1,4-Bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines in synthesis: Stereoselective homo- and hetero-Diels-Alder reactions

Article abstract of DOI:10.1055/s-2005-917073

Palladium-catalysed coupling of a vinylstannane or vinyl boronic acids with 5-iodo-1,4-bis(tosyl)-1,2,3,4-tetrahydropyridines yields 1,3-dienes. These participate in homo- and hetero-Diels-Alder reactions with unsaturated carbonyl compounds and with nitroso species generated in situ to give novel bicyclic compounds in a highly stereoselective fashion. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-917073

LETTER
2643
1,4-Bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines in Synthesis: Stereoselective
Homo- and Hetero-Diels–Alder Reactions
1
, 4-Bis(ar
e
ylsulfonyl)-
a
1,2,3,4-tetr
n
ahydropyridi
-
nes in S
C
ynthesis laude Adelbrecht,a Donald Craig,*a Alice J. Fleming,a Fionna M. Martinb
a
Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
Fax +44(20)75945868; E-mail: d.craig@imperial.ac.uk
b
Eli Lilly & Co., Lilly Research Centre, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, UK
Received 21 July 2005
methylethyl)aziridine2 using our standard two-step
method,1a followed by t-BuOK-catalysed C-4-epimerisa-
tion, providing exclusively the 2R,4S-isomer in excellent
overall yield. This was combined with a slight excess of
Abstract: Palladium-catalysed coupling of a vinylstannane or vinyl
boronic acids with 5-iodo-1,4-bis(tosyl)-1,2,3,4-tetrahydro-
pyridines yields 1,3-dienes. These participate in homo- and hetero-
Diels–Alder reactions with unsaturated carbonyl compounds and
with nitroso species generated in situ to give novel bicyclic com- N-iodosuccinimide and a sub-stoichiometric quantity of
Koser’s reagent7 in CH2Cl2 under reflux to give the iodo-
pounds in a highly stereoselective fashion.
tetrahydropyridine; subsequent treatment with tri-n-bu-
tylvinylstannane and Pd2dba3-tris(2-furyl)phosphine
provided 4 in high overall yield from 3 (Scheme 1). The
analogous coupling reactions of tri-n-butylvinylstannane
with the corresponding bromide derived from 3 were sub-
stantially less efficient. We evaluated also alternative
Pd(0)-catalysed methods for diene assembly which avoid-
ed the use of organostannanes. Substrate 4 was readily
prepared using the Suzuki reaction, in which the iodotet-
rahydropyridine made from 3 previously was coupled
with freshly-made, crude ethenylboronic acid in the
presence of [Pd(PPh3)4] and base. Diene 5 was made in an
analogous fashion, again in execellent yield. Finally,
diene 6 was prepared in high yield from commercially
available E-2-phenylethenylboronic acid with the iodo-
tetrahydropyridine (Scheme 1).
Key words: Diels–Alder reaction, nitroso dienophile, palladium-
catalysed coupling, stereoselective synthesis, tetrahydropyridine
Over the past several years we have been investigating the
synthesis and chemistry of 1,4-bis(arylsulfonyl)-1,2,3,4-
tetrahydropyridines (1).1,2 Inspired by Overman’s total
synthesis of the alkaloid (+)-aloperine, in which the in-
tramolecular Diels–Alder reaction of a substrate possess-
ing an alkenyl-substituted tetrahydropyridine played a
key role,3a we became interested in evaluating the cy-
cloaddition behaviour of substrates 2 containing a 1,3-di-
ene partially embedded in the tetrahydropyridine core
(Figure 1).4 It occurred to us that the Diels–Alder reac-
tions of 2 with all-carbon dienophiles would offer rapid,
stereoselective entries to octahydroquinoline-containing
structures, whilst combination of 2 with heterodienophiles
possessing N=X groups followed by reductive cleavage
would provide structurally complex (aminoalkyl)pipe-
ridines and potentially aminoacids. This Letter reports the
preliminary results of our investigations.5
Ts
Ts
i, ii
67%
N
i-Pr
N
i-Pr
Ts
Ts
3
4
i
80%
Ts
Ts
R2
Ts
R2
Ts
1
2
I
R1
iii
R2
N
R1
N
R1
Ts
Ts
N
i-Pr
N
i-Pr
Ts
Ts
Figure 1
4: R1 = R2 = H:
5: R1 = H, R2 = Me: 88%
6: R1 = Ph, R2 = H: 86%
80%
To maximise flexibility in the synthesis of 2, we elected
to assemble the 1,3-diene moiety through Pd(0)-catalysed
reactions of a suitably modified tetrahydropyridine nucle-
us with olefinic coupling partners such as vinylstannanes
and vinylboronic acids; Comins6 and Overman3a had both
previously demonstrated the viability of this approach.
