Novel intramolecular [4 + 1] and [4 + 2] annulation reactions employing cascade radical cyclizations

Article abstract of DOI:10.1021/jo0258397

Tributyltin hydride and tris(trimethylsilyl)silane promote sequential/cascade free radical cyclization reactions of dienoate tethered vinyliodides or alkynes. These processes produce [4 + 1] and [4 + 2] annulated products. In contrast, the electrochemical reductions of the vinyliodides afford monocyclic compounds. Both the regiochemical and stereochemical courses of the sequential radical cyclizations strongly depend on substrate structure. Especially important is the balance between steric and stereoelectronic (Baldwin's rules) factors that serve to control cyclization regiochemistry.

Full text of DOI:10.1021/jo0258397

Novel In tr a m olecu la r [4 + 1] a n d [4 + 2] An n u la tion Rea ction s
Em p loyin g Ca sca d e Ra d ica l Cycliza tion s
Kiyosei Takasu,* Hiroshi Ohsato, J un-ichi Kuroyanagi, and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University,
Aobayama, Sendai 980-8578, J apan
mihara@mail.pharm.tohoku.ac.jp
Received April 18, 2002
Tributyltin hydride and tris(trimethylsilyl)silane promote sequential/cascade free radical cyclization
reactions of dienoate tethered vinyliodides or alkynes. These processes produce [4 + 1] and [4 + 2]
annulated products. In contrast, the electrochemical reductions of the vinyliodides afford monocyclic
compounds. Both the regiochemical and stereochemical courses of the sequential radical cyclizations
strongly depend on substrate structure. Especially important is the balance between steric and
stereoelectronic (Baldwin’s rules) factors that serve to control cyclization regiochemistry.
In tr od u ction
Formation of bi- and polycyclic structures from acyclic
polyene precursors is a fundamentally important strategy
used by synthetic organic chemists. Intramolecular cy-
cloaddition reactions are perhaps the most common
processes in this broad family.1 Particularly illustrative
of this family are Diels-Alder reactions, which have been
fully explored and utilized as key elements in the
synthesis of complex natural products.2 Recently, several
new annulation reactions of acyclic polyenes, based on
transition metal catalyzed processes, have been devel-
oped.3 These methods bring about annulation reactions
that correspond to [m + n], and [l + m + n] cycloaddi-
tions.
Recently, cascade or domino reactions have shown
great utility as attractive and highly effective methods
to prepare polycyclic ring systems in one step from acyclic
precursors.4,5 Examples of this are found in the cascade-
type, intramolecular double Michael and Michael-aldol
reactions, which serve as efficient annulation processes.6
F IGURE 1. Typical cascade reaction (left), boomerang-type
cascade reaction (right), and the concept of present study.
In these reactions, nucleophilic functions in the sub-
strates are changed to electrophilic centers following the
initial reaction steps and the original electrophilic groups
become nucleophiles in the second steps of the cascade
sequences. In each of these pathways, the reaction
centers move in a “boomerang” fashion away from and
then back to the same functional group via intervening
functional groups (Figure 1).
We envisaged an extension of the boomerang concept
to radical cascade reactions, in which a vinyl radical motif
initially acts as a radical donor and then as an acceptor.7,8
Previously, we reported the results of studies of a cascade
radical reaction of this type, in which halopolyenes,
undergo [2 + 1] annulations.8a Below, we describe the
results of an investigation of novel, radical cascade,
intramolecular [4 + 1] and [4 + 2] annulation reactions9
of dienoate tethered iodoolefins (Figure 2). Factors con-
* To whom correspondence should be addressed. Phone: +81-22-
217-6887. Fax: +81-22-217-6877.
(1) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1990.
(2) For reviews, see: (a) Ciganek, E. Org. React. 1984, 19, 1-374.
(b) Fallis, A. G. Acc. Chem. Res. 1999, 32, 464-474.
(3) For a review, see: (a) Leutens, M.; Klute, W.; Tam, W. Chem.
Rev. 1996, 96, 49-92. Representative examples: (b) Dzwiniel, T. L.;
Etkin, N.; Stryker, J . M. J . Am. Chem. Soc. 1999, 121, 10670-10641.
(c) O’Mahony, D. J . R.; Belanger, D. B.; Livinghouse, T. Synlett 1998,
443-445. Wender, P. A.; Dyckman, A. J .; Husfeld, C. O.; Kadereit, D.;
Love, J . A.; Rieck, H. J . Am. Chem. Soc. 1999, 121, 10442-10443. (d)
Trost, B. M.; Chan, D. M. J . Am. Chem. Soc. 1982, 104, 3733-3735.
(4) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115-136. (b) Parsons, P.
J .; Penkett, C. S.; Shell, A. J . Chem. Rev. 1996, 96, 195-206. (c) Poli,
G.; Giambastiani, G.; Heumann. A. Tetrahedron 2000, 56, 5959-5989.
(5) For reviews of cascade radical reactions, see: (a) Curran D. P.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Semmelhack, M. F., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 818-
827. (b) J asperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991,
91, 1237-1286. (c) Malacria, M. Chem. Rev. 1996, 96, 289-306.
