Synthesis of δ-thiolactams by the aza-Diels-Alder reaction of in situ generated allenyltrimethylsilylthioketenes with imines

Article abstract of DOI:10.1016/j.tetlet.2006.08.104

Allenyltrimethylsilylthioketenes, generated in situ through [3,3] sigmatropic rearrangement of trimethylsilylethynyl propargyl sulfides, underwent facile [4+2] cycloaddition with imines to afford the corresponding δ-thiolactams. The resulting 2-trimethylsilyl-4-methylenetetrahydroquinolidine-2-thione, obtained by the [4+2] cycloaddition using piperideine as a dienophile, was transformed into (±)-lupinine in six steps.

Full text of DOI:10.1016/j.tetlet.2006.08.104

Tetrahedron Letters 47 (2006) 7763–7766
Synthesis of d-thiolactams by the aza-Diels–Alder reaction of
in situ generated allenyltrimethylsilylthioketenes with imines
Shigenobu Aoyagi,* Michiko Hakoishi, Mariko Suzuki, Yusuke Nakanoya,
Kazuaki Shimada and Yuji Takikawa
Department of Chemical Engineering, Faculty of Engineering, Iwate University 4-3-5 Ueda, Morioka 020-8551, Japan
Received 9 July 2006; revised 19 August 2006; accepted 24 August 2006
Available online 18 September 2006
Abstract—Allenyltrimethylsilylthioketenes, generated in situ through [3,3] sigmatropic rearrangement of trimethylsilylethynyl
propargyl sulfides, underwent facile [4+2] cycloaddition with imines to afford the corresponding d-thiolactams. The resulting 2-tri-
methylsilyl-4-methylenetetrahydroquinolidine-2-thione, obtained by the [4+2] cycloaddition using piperideine as a dienophile, was
transformed into ( )-lupinine in six steps.
Ó 2006 Elsevier Ltd. All rights reserved.
The [4+2] cycloaddition of dienes and imines,1 including
catalytic asymmetric cycloaddition,2,3 has been widely
studied in the light of their synthetic utilities for the
short access to indolizidines and quinolizidines of bio-
logical relevance. In many cases, Danishefsky’s diene
and the related dienes were employed for the required
functionalities of the target products.1,3 Recently, aza-
Diels–Alder reactions of trialkylvinylketenes with N-
trimethylsilyl imines were reported,4 but the multi-step
access to trialkylsilylketenes involving the Curtius rear-
that allenyltrimethylsilylchalcogenoketenes, composed
of nucleophilic allylsilane moieties and electrophilic
chalcogenoketene moieties would serve as highly-reac-
tive dienes for polarized dienophiles, especially for an
imine (Eq. 1). In this letter, we wish to describe a simple
and are efficient preparation of unsaturated d-thiolac-
tams through [4+2] cycloaddition of allenyltrimethyl-
silylthioketenes 2 and imines 3. An efficient synthesis
of ( )-lupinine6 by using the cycloaddition of 2 as the
key step is also reported.
R2
N
S
S
R2
R4
Me3 Si
•
•
R3
R4
Me3Si
R1
Me3Si
R1
S
N
3
ð1Þ
[4 +2]
R1
[3,3]
R3
1
2
4
rangement or the ring opening of cyclobutenone caused
a limitation of the synthetic utility and versatility of the
method. In our laboratory, generation of allenylchalco-
genoketenes by the [3,3] sigmatropic rearrangement of
alkynyl propargyl chalcogenides was established by a
trapping experiment using secondary amines to provide
a,b,c,d-unsaturated chalcogenoamides.5 We envisaged
At the outset, we examined the [4+2] cycloaddition of
allenyltrimethylsilylthioketenes 2 generated by the [3,3]
sigmatropic rearrangement of trimethylsilylethynyl
propargyl sulfides 1 with a variety of imines. Trimethyl-
silyl propargyl sulfide 1a, which underwent [3,3] sigma-
tropic rearrangement even at rt, was prepared in situ
by sequential treatment of trimethylsilylacetylene in
THF with (1) n-BuLi (1.1 equiv); (2) elemental sulfur
(1.1 equiv) and (3) propargyl bromide (1.1 equiv) at
0 °C. Then, an imine (0.5 equiv) was added to the reac-
tion mixture at 0 °C, and the reaction temperature was
*
Corresponding author. Tel.: +81 19 621 6324; fax: +81 19 621
6323; e-mail: aoyagi@iwate-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.104