With this in mind, 3 was synthesised from 1-tolylsulfonyl-
3,3-dimethoxypropane and (R)-1-tolylsulfonyl-2-(1-
Scheme 1 Reagents and conditions: (i) N-iodosuccinimide (1.05
equiv), PhI(OH)(OTs) (0.1 equiv), CH2Cl2, reflux, 16 h; (ii) n-
Bu3SnCH=CH2 (1.1 equiv), Pd2dba3 (0.06 equiv), (2-furyl)3P (0.12
equiv), DMF, 70 °C, 16 h; (iii) R1CH=C(R2)B(OH)2 (2.5 equiv),
[Pd(PPh3)4] (0.05 equiv), Na2CO3 (10 equiv), dioxane, 80 °C, 16 h
With efficient syntheses of 4–6 established, attention was
turned to their Diels–Alder reactions. Heating of an
equimolar mixture of 4 and maleic anhydride in CDCl3
(ca. 1.3 M) at 65 °C for 2 hours gave in quantitative yield
a single cycloadduct, as shown by 1H NMR spectroscopic
SYNLETT 2005, No. 17, pp 2643–2647
Advanced online publication: 05.10.2005
DOI: 10.1055/s-2005-917073; Art ID: D20605ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.1
0
.2
0
0
5

2644
J.-C. Adelbrecht et al.
LETTER
analysis of the crude product. A portion of this material 1H NMR analysis of the crude cycloadduct. Subjection of
was dissolved in MeOH–CH2Cl2 and treated with the chromatographically purified product mixture to
TMSCHN2 to give the corresponding dimethyl diester 7 in LiAlH4 reduction followed by 3,5-dinitrobenzoate ester
74% overall yield from 4 (Scheme 2). The structure of 7 formation enabled separation. X-ray crystallographic
was unambiguously assigned by X-ray crystallographic analysis of the major isomeric ester allowed unambiguous
analysis (Figure 2).8
assignment of structure 9 (Figure 3), and therefore assign-
ment of structure 10a to the major cycloadduct
(Scheme 3).
Ts
Ts
i, ii
Ts
Ts
74%
N
i-Pr
MeO2C
MeO2C
N
i-Pr
i–iii
Ts
H
Ts
40%
Ts
4
7
N
i-Pr
N
i-Pr
Ts
H
Ts
RO
8
4
9
O
N
i-Pr
R = 3,5-(O2N)2C6H3CO
H
Ts
Ts
Ts
O
O
Scheme 2 Reagents and conditions: (i) maleic anhydride (1 equiv),
CDCl3 (ca. 1.3 M), 65 °C, 2 h; (ii) TMSCHN2 (4 equiv), MeOH–
CH2Cl2 (1.5:1), r.t., 2 h
N
i-Pr
N
i-Pr
H
Ts
H
Ts
OHC
OHC
10a
10b
Scheme 3 Reagents and conditions: (i) acrolein (1.2 equiv), CDCl3
(ca. 0.9 M), 53 °C, 24 h; (ii) LiAlH4 (1.35 equiv), THF, r.t., 30 min;
(iii) 3,5-(O2N)2C6H3COCl (1.3 equiv), Et3N (2 equiv), DMAP (0.05
equiv), CH2Cl2, 0 °C, 20 min
Figure 2 The molecular structure of 7
The formation of 7 from 4 in the sequence shown in
Scheme 2 clearly shows the structure of the maleic anhy-
dride [4+2] cycloadduct to be 8. Formation of 8 indicates
preferred endo approach of the dienophile to the a-face of
4, syn to the C-2 isopropyl group. This is in contrast to the
results of Comins,5 who obtained exclusively Diels–Alder
products from N-carbamoyl-2,3-dihydro-4-pyridones
corresponding to dienophile approach anti to the C-2 sub-
stituent. We attribute this striking reversal in stereoselec-
tivity to the preferred orientation of the N-tolylsulfonyl
substituent anti to the C-2 isopropyl moiety because of
mutual steric buttressing. This observation is in accord
with the behaviour of 1 (R1 = n-C11H23, R2 = H) in SN1¢1a
and dihydroxylation1d reactions, and that of 1 (R1 = n-
C11H23, R2 = Me)9 in cationic hydrogenation1b processes.
