Development of a [3+3] approach to tetrahydropyridines and its application in indolizidine alkaloid synthesis

Article abstract of DOI:10.1016/j.tet.2008.01.071

A stepwise [3+3] annelation sequence is described that generates tetrahydropyridines from the corresponding aziridines. The scope of this process is described and its potential for the stereoselective synthesis of indolizidines is highlighted by the synth

Full text of DOI:10.1016/j.tet.2008.01.071

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2951e2961
www.elsevier.com/locate/tet
Development of a [3þ3] approach to tetrahydropyridines
and its application in indolizidine alkaloid synthesis
Lisa C. Pattenden a, Harry Adams a, Stephen A. Smith b, Joseph P.A. Harrity a,
*
a Department of Chemistry, University of Sheffield, Sheffield S3 7HF, UK
b GlaxoSmithKline Research and Development, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
Received 25 October 2007; received in revised form 3 January 2008; accepted 17 January 2008
Available online 25 January 2008
Abstract
A stepwise [3þ3] annelation sequence is described that generates tetrahydropyridines from the corresponding aziridines. The scope of this
process is described and its potential for the stereoselective synthesis of indolizidines is highlighted by the synthesis of (ꢀ)-monomorine.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
[3+3]
RN
N
R
Aziridines are extremely useful building blocks in organic
synthesis because of their ability to function as reactive electro-
philic substrates.1 Recent work in our laboratory2,7 has focused
on the exploitation of aziridines in [3þ3] annelation processes
for the stereoselective synthesis of piperidines3,4 by the addition
of a suitable conjunctive reagent. Specifically, we have shown
that trimethylenemethane (TMM; 1) equivalents 2 and 3 can
serve as useful reagents for the synthesis of piperidines bearing
an exomethylene motif. In an effort of expanding the scope of
the [3þ3] annelation manifold, we have been investigating
alternative conjunctive reagents with a view to prepare piperi-
dines with the potential for alternative modes of functionalisa-
tion. Indeed, we anticipated that synthon 4 would allow us to
generate tetrahydropyridines by a manner akin to the sulfone
based three-carbon homologating reagent 5 developed by Craig
and co-workers.5 Our preliminary studies demonstrated that the
BrMgO
MgBr
PdL2
2
1
3
MgBr
O
Ts
OMe
4
O
OMe
5
6
Figure 1. A [3þ3] annelation strategy to piperidines.
2. Results and discussion
Previous studies on annelation reactions of aziridines high-
lighted that N-tosyl 2-alkylaziridines were generally most reac-
tive towards TMM-based conjunctive reagents and we therefore
began our investigations with these substrates. With regard to
Buchi Grignard reagent 66 served as a suitable reagent for this
¨
purpose,7 we report herein a full account of the development
of this [3þ3] methodology and the exemplification of its
employment in the stereoselective preparation of indolizidines
by the total synthesis of (ꢀ)-monomorine (Fig. 1).
the Grignard reagent, Buchi had reported that 6 decomposes
¨
at temperatures above 35 ꢁC,6,8 in contrast, however, 1,3-diox-
ane reagent 79 has been reported to be more thermally stable.
We therefore set out to compare the efficiency of the
tetrahydropyridine forming reaction with each of these reagents
and our results are shown in Scheme 1.
* Corresponding author. Tel.: þ44 114 222 9496; fax: þ44 114 222 9346.
E-mail address: j.harrity@sheffield.ac.uk (J.P.A. Harrity).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.071

2952
L.C. Pattenden et al. / Tetrahedron 64 (2008) 2951e2961
( )n
O
but that limitations could arise during the cyclisation step
O
Bn
20 mol% CuBr.DMS
( )n
O
when acid labile groups were introduced (silyl ether and
N-Dpp, entries 4 and 6, respectively). We decided to exploit
these specific substrates to develop some alternative cyclisa-
tion protocols that would allow such functional groups to be
included in this annelation process, our results are outlined
in Scheme 2. In the case of silyl ether 21, simply switching
+
O
THF, 16 h
N
Ts
MgBr
-78 °C to RT
Bn
NHTs
8
2 equiv
n=1; 6
n=2; 7
n=1; 9; 98%
n=2; 10; 74%
O
from HCl
to TFA allowed us to isolate the desired hetero-
(aq)
( )n
1 M HCl(aq)
O
cycle 27 in significantly improved yield. Carrying out similar
Brønsted acid screening in the case of 23 failed to uncover
conditions for cyclisation without cleavage of the Dpp-group.
We therefore endeavoured to carry out a tandem deprotection
of the acetal and Dpp-groups. We hoped that these conditions
would also promote cyclisation such that the enamine could be
N-protected with Cbz. In the event, we were able to telescope
this process and deliver 30 in good yield over two steps.
Bn
N
Ts
Bn
NHTs
n=1; 9: Acetone, RT. 11; 88%
n=2; 10: THF, reflux. 11; 81%
Scheme 1. Addition of functionalised Grignard reagents to aziridines.
Addition of 2 equiv of reagents 6 and 7 to aziridine 8 re-
sulted in formation of the corresponding adducts in good to
excellent yield. In addition, acid catalysed cyclisation took
place in good yield in both cases to provide the desired tetra-
hydropyridine 11. Whilst these studies highlighted that both
Grignard reagents were suitable for the formation of tetrahy-
dropyridines, the higher yields observed when using 6 coupled
with the milder cyclisation conditions required in the case of 9
prompted us to continue our investigations with 1,3-dioxolane
6. Accordingly, the scope of the stepwise annelation with
regard to 2-alkylaziridines is highlighted in Table 1. We found
that Ts-protected substrates bearing simple alkyl substituents
underwent smooth addition and cyclisation reactions to deliver
the corresponding heterocycles in good yield (entries 1 and 2).
Bn-protected alcohol 14 also efficiently delivered the corre-
sponding tetrahydropyridine 26, in contrast, however, silyl
protected analogue 15 underwent high yielding addition to 6
but the subsequent cyclisation proceeded in low yield (entries
3 and 4). We undertook a brief study of alternative N-protect-
ing groups and found the SES-group to be compatible with this
process (entry 5), unfortunately, however, the Dpp-protected
substrate 17 was incompatible with the cyclisation conditions
albeit after a very high yielding reaction with Grignard 6.
O
O
TFA
Acetone
69%
N
Ts
TBDPSO
TBDPSO
NHTs
21
27
O
1. HCl.OEt2
CH2Cl2, MeOH
2. CbzCl, Et3N
cat. DMAP, MeCN
65%
O
Bn
N
Cbz
Bn
NHDpp
23
30
Scheme 2. Alternative cyclisation conditions.
We next turned our attention to the [3þ3] annelation of bi-
cyclic and spirocyclic aziridines in an effort to obtain more
heavily substituted piperidine derivatives, our results are
shown in Scheme 3. Once again, we found that the Cu-cata-
lysed alkylation step proceeded in high yield in all cases,
but we were disappointed to find that the cyclisation step pro-
vided only modest yields of tetrahydropyridines 33 and 36.
During these studies we noted that spiropiperidine 39 crys-
tallised from solution during cyclisation and that this product
was generated in excellent yield. This observation prompted
us to speculate that enamide formation could be taking place
Table 1
[3þ3] Annelation reactions
O
MgBr
O
R1
O
O
1 M HCl(aq)
Acetone
O
H
N
20 mol% CuBr.DMS
THF, -78 °C to RT
R1
N
x; 20% CuBr.DMS
THF, -78 °C to RT
77%
O
O
HCl.ether
Acetone
63%
R2
R1
NHR2
18-23
R2
24-29
NTs
N
NHTs
32
12-17
R1
H
33
Ts
31
Entry
R2
Addition
product (%)
Piperidine (%)
HCl.ether
Acetone
54%
x; 20% CuBr.DMS
THF, -78 °C to RT
90%
NTs
O
N
1
2
3
4
5
6
(S)-Me
iPr
Ts
Ts
Ts
Ts
12
13
14
15
16
17
18 (70)
19 (82)
20 (87)
21 (87)
22 (88)
23 (94)
24 (84)
25 (98)
26 (73)
27 (8)
Ts
NHTs
34
NTs
35
36
CH2OBn
(S)-CH2OTBDPS
(S)-Me
Bn
O
t
SES
Dpp
28 (62)
29 (0)
Bu
HCl(aq)
x; 20%CuBr.DMS
O
N
THF, -78 °C to RT
79%
Acetone
83%
Ts
t
NHTs
38
Scheme 3. Synthesis of bicycles and spirocycles.
Bu
t
Bu
37
39
The studies outlined in Table 1 highlighted that the Cu-cat-
alysed Grignard addition chemistry showed good generality

L.C. Pattenden et al. / Tetrahedron 64 (2008) 2951e2961
2953
HCl(aq)
reaction times (up to 28 h). In contrast, however, bicycle 33
and spirocycle 36 were both found to readily hydrolyse to
the corresponding aldehydes 4010 and 41 (Scheme 4).
The stark difference in hydrolytic stability of tetrahydro-
pyridines 25, 33 and 36 can be rationalised based on relative
allylic strain present in each case.11 As outlined in Figure 2,
piperidine 25 can adopt a conformation whereby the alkyl sub-
stituent is orientated in a pseudo-axial position to avoid a steric
interaction with the SeO moiety.5a In contrast, both the bicy-
cle 33 and spirocycle 36 require pseudo-equatorial alkyl sub-
stituents and therefore the A1,3 clash cannot be avoided in
either case.
