Stereoselectivity in intramolecular cyclization of non-conjugated unsaturated ketones by electroreduction

Article abstract of DOI:10.1246/cl.2002.1254

This study showed some decrease in stereoselectivity in electroreductive intramolecular cyclization of nitrogen-containing non-conjugated enones in comparison with high stereoselectivity for the corresponding enones possessing an all-carbon-chain or a sulfur-containing chain. This phenomenon may provide some actual experimental supports for the remarkable stereochemical features of the electroreductive cyclization.

Full text of DOI:10.1246/cl.2002.1254

1254
Chemistry Letters 2002
Stereoselectivity in Intramolecular Cyclization of Non-conjugated
Unsaturated Ketones by Electroreduction
Ikuzo Nishiguchi,Ã Satoshi Goda, Kouji Yamada, Yoshimasa Yamamoto, and Hirofumi Maekawa
Department of Chemistry, Nagaoka University of Technology, 1603-1, Kamitomioka-cho, Nagaoka, Niigata 940-2188
(Received September 17, 2002; CL-020794)
This study showed some decrease in stereoselectivity in
synthetic intermediates of a variety of biologically active
compounds,5 as shown in Scheme 1.
electroreductive intramolecular cyclization of nitrogen-contain-
ing non-conjugated enones in comparison with high stereose-
lectivity for the corresponding enones possessing an all-carbon-
chain ora sulfur-containing chain. This phenomenon mayprovide
some actual experimental supports for the remarkable stereo-
chemical features of the electroreductive cyclization.
Electroreduction of a series of heteroatom-containing non-
conjugated unsaturated ketones (1)–(3) was generally carried out
in a mixed solvent of methanol and 1,4-dioxane (or tetrahy-
drofuran) containing tetraethylammonium p-toluenesulfonate
(Et4NOTs) as a supporting electrolyte at ambient temperature
(15–30 ꢀC) under constant-current conditions (current density:
10 mA/cm2) using an undivided cell equipped with aluminum
plates6 as the anode and the cathode after 10 F/mole of electricity
passed through the system.
Electroreduction of sulfur-containing non-conjugated en-
ones, 3-allylthio ketones (1), brought about intramolecular
cyclization to give the corresponding cis-3,4-dialkylthiacycloal-
kan-4-ols (4)7 exclusively in 57–40% yields (Table 1).
It was reported that electroreductive intramolecular coupling
of non-conjugated enones brought about stereoselective 5-exo- or
6-exo-cyclization to give cis-1,2-dialkylcycloalkanols exclu-
sively in good to excellent yields (Scheme 1).1 Although this
electrochemical intramolecular cyclization may be quite inter-
esting and useful in organic synthesis because of excellent yield,
high regio- and stereoselectivity, and mild conditions, and many
applications have been accomplished,2{4 high cis-dialkyl stereo-
chemistry has been elucidated only by a speculated hypothesis
without any experimental supports.1b
Table 1. Electroreduction of Sulfur-Containing Non-conjugated Enones
R2
O
R2
OH
R1
R1
R2
OH
R1
S
+e
+
R1
R3
R3
Et4NOTs
MeOH / 1,4-Dioxane
R3
CH2R1
S
S
OH
1
4
O
7
+e
Yield 68~98 %
(cis > 99 %)
Entry
R1
R2
R3
Yield 4/%a
Yield 7/%a
R2
Et4NOTs / DMF
R2
1
2
H
H
H
H
Me
Et
57
40
1
8
R2
O
R2
OH
R1
R1
S
aGC yield.
+e
Et4NOTs
MeOH / 1,4-Dioxane
R3
R3
Yield 57~40 %
cis > 99 %
This electroreductive intramolecular cyclization is also
applicable to non-conjugated enones, 2-(N-allylamino) ketones
(2) and 3-(N-allylamino) ketones (3), that contain an amino
nitrogen atom in the main chain between the carbonyl groupand
the olefinic moiety, giving the corresponding pyrrolidine (5)7 and
piperidine derivatives (6)7 as the main products in moderate
yields. However, the stereoselectivity of this intramolecular
cyclization decreased to some extent in comparison with the case
of carbon and sulfur analogues (Table 2).