(6) For reviews, see: (a) Ihara, M.; Fukumoto, K. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1010-1022. (b) Takasu, K. Yakugaku Zasshi
2001, 121, 887-898.
(7) (a) Beckwith, A. L. J ., O’Shea, D. M. Tetrahedron Lett. 1986,
27, 4525-4528. (b) Stork, G.; Mook, R., J r. Tetrahedron Lett. 1986,
27, 4529-4532. (c) Curran, D. P.; Sun, S. Aust. J . Chem. 1995, 48,
261-267. (d) Haney, B. P.; Curran, D. P. J . Org. Chem. 2000, 65, 2007-
2013. (e) Kitagawa, O.; Yamada, Y.; Fujiwara, H.; Taguchi, T. J . Org.
Chem. 2002, 67, 922-927.
(8) (a) Takasu, K.; Kuroyanagi, J .; Katsumata, A.; Ihara, M.
Tetrahedron Lett. 1999, 40, 6277-6280. (b) Takasu, K.; Maiti, S.;
Katsumata, A.; Ihara, M. Tetrahedron Lett. 2001, 42, 2157-2160.
(9) For previous reported examples of intermolecular [4 + 1] radical
annulation, see: (a) Curran, D. P.; Liu, H. J . Am. Chem. Soc. 1991,
113, 2127-2132. (b) Ryu, I.; Kusano, K.; Hasegawa, M.; Kambe, N.
Sonoda, N. J . Chem. Soc., Chem. Commun. 1991, 1018-1019. For
previous reported examples of intermolecular [4 + 2] radical annula-
tion, see: (c) Leardini, R.; Nanni, D.; Pedulli, R.; Tundo, A.; Zanardi,
G. J . Chem. Soc., Perkin Trans. 1 1986, 1591-1594.
10.1021/jo0258397 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/18/2002
J . Org. Chem. 2002, 67, 6001-6007
6001

Takasu et al.
allyllic moiety, whereas substrates 5, 6, and 7 possess
3-iodoallylic, 3-iodohomoallylic and propargylic group-
ings, respectively. It is important note that these sub-
stances would be rather unsuitable Diels-Alder sub-
strates because each contains trans geometry between
an ester function and a bulky â-substituent that blocks
adoption of the required s-cis diene conformation.
F IGURE 2. Boomerang-type [4 + 1] and [4 + 2] radical
cascade reaction.
TABLE 1. Ra d ica l Rea ction of 1 by Usin g TBTH or
Electr olysis
run
conditions
yield (%) of 3
1
2
TBTH, AIBN, benzene, refluxa
56
65
Ni(cyclam)2+, DMF, -1.5 V, rt
Su bstr a te P r ep a r a tion . The substrates 4-7 were
synthesized by sequences involving coupling of the
1-bromo-2,4-dienoates 10 or 13 with iodoalkenes 15a -f
or alkyne 19 (Scheme 1). Dienoate 10, having a â-phenyl
substituent, was prepared from ketone 812 by Peterson
olefination to give (2E,4E)-9, followed by the allylic
bromination. Siloxydienoate (2Z,4E)-13 was prepared
from the known ketoester 1113 by sequential enol silyla-
tion and allylic bromination. Whereas Peterson olefina-
tion of 8 affords a 3:2 mixture of (2E,4E)- and (2Z,4E)-9,
enol silylation of 11 with TBSCl in the presence of NEt3
furnishes (2Z,4E)-12 as the sole stereoisomer. Separation
by column chromatography was used to obtain pure
(2Z,4E)-9 and its (2E,4E) isomer.
The sulfonamide segments of 15a -c were prepared by
alkylation of p-toluenesulfonamide with the correspond-
ing iodoalkenyl methanesulfonates 14a -c. Substrates
15d ,e were synthesized by Mitsunobu reaction of the
iodoalkenyl alcohol 16a ,b 14,15 with N-Boc-p-toluene-
sulfonyl amide, followed by the carbamate removal. The
route employed to prepare 15f starts with mesylation of
1714 followed by SN2′ reaction with sodium azide. This
sequence produces the alkenyl azide 18, which is trans-
formed to 15f by reduction followed by the treatment with
p-toluenesulfonyl chloride. Coupling reactions of the
halodienoates with the tosylamides give 4a -d , 5a -c, 6,
and 7.
a
TBTH (1.2 equiv) and AIBN (0.5 equiv) were added deopwise
over 1 h.
trolling the regiochemical and stereochemical courses of
these processes are also described.10
Resu lts a n d Discu ssion
Rea ction Design . In initial experiments, we exam-
ined the radical cyclization reactions of the linear trienoate
ester 1, mediated by either tributyltin hydride-azodi-
isobutyronitrile (TBTH-AIBN) or cathodic electrolysis11
mediated by nickel(II) cyclam (Table 1). Trienoate 1 was
chosen as a probe because the first radical cyclization step
would generate intermediate 2, a capto-dative (acyl-vinyl
radical) stabilized radical expected to participate in a
succeeding radical cyclization process. However, reaction
of 1 under both initiation conditions described above
affords only the monocyclic product 3 having trans-â,γ-
unsaturated ester moiety. The results suggested that the
capto-dative radical intermediate 2 was indeed formed
in the first cyclization step but the ensuing cyclization
process is prohibited by the trans geometry of the
intermediate.
