to
the residue, and the whole was vigorously stirred at room
temperature for 1 h. The organic phase was separated, dried
(MgSO4), and concentrated. The residue was chromatographed
on silica gel [hexane–AcOEt (10 : 1)] to give a mixture of
the (E) and (Z) geometrical isomers (in a ratio of 58 : 42)
of methyl 9-benzoyl-4-(trimethylsilylmethylene)-9-azabicyclo-
[3.3.1]nonane-1-carboxylate 17a (360 mg, 98%), mp 98.5–99 ЊC
[from petroleum ether (distillation range 80–110 ЊC)] (Found:
C, 67.80; H, 8.16; N, 3.80. C21H29NO3Si requires C, 67.89; H,
7.87; N, 3.77%); νmax (CCl4)/cmϪ1 1745 and 1650; δH (300 MHz;
CDCl3) (the line-broadening of each signal occurred due to
slow conformational exchange on the 1H-NMR time scale)
Ϫ0.28 (9 H × 58/100, br s), 0.09 (9 H × 42/100, br s), 1.60–2.05
(6 H, unresolved m), 2.15–2.88 (4 H, unresolved m), 3.707
(3 H × 42/100, s), 3.713 (3 H × 58/100, s), 4.47 (0.42 H, br s),
4.75 (0.58 H, br s), 4.88–5.18 (0.42 H, br), 5.20 (0.58 H, br s),
7.36–7.46 (3 H, m, ArH) and 7.47–7.55 (2 H, m, ArH).
Scheme 4 Reagents and conditions: i, NaBH4, MeOH; ii, Martin
sulfurane, benzene, 80 ЊC; iii, LDA, THF, Ϫ78 ЊC; then Comins’
reagent; iv, Me2NHؒBH3, cat. Pd(PPh3)4, K2CO3, MeCN, 40 ЊC; v, BH3ؒ
THF, THF; then aq. NaOH, H2O2; vi, TPAP, NMO, 4Å-MS, CH2Cl2.
Hydroboration of the alkene 23 with borane–THF complex
and oxidation of the intermediate gave a mixture of two
alcohols which were separated by silica gel chromatography to
give the alcohols 26 and 27 in 31 and 39% yield, respectively.
In an attempt to improve the regioselectivity, 9-BBN was
used instead of borane–THF complex but the starting material
was recovered unchanged. The structure and stereochemistry
of the alcohol 26 were confirmed by oxidation with TPAP–
NMO14 to the ketone 19c (95% yield) and the aforementioned
smooth dehydration with Martin sulfurane to the alkene 23
(85% yield). The assigned stereochemistry of the alcohols
22 and 26 is consistent with the view that both hydride and
borane approach from the less crowded convex face of the
ketone 19c and the alkene 23, respectively. The structure and
stereochemistry of the alcohol 27 were assigned on the basis
Radical cyclisation of compound 16b
Following the general procedure, 16b (202 mg, 0.46 mmol) was
treated with Bu3SnH (332 mg, 1.14 mmol) and AIBN (22 mg,
0.13 mmol) in toluene (45 cm3) and the crude mixture
was chromatographed on silica gel [hexane–AcOEt (20 : 1)].
The first fraction gave a mixture of (E) and (Z) geometrical
isomers of 9-benzoyl-2-(trimethylsilylmethylene)-9-azabicyclo-
[3.3.1]nonane 17b (96 mg, 67%) as a colourless oil (Found: Mϩ,
313.1856. C19H27NOSi requires M, 313.1862); νmax (film)/cmϪ1
1631; δH (400 MHz; CDCl3) (because of the presence of mainly
two rotamers for each geometrical isomer, the spectrum cannot
be well analysed due to its complexity) Ϫ0.27, 0.10, 0.13 and
0.20 (total 9 H, all s, SiMe3, in the proportions ca. 37 : 18 : 16 : 29,
respectively), 1.22–2.26, 2.33–2.47, 2.56–2.64 and 2.74–2.90
(total 10 H, all m), 3.89–3.99 (m), 4.25 (br s), 4.53 (br s), 4.69–
4.72 (m), 4.90–5.40 (m), 5.09–5.15 (br), 5.18 (br s), 5.30 (br s),
5.38 (br s), 5.43 (br s) and 5.55 (br s) (total 3 H) and 7.34–7.42
(5 H, m, ArH).
