Radical deoxygenation of 3-azatricyclo[2.2.1.02,6]heptan-5-ols to 2-azabicyclo[2.2.1]hept-5-enes and 1,2-dihydropyridines

Article abstract of DOI:10.1016/j.tet.2009.07.022

Additions of alkyl or aryl Grignard reagents, or pyridin-3-yl-lithiums or lithium alkoxides, to exo-5,6-epoxy-7-(tert-butoxycarbonyl)-2-tosyl-7-azabicyclo[2.2.1]hept-2-ene lead to 7-substituted-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols. Rad

Full text of DOI:10.1016/j.tet.2009.07.022

Tetrahedron 65 (2009) 7825–7836
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Radical deoxygenation of 3-azatricyclo[2.2.1.02,6]heptan-5-ols
to 2-azabicyclo[2.2.1]hept-5-enes and 1,2-dihydropyridines
,
a
a
a
David M. Hodgson a , Matthew L. Jones , Christopher R. Maxwell , Andrew R. Cowley ,
*
Amber L. Thompson a, Osamu Ichihara b, Ian R. Matthews c
a Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
b Evotec (UK) Ltd, 114 Milton Park, Abingdon, Oxfordshire OX14 4SA, UK
c Syngenta, Jealott’s Hill International Research Centre, Berkshire RG42 6EY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Additions of alkyl or aryl Grignard reagents, or pyridin-3-yl-lithiums or lithium alkoxides, to exo-5,6-
epoxy-7-(tert-butoxycarbonyl)-2-tosyl-7-azabicyclo[2.2.1]hept-2-ene lead to 7-substituted-1-tosyl-3-aza-
tricyclo[2.2.1.02,6]heptan-5-ols. Radical deoxygenations of 7-alkyl-1-tosyl-3-azatricyclo[2.2.1.02,6]heptan-5-ols
give 7-alkyl-4-tosyl-2-azabicyclo[2.2.1]hept-5-enes, whereas 7-aryl-1-tosyl-3-azatricyclo[2.2.1.02,6]heptan-
5-ols give 2-(arylmethyl)-5-tosyl-1,2-dihydropyridines.
Received 21 April 2009
Received in revised form 16 June 2009
Accepted 2 July 2009
Available online 9 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
system, homoallylic radical 3 (ent-3) forms regardless of which
cyclopropyl bond cleaves from radical 2.
Radical cyclisations and rearrangements are versatile processes
for the synthesis of ring systems.1 An important radical process is the
cyclopropylmethyl–homoallyl rearrangement.2 Bridged nortricyclyl
(tricyclo[2.2.1.02,6]heptanyl)–norbornenyl (bicyclo[2.2.1]heptenyl)
examples were well-studied in the 1950s and 1960s. For example,
starting from nortricyclyl bromide 1 or norbornenyl bromide 4, re-
action with Bu3SnH and AIBN at low concentration of H-atom donor
led to the same (approximately equal) mixture of nortricyclane 5 and
norbornene 6 (Scheme 1), whereas varying the concentration led to
varying proportions of nortricyclane 5 and norbornene 6, fromwhich
it was concluded that the process involves classical radicals 2 and 3,
rather than a single non-classical species.3 Formation of significant
quantities of nortricyclane 5 is partly a reflection of strain in the
norbornenyl system. Note also that, in this degenerate/symmetrical
In contrast to the generation of a mixture of nortricyclane 5 and
norbornene 6 from radical reduction of nortricyclyl bromide 1
(Scheme 1), we previously showed during the development of novel
analgesics (e.g., 10) related to epibatidine 11 (Scheme 2) that radical
deoxygenation of 7-azanortricyclanols
7 selectively gave 6-
substituted 2-azabicyclo[2.2.1]hept-5-enes 9, even when R is po-
tentially radical stabilising (e.g., aryl).4 The potential dative stabilising
effect of an a
-nitrogen in the product-producing radical5 likely di-
rects this homoallylic radical rearrangement.6 An earlier example of
the influence of nitrogen on a homoallylic radical rearrangement was
observed by Rigby and Pigge in an 8-azabicyclo[3.2.1] system.7 We
have subsequently used this concept in the synthesis of other aza-
cycles,8 including kainic acid,9 ibogamine10 and fused aromatic sys-
tems.11 In the present paper we detail studies originally designed to
Boc
Bu3Sn
Bu3Sn
Br
Br
Boc
N
Boc
N
N
1. ClCOCO2Me,
DMAP
OH
R
R
3
2
1
4
R
2. Bu3SnH,
AIBN
8
9
7
+
H
5
6
N
Cl
N
Cl
N
H
N
Scheme 1.
10
11 epibatidine
* Corresponding author. Fax: þ44 (0)1865 285002.
E-mail address: david.hodgson@chem.ox.ac.uk (D.M. Hodgson).
Scheme 2.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.022

7826
D.M. Hodgson et al. / Tetrahedron 65 (2009) 7825–7836
broaden the scope of the above strategy to give differently
substituted 2-azabicyclo[2.2.1]hept-5-enes,12 but, which have also
led to finding an extended radical rearrangement process to give 1,2-
dihydropyridines,13 as well as alternative fragmentation–rearrange-
ment modes in heterosubstituted systems.
N
MeO
OH
MeO
a
N
Boc
N
Boc
N
O
SMe
b
13
S
Ts
Ts
18
14e
c
2. Results and discussion
MeO
N
MeO
N
Boc
N
Boc
N
Epoxide 13 (readily available from cycloaddition of the com-
mercial materials N-Boc pyrrole and tosyl ethyne,14 followed by
epoxidation of the resulting bicyclic diene 12)15 underwent exo-
O
SMe
SSnBu3
Ts
Ts
selective attack at the a,b-unsaturated sulfone functionality with
20
19
alkyl Grignard reagents, to give the corresponding substituted 7-
azanortricyclanols 14a–c in excellent yields (90–96%, Scheme 3).
While conjugate reduction–transannular cyclisation using LiAlH4
gave the parent 7-azanortricyclanol 14d (42%), the latter was more
reproducibly accessed by base-induced transannular cyclisation16
of sulfone epoxide 16 (available from bicyclic diene 12 by conjugate
reduction using NaBH4 to give known alkene 15,14 followed by ep-
oxidation with MCPBA). Subsequent radical deoxygenation (via the
xanthates)17 of 7-azanortricyclanols 14a–d using Bu3SnH (2 equiv)
gave the anticipated 2-azabicyclo[2.2.1]heptenes 17a–d (45–65%).18
Boc
N
Boc
N
N
N
d
OMe
Ts
X
OMe
21a
22 (X = Ts)
23 (X = H)
e
Scheme 4. (a) 6-Methoxypyridin-3-ylLi, THF, ꢀ78 ꢁC, 78%); (b) KH, CS2, MeI, THF, 80%;
(b) Bu3SnH, AIBN, toluene, reflux, 78%; (c) H2 (2 atm), 10% Pd/C, toluene, 87%; (d) 6%
Na-Hg, MeOH, 55%.
Boc
N
Boc
N
Boc
N
Boc
Boc
N
N
R
OH
O
a15
Ar
Ar
OH
b
a
b, c
13
Ts
Ts
Ts
Ts
13
Ts
Ts
12
c14
14a (R = Me)
14b (R = i-Pr)
14c (R = t-Bu)9
14d (R = H)
Ts
14f (Ar = 4-MeOC6H4)
14g (Ar = Ph)
14h (Ar = pyridin-3-yl)
21b (Ar = 4-MeOC6H4)
21c (Ar = Ph)
21d (Ar = pyridin-3-yl)
e
Boc
N
Boc
N
f, g
d
O
d
(from 14f)
f, g
(to 21b)
MeO
MeO
Boc
N
Boc
15
16
Boc
N
N
O
17a (R = Me)
17b (R = i-Pr)
17c (R = t-Bu)9
17d (R = H)
e
R
OH
Ts
Ts
24
25
Ts
Scheme 5. (a) ArMgBr, THF, 0 ꢁC (Ar¼4-MeOC6H4, 72%; Ph, 82%), or pyridin-3-ylLi,
TMEDA, THF, ꢀ78 ꢁC, 74%, (b) KH, CS2, MeI, THF (Ar¼4-MeOC6H4, 84%; Ph, 95%; pyr-
idin-3-yl, 77%); (c) Bu3SnH, AIBN, toluene, reflux (R¼4-MeOC6H4, 62%; Ph, 65%; pyr-
idin-3-yl, 52%); (d) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC, 98%; (e) i-PrMgCl, THF, 77%;
(f) KH, CS2, MeI, THF, 72%; (g) Bu3SnH, AIBN, toluene, reflux, 33%.
Scheme 3. (a) MCPBA, CH2Cl2, reflux, 62%; (b) RMgBr, THF, ꢀ78 ꢁC (R¼Me, 96%; i-Pr,
90%; t-Bu, 92%), or (R¼H) LiAlH4, THF, 42%; (c) NaBH4, MeOH, 73%; (d) MCPBA, CH2Cl2,
reflux, 40%; (e) MeLi, THF, 0 ꢁC, 67%; (f) KH, CS2, MeI, THF [R¼Me (57%), t-Bu (92%), H
(59%)], or 1,10-thiocarbonyldiimidazole, CH2Cl2 [R¼i-Pr (92%)]; (g) Bu3SnH, AIBN, tol-
uene, reflux [R¼Me (65%), i-Pr (52%), t-Bu (45%), H (59%)].
In attempting to apply the above chemistry towards new epi-
batidine analogues, Bu3SnH (2 equiv)-induced deoxygenation of
the xanthate 18 (0.02 M in toluene) of 6-methoxypyridin-3-yl
lithium-derived 7-azanortricyclanol 14e (78%) was examined
(Scheme 4). However, none of the expected 2-azabicyclo[2.2.1]-
hept-5-ene 17 (R¼6-methoxypyridin-3-yl) was detected, but rather
the reaction proceeded cleanly to give 1,2-dihydropyridine 21a
(78%). All spectroscopic data (including 1H–1H and 1H–13C corre-
lation spectra) were fully in accord with the structural assignment.
Use of Bu3SnD instead of Bu3SnH in the deoxygenation resulted in
deuterium incorporation in the methylene group of 1,2-dihy-
dropyridine 21a; the latter is what would be expected from the 19
to 20 fragmentation pathway indicated in Scheme 4. Further sup-
porting evidence for the product of deoxygenation was obtained by
partial hydrogenation and desulfonylation; the resulting tetrahy-
dropyridines 22 and 23 both exhibited analytical data consistent19
with the proposed structures.
14f (R¼4-MeOC6H4; the structural assignment was supported by
X-ray crystallographic analysis20) initially gave a modest yield (31%)
of the corresponding dihydropyridine 21b (R¼4-MeOC6H4). This
might be due to stannyl radical attack on the product, since sub-
jecting dihydropyridine 21b (R¼4-MeOC6H4) to the reaction condi-
tions resulted in 60% decomposition, whereas simply boiling
dihydropyridine 21b (R¼4-MeOC6H4) in toluene for 2 h resulted in no
discernible decomposition (1H NMR analysis). With these observa-
tions in mind, we reduced the quantity of Bu3SnH to 1.1 equiv and
increased the time over which it was added from 20 min to 2.25 h.
These latter conditions gave the desired dihydropyridine 21b (R¼4-
MeOC6H4) in satisfactory and reproducible yields (62%). Variation of
the thiocarbonyl moiety (thiocarbonylimidazolyl or CSOPh) gave 1,2-
dihydropyridine 21b (R¼4-MeOC6H4) in 43% and 59% yields,
respectively. Similar yields of 1,2-dihydropyridines 21c,d were ob-
served with phenyl and pyridin-3-yl substituents. The influence of
the relative configuration at the radical progenitor on the viability of
the deoxygenation/rearrangement chemistry was explored using
endo-alcohol 25,21 prepared by Swern oxidation of 7-azanor-
tricyclanol 14f (R¼4-MeOC6H4) to the ketone 24 (98%), followed by
reduction using i-PrMgBr (77%). In the event, endo-alcohol 25
Presuming that dihydropyridine formation might be favoured by
R in 14 (Scheme 3) being an electrondonatingand/oraryl substituent,
we examined additional 7-azanortricyclanols 14 bearing such func-
tionality (Scheme 5). However, the xanthate of 7-azanortricyclanol

