Contribution
Development of New Iodocyclization and Radical Cycloaddition Reaction
Lecturer Osamu Kitagawa
Professor Takeo Taguchi
Laboratory of Synthetic Organic Chemistry, School of Pharmacy
Tokyo University of Pharmacy and Life Science
1. Introduction
Alicyclic and N-heterocyclic compounds are basic structures that are often found in natural products, medical and
agricultural drugs as well as other functional materials.
Given their importance, there are already many reports
regarding the synthetic methods of these cyclic compounds,
such as the cyclization reactions. The importance of new
cyclization reactions lies in the novelty and exhibition of
high-selectivity, as well as the possibility of easy procurement and synthesis of cyclization precursors. It is difficult
to say if any of these reports about cyclization reaction meet
all of these criteria.
As new cyclization reactions, we have recently
succeeded in developing an iodocyclization
(halocyclization) reaction mediated by metallic reagents
and a radical [3+2] cycloaddition reaction using the
iodoalkylated three-membered ring compounds obtained
by our iodocyclization reaction (Scheme 1, Formulas 2 and
3). These reactions can be conducted using precursors
which can be readily synthesized in short steps to give
carbocyclic and N-heterocyclic compounds with high regioand stereo-selectivity. In this article we describe these
reactions which we have been working on for the last 10
years or so.
Halocyclization is a reaction whereby the intramolecular nucleophilic species (or group) attacks the carboncarbon double bond activated by electrophilic halogenating reagents to give cyclic compounds. This is widely used
for synthesizing heterocyclic compounds and
functionalization of alkenes. 1) The first report on
halocyclization reactions dates back to about 100 years
ago;2) however, there is almost no difference regarding the
reagents and the reaction conditions used in modern times
from those reported 100 years ago. The old and new
(Conventional halocyclization)
NuH
X
X2
NuH
Nu
X2
( )n
(1)
( )n
( )n
-HX
X2 = I2, Br2, NIS, NBS
NuH = COOH, OH, NHR
(Our halocyclization)
NuH
I
MLn, I2
Nu MLn-1
I2
( )n
Nu
(2)
( )n
( )n
"activation of nucleophile"
"control of selectivity"
MLn = metallic reagent
(Radical [3+2] cycloaddtion with iodoalkylated
three-membered ring compounds)
NuH
MLn, I2
Nu
Et3B
I
Nu
R
(3)
R
Nu
R
Nu
R
I
Nu
Scheme 1. Halocyclization and radical [3+2] cycloaddition.
methods simply involve adding the halogenating reagents
to the substrate or simultaneously adding a base such as
NaHCO3 in order to trap the generated hydrogen halide
(Scheme 1, Formula 1).
On the other hand, metallic reagents are now
indispensable reagents for developing new synthetic
reactions and manifesting selectivity. However, there have
been few report in which metallic reagents were effectively
used for halocyclization. This is caused by the fact that
halogenating reagents react readily with most metallic
reagents. We have focused our attention on the fact that
iodine can stably coexist with some metallic reagents, which
resulted in the successful development of an iodocyclization
reaction possessing excellent selectivity, hitherto unknown.
This is achieved by performing an iodocyclization reaction
in the presence of a certain type of metallic reagent
(Scheme 1, Formula 2). 3) We also found that iodomethyl
cyclopropane and iodoaziridine derivatives, obtained by
these reactions, can act as excellent precursors for
homoallyl radicals and azahomoallyl radicals respectively.
Thus we have succeeded in developing iodine atom
transfer type [3+2] cycloaddition reactions with various
alkenes (Scheme 1, Formula 3). The details of these
reactions are discussed below.
2. Iodocarbocyclization Reaction
As typified by halolactonization and haloaminocyclization, in the halocyclozation reactions the
intramolecular nucleophiles generally consist of hetero
atoms such as oxygen and nitrogen atoms (Scheme 1,
Formula 1). In contrast, the so-called ‘halocarbocyclization
reaction’ which involves carbon nucleophile, especially
carbanion, were not known. When carbanions are involved,
as indicated in Scheme 2, the direct halogenation of the
carbanion (Path b) precedes the halocarbocyclization (Path
a); therefore, halocarbocyclizations are difficult to realize.