The second fraction gave 10b-[4-(trimethylsilyl )but-3-ynyl]-
1,2,3,4,6,10b-hexahydropyrido[2,1-a]isoindol-6-one 20 (32 mg,
22%) as a colourless oil (Found: Mϩ, 311.1700. C19H25NOSi
requires M, 311.1705); νmax (film)/cmϪ1 2175 and 1693; δH (400
MHz; CDCl3) (a mixture of mainly three rotamers in the pro-
portions 75 : 21 : 4, for the major rotamer) 0.09 (9 H, s, SiMe3),
1.25–1.39 (2 H, m), 1.47 (1 H, ddd, J 17.0, 11.2 and 5.1), 1.69–
1.89 (5 H, m), 2.01 (1 H, ddd, J 14.3, 11.2 and 5.1), 2.15 (1 H, br
d, J 13.4), 2.54 (1 H, ddd, J 14.3, 11.2 and 5.3), 2.89 (1 H, td,
J 13.4 and 3.3), 4.42 (1 H, ddt, J 13.4, 5.1 and 1.3), 7.37 (1 H, dt,
J 7.5 and 1.1, ArH), 7.44 (1 H, td, J 7.5 and 1.1, ArH), 7.54
(1 H, td, J 7.5 and 1.3, ArH) and 7.84 (1 H, dt, J 7.5 and 1.3,
ArH).
1
of H NMR spectroscopic evidence (the axial proton at the
3-position appeared at δ 4.62 as a triplet of triplets with
coupling constants of 11.0 and 6.4 Hz) and oxidation with
TPAP–NMO to the ketone 28 quantitatively. The ketone 28
is a potential precursor for the synthesis of ( )-euphococcinine
29.
In summary, we have revealed that 2-(but-3-ynyl)-1-(o-iodo-
benzoyl)piperidines undergo radical translocation and 6-exo-
dig cyclisation to give the 9-azabicyclo[3.3.1]nonane ring system
in high yields.
Experimental
Mps were measured on a Yanaco MP-J3 micro melting-point
apparatus and are uncorrected. IR spectra were recorded on a
JASCO-IR-A-100 or a JASCO-FT/IR-410 spectrophotometer.
1H NMR (60, 300 and 400 MHz) and 13C NMR (75.4 and
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J. Chem. Soc., Perkin Trans. 1, 2002, 1438–1443

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Methyl 9-benzoyl-4-methylene-9-azabicyclo[3.3.1]nonane-1-
carboxylate 18a
327.2021. C20H29NOSi requires M, 327.2018); νmax (film)/cmϪ1
1651; δH (400 MHz; CDCl3) Ϫ0.31 (9 H × 1/2, s), 0.08 (9 H ×
1/2, s), 1.57–2.28 (8 H, m), 1.66 (3 H × 1/2, s), 1.70 (3 H × 1/2,
s), 2.37–2.53 (1 H, m), 2.59–2.71 (0.5 H, m), 2.79–2.92 (0.5 H,
m), 4.29 (0.5 H, br s), 4.61 (0.5 H, br s), 4.93 (0.5 H, br s), 5.14
(0.5 H, br s) and 7.32–7.53 (5 H, m, ArH).
To a solution of 17a (300 mg, 0.80 mmol) in DCM (5 cm3) was
added trifluoroacetic acid (226 mg, 1.98 mmol) at 0 ЊC and the
whole was stirred for 15 min. The mixture was evaporated
in vacuo and the residue was chromatographed on silica gel
[hexane–AcOEt (20 : 1)] to give 18a (172 mg, 72%), mp 113–114
ЊC (from hexane–AcOEt) (Found: C, 72.32; H, 7.05; N, 4.71.