D.M. Hodgson et al. / Tetrahedron 65 (2009) 7825–7836
7827
underwent deoxygenation to give dihydropyridine 21b (R¼4-
MeOC6H4), but in reduced yield (33%) compared to when using
exo-alcohol 14f (R¼4-MeOC6H4).
The effect of an alternative electron withdrawing group to the
sulfone substituent was also investigated, with ester-substituted 7-
azanortricyclanol 34 (Scheme 8). This alcohol was prepared by
debromination25 of the known diene 31,26 followed by epoxidation
and subsequent addition of 4-MeOC6H4MgBr. Reaction of the cor-
responding thiocarbonylimidazole with Bu3SnH gave 1,2-dihy-
dropyridine 35 as the only isolable product (46%).
Investigation of the effect on the deoxygenation/rearrangement
of a heteroatom directly bonded to the azanortricyclanol was ex-
amined by the addition of alkoxides and a lithium amide to epoxide
13. With methoxy and p-methoxybenzyloxy substituents, the
yields of the corresponding 1,2-dihydropyridines 21e,f were con-
siderably reduced (37–10%, Scheme 6), however in the latter case
removal of the PMB group using DDQ and X-ray crystallographic
analysis of the dinitrobenzoate derivative 21g of the resulting al-
cohol provided confirmation of the presence of the 1,2-dihy-
dropyridine motif (Scheme 6).22 The origins of the lower
deoxygenation yields with 7-azanortricyclanols 14i,j are not clear.
In the deoxygenation of the methoxy-substituted azanortricyclanol
14i, partial recovery (20%) of the corresponding unreacted xanthate
(which also, unusually, required heating for it to be formed in good
yield) could be indicative of a less efficient radical chain process.
Also, attempted deoxygenation of the thiocarbonate 26 of 7-aza-
nortricyclanol 14j (R¼4-MeOC6H4CH2) caused elimination to give
pyridine carbonate 28 (72%).23 The electron rich PMB ether in the
thiocarbonate 26 likely induces bond cleavages in the azatricyclic
nucleus similar to those shown in 19, but in a heterolytic manner as
shown in 26 below, to give 1,2-dihydropyridine aldehyde 27 from
which rearrangement provides the aromatic product 28.24
Boc
N
Boc
N
Boc
N
Br
O
a
b
c
MeO2C
MeO
MeO2C
MeO2C
31
32
33
Boc
Boc
N
N
OH
C6H4OMe
d,e
MeO2C
MeO2C
35
34
Scheme 8. (a) Zn/Ag, MeOH, 80%; (b) MCPBA, NaHCO3, CH2Cl2, 44%; (c) 4-MeOC6H4MgBr,
THF, 0 ꢁC, 46%; (d) 1,10-thiocarbonyldiimidazole, CH2Cl2, quant.; (e) Bu3SnH, AIBN, tolu-
ene, reflux, 46%.
3. Conclusion
Boc
N
Boc
N
The present study shows that the outcome of deoxygenation of
(1-tosyl)-3-azatricyclo[2.2.1.02,6]heptan-5-ols (7-azanortricyclanols)
is significantly influenced by the nature of the substituent at the
7-position. Alkyl (or no) substitution at the 7-position as in 14a–d
(and similarly, from our earlier study,4 5-alkyl or 5-(hetero)aryl
substitution in systems 7 lacking the tosyl group) leads to 2-aza-
bicyclo[2.2.1]hept-5-enes (e.g., 17). In certain cases, the 7-alkyl-4-
tosyl-2-azabicyclo[2.2.1]hept-5-ene products 17 may be more
concisely obtained by direct (n)-alkyl radical addition–homoallylic
OR
RO
OH
a
b
13
Ts
21e (R = Me)
21f (R = MeOC6H4CH2)
Ts
14i (R = Me)
14j (R = MeOC6H4CH2)
c
21g (R = 3,5-(NO2)2C6H3CO)
d
Ot-Bu
Ot-Bu
radical rearrangement from diene 12. In all these examples, a-N
stabilisation of the product-forming radical likely plays a significant
role. 7-Aryl substitution of (1-tosyl)-3-azatricyclo[2.2.1.02,6]-
heptan-5-ols leads on radical deoxygenation to a more extended
rearrangement to generate 1,2-dihydropyridines 21, with the
overriding driving forces likely being a combination of benzylic
radical stabilisation and full relief of ring strain. The latter extended
rearrangement is of interest as a new method for accessing dihy-
dropyridines, which are important as biologically active agents.27
One common method to prepare dihydropyridines is by nucleo-
philic addition of organometallics to N-acylpyridinium salts,
although the regioselectivity of addition (C-2/C-4) can sometimes
be problematic.28 For example, regioisomeric mixtures were
obtained in the addition of Grignard reagents to the N-benzoyl-
pyridinium salt of a pyridin-3-yl sulfonamide.29 In the present
study, reductive deoxygenation of 3-azatricyclo[2.2.1.02,6]heptan-
5-ols 14/34 [bearing an aryl or methoxy substitutent in the 7-po-
sition and an electron withdrawing group (sulfone or ester) at C-1]
is shown to provide a regiospecific route to 2,5-disubstituted 1,2-
dihydropyridines 21/35. More mesomerically electron donating
substituents at the 7-position (e.g., alkoxy, dialkylamino) reduce
the efficiency of dihydropyridine formation and lead to alternative
fragmentation–rearrangement modes.
O
Boc
O
O
O
N
PMB
O
OC(S)OPh
N
N
H
Ts
Ts
Ts
26
27
28
Scheme 6. (a) R¼Me: MeOLi, MeOH, reflux, 90%; R¼4-MeOC6H4CH2: 4-MeOC6H4-
CH2ONa, THF, 58%; (b) R¼Me: NaH, CS2, MeI, THF, reflux, 77%, then Bu3SnH, AIBN,
toluene, reflux, 37%; R¼4-MeOC6H4CH2: KH, CS2, MeI, THF, then Bu3SnH, AIBN, tolu-
ene, reflux, 10%; (c) DDQ, H2O, CH2Cl2, then 3,5-(NO2)2C6H3COCl, Et3N, CH2Cl2, 10%; (d)
PhOC(S)Cl, DMAP, MeCN, 56%, then Bu3SnH, AIBN, reflux, 72%.
In the case of the diethylamino system 14k, attempted de-
oxygenation of the corresponding xanthate with Bu3SnH returned
only starting material. In contrast, the corresponding phenyl thiocar-
bonate gave no dihydropyridine, with only the enamine 30 (Scheme
7) being isolated (likely formed via iminium 29) from reflux in
cumene under either free radical deoxygenation conditions (27%, no
reaction was observed in refluxing toluene), or simple thermal con-
ditions (38%). NOESY correlation between the proton marked HA and
the ethyl groups supports the E-geometry of the enamine 30 shown.
Boc
N
Boc
N
Boc
N
+
Et2N
−H+
Ts
OH
NEt2
Et2N
a
4. Experimental section
b
13
HA
Ts
Ts
4.1. Materials and methods
14k
29
30
All reactions requiring anhydrous conditions were conducted in
flame-dried apparatus under an atmosphere of argon. Syringes and
Scheme 7. (a) Et2NH, CH2Cl2, then MeLi, THF, 74%; (b) PhOC(S)Cl, DMAP, CH2Cl2, 78%,
then cumene, reflux, 38%.

7828
D.M. Hodgson et al. / Tetrahedron 65 (2009) 7825–7836
needles for the transfer of reagents were oven-dried and allowed to
cool in a desiccator over P2O5 before use. Ethers were distilled from
benzophenone ketyl, hydrocarbons from CaH2 and alcohols from
their magnesium alkoxides. All reactions were monitored by TLC,
using commercially available (Merck or Camlab) plates pre-coated
with a 0.25 mm layer of silica containing a fluorescent indicator.
Visualisation of reaction components was achieved with 254 nm
light, and with vanillin or KMnO4 dips. Unless stated otherwise
organic layers were dried using MgSO4, evaporated with a Buchi
rotary evaporator, followed by drying on a high vacuum oil pump
(w1 mmHg). Column chromatography was carried out on Kieselgel
4.3. 3-(tert-Butoxycarbonyl)-7-isopropyl-1-tosyl-3-
azatricyclo[2.2.1.02,6]heptan-5-ol (14b)
i-PrMgCl (2.0 M in THF; 0.62 mL, 1.2 mmol) was added to a so-
lution of epoxide 1315 (300 mg, 0.83 mmol) in THF (20 mL) at ꢀ78 ꢁC.
The solution was warmed to rt over 2.5 h and then saturated aq
NH4Cl (10 mL) added and the mixture extracted with Et2O (3ꢂ25
mL). The combined organic layers were washed with brine, dried
and evaporated under reduced pressure to give an oil, which
crystallised slowly. Trituration with Et2O gave a white solid, 7-
azanortricyclanol 14b (302 mg 90%); Rf 0.5 (Et2O); mp 169 ꢁC.
Found: C, 61.6; H, 7.4; N, 3.4. C21H29O5NS requires C, 61.9; H, 7.2; N,
3.4%. IR (KBr) 3310br, 2969w, 1677s, 1453s, 1314m, 1170m, 1138s
60 (40–63
m
m). Petrol refers to the fraction with bp 40–60 ꢁC.
Unless otherwise stated, IR spectra were recorded using a Perkin–
Elmer 1750 FTIR spectrophotometer. Peak intensities are specified
as strong (s), medium (m) or weak (w). Only selected absorbancies
are reported. 1H NMR spectra of compounds were recorded in
CDCl3 unless otherwise stated, using a Varian Gemini 200 (200
MHz), Bruker DPX400 (400 MHz) or AMX500 spectrometer (500
and 1090m cmꢀ1
;
dH (400 MHz) 7.74 (2H, d, J 8, 2ꢂCH of Ts), 7.33
(2H, d, J 8, 2ꢂCH of Ts), 4.53 (1H, d, J 5, NCHCTs), 3.99 (1H, s,
NCHCHi-Pr), 3.75 (1H, s, CHOH), 3.30 (1H, br s, CHi-Pr), 2.43 (3H, s,
CH3 of Ts), 2.28 (1H, s, TsCCHCHOH), 2.01 (1H, br s, CHCH3), 1.44
(9H, s, 3ꢂCH3), 0.91 (3H, d, J 7, CHCH3) and 0.85 (3H, d, J 7, CHCH3);
dC (100 MHz) 154.1 (C]O), 144.8 (Cquat of Ts), 136.6 (Cquat of Ts),
129.9 (2ꢂCH of Ts),127.7 (2ꢂCH of Ts), 81.0 (CMe3), 72.6 (COH), 65.8
(NCH), 57.8 (CHi-Pr), 48.3 (CTs), 47.9 (CHCH3), 38.2 (NCHCTs), 28.3
(3ꢂCH3), 27.3 (TsCCHCHOH), 26.0 (CH3 of i-Pr), 22.3 (CH3 of i-Pr)
and 21.6 (CH3 of Ts); m/z (CI, NH3) 425 (MþNHþ4 , 38%), 369 (100),
308 (26), 215 (14) and 154 (24) (Found: MþNHþ4 , 425.2112.
C21H33O5N2S requires M, 425.2110.).
MHz). Chemical shifts (d) are reported relative to CHCl3 (d 7.27).
Coupling constants (J) are given in hertz and multiplicities are given
as multiplet (m), doublet (d), triplet (t) or quartet (q). 13C NMR
spectra were recorded on the Bruker DPX400 (100 MHz) or
AMX500 (125 MHz). Chemical shifts are reported relative to CDCl3
(central line of triplet
d
77.0) unless stated otherwise. 1H–1H and
1H–13C COSY spectra were used to aid peak assignments. Mass
spectra were obtained from the EPSRC Mass Spectrometry Service
Centre, Swansea with a Micromass, ZAB-E instrument or 900 XLT
high resolution double focussing mass spectrometer with tandem
ion trap. Alternatively they were recorded in-house using a VG
mass Lab. TRIO1 (GCMS) or Micromass platform APCI spectrometer.
Diffraction data were measured using an Enraf-Nonius KappaCCD
4.4. 8-(tert-Butoxycarbonyl)-6-tosyl-8-aza-3-
oxatricyclo[3.2.1.02,4]octane (16)
To a solution of alkene 1514 (3.6 g, 10 mmol) in CH2Cl2 (70 mL)
was added m-CPBA (55% w/w remainder water; 4.5 g, 15 mmol)
in one portion. The reaction mixture was heated to reflux for 2
days, then cooled to rt. The mixture was washed with 10% aq
sodium bisulphite (100 mL), saturated NaHCO3 (100 mL) and
brine (100 mL). The organic phase was dried and evaporated
under reduced pressure. Purification of the residue by column
chromatography (50/80% Et2O in petrol) gave a white crystal-
line solid, epoxide 16 (929 mg, 40%); Rf 0.6 (Et2O); mp 180 ꢁC
(sharp). Found: C, 58.9; H, 6.5; N, 3.7. C18H23O5NS requires C,
59.2, H, 6.3, N, 3.8%.; IR (KBr) 2985w, 2938w, 1706s, 1399m,
1365m, 1320m, 1287m, 1250m, 1149s, 1090m, 664m and 590m
diffractometer
(graphite-monochromated
MoKa
radiation,
l
¼0.71073 Å) and intensity data were integrated and scaled using
the DENZO-SMN package.30 The structures were all solved using
the direct-methods program SIR92,31 which located all non-hy-
drogen atoms. Subsequent full-matrix least-squares refinement
was carried out using the CRYSTALS program suite32 and co-
ordinates and anisotropic thermal parameters of all non-hydrogen
atoms were refined. Hydrogen atoms were visible in the difference
map and initially refined with soft-restraints before refinement
with a riding model.
cmꢀ1
;
dH (500 MHz; DMSO; 370 K) 7.84 (2H, d, J 8, 2ꢂCH of Ts),
4.2. 3-(tert-Butoxycarbonyl)-7-methyl-1-tosyl-3-
7.49 (2H, d, J 8, 2ꢂCH of Ts), 4.30 (1H, s, NCHCTs), 4.26 (1H, d, J 4,
NCH), 4.03 (1H, ddd, J 9.7, 5, 4.8, TsCH), 3.79 (1H, d, J 3.5, OCH),
3.61 (1H, d, J 3.5, OCH), 2.46 (3H, s, CH3 of Ts), 2.08 (1H, br,
CHaHb), 1.79 (1H, dd, J 12.7, 5, CHaHb) and 1.38 (9H, s, 3ꢂCH3); dC
(125 MHz; DMSO; 370 K) 156.5 (C]O), 145.7 (Cquat of Ts), 137.6
(Cquat of Ts), 131.0 (2ꢂCH of Ts) 128.5 (2ꢂCH of Ts), 80.5 (CMe3),
65.7 (TsC), 59.4 (NCH), 58.2 (NCH), 50.0 (CHO), 47.9 (CHO), 28.8
(3ꢂCH3), 28.0 (CH2) and 21.9 (CH3 of Ts); m/z (CI, NH3) 383.2
(MþNHþ4 , 23%), 366.2 (MþHþ, 19), 327.2 (50), 266.1 (54), 229.2
(26), 200.1 (51), 173.1 (30), 129.1 (19) and 112.3 (100) (Found:
MþHþ, 366.1380. C18H24O5NS requires M, 366.1375.).
azatricyclo[2.2.1.02,6]heptan-5-ol (14a)
MeMgBr (3.0 M in THF; 138
mL, 0.413 mmol) was added to
a solution of epoxide 1315 (100 mg, 0.275 mmol) in THF (7 mL) at
ꢀ78 ꢁC. The solution was then allowed to warm to rt over 9 h.
Saturated aq NH4Cl (3 mL) was then added and the mixture
extracted with Et2O (3ꢂ10 mL). The combined organic layers were
washed with brine, dried and evaporated under reduced pressure.
Purification of the residue by recrystallisation (EtOAc–petrol) gave
a white solid, 7-azanortricyclanol 14a (100 mg, 96%); Rf 0.1 (60%
Et2O in petrol); mp 175–176 ꢁC (dec). Found: C, 60.3; H, 6.6; N, 3.7.
C19H25O5NS requires C, 60.1; H, 6.6; N, 3.7%. IR (KBr) 3456br,
2977m, 2930m, 1698s, 1597m, 1393m, 1302m, 1146m and 1089m
4.5. 3-(tert-Butoxycarbonyl)-1-tosyl-3-
azatricyclo[2.2.1.02,6]heptan-5-ol (14d)
cmꢀ1
;
dH (400 MHz) 7.75 (2H, d, J 8, 2ꢂCH of Ts), 7.35 (2H, d, J 8,
2ꢂCH of Ts), 4.78 (1H, br s, NCHCTs), 3.87–3.68 (2H, m, NCHCHMe,
CHOH), 2.46 (3H, s, CH3 of Ts), 2.34 (1H, d, J 5, TsCCHCHOH), 2.20
(1H, br s, OH), 1.91 (1H, q, J 6.5, CHCH3), 1.47 (9H, s, 3ꢂCH3) and 0.89
(3H, d, J 6.5, CH3CH); dC (100 MHz) 155.8 (C]O), 144.8 (Cquat of Ts),
136.9 (Cquat of Ts), 130.0 (2ꢂCH of Ts), 127.8 (2ꢂCH of Ts), 81.3
(CMe3), 72.1 (COH), 62.7 (NCH), 49.5 (TsC), 38.0 (NCHCTs, MeCH),
28.2 (3ꢂCH3), 27.5 (TsCCHCHOH), 21.6 (CH3 of Ts) and 12.0 (CH3);
m/z (CI, NH3) 397 (38%, MþNH4þ), 341 (73) and 124 (100) (Found:
MþNHþ4 , 397.1802. C19H29O5N2S requires M, 397.1797.).
To a cooled (0 ꢁC) solution of epoxide 16 (100 mg, 0.27 mmol) in
THF (5 mL) was added MeLi (1.2 M in THF; 0.34 mL, 0.41 mmol)
dropwise. The orange solution was stirred at 0 ꢁC for 2 h, then
saturated aq NH4Cl (2 mL) added. The aqueous phase was separated
and extracted with Et2O (3ꢂ10 mL). The combined organic extracts
were washed (brine), dried and evaporated under reduced pres-
sure. Purification of the residue by column chromatography (Et2O)
gave a white solid foam, 7-azanortricyclanol 14d (67 mg, 67%); Rf 0.5
(Et2O); mp 156–157 ꢁC. Found: C, 59.1; H, 6.5; N, 3.7. C18H23NO5S