Figure 3 The molecular structure of 9
The preferred formation of 10a in the cycloaddition reac-
tion of 4 with acrolein mirrors the endo-, syn-selectivity
observed with maleic anhydride. The erosion of endo-
selectivity (ratio 10a:10b = ca. 4.5:1) in comparison with
the maleic anhydride reaction may be a consequence of
the lower reactivity of acrolein as a dienophile, and is in
keeping with similar decreases in diastereomer ratios
observed for singly-activated dienophiles in Comins’
work. Again, the diastereofacial selectivity with respect to
the diene is opposite to that observed for the 2,3-dihydro-
4-pyridone-derived dienes.5
We next examined the reaction of 4 with acrolein. As
anticipated, the cycloaddition was slower than that with
maleic anhydride, giving in 79% yield an inseparable
mixture of two products in a 82:18 ratio as determined by
We next looked at the hetero-Diels–Alder reactions of
1,3-dienes 4–6.10 These were carried out in dichloro-
methane at ambient temperature with nitroso dienophiles
Synlett 2005, No. 17, 2643–2647 © Thieme Stuttgart · New York

LETTER
1,4-Bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines in Synthesis
2645
XN=O (11a: X = Boc; 11b: X = CBz; 11c: X = Ph) gen-
–
erated in situ in the case of 11a,b by Bu4N+IO4 -mediated
oxidation11 of the corresponding hydroxylamines.12 All
three dienes reacted with the three dienophiles to give
single products (Scheme 4, Table 1).
R2
Ts
R2
Ts
R1
R1
X
i
N
N
i-Pr
O
N
i-Pr
Ts
H
Ts
4–6
12–14
Scheme 4 Reagents and conditions: (i) reactions with 11a,b: add
XNHOH (2.2 equiv) to solution of diene and Bu4NIO4 (2 equiv) in
CH2Cl2 (0.12–0.15 M), r.t., 15 min; reactions with 11c: PhNO (1
equiv), CH2Cl2 (0.1 M), r.t., 1–48 h
The structure of cycloadduct 12a was unequivocally
established by X-ray crystallographic analysis (Figure 4),
demonstrating that in common with maleic anhydride and
acrolein, approach of the hetero-dienophile had occurred
exclusively syn to the isopropyl group. The assignment of
stereochemistry in the other cycloadducts followed from
the similarity in the chemical shifts of the O–CH–N
methine protons. The yields of the cycloaddition reactions
of 5 were consistently lower than for 4 and 6, perhaps
reflecting a less pronounced preference for the reactive
cisoid over the unreactive transoid diene conformation on
account of allylic 1,3-strain between the diene methyl
group and the sulfonyl-substituted C-4 carbon atom in the
piperidine ring (Scheme 5).
Figure 4 The molecular structure of 12a
Me Ts
Ts
N
i-Pr
N
i-Pr
Ts
Ts
5
reactive
unreactive
R1
Ts
Ts
R1
N
i-Pr
N
i-Pr
In conclusion, we have shown that 5-alkenyl-1,4-bis(4-
tolylsulfonyl)-1,2,3,4-tetrahydropyridines are readily
available 1,3-dienes which enter into homo- and hetero-
Diels–Alder reactions with high stereoselectivity and
complete regioselectivity. Application of this chemistry to
natural and unnatural products synthesis is ongoing and
will be the subject of future reports from this laboratory.