7764
S. Aoyagi et al. / Tetrahedron Letters 47 (2006) 7763–7766
1
elevated to rt and the reaction mixture was stirred at
rt for 12 h (Table 1, entries 1–7). Sulfides 1b and 1c,
prepared in the analogous procedure reported for
selenides,5a,b were heated in benzene at refluxing
temperature in the presence of an imine (0.5 equiv)
(Table 1, entries 8 and 9), and the crude products were
purified by column chromatography on silica gel to
afford cycloadducts 4 as air-stable yellow compounds.
All the results are summarized in Table 1.
The structures of 4 were fully confirmed by MS, IR, H
NMR, 13C NMR and elemental analysis. In the 1H
NMR spectra of 4a–g, a set of characteristic signals as-
signed to a vinylic proton and two exo methylene protons
of 4 were observed, and the 13C NMR signals assigned to
thiocarbonyl carbon of 4 were also observed at 187–
194 ppm. The structures of d-thiolactams 4 were finally
confirmed by the X-ray crystallographic analysis of 4i,
and the ORTEP drawing of 4i is shown in Figure 1.7
Table 1. Aza-Diels–Alder reaction of in situ generated allenyltrimethylsilylthioketene 2 and imine 3
Entry
Sulfide 1
Imine 3a
Solvent
Temperature (°C)
Time (h)
Product
Yieldb (%)
S
S
S
Bn
N
Me3Si
S
Me3Si
Bn
N
N
1
THF
0–rt
12
75
Me
1ac
Me
3a
4a
Bn
Me3Si
Me3Si
Bn
N
2
3
1ac
THF
THF
0–rt
0–rt
12
12
35
Me
Bn
Me
Ph
Me
3b
Me
4b
Bn
N
N
1ac
3
Ph
3c
4c
S
S
N
N
Me3Si
Me3Si
N
N
4
5
1ac
THF–Et2O
THF–Et2O
0–rt
0–rt
12
12
78
66
3dd
4d
1ac
3ed
4e
S
S
N
Me3Si
Me3Si
N
6
7
1ac
THF
THF
0–rt
0–rt
12
12
77
56
Me
3f
Me
N
4f
N
1ac
n-Bu
3g
n-Bu
4g
S
S
Me3Si
Me
S
S
Me3Si
Me
N
8
9
3f
3f
Benzene
Benzene
Reflux
Reflux
14
14
74
82
1b
1c
Me
4h
4i
Me3Si
Ph
Me3Si
Ph
N
Me
a 0.5 M amount to 1.
b Isolated yield based on the imine used.
c Prepared in situ by the sequential treatment of trimethylsilylacetylene with n-BuLi (1.1 equiv), elemental sulfur (1.0 equiv) and propargyl bromide
(1.1 equiv) at 0 °C in THF.
d Prepared according to the reported procedure9 and the etherial solution of the crude imines 3d and e were used without concentration and
purification.