D.M. Hodgson et al. / Tetrahedron 65 (2009) 7825–7836
7829
requires C, 59.2; H, 6.3; N, 3.8%. IR (KBr) 3469br, 3200br, 2979m,
2933m, 1705s, 1598m, 1453m, 1369s, 1316s, 1302s, 1167s, 1146s,
onto the top of a silica gel column and eluted with 80% Et2O in
petrol to give the corresponding thiocarbamate (105 mg, 92%).
Diagnostic data: dH (200 MHz) 8.28 (1H, d, J 4, NCH]), 7.56 (1H, s,
NCH]), 7.07–6.98 (1H, m, NCH]), 5.21 (0.5H, s, CHO) and 5.19
(0.5H, s, CHO). The above thiocarbamate (100 mg, 0.19 mmol) was
dissolved in toluene (20 mL), AIBN (10 mg, 0.06 mmol) was added
1091s and 670s cmꢀ1
;
dH (400 MHz) 7.69 (2H, d, J 8, 2ꢂCH of Ts),
7.29 (2H, d, J 8, 2ꢂCH of Ts), 4.20 (1H, d, J 5, NCHCTs), 4.00–3.92 (2H,
m, NCH and CHO), 2.48 (1H, d, J 5, TsCCHCHOH), 2.38 (3H, s, CH3 of
Ts), 1.82 (1H, d, J 9, OH, removed with D2O shake), 1.65 (1H, d, J 11,
CHaHb), 1.39 (1H, m, CHaHb) and 1.32 (9H, s, 3ꢂCH3); dC (100 MHz)
156.5 (C]O), 143.3 (Cquat of Ts), 136.1 (Cquat of Ts), 130.4 (2ꢂCH of
Ts), 128.5 (2ꢂCH of Ts), 82.0 (CMe3), 74.7 (COH), 66.3 (NCH), 58.8
(TsC), 47.3 (NCHCTs), 39.4 (CH2), 31.3 (TsCCHCHOH), 28.5 (3ꢂCH3 of
Boc), 22.0 (CH3 of Ts); m/z (CI, NH3) 383.3 (MþNHþ4 , 80%), 366.2
(MþHþ, 15), 327.2 (100) (Found: MþHþ, 366.1379. C18H24NO5S re-
quires M, 366.1375.).
and the mixture heated to reflux. Bu3SnH (104 mL, 0.39 mmol) was
then added over 15 min. After 1 h, the reaction mixture was cooled
and evaporated under reduced pressure. The residue was dissolved
in CH2Cl2 (10 mL) and stirred vigorously with aq NaOH (1 M; 10
mL) for 1 h. The organic layer was washed with aq NaOH (1 M; 10
mL), then brine, dried and evaporated under reduced pressure.
Purification of the residue by column chromatography (50% Et2O in
petrol) gave a colourless oil, 2-azabicyclo[2.2.1]heptene 17b (39 mg,
52%); Rf 0.8 (Et2O); IR (film) 2963m, 2873w, 1698s, 1598w, 1477w,
4.6. 2-(tert-Butoxycarbonyl)-7-methyl-4-tosyl-2-
azabicyclo[2.2.1]hept-5-ene (17a)
1456w, 1392s, 1367s, 1320m, 1304m and 1256w cmꢀ1
; dH (400
MHz) (split by rotamers 3:7 ratio) 7.82–7.80 (2H, m, 2ꢂCH of Ts),
7.41–7.28 (2H, m, 2ꢂCH of Ts), 6.44 (0.3H, dd, J 5.5, 2, CHCH]), 6.32
(0.7H, dd, J 5.5, 2.5, CHCH]), 6.09 (0.3H, d, J 5.5, CHCH]CH), 6.23
(0.7H, d, J 5.5, CHCH]CH), 4.65 (0.3H, br s, CHCH]), 4.49 (0.7H, br
s, CHCH]), 4.00–3.95 (1H, m, NCH2), 2.68 (1H, d, J 9, NCH2), 2.67
(0.9H, s, CH3 of Ts), 2.47 (2.1H, s, CH3 of Ts), 2.13 (0.7H, d, J 8, CHi-
Pr), 2.02 (0.3H, d, J 8, CHi-Pr), 1.94–1.81 (1H, m, CH of i-Pr), 1.40 (9H,
s, t-Bu), 1.26–1.18 (3H, m, CH3 of i-Pr) and 0.98 (3H, d, J 7, CH3 of i-
Pr); dC (100 MHz, some signals split by rotamers) 155.2 (C]O),
145.2 (Cquat of Ts), 137.2 (CHCH]), 136.2 (Cquat of Ts), 135.5
(CHCH]CH), 130.0 (2ꢂCH of Ts), 128.9 (2ꢂCH of Ts), 80.1 (CMe3),
75.6 (TsC), 69.6, 69.2 (NCH), 63.8, 62.4 (CHi-Pr), 46.0, 45.6 (NCH2),
28.3 (3ꢂMe), 25.8 (CH of i-Pr), 23.4 (CH3 of i-Pr), 21.6 (CH3 of i-Pr)
and 21.6 (CH3 of Ts); m/z (Found: MþHþ, 392.1902. C21H30O4NS
requires M, 392.1895.).
A solution of 7-azanortricyclanol 14a (240 mg, 0.63 mmol) in
THF (3 mL) was added dropwise to a slurry of KH (30% dispersion
in mineral oil; 108 mg, 0.95 mmol) in THF (3 mL) at 0 ꢁC. The
solution was then warmed to rt and stirred for 20 min, then cooled
to 0 ꢁC and CS2 (47
for a further 10 min before addition of MeI (47
m
L, 0.76 mmol) added. The mixture was stirred
L, 0.76 mmol). The
m
solution was then warmed to rt and stirred for 20 min before
water (5 mL) was added dropwise. The aqueous layer was
extracted with Et2O (3ꢂ20 mL) and the combined organic layers
were washed with brine, dried and evaporated under reduced
pressure. Purification of the residue by column chromatography
(40% Et2O in petrol) gave an off-white solid, the corresponding
xanthate (168 mg; 57%). Diagnostic data: dH (200 MHz) 5.25 (0.5H,
s, CHO), 5.17 (0.5H, s, CHO) and 2.43 (3H, s, SCH3). The above
xanthate (165 mg, 0.35 mmol) was dissolved in toluene (16 mL),
AIBN (10 mg, 0.06 mmol) was added and the mixture heated to
4.8. 2-(tert-Butoxycarbonyl)-4-tosyl-2-azabicyclo[2.2.1]-
reflux. Bu3SnH (217
m
L, 0.81 mmol) was added over 5 min. After 2
hept-5-ene (17d)
h, the reaction mixture was cooled and evaporated under reduced
pressure. The residue was dissolved in CH2Cl2 (10 mL) and stirred
vigorously with aq NaOH (1 M; 10 mL) for 1 h. The organic layer
was washed with aq NaOH (1 M; 10 mL), then brine, dried and
evaporated under reduced pressure. Purification of the residue by
column chromatography (40% Et2O in petrol) gave a colourless oil,
2-azabicyclo-[2.2.1]heptene 17a (83 mg, 65%); Rf 0.4 (50% Et2O in
petrol); IR (film) 2975m, 1699s, 1597w, 1478w, 1456m, 1393s,
To a cooled (0 ꢁC) stirred slurry of KH (164 mg, 1.23 mmol; 30%
w/w dispersion in mineral oil) in THF (3 mL) was added a solution
of alcohol 14d (150 mg, 0.41 mmol) in THF (2 mL). The reaction
mixture was warmed to rt and stirred for 20 min. CS2 (128
ml, 2.05
mmol) was added then after 15 min MeI (128 l, 2.05 mmol). After
m
30 min the reaction mixture was quenched with water (5 mL), the
aqueous layer was separated and extracted with Et2O (3ꢂ10 mL).
The combined organic layers were washed (brine), dried and
evaporated under reduced pressure. Purification of the residue by
column chromatography (40% Et2O in light petroleum) gave a light
brown oil, the corresponding xanthate (110 mg, 59%). Diagnostic
data: dH (200 MHz) 2.50 (3H, s, SCH3). The above xanthate (110 mg,
0.24 mmol) and AIBN (8 mg) were dissolved in toluene (9 mL) and
1317m, 1303m, 1168s, 1139s and 1088m cmꢀ1
; dH (400 MHz) (split
by rotamers 1:1 ratio) 7.80 (2H, d, J 8, 2ꢂCH of Ts), 7.37 (2H, d, J 8,
2ꢂCH of Ts), 6.45 (0.5H, dd, J 5.5, 2, CHCH]), 6.36 (0.5H, dd, J 5.5,
2, CHCH]), 6.31 (0.5H, d, J 5.5, CHCH]CH), 6.23 (0.5H, d, J 5.5,
CHCH]CH), 4.37 (0.5H, br s, CHCH]), 4.25 (0.5H, br s, CHCH]),
3.92 (0.5H, d, J 9, NCH2), 3.86 (0.5H, d, J 9, NCH2), 2.91 (0.5H, d, J 9,
NCH2), 2.83 (0.5H, d, J 9, NCH2), 2.45 (3H, s, CH3 of Ts), 2.14 (0.5H,
q, J 6.5, CHCH3), 1.86 (0.5H, q, J 6.5, CHCH3), 1.41, 1.43 (9H, 2ꢂs, But),
1.20 (1.5H, d, J 6.5, CH3CH) and 1.17 (1.5H, d, J 6.5, CH3CH); dC (100
MHz, split by rotamers) 155.9, 155.5 (C]O), 145.4, 145.3 (Cquat of
Ts), 136.8, 136.1 (CHCH]), 135.6, 135.5 (CHCH]CH), 134.8, 134.6
(Cquat of Ts), 130.0, 129.8 (2ꢂCH of Ts), 128.7, 128.6 (2ꢂCH of Ts),
80.3, 80.2 (CMe3), 76.0, 75.4 (TsC), 66.1, 64.6 (NCH), 55.7, 53.4
(CHCH3), 44.0, 43.4 (NCH2), 28.3 (3ꢂMe), 21.6 (CH3 of Ts) and 12.3
and 11.9 (CH3CH); m/z (CI, NH3) 381 (55%, MþNHþ4 ), 364 (100,
MþHþ) and 342 (33) (Found: MþHþ, 364.1583. C19H26O4NS re-
quires M, 364.1582.).
the mixture heated to reflux. Bu3SnH (97 ml, 0.36 mmol) was added
dropwise over 10 min. After 2 h, the reaction mixture was cooled
and evaporated under reduced pressure. Purification of the residue
by column chromatography (40% Et2O in petrol) gave a clear col-
ourless oil, 2-azabicyclo[2.2.1]heptene 17d (49 mg, 59%); Rf 0.2 (40%
Et2O in petrol); IR (film) 2925m, 1697s, 1400m, 1364m, 1306m,
1173m, 1139s, 1087m, 868w, 811w and 664s cmꢀ1
; dH (400 MHz)
(spectrum broad due to rotamers) 7.81 (2H, d, J 8, 2ꢂCH of Ts), 7.38
(2H, d, J 8, 2ꢂCH of Ts), 6.53–6.30 (2H, m, 2ꢂCH]), 4.77–4.67 (1H,
m, NCH), 3.73–3.65 (1H, m, NCHaHb), 2.88–2.84 (1H, m, NCHaHb),
2.46 (3H, s, CH3 of Ts), 2.08–1.80 (2H, m, CH2) and 1.41 (9H, s, t-Bu);
dC (100 MHz) (spectrum broadened/split by rotamers) 161.0 (C]O),
145.4 (Cquat of Ts), 137.0, 136.3 (Cquat of Ts), 132.8 (CH]), 132.4
(CH]), 130.0 (2ꢂCH of Ts), 128.9 (2ꢂCH of Ts), 80.3 (CMe3), 75.5
(TsC), 61.3, 60.1 (NCH), 49.6 (CH2), 47.1, 46.6 (NCH2), 28.3 (3ꢂCH3)
and 21.7 (CH3 of Ts); m/z (CI, NH3) 367.3 (MþNHþ4 , 60%), 350.2
(MþHþ, 100) (Found: MþHþ, 350.1432. C18H24NO4S requires M,
350.1426).
4.7. 2-(tert-Butoxycarbonyl)-7-isopropyl-4-tosyl-2-
azabicyclo[2.2.1]hept-5-ene (17b)
1,10-Thiocarbonyldiimidazole (177 mg, 0.99 mmol) was added
to a solution of 7-azanortricyclanol 14b (90 mg, 0.22 mmol) in
CH2Cl2 (1.5 mL) at rt. After 14 h, the reaction mixture was poured