In order to gather some evidence for this proposal we decided
to obtain solid state structures of these compounds. In the event,
compounds 25 and 39 provided suitable crystals for X-ray crys-
tallographic analysis and these are outlined in Figure 3. The iPr-
substituted piperidine derivative 25 displayed a pseudo-axial
alkyl group and showed the expected sulfonamide conformation
whereby the nitrogen-lone pair adopts a gauche orientation with
respect to the OeSeO unit.12 Moreover, the N-atom showed
a reasonable degree of pyramidalisation, the sum of internal
bondangles werefoundtobe 352.8ꢁ. In contrast, thesulfonamide
conformation present in the spiropiperidine 39 was found to de-
viate from the expected antiperiplanar arrangement (with respect
to the N-lone pair and SeC bond) such that one SeO bond eclip-
ses a NeC bond. This conformation presumably minimises
unfavourable A1,3 interactions outlined in Figure 2. Moreover,
the length of the CeN bond bearing the spiro substituted ring
is longer than that bearing the iPr-moiety (cf. N(1)eC(1) in 39
Acetone
O
O
N
N
N
Ts
Ts
HTs
25
>95 : <5
H
H
H
HCl(aq)
Acetone
N
N
N
H
33
Ts
Ts
HTs
40
3 : 1
2 : 3
HCl(aq)
Acetone
O
N
N
N
Ts
Ts
HTs
36
41
Scheme 4. Tetrahydropyridine stability.
reversibly in solution in these cases. In order to probe this pos-
sibility, we subjected tetrahydropyridines 25, 33 and 36 to 1 M
HCl (aq) and examined the crude reaction mixtures by 1H NMR
spectroscopy. The 6-alkyl substituted heterocycle 25 was
found to be stable towards hydrolysis, even after prolonged
Ar
S
Ar
O
O
O S
N
O
Ar
N
N
O
S
H
O
i
Pr
25
33
36
Figure 2. Proposed origin of hydrolytic stability.
ꢁ
˚
Figure 3. ORTEP diagrams of 25 and 39; selected bond distances [A] and angles [ ]. Compound 25: S(1)eO(2) 1.4317 (12), S(1)eO(3) 1.4349 (12), S(1)eC(9)
1.7616 (16), S(1)eN(1) 1.6451 (13), N(1)eC(5) 1.4225 (19), N(1)eC(1) 1.4879 (19), C(5)eC(4) 1.323 (2); O(2)eS(1)eO(3) 120.36 (7), N(1)eS(1)eC(9) 106.22
(7), C(1)eN(1)eS(1) 118.84 (10), C(5)eN(1)eS(1) 117.41 (11), C(1)eN(1)eC(5) 116.58 (12). Compound 39: S(1)eO(2) 1.4373 (13), S(1)eO(3) 1.4377 (13),
S(1)eC(15) 1.7685 (18), S(1)eN(1) 1.6353 (15), N(1)eC(5) 1.422 (2), N(1)eC(1) 1.516 (2), C(5)eC(4) 1.323 (3); O(2)eS(1)eO(3) 117.77 (8), N(1)eS(1)e
C(15) 106.02 (8), C(1)eN(1)eS(1) 124.23 (12), C(5)eN(1)eS(1) 117.69 (13), C(1)eN(1)eC(5) 117.32 (14).

2954
L.C. Pattenden et al. / Tetrahedron 64 (2008) 2951e2961
vs 25). Finally, the N-atom is unusually planar13 in this case, the
sum of the internal bond angles were found to be 358.8ꢁ.
Having established the scope of the [3þ3] annelation pro-
cess, we decided to employ this methodology in the synthesis
of indolizidine alkaloids. Specifically, we opted to prepare
(ꢀ)-monomorine, the unnatural antipode of (þ)-monomorine,
the trail-laying pheromone of the ant, Monomorium pharaonis
L. that has also been found recently in amphibian skin ex-
tracts.14 Our synthetic route is outlined in Scheme 5.
These compounds can be further elaborated towards indolizidine
derivatives with excellent levels of diastereocontrol. The poten-
tial exploitation of this methodology in the preparation of alka-
loids has been highlighted by a short stereocontrolled synthesis
of (ꢀ)-monomorine.
4. Experimental
4.1. General
Aziridines 12e17, 31, 34, 37 were prepared according to
reported procedures.2e,5a Reactions were conducted in oven- or
flame-dried glassware under an inert atmosphere of dry nitrogen.
Flash chromatography was performed on silica gel (BDH Silica
Gel 60 43e60, or Fluorochem Davisil silica gel 43e60). Thin
layer chromatography (TLC) was performed on aluminium
backed platespre-coated with silica (0.2 mm, Merck DC-alufolien
Kieselgel 60 F254) and were developed using standard visualising
agents: ultraviolet light or potassium permanganate. 1H/13C NMR
spectra were recorded on Bruker AC-250 or Av1-250 instrument
or AMX-400 or AV1-400 instrument. 1H NMR: chemical shifts
are reported in parts per million with the solvent resonance as
the internal standard (CHCl3: d 7.27 ppm). Data are reported
as follows: chemical shift, integration, multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, br¼broad, m¼multiplet), cou-
pling constants (J) in hertz, and assignment. 13C NMR spectra
were recorded with complete proton decoupling. Chemical shifts
are reported in parts per million with the solvent resonance as the
internal standard (CDCl3: d 77.0 ppm). Infrared (FTIR) spectra
were recorded on a PerkineElmer Paragon 100 FTIR spectropho-
tometer, nmax in cmꢀ1. Low resolution mass spectra were recorded
on Micromass Autospec, operating in E.I., C.I. or FAB mode; or
a PerkineElmer Turbomass Benchtop GCeMS operating in
either EI or CI mode. High-resolution mass spectra (HRMS)
recorded for accurate mass analysis, were performed on either
a MicroMass LCT operating in Electrospray mode (TOF ESþ)
or a MicroMass Prospec operating in either FAB (FABþ), EI
(EIþ) or CI (CIþ) mode. Elemental microanalysis were performed
using a PerkineElmer 2400 CHNS/O Series II Elemental Analy-
ser. Melting points were performed on recrystallised solids and
recorded on a Gallenkamp melting point apparatus and are uncor-
rected. All solvents and reagents were purified using standard
laboratory techniques according to methods published in Ref. 18 .
1. 6, 20 mol% CuBr.DMS
N
N
SiMe3
2. HCl(aq), acetone
95%
Ts
Ts
TFA
92% (100:0)
(R)-12
(R)-24
1. BH3.DMS
N
N
2. H2O2, NaOH(aq)
75%
Ts
43
Ts
42
OH
1. Swern
2. NaO2Cl, NaH2PO4
2-methyl-3-butene
H
Mg, MeOH
69%
N
N
3. SOCl2, MeOH
76%
Ts
MeO2C
44
O
45
H
N
O
H
1. BuLi
2. HCl.ether
H2/Pd/C
22%
over two steps
NH.HCl
(-)-Monomorine 46
Scheme 5. Synthesis of (ꢀ)-monomorine.
We began by performing the [3þ3] annelation sequence on
aziridine (R)-12. This process was conveniently carried out on
multigram scale without purification of the intermediate
Grignard adduct to provide the piperidine (R)-24 in high yield
over the two steps. Acid catalysed allylation at C-2 took place
in excellent yield and diastereoselectivity to furnish cis-42, which
was subjected to hydroboration to provide alcohol 43. Previous
work within our group had shown that indolizidinones could be
prepared by a one-pot Ts-deprotection cyclisation sequence
on to an appended ester,15 hence we decided to explore this strat-
egy. Accordingly, sequential oxidation and esterification of
43 proceeded uneventfully. Pleasingly, treatment of 44 with
Mg/MeOH provided lactam 45 in 69% yield (83% based on
recovered starting material). Lactam 45 had previously been
converted to monomorine by Shono and co-workers by addition
of BuLi, followed by NaBH4 reduction, but with poor diastereo-
control.16 In an effort to improve on this, we isolated 46 after
BuLi addition and subjected this to the more selective
(>95:5)17 hydrogenation to furnish (ꢀ)-monomorine in 22%
yield over two steps.
4.1.1. Preparation of the Bu¨chi Grignard reagent (6)
To a 50 mL two-necked flask fitted with a reflux condenser
were added magnesium turnings (484 mg, 17.25 mmol,
1.7 equiv) and THF (10 mL), then 2-(2-bromoethyl)-[1,3]dioxo-
lane(1.2 mL, 10.2 mmol, 1 equiv)wasaddedslowly.Thesolution
was allowed to cool to room temperature and the concentration of
the Buchi Grignard solution assessed by titration.19
¨
4.1.2. Preparation of the Grignard reagent (7)
3. Conclusion
To a 10 mL two-necked flask fitted with a reflux condenser
were added magnesium turnings (212 mg, 8.82 mmol, 2 equiv)
and THF (4.5 mL), then 2-(2-bromoethyl)-[1,3]dioxane
(0.6 mL, 4.41 mmol, 1 equiv) was added. The solution was
Wereportatwostepannelationprocessthat deliversfunction-
alised piperidine derivatives from readily available aziridines.

L.C. Pattenden et al. / Tetrahedron 64 (2008) 2951e2961
2955
heated gently until reflux then the mixture was allowed to cool to
room temperature and the concentration of the Grignard solution
assessed by titration.19
NH), 4.37 (1H, t, J¼5.0 Hz, OCHCH2), 6.95e7.03 (2H, m,
AreH), 7.15e7.28 (5H, m, AreH), 7.63 (2H, d, J¼8.0 Hz,
AreH); 13C NMR (62.9 MHz, CDCl3): d 19.8, 21.5, 25.8,
33.3, 34.5, 41.0, 54.9, 66.8, 101.9, 126.5, 127.0, 128.5, 129.5,
129.6, 137.2, 137.8, 143.0; FTIR (thin film): 3279 (br), 2954
(s), 2857 (s), 1599 (m), 1495 (m), 1434 (s), 1378 (s), 1327 (s),
1288 (s), 1145 (s), 1091 (s) cmꢀ1; HRMS (TOF ES) calcd for
C22H29NO4SNa: 426.1715, found: 426.1730. Anal. Calcd for
C22H29NO4S: C, 65.48; H, 7.24; N, 3.47; S, 7.95. Found: C,
65.24; H, 7.30; N, 3.37; S, 7.97.
4.2. General procedure for the synthesis of acetal adducts
A solution of CuBr$DMS (0.4 equiv) in DMS was added to
an aliquot of Grignard solution (0.3e0.4 M, 2 equiv) at ꢀ78 ꢁC
and stirred for 1 h. Then a solution of aziridine (1 equiv) in THF
was added at ꢀ78 ꢁC and the reaction mixture stirred for
10 min. The solution was allowed to warm to room temperature
overnight. The reaction was quenched with water and the or-
ganic layer was separated. The aqueous layer was re-extracted
with EtOAc, the organic layers were combined and washed
with brine. The solution was dried over MgSO4 and concen-
trated under reduced pressure. The residue was purified by
column chromatography.