C18H21NO3 requires C, 72.22; H, 7.07; N, 4.68%); νmax (CCl4)/
cmϪ1 1740 and 1650; δH (60 MHz; CDCl3) 1.6–2.9 (10 H, m),
3.68 (3 H, s, OMe), 4.4–4.5 (1 H, m, 5-H), 4.50 and 4.78 (total
9-Benzoyl-1-methyl-4-methylene-9-azabicyclo[3.3.1]nonane 18c
Following the procedure described for the preparation of 18a,
17b (310 mg, 0.95 mmol) was treated with trifluoroacetic acid
(236 mg, 2.07 mmol) in DCM (5 cm3) and the crude product
was chromatographed on silica gel [hexane–AcOEt (20 : 1)]
to give 18c (215 mg, 89%) as a colourless oil (Found: Mϩ,
255.1630. C17H21NO requires M, 255.1623); νmax (film)/cmϪ1
1648; δH (300 MHz; CDCl3) 1.57–2.19 (7 H, m), 1.69 (3 H, s,
1-Me), 2.29–2.46 (2 H, m), 2.65–2.78 (1 H, m), 4.34–4.37 (1 H,
unresolved m, 5-H), 4.47 (1 H, br s, alkenic), 4.73–4.76 (1 H, m,
alkenic), 7.33–7.43 (3 H, m, ArH) and 7.47–7.51 (2 H, m, ArH);
δC (75.5 MHz; CDCl3) 19.7, 30.3, 31.1, 31.5, 37.0, 38.8, 55.2,
60.6, 109.2, 127.5, 128.3, 129.9, 138.5, 146.7 and 173.7.
2 H, both br s, C᎐CH ) and 7.2–7.7 (5 H, m, ArH).
᎐
2
Methyl 9-benzoyl-4-oxo-9-azabicyclo[3.3.1]nonane-1-
carboxylate 19a
A stream of ozone-enriched oxygen was passed through a solu-
tion of 18a (90 mg, 0.30 mmol) in DCM (5 cm3) at Ϫ78 ЊC for
10 min. After purge of any unchanged excess of ozone by nitro-
gen flow, triphenylphosphine was added (87 mg, 0.33 mmol)
to the reaction mixture, which was then stirred at room tem-
perature for 15 min. The mixture was evaporated in vacuo and
the residue was chromatographed on silica gel [hexane–AcOEt
(10 : 1)] to give 19a (54 mg, 60%), mp 149.5–150 ЊC (from
hexane–AcOEt) (Found: C, 67.81; H, 6.16; N, 4.72. C17H19NO4
requires C, 67.76; H, 6.36; N, 4.65%) (Found: Mϩ, 301.1309.
C17H19NO4 requires M, 301.1314); νmax (film)/cmϪ1 1732 and
1646; δH (400 MHz; CDCl3) 1.45–1.59 (1 H, m), 1.76–1.93 (4 H,
m), 2.01–2.09 (1 H, br), 2.26 (1 H, td, J 13.5 and 4.2), 2.43–2.62
(2 H, unresolved m), 3.13–3.39 (1 H, br), 3.76 (3 H, s, OMe),
4.32 (1 H, dd, J 6.2 and 3.7, 5-H), 7.39–7.44 (2 H, m, ArH) and
7.46–7.54 (3 H, m, ArH).
9-Benzoyl-1-methyl-9-azabicyclo[3.3.1]nonan-4-one 19c
Following the procedure described for the preparation of 19a,
18c (263 mg, 1.03 mmol) was treated with ozone-enriched
oxygen in DCM (5 cm3) and then triphenylphosphine (278 mg,
1.06 mmol). The crude mixture was chromatographed on silica
gel [hexane–AcOEt (10 : 1)] to give 19c (189 mg, 71%), mp 56–
57 ЊC (from hexane) (Found: Mϩ, 257.1414. C16H19NO2
requires M, 257.1416); νmax (KBr)/cmϪ1 1724 and 1651; δH (300
MHz; CDCl3) 1.44–2.05 (7 H, m), 1.83 (3 H, s, 1-Me), 2.38–2.52
(2 H, m), 2.61–2.73 (1 H, m), 4.19 (1 H, br t, J 4.0, 5-H) and
7.35–7.50 (5 H, m, ArH); δC (75.5 MHz; CDCl3) 18.7, 28.1,
30.7, 31.6, 37.7, 40.9, 55.4, 65.8, 127.7, 128.7, 130.8, 136.9,
174.5 and 213.8.