7830
D.M. Hodgson et al. / Tetrahedron 65 (2009) 7825–7836
4.9. 3-(tert-Butoxycarbonyl)-7-(6-methoxypyridin-3-yl)-1-
(C4), 110.5 (C5 of pyridine), 84.0 (CMe3), 53.4 and 53.3 (OMe and
CHN), 37.0 (ArCH2), 28.3 and 27.9 (3ꢂMe) and 21.6 (ArCH3); m/z (CI)
457 (MþHþ, 100%), 401 (40) and 357 (MꢀBoc, 20) (Found: MþHþ,
457.1789. C24H29N2O5S requires M, 457.1797.).
tosyl-3-azatricyclo[2.2.1.02,6]heptan-5-ol (14e)
n-BuLi (2.1 M in hexanes; 5.90 mL, 12.4 mmol) was added
dropwise over 15 min to a stirred solution of 5-bromo-2-methoxy-
pyridine33 (3.11 g,16.5 mmol) in THF (125 mL) at ꢀ78 ꢁC. After 0.5 h,
epoxide 13 (3.0 g, 8.3 mmol) in THF (100 mL) was added via can-
nula. The reaction mixture was stirred for 2 h at ꢀ78 ꢁC. Saturated
aq NH4Cl (50 mL) was then added and the mixture extracted with
Et2O (3ꢂ80 mL). The combined organic layers were washed with
brine, dried and evaporated under reduced pressure to give
a brown oil. Purification of the residue by column chromatography
(Et2O) gave a white foam, 7-azanortricyclanol 14e (3.07 g, 78%); Rf
(Et2O) 0.19. Found: C, 61.0; H, 5.9; N, 5.8. Calcd for C24H28N2O6S: C,
61.0; H, 6.0; N, 5.9%.; IR (film) 3428br m, 2980s, 1704s, 1608m,
4.11. 1-(tert-Butoxycarbonyl)-2-(6-methoxypyridin-3-
yl)methyl-5-tosyl-1,2,3,4-tetrahydropyridine (22)
Pd/C (10%, 55 mg) was added to a solution of 1,2-dihydropyr-
idine 21a (90 mg, 0.20 mmol) in toluene (15 mL) and the reaction
mixture was stirred under H2 (2.0 atm) for 14 h. The catalyst was
filtered off and the solvent evaporated under reduced pressure.
Purification of the residue by column chromatography (50% Et2O–
petrol) gave a clear colourless oil, tetrahydropyridine-sulfone 22 (80
mg, 87%); Rf (60% Et2O–petrol) 0.31; IR (film) 2978m, 1721s, 1639s,
1496s, 1394s, 1259s, 1147s and 1091s cmꢀ1
;
dH (500 MHz) 7.78 (1H,
1494s, 1392s,1290s,1143s and 1090s cmꢀ1
; dH (400 MHz) 8.23–7.96
d, J 2.0, C(2 of pyridine)H), 7.42 (2H, d, J 8.0, 2ꢂCH of Ar), 7.25–7.11
(3H, m, C(4 of pyridine)H and 2ꢂCH of Ar), 6.42 (1H, br s, C(5 of
pyridine)H), 4.67 (1H, br s, C(2)H), 4.09 (1H, br s, CHOH), 3.93–3.87
(1H, m, C(4)H), 3.88 (3H, s, OMe), 2.98 (1H, br s, C(7)H), 2.62 (1H, br
s, C(6)H), 2.40 (3H, s, ArCH3), 1.88 (1H, br s, OH) and 1.59–1.20 (9H,
(1H, m, C]CH), 7.88–7.81 (1H, m, C(2 of pyridine)H), 7.76 (2H, app.
d, J 8.5, 2ꢂCH of Ar), 7.39–7.33 (1H, m, C(4 of pyridine)H), 7.30 (2H,
app. d, J 8.5, 2ꢂCH of Ar), 6.67 (1H, d, J 8.5, C(5 of pyridine)H), 4.44–
4.25 (1H, m, NCH), 3.88 (3H, s, OMe), 2.68–2.63 (1H, m, H of
C(2)H2), 2.45–2.40 (4H, m, ArCH3 and H of ArCH2), 2.26–2.19 (2H,
m, CH2), 1.81–1.77 (1H, m, H of ArCH2) and 1.58–1.44 (10H, m, H of
CH2, t-Bu); dC (100 MHz) (C6quat not observed) 163.3 (C6quat of
pyridine), 151.1 (C]O), 146.9 (C2 of pyridine), 143.6 (Cquat of Ar),
139.4 (C4 of pyridine), 137.8 (C3quat of pyridine), 133.5 (C]CH),
129.7 (2ꢂCH of Ar), 127.6 (2ꢂCH of Ar), 125.4 (Cquat of Ar), 110.8 (C5
of pyridine), 83.2 (CMe3), 53.3 (OMe), 51.6 (CHN), 33.8 (ArCH2), 28.0
(3ꢂMe), 22.3 (CH2), 21.5 (ArCH3) and 16.4 (CH2); m/z (EI) 458 (Mþ,
45%), 402 (60), 358 (MꢀBoc, 90) and 280 (100) (Found: Mþ,
458.1868. C24H30N2O5S requires M, 458.1875.).
br s, t-Bu); 1H NMR NOE experiments: irradiation at
d 4.09 saw
enhancement at 2.98 (7.6%), 2.62 (3.6%) and 1.88 (3%); dC (125 MHz)
(C6quat of pyridine), 154.9 (C]O), 146.3 (C2 of pyridine), 144.9 (Cquat
of Ar), 138.1 (C4 of pyridine), 136.0 (Cquat of Ar), 129.7 (2ꢂCH of Ar),
128.1 (2ꢂCH of Ar), 122.4 (C3quat of pyridine), 110.2 (C5 of pyridine),
81.6 (CMe3), 72.9 (CHOH), 63.8 (C4), 53.4 (OMe), 49.8 (C1quat), 44.3
(C7), 38.5 (C2), 28.1 (3ꢂMe), 26.5 (C6) and 21.6 (ArCH3); m/z
(Found: MþHþ, 473.1746. C24H29N2O6S requires M, 473.1746.).
4.10. 1-(tert-Butoxycarbonyl)-2-(6-methoxypyridin-3-
yl)methyl-5-tosyl-1,2-dihydropyridine (21a)
4.12. 1-(tert-Butoxycarbonyl)-2-(6-methoxypyridin-3-
yl)methyl-1,2,3,4-tetrahydropyridine (23)
A solution of alcohol 14e (535 mg, 1.13 mmol) in THF (5 mL) was
added dropwise to a suspension of KH (30% dispersion in mineral
oil; 226 mg, 1.70 mmol) in THF (10 mL) at 0 ꢁC. After stirring for 20
Na–Hg35 (6%, 0.7 g) and Na2HPO4 (300 mg, 0.028 mol) were
added to a stirred solution of tetrahydropyridine-sulfone 22 (X¼Ts)
(70 mg, 0.15 mmol) in anhydrous MeOH (4 mL) at ꢀ20 ꢁC. The re-
action mixture was warmed to 25 ꢁC over 4 h, then water (10 mL)
was added and the reaction mixture filtered. The filtrate was
extracted with CH2Cl2 (4ꢂ5 mL) and the combined organic layers
washed with brine, dried and evaporated under reduced pressure.
Purification of the residue by column chromatography (50% Et2O–
petrol) gave a clear colourless oil, tetrahydropyridine 23 (25 mg,
55%); Rf (75% Et2O–petrol) 0.73; IR (film) 2931m, 1693s, 1650s,
min at 25 ꢁC, the solution was re-cooled to 0 ꢁC and CS2 (211
m
L, 3.40
mmol) was added. The mixture was stirred for 15 min at 0 ꢁC, then
MeI (211 L, 3.40 mmol) was added and the reaction mixture was
m
stirred for 20 min at 25 ꢁC. Water (20 mL) was added and the
aqueous layer was extracted with Et2O (3ꢂ25 mL). The combined
organic layers were washed with brine, dried and evaporated under
reduced pressure. Purification of the residue by column chroma-
tography (60% Et2O in petrol) gave a white solid foam, the corre-
sponding xanthate 18 (509 mg, 80%). Diagnostic data: dH (400 MHz)
5.60 (0.5H, s, CHO), 5.56 (0.5H, s, CHO), 2.47 (1.5H, s, SCH3) and 2.45
(1.5H, s, SCH3). The above xanthate (169 mg, 0.31 mmol) and AIBN
(10 mg, 0.061 mmol) were dissolved in degassed toluene (13 mL)
1610s, 1494s, 1360s, 1289s, 1162s and 1060m cmꢀ1
; dH (500 MHz)
(3:2 mixture of rotational isomers observed) 8.00–7.92 (1H, m, C(2
of pyridine)H), 7.52 and 7.37 (1H, 2ꢂd, J 8.5, C(4 of pyridine)H), 6.87
and 6.70 (1H, 2ꢂd, J 8.5, C(6)H), 6.70–6.64 (1H, m, C(5 of pyr-
idine)H), 4.99 and 4.85 (1H, 2ꢂbr s, C(5)H), 4.45 and 4.27 (1H, 2ꢂbr
s, C(2)H), 3.92 (3H, s, OMe), 2.94–2.53 (2H, m, ArCH2), 2.21–2.12
(1H, m, H of CH2), 2.07–1.96 (1H, m, CH2), 1.76–1.61 (2H, m, CH2)
and 1.43–1.31 (9H, m, t-Bu); dC (125 MHz) (3:2 mixture of rotational
isomers observed) 163.0 (C6quat of pyridine),151.9 (C]O),146.9 and
146.7 (C2 of pyridine), 139.8 and 139.6 (C4 of pyridine), 129.6
(C3quat of pyridine), 124.2 and 123.7 (C6), 110.6 (C5 of pyridine),
105.1 and 104.5 (C5), 80.5 (CMe3), 53.3 (OMe), 52.2 and 50.5 (NCH),
33.2 and 32.8 (ArCH2), 28.3 and 28.2 (3ꢂMe), 23.4 and 22.8 (CH2)
and 17.5 (CH2); m/z (EI) 304 (Mþ, 20%), 233 (30) and 204 (MꢀBoc,
100) (Found: Mþ, 304.1784. C17H24N2O3 requires M, 304.1784.).
and the mixture heated to 110 ꢁC, then Bu3SnH (190
mL, 0.71 mmol)
was added over 20 min. After 2 h, the reaction mixture was allowed
to cool and evaporated under reduced pressure to give a yellow oil,
which was treated exactly according to the procedure of Curran and
Chang34 to remove tin by-products. Final purification by column
chromatography (60% Et2O in petrol) gave a clear colourless oil, 1,2-
dihydropyridine 21a (107 mg, 78%); Rf (60% Et2O–petrol) 0.31; IR
(film) 2980m, 2946w, 1724s, 1608m, 1494s, 1394s, 1290s, 1259s and
1144s cmꢀ1
; dH (400 MHz) 7.80–7.76 (1H, m, C(2 of pyridine)H),
7.69–7.63 (3H, m, 2ꢂCH of Ar and C(6)H), 7.31–7.27 (3H, m, 2ꢂCH of
Ar and C(4 of pyridine)H), 6.67 and 6.55 (1H, 2ꢂd, J 8.5, C(5 of
pyridine)H), 6.13 (1H, d, J 10.0, C4), 5.48 (1H, dd, J 10.0, 5.5, C3), 4.90
(1H, br s, NCH), 3.89 (3H, s, OMe), 2.71 (1H, dd, J 13.5, 7.5, H of CH2),
2.55 (1H, dd, J 13.5, 5.0, H of CH2), 2.43 (3H, s, ArCH3) and 1.50 and
1.43 (9H, 2ꢂs, t-Bu); dC (100 MHz) 163.2 (C6quat of pyridine), 151.6
(C]O), 147.2 (C2 of pyridine), 143.8 (Cquat of Ar), 139.7 (C4 of pyr-
idine), 138.2 (C5quat), 133.7 (Cquat of Ar), 129.8 (2ꢂCH of Ar), 128.9
(C6), 127.2 (2ꢂCH of Ar), 123.7 (C3quat of pyridine), 121.7 (C5), 118.3
4.13. 3-(tert-Butoxycarbonyl)-7-(4-methoxyphenyl)-1-tosyl-
3-azatricyclo[2.2.1.02,6]heptan-5-ol (14f)
4-Methoxyphenylmagnesium bromide (0.50 M in THF; 8.25 mL,
4.13 mmol) was added to solution of epoxide 13 (1.00 g, 2.75 mmol)
in THF (10 mL) at 0 ꢁC. The reaction mixture was allowed to warm to