In fact, even when a soft carbanion, such as 4-pentenylmalonate anion (prepared from 4-pentenylmalonate 1a and
potassium hydride) was used, no iodocarbocyclization
product was obtained at all from the reaction with NIS and
only α-iodomalonate was formed (Scheme 2).4)
2.1. Iodocarbocyclization Reaction of Alkenylated Malonates
We have found that, when a reaction between
4-pentenylmalonate 1a and iodine is conducted in the
presence of titanium alkoxide and copper oxide (II), αiodomalonate is not generated while iodocarbocyclization
product 2a is obtained in a high yield (83%) (Scheme 2). 5)
This reaction proceeds via the titanium enolate, as shown
in Scheme 3. In the absence of titanium alkoxide no
cyclized product 2a was formed. When copper oxide (II)
was not added, the yield of 2a slightly decreased to 74%.
These results indicate that the key to success in this
reaction is the use of a weak base such as titanium alkoxide,
while using a strong base would lead an α-iodination
reaction.
This reaction proceeds with complete regioselectivity
(5- exo -cyclization) and high stereospecificity ( transaddition). Thus, when ( E)- and (Z)-4-hexenylmalonate 1b
and 1c were used, the bicyclic lactones 3b and 3c having
three consecutive chiral centers were fomed in a highly
stereospecific manner through substitution reaction of the
primarily formed secondary iodide with ester carbonyl group
(Scheme 3). Furthermore, malonate (1d) also reacted with
complete selectivity to produce the bicylic compound 2d
having mode to give adjacent two quaternary carbons
(Scheme 3). In addition, the cyclization reaction of
allylmalonate 1e also proceeded with complete 3- exo iodomethylcyclopropane 2e in high yield (Scheme 3).6)
R2
R1
CO2Me
CO2Me
R1
CH2Cl2, rt
MeO
1b (R1 = Me, R2 = H)
1c (R1 = H, R2 = Me)
O
R2
H
MeI
R1
3b (96%, 3b/3c = 16)
3c (96%, 3b/3c = 1/48)
R2
Ti(Oi-Pr)4, I2
CO2Me
CH2Cl2, rt
H
1d
R
R'
( )n
(minor)
X2
path b
X2
CO2Me
X
CO2Me
CO2Me
R
R'
( )n
( )n
1a
CO2Me
1e
( )n
R
R'
1) Ti(Oi-Pr)4
CuO
2) I2
CO2Me
1) KH
2) NIS
Ti(Oi-Pr)4
I2, CuO
R'
X2
CO2Me
2a (83%)
X
( )n
(major)
I
R
R
R'
I
CO2Me
CO2Me
I
CO2Me
path a
O
Ti(Oi-Pr)n
O
MeO2C
CO2Me
1
I R
O
5-exo-cyclization
trans-addition
CO2Me
H
R2 OMe
I2
Ti(Oi-Pr)4
I2, CuO
CH2Cl2, rt
MeO2C
2d (77%)
CO2Me
I
2e (96%)
Scheme 3. Ti(OR) 4-mediated iodocarbocyclization of
various alkenylated malonates.
CO2Me
CO2Me
(90%)
Scheme 2. Halocarbocyclization and direct halogenation.
2.2. Catalytic Asymmetric Iodocarbocyclization Reaction
Based on the consideration of titanium enolate intermediate in the present reaction, we examined the
enantioselective iodocarbocyclization reaction mediated by
a variety of chiral titanium reagents. We considered that if
chiral titanium enolate intermediate is generated, the
enantiofacial differentiation of the alkene moiety would be
realized at the cyclization step. Consequently, in the presence of Ti(TADDOLate)2 complex the iodocarbocyclization
of various alkenylated malonates 1a, 1f and 1g proceeded
highly enantioselectively to give the products 2a, 2f and
2g, respectively.7) If 2,6-dimethoxypyridine (DMP) is added
as the hydrogen iodide scavenger, a high enantioselectivity
(>96% ee) was demonstrated even when a catalytic amount
(20 mol%) of Ti(TADDOLate)2 complex was used (Scheme
4).8) Without DMP, Ti(TADDOLate) 2 complex is decomposed by hydrogen iodide generated as the reaction
proceeds, resulting in a drastic decrease in both chemical
yield and optical purity of the product. These are the first
examples of catalytic asymmetric reaction in the field of
halocyclization reaction.