4.2.3. (S)-N-(4-[1,3]Dioxolan-2-yl-1-methyl-butyl)-4-methyl-
benzenesulfonamide (18)
Following the general procedure, a solution of CuBr$DMS
(135 mg, 0.66 mmol, 0.4 equiv) in DMS (2 mL) was added to
the Buchi Grignard solution (6) (7 mL, 0.47 M, 3.29 mmol,
¨
2 equiv) followed by (12) (347 mg, 1.65 mmol, 1 equiv) in
THF (3 mL). Purification by column chromatography (using
a continuous gradient from petroleum ether and ending with
5:1 petroleum ether/EtOAc) yielded (18) as a colourless solid,
360 mg, 70%. Mp 89e93 ꢁC; [a]D25 ꢀ27 (c 0.009, CH2Cl2);
1H NMR (250 MHz, CDCl3): d 1.03 (3H, d, J¼6.5 Hz,
CHCH3), 1.21e1.71 (6H, m, CH2), 2.42 (3H, s, AreCH3),
3.21e3.39 (1H, m, NHCH), 3.78e3.97 (4H, m, OCH2CH2O),
4.33 (1H, d, J¼8.0 Hz, NH), 4.75 (1H, t, J¼4.5 Hz, OCHCH2),
7.26e7.32 (2H, m, AreH), 7.72e7.78 (2H, m, AreH); 13C
NMR (62.9 MHz, CDCl3): d 20.0, 21.5, 21.6, 33.3, 37.2, 49.9,
64.8, 10.2, 127.0, 129.6, 138.2, 143.1; FTIR (thin film): 3272
4.2.1. (R)-N-(1-Benzyl-4-[1,3]dioxolan-2-yl-butyl)-4-methyl-
benzenesulfonamide (9)
Following the general procedure, a solution of CuBr$DMS
(93 mg, 0.45 mmol, 0.4 equiv) in DMS (1 mL) was added to
the Buchi Grignard (6) solution (1.8 mL, 0.4 M, 0.72 mmol,
¨
2 equiv), followed by (8) (103 mg, 0.36 mmol, 1 equiv) in
THF (1 mL). Purification by column chromatography (using
a continuous gradient from petroleum ether and ending with
5:1 petroleum ether/EtOAc) yielded (9) as a colourless solid,
138 mg, 98%. Mp 115e116 ꢁC; [a]D25 ꢀ13 (c 1.0, CH2Cl2);
1H NMR (250 MHz, CDCl3):
d
1.13e1.51 (6H, m,
(br), 2950 (m), 1323 (m), 1160 (s), 1092 (m), 1030 (w) cmꢀ1
;
m/z (TOF ES): 252, 320, 336 (MNaþ); HRMS (TOF ES) calcd
for C15H23NO4SNa: 336.1245, found: 336.1259.
CH2CH2CH2), 2.33 (3H, s, AreCH3), 2.59 (2H, d,
J¼6.5 Hz, AreCH2), 3.25e3.45 (1H, m, NHCH), 3.67e3.89
(4H, m, OCH2CH2O), 4.51 (1H, d, J¼8.0 Hz, NH), 4.64
(1H, t, J¼4.5 Hz, OCHCH2), 6.87e6.98 (2H, m, AreH),
7.06e7.21 (5H, m, AreH), 7.57 (2H, d, J¼8.0 Hz, AreH);
13C NMR (62.9 MHz, CDCl3): d 19.8, 21.5, 33.3, 34.1, 41.2,
54.9, 64.8, 104.2, 126.5, 127.0, 128.5, 129.5, 129.6, 137.2,
137.8, 143.1; FTIR (thin film): 3279 (br), 2950 (s), 2877 (s),
1599 (m), 1495 (m), 1454 (s), 1417 (s), 1327 (s), 1158 (s),
1091 (s), 1030 (s) cmꢀ1; HRMS (TOF ES) calcd for
C21H27NO4SNa: 412.1559, found: 412.1553. Anal. Calcd for
C21H27NO4S: C, 64.75; H, 6.99; N, 3.60; S, 8.23. Found: C,
64.48; H, 7.25; N, 3.56; S, 8.35.
4.2.4. N-(4-[1,3]Dioxolan-2-yl-1-isopropyl-butyl)-4-methyl-
benzenesulfonamide (19)
Following the general procedure, a solution of CuBr$DMS
(137 mg, 0.67 mmol, 0.4 equiv) in DMS (2 mL) was added to
the Buchi Grignard solution (8 mL, 0.4 M, 3.33 mmol, 2 equiv)
¨
followed by (13) (396 mg, 1.67 mmol, 1 equiv) in THF (2 mL).
Purification by column chromatography (using a continuous
gradient from petroleum ether and ending with 5:1 petroleum
ether/EtOAc) yielded (19) as a colourless solid, 469 mg, 82%.
Mp 117e120 ꢁC; 1H NMR (250 MHz, CDCl3): d 0.78
(6H, d, J¼6.5 Hz, CH(CH3)2), 1.04e1.80 (7H, m,
CH2CH2CH2CH(CH3)3), 2.41 (3H, s, AreCH3), 3.01e3.13
(1H, m, NCH), 3.75e3.96 (4H, m, OCH2CH2O), 4.30 (1H, d,
J¼9.0 Hz, NH), 4.69 (1H, t, J¼4.5 Hz, OCHCH2), 7.29 (2H, d,
J¼8.5 Hz, AreH), 7.75 (2H, d, J¼8.5 Hz, AreH); 13C NMR
(62.9 MHz, CDCl3): d 17.5, 18.3, 20.1, 21.5, 31.0, 31.4, 33.4,
59.1, 64.8, 104.2, 127.0, 129.5, 138.6, 142.9; FTIR (thin film):
3281 (w), 2958 (m), 2875 (m), 1323 (s), 1160 (s), 1093 (s),
1029 (s) cmꢀ1; m/z (TOF ES): 280, 364 (MNaþ); HRMS (TOF
ES) calcd for C17H27NO4SNa: 364.1559, found: 364.1553.
4.2.2. N-(1-Benzyl-4-[1,3]dioxan-2-yl-butyl)-benzenesulfon-
amide (10)
Following the general procedure, a solution of CuBr$DMS
(23 mg, 0.11 mmol, 0.4 equiv) in DMS (0.5 mL) was added to
the Grignard solution (7) (1.4 mL, 0.4 M, mmol, 2 equiv) fol-
lowed by (8) (80 mg, 0.28 mmol, 1 equiv) in THF (1.5 mL).
Purification by column chromatography (using a continuous
gradient from petroleum ether and ending with 5:1 petroleum
ether/EtOAc) yielded (10) as a colourless solid, 84 mg, 74%.
Mp 108e110 ꢁC; [a]D25 ꢀ12 (c 1.0, CH2Cl2); 1H NMR
(250 MHz, CDCl3): d 1.11e1.25 (8H, m, CH2), 2.40 (3H, s,
AreCH3), 2.66 (2H, d, J¼6.5 Hz, AreCH2), 3.31e3.47 (1H,
m, CHN), 3.69 (2H, dd, J¼12.0, 2.0 Hz, OCH2), 4.06 (2H,
ddd, J¼12.0, 5.0, 1.5 Hz, OCH2), 4.32 (1H, d, J¼8.0 Hz,
4.2.5. N-(1-Benzyloxymethyl-4-[1,3]dioxolan-2-yl-butyl)-4-
methyl-benzenesulfonamide (20)
Following the general procedure, a solution of CuBr$DMS
(51 mg, 0.25 mmol, 0.4 equiv) in DMS (1 mL) was added to

2956
L.C. Pattenden et al. / Tetrahedron 64 (2008) 2951e2961
the Buchi Grignard solution (6) (3.3 mL, 0.38 M, 1.25 mmol,
¨
OCH2CH2O), 4.79 (1H, t, J¼4.5 Hz, OCHCH2); 13C NMR
(62.9 MHz, CDCl3): d ꢀ2.0, 10.7, 20.3, 22.5, 33.4, 37.7, 50.0,
50.2, 64.8, 104.2; FTIR (thin film): 3544 (w, br), 3278 (br),
2 equiv), followed by (14) (199 mg, 0.63 mmol, 1 equiv) in
THF (1.5 mL). The residue was purified by column chromatog-
raphy (using a continuous gradient from petroleum ether and
ending with 2:1 petroleum ether/EtOAc) yielded (20) as a clear
2953 (s), 2895 (m), 1316 (s), 1250 (s), 1134 (s), 1027 (m) cmꢀ1
;
m/z (TOF ES): 346 (MNaþ), 363 (MKþ); HRMS (TOF ES) calcd
for C13H29NO4SiSNa: 346.1484, found: 346.1497.
1
oil, 215 mg, 82%. H NMR (250 MHz, CDCl3): d 1.20e1.63
(6H, m, CH2), 2.39 (3H, s, AreCH3), 3.16e3.37 (3H, m,
OCH2CHN), 3.74e3.97 (4H, m, OCH2CH2O), 4.33 (2H, s,
AreCH2O), 4.73 (1H, t, J¼4.5 Hz, OCHCH2), 4.87 (1H, d,
J¼7.5 Hz, NH), 7.16e7.37 (7H, m, AreH), 7.71 (2H, d,
J¼8.5 Hz, AreH); 13C NMR (62.9 MHz, CDCl3): d 20.1,
21.5, 32.3, 33.3, 53.5, 64.8, 71.0, 73.1, 104.2, 127.0, 127.6,
127.7, 128.4, 129.5, 137.7, 138.0, 143.1; FTIR (thin film):
3278 (br), 2952 (m), 2870 (m), 1454 (w), 1330 (m), 1161 (s),
1121 (m), 1092 (s) cmꢀ1; m/z (TOF ES): 203, 358, 442
(MNaþ); HRMS (TOF ES) calcd for C22H29NO5NaS:
442.1664, found: 442.1645.
