Tandem cross metathesis and intramolecular aza-Michael reaction to synthesize bicyclic piperidines and indolizidine 167E

Article abstract of DOI:10.1016/j.tetlet.2012.08.031

We have successfully transformed the terminal alkenes of dihydropyridones to the α,β-unsaturated esters by cross metathesis (CM). After detosylation the secondary amides can undergo the intramolecular aza-Michael reaction to give the bicyclic piperidine s

Full text of DOI:10.1016/j.tetlet.2012.08.031

Tetrahedron Letters 53 (2012) 5552–5554
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Tetrahedron Letters
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Tandem cross metathesis and intramolecular aza-Michael reaction
to synthesize bicyclic piperidines and indolizidine 167E
⇑
Shang-Shing P. Chou , Jhih-Liang Huang
Department of Chemistry, Fu Jen Catholic University, New Taipei City 24205, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
We have successfully transformed the terminal alkenes of dihydropyridones to the
a,b-unsaturated
Received 29 May 2012
Revised 16 July 2012
Accepted 7 August 2012
Available online 14 August 2012
esters by cross metathesis (CM). After detosylation the secondary amides can undergo the intramolecular
aza-Michael reaction to give the bicyclic piperidine structures. The stereoselectivity of the aza-Michael
reaction is determined by the size of the newly formed ring. With simple transformations we have also
achieved the synthesis of indolizidine 167E.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cross metathesis
Intramolecular aza-Michael reaction
Aza-Diels–Alder reaction
Bicyclic piperidines
Indolizidine 167E
The piperidine ring is among the most abundant molecular frag-
ments in both natural and synthetic compounds with various bio-
logical activities.1 The aza-Diels–Alder reaction is one of the most
versatile routes to substituted piperidines.2 Among the piperidine
natural products are the bicyclic indolizidines and quinolizidines.3
We have reported a new aza-Diels–Alder reaction of thio-substi-
tuted 3-sulfolenes (1) with p-toluenesulfonyl isocyanate (PTSI) to
give the cyclized products 2 which upon treatment with acid or
base afford the conjugated products 3 (Scheme 1),4 and we have
used this method to synthesize some indolizidines and
quinolizidines.5
mal stability of G2 as compared to G1. However, some unreacted
starting material was still recovered. Addition of p-cresol
(0.5 equiv) completed the reaction and further increased the yield
of 4b (entry 4). Thermal heating in refluxing toluene with catalyst
G2 and p-cresol also gave a good yield of 4b, but required a much
longer time (entry 5). Under the above standard reaction condi-
tions (Table 1, entries 4 and 5), the CM products 4a and 4c were
also obtained in good yields (Table 2). The CM reactions were also
carried out under thermal conditions all gave slightly lower yields
Cross metathesis (CM) is a convenient route to make function-
alized olefins from simple alkenes.6 We now describe the combina-
tion of CM with our previous aza-Diels–Alder methodology to
SPh
SPh
Ts
NaHCO3
N C O
SPh
acid
or base
R
N
Ts
O
hydroquinone (cat.)
Tol, reflux, 4.5 h
R
N
Ts
O
R
synthesize tetrahydropyridinones 4 containing the
a,b-unsatu-
S
O2
rated ester group, which upon N-detosylation can undergo intra-
molecular aza-Michael reaction7,8 to give the bicyclic piperidine
products 5 (Scheme 2).
1
3
2
Scheme 1. Preparation of dihydropyridones 3.
We first studied the CM reactions of compound 3b with methyl
acrylate (10 equiv) in toluene in the presence of the Grubbs’ cata-
lysts G1 and G2 to give the conjugated ester 4b (Table 1). The use of
G1 under microwave heating at 150 °C did not give any CM product
4b (entry 1). Inclusion of p-cresol (0.5 equiv) gave a very low yield
of product 4b (entry 2), probably because p-cresol could stabilize
the Grubbs’ catalyst.9 Use of catalyst G2 under microwave heating
(entry 3) gave a good yield of 4b. This might be due to higher ther-
SPh
SPh
SPh
CO2Me
N
O
( )
( )
N
Ts
O
n
n
( )
N
Ts
O
(CM)
n
aza-Michael
MeO2C
n = 1-3
MeO2C
4
5
3
⇑
Corresponding author. Tel.: +886 2 29053139; fax: +886 2 29053185.
E-mail address: chem1004@mails.fju.edu.tw (S.-S.P. Chou).
Scheme 2. Tandem cross-metathesis and aza-Michael reaction.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.031