This catalytic asymmetric iodocarbocyclization reaction is also applicable to the enantiotopic group selective
reaction. For instance, when the iodocarbocyclization of
bisalkenylmalonate 1h is performed under the above
conditions, only one of the prochiral alkenes in malonate
1h reacted giving rise to the trisubstituted cyclopentane
derivative 2h with an extremely high enantio excess (99%
ee) (Scheme 4). The cyclized product 2h can be converted
to boschnialactone, an iridoid natural product, in high yield,
via the path indicated in Scheme 4.
2.3. Iodocarbocyclization Reaction of Various Alkenylated
Active Methines
The above-mentioned iodocarbocyclization reaction is
applicable only to alkenylated malonate. No products were
generated in the case of iodocarbocyclization of 4-pentenyl2-phosphonoacetate 1i and sulfonyl acetate 1j in the
presence of titanium alkoxide and iodine. It seems that this
is because the titanium enolates of 1i and 1j were not
generated under the above-mentioned conditions. We have
found that when titanium tetrachloride and triethylamine
are used, the titanium enolate is effectively generated from
a variety of alkenylated active methine compounds 1i-1l,
and that by subsequently adding iodine,
iodocarbocyclization products 2i-2l are obtained in good
yield (Scheme 5).9)
1) TiCl4, Et3N
2) I2
X
CO2Me
I2
O
CH2Cl2, rt
1i X = P(O)(OEt)2
1j X = PhSO2
1k X = CN
X
I
1) TiCl4, Et3N
P(O)(OEt)2 2) I2
(Enantiofacial selective reaction)
X
1l
CO2Me
Ti(TADDOLate)2 (0.2 eq)
I2 (4 eq), DMP (2 eq)
CO2Me
CH2Cl2-THF (4:1), -78 °C
1a X = CH2
1f X = CMe2
1g X = O
X
O O OH
Ti
O
O
O
"chiral Ti-enolate"
Ph
CO2Me
Me O
CO2Me
Me O
2a (87%, 98% ee)
2f (76%, 98% ee)
2g (60%, 96% ee)
CH2Cl2-THF (4:1), -78 °C
2
MeO
N
∆
CO2Me
I
2h
O
O
H
H
1) 1N NaOH
2) ∆, xylene
(96 %)
(75%)
HO
1) LiAlH4
2) NaH, BnBr
H
OBn
OBn
O
H
3h 80% (99% ee)
1) BH3/THF
2) Jones Oxi
3) H2/Pd-C
O
H
O
H
6
(98%)
H
4
1) TsCl, Py
2) NaI, Zn
O
EtO2C
P(O)(OEt)2
I
2l (78%, 2/1)
OMe
DMP (HI scavenger)
CO2Me
1h
MeO2C
+
Scheme 5. TiCl 4 -mediated iodocarbocyclization of
various alkenylated active methine compounds.
(Enantiotopic group selective reaction and its application to
synthesis of boschnialactone)
CO2Me
I
Ti
O
Ph
Ti(TADDOLate)2
Ti(TADDOLate)2 (0.2 eq)
I2 (4 eq), DMP (2 eq)
P(O)(OEt)2
Ph
O
Ph
CO2Me
EtO2C
2i (78%, 12/1)
2j (81%, 8.6/1)
CO2Me 2k (92%, 1.4/1)
X
+
OMe
MeO
I
X
I2
CH2Cl2, rt
TiCl3
I
X
CO2Me
CO2Et
OMe
(65%)
5
H
O
O
H
(+)-boschnialactone
Scheme 4. Catalytic asymmetric iodocarbocyclization
with chiral titanium alkoxide.
Interestingly, when the iodocarbocyclization reaction
was applied to alkynyled malonate 1m, inversed stereoselectivity was observed depending on the titanium reagent
used.9) When 1m was reacted with titanium alkoxide and
iodine, (E)-2m was obtained with high selectivity (E/Z =
28) through the iodocarbocyclization reaction (trans addition). When 1m was reacted with titanium tetrachloride, triethylamine, and iodine, the reaction proceeded
through an intramolecular carbotitanation of the the
titanium enolate to the alkyne (cis-addition) to generate the
(Z )-vinyl titanium intermediates which on subsequently
iodination gives (Z)-2m with complete stereoselectivity
(Scheme 6).
Therefore, when titanium tetrachloride is used, the
alkyne bond would be activated by the strong Lewis acidity
of the titanium atom of trichlorotitanium enolate intermediates to promote carbotitanation prior to the iodocarbocyclization.