4.2.8. N-(1-Benzyl-4-[1,3]dioxolan-2-yl-butyl)-diphenyl-
phosphinamide (23)
Following the general procedure, a solution of CuBr$DMS
(36 mg, 0.76 mmol, 0.4 equiv) in DMS (0.5 mL) was added to
the Buchi Grignard solution (6) (1.8 mL, 0.5 M, 0.88 mmol,
¨
2 equiv) followed by (17) (146 mg, 0.44 mmol, 1 equiv) in
THF (1 mL). Purification by column chromatography (using
a continuous gradient from petroleum ether to EtOAc followed
by 1:9 MeOH/CH2Cl2) yielded (23) as a colourless solid,
180 mg, 94%. Mp 144e146 ꢁC; 1H NMR (250 MHz,
CDCl3): d 1.53e1.84 (6H, m, CH2), 2.72 (1H, dd, J¼5.0,
10.5 Hz, NH), 2.82 (1H, dd, J¼6.5, 13.5 Hz, AreCH2), 2.93
(1H, dd, J¼6.0, 13.5 Hz, AreCH2), 3.20e3.35 (1H, m,
NHCH), 3.80e3.99 (4H, m, OCH2CH2O), 4.67e4.81 (1H,
m, OCHCH2), 7.12e7.55 (11H, m, AreH), 7.60e7.71 (2H,
m, AreH), 7.81e7.92 (2H, m, AreH); 31P NMR (250 MHz,
CDCl3): d 21.5; 13C NMR (62.9 MHz, CDCl3): d 20.1, 33.5,
36.4 (d, J¼3 Hz), 42.8 (d, J¼5 Hz), 53.0, 64.7, 104.2, 126.3,
128.2, 128.4 (d, J¼9 Hz), 129.8, 131.6 (d, J¼9 Hz), 132.1
(d, J¼9 Hz), 133.9 (d, J¼32 Hz), 138.3; FTIR (thin film):
3187 (br), 2947 (w), 1438 (s), 1187 (s), 1110 (s) cmꢀ1; m/z
(TOF ES): 436 (MHþ); HRMS (TOF ES) calcd for
C26H31NO3P: 436.2042, found: 436.2037.
4.2.6. N-[1-(tert-Butyl-diphenyl-silanyloxymethyl)-4-[1,3]-
dioxolan-2-yl-butyl]-4-methyl-benzenesulfonamide (21)
Following the general procedure, a solution of CuBr$DMS
(119 mg, 0.58 mmol, 0.4 equiv) in DMS (1 mL) was added to
the Buchi Grignard solution (6) (7.4 mL, 0.4 M, 2.96 mmol,
¨
2 equiv) followed by (15) (689 mg, 1.45 mmol, 1 equiv) in
THF (2 mL). Purification by column chromatography (using
a continuous gradient from petroleum ether and ending with
2:1 petroleum ether/EtOAc) yielded (21) as a clear oil, 716 mg,
87%. [a]2D1 ꢀ10 (c 0.01, CH2Cl2); 1H NMR (250 MHz,
CDCl3): d 1.02 (9H, s, SiC(CH3)3), 1.19e1.40 (2H, m, CH2),
1.51e1.64 (4H, m, CH2), 2.41 (3H, s, AreCH3), 3.16e3.29
(1H, m, CHNH), 3.38 (1H, dd, J¼4.0, 10.5 Hz, OCH2CHN),
3.46 (1H, dd, J¼3.5, 10.5 Hz, OCH2CHN), 3.78e3.97 (4H,
m, OCH2CH2O), 4.74 (1H, t, J¼4.5 Hz, OCHCH2), 4.83
(1H, d, J¼8.0 Hz, NH), 7.24 (2H, d, J¼8.0 Hz, AreH),
7.32e7.58 (10H, m, AreH), 7.70 (2H, d, J¼8.0 Hz, AreH);
13C NMR (62.9 MHz, CDCl3): d 19.1, 19.9, 21.4, 26.7, 31.9,
33.3, 54.8, 64.6, 64.7, 104.1, 126.8, 127.6, 129.5, 129.7,
132.7, 135.4, 138.0, 142.9; FTIR (thin film): 3271 (br), 2931
(m), 2858 (m), 1427 (m), 1331 (m), 1162 (s), 1113 (s), 1090
(s) cmꢀ1; m/z (TOF ES): 428, 506, 590 (MNaþ); HRMS
(TOF ES) calcd for C31H41NO5NaSiS: 590.2372, found:
590.2374.
4.2.9. N-[2-(2-[1,3]Dioxolan-2-yl-ethyl)-cyclohexyl]-4-
methyl-benzenesulfonamide (32)
Following the general procedure, a solution of CuBr$DMS
(70 mg, 0.34 mmol, 0.4 equiv) in DMS (1 mL) was added to
the Buchi Grignard solution (6) (4 mL, 0.43 M, 1.70 mmol,
¨
2 equiv), followed by (31) (215 mg, 0.85 mmol, 1 equiv) in
THF (1 mL). Purification by column chromatography (using
a continuous gradient from petroleum ether and ending with
5:1 petroleum ether/EtOAc) yielded (32) as a colourless solid,
234 mg, 78%. Mp 170e174 ꢁC; 1H NMR (250 MHz, CDCl3):
d 0.81e1.28 (6H, m, CH2), 1.34e1.88 (7H, m, CH2), 2.40
(3H, s, AreCH3), 2.73e2.91 (1H, m, CHN), 3.74e3.99 (4H,
m, OCH2CH2O) 4.50 (1H, d, J¼8.5 Hz, NH), 4.68 (1H, t,
J¼4.5 Hz, OCHCH2), 7.29 (2H, d, J¼8.0 Hz, AreH), 7.76
(2H, d, J¼8.0 Hz, AreH); 13C NMR (62.9 MHz, CDCl3):
d 21.5, 25.0 (ꢂ2), 26.4, 30.7, 30.8, 34.6, 42.7, 57.3, 64.8,
104.7, 127.0, 129.6, 138.6, 143.0; FTIR (thin film): 3268 (br),
2929 (m), 2857 (m), 1325 (m), 1160 (s), 1092 (m), 1072
(w) cmꢀ1; m/z (ES): 292, 376 (MNaþ), 392 (MKþ), 729
(2MNaþ); HRMS (ES) calcd for C18H27O4SNa: 376.1559,
found: 376.1543.
4.2.7. (S)-2-Trimethylsilanyl-ethanesulfonic acid (4-[1,3]di-
oxolan-2-yl-1-methyl-butyl)-amide (22)
Following the general procedure, a solution of CuBr$DMS
(37 mg, 0.18 mmol, 0.5 equiv) in DMS (2 mL) was added to the
Buchi Grignard solution (6) (2.8 mL, 0.34 M, 0.91 mmol,
¨
2.5 equiv) followed by (16) (79 mg, 0.36 mmol, 1 equiv) in
THF (1 mL). Purification by column chromatography (using
a continuous gradient from petroleum ether and ending with 5:1
petroleum ether/EtOAc) yielded (22) as a colourless solid,
1
102 mg, 88%. Mp 76e78 ꢁC; [a]D25 þ40 (c 1.0, CH2Cl2); H
NMR (250 MHz, CDCl3): d ꢀ0.30 to 0.04 (9H, m, Si(CH3)3),
0.93e1.03 (2H, m, SCH2CH2Si), 1.19 (3H, d, J¼6.5 Hz,
NCHCH3), 1.35e1.69 (6H, m, CH2), 2.82e2.92 (2H, m,
SCH2CH2Si), 3.34e3.47 (1H, m, CHNH), 3.75e3.95 (4H, m,
4.2.10. N-[1-(3-[1,3]Dioxolan-2-yl-propyl)-cyclohexyl]-4-
methyl-benzenesulfonamide (35)
Following general procedure, a solution of CuBr$DMS
(35 mg, 0.17 mmol, 0.4 equiv) in DMS (0.5 mL) was added

L.C. Pattenden et al. / Tetrahedron 64 (2008) 2951e2961
2957
to the Buchi Grignard solution (6) (2 mL, 0.43 M, 0.85 mmol,
2 equiv) followed by (34) (113 mg, 0.43 mmol, 1 equiv) in
THF (0.5 mL). Purification by column chromatography (using
a continuous gradient from petroleum ether and ending with
5:1 petroleum ether/EtOAc) yielded (35) as a colourless solid,
141 mg, 90%. Mp 109e111 ꢁC; 1H NMR (250 MHz, CDCl3):
d 1.16e1.79 (16H, m, CH2), 2.40 (3H, s, AreCH3), 3.78e
3.96 (4H, m, OCH2CH2O), 4.38 (1H, s, NH), 4.68 (1H, t,
J¼5.0 Hz, OCHCH2), 7.28 (2H, d, J¼8.5 Hz, AreH), 7.78
(2H, d, J¼8.5 Hz, AreH); 13C NMR (100.6 MHz, CDCl3):
d 17.5, 21.4, 21.5, 25.3, 33.7, 35.9, 38.3, 59.7, 64.7, 104.4,
126.9, 129.4, 140.6, 142.7; FTIR (thin film): 3280 (br), 2935
(m), 2864 (m), 1329 (m), 1152 (s), 1094 (m) cmꢀ1; m/z (TOF
ES): 306, 390 (MNaþ), 406; HRMS (TOF ES) calcd for
C19H29NO4SNa: 390.1715, found: 390.1700.
108 ꢁC; [a]D25 þ290 (c 1.0, CH2Cl2); 1H NMR (250 MHz,
CDCl3): d 0.72e0.90 (1H, m, CH2), 1.28e1.42 (1H, m,
CH2), 1.74 (1H, dt, J¼18.5, 5.5 Hz, CH2), 1.92e2.12 (1H,
m, CH2), 2.33 (3H, s AreCH3), 2.66 (1H, dd, J¼13.5,
10.5 Hz, AreCH2), 2.92 (1H, dd, J¼13.5, 5.0 Hz, AreCH2),
3.98e4.10 (1H, m, NCHCH2), 4.94e5.05 (1H, m,
NCH]CHCH2), 6.62 (1H, d, J¼8.0 Hz, NCH]CHCH2),
7.09e7.29 (7H, m, AreH), 7.60 (2H, d, J¼8.0 Hz, AreH);
13C NMR (62.9 MHz, CDCl3): d 17.1, 20.9, 21.5, 38.1, 54.3,
108.2, 123.6, 126.5, 126.9, 128.5, 129.4, 129.7, 136.3,
138.0, 143.4; FTIR (thin film): 3086 (m), 3063 (m), 3028
(s), 2927 (s), 2857 (s), 1917 (w), 1807 (w), 1737 (m), 1646
(s), 1597 (s), 1495 (s), 1455 (s), 1401 (s), 1344 (s), 1305 (s),
1261 (s), 1167 (s), 1098 (s), 1049 (s), 1018 (s) cmꢀ1; HRMS
(TOF ES) calcd for C19H23NO2S: 328.1371, found:
328.1386. Anal. Calcd for C19H22NO2S: C, 69.69; H, 6.46;
N, 4.28; S, 9.79. Found: C, 69.53; H, 6.53; N, 4.26; S, 9.84.