Our attention next focused on trienoate substrates that
contain bulky substituents at the â-position in the
dienoates in order to control the configuration of the
olefinic moiety in the initially formed radical intermedi-
ate. For this purpose, several substrates possessing
iodoolefinic and â-substituted dienoate moieties (e.g., 4a -
d , 5a -c, 6. and ω-alkynyldienoate 7) were designed.
Substances of general structure 4 all contain a 2-iodo-
Ra d ica l Cycliza tion Rea ction s of th e 2-Iod ovin yl-
d ien oa tes 4. Cascade 5-exo,6-endo cyclization reactions
of the 2-iodovinyl-dienoate ester 4a were carried out
under a variety of different conditions (Table 2). Reaction
of 4a by slow addition (1 h) of TBTH (1.2 equiv) and AIBN
(12) Fuson, R. C.; Christ, R. E.; Whitman, G. M. J . Am. Chem. Soc.
1936, 58, 2450-2452.
(10) A part of this work was published as preliminary communica-
tion: Takasu, K.; Kuroyanagi, J .; Ihara, M. Org. Lett. 2000, 2, 3579-
3581.
(11) (a) Ozaki, S.; Matsushita, H.; Ohmori, H. J . Chem. Soc., Chem.
Commun. 1992, 1120-1122. (b) Ihara, M.; Katsumata, A.; Setsu, F.;
Tokunaga, Y.; Fukumoto, K. J . Org. Chem. 1996, 61, 677-684. (c)
Katsumata, A.; Takasu, K.; Ihara, M. Heterocycles 1999, 51, 733-736.
(13) Crabtree, S. R.; Mander, L. N.; Sethi, S. P. Org. Synth. 1992,
70, 256-264.
(14) Gras, J .-L.; Chang, Y. Y. K. W.; Bertrand, M. Tetrahedron Lett.
1996, 37, 8743-8746.
(15) Cowell, A.; Stille, J . K. J . Am. Chem. Soc. 1980, 102, 4193-
4198.
6002 J . Org. Chem., Vol. 67, No. 17, 2002

[4 + 1] and [4 + 2] Annulation Reactions
TABLE 2. Ra d ica l Rea ction of 2-Iod oa llylic Su bstr a te
4a
SCHEME 1. Syn th etic P r oced u r e for Su bstr a tes
4a -d , 5a -c, 6, a n d 7a
yield (%)
run
conditions
20a
21a
1
2
3
4
5
6
7
TBTH, AIBN, benzene, refluxa
TBTH, AIBN, benzene, refluxb
(TMS)3SiH, AIBN, benzene, refluxb
benzene, reflux
40
63
66
0
0
0
20
0
0
0
0
TBTH, benzene, reflux
Ni(cyclam)2+, DMF, -1.5 V, rt
Ni(cyclam)2+, DMF, -1.5 V, 100 °C
85
86
0
a
TBTH (1.2 equiv) and AIBN (0.5 equiv) were added dropwise
b
over 1 h. Hydride (1.2 equiv) and AIBN (0.5 equiv) were added
dropwise over 2 h.
SCHEME 2a
a
(a) TBTH, AIBN, benzene, reflux; (b) AcOH, H2O, THF, rt.
SCHEME 3a
a
(a) TMSCH2CO2Me, cHex2NLi, THF, -78 °C; (b) NBS, benzoyl
peroxide, CCl4, reflux; (c) TBSCl, NEt3, DMAP, CH2Cl2, rt; (d)
TsNH2, K2CO3, acetone, reflux; (e) 10, K2CO3, acetone, reflux; (f)
13, NaH, DMF, rt; (g) TsNHBoc, DEAD, PPh3, THF, rt; (h) TFA,
CH2Cl2, rt; (i) MsCl, NEt3, CH2Cl2, rt; (j) NaN3, DMF, 60 °C; (k)
LiAlH4, Et2O, rt; (l) TsCl, NEt3, CH2Cl2, rt.
a
c, R ) Ph; d , R ) OTBS.
produced. Instead, monocyclic product 21a is formed
under these conditions in 85% and 86% yield at ambient
temperature or 100 °C (runs 6 and 7). Radical reaction
of â-siloxy substituted from 4b under the TBTH-AIBN
slow addition conditions furnishes the cis-fused bicyclic
[4 + 2] product 20b (Scheme 2). Silyl enol ether 20b is
quantitatively transformed into the ketoester 22 by
treatment with aqueous acetic acid.
Radical cyclization reactions of 4c and 4d , both of
which possess methyl substitution on the terminal olefin
center, follow a different regiochemical course (Scheme
3). For example, TBTH treatment of 4c affords the
azabicyclo[4.3.0]nonene 20c as a minor product (11%)
along with the predominant azabicyclo[3.3.0]nonenes 23c
and 24c in respective yields of 25% and 36%. The [4 +
1] intramolecular annulated products 23c and 24c are
formed through a pathway involving cascade 5-exo,5-exo
cyclization. In the similar manner, 4d also yields a
mixture of regioisomers 20d , 23d , and 24d under these
radical cyclization conditions.