3. Iodoaminocyclization Reaction
I
CO2Me
E-2m (84%, E/Z = 28)
CO2Me
I2
OMe
MeO
O
Ti(Oi-Pr)4, I2
CH2Cl2, rt
trans-addition
O
Ti(Oi-Pr)n
CO2Me
CO2Me
1m
TiCl3
1) TiCl4, Et3N
2) I2
CO2Me
CH2Cl2, rt
cis-addition
CO2Me
I
The iodoaminocyclization reaction has already been
reported 11) and thus it is not necessarily a novel reaction,
though some issues still remain to be solved. For instance,
N - or O-cyclization is possible with the substrates having
an ambident nucleophilic centers such as amide,
carbamate, and urea. In these cases, N-cyclization has not
been prevalent. Furthermore, haloaminocyclization to form
the three-membered aziridine ring, i.e., haloaziridination
reaction, has never been reported. We have succeeded in
developing a method for N-selective cyclization of ambident
nucleophiles including the haloaziridination reaction.
CO2Me
Z-2m (79%, Z only)
CO2Me
Scheme 6. Iodocarbocyclization and intermolecular
carbotitanation of alkynylated malonates.
Furthermore, we examined iodocarbocyclization of
difluoroalkenylated malonates and obtained satisfactory
results by using tin tetrachloride and triethylamine.10) Which
a 5- endo cyclization product 2n was obtained from
reaction of 4,4-difluoro-3-butenylmalonate 1n, and a 5-exo
cyclization product 2o was obtained as the principal
component from reaction of 5,5-difluoro-4-pentenyl
malonate 1o (Scheme 7), which was similar to the reaction
of the non-fluorinated substrate 1a. The
iodocarbocyclization reaction of 3-butenylmalonate, a nonfluorinated counter part of 1n, was examined under
various conditions; however, no cyclized product could be
isolated. Therefore, it is evident that the endo-cyclization
selectivity of 1n is caused by the effect of the fluorine
substituent.
F
F
CO2Me
CO2Me
( )n
1) SnCl4, Et3N
2) I2
1o (n=2)
It is well known, that in the halocyclization reactions of
alkenylated amide, carbamate, and urea derivatives, Ocyclization is preferred to N -cyclization. This is readily
understood in terms of the HSAB theory as shown in
Scheme 8. We have found that the iodocyclization
reaction of an ambident nucleophile proceeds with a
complete N-cyclization selectivity when mediated by a
lithium reagent. 12) For instance, the iodocyclization
reaction of N-allylurea 7a gave only O-cyclized product 8a'
under normal conditions using sodium bicarbonate
(I2 -NaHCO3), while a reaction using n-BuLi or LiAl(Ot-Bu)4
gave N -cyclization product 8a with almost complete
selectivity (Scheme 8). Although the effect of lithium
reagents on the N -cyclization selectivity have not been
clear, we have shown that this selectivity was greatly influenced by the metallic reagent used. When sodium hydride
was used, a mixture of N-cyclization product 8a and Ocyclization product 8a ' was obtained.
I
F
CH2Cl2, rt
MeO2C
1n (n=1)
3.1. N-Selective Iodoaminocyclization Reaction of
Alkenylted Amide, Carbamate, and Urea Derivatives
or
F
CO2Me
MeO2C
CO2Me
2n (5-endo, 70%)
2o (5-exo, 58%)
X
O
( )n
NR
Y
NHR N-cyclization X
O-cyclization
X2 ( )n
Y
(major)
Scheme 7. Iodocarbocyclization of difluoroalkenylated
malonates.
7a
NR
( )n
Y
O
1) Additive
2) I2
I
NCO2Et
N
H
O
Additive
NaHCO3
NaH
n-BuLi
LiAl(Ot-Bu)4
O
8a (N-cyclization)
O
(minor)
hard
nucleophile
NHCO2Et
N
H
As shown above, the iodocarbocyclization reaction
developed by us is applicable to various alkenylated and
alkynylated active methine compounds. The reaction
proceeds with complete regioselectivity and with high
stereoselectivity. Furthermore, the cyclization precursor (1)
can be synthesized in a short steps in a satisfactory yield,
by means of an alkylation reaction of active methylene
compounds.
soft
nucleophile
hard
electrophile
CF2I
I
O
+
N
H
NCO2Et
8a' (O-cyclization)
0%
45%
77%
21%
88%
trace
88%
0%
Scheme 8. Halocyclization of ambident nucleophile.