Ts
Ts
4
Scheme 5
Table 1 Hetero-Diels–Alder Reactions of 4–6
Entry
Diene
R1
H
R2
H
X
Product
12a
Yield (%)a
1
2
3
4
5
6
7
8
9
4
4
4
5
5
5
6
6
6
Boc
76
70
98
55
50
24
73
67
67
H
H
CBz
Ph
12b
12c
H
H
H
Me
Me
Me
H
Boc
CBz
Ph
13a
H
13b
13c
H
Ph
Ph
Ph
Boc
CBz
Ph
14a
H
14b
14c
H
a Yields are for chromatographically purified products.
Synlett 2005, No. 17, 2643–2647 © Thieme Stuttgart · New York

2646
J.-C. Adelbrecht et al.
LETTER
A solution of (2R,4S)-2-(1-methylethyl)-1,4-bis(4-tolylsulfonyl)-5-
vinyl-1,2,3,4-tetrahydropyridine (4, 0.849 mmol, 390 mg, 1 equiv)
and maleic anhydride (0.849 mmol, 84 mg, 1 equiv) in CDCl3 (350
mL) was heated to 65 °C for 2.5 h. The mixture was concentrated
under reduced pressure to afford the crude cycloadduct as a light
brown solid.
meta-Ts), 7.23 (2 H, d, J = 8.0 Hz, meta-Ts), 5.80 (1 H, br s, –CH=),
4.47 (1 H, br s, H-8a), 3.73–3.63 (2 H, m, H-4 and H-2), 3.38–3.31
(1 H, m, CHCHO), 2.48 (3 H, s, CH3 of Ts), 2.41 (3 H, s, CH3 of
Ts), 2.30–1.85 (3 H, m, H-3, CH2–CH=), 1.76–1.61 (2 H, m, H-7),
1.58 [1 H, doublet of septets, J = 10.5, 6.5 Hz, CH(CH3)2], 1.38 (1
H, ddd, J = 15.5, 11.5, 4.0 Hz, H-3), 0.87 [3 H, s, J = 6.5 Hz,
CH(CH3)2], 0.72 [3 H, s, J = 6.5 Hz, CH(CH3)2]. 13C NMR (67.5
MHz): d = 205.5 (CH0), 145.1 (ipso-Ts), 144.2 (ipso-Ts), 138.2
(–CH=), 134.8 (para-Ts), 133.4 (para-Ts), [130.0, 129.7, 129.2,
128.2 (ortho and meta)], 122.6 (CH=C–), 61.7 (C-4), 60.2 (C-2),
53.4 (C-6), 49.4 (CHCHO), 30.6 [CH(CH3)2], 22.8 (CH2CH=), 22.3
(C-3), 22.0 (C-8), 21.7 (CH3 of Ts), 21.7 (CH3 of Ts), 20.6
[CH(CH3)2], 20.0 [CH(CH3)2].