9-Benzoyl-2-methylene-9-azabicyclo[3.3.1]nonane 18b
Following the procedure described for the preparation of 18a,
17b (40 mg, 0.13 mmol) was treated with a solution of tri-
fluoroacetic acid (41 mg, 0.36 mmol) in DCM (3 cm3). The
crude product was chromatographed on silica gel [hexane–
AcOEt (7 : 1)] to give 18b (22 mg, 70%) as a colourless
oil (Found: Mϩ, 241.1465. C16H19NO requires M, 241.1467);
νmax (film)/cmϪ1 1628; δH (400 MHz; CDCl3, for a mixture of
two rotamers in a ratio of 1 : 1) 1.52–1.83 (5 H, m), 1.90–2.05
(2.5 H, m), 2.11–2.21 (0.5 H, m), 2.32–2.41 (1 H, m), 2.58–2.68
(1 H, m), 3.91–3.97 (0.5 H, unresolved m), 4.30 (0.5 H, br s),
4.54 (0.5 H, br s), 4.81 (0.5 H, br s), 4.92–4.99 (1.5 H,
unresolved m), 5.35 (0.5 H, br s) and 7.37–7.42 (5 H, m, ArH).
9-Benzoyl-4ꢀ-hydroxy-1-methyl-9-azabicyclo[3.3.1]nonane 22
To a solution of 19c (395 mg, 1.54 mmol) in methanol (7 cm3)
was added NaBH4 (43 mg, 1.13 mmol) at room temperature
and the whole was stirred for 5 min. 5% HCl (5 cm3) was added
to the mixture and the solution was extracted with AcOEt. The
organic layer was dried and concentrated. The residue was
chromatographed on silica gel [hexane–AcOEt (1 : 1)] to give 22
(324 mg, 81%), mp 155–156 ЊC (from AcOEt) (Found: Mϩ,
259.1565. C16H21NO2 requires M, 259.1572); νmax (film)/cmϪ1
3388, 1645 and 1620; δH (300 MHz; CDCl3) 1.54–1.80 (4 H, m),
1.61 (3 H, s, 1-Me), 1.85 (1 H, br s, OH), 1.92–2.15 (6 H, m),
3.81 (1 H, t, J 5.2), 3.95 (1 H, ddd, J 9.5, 7.5 and 5.2) and 7.33–
7.50 (5 H, m, ArH); δC (75.5 MHz; CDCl3) 20.5, 22.7, 30.1,
30.6, 36.9, 37.4, 54.8, 57.3, 69.9, 127.1, 128.5, 130.0, 138.4 and
173.9.
9-Benzoyl-9-azabicyclo[3.3.1]nonan-2-one 19b
Following the procedure described for the preparation of 19a,
18b (22 mg, 0.09 mmol) was treated with ozone-enriched
oxygen in DCM (5 cm3) and then triphenylphosphine (20 mg,
0.08 mmol). The crude mixture was chromatographed on silica
gel [hexane–AcOEt (10 : 1)] to give 19b (17 mg, 78%), mp 87.5–
88.5 ЊC (from hexane–AcOEt) (Found: Mϩ, 243.1256.
C15H17NO2 requires M, 243.1259); νmax (KBr)/cmϪ1 1729 and
1633; δH (400 MHz; CDCl3) 1.49–1.84, 1.88–2.01 and 2.12–2.19
(total 7 H, all m), 2.35–2.69 (3 H, m), 4.17 (br s) and 4.25 (br d,
J 9.5) (total 1 H), 5.14–5.21 (1 H, br) and 7.33–7.49 (5 H, m,
ArH).