An iodoaminocyclization reaction that uses a lithium
reagent is applicable to various alkenylated urea,
carbamate, and amide derivatives 7a-7f and in all cases,
N-cyclized products 8 were exclusively obtained in satisfactory yield and with complete selectivity (Scheme 9).
Furthermore, this reaction is applicable not only to form
five-membered ring cpmpounds, but also to form sixmembered rings, as in the cases of 7b and 7e (n=2).
Fukuyama et al. recently reported that this reaction is also
useful for the construction of the nitrogen-containing quaternary center.13)
The cyclization substrates for this reaction, alkenylated
urea, carbamate, and amide derivatives 7, can be readily
synthesized by reactions of commercially available N alkoxycarbonylisocyanates with alkenyl alcohols,
alkenylamines, and alkenylmagnesium reagents.
( )n
Y
7
NHCO2R
O
1) LiAl(Ot-Bu)4
2) I2
toluene, 0 °C
"complete
N-selectivity"
7b (Y = NH, R = Et, n = 2)
7c (Y = O, R = Et, n = 1)
7d (Y = O, R = t-Bu, n = 1)
7e (Y = O, R = Et, n =2)
7f (Y = CH2, R = Et, n = 1)
I
( )n
Y
NCO2R
O
8 (62-88 %)
Y = O, NR, CH2
R = Et, Bn, t-Bu
n = 1, 2
I2, NBS or NIS
no reaction
NHTs
9a
1)Additive
2) I2
TsN
I
10a
Yield
53%
81%
94%
Additive
n-BuLi
NaH
t-BuOK
Scheme 10. Additive effect in iodoaziridination reaction.
Iodoaziridination reaction using t-BuOK and iodine was
applied to various N-allyltosylamide derivatives 9a-9e, to
give the products 10a-10e in satisfactory yield. The reactions proceeded with complete regioselectivity (3- exo cyclization) and stereoselectivity (trans-addition). Moreover,
reactions of N-cycloalkenyltosylamide such as 9f and 9g
also proceeded in satisfactory yield to afford the bicyclic
iodoaziridine 10f and 10g.
8b (86%)
8c (85%)
8d (68%)
8e (73%)
8f (69%)
R3
R1
Scheme 9. Regio-controlled iodoaminocyclization of
ambident nucleophile mediated by lithium reagent.
NHTs
9
I2
toluene
R3
R1
1
R2
"3-exo-cyclization"
"trans-addition"
NHTs t-BuOK (1 equiv)
I2 (3 equiv)
( )n
TsN
R
toluene
R2
9b (R1 = R2 = H, R3 = Me)
9c (R1 = R2 =Me, R3 = H)
9d (R1 = Me, R2 = R3 = H)
9e (R1 = R3 = H, R2 = Me)
3.2. Iodoaziridination Reaction of N-Allyltosylamide
Derivatives
Ts 3
K N R
1) t-BuOK (1 equiv)
2) I2 (3 equiv)
R2
10
I
10b (90%)
10c (74%)
10d (80%)
10e (88%)
NTs
( )n
10f (n = 1, 92%)
10g (n = 2, 63%)
I
9f (n = 1), 9g (n = 2)
For the three-membered ring-forming reaction using
halocyclization, there is one report on halo epoxidation
reaction of allyl alcohol derivative.14) However, only limited
substrates gave the products in satisfactory yield. As
described above, we found that in the iodocarbocyclization
reaction of allylated active methine compounds 1e and 1l,
the iodomethylcyclopropane derivatives 2e and 2l were
obtained in good yield (Schemes 3 and 5). This result
indicates that a three-membered ring-forming reaction
using halocyclization would be feasible. With this in mind,
we examined the three-membered haloaminocyclization reactions (haloaziridination reactions), which had not been
previously reported.
As shown in Scheme 10, with N-allyltosylamide 9a
occured no reaction when just treating with the halogenati n g re agent . O n t h e o th e r h a n d , w e fo u n d t hat
iodomethylaziridine 10a was obtained in satisfactory yield
when this reaction was run in the presence of an alkali
metal reagent and iodine. 15) For the metallic reagent,
t-BuOK was the most effective, giving 10a in 94% yield.
Scheme 11. Iodoaziridination of various N-allyltosylamides.
Next, we would like to report radical [3+2] cycloaddition reaction using iodoalkylated three-membered ring compounds 2e and 10, which were synthesized in the manner
described above.