1H NMR (270 MHz): d = 7.73 (2 H, d, J = 8.5 Hz, ortho-Ts), 7.41–
7.18 (6 H, m, ortho-Ts and meta-Ts), 6.24 (1 H, br s, –CH=), 4.66
(1 H, br d, J = 7.0 Hz, H-8a), 4.35 (1 H, t, J = 8.5 Hz, H-8), 3.77 (1
H, br t, J = 9.0 Hz, H-4), 3.44 (1 H, ddd, J = 11.0, 7.5, 4.5 Hz, H-7),
3.27–3.23 (1 H, m, H-2), 2.66–2.28 (2 H, m, CH2–CH=), 2.46 (3 H,
s, CH3 of Ts), 2.28 (3 H, s, CH3 of Ts), 1.45–1.11 [2 H, m,
CH(CH3)2 and H-3], 0.96 [3 H, d, J = 6.5 Hz, CH(CH3)2], 0.96–0.71
(1 H, m, H-3), 0.59 [3 H, d, J = 6.5 Hz, CH(CH3)2]. 13C NMR (67.5
MHz): d = 172.6 (–COOCH3), 168.2 (COOCH3), 145.4 (ipso-Ts),
144.2 (ipso-Ts), 135.0 (–CH=), 133.2 (para-Ts), 132.6 (para-Ts),
[130.0, 129.9, 128.8, 128.3 (ortho and meta)], 123.6 (CH=C–), 60.0
(C-4), 59.1 (C-2), 49.9 (C-6), 47.2 (C-8), 39.0 (C-7), 30.5
[CH(CH3)2], 23.6 (CH2CH=), 23.1 (C-3), 21.7 (CH3 of Ts), 21.7
(CH3 of Ts), 21.0 [CH(CH3)2], 19.8 [CH(CH3)2]. MS (CI): m/z =
575 [M + NH4]+, 558 [M + H]+, 402, 248, 174.
To a solution of (2R,4S,8RS,8aR)-2-(1-methylethyl)-1,4-bis-(4-
tolylsulfonyl)-1,2,3,4,6,7,8,8a-octahydro-quinoline-8-carbalde-
hyde (10a,b, 108 mg, 0.20 mmol) in THF (2 mL) at r.t. was added
LiAlH4 (265 mL of a 1 M solution in hexanes, 1.35 equiv) causing
the colourless solution to turn yellow. After 30 min the reaction was
quenched with EtOAc followed by the addition of sat. aq Rochelle
salt. The mixture was stirred for 16 h and then extracted with EtOAc
(3 × 10 mL). The combined organic layers were washed with brine
(10 mL), dried (MgSO4) and concentrated under reduced pressure
to yield the corresponding primary alcohols. To a solution of the
crude product (75 mg) in CH2Cl2 (1 mL) was added Et3N (30 mL,
0.21 mmol, 2 equiv), DMAP (0.05 equiv) and 3,5-dinitrobenzoyl
chloride (33 mg, 0.141 mmol, 1.3 equiv) at 0 °C. After 20 min the
reaction was quenched with sat. aq NH4Cl, extracted with EtOAc,
and washed with brine and dried (MgSO4). Concentration under
reduced pressure and flash chromatography (25% EtOAc–PE)
yielded (2R,4S,8R,8aR)-2-(1-methylethyl)-1,4-bis-(4-tolylsulfo-
nyl)-1,2,3,4,6,7,8,8a-octahydroquinolin-8-ylmethyl 3,5-dinitroben-
zoate (9) as a colourless solid (52 mg, 51% over two steps based on
10a present in starting material, 42% based on 82:18 10a:10b mix-
ture), mp 124–125 °C (dec.); [a]D25 –43 (c 1.1, CH2Cl2).
Part of the crude mixture (0.141 mmol, 77 mg, 1 equiv) in solution
in MeOH–CH2Cl2 (1.5:1, 2 mL) was treated at r.t. with trimethyl-
silyldiazomethane (0.55 mL of a 1 M solution in hexanes, 4 equiv).
The reaction mixture was stirred for 2 h. Concentration under
reduced pressure and chromatography (40% EtOAc–PE) yielded
(2R,4S,7R,8R,8aR)-2-(1-methylethyl)-1,4-bis-(4-tolylsulfonyl)-
1,2,3,4,6,7,8,8a-octahydroquinoline-7,8-dicarboxylic acid dimethyl
ester (7, 60 mg, 74% over 2 steps) as a colourless solid, mp 140 °C
(dec.); [a]D25 –16 (c 3.4, CH2Cl2).