S.-S.P. Chou, J.-L. Huang / Tetrahedron Letters 53 (2012) 5552–5554
5553
Table 1
Table 3
Cross metathesis of compound 3b with methyl acrylate
Intramolecular aza-Michael reaction of compounds 5b–d
SPh
SPh
SPh
SPh
SPh
CO2Me
(10 eq)
H
Table 3
( )
( )2
N
Ts
O
( )
N
O
N
H
O
N
H
O
( )
n
N
Ts
O
Toluene
n
n
( )
MeO
n
MeO2C
MeO2C
MeO2C
MeO2C
4a, n = 1
4b, n = 2
4c, n = 3
3a, n = 1
3b, n = 2
3c, n = 3
7
5a, n = 1
6a, n = 1, cis/trans (1:1)
6b, n = 2, trans only
6c, n = 3, trans only
5b, n = 2
5c, n = 3
PCy3
Ru
PCy3
MesN
Cl
Cl
NMes
Cl
Cl
Entry
5
Reaction Conditions
Product (%Yield)a
Ru
PCy3
Ph
Ph
1
2
5b
5b
NaOH (0.1 equiv), MeOH, reflux, 4.5 h
NaOH (0.1 equiv), MeOH, sealed tube,
100 °C, 4 h
6b:7:5b (29:29:42)b
6b:7:5b (10:31:59)b
G2
G1
3
4
5
6
7
5b
5a
5a
5c
5c
NaH (0.5 equiv), THF, reflux, 20 min
NaH (0.5 equiv), THF, reflux, 20 min
NaH (0.5 equiv), THF, rt, 20 min
NaH (0.5 equiv), THF, reflux, 7 h
NaH (0.5 equiv), THF, sealed tube,
110 °C, 30 min
6b (88)
6a (72)c
6a (74)
NR
Entry
Cat.
Reaction conditions
Product (%Yield)
1
2
3
4
5
G1
G1
G2
G2
G2
MW, 150 °C, 30 min
p-cresol (0.5 equiv), MW, 150 °C, 3.5 h
MW, 150 °C, 30 min
p-cresol (0.5 equiv), MW, 150 °C, 30 min
p-cresol (0.5 equiv), reflux, 3.5 h
NR
4b (16), 3b (60)
4b (88), 3b (10)
4b (96)
6c (48)
4b (91)
a
Isolated yield of the purified product.
The ratio was determined from the crude 1H NMR.
b
c
The 1:1 ratio of cis/trans isomers was determined by 1H NMR.
Table 2
CM reactions of compounds 3 under microwave and thermal conditions
tion at room temperature (entry 5) still gave the same result. The
reaction of compound 5c with NaH in refluxing THF (entry 6) gave
only the recovered starting material. Formation of a seven-mem-
bered ring was probably disfavored by the entropy factor. Heating
the reaction mixture in a sealed tube at 110 °C (entry 7), however,
resulted in the formation of product 6c as a single diastereomer in
fair yield. The trans stereochemistry of compounds 6b and 6c was
determined by their NOESY spectra, which showed cross signals
Entry
3
Product
%Yield (condition)
1
2
3
3a
3b
3c
4a
4b
4c
91 (A)a; 85 (B)b
96 (A); 91 (B)
94 (A); 88 (B)
a
Condition A: p-cresol (0.5 equiv), toluene, MW, 150 °C, 30 min.
Condition B: p-cresol (0.5 equiv), toluene, reflux, 3.5 h.
b
between a-hydrogens of the ester group and hydrogen at the ring
junction (Fig. 1).
SPh
SPh
Based on the literature results of the diastereoselectivity of aza-
Michael reactions11 and the Curtin–Hammett principle,12 we pro-
pose the mechanism for stereospecific formation of trans bicyclic
products 6b and 6c as in Scheme 4. The antiperiplanar transition
state involved in structure A has lower energy than the synclinal
transition state involved in structure B not only because the former
has better orbital overlap but also due to the A1,3 strain present in
the latter. However, the antiperiplanar approach A would not be as
favorable when the tether is one carbon short for compound 5a
(n = 0 in Scheme 4). Hence product 6a was obtained as a 1:1 mix-
ture of cis and trans isomers.
Further treatment of the 1:1 cis/trans mixture of compound 6a
with LiAlH4 at low temperature gave products 8a and 8b, which
could be separated by column chromatography (Scheme 5). The
stereochemistry of compounds 8a and 8b was confirmed by the
NOESY spectra, and the structure of compound 8a was also estab-
lished by X-ray crystallography (Fig. 2).
Bu3SnH (2.2 eq), AIBN (0.6 eq)
( )
( )
n
N
Ts
O
N
H
O
n
Tol, reflux, 40 min to 2.5 h
MeO2C
MeO2C
4a, n = 1
4b, n = 2
4c, n = 3
5a, n = 1 (77%)
5b, n = 2 (80%)
5c, n = 3 (85%)
Scheme 3. Detosylation of compounds 4.
and required a longer reaction time than those under microwave
conditions. The ,b-unsaturated ester group of compounds 4 was
a
assigned as the trans C@C double bond from the coupling constants
of their 1H NMR spectra.
The N-tosyl group of amides 4a–c was cleaved without affecting
the
a
,b-unsaturated ester group by the Parsons’ method10 of
Bu3SnH/AIBN. The lactams 5a–c were obtained in good yields
Bromination of compound 8a with PBr3, followed by treatment
with Bu3SnH/AIBN led to the debromination product 9 (Scheme 6).
Further reaction with Raney nickel both cleaved the C–S bond and
(Scheme 3).
The reaction of compounds 5a–c with base was then studied,
and the results are summarized in Table 3. Reaction of compound
5b with a catalytic amount of NaOH in refluxing MeOH gave the
desired aza-Michael product 6b only in low yield, together with
a significant amount of unreacted starting material 5b and the
methoxide addition product 7 (entry 1). Heating compound 5b in
a sealed tube at 100 °C (entry 2) led to an even lower yield of prod-
uct 6b. The reaction of compound 5b with NaH (0.5 equiv) in
refluxing THF, however, gave a good yield of product 6b (entry 3)
as a single diastereomer. Similar reaction of compound 5a with
NaH/THF (entry 4) also gave a good yield of product 6a, but as a
1:1 mixture of cis/trans isomers as determined by 1H NMR. Reac-
SPh
N
SPh
H
H
O
N
O
CO2Me
CO2Me
H
H
H
H
6c
6b
Figure 1. NOESY correlations of compounds 6b and 6c.