S. Aoyagi et al. / Tetrahedron Letters 47 (2006) 7763–7766
7765
It is worth noting that 2 underwent facile cycloaddition
with a highly regioselective mode without the formation
of b-thiolactams8 in all cases.4a Treatment of allenyl-
phenylthioketene, generated in an analogous procedure
using phenylacetylene in place of trimethylsilylacetylene,
with 2-methylpyrroline 3f afforded neither [4+2]
cycloadduct 4 nor [2+2] cycloadduct, as expected. This
result indicates the essential role of trimethylsilyl group
in the present [4+2] cycloaddition. Advantageously,
piperideine 3d and pyrroline 3e9 could be employed to
this reaction as dienophiles under the mild reaction
conditions without trimerization (Table 1, entries 4
and 5). The cycloadducts derived from these cyclic
imines would serve as precursors for a variety of indo-
lizidine or quinolizidine alkaloids. In contrast with
the cases of trialkylsilylvinylketenes,4a the cycloaddi-
tions of allenyltrimethylsilylthioketenes 2 underwent
facile cycloaddition with N-alkyl imines 3 having
protons a to the imino group. However, the use of aryl
aldimine 3c for the dienophile gave a poor result (Table
1, entry 3), and neither N-Ts nor N-PMP derivatives of
these imines 3b and 3c was effective for cycloaddition
with 2.
To demonstrate the synthetic utility of the aza-Diels–
Alder reaction, we attempted the transformation of
thiolactam 4d into ( )-lupinine as shown in Scheme 1.
To the best of our knowledge, the synthesis of lupinine
using the aza-Diels–Alder reaction as the key step was
not reported. Thus, 4d was treated with mCPBA
(2.0 equiv) in CHCl3 at 0 °C–rt for 30 min to afford cor-
responding lactam 5 in 72% yield.10 The regioselective
olefin oxidation of 5 by using NMO in the presence of
OsO4 catalyst (2 mol %) furnished diol 6 in 75% yield
as a single diastereomer. The subsequent treatment of
6 with TsOH (2.0 equiv) in the presence of 2-trimethyl-
silylethanol (2.5 equiv) afforded tetrahydroquinolidin-
1-one 7 in 76% yield through desilylation, dehydration
and protection in a one-pot procedure. However, a sim-
ilar reaction using BnOH (2.5 equiv), in place of 2-tri-
methylsilylethanol, afforded the corresponding benzyl
ether in 22% yield, and an analogous reaction without
the use of alcohol only gave 3-hydroxymethyltetrahy-
droquinolidin-1-one in a much very low yield. Protected
tetrahydroquinolidin-1-one 7 underwent hydrogenation
in the presence of a catalytic amount of PtO2 leading
to 8 quantitatively,11 and the subsequent deprotection
of 8 by the treatment of BF3OEt2 afforded 9 in 64% yield
as a single isomer.12 The relative stereochemistry be-
tween the bridgehead methine protons and the oxymeth-
ylene groups in 8 and 9 were determined to be anti by
NOE experiments. Finally, reduction of 9 by LiAlH4
gave ( )-lupinine 10 in 92% yield, and the spectral data
of synthetic 10 were identical with those reported.6c
In conclusion, we developed a novel aza-Diels–Alder
reaction of allenyltrimethylsilylthioketenes 2 and imines
3 to provide unsaturated d-thiolactams 4. Especially,
thiolactam 4d, derived from piperideine 3d, was con-
verted into ( )-lupinine 10 in six steps, and the synthetic
potentiality of the [4+2] cycloaddition protocol using 2
as convenient access to the precursors for variety of
naturally-occuring alkaloids is just demonstrated. Fur-
ther application of this methodology for the synthesis
of various polycyclic alkaloids is now in progress in
our laboratory.
Figure 1. ORTEP drawing of thiolactam 4i.
O
O
O
Me3Si
Me3Si
b
c
a
N
N
N
4d
OH
OH
OCH2CH2SiMe3
5
6
7
O
O
N
H
d
N
f
e
N
H
H
CH2OH
( )-Lupinine (10)
OCH2CH2SiMe3
OH
8
9
Scheme 1. Reagents and conditions: (a) mCPBA (2.0 equiv), CHCl3, 0 °C–rt, 30 min, 72%; (b) NMO (2.2 equiv), OsO4 (2.0 mol %), dioxane–H2O
(v:v = 1:1), rt, 12 h, 75%; (c) Me3SiCH2CH2OH (2.0 equiv), TsOH (2.5 equiv), reflux, 5 h, 76%; (d) H2 (75 psi), PtO2 (5 mol %), MeOH, rt, 14 h,
quant.; (e) BF3 ÆOEt2 (1.2 equiv), CH2Cl2, 0 °C–rt, 1 h, 64% and (f) LiAlH4 (1.0 equiv), Et2O, reflux, 1 h, 92%.