IR (CH2Cl2): 2953, 2869, 1730, 1593, 1303, 1185, 1161, 1146, 911,
742 cm–1. 1H NMR (270 MHz): d = 7.77 (2 H, d, J = 8.5 Hz, ortho-
Ts), 7.42–7.34 (4 H, m, meta-Ts), 7.25 (2 H, d, J = 8.5 Hz, ortho-
Ts), 5.86–5.84 (1 H, m, –CH=), 4.52 (1 H, br s, H-8a), 4.21 (1 H,
dd, J = 6.5, 3 Hz, H-2), 3.76–3.65 (1 H, m, H-4), 3.69 (3 H, s,
OCH3), 3.65 (3 H, s, OCH3), 3.11 (1 H, dt, J = 11.0, 3.0 Hz, H-8),
3.11 (1 H, ddd, J = 11.5, 4.5, 3.5 Hz, H-7), 2.83–2.71 (1 H, m, CH2–
CH=), 2.47 (3 H, s, CH3 of Ts), 2.41 (3 H, s, CH3 of Ts), 2.25–2.18
(1 H, m, CH2–CH=), 1.64 [1 H, doublet of septets, J = 11.0, 6.5 Hz,
CH(CH3)2], 1.54 (1 H, ddd, J = 15.0, 9.0, 2.5 Hz, H-3), 1.32 (1 H,
ddd, J = 15.5, 11.5, 4.0 Hz, H-3), 0.69 [3 H, s, J = 6.5 Hz,
CH(CH3)2], 0.63 [3 H, s, J = 6.5 Hz, CH(CH3)2]. 13C NMR (67.5
MHz): d = 172.7 (COOCH3), 171.2 (COOCH3), 145.1 (ipso-Ts),
144.0 (ipso-Ts), 135.9 (–CH=), 135.2 (para-Ts), 133.5 (para-Ts),
[129.9, 129.7, 129.1, 128.5 (ortho and meta)], 120.5 (CH=C–), 61.4
(C-4), 59.4 (C-2), 54.4 (C-6), 52.2 (CH3O), 51.7 (CH3O), 46.0 (C-
8), 40.4 (C-7), 29.7 (CH(CH3)2), 25.3 (CH2CH=), 22.7 (C-3), 21.7
(CH3 of Ts), 21.6 (CH3 of Ts), 20.9 [CH(CH3)2], 19.8 [CH(CH3)2].
MS (CI): m/z = 621 [M + NH4]+, 604 [M + H]+. Anal. Calcd for
C30H37NO8S2: C, 59.68; H, 6.18; N, 2.32%. Found: C, 59.76; H,
6.24; N, 2.24.
IR (CH2Cl2): 2963, 2926, 1730, 1711, 1546, 1343, 1164, 1142,
1086, 977, 814 cm–1. 1H NMR (270 MHz): d = 9.21 (3 H, s, Ar-H
of dinitrophenyl), 7.73 (2 H, d, J = 8.0 Hz, ortho-Ts), 7.41–7.36 (4
H, m, meta-Ts), 7.25 (2 H, d, J = 8.0 Hz, ortho-Ts), 5.82 (1 H, br s,
–CH=), 4.71 (1 H, dd, J = 11.0, 5.5 Hz, CH2OCO), 4.53–4.46 (2 H,
m, H-4 and H-8a), 3.66 (1 H, t, J 11.5, 5.5 Hz, CH2OCO), 3.60 (1
H, t, J = 10.0 Hz, H-4), 3.46 (1 H, br s, CHCH2OCO), 3.38 (1 H, br
d, J = 10.5 Hz, H-2), 2.51 (3 H, s, CH3 of Ts), 2.43 (3 H, s, CH3 of
Ts), 2.20–1.87 (2 H, m, CH2–CH=), 1.87–1.54 (3 H, m, H-7 and H-
3), 1.25–1.20 [2 H, m, H-3 and CH(CH3)2], 1.08 [3 H, s, J = 6.5 Hz,
CH(CH3)2], 0.74 [3 H, d, J = 6.5 Hz, CH(CH3)2]. 13C NMR (67.5
MHz): d = 162.8 (C=O), 148.7, (Ar-C of dinitrophenyl), 145.0
(ipso-Ts), 144.0 (ipso-Ts), 137.4 (–CH=), 135.0 (para-Ts), 134.0
(Ar–C of dinitrophenyl), 133.4 (para-Ts), [130.0, 129.9, 129.6,
129.1, 128.0 (ortho and meta) and Ar–C of dinitrophenyl], 122.7
(Ar–C of dinitrophenyl), 122.3 (CH=C–), 65.1 [CH2–O(C=O)],
61.9 (C-4), 59.4 (C-2), 54.6 (C-6), 36.3 (CHCH2OCO), 31.1
[CH(CH3)2], 23.1 (CH2CH=), 22.7 (C-3), 21.7 (CH3 of Ts), 21.7
(CH3 of Ts), 21.2 (C-8), 20.5 [CH(CH3)2], 20.4 [CH(CH3)2]. Anal.