(0.5 equiv) at reflux in benzene affords the bicyclic and
monocyclic products 20a (40%) and 21a (20%), respec-
tively (run 1). When TBTH and AIBN are added more
slowly (2 h) to a solution of 4a , only 20a is formed in
63% yield and as a single diastereomer (run 2). In
addition, 20a is formed as the sole product when tris-
(trimethylsilyl)silane ((TMS)3SiH)16 in the presence of
AIBN is used as a radical source (run 3). Substrate 4a is
unreactive under benzene reflux conditions in the ab-
sence of a radical source (runs 4 and 5). This observation
strongly suggests that the [4 + 2] annulation reactions
are not the result of a Diels-Alder process.
In contrast to these results, when 4a is subjected to
indirect cathodic electrolysis,12 no bicyclic products are
(16) (a) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188-194. (b)
Chatgilialoglu, C.; Ferreri, C.; Gimisis, T. In The Chemistry of Organic
Silicon Compounds; Rappoport, Z., Apeloig, Y., Eds.; Wiley: Chichester,
1997; Vol. 2; pp 1539-1579. (c) Chatgilialoglu, C. In Radical in Organic
Synthesis; Renaud, O., Sibi, P., Eds; Wiley: Weinheim, 2001; pp 28-
49.
The differences in regiochemistry observed in reactions
of 4a ,b vs 4c,d appear to be the consequence of steric
effects that govern the direction of the second radical
J . Org. Chem, Vol. 67, No. 17, 2002 6003

Takasu et al.
TABLE 3. Ra d ica l Rea ction of 3-Iod oa llylic Su bstr a tes
5a -c
yield (%)
run
substrate
conditionsa
26
27
28
F IGURE 3. Transition-state model of 4 after the first cycliza-
tion.
1
2
3
4
5
5a (R1 ) R2 ) H)
A
B
C
A
A
25
28
0
27
20
40
42
0
28
39
0
0
47
11
0
5a
5a
cyclization step in the sequence (Figure 3). In the cases
of 4a ,b, the capto-dative radical intermediates 25 (R′ )
H), formed by initial 5-exo-trig cyclizations, cyclize by
preferential addition to the unsubstituted terminal sp2
carbons (6-endo-trig).17 The stereochemistry of these
processes results from the steric repulsion between
phenyl substituent and ester moiety (i.e., 25A leading to
20 is lower in energy than 25B leading to 23 or 24). In
contrast, methyl substitution at the terminal olefinic
carbons in the intermediates 25 (R1 ) Me), arising from
4c and 4d causes 5-exo-trig cyclization17,18 leading to the
production of 23 and 24. On the other hand, the prefer-
ence for formation of monocyclic products in the electro-
lytic processes is likely the result of rapid one-electron
reduction of the radical intermediate 25 to form stable
enolate anion.
Ra d ica l Cycliza tion Rea ction s of th e 3-Iod oa llyl-
d ien oa tes 5. The length of the chain between the radical
donor and olefin radical acceptor influences the regio-
chemistry and stereochemistry of boomerang-type radical
cascade reactions. The radical cyclization reactions of the
3-iodoallylic substrates 5a -c, involving initial longer
chain “outside” vinyl radical intermediates, were ex-
plored. Treatment of 5a with TBTH or (TMS)3SiH in the
presence of AIBN leads to formation of fused [4 + 1]
products 26a and 27a in 25-28% and 40-42%, respec-
tively (Table 3, runs 1 and 2). The regioselectivity of the
second cyclization step in this case is controlled by a
stereoelectronic effect in which the trajectory leading to
5-exo cyclization is favored over that giving [4 + 2]
products by a 6-endo process. Under electrolytic reduction
conditions, 5a yields only the monocyclic piperidine 28a
(run 3). The reaction of 5b, which contains a methyl
substituent on the terminal olefinic carbon, also furnishes
[4 + 1] internal adducts 26b and 27b along with 28b
(run 4). It is noteworthy that chirality at the allylic amide
center of substrate 5c induces chirality at the newly
formed stereogenic center at the first cyclization stage
in the product. Treatment of 5c with TBTH-AIBN
produces a mixture of 26c and 27c, both diastereomers
having the same relative configurations at the chiral
5b (R1 ) Me, R2 ) H)
5c (R1 ) H, R2 ) Me)
a
Condition A: TBTH (1.2 equiv), AIBN (0.5 equiv), benzene,
reflux. Condition B: (TMS)3SiH (1.2 equiv), AIBN (0.5 equiv),
benzene, reflux. Condition C: Ni(cyclam)2+, DMF, -1.5 V, 100 °C
F IGURE 4. Transition-state model of 5c at the first cycliza-
tion.
centers in the six-membered rings (run 5). Importantly,
26c is quantitatively obtained as a sole diastereomer by
treatment of a mixture of 26c and 27c with DBU. The
presumed transition state model of the first radical
cyclization step in the reaction of 5c Figure 4) possesses
conformation 29A rather than 29B, in which the methyl
substituent and dienoate moiety are oriented equatorial
in the forming six-membered ring.