4.2.11. N-[4-tert-Butyl-1-(3-[1,3]dioxolan-2-yl-propyl)-
cyclohexyl]-4-methyl-benzenesulfonamide (38)
Following the general procedure, a solution of CuBr$DMS
(45 mg, 0.22 mmol, 0.4 equiv) in DMS (1 mL) was added to
the Buchi Grignard solution (6) (4 mL, 0.28 M, 1.12 mmol,
2 equiv), followed by (37) (180 mg, 0.56 mmol, 1 equiv) in
THF (2 mL). Purification by column chromatography (using
a continuous gradient from petroleum ether and ending with
3:1 petroleum ether/EtOAc) yielded (38) as a colourless solid,
189 mg, 79%. Mp 133e134 ꢁC; 1H NMR (250 MHz, CDCl3):
d 0.80e1.10 (2H, m), 0.78 (9H, s, C(CH3)3), 1.18e1.65 (11H,
m, CH2), 1.75e1.86 (2H, m, CH2), 2.41 (3H, s, AreCH3),
3.79e3.99 (4H, m, OCH2CH2O), 4.47 (1H, s, NH), 4.74 (1H,
t, J¼4.5 Hz, OCHCH2), 7.28 (2H, d, J¼8.5 Hz, AreH), 7.77
(2H, d, J¼8.5 Hz, AreH); 13C NMR (62.9 MHz, CDCl3):
d 17.3, 21.5, 23.0, 27.5, 32.2, 33.3, 33.7, 36.2, 47.0, 59.9,
64.8, 104.5, 126.9, 129.4, 141.0, 142.7; FTIR (thin film): 3273
(br), 2948 (s), 2868 (m), 1331 (m), 1156 (s), 1094 (m), 1032
(w) cmꢀ1; m/z (TOF ES): 446 (MNaþ); HRMS (TOF ES) calcd
for C23H37NO4SNa: 446.2341, found: 446.2357.
4.3.2. (R)-2-Benzyl-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-
pyridine (11) from (10)
To (10) (50 mg, 0.12 mmol, 1 equiv), was added THF
(2 mL) and 1 M HCl(aq) (2 mL). The reaction was heated to re-
flux and allowed to stir for 16 h. The mixture was then cooled to
room temperature, quenched with K2CO3(aq), and the product
extracted with EtOAc. The organic layer was separated, dried
over MgSO4 and the solvent removed under reduced pressure.
The residue was purified by column chromatography (using
a continuous gradient from petroleum ether and ending with
19:1 petroleum ether/EtOAc) yielded (10) as a colourless solid,
32 mg, 78%.
4.3.3. (S)-2-Methyl-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-
pyridine (24)
Following the general procedure, HCl(aq) (1 M, 1.4 mL,
1.40 mmol, 7.7 equiv) was added to a solution of (18)
(56 mg, 0.18 mmol, 1 equiv) in acetone (3.6 mL). Purification
by column chromatography (using a continuous gradient from
petroleum ether and ending with 19:1 petroleum ether/EtOAc)
yielded (24) as a yellow oil, 38 mg, 84%. [a]2D5 þ511 (c 0.009,
4.3. General procedure for the synthesis of
tetrahydropyridines
1
CH2Cl2); H NMR (250 MHz, CDCl3): d 0.99e1.12 (1H, m,
HCl(aq) (1 M, 7.5 equiv) was added to a solution of acetal ad-
duct (1 equiv) in acetone and the reaction mixture stirred over-
night at room temperature. The reaction was quenched with
a saturated solution of K2CO3 and the product was extracted
with EtOAc, dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by column chromatography
(using a continuous gradient from petroleum ether and ending
with 19:1petroleumether/EtOAc)togive the tetrahydropyridine.
CH2), 1.17 (3H, d, J¼6.5 Hz, CHCH3), 1.38e1.49 (1H, m,
CH2), 1.56e1.89 (1H, m, CH2), 1.75e2.08 (1H, m, CH2),
2.41 (3H, s, AreCH3), 4.02e4.15 (1H, m, CH2CHN), 4.94e
5.02 (1H, m, NCHC]CH), 6.58e6.65 (1H, m, NCH]CH),
7.29 (2H, d, J¼8.0 Hz, AreH), 7.68 (2H, d, J¼8.0 Hz,
AreH); 13C NMR (62.9 MHz, CDCl3): d 16.9, 18.2,
21.5, 25.2, 48.5, 107.7, 123.2, 126.8, 129.6, 136.4, 143.3;
FTIR (thin film): 3063 (w), 2977 (m), 2929 (m), 2848 (w),
1645 (m), 1362 (s), 1340 (s), 1262 (m), 1170 (s), 1136 (m),
1103 (s) cmꢀ1; m/z (TOF ES): 252 (MHþ), 274 (MNaþ);
HRMS (TOF ES) calcd for C13H18NO2S: 252.1058, found:
252.1048.
4.3.1. (R)-2-Benzyl-1-(toluene-4-sulfonyl)-1,2,3,4-
tetrahydropyridine (11) from (9)
Following the general procedure, HCl(aq) (1 M, 2 mL,
2.0 mmol, 7.5 equiv) was added to a solution of (9) (104 mg,
0.267 mmol, 1 equiv) in acetone (2 mL). Purification by col-
umn chromatography (using a continuous gradient from petro-
leum ether and ending with 19:1 petroleum ether/EtOAc)
yielded (11) as a colourless solid, 77 mg, 88%. Mp 106e
4.3.4. 2-Isopropyl-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-
pyridine (25)
Following the general procedure, HCl(aq) (1 M, 4 mL,
4.0 mmol, 7.1 equiv) was added to a solution of (19) (190 mg,

2958
L.C. Pattenden et al. / Tetrahedron 64 (2008) 2951e2961
0.56 mmol, 1 equiv) in acetone (4 mL) and stirred overnight at
room temperature. Purification by column chromatography (us-
ing a continuous gradient from petroleum ether and ending with
19:1 petroleum ether/EtOAc) yielded (25) as a colourless solid,
m, AreH), 7.35e7.49 (6H, m, AreH), 7.59e7.70 (6H, m,
AreH); 13C NMR (62.9 MHz, CDCl3): d 16.8, 19.2, 19.5,
21.5, 26.9, 53.3, 61.9, 108.4, 123.6, 126.9, 127.7, 129.6,
129.7, 133.4, 135.6, 136.0, 143.3; FTIR (thin film): 3071
(w), 2931 (m), 2858 (m), 1650 (w), 1428 (m), 1361 (m),
1169 (s), 1106 (s), 814 (w), 703 (s) cmꢀ1; m/z (TOF ES):
428, 506 (MHþ), 528 (MNaþ); HRMS (TOF ES) calcd for
C29H36NO3SiS: 506.2185, found: 506.2194.
1
154 mg, 98%. Mp 84e88 ꢁC; H NMR (250 MHz, CDCl3):
d 0.61e0.78 (1H, m, CH3(CH3)CH), 0.90 (3H, d, J¼6.5 Hz,
CH3(CH3)CH), 1.11 (3H, d, J¼6.5 Hz, CH3(CH3)CH), 1.55e
1.97 (4H, m, CH2), 2.42 (3H, s, AreCH3), 3.52 (1H, dt,
J¼10.0, 2.5 Hz, CH2(CH)CHN) 5.05e5.13 (1H, m,
NCH]CH), 6.54e6.61 (1H, m, NCH]CH), 7.31 (2H, d,
J¼8.0 Hz, AreH), 7.68 (2H, d, J¼8.0 Hz, AreH); 13C NMR
(62.9 MHz, CDCl3): 17.6, 19.0, 20.6, 20.8, 21.5, 27.5, 59.13,
111.4, 123.9, 127.0, 129.6, 136.0, 143.2; FTIR (thin film):
2961 (m), 1644 (w), 1354 (w), 1340 (s), 1171 (s), 1092
(m) cmꢀ1; m/z (ES): 280 (MHþ). HRMS (ES) calcd for
C15H22O2S: 280.1371, found: 280.1364.
4.3.7. (S)-2-Methyl-1-(2-trimethylsilanylethane-sulfonyl)-
1,2,3,4-tetrahydropyridine (28)
Following the general procedure, HCl(aq) (1 M, 1.1 mL,
1.1 mmol, 8.3 equiv) was added to a solution of (22) (42 mg,
0.13 mmol, 1 equiv) in acetone (1.3 mL). Purification by col-
umn chromatography (using a continuous gradient from petro-
leum ether and ending with 19:1 petroleum ether/EtOAc) gave
(28) as a colourless oil, 20 mg, 62%. [a]2D5 þ271 (c 0.009,
1
4.3.5. 2-Benzyloxymethyl-1-(toluene-4-sulfonyl)-1,2,3,4-tetra-
hydropyridine (26)
CH2Cl2); H NMR (250 MHz, CDCl3): d ꢀ0.10 to 0.10 (9H,
m, Si(CH3)3), 0.90e1.03 (2H, m, SCH2CH2Si), 1.20 (3H, d,
J¼6.5 Hz, NCHCH3), 1.62e1.77 (2H, m, CH2), 1.89e2.17
(2H, m, CH2), 2.81e2.95 (2H, m, SCH2CH2Si), 4.09e4.21
(1H, m, CH3CHN), 4.83e4.91 (1H, m, NCH]CH), 6.39e
6.46 (1H, m, NCH]CH); 13C NMR (62.9 MHz, CDCl3):
d ꢀ2.0, 10.4, 16.9, 18.4, 26.8, 48.8, 48.9, 105.2, 125.9;
FTIR (thin film): 3508 (br), 2952 (s), 1648 (m), 1337 (s),
1251 (s), 1156 (s), 1100 (m), 1000 (s) cmꢀ1; m/z (TOF ES):
262 (MHþ); HRMS (TOF ES) calcd for C11H24NO2SiS:
262.1297, found: 262.1305.