Calcd for C34H37N3O10S2: C, 57.37; H, 5.24; N, 5.90%. Found: C,
57.39; H, 5.22; N, 5.83.
To a solution of (2R,4S)-2-(1-methylethyl)-1,4-bis(4-tolylsulfo-
nyl)-5-vinyl-1,2,3,4-tetrahydropyridine (4, 0.246 mmol, 113 mg, 1
equiv) in CDCl3 (250 mL) was added freshly distilled acrolein
(0.295 mmol, 30 mL, 1.2 equiv). The reaction mixture was heated at
53 °C for 24 h and the solvent evaporated under reduced pressure.
1H NMR Analysis of the crude product indicated a diastereoisomer-
ic ratio of 82:18. Chromatography (25% EtOAc–PE) yielded an in-
separable mixture of (2R,4S,8R,8aR)-2-(1-methylethyl)-1,4-bis-(4-
tolylsulfonyl)-1,2,3,4,6,7,8,8a-octahydroquinoline-8-carbaldehyde
(10a) and (2R,4S,8S,8aR)-2-(1-methylethyl)-1,4-bis(4-tolylsulfo-
nyl)-1,2,3,4,6,7,8,8a-octahydroquinoline-8-carbaldehyde (10b, 108
mg, 79%) as a colourless solid; data for 10a taken from the mixture.
To a stirred solution of (2R,4S)-2-isopropyl-1,4-bis-(toluene-4-sul-
fonyl)-5-vinyl-1,2,3,4-tetrahydropyridine (4, 13 mg, 0.03 mmol, 1
equiv) in CDCl3 (0.5 mL) was added nitrosobenzene (3 mg, 0.03
mmol, 1 equiv). After 40 min at r.t. the reaction was complete as ev-
1
idenced by H NMR analysis. The reaction mixture concentrated
under reduced pressure. Flash chromatography (50% Et2O–PE)
gave (5S,7R,8aR)-7-(1-methylethyl)-2-phenyl-5,8-bis(4-tolylsulfo-
nyl)-3,5,6,7,8,8a-hexahydro-2H-pyrido[3,2-e][1,2]oxazine (12c,
15.8 mg, 0.03 mmol, 98%); Rf 0.19 (50% Et2O–PE). 1H NMR (500
MHz): d = 7.85 (2 H, d, J = 8.5 Hz, ortho PhSO2), 7.60 (2 H, d, J =
8.0 Hz, ortho PhSO2), 7.26–7.35 (6 H, m, 4 × Ph and meta PhSO2),
1H NMR (270 MHz): d = 10.0 (1 H, s, CHO), 7.72 (2 H, d, J = 8.5
Hz, ortho-Ts), 7.40 (2 H, 8.0, ortho-Ts), 7.36 (2 H, d, J = 8.0 Hz,
Synlett 2005, No. 17, 2643–2647 © Thieme Stuttgart · New York

LETTER
1,4-Bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines in Synthesis
2647
7.18 (2 H, d, J = 7.5 Hz, meta PhSO2), 7.01 (1 H, t, J = 7.5 Hz, Ph),
6.15 (1 H, s, OCHN), 5.75 (1 H, dd, J = 16.5, 8.0 Hz, CCHCH2),
3.91–3.96 (2 H, m, 1 × CCHCH2 and NTsCH), 3.73 (1 H, d, J = 16.5
Hz, 1 × CCHCH2), 3.41–3.50 [1 H, m, CHCH(CH3)2], 2.47 (3 H, s,
ArCH3), 2.46 (3 H, s, ArCH3), 2.00 (1 H, m, 1 × CHTsCH2), 1.68–
1.78 [2 H, 1 × CHTsCH2 and CH(CH3)2], 0.85 [3 H, d, J = 6.5 Hz,
(4) For anionic addition reactions to N-heterocyclic 1,3-dienes
derived from aminoacids, see: Carballares, S.; Craig, D. J.