Ra d ica l Cycliza tion Rea ction s of th e 3-Iod oh om o-
a llyl-d ien oa te 6. Cascade 6-exo,5-exo radical cyclization
reaction of iodotrienoate 6, which has a longer tether as
compared to 4, with TBTH or (TMS)3SiH in the presence
of AIBN leads to formation of the [4 + 1] internal adduct
bicyclo[4.3.0]nonene 26b, which is the same product
leading from 5b, as a single diastereomer (runs 1 and 2,
Table 4). The source of regiochemical and stereochemical
control in production of 26b from 6 derives from repulsion
between the phenyl ring and the ester group and the
axially oriented hydrogen in the forming piperidine ring
(see 31A and 31B in Figure 5). Electrolysis of 6 affords
the monocyclic product 30 (run 3).
Ra d ica l Cycliza tion Rea ction s of Yn ed ien oa te 7.
In Table 5 are summarized the results obtained from
studies with the ynedienoate substrate 7. When 7 is
treated with TBTH-AIBN in refluxing benzene for 4 h,
two diastereomeric bicyclic [4 + 2] products, 32 and 33,
are generated in 40% and 10% yield, respectively (run
1). Although an intramolecular Diels-Alder process could
produce these [4 + 2] products, reaction of 7 under
similar conditions, in the absence of TBTH-AIBN,
results in exclusive and low yielding formation of dia-
stereomerically pure 33 (run 2). Thus, the annulation
(17) The radical addition of alkyl radical with intramolecular di-
and trisubstituted olefin often predominates 6-endo-trig cyclization over
the 5-exo-trig one. (a) Beckwith, A. L. J . Tetrahedron 1981, 37, 3073-
3100. (b) Beckwith, A. L. J .; Schiesser, C. H. Tetrahedron 1985, 41,
3925-3941.
(18) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734-735.
6004 J . Org. Chem., Vol. 67, No. 17, 2002

[4 + 1] and [4 + 2] Annulation Reactions
TABLE 4. Ra d ica l Rea ction of 3-Iod oh om oa llylic
Su bstr a te 6
radical 34. This intermediate undergoes 5-exo-trig radical
addition to furnish the intermediate radical 35, whose
conformation should be similar to 25B (Figure 3). Sub-
sequent 6-endo radical cyclization to give tertiary radical
36, followed by â-stannyl radical elimination, then gives
[4 + 2] internal adduct 32. Thus, the process is catalytic
in the stannyl radical. Although a higher reaction tem-
perature is necessary to bring about complete consump-
tion of the substrate, treatment of 7 with only 0.5 equiv
of TBTH affords 32 and 33 in 56% and 22% yield,
respectively (run 3 in Table 5). As an aside, both dienes
32 and 33 undergo slow oxidation to form the heteroaro-
matic compound 37.
yield (%)
run
conditions
26b
30
1
2
3
TBTH, AIBN, benzene, refluxa
(TMS)3SiH, AIBN, benzene, refluxa
Ni(cyclam)2+, DMF, -1.5 V, rt
45
36
0
0
0
36
a
Hydride (1.2 equiv) and AIBN (0.5 equiv) were added dropwise
over 2 h.
Con clu sion
The investigation described above has led to the
development a novel methodology for ring formation
based on a boomerang-type cascade radical process. In
these pathways, iodoalkenyl and alkynyl moieties can act
as both radical donors and acceptors. The processes
provide [4 + 2] or [4 + 1] annulated heterocyclic products,
whose regiochemistry and stereochemistry are dependent
on the structure of the substrate. Especially important
in determining the regioselectivities and stereoselectivi-
ties of these reactions are steric and/or stereoelectronic
effects on the transition states of the second radical
cyclization steps, which govern whether 5-exo-trig or
6-endo-trig processes are preferred. In addition, the
results show that the stepwise radical annulation method
is effective in bringing about [4 + 2] intramolecular
cycloadditions of s-trans-diene substrates, which resist
Diels-Alder reactions.
F IGURE 5. Transition-state model of 6 after the first cycliza-
tion.
TABLE 5. Ra d ica l Rea ction of P r op a r gylic Su bstr a te 7
yield (%)
run
conditions
32
33
1
2
3
TBTH (2.0 equiv), AIBN, benzene, reflux, 4 ha 40
10
20
22
benzene, reflux, 48 h
0
TBTH (0.5 equiv), AIBN, toluene, reflux, 4 ha
56
Finally, the core ring systems of the nitrogen hetero-
cycles, prepared in this study by using the boomerang-
type cascade radical reaction, are classified as isoindoles,
[2]pyrindines, and cyclopenta[c]pyrroles. Although these
skeletal types are rarely found in nature, they have
attracted interest as medicinally important targets.19
Further studies are underway in this laboratory that are
aimed at developing routes to biologically active hetero-
cycles in these families.
a
TBTH and AIBN (0.5 equiv) were added dropwise over 3 h.