Dehydration of 22 with Martin sulfurane
To a solution of 22 (100 mg, 0.39 mmol) in benzene (10 cm3)
was added Martin sulfurane {bis[α,α-bis(trifluoromethyl)-
phenylmethyloxy]diphenyl-λ4-sulfane} (1.04 g, 1.54 mmol) and
the solution was heated under reflux for 16 h. After cooling,
the reaction mixture was diluted with saturated aq. NaHCO3
and the organic phase was separated. The aqueous phase was
extracted with diethyl ether, then the combined organic phase
was washed with brine, dried (MgSO4), and concentrated. The
crude material was chromatographed on silica gel [hexane–
AcOEt (15 : 1)]. The first fraction gave 9-benzoyl-1-methyl-9-
azabicyclo[3.3.1]non-3-ene 23 (5 mg, 5%) as a colourless oil
(Found: Mϩ, 241.1461. C16H19NO requires M, 241.1467); νmax
(film)/cmϪ1 1649; δH (400 MHz; CDCl3) 1.39 (1 H, dtd, J 12.9,
4.3 and 2.4), 1.54–1.61 (2 H, m), 1.68 (3 H, s, 1-Me), 1.77 (1 H,
dt, J 12.9 and 4.0), 1.83 (1 H, ddd, J 12.6, 4.3 and 1.6), 1.92
(1 H, tt, J 12.6 and 4.0), 2.03 (1 H, ddd, J 18.6, 4.3 and 1.9), 2.72
Radical cyclisation of compound 16c
Following the general procedure, 16c (140 mg, 0.31 mmol) was
treated with Bu3SnH (203 mg, 0.70 mmol) and AIBN (14 mg,
0.09 mmol) in toluene (50 cm3) and the crude mixture was
chromatographed on silica gel [hexane–AcOEt (20 : 1)] to give a
mixture of (E) and (Z) geometrical isomers (in a ratio of 1 : 1)
of 9-benzoyl-1-methyl-4-(trimethylsilylmethylene)-9-azabicyclo-
[3.3.1]nonane 17c (96 mg, 95%) as a colourless oil (Found: Mϩ,
J. Chem. Soc., Perkin Trans. 1, 2002, 1438–1443
1441

View Article Online
(1 H, br d, J 18.6), 4.33 (1 H, t like br s), 5.47 (1 H, dddd, J 9.8,
4.3, 2.4 and 1.9), 5.95 (1 H, dddd, J 9.8, 4.3, 3.1 and 0.7), 7.35–
7.43 (3 H, m, ArH) and 7.51–7.54 (2 H, m, ArH); δC (100.5
MHz; CDCl3) 17.4, 27.8, 30.5, 38.0, 41.6, 54.8 (CH), 55.0
(quaternary), 126.5, 127.5, 128.3, 129.1, 129.9, 138.4 and 173.7.
The second fraction gave 9-benzoyl-4β-[bis(trifluoromethyl )-
phenylmethoxy]-1-methyl-9-azabicyclo[3.3.1]nonane 24 (106 mg,
57%) as a colourless oil (Found: Mϩ, 485.1787. C25H25F6NO2
requires M, 485.1789); νmax (film)/cmϪ1 1653; δH (300 MHz;
CDCl3) 1.50–1.82 (4 H, m), 1.57 (3 H, s, 1-Me), 1.92–2.32 (6 H,
m), 3.89–4.01 (2 H, m) and 7.21–7.46 (10 H, m, ArH).
ЊC (from hexane–AcOEt) (Found: C, 73.71; H, 8.30; N, 5.11.