Organomet. Chem. 2001, 624, 381.
(5) During the early stages of this work Comins and co-workers
reported highly stereoselective [4+2] cycloaddition
reactions of N-carbamoyl-2,3-dihydro-4-pyridones
possessing alkenyl groups at the 5-position. See:
(a) Kuethe, J. T.; Brooks, C. A.; Comins, D. L. Org. Lett.
2003, 5, 321. (b) Kuethe, J. T.; Comins, D. L. Tetrahedron
Lett. 2003, 44, 4179. (c) Comins, D. L.; Kuethe, J. T.;
Miller, T. M.; Fevrier, F. C.; Brooks, C. A. J. Org. Chem.
2005, 70, 5221.
CH(CH3)A(CH3)B], 0.79 [3 H, d, J = 6.5 Hz, CH(CH3)A(CH3)B]. 13
C
NMR (67.5 MHz): d = 132.3, 129.7, 129.4, 128.8, 128.1, 122.3,
115.5, 84.8, 82.0, 65.8, 61.5, 59.6, 51.4, 31.0, 29.4, 24.3, 21.7, 21.6,
20.4, 20.2. MS (CI): m/z = 577, 567 [M + H]+, 477, 411, 304, 174,
150, 109, 94. HRMS: m/z [MH]+ calcd for C30H34N2O5S2:
567.1987; found: 567.1985.
(6) Comins, D. L.; Joseph, S. P.; Chen, X. Tetrahedron Lett.
1995, 36, 9141.
(7) (a) Angara, G. J.; McNelis, E. Tetrahedron Lett. 1991, 32,
2099. (b) Bovonsombat, P.; Angara, G. J.; McNelis, E.
Tetrahedron Lett. 1994, 35, 6787.
(8) We thank Dr. A. J. P. White (Imperial College) for the X-ray
structure determinations. Full details will be reported
elsewhere.
Acknowledgment
We thank the Department of Chemistry, Imperial College London
and Roche Products Ltd, Welwyn Garden City (PhD Studentship to
J.-C. A.), and EPSRC and Lilly Research Centre (supported DTA
PhD Studentship to A. J. F.) for support.
(9) Williams, M. R. V. PhD Thesis; University of London: UK,
1998.
(10) For reviews of the nitroso-Diels–Alder reaction and leading
references, see: (a) Yamamoto, H.; Momiyama, N. Chem.
Commun. 2005, 3514. (b) Vogt, P. F.; Miller, M. J.
Tetrahedron 1998, 54, 1317.
(11) Santianello, E.; Manzocchi, A.; Farachi, C. Synthesis 1980,
563.
(12) Nitrosobenzene was purchased from Aldrich Chemical Co.
and used as supplied.
References
(1) (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.; Thorimbert, S. Tetrahedron Lett. 2001, 42,
8369. (d) Adelbrecht, J.-C.; Craig, D.; Dymock, B. W.;
Thorimbert, S. Synlett 2000, 467.
(2) Berry, M. B.; Craig, D. Synlett 1992, 41.
(3) (a) Brosius, A. D.; Overman, L. E.; Schwink, L. J. Am.
Chem. Soc. 1999, 121, 700. (b) For a related approach, see:
Passarella, D.; Angoli, M.; Giardini, A.; Lesma, G.; Silvani,
A.; Danieli, B. Org. Lett. 2002, 4, 2925.
Synlett 2005, No. 17, 2643–2647 © Thieme Stuttgart · New York