D.M. Hodgson et al. / Tetrahedron 65 (2009) 7825–7836
7831
rt over 2 h. After this time the reaction mixture was poured into
saturated aq NH4Cl (20 mL) and extracted with Et2O (3ꢂ50 mL). The
combined organic layers were washed with brine, dried and
evaporated under reduced pressure. Purification of the residue by
column chromatography (80/100% Et2O in petrol) gave a white
crystalline solid, 7-azanortricyclanol 14f (930 mg, 72%); Rf 0.5
(Et2O); mp 196–197 ꢁC (dec) (Et2O). Found: C, 64.01; H, 6.39; N,
3.00. C25H29O6NS requires C, 63.68; H, 6.20; N, 2.97%. IR 3737br,
2978m, 2932m,1704s,1614m,1515s,1427m,1368m,1312m,1304m,
azanortricyclanol 14h (900 mg, 74%); Rf 0.2 (EtOAc); mp 199 ꢁC
(dec); IR (KBr) 3084w, 2967w, 1708s, 1431s, 1305s, 1148s, 1133m,
1092m, 874m and 674m cmꢀ1
; dH (400 MHz) 8.43 (1H, s, CH of Py),
8.26 (1H, s, CH of Py), 7.47–7.32 (3H, m, 2ꢂCH of Ts, CH of Py), 7.19
(2H, d, J 7, 2ꢂCH of Ts), 7.04 (1H, s, CH of Py), 4.76 (1H, s, NCHCTs),
4.12 (1H, s, NCHCHPy), 4.02–3.89 (1H, m, CHOH), 3.11–2.93 (1H, m,
PyCH), 2.63 (1H, s, TsCCHCHO), 2.41 (3H, s, CH3 of Ts), 2.15–1.92 (1H,
br, OH) and 1.63–1.05 (9H, m, t-Bu); dC (100 MHz) 154.7 (C]O),
149.3 (C2 of Py), 148.5 (C6 of Py), 145.1 (Cquat of Ts), 135.9 (Cquat of
Ts), 135.8 (C4 of Py), 129.9 (2ꢂCH of Ts), 128.0 (2ꢂCH of Ts), (Cquat of
Py not observed), 123.1 (C5 of Py), 81.7 (CMe3), 73.0 (CHOH), 68.0
(NCH), 49.8 (TsC), 44.96 (CHPy), 39.0 (NCHCTs), 28.1 (3ꢂCH3 of
Boc), 26.6 (TsCCHCHOH) and 21.6 (CH3 of Ts); m/z (CI, NH3) 443
(MþHþ, 12%), 259 (10) and 90 (100) (Found: MþHþ, 443.1638,
C23H26O5N2S requires M, 443.1640.).
1250s, 1144s and 676m cmꢀ1
;
dH (400 MHz) 7.37 (2H, br s, 2ꢂCH2 of
Ts), 7.11 (2H, br s, 2ꢂCH2 of Ts), 6.87 (2H, br s, 2ꢂCH2 of MeOAr),
6.58 (2H, br s, 2ꢂCH2 of MeOAr), 4.65 (1H, br s, NCHCTs), 4.02 (1H,
br s, NCH), 3.86 (1H, br s, CHOH), 3.72 (3H, s, OMe), 3.01–2.59 (3H,
m, CHArOMe, TsCCHCHOH, OH), 2.37 (3H, s, CH3 of Ts) and 1.47–1.18
(9H, m, 3ꢂCH3 of Boc); dC (100 MHz) 155.2 (Cquat of MeOAr), (car-
bonyl not observed), 144.4 (Cquat of Ts), 136.3 (Cquat of Ts), 129.5
(2ꢂCH2 of Ts), 129.3 (2ꢂCH2 of Ts), 128.1 (2ꢂCH of MeOAr), 125.6
(Cquat of MeOAr), 113.4 (2ꢂCH2 of MeOAr), 81.1 (CMe3), 72.7
(CHOH), 65.1 (NCH), 55.1 (OMe), 50.1 (TsC), 46.8 (CHArOMe), 38.6
(NCHCTs), 28.1 (3ꢂCH3 of Boc), 26.6 (TsCCHCHOH) and 21.5 (CH3 of
Ts); m/z (CI, NH3) 489 (MþNHþ4 , 48%), 433 (75), 216 (28), 200 (72),
186 (46) and 108 (100) (Found: MþHþ, 472.1783. C25H30O6NS re-
quires M, 472.1794.).
4.16. 1-(tert-Butoxycarbonyl)-2-(4-methoxyphenyl)methyl-5-
(p-tolylsulfonyl)-1,2-dihydropyridine (21b)
A solution of 7-azanortricyclanol 14f (350 mg, 0.74 mmol) in
THF (4 mL) was added dropwise to a slurry of KH (30% dispersion in
mineral oil; 148 mg, 1.11 mmol) in THF (4 mL) at 0 ꢁC. After 20 min,
CS2 (55
mL, 0.88 mmol) was added and the mixture stirred for
a further 15 min before addition of MeI (55
m
L, 0.88 mmol). The
4.14. 3-(tert-Butoxycarbonyl)-7-phenyl-1-tosyl-3-
solution was then warmed to rt for 20 min, after which time water
(20 mL) was added dropwise. The aqueous layer was extracted with
Et2O (3ꢂ20 mL) and the combined organic layers were dried and
evaporated under reduced pressure. Purification of the residue by
column chromatography (40% Et2O in petrol) gave a white solid
foam, the corresponding xanthate (350 mg, 84%); Rf 0.5 (50% Et2O in
petrol); IR (film) 3103w, 2978m, 2931m, 2837w, 2253w, 1709s,
1613m, 1514s, 1392s, 1319s, 1304s, 1251s, 1211s, 1161s, 1119s, 1078s,
azatricyclo[2.2.1.02,6]heptan-5-ol (14g)
PhMgBr (1.0 M in THF; 4.13 mL, 4.13 mmol) was added to a so-
lution of epoxide 13 (1.00 g, 2.75 mmol) in THF (50 mL) at 0 ꢁC. The
reaction mixture was allowed to warm to rt and stirred for 3 h. After
this time the reaction mixture was poured into saturated aq NH4Cl
(100 mL) and extracted with Et2O (3ꢂ100 mL). The combined or-
ganic layers were washed with brine, dried and evaporated under
reduced pressure. Purification of the residue by column chroma-
tography (80/100% Et2O in petrol) gave a white crystalline solid,
7-azanortricyclanol 14g (1.00 g, 82%); Rf 0.5 (Et2O); mp 191 ꢁC
(Et2O). Found: C, 65.4; H, 5.8; N, 3.1. C24H27O5SN requires C, 65.3; H,
6.2; N, 3.2%. IR (KBr) 3431br, 2977m, 2930w, 1703s, 1426m, 1368m,
1316s, 1303s, 1126m, 1089m, 865m, 705m, 674m, 593m and 565m
1035m, 913m, 863m, 831m, 732s, 678s and 598s cmꢀ1
; dH (400
MHz) (shows rotamers 4:6 ratio) 7.42 (0.8H, d, J 8, 2ꢂCH of Ts), 7.33
(1.2H, d, J 8, 2ꢂCH of Ts), 7.17 (0.8H, d, J 8, 2ꢂCH of Ts), 7.01 (1.2H, d, J
8, 2ꢂCH of Ts), 6.95 (0.8H, d, J 9, 2ꢂCH of MeOAr), 6.89 (1.2H, d, J 9,
2ꢂCH of MeOAr), 6.64 (0.8H, d, J 9, 2ꢂCH of MeOAr), 6.55 (1.2H, d, J
9, 2ꢂCH of MeOAr), 5.51 (0.4H, t, J 1, CHO), 5.50 (0.6H, t, J 1, CHO),
4.75 (0.6H, dd, J 4.5, 0.5, NCHCTs), 4.73 (0.4H, dd, J 4.4, 0.5, NCHCTs),
4.36–4.34 (1H, m, NCH), 3.75 (1.2H, s, OMe), 3.74 (1.8H, s, OMe),
3.21 (0.6H, s, CHArOMe), 3.05 (0.4H, s, CHArOMe), 2.98–2.95 (0.6H,
m, CHCHO), 2.88–2.85 (0.4H, m, CHCHO), 2.53 (1.8H, s, CH3S), 2.52
(1.2H, s, CH3S), 2.41 (1.2H, s, CH3 of Ts), 2.37 (1.8H, s, CH3 of Ts), 1.51
(3.6H, s, 3ꢂCH3 of Boc) and 1.30 (5.4H, s, 3ꢂCH3 of Boc); dC (100
MHz) (shows rotamers) 215.3, 215.0 (C]S), 159.2, 159.1 (Cquat of
MeOAr), 154.5, 153.7 (C]O), 144.8, 144.5 (Cquat of Ts), 136.0 (Cquat of
Ts), 129.64, 129.60 (2ꢂCH of Ts), 129.4 (2ꢂCH of MeOAr), 128.3,
128.2 (2ꢂCH of Ts), 125.2, 125.0 (Cquat of MeOAr), 113.5, 113.4 (2ꢂCH
of MeOAr), 81.9, 81.4 (CHO), 81.3, 81.2 (CMe3), 62.0, 61.2 (NCH),
55.2, 55.1 (OMe), 50.1, 50.0 (CTs), 46.6, 46.4 (CHArOMe), 39.5, 39.0
(NCHCTs), 28.4, 28.1 (3ꢂCH3 of Boc), 25.0, 24.5 (TsCCHCHO), 21.6,
21.5 (CH3 of Ts) and 19.4, 19.2 (CH3S); m/z (ESþ) 579 (MþNH4þ, 82%),
54 (60), 462 (50), 398 (85), 395 (43) and 354 (100) (Found: MþNHþ4 ,
579.1670. C27H35O6N2S3 requires M, 579.1657). A solution of
cmꢀ1
;
dH (400 MHz) 7.38 (2H, br s, 2ꢂCH of Ts), 7.12–6.95 (7H, m,
2ꢂCH of Ts, 5ꢂCH of Ph), 4.69 (1H, s, NCHCTs), 4.05 (1H, s, NCH),
3.92–3.88 (1H, m, CHOH), 3.07–2.95 (1H, m, PhCH), 2.46 (1H, br s,
TsCCHCHOH), 2.37 (3H, s, CH3 of Ts) and 1.47–1.17 (10H, m, 3ꢂCH3
of Boc, OH); dC (100 MHz) 154.6 (C]O), 144.5 (Cquat of Ts), 136.2
(Cquat of Ts), 133.6 (CH of Ph), 129.5 (2ꢂCH of Ts), 128.2 (2ꢂCH of
Ph), 128.1 (2ꢂCH of Ph), 128.0 (2ꢂCH of Ts), 127.2 (Cquat of Ph), 80.9
(CMe3), 72.9 (CHOH), 65.1 (NCH), 50.0 (TsC), 47.6 (PhCH), 38.2
(NCHCTs), 28.0 (3ꢂCH3 of Boc), 26.4 (TsCCHCHOH) and 21.5 (CH3 of
Ts); m/z (CI, NH3) 459 (MþNHþ4 , 43%), 403 (100), 186 (60), 170 (72),
156 (39) and 108 (71) (Found: MþHþ, 442.1679. C24H28O5SN re-
quires M, 442.1688.).
4.15. 3-(tert-Butoxycarbonyl)-7-(pyridin-3-yl)-1-tosyl-3-
azatricyclo[2.2.1.02,6]heptan-5-ol (14h)
Bu3SnH (211 mL, 0.78 mmol, 1.1 equiv) and AIBN (23 mg, 0.14 mmol,
To a cooled (ꢀ78 ꢁC) solution of n-BuLi (1.6 M in hexanes; 2.6
0.2 equiv) in toluene (5 mL) was added via syringe pump over 2.25
h to a solution of the above xanthate (400 mg, 0.71 mmol) in tol-
uene (25 mL) at reflux. The mixture was then stirred for an addi-
tional 45 min before being cooled and worked-up by the method of
Curran and Chang.34 Purification of the residue by column chro-
matography (30/50% Et2O in petrol) gave a colourless oil, 1,2-
dihydropyridine 21b (202 mg, 62%); Rf 0.5 (60% Et2O in petrol); IR
(film) 2979m, 2933m, 1723s, 1633m, 1596m, 1513s, 1393m, 1370m,
1288s, 1250s, 1176m, 1144s, 1088s, 814m, 732m, 715m, 662s and
mL, 4.2 mmol) in Et2O (30 mL) was added dropwise a solution of 3-
bromopyridine (440 ml, 4.6 mmol) in Et2O (10 mL), followed by
TMEDA (0.70 mL, 4.6 mmol). The mixture was allowed to stir for 30
min, then a solution of epoxide 13 (1.0 g, 2.75 mmol) in THF (5 mL)
was added dropwise. The reaction mixture was stirred at ꢀ78 ꢁC for
1 h, then allowed to warm slowly to rt overnight. Saturated aq
NH4Cl (40 mL) was added and the mixture was extracted with
EtOAc (3ꢂ80 mL). The combined organic layers were dried and
evaporated under reduced pressure. Purification of the residue by
column chromatography (EtOAc) gave a white crystalline solid, 7-
579s cmꢀ1
2ꢂCH of Ts), 7.30 (2H, d, J 8, 2ꢂCH of Ts), 6.97 (2H, d, J 8, 2ꢂCH of
; dH (500 MHz) 8.01–7.75 (1H, m, ]CHN), 7.70 (2H, d, J 8,

7832
D.M. Hodgson et al. / Tetrahedron 65 (2009) 7825–7836
MeOAr), 6.76 (2H, d, J 8, 2ꢂCH of MeOAr), 5.90–6.10 (1H, m, CCH]),
5.41 (1H, dd, J 10, 5.5, CHCH]), 5.01–4.89 (1H, m, CHN), 3.77 (3H, s,
OMe), 2.69 (1H, dd, J 13 and 8, H of CH2), 2.59 (1H, dd, J 13 and 5, H
of CH2), 2.43 (3H, s, Me of Ts) and 1.48 (9H, s, t-Bu); dC (100 MHz)
158.4 (Cquat of MeOAr), 151.3 (C]O) 143.7 (Cquat of Ts), 138.3 (Cquat
of Ts), 133.7 (]CHN), 130.5 (2ꢂCH of Ts), 130.0 (2ꢂCH of MeOAr),
127.6 (Cquat of MeOAr), 127.2, (2ꢂCH of Ts), 122.5 (CHCH]), (TsCquat
not observed), 118.2 (CCH], br), 114.3 (2ꢂCH of MeOAr), 83.6
(CMe3), 55.2 (OMe), 53.8 (CHN, br), 39.9 (ArCH2), 28.5 (3ꢂMe of
Boc) and 22.2 (Me of Ts); dC (100 MHz; DMSO; 373 K) 159.3 (Cquat of
MeOAr), 152.0 (C]O) 144.5 (Cquat of Ts), 139.4 (Cquat of Ts), 134.1
(]CHN), 131.3 (2ꢂCH of Ts), 130.7 (2ꢂCH of MeOAr), 128.7 (Cquat of
MeOAr), 127.6, (2ꢂCH of Ts), 124.3 (CHCH]), 119.9 (TsCquat), 118.0
(CCH], br), 114.9 (2ꢂCH of MeOAr), 84.3 (CMe3), 56.1 (OMe), 54.9
(CHN, br), 40.2 (ArCH2), 28.4 (3ꢂMe of Boc) and 21.7 (Me of Ts); m/z
(CI, NH3) 473 (MþNHþ4 , 100%) and 354 (30) (Found MþNH4,
473.2098. C25H33O5N2S requires M, 473.2110.).
SCH3) and 2.40 (1.5H, s, SCH3). Reaction of the above xanthate (350
mg, 0.66 mmol), Bu3SnH (194 L, 0.72 mmol) and AIBN (21 mg, 0.13
m
mmol) as described in the preparation of 21b gave, after purifica-
tion by column chromatography (80% Et2O in petrol) a colourless
oil, 1,2-dihydropyridine 21d (146 mg, 52%); Rf 0.3 (Et2O); IR (film)
2979m, 2929m, 1723s, 1634m, 1595m, 1394m, 1370m, 1287s, 1144s
and 1088s cmꢀ1
; dH (500 MHz) 8.41 (1H, s, Py), 8.30 (1H, s, Py),
7.83–7.61 (3H, m, NCH], 2ꢂCH of Ts), 7.39 (1H, s, Py), 7.32 (2H, d, J
7.5, 2ꢂCH of Ts), 7.11 (1H, s, Py), 6.16 (1H, d, J 9, TsCCH]), 5.47 (1H,
dd, J 9, 5, CHCH]), 5.02 (1H, br, NCH), 2.84 (1H, dd, J 13, 7.5, CHaHb),
2.70 (1H, dd, J 13, 5.5, CHaHb), 2.45 (3H, s, CH3 of Ts) and 1.63–1.05
(9H, br, 3ꢂCH3 of Boc); dC (125 MHz) 151.5 (C]O), 150.6 (C2 of Py),
148.0 (C6 of Py), 143.8 (Cquat of Ts), 138.1 (C4 Py), 136.9 (Cquat of Ts),
133.5 (NCH]), 131.1 (C3 of Py), 129.8 (2ꢂCH of Ts), 127.2 (2ꢂCH of
Ts), 125.4 (CTs), 123.0 (C5 of Py), 121.1 (PyCHCH]), 118.5 (TsCCH]),
84.0 (CMe3), 53.4 (NCH), 37.8 (CH2), 27.9 (3ꢂCH3 of Boc) and 21.5
(CH3 of Ts); m/z (CI, NH3) 427 (MþHþ, 100%), 352 (20) and 273 (80)
(Found: MþHþ, 427.1696. C23H27N2O4S requires M, 427.1691.).
4.17. 1-(tert-Butoxycarbonyl)-2-benzyl-5-tosyl-1,2-
dihydropyridine (21c)
4.19. 3-tert-Butoxycarbonyl-7-(4-methoxyphenyl)-1-tosyl-3-
azatricyclo[2.2.1.02,6]heptan-5-one (24)
A solution of 7-azanortricyclanol 14g (600 mg, 1.36 mmol) in
THF (5 mL) was added dropwise to a slurry of KH (30% dispersion in
mineral oil; 272 mg, 2.04 mmol) in THF (10 mL) at 0 ꢁC. After 1 h,
DMSO (336 mL, 4.73 mmol) was added to a solution of (COCl)2
(216
m
L, 2.47 mmol) in CH2Cl2 (12 mL) at ꢀ78 ꢁC. After 10 min, al-
CS2 (254
mL, 4.08 mmol) was added and the mixture stirred for
cohol 14f (968 mg, 2.05 mmol) in CH2Cl2 (5 mL) was added drop-
wise. After a further 20 min Et3N (1.7 mL, 6.98 mmol) was added
and the reaction mixture allowed to warm to rt. The reaction
mixture was then poured into water (10 mL) and extracted with
CH2Cl2 (3ꢂ10 mL). The combined organic layers were washed with
brine, dried and evaporated under reduced pressure. Purification of
the residue by column chromatography (Et2O) and recrystallisation
(EtOAc) gave a white solid, ketone 24 (947 mg, 98%); Rf 0.5 (Et2O);
mp 205 ꢁC (dec); IR (film) 3106m, 2982w, 1784s, 1689s, 1516s,
a further 15 min before addition of MeI (254
m
L, 4.08 mmol). The
solution was then warmed to rt for 20 min, after which time water
(10 mL) was added dropwise. The mixture was extracted with Et2O
(3ꢂ20 mL) and the combined organic layers dried and evaporated
under reduced pressure. Purification of the residue by column
chromatography (40% Et2O in petrol) gave an off-white solid foam,
the corresponding xanthate (689 mg; 95%). Diagnostic data: dH (400
MHz) 5.55 (1H, s, CHO) and 2.50 (3H, s, SCH3). Reaction of the above
xanthate (335 mg, 0.63 mmol), Bu3SnH (187
mL, 0.69 mmol) and
1420s, 1318m, 1255s, 1148s, 847m, 671s and 587s cmꢀ1
; dH (400
AIBN (21 mg, 0.13 mmol) as described in the preparation of 21b
gave, after purification by column chromatography (40% Et2O in
petrol) a colourless oil, 1,2-dihydropyridine 21c (174 mg, 65%); Rf 0.3
(20% Et2O in petrol); IR (film) 2984 m,1722s,1287s,1144s and 1087s
MHz) 7.45 (2H, d, J 8, CH of Ts), 7.20 (2H, d, J 8, CH of Ts), 7.00 (2H, d,
J 8.5, CH of MeOAr), 6.70 (2H, d, J 8.5, CH of MeOAr), 5.30 (1H, dd, J 5,
1, NCH), 3.8 (1H, s, NCH), 3.77 (3H, s, OMe), 3.31 (1H, s,
TsCCHCHOH), 2.67 (1H, dd, J 5.1, 1.0, CHArOMe), 2.42 (3H, s, CH3 of
Ts) and 1.31 (9H, s, t-Bu); dC (100 MHz) 198.4 (C]O), 159.5 (Cquat of
ArOMe), 153.0 (C]O), 145.3 (Cquat of Ts), 135.7 (Cquat of Ts), 129.9
(2ꢂCH of Ts), 129.5 (2ꢂCH of Ts), 128.3 (2ꢂCH of ArOMe), 124.2
(Cquat of ArOMe), 113.8 (2ꢂCH of ArOMe), 82.0 (CMe3), 64.0 (NCH),
55.2 (OMe), 54.7 (TsC), 48.5 (CHArOMe), 44.1 (NCH), 28.1 (3ꢂCH3 of
Boc), 27.6 (TsCCHCHOH) and 21.6 (CH3 of Ts); m/z (CI, NH3) 487.2
(MþNHþ4 , 5%), 431.1 (100), 370.1 (80), 216.1 (25) and 167.1 (20)
(Found: MþNHþ4 , 487.1884. C25H31O6N2S requires M, 487.1903.).
cmꢀ1
; dH (400 MHz) 7.93–7.79 (1H, m, NCH]), 7.72 (2H, d, J 8,
2ꢂCH of Ts), 7.32 (2H, d, J 8, 2ꢂCH of Ts), 7.24–7.19 (3H, m, CH of Ph),
7.06 (2H, d, J 8, 2ꢂCH of Ph), 6.12 (1H, d, J 9.5, TsCCH]), 5.47 (1H,
dd, J 9.5, 5.5, PhCHCH), 4.94 (1H, br s, NCH), 2.75 (1H, dd, J 13, 8, H of
PhCH2), 2.68 (1H, dd, J 13, 6, H of PhCH2), 2.44 (3H, s, CH3 of Ts) and
1.50, 1.48 (9H, 2ꢂs, 3ꢂCH3 of Boc); dC (100 MHz) (C]O and NCH not
observed), 143.7 (Cquat of Ts), 138.3 (Cquat of Ts), 135.7 (CH of Ph),
133.7 (NCH]), 129.8 (2ꢂCH of Ts), 129.6 (2ꢂCH of Ph), 128.3 (2ꢂCH
of Ph), 127.3 (2ꢂCH of Ts), 126.7 (TsCCH]), 122.4 (PhCHCH]), 121.4
(TsCquat), 83.7 (CMe3), 39.3 (PhCH2), 27.9 (3ꢂCH3 of Boc) and 21.6
(CH3 of Ts); m/z (CI, NH3) 443 (MþNHþ4 , 100%) (Found: MþNH4þ,
443.2003. C24H31O4N2S requires M, 443.2005.).
4.20. endo 3-(tert-Butoxycarbonyl)-7-(4-methoxyphenyl)-1-
tosyl-3-azatricyclo[2.2.1.02,6]heptan-5-ol (25)
i-PrMgCl (2.0 M in Et2O; 0.42 mL, 0.85 mmol) was added to
a solution of ketone 24 (255 mg, 0.54 mmol) in THF (25 mL) at 0 ꢁC.
The reaction mixture was warmed to rt and stirred for 3 h, then
saturated aq NH4Cl (25 mL) added. The aqueous layer was extracted
with Et2O (3ꢂ50 mL) and the combined organic layers were dried
and evaporated under reduced pressure. Purification of the residue
by column chromatography (80/100% Et2O in petrol) gave endo-
alcohol 25 (197 mg, 77%); Rf 0.6 (Et2O); IR (film) 3460br, 2977w,
2932w, 1705s, 1515s, 1421m, 1251s, 1145s, 1089s, 671s and 582m
4.18. 1-(tert-Butoxycarbonyl)-2-(pyridin-3-yl)methyl-5-tosyl-
1,2-dihydropyridine (21d)
A solution of 7-azanortricyclanol 14h (500 mg, 1.13 mmol) in
THF (2 mL) was added dropwise to a slurry of KH (30% dispersion in
mineral oil; 226 mg,1.69 mmol) in THF (10 mL) at 0 ꢁC. After 30 min,
CS2 (107
mL, 1.69 mmol) was added and the mixture stirred for
a further 15 min before addition of MeI (86
mL, 1.36 mmol). The
solution was then warmed to rt for 20 min, after which time water
(5 mL) was added dropwise. The mixture was extracted with Et2O
(3ꢂ10 mL) and the combined organic layers were dried and evap-
orated under reduced pressure. Purification of the residue by col-
umn chromatography (80% Et2O in petrol) gave an off-white solid
foam, the corresponding xanthate (461 mg, 77%). Diagnostic data:
dH (200 MHz) 5.56 (0.5H, s, CHO), 5.51 (0.5H, s, CHO), 2.43 (1.5H, s,
cmꢀ1
; dH (400 MHz) (spectrum split by rotamers 1:1 ratio) 7.48 (1H,
d, J 7.5, 2ꢂCH of Ts), 7.41 (1H, d, J 7.5, 2ꢂCH of Ts), 7.17 (1H, d, J 7.5,
2ꢂCH of Ts), 7.08 (1H, d, J 7.5, 2ꢂCH of Ts), 6.95 (1H, d, J 7.5, 2ꢂCH of
MeOAr), 6.84 (1H, d, J 7.5, 2ꢂCH of MeOAr), 6.65 (1H, d, J 7.5, 2ꢂCH
of MeOAr), 6.55 (1H, d, J 7.5, 2ꢂCH of MeOAr), 4.64 (1H, d, J 5.5,
NCHCTs), 4.01 (1H, s, CHOH), 3.83–3.55 (5H, m, OMe, NCHCHAr and
CHAr), 2.57 (0.5H, s, TsCCHCHOH), 2.50 (0.5H, s, TsCCHCHOH), 2.38