4. Radical [3+2] Cycloaddition Reaction Using
Iodomethylcyclopropane Derivatives
The radical [3+2] cycloaddition reaction of homoallyl
radicals with alkenes, is useful for the one-step synthesis
of cyclopentane compounds, and many reports dealing this
reaction have been appeared (Scheme 12).16) The usual
homoallyl radical is a nucleophilic radical, which reacts with
electron-deficient alkenes such as α,β-unsaturated carbonyl compounds (Scheme 12). In contrast, allyl substituted
active methine radicals are known as electrophilic homoallyl
radicals, and these are synthetically very useful because
they can react with enol ether and simple alkyl substituted
alkenes. Meanwhile, the vinylcyclopropane derivative Ι17)
and iodomalonate ΙΙ 18), the precursors of the allylated
active methine radicals so far reported, possess an
alkene part and therefore, the generated allyl activated
methine radical possibly attacks the alkene group of other
radical precursor molecule, which is an undesired side
reaction (Scheme 12). In order to avoid these side
reactions, a large excess amount of alkene must be used
or an alkene with high reactivity must be used. However,
these are not always definite solutions.
R
E1
"electron-defficient
alkenes"
"simple
alkenes"
E2
2
E
"electrophilic
radical"
"nucleophilic
radical"
E1 = E2 = electronwithdrawing group
(Possible side reaction in the
reaction with I or II)
(Known allylated active methine
radical precursors)
R
E
E
I
E
E
E
E
I
E
E
or
E
II
I
The radical cycloaddition reactions of the
iodomethylcyclopropane 2e with a variety of alkenes
provided satisfactory results (Scheme 14). 19) For instance,
when the reaction between 2e and silylenol ether was
conducted using triethylborane as a radical initiator, we
obtained the iodine atom transfer cycloaddition product 11a
in high yield (79%). On the other hand, the reaction with
alkyl-substituted alkene such as 1-hexene required the
presence of Yb(OTf)3 in addition to triethylborane; without
Yb(OTf) 3 , the yield dropped significantly to 22%. It was
considered that Yb(OTf)3 enhances the electrophilicity of
the allylmalonate radical and promotes the reaction by
forming a chelated complex with the malonate carbonyl
group. This reaction is applicable to a variety of alkenes. It
is worth noting that even a 1,2-disubstituted alkene, which
is generally unreactive by conventional methods because
of the low reactivity can undergo the cycloaddition reaction
in a satisfactory yield. For instance, bicyclo[3.3.0]octane
derivative 11d was obtained in a yield of 70% from the
reaction with cyclopentene (Scheme 14). Furthermore, at
a low temperature (0 °C and below), higher stereoselectivity
was observed in the reactions with alkyl-substituted
alkenes, when compared with that by conventional
methods.
(E = CO2R, CN)
I
E
E
E
II
E
E
CH2Cl2, 0 °C
2e (E = CO2Me)
E
E
I
radical
initiator
E
E
R
E
E
2e (E = CO2Me)
R
R
E
E
E
E
R
I
E
E
11
Scheme 13. Radical iodine atom transfer [3+2] cycloaddition with iodomethylcyclopropane.
R2
E
E
11
cis/trans Yield
Products 11
11a (R1= OH, R2= H)
1/1.8
1-hexene
11b (R1=H, R2=n-Bu)
8.8
22%
1-hexene
Yb(OTf)3 11b (R1=H, R2=n-Bu)
11.2
82%
methylene
cyclohexane
Yb(OTf)3 11c (R1=R2= -(CH2)5-)
CH2=CHOTMS
We considered that iodomethylcyclopropane-1,1dicarboxylate 2e, which can readily be synthesized by the
above-mentioned iodocarbocyclization of allylmalonate 1e
(Scheme 3), could be an efficient allylated active methine
radical precursor. We anticipated that when 2e is treated
with a radical initiator, the allylmalonate radical would be
generated through regioselective cleavage of the
cyclopropylmethyl radical. The resulting allyl radical is
expected to undergo an iodine atom transfer [3+2] cycloaddition reaction with an alkene (Scheme 13). In this
manner, 2e was assumed to be an allylated active methine
radical precursors with alkene moiety protected.
(2 eq)
Additive
Alkenes
I
+
I
Scheme 12. [3+2] Cycloaddition with homoallyl radical
species.
R1
Et3B
Additive
R2
R1
Et3B
Yb(OTf)3
2e
+
CH2Cl2, 0 °C
(5 eq)
I
E
79%
88%
H
E H
11d (E=CO2Me)
70% (single stereoisomer)
Scheme 14. Radical [3+2] cycloaddition of 2e with
various alkenes.