S
4
1
R1
R1
R2
5 (n=1) :
Yield 76~59 %
cis : trans
R2
+e
Et4NOTs
MeOH / 1,4-Dioxane
OH
R3
O
n
80 : 20 ~ 52 : 48
N
N
Bn
R3
n
Bn
6(n=2) :
Yield 63~46 %
cis : trans
76 : 24 ~ 75 : 25
2
(n=1)
(n=2)
3
Introduction of a variety of substituents on the nitrogen atom
of N-containing non-conjugated enones provided interesting
information for some decrease in stereoselectivity in the
electroreduction of 2 and 3. As shown in Table 3, sterically
bulky groups did not give any difference in stereoselectivity while
introduction of electron-withdrawing groups such as acetyl and
benzyloxycarboxy groups brought about distinctive effect in
stereoselectivity of the electroreductive cyclization (Table 3).
In the previously proposed mechanism,1b the first electron
transfer from cathode to the carbonyl groupof the substrates
generated the corresponding anion radical species, which
subsequently interacted with the olefinic moiety. In the cyclized
intermediate, which was formed by the interaction of the anion
radical with the inner carbon atom of the C–C double bond
Scheme 1.
In this study, we wish to report the effects of a heteroatom
such as a nitrogen or a sulfur atom on the stereoselectivity in
electroreductive cyclization of non-conjugated enones containing
the heteroatom between an olefinic moiety and a carbonyl group,
providing some actual experimental supports for the high
stereoselectivity. Thus, electroreduction of 3-(allylthio) ketones
(1), 2-(N-allylamino) ketones (2), and 3-(N-allylamino) ketones
(3) led to selective intramolecular cyclization to give the
corresponding heteroatom-containing cyclic alcohols, 4-hydro-
xytetrahydrothiopyrans (4), 3-hydroxypyrrolidines (5), 4-hydro-
xypiperidine (6), as the main products, respectively, in moderate
to excellent yields, which may be expected to be useful as
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
1255
Table 2. Electroreductive Cyclization of N-Containing Non-conjugated
Enones
selectivity because it may decrease the electron density of a lone
pair of the nitrogen atom to provide some decrease in the
electronic disturbance (Scheme 3).
R1
R1
R2
R2
Repulsion
more
R1
+e
R1
δ
Repulsion
OH
R3
O
n
cis / trans
76 / 24
Lower
δ
OH
R2
Et4NOTs
MeOH / 1,4-Dioxane
N
O
+e
N
R3
+2H+
n
Bn
R2
Bn
N
N
5(n=1), 6(n=2)
Stereoselectivity
2(n=1) ,3(n=2)
Bn
Bn
Entry
R1
R2
R3
n
Yield/%a
cis : trans
less
Repulsion
Repulsion
R1
R1
δ
1
2
3
4
5
6
H
H
H
Me
Me
H
Me
Me
Me
tBu
Me
Et
1
1
1
1
2
2
76
69
69
59
63
46
70 : 30
74 : 26
80 : 20
52 : 48
76 : 24
75 : 25
OH
R2
δ
cis / trans
81~80 / 19~20
Higher
+e
O
Me
H
+2H+
R2
N
N
EWG
H
H
EWG
Stereoselectivity
EWG=COCH3 or
COOCH2C6H5
H
H
aGC yield.
Scheme 3.
Table 3. Effect of Substituents on the Nitrogen Atom of N-Containng
Enones
Electroreductive cyclization of the sulfur-containing non-
conjugated enones gives the higher stereoselectivity in contrast
with the lower stereoselectivity in that of the nitrogen analogues.
This difference may be explained by bond length between the
carbon atom and the heteroatom. That is, the bond length between
+e
Et4NOTs
MeOH / 1,4-Dioxane
OH
Me
O
N
N
n
Me
R
n
R
ꢀ
the carbon atom and sulfur atom is 1.81–1.83 A and that between
Entry
R
n
Conv./%
Yield/%a
cis/trans
8
ꢀ
the carbon atom and nitrogen atom is 1.45–1.46 A. This means
1
2
3
4
5
6
PhCH2
n-Bu
1-Ethylpropyl
1
1
1
2
2
2
83
87
89
76
67
69
70/30
73/27
73/27
that a lone pair electron of sulfur is much more remote to the
cyclized center than that of nitrogen, giving little electronic
disturbance.