Exp er im en ta l Section
Gen er a l. All reactions were carried out under an inert
atmosphere, and the organic extracts obtained on workup were
dried over MgSO4 or Na2SO4, filtered, and concentrated in
1
vacuo. Unless otherwise described, H and 13C NMR spectra
were recorded at 300 and 75 MHz, respectively, and are
reported in ppm downfield from TMS for the 1H NMR and
relative to the central CDCl3 resonance for the 13C NMR. The
structures and stereochemistry of all new synthetic compounds
F IGURE 6. Plausible mechanism of the radical reaction of
7.
reaction of 7 promoted by TBTH-AIBN is at least in part
the consequence of a radical process. Actually, the
stereochemistry of 32 is not in accord with its formation
by a Diels-Alder reaction, whereas that of 33 is. A
plausible mechanism for the formation of 32 from 7 is
shown in Figure 6. It is well-known that vinyl radicals
are generated from alkynes by the addition of stannyl
radicals. Accordingly, tributyltin radical addition to the
less hindered terminal sp carbon of 7 generates the vinyl
(19) (a) Mellor, J . M.; Wagland, A. M. J . Chem. Soc., Perkin Trans.
1 1989, 997-1005. (b) Mutti, S.; Daubie´, C.; Decalognem F.; Fournier,
R.; Rossei, P. Tetrahedron Lett. 1996, 37, 3125-3128. (c) Mutti, S.;
Daubie´, C.; Malpart, J .; Raddisson, X. Tetrahedron Lett. 1996, 37,
8743-8746. (d) Murray, W. V.; Sun, S.; Turchi, I. J .; Brown, F. K.;
Gauthier, A. D. J . Org. Chem. 1999, 64, 5930-5940. (e) Stefanska, A.
L.; Cassels, R.; Ready, S. J .; Warr, S. R. J . Antibiot. 2000, 53, 357-
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J . Antibiot. 2000, 53, 364-372.
J . Org. Chem, Vol. 67, No. 17, 2002 6005

Takasu et al.
were assigned based on 1D and/or 2D NMR spectroscopic data.
All substance were isolated as oils, unless otherwise noted,
and were >90% pure as judged by NMR analysis.
residue was purified with column chromatography on silica
gel (20% EtOAc/hexane) to give 15a (1.46 g, 60%) as colorless
needles (recrystallized from Et2O), mp 62-63 °C. IR (neat): ν
3250, 1610, 1590, 1420, 1320, 800, 660 cm-1 1H NMR
.
Meth yl (2E,4E)-3-P h en yl-2,4-h exa d ien oa te (9). Dicyclo-
hexylamine (0.55 mL, 2.75 mmol) was dissolved in THF (5 mL).
The solution was then cooled to -78 °C and treated with BuLi
(1.53 M solution in hexanes; 1.8 mL, 2.75 mmol). To the
mixture was added methyl (trimethylsilyl)acetate (0.45 mL,
2.75 mmol) dropwise at -78 °C. To the resulting solution was
added phenylpropenyl ketone (8)12 (134 mg, 0.92 mmol) in THF
(2 mL) at -78 °C, and the mixture was stirred for 1 h at the
same temperature. After addition of finely ground sodium
bisulfate monohydrate (0.40 g), the mixture was stirred for
10 min and allowed to heat to room temperature. After the
removal of the solids, the resulting solution was extracted with
EtOAc. The combined organic extracts were washed with
brine, dried, and concentrated. Chromatography of the residue
on silica gel (5% EtOAc/hexane) furnished (2E,4E)-9 (70. 0 mg,
38%) as colorless needles, and its geometrical (2Z,4E)-isomer
(48.0 mg, 26%) as colorless oil.
(CDCl3): δ 7.76 (d, 2H, J ) 8.1 Hz), 7.30 (d, 2H, J ) 8.1 Hz),
6.28 (d, 1H, J ) 1.8 Hz), 5.74 (d, 1H, J ) 1.8 Hz), 5.65 (t, 1H,
J ) 6.3 Hz), 3.78 (d, 2H, J ) 6.3 Hz), 2.42 (s, 3H). 13C NMR
(CDCl3): δ 143.7, 137.0, 129.8, 127.2, 104.8, 54.3, 21.4. LRMS
(m/z): 338 (M+ + 1), 336 (M+ - 1). Anal. Calcd for C10H12
-
INO2S: C, 35.61; H, 3.59; N, 4.16. Found: C, 35.92; H, 3.74;
N, 4.05.
N-(2-Iod o-2-p r op en yl)-N-[(2E,4E)-5-m eth oxyca r bon yl-
4-p h en yl-2,4-p en ta d ien yl]-p-tolu en esu lfon a m id e (4a ). To
a solution of 10 (285 mg, 1.01 mmol) and 15a (341 mg, 1.01
mmol) in acetone (20 mL) was added K2CO3 (140 mg, 1.01
mmol) at room temperature, and the reaction mixture was
refluxed for 12 h. After concentration of the mixture, which
was subjected to silica gel chromatography (10% EtOAc/
hexane) to furnish 4a (456 mg, 84%) as colorless needles (from
Et2O), mp 92-93 °C. IR (neat): ν 2930, 1700, 1580, 1340, 1150
(2E,4E)-9: mp 62-63 °C (colorless needles from Et2O). IR
1
cm-1. H NMR (CDCl3): δ 7.70-7.64 (m, 3H), 7.38-7.14 (m,
(neat): ν 1720, 1700, 1590, 1430, 1230, 1160 cm-1 1H NMR
.