C16H21NO2 requires C, 74.10; H, 8.16; N, 5.40); (Found: Mϩ,
259.1575. C16H21NO2 requires M, 259.1572); νmax (film)/cmϪ1
3399, 1639 and 1624; δH (400 MHz; CDCl3, OH was not
observed) 1.48–2.10 (8 H, m), 1.58 (3 H, s, 1-Me), 2.25–2.38
(2 H, m), 3.75–3.78 (1 H, unresolved m), 3.99–4.03 (1 H,
unresolved m), 7.33–7.41 (3 H, m, ArH) and 7.52–7.56 (2 H, m,
ArH); δC (100.5 MHz; CDCl3) 19.5, 25.9, 29.3, 31.3, 32.1, 38.5,
55.1, 58.9, 69.9, 127.7, 128.3, 129.8, 138.9 and 175.1.
The second fraction gave 9-benzoyl-3β-hydroxy-1-methyl-9-
azabicyclo[3.3.1]nonane 27 (16 mg, 39%), mp 167–68 ЊC (from
hexane–AcOEt) (Found: C, 73.91; H, 8.17; N, 5.29%) (Found:
Mϩ, 259.1562); νmax (film)/cmϪ1 3399, 1645 and 1623; δH (400
MHz; CDCl3, OH was not observed) 1.50–1.68 (3 H, m), 1.68
(3 H, s, 1-Me), 1.69–1.81 (3 H, m), 1.86 (1 H, ddd, J 13.3, 11.0
and 2.3), 1.94 (1 H, ddt, J 13.3, 6.4 and 1.8), 1.97–2.07 (1 H, m),
2.03 (1 H, ddd, J 13.3, 6.4 and 1.5), 4.04–4.08 (1 H, unresolved
m), 4.62 (1 H, tt, J 11.0 and 6.4), 7.36–7.42 (3 H, m, ArH) and
7.49–7.53 (2 H, m, ArH); δC (100.5 MHz; CDCl3) 21.1, 29.5,
31.0, 37.1, 39.9, 47.8, 54.0, 56.4, 64.8, 127.1, 128.5, 130.0, 138.4
and 173.5.
9-Benzoyl-4-(trifluoromethylsulfonyloxy)-1-methyl-9-
azabicyclo[3.3.1]non-3-ene 25
To a solution of LDA [1.94 mmol, prepared from diisopro-
pylamine (197 mg, 1.94 mmol) and a 1.6 mol dmϪ3 solution of
butyllithium in hexane (1.25 cm3, 1.94 mmol) at 0 ЊC] in THF
(2 cm3) was added dropwise a solution of 19c (200 mg,
0.77 mmol) in THF (2 cm3) and the whole was stirred at Ϫ78 ЊC
for 1 h. To this mixture was added a solution of Comins’
reagent {2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloro-
pyridine} (458 mg, 1.17 mmol) at Ϫ20 ЊC and the reaction
mixture was allowed to warm to room temperature overnight.
After the mixture had been diluted with 5% HCl at 0 ЊC it
was extracted with diethyl ether and the extract was washed
successively with 5% aq. NaOH and brine, dried (MgSO4), and
concentrated. The residue was chromatographed on silica gel
[hexane–AcOEt (15 : 1)]. The first fraction gave 25 (188 mg,
63%) as a colourless oil (Found: Mϩ, 389.0903. C17H18F3NO4S
requires M, 389.0908); [Found: (M ϩ H)ϩ, 390.0983. C17H19-
F3NO4S requires MHϩ, 390.0987]; νmax (film)/cmϪ1 1660, 1419,
1211 and 1142; δH (400 MHz; CDCl3) 1.61–1.75 (3 H, m), 1.69
(3 H, s, 1-Me), 1.77–1.92 (3 H, m), 2.21 (1 H, dd, J 18.5 and 4.9,
one of 2-H2), 2.94 (1 H, ddt, J 18.5, 3.1 and 1.5, one of 2-H2),
4.37 (1 H, br s, 5-H), 5.98 (1 H, dd, J 4.9 and 3.1, 3-H), 7.34–
7.49 (3 H, m, ArH) and 7.54–7.58 (2 H, m, ArH); δC (100.5
MHz; CDCl3) 17.4 (CH2), 25.3 (CH2), 29.3 (1-Me), 35.8 (CH2),
40.8 (CH2), 54.1 (1-C), 56.2 (5-C), 119.2 (3-C), 127.9 (ArC),
128.5 (ArC), 131.0 (ArC), 136.6 (ArC), 145.5 (2-C) and 174.8
Dehydration of 26 with Martin sulfurane
Following the procedure described for the dehydration of 22, 26
(9 mg, 34 µmol) was treated with a solution of Martin sulfurane
(93 mg, 138 µmol) in benzene (5 cm3) and the crude product was
purified by column chromatography on silica gel [hexane–
AcOEt (15 : 1)] to give 23 (7 mg, 85%).