As a conclusion, the decrease in stereoselectivity caused by
the presence of a nitrogen atom in a main chain of non-conjugated
enones may be also a strong support for our initial proposal
concerning high stereoselectivity in their electroreductive
cyclization.
H
Ac
Complex Mixture
88
90
53
55
80/20
81/19
Cbz
aGC yield.
through a radical-type of cyclization, both the oxygen atom and
the terminal carbon atom of the C–C double bond possessed some
negative charges, which kept both moieties away from each other.
As the result, the stereochemistry of two alkyl groups on the ring
was formed with cis configuration selectively. However, the
stereoselectivity of the present electroreductive cyclization
leading to the pyrrolidine and piperidine derivatives decreased
to 52–80% vs 48–20% for cis vs trans configuration (Scheme 2).
This work was partially supported by Grants-in-Aid
(No.14044031) and The 21 Century COE Program for Scientific
Research from Ministry of Education, Culture, Sports, Science
and Technology, Japan.
References and Notes
1
a) T. Shono and M. Mitani, J. Am. Chem. Soc., 93, 5284 (1971). b) T. Shono,
I. Nishiguchi, H. Ohmizu, and M. Mitani, J. Am. Chem. Soc., 100, 545
(1978).
R1 R2
O
R1
R1
R1 R2
O
R2
O-
R2
2
For related studies, see: a) J. E. Swartz, T. J. Mahachi, and E. Kariv-Miller, J.
Am. Chem. Soc., 110, 3622 (1988). b) J. E. Swartz, E. Kariv-Miller, and S. J.
Harrold, J. Am. Chem. Soc., 111, 1211 (1989). c) F. Lombardo, R. A.
Newmark, and E. Kariv-Miller, J. Org. Chem., 56, 2411 (1991). d) S.
Kashimura, M. Ishifune, Y. Murai, N. Moriyoshi, and T. Shono, Tetrahedron
Lett., 36, 5029 (1980).
OH
+e
+e
X
+2H+
X
R3
R3
X
X
R3
R3
n
n
n
n
n=1 or 2 R1,R2,R3 = Alkyl Group
3
4
For electroreductive intramolecular cyclization between a keto groupand an
acetylenic or an allenic bond, see: a) T. Shono, I. Nishiguchi, and H. Ohmizu,
Chem. Lett., 1976, 1233. b) G. Pattenden and G. M. Robertson, Tetrahedron
Lett., 24, 4617 (1983).
For electroreductive intramolecular coupling of an ester with an alkene, see:
S. Kashimura, Y. Murai, M. Ishifune, M. Masuda, M. Shinomura, H. Murase,
and T. Shono, Acta Chem. Scand., 53, 949 (1999).
D. J. Robins, ‘‘Rodd’s Chemistry of Carbon Compounds,’’ ed. by M. Ansell
Supplement to Vol. IVB, Elsevier, Amsterdam (1985), pp 1–68.
The similar electroreduction of nitrogen-containing non-conjugated enone
(2) using various metals other than Al as the electrodes was found to give the
product (5) in the following yields: Carbon (8%), Zn (7%), Sus (0%), and Pt
(0%).
All of the products in this study were identified by a variety of spectroscopic
methods (1H NMR, 13C NMR, IR, MASS) and elemental analysis.
‘‘Kagaku Binran (Chemical Encyclopedia),’’ 4th ed., Basic Ver. II, ed. by
The Chemical Society of Japan, Maruzen, Tokyo (1993), pp 622–655.
Y= Bn, Ac, Boc
Scheme 2.
X=CH2, S, N-Y
The following explanation may figure out why nitrogen-
containing non-conjugated enones give the less stereoselectivity.
We propose that the lone pair electron of the nitrogen atom of the
nitrogen-containing non-conjugated enones may make some
disturbance of the electronic repulsion between the oxygen atom
and the terminal carbon atom of the C–C double bond to result in
some decrease in the stereoselectivity. As the strong support of
this hypothesis, the introduction of an electron-withdrawing
groupon the nitrogen atom such as an acetyl groupor a
benzyloxycarbonyl groupbrings about some increase in stereo-
5
6
7
8