D.M. Hodgson et al. / Tetrahedron 65 (2009) 7825–7836
7833
(1.5H, s, CH3 of Ts), 2.36 (1.5H, s, CH3 of Ts), 1.78 (1H, s, OH), 1.46
(4.5H, s, Boc) and 1.16 (4.5H, s, Boc); dC (100 MHz) (spectrum split
by rotamers) 158.8, 158.6 (Cquat of MeOAr), 153.9, 153.2 (C]O),
144.3 (Cquat of Ts), 136.2 (Cquat of Ts), 129.6 (2ꢂCH of Ts), 128.2
(2ꢂCH of Ts), 128.0 (2ꢂCH of MeOAr), 125.8 (Cquat of MeOAr), 113.4
(2ꢂCH of MeOAr), 81.2, 80.6 (CMe3), 73.5, 73.3 (CHO), 63.9, 62.8
(NCH), 55.1 (OMe), 49.0 (TsC), 46.8, 46.5 (MeOArCH), 41.9, 41.6
(NCH), 28.4, 28.0 (3ꢂCH3 of Boc), 27.8 (TsCCHCHOH), 21.6 (CH3 of
Ts); m/z (ESþ) 494.2 (MþNaþ, 27%), 489.2 (MþNHþ4 , 30), 472.2
(MþHþ, 10), 457.1 (100), 448.1 (90) (Found: MþNHþ4 , 489.2049.
C25H33O6N2S requires M, 489.2059.).
(2ꢂCH of MeOAr), 81.25 (CMe3), 77.5 (CHOH), 71.2 (CH2OCH), 68.4
(CH2), 60.0 (NCH), 55.2 (OMe), 49.4 (TsC), 39.6 (NCHCTs), 28.9
(TsCCHCHOH), 27.8 (3ꢂCH3 of Boc) and 21.5 (CH3 of Ts); m/z (CI,
NH3) 519.3 (MþNHþ4 , 100%), 463.2 (17), 402.2 (30) and 343.2 (17)
(Found: MþNHþ4 , 519.2173. C26H35N2O7S requires M, 519.2165.).
4.23. 1-(tert-Butoxycarbonyl)-2-methoxymethyl-5-tosyl-1,2-
dihydropyridine (21e)
A solution of 7-azanortricyclanol 14i (220 mg, 0.56 mmol) in
THF (3 mL) was added dropwise to a slurry of NaH (60% dispersion
in mineral oil; 72 mg, 1.8 mmol) in THF (2 mL). The mixture was
4.21. 3-(tert-Butoxycarbonyl)-7-methoxy-1-tosyl-3-
heated to reflux for 1 h, then CS2 (186
was added and heating continued for 30 min. MeI (186
m
L, 3.0 mmol) in THF (1 mL)
L, 3.0
azatricyclo[2.2.1.02,6]heptan-5-ol (14i)
m
mmol) was then added and the mixture heated for a further 30 min.
After this time, the mixture was cooled and water (1 mL) cautiously
added, followed by saturated aq NH4Cl (15 mL). The aqueous phase
was extracted with Et2O (2ꢂ30 mL), and the combined organic
layers washed with brine, dried and evaporated under reduced
pressure. Purification of the residue by column chromatography
(40% Et2O in petrol) gave a pale cream foam, the corresponding
xanthate (209 mg, 77%). Diagnostic data: dH (200 MHz) 5.54 (0.7H, s,
CHO), 5.46 (0.3H, s, CHO), 2.52 (2.1H, s, SCH3) and 2.50 (0.9H, s,
SCH3). Reaction of the above xanthate (209 mg, 0.43 mmol),
Lithium ribbon (17 mg, 2.5 mmol) was carefully added to dry
MeOH (20 mL). The solution was allowed to return to rt and ep-
oxide 13 (300 mg, 0.83 mmol) was added in one portion. The
mixture was heated to reflux for 3 days. Water (10 mL) and Et2O (10
mL) were then added and the aqueous layer separated and
extracted with Et2O (2ꢂ20 mL). The combined organic layers were
washed with brine, dried and evaporated under reduced pressure.
Purification of the residue by column chromatography gave a white
solid foam, 7-azanortricyclanol 14i (294 mg, 90%); Rf 0.3 (Et2O).
Found: C, 57.8; H, 6.5; N, 3.5. C19H25O6NS requires C, 57.7; H, 6.4; N,
3.5%. IR (KBr) 3425br, 2979m, 2931m, 1699s, 1598m, 1386s, 1317s,
Bu3SnH (128 mL, 0.47 mmol) and AIBN (14 mg, 0.09 mmol) as de-
scribed in the preparation of 21b gave, after purification by column
chromatography (20/30% Et2O in petrol) a colourless oil, 1,2-
dihydropyridine 21e (61 mg, 37%, 46% based on recovered xan-
thate); Rf 0.4 (50% Et2O in petrol); IR (film) 2980m, 2931m, 1725s,
1634m, 1596m, 1456m, 1393m, 1370m, 1321s, 1289s, 1259m, 1144s,
1145s,1089s,1006m, 868m and 680m cmꢀ1
; dH (400 MHz) 7.79 (2H,
d, J 8, 2ꢂCH of Ts), 7.31 (2H, d, J 8, 2ꢂCH of Ts), 4.22 (1H, s, NCH), 4.11
(1H, d, J 5, NCHCTs), 3.97 (1H, s, MeOCH), 3.76 (1H, s, CHOH), 3.09
(3H, s, OMe), 2.70 (1H, d, J 5, TsCCHCHOH), 2.43 (4H, s, CH3 of Ts,
OH) and 1.37–1.26 (9H, m, t-Bu); dC (100 MHz) 157.0 (C]O), 144.3
(Cquat of Ts), 137.7 (Cquat of Ts), 129.2 (2ꢂCH of Ts), 128.6 (2ꢂCH of
Ts), 81.1 (CMe3), 79.8 (COH), 68.4 (COMe), 59.9 (NCH), 56.6 (MeO),
49.7 (TsC), 39.4 (NCHCTs), 29.4 (TsCCHCHOH), 27.6 (3ꢂCH3 of Boc)
and 21.5 (CH3 of Ts); m/z (CI, NH3) 413 (MþNHþ4 , 68%), 357 (28), 296
(20) and 108 (100) (Found: MþNHþ4 , 413.1751. C19H29O6N2S re-
quires M, 413.1746.).
1089s, 1057m, 1019m, 814m, 731m, 716m and 661s cmꢀ1
; dH (400
MHz) 7.85 (1H, br s, NCH]), 7.75 (2H, d, J 8, 2ꢂCH of Ts), 7.30 (2H, d,
J 8, 2ꢂCH of Ts), 6.19 (1H, d, J 10, TsCCH]), 5.55 (1H, dd, J 10, 5.5,
CHCH]), 4.97 (1H, br s, NCH), 3.30–3.21 (5H, m, CH2, OMe), 2.42
(3H, s, CH3 of Ts) and 1.54 (9H, s, 3ꢂCH3 of Boc); dC (100 MHz) (C]O
not observed), 143.7 (CquatMe of Ts), 138.4 (Cquat of Ts), 134.3
(NCH]), 129.7 (2ꢂCH of Ts), 127.2 (2ꢂCH of Ts), (TsCquat not ob-
served), 120.0 (CHCH]), 119.3 (TsCCH]), 83.8 (CMe3), 73.1
(CH2OMe), 59.1 (OMe), 51.9 (NCH), 28.0 (3ꢂCH3 of Boc) and 21.5
(CH3 of Ts); m/z (CI, NH3) 397 (MþNHþ4 , 35%), 278 (72), 248 (97),
234 (100) and 124 (45) (Found: MþNHþ4 , 397.1791. C19H29O5N2S
requires M, 397.1797.).
4.22. 3-(tert-Butoxycarbonyl)-7-(4-methoxybenzyloxy)-1-
tosyl-3-azatricyclo[2.2.1.02,6]heptan-5-ol (14j)
4-Methoxybenzyl alcohol (243 mg, 1.76 mmol) in THF (5 mL)
was added to a stirred slurry of NaH (66 mg, 1.65 mmol; 60% w/w
dispersion in mineral oil) at 0 ꢁC. After 0.5 h, epoxide 13 (400 mg,
1.10 mmol) in THF (5 mL) was added. The reaction mixture was
warmed to rt and stirred for 22 h. Water (10 mL) was then added
and the aqueous layer extracted with Et2O (3ꢂ20 mL). The com-
bined organic layers were washed with brine, dried and evaporated
under reduced pressure. Purification of the residue by column
chromatography (60/100% Et2O in light petroleum) gave a white
crystalline solid, alcohol 14j (319 mg, 58%); Rf 0.4 (Et2O); mp 150–
151 ꢁC (Et2O). Found: C, 62.3; H, 6.4; N, 2.8. C26H31NO7S requires C,
62.3; H, 6.2; N, 2.8%. IR (film) 3278br, 2978m, 2932m,1681s, 1612m,
1515s, 1465m, 1396s, 1302s, 1252s, 1175s, 1090s, 1036m, 1019m and
4.24. tert-Butyl 2-[(4-methoxybenzyloxy)methyl]-5-
tosylpyridine-1(2H)-carboxylate (21f)
A solution of 7-azanortricyclanol 14j (210 mg, 0.42 mmol) in THF
(2 mL) was added dropwise to a slurry of KH (30% dispersion in
mineral oil; 168 mg, 1.26 mmol) in THF (3 mL) at 0 ꢁC. The reaction
mixture was warmed to rt, stirred for 20 min and CS2 (131
mL, 2.1
mmol) was added. After a further 10 min, MeI (131 L, 2.10 mmol)
m
was added and the mixture stirred for 30 min. Water (10 mL) was
then added, the aqueous layer extracted with Et2O (3ꢂ20 mL) and
the combined organic layers washed with brine, dried and evapo-
rated under reduced pressure to give the corresponding xanthate as
a yellow oil. Diagnostic data: dH (400 MHz) 5.47 (0.8H, s, CHO), 5.37
(0.2H, s, CHO), 2.41 (0.6H, s, SCH3) and 2.45 (2.4H, s, SCH3). The
above crude xanthate was dissolved in toluene (15 mL), AIBN (14
mg, 0.08 mmol) was added and the mixture heated to reflux.
680m cmꢀ1
; dH (400 MHz; CDCl3) (shows rotamers 1:4 ratio) 7.74
(0.4H, d, J 7.5, 2ꢂCH of Ts), 7.69 (1.6H, d, J 8, 2ꢂCH of Ts), 7.20 (0.4H,
d, J 7.5, 2ꢂCH of Ts), 7.08 (1.6H, d, J 8, 2ꢂCH of Ts), 6.99 (1.6H, d, J 8.5,
2ꢂCH of MeOAr), 6.95–6.80 (0.8H, m, 4ꢂCH of MeOAr), 6.77 (1.6H,
d, J 8.5, 2ꢂCH of MeOAr), 4.56 (0.2H, d, J 4, NCHTs), 4.34 (0.2H, d, J
14, CHOH) 4.34–4.28 (1.6H, m, CH2), 4.18 (0.8H, d, J 5, NCHTs), 4.16–
4.06 (1.2H, m, CHOH, CH2), 3.99 (1H, d, J 10, NCH), 3.94 (1H, s,
CHOCH2), 3.80 (3H, s, OMe), 3.82–3.68 (2H, m, TsCCHCHOH, OH),
2.39 (0.6H, s, CH3 of Ts), 2.33 (2.4H, s, CH3 of Ts) and 1.26 (9H, s,
3ꢂCH3 of Boc); dC (100 MHz; CDCl3) 159.2 (Cquat of MeOAr), 156.7
(C]O), 144.1 (Cquat of Ts), 137.5 (Cquat of Ts), 130.0 (2ꢂCH of Ts),
129.1 (2ꢂMeOAr), 128.7 (Cquat of MeOAr), 128.4 (2ꢂCH of Ts), 113.3
Bu3SnH (169
mL, 0.63 mmol) was then added and the heating
continued for 2 h. Workup by the method of Curran and Chang34
and purification of the residue by column chromatography (50%
Et2O in petrol) gave 1,2-dihydropyridine 21f as a colourless oil (21
mg, 10%); Rf 0.25 (50% Et2O in petrol); IR (film) 2977m, 1723s,
1613m, 1514m, 1455m, 1393m, 1370m, 1289s, 1257s, 1144s, 1089s,
1033m, 814m, 732m and 661s cmꢀ1
; dH (500 MHz) 7.85 (1H, br s,