A cascade reactions could be performed when the
cycloaddition reaction of 2e is conducted with 1,4-diene
derivative. This involves three separate carbon-carbon bond
formation, that is, the initial [3+2] cycloaddition reaction is
followed by a 5-exo cyclization, which produces the bicyclo
[3.3.0]octane derivative 11 in one step (Scheme 15).20)
A complete regioselectivity was observed in the reaction of
2e with an unsymmetrical 1,4-diene derivative (R≠H).
For instance, in the reaction with 1,4-hexadiene (R=Me),
the initial reaction by the allylmalonate radical occurred
exclusively at the most reactive 1-alkene position.
Products derived from the initial attack of the active methine
radical at the 1,2-disubstituted alkene moiety were not
detected. Consequently, we established that radical
cycloaddition using 2e provides a useful one-step synthetic
method not only for cyclopentane ring formation but also
for bicyclo[3.3.0]octane ring formation.
N
"nucleophilic"
"homoallyl radical"
S
N
O
O
"azahomoallyl radical"
t-BuSH
OEt H+, hν
+
N
R
"electrophilic"
"less reactive"
R
R
(100 eq)
N
E
I
Et3B
Yb(OTf)3
R
+
OEt
N
R
H
R=C7H15, (56%)
Newcomb et al (1990)
R
E
H3C
OEt
Scheme 16. [3+2] Cycloaddition with azahomoallyl
radical species.
CH2Cl2, 0 °C
2e (E = CO2Me)
E
E
H
H
I
E
E
H
R
DBU
E
E
R
H
11e (R=H) 78%, 11f (R=Me) 75%
Scheme 15. Radical cascade cycloaddition of
iodomethylcyclopropane with 1,4-dienes.
5. Radical [3+2] Cycloaddition Reaction Using
Iodoaziridine Derivatives
Next, we would like to describe the radical [3+2]
cycloaddition reaction using the iodoaziridine derivative 10
(Scheme 17). This reaction is similar to the reactions using
iodoalkylcyclopropanes. The [3+2] cycloaddition reaction
of azahomoallyl radicals (2-alkenylamine radical) with
alkenes, provides a one-step synthetic route to pyrrolidine
derivatives. In contrast to a number of examples with
homoallyl radicals, only one report by Newcomb et al. has
described such a reaction (Scheme 16),21) in which there
remained various issues, such as:
We anticipated that iodoaziridine derivatives would be
efficient azahomoallyl radical precursors. Furthermore,
these precursors could be readily synthesized by the abovementioned iodocarbocyclization of N -allyltosylamide
derivatives. When iodoaziridine 10a is treated with
triethylborane, the allylamidyl radical should be generated
through regioselective cleavage of the initially generated
aziridinylmethyl radical. The subsequent [3+2] cycloaddition reaction might proceed in the presence of alkenes to
give the pyrrolidine derivatives. The nitrogen radical is an
electrophilic radical (Scheme 16) whose reactivity is known
to improve as the electron density is decreased (Scheme
17). Therefore, the tosylamidyl radical generated from 10a
was also expected to possess higher reactivity toward
alkenes than the usual aminyl radical.
Ts
N
Most of the reactions between nitrogen radicals and
alkenes, are limited to intramolecular 5-exo cyclization,
which is due to entropy effects. 22) Only a few examples
regarding intermolecular versions were reported because
the reactivity of the nitrogen radical is known to be
significantly lower than that of the carbon radical. Furthermore, efficient nitrogen radical precursors have not been
developed.
R
Ts
N
TsN
10a
R
R
N
Ts
(more reactive)
>
R
N
R
I
N
Ts
N
Ts
TsN
R
1) A large excess of alkene (100 equiv) was required, and
the yield was only 50-59%.
2) Only three examples using enol ether derivatives, a
sole structural variant, were shown and thus, the
application and limitation of the reaction remain
unclear.
3) A Brønsted acid was required in order to generate an
allylamminium radical, which is more reactive species.
radical
initiator
I
R'
(less reactive)
<
12
R
R'
N
H
(more reactive)
Scheme 17. Radical iodine atom transfer [3+2] cycloaddition with iodoaziridine.