Following the general procedure, HCl(aq) (1 M, 1.6 mL,
1.6 mmol, 7.5 equiv) was added to a solution of (20) (90 mg,
0.22 mmol, 1 equiv) in acetone (2.2 mL). Purification by col-
umn chromatography (using a continuous gradient from petro-
leum ether and ending with 19:1 petroleum ether/EtOAc)
1
yielded (26) as a clear oil, 56 mg, 73%. H NMR (250 MHz,
CDCl3): d 0.82e1.01 (1H, m, CH2), 1.69e1.97 (3H, m,
CH2), 2.41 (3H, s, AreCH3), 3.45 (1H, dd, J¼9.5, 9.5 Hz,
OCH2CH), 3.57 (1H, dd, J¼5.5, 9.5 Hz, OCH2CH), 4.09e
4.19 (1H, m, CH2CHN), 4.49 (1H, d, J¼12.0 Hz, Are
CH2O), 4.59 (1H, d, J¼12.0 Hz, AreCH2O), 4.93e5.01
(1H, m, NCH]CH), 6.58e6.64 (1H, m, NCH]CH), 7.24e
7.38 (7H, m, AreH), 7.68 (2H, d, J¼8.5 Hz, AreH); 13C
NMR (62.9 MHz, CDCl3): d 16.9, 19.9, 21.5, 51.5, 68.4,
73.2, 108.4, 123.6, 126.9, 127.6 (ꢂ2), 128.4, 129.6, 135.9,
138.1, 143.5; FTIR (thin film): 2926 (m), 1719 (w), 1648
(w), 1453 (w), 1344 (m), 1167 (s), 1102 (s) cmꢀ1; m/z (TOF
ES): 275, 358 (MHþ), 380 (MNaþ); HRMS (TOF ES) calcd
for C20H24NO3S: 358.1477, found: 358.1486.
4.3.8. 2-Benzyl-3,4-dihydro-2H-pyridine-1-carboxylic acid
benzyl ester (30)
An ether solution of HCl (1 M, 1.0 mL, 1.00 mmol, 3 equiv)
was added to a solution of (23) (145 mg, 0.33 mmol, 1 equiv) in
CH2Cl2 (3 mL) and MeOH (0.3 mL). The solution was stirred
at room temperature overnight and concentrated under reduced
pressure.
The crude mixture was redissolved in MeCN (3.3 mL) fol-
lowed by the addition of benzyl chloroformate (188 mL,
1.32 mmol, 4 equiv), Et3N (97 mL, 0.72 mmol, 2.1 equiv) and
DMAP (8 mg, 0.07 mmol, 0.2 equiv) at room temperature
and stirred for 24 h. The reaction mixture was concentrated un-
der reduced pressure. The crude mixture was diluted with Et2O
then washed with K2CO3(aq) solution. The aqueous layer was
extracted with Et2O. The organic layers were combined,
washed with brine, dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column chroma-
tography (using a continuous gradient from petroleum ether and
ending with 19:1 petroleum ether/EtOAc) to yield (30) as a col-
4.3.6. 2-(tert-Butyl-diphenyl-silanyloxymethyl)-1-(toluene-
4-sulfonyl)-1,2,3,4-tetrahydropyridine (27)
Trifluoroacetic acid (90 mL, 1.135 mmol, 5 equiv) was
added to a solution of (21) (129 mg, 0.227 mmol, 1 equiv) in
acetone (distilled) (2.3 mL) at room temperature and left stir-
ring overnight. The reaction was quenched with NaHCO3, ex-
tracted with EtOAc. The organic layers were combined,
washed with brine, dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column chroma-
tography (using a continuous gradient from petroleum ether
and ending with 19:1 petroleum ether/EtOAc) to give (27)
as a colourless oil, 79 mg, 69%. [a]2D1 ꢀ34 (c 0.01, CH2Cl2);
1H NMR (250 MHz, CDCl3): d 0.80e1.12 (1H, m, CH2),
1.07 (9H, s, SiC(CH3)3), 1.70e1.81 (2H, m, CH2), 1.95e
2.08 (1H, m, CH2), 2.42 (3H, s, AreCH3), 3.57 (1H, dd,
J¼10.0, 10.0 Hz, OCH2), 3.80 (1H, dd, J¼5.0, 10.0 Hz,
OCH2), 3.98e4.10 (1H, m, NCH), 4.87e4.97 (1H, m,
NCH]CH), 6.57 (1H, m, NCH]CH), 7.24e7.31 (2H,
1
ourless oil, 66 mg, 65%. H NMR (250 MHz, CDCl3) two ro-
tamers: d 1.61e1.78 (2H, m, CH2), 1.93e2.10 (1H, m, CH2),
2.15e2.33 (1H, m, CH2), 2.62e2.76 (1H, m, AreCH2),
2.83e3.00 (1H, m, AreCH2), 4.38e4.60 (1H, m, NCH), 4.93
(0.5H, d, J¼12.0 Hz, AreCH2O), 4.87e4.97 (0.5H, m,
NCH]CH), 5.00e5.09 (0.5H, m, NCH]CH), 5.15 (0.5H, d,
J¼12.0 Hz, AreCH2O), 5.19 (1H, s, AreCH2O), 6.79e6.87
(0.5H, d, J¼8.5 Hz, NCH]CH), 6.91e6.98 (0.5H, d,
J¼8.5 Hz, NCH]CH), 7.07e7.42 (10H, m, AreH); 13C

L.C. Pattenden et al. / Tetrahedron 64 (2008) 2951e2961
2959
NMR (100.6 MHz, CDCl3) two rotamers: d 17.4, 17.4, 22.2,
4.3.11. 9-tert-Butyl-1-(toluene-4-sulfonyl)-1-aza-spiro-
[5.5]undec-2-ene (39)
23.2, 36.5, 37.2, 52.0, 52.4, 67.4, 67.4, 105.6, 106.1, 123.6,
124.0, 126.3, 128.0, 128.1, 128.4, 128.5, 129.2, 129.3, 136.1,
136.4, 138.4, 138.6, 152.7, 153.3; FTIR (thin film): 3401 (br),
3029 (w), 2929 (w), 2845 (w), 1704 (s), 1654 (s), 1414 (s),
1330 (s), 1234 (m), 1111 (m), 1076 (m), 699 (s) cmꢀ1; m/z
(TOF ES): 308 (MHþ), 330 (MNaþ); HRMS (TOF ES) calcd
for C20H22NO2: 308.1651, found: 308.1636.
Following the general procedure, HCl(aq) (1 M, 1.7 mL,
1.7 mol, 7.1 equiv) was added to a solution of (38) (100 mg,
0.24 mmol, 1 equiv) in acetone (2.4 mL). Purification by col-
umn chromatography (using a continuous gradient from petro-
leum ether and ending with 19:1 petroleum ether/EtOAc) gave
1
(29) as a colourless solid, 69 mg, 83%. Mp 139e142 ꢁC; H
NMR (250 MHz, CDCl3): d 0.74 (9H, s, C(CH3)3), 0.89e
1.09 (3H, m, CH2), 1.44e1.65 (6H, m, CH2), 1.86e1.95
(2H, m, CH2), 1.99e2.15 (2H, m, CH2), 2.34 (3H, s, Are
CH3), 4.83e4.91 (1H, m, NCH]CH), 6.86e6.92 (1H, m,
NCH]CH), 7.20 (2H, d, J¼8.0 Hz, AreH), 7.62 (2H, d,
J¼8.0 Hz, AreH); 13C NMR (62.9 MHz, CDCl3): d 18.6,
21.5, 23.1, 27.5, 28.1, 32.2, 33.0, 46.9, 62.1, 105.0, 126.5
(ꢂ2), 129.5, 140.9, 142.8; FTIR (thin film): 2943 (s), 1657
(m), 1325 (m), 1255 (m), 1162 (s), 1098 (s) cmꢀ1; m/z (TOF
ES): 384 (MNaþ); HRMS (TOF ES) calcd for
C21H31NO2SNa: 384.1973, found: 384.1965.
4.3.9. 1-(Toluene-4-sulfonyl)-1,4,4a,5,6,7,8,8a-octahydro-
qunoline (33)
HCl in ether (1 M, 1.2 mL, 1.23 mol, 5 equiv) was added to
a solution of (32) (87.2 mg, 0.25 mmol, 1 equiv) in ether
(2.5 mL) and acetone (1 mL). Then THF (2 mL) was added
and stirred at room temperature for 4 h. The reaction mixture
was poured into a saturated solution of K2CO3 (10 mL) and
the product was extracted with EtOAc, dried over MgSO4
and concentrated under reduced pressure. The residue was pu-
rified by column chromatography (using a continuous gradient
from petroleum ether and ending with 19:1 petroleum ether/
EtOAc) yielded (33) as a colourless solid, 45 mg, 63%. Mp
4.3.12. 4-Methyl-N-[1-(4-oxo-butyl)-cyclohexyl]-benzene-
sulfonamide (41)
1
71e73 ꢁC; H NMR (250 MHz, CDCl3): d 0.84e1.03 (1H,
A hydrogen chloride solution in ether (1 M, 0.9 mL, 0.9 mol,
6.9 equiv) was added to a solution of (36) (40 mg, 0.13 mmol,
1 equiv) in acetone (2.6 mL). The mixture was stirred at room
temperature overnight. The reaction was quenched with a satu-
rated solution of K2CO3, the product was extracted with ethyl
acetate, dried over MgSO4 and concentrated under reduced
pressure. Data for (41): 1H NMR (250 MHz, CDCl3): d 1.21e
1.77 (14H, m, CH2), 2.25 (2H, dt, J¼1.5, 7.0 Hz, CH2C(O)H),
2.42 (3H, s, AreCH3), 4.31 (1H, s, NH), 7.26e7.31 (2H, m,
AreH), 7.79 (2H, d, J¼8.5 Hz, AreH), 9.68 (1H, t,
J¼1.5 Hz); 13C (100.6 MHz): d 15.6, 21.5 (ꢂ2), 25.3, 33.0,
36.0, 43.8, 59.6, 126.9, 129.5, 140.5, 142.9, 202.4; FTIR (thin
film): 3288 (br), 2936 (m), 2862 (m), 1723 (m), 1598 (w),
1330 (m), 1318 (m), 1288 (m), 1152 (s), 1094 (m) cmꢀ1; m/z
(TOF ES): 346 (MNaþ), 362 (MKþ); HRMS (TOF ES) calcd
for C17H25NO3SNa: 346.1453, found: 346.1440.
m, CH), 1.14e1.65 (6H, m, CH2), 1.68e1.87 (3H, m, CH2),
2.42 (3H, s, AreCH3), 2.63e2.76 (2H, m, CH2), 5.00e5.10
(1H, m, NCH]CH), 6.67e6.74 (1H, m, NCH]CH), 7.31
(2H, d, J¼8.5 Hz, AreH), 7.66 (2H, d, J¼8.5 Hz, AreH);
13C NMR (62.9 MHz, CDCl3): d 21.6, 25.3 (ꢂ2), 28.6, 32.7,
33.3, 39.3, 61.6, 109.1, 127.1, 127.4, 129.5, 135.7, 143.4;
FTIR (thin film): 2927 (m), 2855 (m), 1658 (w), 1346 (m),
1241 (w), 1170 (s), 1092 (m) cmꢀ1; m/z (TOF ES): 292
(MHþ), 314 (MNaþ); HRMS (TOF ES) calcd for
C16H22NO2S: 292.1371, found: 292.1359.