7834
D.M. Hodgson et al. / Tetrahedron 65 (2009) 7825–7836
NCH]), 7.72 (2H, d, J 8, 2ꢂCH of Ts), 7.27 (2H, d, J 8, 2ꢂCH of Ts), 7.15
(2H, d, J 8.5, 2ꢂCH of MeOAr), 6.85 (2H, d, J 8.5, 2ꢂCH of MeOAr),
6.19 (1H, d, J 10, TsCCH]), 5.55 (1H, dd, J 10, 5.5, CHCH]), 5.04 (1H,
br s, NCH), 4.40 (1H, d, J 11.5, H of ArCH2O), 4.32 (1H, d, J 11.5, H of
ArCH2O), 3.81 (3H, s, OMe), 3.34 (1H, dd, J 10 and 5, H of CHCH2O),
3.28 (1H, dd, J 10 and 6, H of CHCH2O), 2.41 (3H, s, CH3 of Ts) and
1.51 (9H, s, 3ꢂCH3 of Boc); dC (125 MHz) (C]O not observed), 159.1
(Cquat of MeOAr), 143.5 (Cquat of Ts), 138.3 (Cquat of Ts), 134.2
(]CHN), 130.1 (Cquat of MeOAr), 129.7 (2ꢂCH of Ts), 129.1 (2ꢂCH of
MeOAr), 127.7 (]CSO2), 127.1 (2ꢂCH of Ts), 119.9 (CHCH]), 119.2
(CCH], br), 113.6 (2ꢂCH of MeOAr), 83.6 (CMe3), 72.6 (ArCH2), 70.0
(CHCH2O), 55.2 (OMe), 52.0 (NCH, br), 27.9 (3ꢂCH3 of Boc) and 21.4
(CH3 of Ts); m/z (CI, NH3) 503 (MþNHþ4 , 100%), 486 (15), 447 (20),
430 (20) and 386 (50) (Found: MþNHþ4 , 503.2212. C26H35O6N2S
requires M, 503.2216.).
160.6 (pyC2), 152.9 (C]O), 148.2 (pyC6), 144.9 (Cquat of Ts), 137.8
(pyC5), 137.6 (Cquat of Ts), 135.9 (pyC4), 130.2 (2ꢂCH of Ts), 127.8
(2ꢂCH of Ts), 120.9 (pyC3), 83.1 (CMe3), 68.0 (OCH2), 27.7 (3ꢂCH3 of
Boc) and 21.6 (CH3 of Ts); m/z (ESþ) 364.1 (MþHþ, 37%) and 308.1
(100) (Found: MþHþ, 364.1211. C18H22O5NS requires M, 364.1219.).
4.27. 3-tert-Butoxycarbonyl-7-diethylamino-1-tosyl-3-
azatricyclo[2.2.1.02,6]heptan-5-ol (14k)
To a solution of epoxide 13 (500 mg,1.37 mmol) in CH2Cl2 (5 mL)
was added HNEt2 (2.5 mL, 0.024 mol) and the mixture stirred at rt.
After 14 h, the mixture was evaporated to dryness under reduced
pressure to reveal a brown foam, the corresponding amino epoxide.
The crude amino epoxide was dissolved in THF (10 mL) then cooled
to 0 ꢁC, MeLi (1.0 M in THF; 2.75 mL, 2.75 mmol) was added and the
mixture stirred for 3 h. Water (10 mL) was added followed by EtOAc
(20 mL). The aqueous layer was separated and washed with EtOAc
(20 mL), then the combined organic layers washed with brine,
dried and evaporated under reduced pressure. Purification of the
residue by column chromatography gave a white solid, tricyclanol
14k (444 mg, 74%); Rf 0.4 (Et2O); IR (film) 3453br, 2974m, 2931m,
2872w, 2816w, 1694s, 1433m, 1316m, 1294m, 1162s, 1142s, 865m,
4.25. tert-Butyl 2-[(3,5-dinitrobenzoyloxy)methyl]-5-
tosylpyridine-1(2H)-carboxylate (21g)
To a solution of dihydropyridine 21f (21 mg, 0.043 mmol) in
CH2Cl2 (1 mL) was added water (59 mL, 0.0033 mmol) and DDQ
(14.7 mg, 0.065 mmol). The mixture was stirred for 3 h at rt, then
CH2Cl2 (4 mL) was added and the organic layer washed with sat-
urated NaHCO3 (2ꢂ5 mL), brine, then dried and evaporated under
reduced pressure. Purification of the residue by column chroma-
tography (70% Et2O in petrol) gave a colourless oil, the corre-
sponding alcohol (3.9 mg, 24%). This labile alcohol (3.9 mg, 10.7
676m and 577m cmꢀ1
; dH (400 MHz) (spectrum broadened by
rotamers) 7.82 (2H, d, J 7.5, 2ꢂCH of Ts), 7.30 (2H, d, J 7.5, 2ꢂCH of
Ts), 4.60 (1H, d, J 5, NCHCTs), 4.05 (1H, s, NCHCHN), 3.68 (1H, s,
CHOH), 3.08 (1H, s, Et2NCH), 2.95–2.05 (8H, m, CH3 of Ts, 2ꢂCH2 of
Et, and TsCCHCHOH), 1.44 (9H, s, 3ꢂCH3 of Boc), 0.85 (6H, s, 2ꢂCH3
of Et); dC (100 MHz) (spectrum broadened by rotamers) 154.1
(C]O), 144.6 (Cquat of Ts), 136.3 (Cquat of Ts), 129.5 (2ꢂCH of Ts),
128.4 (2ꢂCH of Ts), 81.2 (CMe3), 70.2 (CHO), 62.2 (Et2NC), 57.7
(NCH), 46.7 (TsC), 42.9 (2ꢂCH2 of Et), 38.2 (NCHCTs), 28.3 (3ꢂCH3 of
Boc), 26.6 (TsCCHCHOH), 21.6 (CH3 of Ts), 13.5 (2ꢂCH3 of Et); m/z
(ESþ) 437.2 (MþHþ, 100%) 409.2 (20) (Found: MþHþ, 437.2103.
C22H33O5N2S requires M, 437.2110.).
mmol) was dissolved in CH2Cl2 (2 mL), NEt3 (30
mL, 214 mmol) and
3,5-dinitrobenzoyl chloride (25 mg, 108 mol) were added and the
m
mixture stirred at rt for 14 h. The reaction mixture was absorbed
onto silica and purified by column chromatography (40% Et2O in
petrol) to give dihydropyridine 21g as a white micro-crystalline
solid (2.4 mg, 42%); Rf 0.3 (50% Et2O in petrol); IR (KBr) 2977m,
1722s, 1613s, 1513s, 1370s, 1513s, 1455m, 1370m, 1288m, 1257m,
1144s, 1034m, 814m and 732m cmꢀ1
; dH (500 MHz) 9.23 (1H, t, J 2,
C4 of ArCO2), 9.11 (2H, d, J 2, C2 and C6 of ArCO2), 7.82 (1H, br s,
NCH]), 7.72 (2H, d, J 8, 2ꢂCH of Ts), 7.29 (2H, d, J 8, 2ꢂCH of Ts),
6.29 (1H, d, J 10, TsCCH]), 5.58 (1H, dd, J 10, 5.5, CHCH]), 5.31 (1H,
br s, NCH), 4.45 (1H, d, J 11, CHaHb), 4.30–4.13 (1H, m, CHaHb), 2.42
(CH3Ar),1.49 (9H, s, 3ꢂCH3 of Boc); dC (125 MHz) 162.4 (C]O),151.2
(C]O), 148.5 (C3 and C5 of Ar), 144.0 (C4 of Ar), 137.7 (C2 and C6 of
Ar), 129.8 (2ꢂCH2 of Ts), 129.5 (NCH]), 129.3 (C1 of Ar), 127.3
(2ꢂCH of Ts), 122.5 (CH]), 120.9 (CH]), 84.6 (CMe3), 27.8 (3ꢂCH3
of Boc), 21.5 (CH3 of Ts); m/z (ESþ) 582.0 (MþNaþ, 55%), 577.1
(MþNHþ4 , 35) and 102.1 (100) (Found: MþNHþ4 , 577.1602.
C25H29N4O10S requires M, 577.1604.).
4.28. 1-tert-Butoxycarbonyl-2-[(diethylamino)methylene]-5-
tosyl-1,2-dihydropyridine (30)
To a solution of tricyclanol 14k (440 mg, 1.0 mmol) in CH2Cl2 (15
mL) was added DMAP (247 mg, 2.02 mmol) then PhOC(S)Cl (153 mL,
1.11 mmol). The mixture was stirred at rt for 14 h. Dry SiO2 was
added and the solvent evaporated. Purification of the residue by
column chromatography (10/50% Et2O in petrol) gave the corre-
sponding thiocarbonate as a white foam (451 mg, 78%); Rf 0.7
(Et2O); IR (film) 2976m, 2933m, 1710s, 1596m, 1490s, 1392s, 1306s,
1278s, 1215s, 1090m, 864m, 773m, 733m and 581m cmꢀ1
; dH (400
MHz) (spectrum split by rotamers 4:6) 7.90 (0.8H, d, J 8.5, 2ꢂCH of
Ts), 7.87 (1.2H, d, J 8, 2ꢂCH of Ts), 7.42–7.18 (5H, m, 2ꢂCH of Ts and
3ꢂCH of OPh), 7.10–7.05 (2H, m, 2ꢂCH of OPh), 5.03 (0.4H, dd, J 1.5
and 1.5, CHO), 4.94 (0.6H, dd, J 1.5 and 1.5, CHO), 4.81 (0.4H, d, J 4.5,
NCHCTs), 4.77 (0.6H, d, J 4.5, NCHCTs), 4.68 (0.6H, s, NCHCO), 4.50
(0.4H, s, NCHCO), 3.13 (0.4H, s, CHNEt2), 2.93 (0.6H, s, CHNEt2), 2.81
(0.4H, ddd, J 4.4, 1.2 and 1.2, TsCCHCHO), 2.75–2.34 (7.6H, m,
0.6ꢂTsCCHCHO, 3ꢂCH3 of Ts and 4ꢂCH2 of NEt2), 1.51 (5.4H, s,
3ꢂCH3 of Boc), 1.48 (3.6H, s, 3ꢂCH3 of Boc) and 0.93 (3.6H, t, J 7.0,
6ꢂCH3 of NEt2); dC (100 MHz) (spectrum split by rotamers) 194.0
(C]S), 154.0 (C]O), 153.3, 153.2 (Cquat of OPh), 145.0, 144.9 (Cquat of
Ts), 136.2, 135.9 (Cquat of Ts), 129.63, 129.58 (2ꢂCH of Ts), 129.54,
129.50 (2ꢂCH of OPh), 128.8, 128.6 (2ꢂCH of Ts), 126.8, 126.7 (CH of
OPh), 121.8, 121.7 (2ꢂCH of OPh), 81.4, 81.0 (CMe3), 80.5, 80.0
(CHO), 62.6, 61.1 (NCHCHO), 57.2, 55.6 (CHNEt2), 46.9, 46.3 (TsCquat),
43.1, 43.0 (2ꢂCH2 of NEt2), 39.5, 38.9 (NCHCTs), 28.3 (3ꢂCH3 of
Boc), 24.3, 23.9 (TsCCHCHO), 21.7 (CH3 of Ts) and 13.5, 13.2 (2ꢂCH3
of NEt2); m/z (CI, NH3) 573.3 (MþHþ, 30%), 419.3 (85), 319.2 (30),
74.2 (100) (Found: MþHþ, 573.2091. C29H37O6N2S2 requires M,
573.2093.). The above thiocarbonate (50 mg, 0.087 mmol) was
4.26. tert-Butyl (5-tosylpyridin-2-yl)methyl carbonate (28)
To a solution of 7-azanortricyclanol 14j (899 mg, 1.79 mmol) in
MeCN (20 mL) was added DMAP (657 mg, 5.38 mmol) and
PhOC(S)Cl (496 mL, 3.58 mmol) and the mixture was stirred at rt for
14 h. Purification of the mixture by column chromatography (10/
60% Et2O in petrol) gave a white foam, the corresponding thiocar-
bonate (623 mg, 56%). The thiocarbonate was dissolved in toluene
(39 mL), AIBN (32 mg, 0.2 mmol) was added and the mixture
heated to reflux. Bu3SnH (289 mL,1.1 mmol) was then added and the
heating continued for 2 h. Workup by the method of Curran and
Chang34 and purification of the residue by column chromatography
(50% Et2O in petrol) gave a clear colourless oil, pyridine carbonate 28
(260 mg, 72%); Rf 0.3 (50% Et2O in petrol); IR (film) 2980w, 2932w,
1747s, 1585m, 1370m, 1326m, 1282s, 1255m, 1160s, 1108m, 1017w,
867w, 814w, 708m and 686s cmꢀ1
; dH (400 MHz) 9.05 (1H, d, J 2,
pyC6-H), 8.19 (1H, dd, J 8, 2, pyC4-H), 7.83 (2H, d, J 8, 2ꢂCH of Ts),
7.49 (1H, d, J 8, pyC3-H), 7.32 (2H, d, J 8, 2ꢂCH of Ts), 5.23 (2H, s,
OCH2), 2.40 (3H, s, CH3 of Ts) and 1.49 (9H, s, Boc); dC (100 MHz)