5554
S.-S.P. Chou, J.-L. Huang / Tetrahedron Letters 53 (2012) 5552–5554
E
E
H
In summary, we have successfully transformed the terminal al-
kenes 3a–c to the ,b-unsaturated esters 4a–c by cross metathesis
H
H
a
H
( )n
( )n
N
N
(CM). After detosylation the amides 5a–c can undergo the intramo-
lecular aza-Michael reaction to give sulfur-substituted bicyclic
compounds 6a–c, the stereoselectivity of which is determined by
the size of the newly formed ring. With simple transformations
we have also achieved the synthesis of indolizidine 167E from
compound 6a.
O
O
PhS
PhS
A
6b, 6c
E = CO2Me
n = 1, 2
H
H
Acknowledgements
H
H
E
E
( )n
( )n
N
N
Financial support by the National Science Council of the Repub-
lic of China (NSC 97-2113-M-030-001-MY3 and NSC 100-2113-M-
030-007) is gratefully acknowledged.
O
O
PhS
PhS
B
Scheme 4. Stereospecific formation of trans-6b and 6c.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2012.08.031.
SPh
SPh
N
SPh
N
LiAlH4 (3.5 eq), THF
H
H
H
N
O
O
O
−78 oC to −10 oC, 2.5 h
References and notes
CO2Me
OH
OH
8b (32%)
6a cis/trans (1 : 1)
8a (35%)
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Figure 2. X-ray crystal structure of compound 8a.
SPh
N
SPh
1) PBr3 (6 eq), ClCH2CH2Cl, reflux, 3 h
H
H
O
N
O
2) Bu3SnH (1.1eq), AIBN (0.4 eq)
Tol, reflux, 2 h
OH
8a
9 (62%)
1) MeMgBr (4 eq), THF
H
H
reflux, 5 h
Raney-Ni (20 eq)
N
O
N
95% EtOH
reflux, 2 h
2) AcOH, 0 oC, 10 min
3) NaBH4 (10 eq), MeOH
0 oC, 2 h
Indolizidine 167E
(59%)
10 (66%)
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Scheme 6. Synthesis of indolizidine 167E.
reduced the C@C bond to give product 10. Following a reported
procedure,13 the treatment of compound 10 with methylmagne-
sium bromide, followed by acidification with acetic acid, and
reduction with sodium borohydride, gave indolizidine 167E, which
was isolated from the venom of the ant Solenopsis (Diplorhoptrum)
conjurata.14 Only two syntheses of indolizidine 167E have been
reported.15
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