7766
S. Aoyagi et al. / Tetrahedron Letters 47 (2006) 7763–7766
26; (d) Danheiser, R. L.; Savariar, S. Tetrahedron Lett.
References and notes
1987, 28, 3299–3302.
5. (a) Shimada, K.; Akimoto, S.; Itoh, H.; Nakamura, H.;
Takikawa, Y. Chem. Lett. 1994, 1743–1746; (b) Shimada,
K.; Akimoto, S.; Takikawa, Y.; Kabuto, C. Chem. Lett.
1994, 2283–2286; (c) Aoyagi, S.; Sugimura, K.; Kanno,
N.; Watanabe, D.; Shimada, K.; Takikawa, Y. Chem.
Lett. 2006, 35, 992–993; (d) Koketsu, M.; Kanoh, M.;
Itoh, E.; Ishihara, H. J. Org. Chem. 2001, 66, 4099–4101.
6. (a) Wenkert, E.; Dave, K. G.; Stevens, V. J. Am. Chem.
Soc. 1968, 90, 6177–6181; (b) Al-awar, R. S.; Joseph, S. P.;
Comins, D. L. J. Org. Chem. 1993, 58, 7732–7739; (c)
Wanner, M. J.; Koomen, G.-J. J. Org. Chem. 1996, 61,
5581–5586; (d) Huang, H. L.; Sung, W. H.; Liu, R. S. J.
Org. Chem. 2001, 66, 6193–6196; (e) Tate, E. W.; Zard, S.
Z. Tetrahedron Lett. 2002, 43, 4683–4686.
´
1. (a) Barluenga, J.; Mateos, C.; Aznar, F.; Valdes, C. J. Org.
Chem. 2004, 69, 7114–7122; (b) Mancheno, O. G.;
˜
´
Arrayas, R. G.; Carretero, J. C. J. Am. Chem. Soc.
2004, 126, 456–457; (c) Barluenga, J.; Mateos, C.; Aznar,
F.; Valdes, C. Org. Lett. 2002, 4, 1971–1974; (d) Furman,
B.; Dziedzic, M. Tetrahedron Lett. 2003, 44, 6629–
6632.
´
2. (a) Stella, L.; Abraham, H.; Feneau-Dupont, J.; Tinant,
B.; Declercq, J. P. Tetrahedron Lett. 1990, 31, 2603–2606;
(b) Maggini, M.; Prato, M.; Scorrano, G. Tetrahedron
Lett. 1990, 31, 6243–6246; (c) Hamley, P.; Helmchen, G.;
Holmes, A. B.; Marshall, D. R.; Mackinnon, J. W. M.;
Smith, D. F.; Ziller, J. W. J. Chem. Soc., Chem. Commun.
1992, 786–788; (d) McFarlane, A. K.; Thomas, G.;
Whiting, A. Tetrahedron Lett. 1993, 34, 2379–2382; (e)
Borrion, E.; Prato, M.; Scorrano, G.; Stivanello, M.
J. Chem. Soc., Perkin Trans. 1 1989, 2245–2250; (f)
Waldmann, H. Synthesis 1994, 535–551.
7. Crystal data for 4i: C19H25NSSi, Mw = 327.56, yellow
prism, monoclinic, P21/n (#14), a = 10.94(3), b = 10.40(4),
3
˚
˚
c = 17.05(6) A, b = 104.296(6)°, V = 1879(10) A , Z = 4,
Dcalcd = 1.16 g/cm3, l(MoKa) = 2.33 cmꢀ1
, R = 0.078,
Rw = 0.090. Crystallographic data (excluding structure
factors) for this structure have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication No. CCDC612745.
3. (a) Hattori, K.; Yamamoto, H. J. Org. Chem. 1992, 57,
3264–3265; (b) Ishihara, K.; Miyata, M.; Hattori, K.;
Tada, T.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116,
10520–10524; (c) Kobayashi, S.; Ishitani, H.; Nagayama,
S. Synthesis 1995, 1195–1202; (d) Kobayashi, S.; Komi-
yama, S.; Ishitani, H. Angew. Chem., Int. Ed. 1998, 37,
979–981; (e) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999,
99, 1069–1094.
8. Schaumann, E. Chem. Ber. 1976, 109, 906–921.
9. Scully, F. E., Jr. J. Org. Chem. 1980, 45, 1515–1517.
10. Kochhar, K. S.; Cottrell, D. A.; Pinnick, H. W. Tetra-
hedron Lett. 1983, 24, 1323–1326.
11. Boekelheide, V.; Lodge, J. P., Jr. J. Am. Chem. Soc. 1951,
73, 3681–3684.
12. Burke, S. D.; Pakovsky, G. J.; Piscopio, A. D. Tetrahedron
Lett. 1986, 27, 3345–3348.
4. (a) Bennett, B.; Okamoto, I.; Danheiser, L. Org. Lett.
1999, 1, 641–644; (b) Loebach, J. L.; Benett, D. M.;
Danheiser, R. L. J. Org. Chem. 1998, 63, 8380–8389; (c)
Danheiser, R. L.; Sard, H. Tetrahedron Lett. 1983, 24, 23–