4.3.10. 1-(Toluene-4-sulfonyl)-1-aza-spiro[5.5]undec-2-ene
(36)
HCl in ether (1 M, 0.3 mL, 0.27 mol, 2.1 equiv) was added
to a solution of (35) (50 mg, 0.14 mmol, 1 equiv) in acetone
(1.4 mL). The mixture was stirred at room temperature over-
night. Reaction was quenched with a saturated solution of
K2CO3 and the product was extracted with EtOAc, dried
over MgSO4 and concentrated under reduced pressure. The
residue was purified by column chromatography (using a con-
tinuous gradient from petroleum ether and ending with 19:1
petroleum ether/EtOAc) yielded (36) as a colourless solid,
4.3.13. (R)-2-Methyl-1-(toluene-4-sulfonyl)-1,2,3,4-tetra-
hydropyridine (24)
Following the general procedure explained in Section 4.2,
a solution of CuBr$DMS (1.2 g, 5.85 mmol, 0.4 equiv) in
DMS (6 mL) was added to the Buchi Grignard (6) solution
¨
(73 mL, 0.4 M, 29.28 mmol, 2 equiv), followed by ((R)-12)
(3.09 g, 14.63 mmol, 1 equiv) in THF (15 mL). Following the
general procedure explained in Section 4.3, HCl(aq) (1 M,
100 mL, 100.0 mmol, 6.8 equiv) was added to a solution of
crude residue in acetone (150 mL). Purification by column chro-
matography (using a continuous gradient from petroleum ether
and ending with 19:1 petroleum ether/EtOAc) yielded ((R)-24)
as a yellow oil, 3.49 g, 95%. [a]2D5 ꢀ508 (c 0.01, CH2Cl2).
1
23 mg, 54%. Mp 119e122 ꢁC; H NMR (250 MHz, CDCl3):
d 1.34e1.42 (4H, m, CH2), 1.50e1.66 (4H, m, CH2), 1.74
(2H, t, J¼6.5 Hz, CH2), 1.93e2.02 (2H, m, CH2), 2.04e2.18
(2H, m, CH2), 2.41 (3H, s, AreCH3), 4.96 (1H, dt, J¼4.0,
8.5 Hz, NCH]CH), 6.97 (1H, dt, J¼2.0, 8.5 Hz, NCH]CH),
7.23e7.29 (2H, m, AreH), 7.69 (2H, d, J¼8.5 Hz, AreH);
13C NMR (100.6 MHz, CDCl3): d 18.6, 21.5, 22.4, 25.2,
28.1, 32.9, 62.3, 105.1, 126.4 (ꢂ2), 129.5, 140.9, 142.8;
FTIR (thin film): 2928 (m), 2864 (w), 1656 (m), 1332 (s),
1252 (m), 1161 (s), 1103 (s) cmꢀ1; m/z (TOF ES): 306
(MHþ), 328 (MNaþ); HRMS (TOF ES) calcd for
C17H24NO2S: 306.1528, found: 306.1521.
4.3.14. (R)-2-Allyl-6-methyl-1-(toluene-4-sulfonyl)-piper-
idine (42)
Toa solution of(R)-24 (5.02 g, 19.97 mmol, 1 equiv)inCH2Cl2
(375 mL) at ꢀ20 ꢁC was added allyltrimethylsilane (12.7 mL,

2960
L.C. Pattenden et al. / Tetrahedron 64 (2008) 2951e2961
79.89 mmol, 6 equiv) and TFA (9.2 mL, 119.83 mmol, 4 equiv).
The reaction mixture was stirred at ꢀ20 ꢁC for 2 h and was then
allowed to warm to room temperature overnight. The reaction
was quenched with NaHCO3 and extracted using CH2Cl2 (ꢂ3 por-
tions). The combined organic layers were washed with water and
brine, dried over MgSO4, filtered and concentrated under reduced
pressure. The residuewas purified by column chromatography (us-
ing a continuous gradient from petroleum ether and ending with
19:1 petroleum ether/EtOAc) to give (42) as a colourless solid,
washed with brine then dried over MgSO4, filtered and concen-
trated under reduced pressure. Withno further purificationtheal-
dehyde was obtained as a colourless oil, 7.04 g.
The aldehyde (3.54 g, 11.45 mmol, 1 equiv) was dissolved in
tert-butanol (160 mL), THF (80 mL) and water (40 mL). 2-
Methyl-3-butene (57.2 mL, 2 M, 114.45 mmol, 10 equiv),
NaH2PO4 (8.24 g, 68.67 mmol, 6 equiv) and sodium chlorite
(6.21 g, 68.67 mmol, 6 equiv) were added to the solution and
the reaction mixture stirred for 30 min at room temperature.
The reaction was quenched with brine and extracted with EtOAc.
TheextractsweredriedoverMgSO4, filtered andconcentrated un-
der reduced pressure. The crude product was redissolved in meth-
anol (40 mL) and thionylchloridewas addedat0 ꢁC. Thereaction
mixturewasallowed towarm toroomtemperature overnight. The
reaction was quenched with a saturated solution of potassium car-
bonate, then the product was extracted with CH2Cl2. The organic
layers were combined and washed with brine, dried over MgSO4,
filtered and concentrated under reduced pressure. The ester was
obtained by column chromatography in 8.5:1.5 petroleum ether/
EtOAc to yield (44) as a colourless solid, 2.85 g, 76%. Mp 62e
64 ꢁC; [a]D21 þ21 (c 1.2, CH2Cl2); 1H NMR (250 MHz, CDCl3):
d 1.05e1.88 (7H, m, CH2), 1.34 (3H, d, J¼7.5 Hz, CH3CHN),
2.02e2.19 (1H, m, CH2), 2.41 (3H, s, AreCH3), 2.49e2.58
(2H, m, CH2C(O)OCH3), 3.69 (3H, s, C(O)OCH3), 3.98e4.18
(2H, m, CHNCH), 7.28 (2H, d, J¼8.0 Hz, AreH), 7.70 (2H, d,
J¼8.0, AreH); 13C NMR (100.6 MHz): d 13.7, 21.5, 21.9, 27.9,
29.0, 30.2, 31.4, 48.1, 51.6ꢂ2, 126.7, 129.6, 138.7, 142.8,
174.0; FTIR (thin film): 2942 (s), 2872 (m), 1738 (s), 1598 (w),
1331 (s), 1286 (m), 1164 (s), 1104 (m) cmꢀ1; m/z (TOF ES):
308, 340 (MHþ); HRMS (TOF ES) calcd for C17H26NO4S:
340.1583, found: 340.1568.
5.40 g, 92%. Mp 66e70 ꢁC; [a]D25 þ32 (c 0.010, CH2Cl2); H
1
NMR (250 MHz, CDCl3): d 1.11e1.45 (4H, m, CH2), 1.32 (3H,
d, J¼7.0 Hz, CH3CH), 1.51e1.77 (2H, m, CH2), 2.31e2.57
(2H, m, CHCH2CHCH), 2.40 (3H, s, AreCH3), 3.96e4.22 (2H,
m, CHNCH), 4.99e5.13 (2H, m, CH]CH2), 5.69e5.88 (1H,
m, CH]CH2), 7.27 (2H, d, J¼8.0 Hz, AreH), 7.71 (2H, d,
J¼8.0 Hz, AreH); 13C NMR (62.9 MHz, CDCl3): d 13.4, 21.5,
21.9, 26.2, 29.4, 40.1, 47.9, 52.1, 117.2, 126.7, 129.5, 136.0,
138.9, 142.6; FTIR (thin film): 2939 (m), 2361 (m), 1332 (m),
1221 (w), 1165 (s), 1105 (m) cmꢀ1; m/z (TOF ES): 294 (MHþ);
HRMS (TOF ES) calcd for C16H24NO2S: 294.1528, found:
294.1535.
4.3.15. Alcohol-3-((2R,6R)-6-methyl-1-tosylpiperidin-2-yl)
propan-1-ol (43)
Borane dimethylsulfide complex (1.20 mL, 12.65 mmol,
3 equiv) was added to a solution of (R)-42 (1.24 g, 4.22 mmol,
1 equiv) in THF (45 mL), cooled to 0 ꢁC and stirred for 3 h.