9-Benzoyl-1-methyl-9-azabicyclo[3.3.1]nonan-3-one 28
To a solution of 27 (9 mg, 34 µmol) in DCM (3 cm3) containing
molecular sieves 4Å (10 mg) were added TPAP (2.4 mg,
6.8 µmol) and NMO (8.1 mg, 69 µmol) at room temperature
and the whole was stirred for 15 min. After filtration of the
insoluble material using AcOEt the filtrate was concentrated.
The residue was chromatographed on silica gel [hexane–AcOEt
(2 : 1)] to give 28 (9 mg, quant.) as a colourless oil (Found: Mϩ,
257.1412. C16H19NO2 requires M, 257.1416); νmax (film)/cmϪ1
1711 and 1650; δH (400 MHz; CDCl3) 1.55–1.75 (4 H, m), 1.74
(3 H, s, 1-Me), 1.83–1.99 (2 H, m), 2.27 (1 H, dt, J 16.3 and 1.5),
2.42 (1 H, dd, J 16.3 and 1.8), 2.47 (1 H, dd, J 16.3 and 7.0),
2.96 (1 H, br d, J 16.3), 4.35–4.39 (1 H, unresolved m, 5-H),
7.40–7.51 (3 H, m, ArH) and 7.58–7.61 (2 H, m, ArH); δC (100.5
MHz; CDCl3) 17.8, 29.6, 30.6, 39.4, 45.2, 51.8, 54.2, 57.2, 127.7,
128.7, 130.9, 137.3, 174.7 and 209.2.
(C᎐O).
᎐
The second fraction gave the unchanged starting material 19c
(53mg, 27% recovery).
9-Benzoyl-1-methyl-9-azabicyclo[3.3.1]non-3-ene 23
To a solution of 25 (45 mg, 0.11 mmol) in acetonitrile (3 cm3)
were added borane–dimethylamine complex (7 mg, 0.11 mmol),
tetrakis(triphenylphosphine)palladium() (7 mg, 5.8 µmol) and
potassium carbonate (16 mg, 0.11 mmol) and the whole was
heated at 40 ЊC for 1 h. After the solution had been diluted with
diethyl ether (5 cm3) and water (5 cm3) the organic phase was
separated and the aqueous phase was further extracted with
diethyl ether. The combined organic phase was dried (MgSO4),
and concentrated. The residue was chromatographed on silica
gel [hexane–AcOEt (15 : 1)] to give 23 (27 mg, 97%) as a colour-
less oil.
Oxidation of alcohol 26 to 19c
Following the procedure described for the preparation of 28, 26
(3.3 mg, 12.7 µmol) was treated with TPAP (1.3 mg, 3.60 µmol)
and NMO (3.0 mg, 25.4 µmol) and the crude material was
chromatographed on silica gel [hexane–AcOEt (10 : 1)] to give
19c (3.1 mg, 95%).
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To a solution of 23 (40 mg, 0.16 mmol) in THF (1 cm3) was
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methyl-9-azabicyclo[3.3.1]nonane 26 (13 mg, 31%), mp 136–137
1442
J. Chem. Soc., Perkin Trans. 1, 2002, 1438–1443

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J. Chem. Soc., Perkin Trans. 1, 2002, 1438–1443
1443