First, we examined reactions between iodoaziridine 10a
and various alkenes (Scheme 18). Reactions with enol ether
and ketene acetal were conducted in the presence of
triethylborane, and both resulted in cycloaddition products
12a-12c in high yield (62-71%). 23,24) As initially anticipated,
the reactivity of N-allyl(tosyl)amidyl radical generated from
this reaction was relatively high and the reactions
proceeded effectively, even in the presence of only twoequivalent of alkenes. Next, we examined the reaction with
alkyl-substituted alkenes, which produced lower yields,
compared to enol ether derivative (Scheme 18). As
mentioned above, the nitrogen radical is an electrophilic
radical, and therefore, its reactivity with an alkene is
decreased as the electron density of the alkene declines.
This was the case in the reaction of 10a with 1-hexene
where the yield was only 34% (12e). The stereoselectivity
in reactions of allylamidyl radical and alkenes was
generally low, and this issue remains to be solved.
R1
Ts
N
R1
I
R2
+
(2 eq)
10a
Alkenes
I
Et3B
R2
N
Ts
C6H6, rt
12
cis/trans
Products 12
CH2=CHOTMS
12a (R1= OH, R2= H)
CH2=C(Me)OMe
12b (R1=Me, R2=OMe)
CH2=C-O(CH2)4O-
12c (R1=R2= -O(CH2)4O-)
methylene
cyclohexane
12d (R1=R2= -(CH2)5-)
1-hexene
12e (R1=H, R2=n-Bu)
Yield
1.3
66%
1/1.7
71%
a
6. Conclusion
As described above, we have succeeded in developing new iodocyclization reactions mediated by metallic
reagents. Furthermore, we have succeeded in developing
a [3+2] cycloaddition reaction using the iodoaziridine as
the radical precursor. The reactions proceed with high
regioselectivity and stereoselectivity using readily
synthesized precursors. Therefore, these are useful
synthetic method of carbocyclic compounds and nitrogen
heterocyclic compounds.
This research was enabled by the efforts made by our
co-researchers appeared in the References section below
and we would like to express our sincere gratitude to them.
We would also like to thank the Ministry of Education for
funding this research and for the Japan Society for the
Promotion of Science for supporting our research.
62%
56%
2.1
34%
a single stereoisomer
Scheme 18. Radical [3+2] cycloaddition of 10a with
various alkenes.
On the other hand, a reaction between a bicyclic
iodoaziridine 10f (n=1), 10g (n=2), and a ketene acetal
proceeded with almost complete stereoselectivity and gave
the bicyclic pyrrolidine derivatives 12f and 12g (Scheme
19). Since the octahydro-indole ring system is a basic
structure that is often found in bioactive natural alkaloids,
we examined asymmetric synthesis of 12g. We conducted
a reaction of the optically active iodoaziridine (+)-10g (94%
ee) with the ketene acetal, which proceeded without
racemization to yield (+)-12g with 93% ee. We are
currently examining the synthesis of octahydro-indole
natural products using optically active (+)-12g.
+
( )n
H Ts
N
TsN
NTs
O
O
Et3B
C6H6, rt
I
O
( )n
O
O
( )n
I
HO
(2 eq)
10f (n=1)
10g (n=2)
(+)-10g (n=2, 94%ee)
"complete
stereoselectivity"
12f (64%)
12g (59%)
(+)-12g (61%, 93%ee)
Scheme 19. Radical [3+2] cycloaddition with bicyclic
iodoaziridines.
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About the Authors:
Osamu Kitagawa, Lecturer
at School of Pharmacy, Tokyo University of Pharmacy and Life Science
[Personal History]
1984 Graduated from Tokyo University of Pharmacy and Life Science.
1989 Completed a Ph.D. at Tokyo University of Pharmacy and Life Science and assumed a position as an
assistant lecturer at the same university.
1993-1994 Post-Doctoral Researcher at University of Kansas.
1995 Assumed current position.
[Expertise]
Synthetic organic chemistry.
Takeo Taguchi, Professor
at School of Pharmacy, Tokyo University of Pharmacy and Life Science
[Personal History]
1969 Graduated from Department of Chemistry, Faculty of Science, Tokyo Institute of Technology.
1974 Completed a Ph.D. at Tokyo Institute of Technology and assumed a position as an assistant lecturer
at the same university.
1976 Lecturer at the School of Pharmacy, Tokyo University of Pharmacy and Life Science
1981 Post-Doctoral Researcher at UCLA.
1989 Assumed current position.
[Expertise]
Synthetic organic chemistry, organic fluorine chemistry.