NaOH(aq) (12.65 mL, 1.0 M, 12.65 mmol, 3 equiv) and H2O2
(30% w/w, 1.43 mL, 12.65 mmol, 3 equiv) were added at 0 ꢁC
and the mixture allowed to warm to room temperature over
1 h. The product was extracted with CH2Cl2 and the extracts
were washed with water, brine then dried over MgSO4, filtered
and concentrated under reduced pressure. The alcohol was ob-
tained by column chromatography in 1:1 petroleum ether/
EtOAc to give (43) as a colourless oil, 984 mg, 75%. [a]D25
þ33.3 (c 0.0096, CH2Cl2); Mp 77e80 ꢁC; 1H NMR
(250 MHz, CDCl3): d 1.18e1.91 (10H, m, CH2), 1.35 (3H, d,
J¼7.0 Hz, CH3CHN), 2.42 (3H, s, AreCH3), 3.63e3.79 (2H,
m, HOCH2), 3.97e4.20 (2H, m, CHNCH), 7.29 (2H, d,
J¼8.0 Hz, AreH), 7.72 (2H, d, J¼8.0 Hz, AreH); 13C NMR:
d 13.5, 21.4, 21.8, 27.4, 29.1, 29.9, 31.7, 48.0, 52.1, 62.4,
126.5, 129.5, 138.7, 142.6; FTIR (thin film): 3520 (br), 2940
(s), 2871 (m), 1598 (w), 1329 (s), 1224 (m), 1163 (s), 1140
(m) cmꢀ1; m/z (TOF ES): 312 (MHþ); HRMS (TOF ES) calcd
for C16H26NO3S: 312.1633, found: 312.1639.
4.3.17. 5-Methyl-hexahydro-indolizin-3-one (45)
Magnesium turnings (934 mg, 38.91 mmol, 30 equiv) were
flame dried in a two-neck flask fitted with a reflux condenser.
The flask was placed under nitrogen and methanol (5.3 mL)
wasaddedfollowedbydropwiseadditionofasolutionoftheester
(422 mg, 1.30 mmol, 1 equiv) in methanol (10.6 mL). The solu-
tion was left at room temperature overnight then heated at reflux
for 1 h. Thereaction wasallowedtocooltoroomtemperatureand
was then quenched with 1 M HCl(aq) until all salts had dissolved.
The product was extracted with EtOAc and the extracts were
washed with brine, dried over MgSO4, filtered and concentrated
under reduced pressure. The lactam was obtained by column
chromatography in EtOAc to give (45) a colourless oil, 138 mg
(69%, recovered 17% ester). [a]2D0 ꢀ102 (c 0.01 g/mL,
1
4.3.16. 2,3-[6-Methyl-1-(toluene-4-sulfonyl)-piperidin-2-
yl]-propionic acid methyl ester (44)
CH2Cl2); H NMR (250 MHz, CDCl3): d 1.12e1.71 (5H, m,
CH2), 1.62 (3H, d, J¼6.5 Hz, CH3CH), 1.75e1.90 (2H, m,
CH2), 2.02e2.16 (1H, m, CH2), 2.36e2.56 (2H, m, C(O)CH2),
3.19e3.37 (2H, m, CHNCH); 13C NMR: d 19.8, 22.8, 25.5,
31.9, 32.6, 33.7, 52.5, 59.3, 175.6; FTIR (thin film): 2934 (s),
2860(s),1682(s) cmꢀ1;m/z(EI):138,153(M);HRMS(EI)calcd
for C9H15NO: 153.1154, found: 153.1152.15
Oxalyl chloride (2.16 mL, 24.77 mmol, 1.2 equiv) was added
to CH2Cl2 (165 mL) at ꢀ78 ꢁC then a solution of DMSO
(3.7 mL, 51.61 mmol, 2.5 equiv) in CH2Cl2 (330 mL)was added
and the reaction mixture stirred for 5 min. A solution of alcohol
(6.43 g, 20.65 mmol, 1 equiv) in CH2Cl2 (165 mL) was added to
the mixture. After 1 h, Et3N (12.1 mL, 86.71 mmol, 4.2 equiv)
was added and the mixturewas allowed towarm to room temper-
ature. The reaction was quenchedwithwater and theproductwas
extracted with CH2Cl2. The combined organic layers were
4.3.18. (ꢀ)-Monomorine
To a solution of (44) (18 mg, 0.177 mmol, 1 equiv) in hex-
ane (2.3 mL) at ꢀ78 ꢁC was added n-BuLi (2.2 M, 160 mL,

L.C. Pattenden et al. / Tetrahedron 64 (2008) 2951e2961
2961
3427; (d) Goodenough, K. M.; Moran, W. J.; Raubo, P.; Harrity, J. P. A.
J. Org. Chem. 2005, 70, 207; (e) Goodenough, K. M.; Raubo, P.; Harrity,
J. P. A. Org. Lett. 2005, 7, 2993; (f) Provoost, O. Y.; Hedley, S. J.;
Hazelwood, A. J.; Harrity, J. P. A. Tetrahedron Lett. 2006, 47, 331.
3. For recent overviews see: (a) Harrity, J. P. A.; Provoost, O. Org. Biomol.
Chem. 2005, 3, 1349; (b) Hsung, R. P.; Kurdyumov, A. V.; Sydorenko, N.
Eur. J. Org. Chem. 2005, 23.
0.35 mmol, 3 equiv). The reaction was allowed to warm to
0 ꢁC and stirred for 1.5 h. The reaction was quenched with
water and warmed to room temperature. The organic layer
was separated and the aqueous layer extracted with diethyl
ether. The organic layers were combined and washed with
Na2CO3(aq) and brine. The organic layers were concentrated
under reduced pressure to give (46) as a cream coloured solid.
1H NMR (250 MHz, CDCl3): d 0.90 (3H, t, J¼7.0 Hz,
CH2CH3), 1.07e3.23 (21H, m), 9.18 (1H, br, NH), 9.39
(1H, br, NH); 13C NMR: d 13.8, 19.4, 22.3, 22.9, 25.8, 27.2,
28.0, 30.5, 38.4, 42.5, 54.6, 57.8, 210.0.
4. (a) Movassaghi, M.; Chen, B. Angew. Chem., Int. Ed. 2007, 46, 565; (b)
Schmidt, A.; Gutlein, J.-P.; Mkrrchyan, S.; Gorls, H.; Langer, P. Synlett
¨
¨
2007, 1305; (c) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129,
5334; (d) Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 6330;
(e) Halliday, J. I.; Chebib, M.; Turner, P.; McLeod, M. D. Org. Lett.
´
2006, 8, 3399; (f) Agami, C.; Dechoux, L.; Hebbe, S.; Menard, C.
Tetrahedron 2004, 60, 5433; (g) Sydorenko, N.; Hsung, R. P.; Darwish,
O. S.; Hahn, J. M.; Liu, J. J. Org. Chem. 2004, 69, 6732; (h) McLaughlin,
M. J.; Hsung, R. P.; Cole, K. C.; Hahn, J. M.; Wang, J. Org. Lett. 2002, 4,
2017; (i) Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Douglas, C. J.;
McLaughlin, M. J.; Mulder, J. A.; Yao, L. J. Org. Lett. 1999, 1, 509.
5. (a) Craig, D.; McCague, R.; Potter, G. A.; Williams, M. R. V. Synlett 1998,
55; (b) Craig, D.; McCague, R.; Potter, G. A.; Williams, M. R. V. Synlett
1998, 58; (c) Adelbrecht, J.-C.; Craig, D.; Dymock, B. W.; Thorimbert, S.
Synlett 2000, 467; (d) Adelbrecht, J.-C.; Craig, D.; Thorimbert, S.
Tetrahedron Lett. 2001, 42, 8369; (e) Adelbrecht, J.-C.; Craig, D.; Flem-
ing, A. J.; Martin, F. M. Synlett 2005, 2643.
The crude residue was diluted in methanol (3.5 mL) and to
this solution was added 10% Pd/C (12 mg). The reaction
mixture was placed under hydrogen balloon and left to stir over-
night. The reaction mixture was filtered through hyflo supercel
with CH2Cl2, then concentrated under reduced pressure. (ꢀ)-
Monomorine was obtained by column chromatography in 9:1
pentane/Et2O as a colourless solid, 5 mg, 22%. [a]2D2 ꢀ30 (c 1,
hexane), (lit. [a]D20 ꢀ26.4 (c 1.0, hexane));20 1H NMR
(400 MHz, CDCl3): d 0.89 (3H, t, J¼7.0 Hz, CH2CH3), 1.14
(3H, d, J¼6.5 Hz, CHCH3), 1.17e1.56 (10H, m, CH2), 1.61e
1.89 (6H, m, CH2), 2.02e2.11 (1H, m, NCH), 2.16e2.26 (1H,
m, NCH), 2.42e2.51 (1H, m, NCH); 13C NMR (100.6 MHz):
d 14.2, 22.9ꢂ2, 24.9, 29.4, 29.8, 30.3, 30.9, 35.8, 39.7, 60.2,
62.9, 67.1; m/z (EI): 138, 149, 194; HRMS (TOF ES) calcd
for C13H26N: 196.2065, found: 196.2068.
6. Buchi, G.; Wuest, H. J. Org. Chem. 1969, 34, 1122.
¨
¨
7. For our preliminary communication of this work see: Pattenden, L. C.;
Wybrow, R. A. J.; Smith, S. A.; Harrity, J. P. A. Org. Lett. 2006, 8, 3089.
8. (a) Sworin, M.; Neumann, W. L. Tetrahedron Lett. 1987, 28, 3217; (b)
Ponaras, A. A. Tetrahedron Lett. 1976, 7, 3105.
9. Stowell, J. C. J. Org. Chem. 1976, 41, 560.
10. Compound 40 appears to exist as a mixture of aldehyde and hemi-aminal.
The characterisation data for this compound are provided in the
Supplementary data.
Acknowledgements
11. Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
12. For discussions see: (a) Paquette, L. A.; Leit, S. M. J. Am. Chem. Soc.
1999, 121, 8126; (b) Bharatam, P. V.; Amita; Gupta, A.; Kaur, D.
Tetrahedron 2002, 58, 1759.
We thank the EPSRC and GSK for financial support.
Supplementary data
13. Ohwada, T.; Okamoto, I.; Shudo, K.; Yamaguchi, K. Tetrahedron Lett.
1998, 39, 7877.
14. For recent synthetic approaches and lead references see: Zhang, S.; Xu,
L.; Miao, L.; Shu, H.; Trudell, M. L. J. Org. Chem. 2007, 72, 3133.
15. Provoost, O. Y.; Hazelwood, A. J.; Harrity, J. P. A. Beilstein J. Org. Chem.
2007, 3, 8.
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.01.071.
16. Shono, T.; Matsumura, Y.; Uchida, K.; Kobayashi, H. J. Org. Chem. 1985,
50, 3243.
References and notes
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