7H), 6.39 (s, 1H), 5.93 (s, 1H), 5.76 (s, 1H), 5.52 (dt, 1H, J )
15.9, 6.9 Hz), 3.96 (s, 2H), 3.94 (s, 2H), 3.74 (s, 3H), 2.39 (s,
3H). 13C NMR (CDCl3): δ 166.5, 154.6, 143.7, 139.4, 136.8,
134.9, 131.5, 129.8, 128.7, 128.5, 128.4, 127.4, 118.2, 105.1,
58.2, 51.3, 49.7, 21.5. LRMS (m/z): 537 (M+). Anal. Calcd for
(CDCl3): δ 7.40-7.33 (m, 3H), 7.12 (d, 2H, J ) 7.7 Hz), 6.36
(d, 1H, J ) 15.2 Hz), 5.86 (s, 1H), 5.59 (dt, 1H, J ) 15.2, 6.9
Hz), 3.54 (s, 3H), 1.79 (d, 3H, J ) 6.9 Hz). 13C NMR (CDCl3):
δ 166.6, 156.0, 137.6, 137.4, 134.8, 128.3, 127.8, 127.6, 117.2,
50.9, 18.5. LRMS (m/z): 202 (M+). Anal. Calcd for C13H14O2:
C, 77.20; H, 6.98. Found: C, 76.88; H, 7.13.
C
23H24INO4S: C, 51.40; H, 4.50; N, 2.61; I, 23.61; S, 5.97.
Found: C, 51.59; H, 4.63; N, 2.46; I, 23.43; S, 6.00.
(2Z,4E)-Isom er : IR (neat): ν 2950, 1710, 1630, 1590, 1490,
Gen er a l P r oced u r e for TBTH a n d (TMS)3SiH Meth od .
To a stirred solution of a reaction substrate (52.0 µmol) in
degassed benzene or toluene (25 mL) were dropwise added Bu3-
SnH (62.4 µmol) or (TMS)3SiH (62.4 µmol) and AIBN (26.0
µmol) or Et3B (15.6 µmol) in benzene (4 mL) over 1 or 2 h using
a syringe pump under reflux condition. After the mixture
stirred under the same temperature for 2 h, the solvent was
removed, and the residue was purified by chromatography on
silica gel (20% EtOAc/hexane).
1300, 1160 cm-1 1H NMR (CDCl3): δ 7.70 (d, 1H, J ) 15.7
.
Hz), 7.37-7.27 (m, 5H), 5.86 (dt, 1H, J ) 15.7, 6.7 Hz), 5.67
(s, 1H), 3.75 (s, 3H), 1.88 (d, 3H, J ) 6.7 Hz). 13C NMR
(CDCl3): δ 166.7, 156.5, 140.5, 138.9, 129.0, 128.8, 128.3, 128.1,
115.4, 50.9, 18.8. LRMS (m/z): 202 (M+). HRMS (m/z) calcd
for C13H14O2 202.0993, found 202.0988.
Meth yl (2E,4E)-6-Br om o-3-ph en yl-2,4-h exadien oate (10).
To a solution of (2Z,4E)-9 (66 mg, 327 µmol) in CCl4 (5 mL)
were added NBS (52.0 mg, 294 µmol) and benzoyl peroxide
(8.0 mg, 33 µmol) at room temperature, and the mixture was
refluxed for 18 h. After concentration of the mixture under
reduced pressure, the residue was subjected to silica gel
chromatography (5% EtOAc/hexane) to give 10 (24 mg, 50%)
as colorless oil. IR (neat): ν 2950, 1710, 1630, 1590, 1430, 1270,
Gen er a l P r oced u r e for Electr olysis. A reaction substrate
(40.0 µmol), NH4ClO4 (80.0 µmol), and [Ni(cyclam)](ClO4)2 (4.0
µmol) were dissolved in DMF (13 mL) containing Et4NClO4
(0.1 M in DMF) in a H-shaped divided cell. The solution was
electrolyzed potentiostatically using a graphite plate as a
cathode at the redox potential of nickel complex at -1.5 V vs
SCE at room temperature under inert gas. After the usual
workup, the extracts were purified by column chromatography,
affording cyclized products.
(1S*,4S*,6R*)-4-Meth oxyca r bon yl-3-p h en yl-8-p-tolu en e-
su lfon yl-8-a za b icyclo[4.3.0]n on -2-en e (20a ). Colorless
needles (recrystallized from Et2O), mp 176-178 °C. IR (neat):
ν 2950, 1730, 1340, 1160, 1090, 660 cm-1. 1H NMR (500 MHz,
CDCl3): δ 7.74 (d, 2H, J ) 8.5 Hz), 7.34-7.16 (m, 7H), 5.88
(dd, 1H, J ) 4.9, 1.8 Hz), 3.69 (m, 2H), 3.53 (dd, 1H, J ) 10.1,
6.7 Hz), 3.38 (s, 3H), 3.13 (dd, 1H, J ) 10.1, 1.8 Hz), 3.05 (t,
1H, J ) 9.7 Hz), 2.81 (m, 1H), 2.43 (s, 3H), 2.36 (m, 1H), 1.92
(dt, 1H, J ) 13.4, 4.9 Hz), 1.54 (m, 1H). 13C NMR (125 MHz,
CDCl3): δ 174.1, 143.4, 140.7, 137.8, 133.7, 129.7, 128.3, 127.5,
127.3, 125.5, 53.1, 51.9, 51.7, 44.6, 38.3, 35.1, 28.6, 21.5. LRMS
(m/z): 411 (M+). Anal. Calcd for C23H25NO4S: C, 67.13; H, 6.12;
N, 3.42; S, 7.79. Found: C, 66.99; H, 6.28; N, 3.36; S, 7.88.