D.M. Hodgson et al. / Tetrahedron 65 (2009) 7825–7836
7835
dissolved in cumene (5 mL) and heated to reflux for 2 h. The re-
action mixture was cooled and the solvent removed under reduced
pressure. Purification of the residue by column chromatography
(30/50% Et2O in petrol) gave a clear colourless oil, enamine 30 (14
mg, 38%); Rf 0.4 (50% Et2O in petrol); IR (film) 2978m, 2934w,1736s,
1628s, 1558w, 1400m, 1370m, 1332s, 1295m, 1140s, 1107m, 1085m
62.6, 61.9 (CHN), 61.6, 60.8 (CHN), 56.8, 56.5 (CHO), 56.4, 56.2 (CHO),
52.1 (OMe) and 28.2, 28.1 (3ꢂCH3 of Boc); m/z (CI, NH3) 285
(MþNHþ4 ,15%), 268 (MþHþ, 95), 256 (12), 247 (11), 243 (22) and 229
(100) (Found: MþHþ, 268.1187. C13H18NO5 requires M, 268.1185.).
4.31. 3-(tert-Butoxycarbonyl)-1-(methoxycarbonyl)-7-(4-
and 733w cmꢀ1
;
dH (400 MHz; C6D6) 7.85 (2H, d, J 8, 2ꢂCH of Ts),
methoxyphenyl)-3-azatricyclo [2.2.1.02,6]heptan-5-ol (34)
7.79 (1H, s, NCH]), 7.70 (1H, dd, J 3.5 and 2, TsCCH), 6.86 (2H, d, J 8,
2ꢂCH of Ts), 6.06 (1H, t, J 3.5, TsCCH]CH), 6.01 (1H, dd, J 3.5 and 2,
]CHNEt2), 2.65 (4H, q, J 7, 2ꢂCH2 of NEt2), 2.00 (3H, s, CH3 of Ts),
1.60 (9H, s, 3ꢂCH3 of Boc) and 0.72 (6H, br, s, 2ꢂCH3 of NEt2); dC
(100 MHz) 148.8 (C]O), 146.7 (CHNBoc), 141.7 (Cquat of Ts), 140.0
(CquatNBoc), 128.9 (2ꢂCH of Ts), 127.2 (2ꢂCH of Ts), 123.3 (TsCCH),
To a cooled (0 ꢁC) solution of epoxide 33 (690 mg, 2.58 mmol) in
THF (50 mL) was added 4-methoxyphenylmagnesium bromide (0.5
M in THF; 10.3 mL, 5.17 mmol). The reaction mixture was stirred for
2 h at 0 ꢁC, then saturated aq NH4Cl (50 mL) was added and the
mixture extracted with Et2O (3ꢂ50 mL). The combined organic
layers were washed with brine, dried and evaporated under
reduced pressure. Purification of the residue by column chroma-
tography (50/100% Et2O in petrol) gave a white foam, 7-azanor-
tricyclanol 34 (443 mg, 46%); Rf 0.2 (80% Et2O in petrol); IR (film)
3423br, 2977w, 1698s, 1515s, 1440m, 1368m, 1307m, 1250s, 1180m,
122.3 (Cquat of Ts), 119.5 (TsCCH]CH), 110.0 (CHNEt), 97.5 (TsCquat
)
83.7 (CMe3), 27.7 (3ꢂCH3 of Boc) and 21.4 (CH3 of Ts) (note: CH2 and
CH3 of NEt2 not observeddvery broad); m/z (ESþ) 859.0 (2 MþNaþ,
70%), 441.0 (MþNaþ, 50), 419.1 (MþHþ, 100), 264.1 (80) and 162.9
(40) (Found: MþHþ, 419.2005. C22H31O4N2S requires M, 419.2005.).
1135m, 1070w, 1035w and 732w cmꢀ1
; dH (400 MHz) (spectrum
4.29. 7-tert-Butyl 2-methyl 7-azabicyclo[2.2.1]hepta-2,5-
diene-2,7-dicarboxylate (32)
split by rotamers 6:4 ratio) 7.04 (2H, d, J 8.4, 2ꢂMeOAr), 6.81 (2H, d,
J 8.4, 2ꢂMeOAr), 4.54 (0.6H, br s, NCHTs), 4.40 (0.4H, br s, NCHTs),
4.20–4.11 (1H, m, CHOH), 3.98 (0.4H, br s, NCH), 3.87 (0.6H, br s,
NCH), 3.76 (3H, s, OMe), 3.61 (3H, s, CO2Me), 3.27 (1H, s, ArCH), 2.29
(1H, br s, CHCHOH), 2.08–1.86 (1H, m, br, OH) 1.40 (3.6H, br s,
3ꢂCH3 of Boc) and 1.06 (5.4H, br s, 3ꢂCH3 of Boc); dC (100 MHz)
169.7 (C]O), 158.6 (Cquat of MeOAr), C]O not observed, 128.8
(2ꢂCH of MeOAr), 128.2 (Cquat of MeOAr), 113.8 (2ꢂCH of MeOAr),
80.3 (CMe3), 73.9 (CHOH), 64.4 (NCH), 55.2 (OMe), 52.0 (CO2Me),
45.3 (CHAr), 38.4 (NCHCTs), 32.7 (CCO2Me) and 27.8 (3ꢂCH3); m/z
(EI) 375 (Mþ, 100%), 319 (79), 302 (70) and 288 (40) (Found: Mþ,
375.1678. C20H25O6N requires M, 375.1682.).
Zinc/silver couple was prepared as follows:25 10% HCl (5 mL) was
added to Zn dust (710 mg, 11.0 mmol) and the reaction mixture
stirred for 5 min. The liquid was decanted and the Zn was washed
with acetone (2ꢂ5 mL) and Et2O (5 mL). A suspension of AgOAc (25
mg, 0.15 mmol) in AcOH (2 mL) was added with stirring to the
digested Zn. After 1 min, the supernatant was decanted and the black
Zn/Ag was washed with AcOH (3 mL), Et2O (4ꢂ5 mL) and MeOH (5
mL). The moist Zn/Ag was added to a stirred solution of bromodiene
3126 (500 mg, 1.50 mmol) in MeOH (5 mL) and the reaction mixture
was stirred for 2 h. The solid was filtered off and the solvent evap-
orated under reduced pressure. Purification by column chromato-
graphy (25% Et2O–hexane) gave a pale yellow oil, debrominated diene
32 (300 mg, 80%); Rf (25% Et2O–hexane) 0.16; IR (film) 2978s, 1712s,
4.32. 1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl)-2-
(4-methoxyphenyl)methyl-1,2-dihydropyridine (35)
1460m, 1368s, 1324s, 1168s and 790m cmꢀ1
;
dH (270 MHz) 7.70 (1H,
1,10-Thiocarbonyldiimidazole (631 mg, 3.54 mmol) was added to
a solution of 7-azanortricyclanol 34 (443 mg, 1.18 mmol) in CH2Cl2
(5 mL). After 14 h the mixture was evaporated under reduced
pressure. Purification of the residue by column chromatography
(80/100% Et2O in petrol) gave a white foam, the corresponding
thiocarbamate (572 mg, 100%). Diagnostic data: dH (400 MHz) 8.29
(1H, s, NCH]), 7.57 (1H, s, NCH]), 7.02 (0.5H, s, NCH]), 6.99 (0.5H,
s, NCH]) and 5.56 (1H, s, CHO). Reaction of the above thio-
br s, C(3)H), 7.13 (1H, br s, HC]CH), 6.98 (1H, br s, HC]CH), 5.42 (1H,
br s, CH), 5.33 (1H, br s, CH), 3.76 (3H, s, OMe) and 1.41 (9H, s, t-Bu);
dC(100 MHz) (broadening due to rotational isomers, C2 not observed)
163.8 (C]O), 155.0 (C]O), 154.4 and 153.8 (C3), 145.0, 144.0, 143.3
and 142.3 (C]C), 81.0 (CMe3), 67.9 and 67.5 (C1), 66.8 and 66.3 (C4),
51.9 and 51.7 (OMe) and 28.4, 28.3, 28.1 and 28.0 (3ꢂMe); m/z (CI)
252 (MþHþ, 10%), 182 (90), 154 (95) and 113 (100) (Found: MþHþ,
252.1235. C13H18NO4 requires M, 252.1236.).
carbamate (535 mg, 1.10 mmol), Bu3SnH (363 mL, 1.35 mmol) and
AIBN (40.0 mg, 0.24 mmol) as described in the preparation of 21b
gave, after purification by column chromatography (10/20% Et2O
in petrol) a clear colourless oil, 1,2-dihydropyridine 35 (181 mg,
46%); Rf 0.4 (20% Et2O in petrol); IR (KBr) 2952m, 2837w, 1713s,
1640m, 1584m, 1513s, 1441m, 1394m, 1369m, 1340m, 1246s, 1150s,
4.30. 8-(tert-Butoxycarbonyl)-6-(methoxycarbonyl)-8-aza-3-
oxatricyclo [3.2.1.02,4]octane (33)
To a solution of debrominated diene 32 (1.52 g, 6.05 mmol) in
CH2Cl2 (60 mL) was added aqueous NaHCO3 (0.5 M; 20 mL) then
MCPBA (70% remainder water; 2.24 g, 9.08 mmol). The mixture was
stirred at rt for 24 h. Saturated Na2SO3 was added until a negative
starch iodide test was obtained. The aqueous phase was extracted
with CH2Cl2 (60 mL) and the combined organic layers were washed
with saturated aqueous NaHCO3 (2ꢂ50 mL) then brine (50 mL) and
dried. Purification of the residue by column chromatography (50/
60% Et2O in petrol) gave a clear colourless oil, epoxide 33 (711 mg,
44%); Rf 0.3 (40% Et2O in petrol); IR (film) 2927m, 1714s, 1369s,
1084m, 1036m, 981m, 852m and 731m cmꢀ1
; dH (400 MHz) 8.00–
7.71 (1H, m, br, NCH]), 7.06 (2H, br s, 2ꢂCH of MeOAr), 6.82 (2H, d,
J 8.5, 2ꢂCH of MeOAr), 6.43 (1H, d, J 9.5, CH]), 5.45 (1H, dd, J 9.5,
5.5, CHCH]), 4.88 (1H, br s, NCH), 3.77 (6H, s, 2ꢂOMe), 2.72 (2H, d,
J 7, CH2) and 1.47 (9H, br s, Boc); dC (100 MHz) (C]O of Boc not
seen) 166.3 (CO2), 158.4 (Cquat of MeOAr), 135.1 (NCH]), 130.6
(2ꢂCH of MeOAr), 128.3 (Cquat of MeOAr), 120.7 (CH]), 120.3
(CHCH]), 113.7 (2ꢂCH of MeOAr), 82.9 (CMe3), 55.2 (ArOCH3), 53.6
(br, NCH), 51.4 (CO2CH3), 39.9 (CH2) and 27.9 (3ꢂCH3 of Boc); m/z
(CI, NH3) 377.2 (MþNHþ4 ,10%), 360 (80), 321 (20), 304 (15), 258 (25),
138 (100) and 121 (25) (Found: MþHþ, 360.1809. C20H26O5N re-
quires M, 360.1811.).
1335m, 1271m, 1227m, 1169m and 1072m cmꢀ1
; dH (400 MHz)
(shows rotamers at 300 K) 7.29–7.27 (1H, m, CH]), 5.03 (0.4H, s,
NCHCCO2Me), 4.90 (0.6H, s, NCHCCO2Me), 4.85 (0.6H, d, J 2.8, NCH),
4.72 (0.4H, d, J 2.7, NCH), 3.79 (1.8H, s, OMe), 3.78 (1.2H, s, OMe), 3.65
(0.4H, d, J 3.65, CHO), 3.62 (0.6H, d, J 3.65, CHO), 3.57 (0.6H, d, J 3.65,
CHO), 3.54 (0.4H, d, J 3.65, CHO), 1.48 (1.8H, s, 3ꢂCH3 of Ts) and 1.47
(1.2H, s, 3ꢂCH3 of Ts); dC (100 MHz) (split by rotamers),181.3 (C]O),
162.8 (C]O),155.8,155.6 (C]),147.1,146.8 (CH]), 80.7, 80.6 (CMe3),
Acknowledgements
We thank the EPSRC for a Research Grant (GR/M55541), and the
EPSRC, Evotec OAI and Syngenta for CASE awards (to M.L.J. and

7836
D.M. Hodgson et al. / Tetrahedron 65 (2009) 7825–7836
12. For review on azabicyclo[2.2.1]heptyl systems, see: Blondet, D.; Morin, C.
Heterocycles 1982, 19, 2155–2182; For recent discussion on synthetic utility, see:
Maison, W. Eur. J. Org. Chem. 2007, 2276–2284.
C.R.M.). We also thank the EPSRC National Mass Spectrometry
Service Center for mass spectra.
13. Preliminary communication: Hodgson, D. M.; Jones, M. L.; Maxwell, C. R.;
Ichihara, O.; Matthews, I. R. Synlett 2005, 325–327.
14. Leung-Toung, R.; Liu, Y.; Muchowski, J. M.; Wu, Y.-L. J. Org. Chem. 1998, 63,
3235–3250.
Supplementary data
15. Jin, Z.; Fuchs, P. L. J. Am. Chem. Soc. 1995, 117, 3022–3028.
16. Afarinkia, K.; Mahmood, F. Tetrahedron Lett. 2000, 41, 1287–1290.
17. Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413–1432.
18. No 1,2-dihydropyridines 21 were observed as by-products from these reactions.
19. Dieter, R. K.; Sharma, R. R. J. Org. Chem. 1996, 61, 4180–4184; McDonald, F. E.;
Chatterjee, A. K. Tetrahedron Lett. 1997, 38, 7687–7690.
ORTEP drawings of 14f, 21g and 25 (Figs. S1–S3). Crystallographic
data (excluding structure factors) for the structures in this paper have
been deposited with the Cambridge Crystallographic Data Centre,
CCDC nos. 237474, 735974 and 735975 for 14f, 21g and 25, re-
spectively. Copies of this information may be obtained free of charge
from the Director, CCDC,12 Union Road, Cambridge CB2 1EZ, UK (fax:
þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk or www: http://
www.ccdc.cam.ac.uk). Supplementary data associated with this arti-
cle canbefoundinthe onlineversion, atdoi:10.1016/j.tet.2009.07.022.
20. Single crystal diffraction data for 14f: C25H29NO6S, Mr¼471.57, monoclinic (P21/
c), a¼18.5776(6) Å, b¼6.0148(2) Å, c¼20.7897(7) Å,
b
¼91.9711(16)ꢁ, V¼2321.7
Å3, Dc¼1.349 Mg/m3, Z¼4,
m
¼0.181 mmꢀ1, 18,822 data collected, 5253 unique
data [R(int)¼0.063], R1¼0.0408, wR2¼0.0464, CCDC 237474.
21. Single crystal diffraction data for 25: C25H29NO6S, Mr¼471.57, triclinic ðP1Þ, a¼6.
1488(2) Å, b¼9.6920(2) Å, c¼19.4435(4) Å,
a
¼85.9004(9)ꢁ,
b
¼84.7239(9)ꢁ,
g
¼84.3066(9)ꢁ, V¼1145.84(5) Å3, Dc¼1.367 Mg/m3, Z¼2,
m
¼0.184 mmꢀ1, 17,784
data collected, 5161 unique data [R(int)¼0.041], R1¼0.0384, wR2¼0.0391, CCDC
References and notes
735975.
22. Single crystal diffraction data for 21g: C25H25N3O10S, Mr¼559.55, triclinic ðP1Þ,
a¼8.5894(2) Å, b¼13.0366(2) Å, c¼13.4603(3) Å,
a
¼117.4440(9)ꢁ,
b¼96.
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