1170 cm-1 1H NMR (CDCl3): δ 7.91 (d, 1H, J ) 15.7 Hz),
.
7.40-7.26 (m, 5H), 5.97 (dt, 1H, J ) 15.7, 7.7 Hz), 5.82 (s,
1H), 4.09 (d, 2H, J ) 7.7 Hz), 3.77 (s, 3H). 13C NMR (CDCl3):
δ 166.4, 154.4, 139.4, 136.6, 130.0, 128.9, 128.8, 128.4, 118.9,
51.3, 32.2. LRMS (m/z): 282, 280 (M+). HRMS (m/z) calcd for
C
13H1379BrO2 280.0099, found 280.0116.
2-Iod o-2-p r op en yl Meth a n esu lfon a te (14a ). To a solu-
tion of 2-iodo-2-propenol21 (5.40 g, 29.4 mmol) in CH2Cl2 (80
mL) were added methanesulfonyl chloride (2.7 mL, 35 mmol)
and Et3N (4.9 mL, 35 mmol) at 0 °C. After being stirred for 2
h at 0 °C, the solution was concentrated and diluted with Et2O
and water. The mixture was extracted with Et2O, washed with
saturated NH4Cl and brine, dried, and concentrated. Silica gel
chromatography of the crude product yielded 14a (6.82 g, 89%)
as colorless oil. IR (neat): ν 3000, 1620, 1610, 1340, 1160, 820
cm-1 1H NMR (CDCl3): δ 6.53 (s, 1H), 6.05 (s, 1H), 4.78 (s,
.
2H), 3.10 (s, 3H). 13C NMR (CDCl3): δ 129.8, 99.3, 75.5, 38.5.
LRMS (m/z): 262 (M+). HRMS (m/z): calcd for C4H7IO3S
261.9159, found 261.9140.
3-[(1Z)-3-Meth oxyca r bon yl-2-p h en yl-1-p r op en yl]-4-m e-
th ylen e-1-p-tolu en esu lfon ylp yr r olid in e (21a ). Colorless
oil. IR (neat): ν 2950, 1730, 1590, 1490, 1340, 1160, 810, 660
cm-1. 1H NMR (CDCl3): δ 7.65 (d, 2H, J ) 8.0 Hz), 7.33-7.27
(m, 5H), 7.12 (dd, 2H, J ) 7.4, 2.2 Hz), 5.25 (d, 1H, J ) 9.5
Hz), 4.94 (m, 2H), 3.96 (d, 1H, J ) 15.0 Hz), 3.69 (dd, 1H, J )
15.0, 1.9 Hz), 3.60-3.55 (m, 4H), 3.34 (s, 2H), 3.24 (m, 1H),
2.84 (t, 1H, J ) 9.5 Hz), 2.42 (s, 3H). 13C NMR (CDCl3): δ
171.6, 147.4, 143.8, 139.0, 138.2, 132.9, 129.8, 128.6, 128.5,
128.0, 127.8, 127.7, 108.4, 53.4, 51.9, 51.8, 44.2, 43.2, 21.5.
LRMS (m/z): 411 (M+). HRMS (m/z): calcd for C23H25NO4S
411.1503, found 411.1483.
N-(2-Iod o-2-p r op en yl)-p-tolu en esu lfon a m id e (15a ). To
a solution of 14a (2.00 g, 7.64 mmol) and p-toluenesulfonamide
(13.0 g, 76.4 mmol) in acetone (50 mL) was added K2CO3 (1.00
g, 7.64 mmol) at room temperature, and the reaction mixture
was refluxed for 18 h. After removal of the solvent, the mixture
was extracted with Et2O, washed with brine, and dried. The
(20) Berges, D. A.; Snipes, E. R.; Chan, G. W.; Kingsbury, W. D.;
Kinzig, C. M. Tetrahedron Lett. 1981, 22, 3557-3560.
(21) Irifune, S.; Kibayashi, T.; Ishii, Y.; Ogawa, M. Synthesis 1988,
366-369.
6006 J . Org. Chem., Vol. 67, No. 17, 2002

[4 + 1] and [4 + 2] Annulation Reactions
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental section and characterization data. This material
is available free of charge via the Internet at http://pubs.
acs.org.
Ack n ow led gm en t. This work was supported in part
by a Grant-In-Aid for Encouragement of Young Scien-
tists and for Scientific Research on Priority Areas (A)
“Exploitation of Multi Element Cyclic Molecules” from
the Ministry of Education, Culture, Sports, Science and
Technology, J apan.
J O0258397
J . Org. Chem, Vol. 67, No. 17, 2002 6007