Highly selective sequential addition and cyclization reactions involving diphenyl diselenide, an alkyne, and alkenes under visible-light irradiation

Article abstract of DOI:10.1002/anie.200250790

A four-component radical coupling of diphenyl diselenide, an alkyne, and two olefins to form substituted cyclopentanes in good yields is described (see scheme). This selective sequential addition and cyclization is facilitated by the rate of carbon-radical trapping by diphenyl diselenide, appropriate for this transformation, and the efficiency of the 5-exo cyclization. EWG = electron-withdrawing group.

Full text of DOI:10.1002/anie.200250790

Communications
Domino Radical Reactions
Highly Selective Sequential Addition and
Cyclization Reactions Involving Diphenyl
Diselenide, an Alkyne, and Alkenes under
Visible-Light Irradiation**
Kaname Tsuchii, Mikio Doi, Toshikazu Hirao, and
Akiya Ogawa*
Dedicated to Professor Noboru Sonoda
on the occasion of his 70th birthday
The development of highly selective carbon–carbon bond-
forming reactions with the simultaneous introduction of
heteroatom functional groups is of great importance in
organic synthesis. A variety of compounds with carbon–
carbon unsaturation can be utilized for this purpose.[1]
However,the use of several such unsaturated compounds
together in a radical reaction usually results in their polymer-
ization. In contrast,we have discovered that the addition of
diphenyl diselenide,which has an appropriate carbon-radical-
capturing ability,[2] depresses the undesired polymerization
and makes it possible to carry out a highly selective sequential
addition of (PhSe)2 to unsaturated compounds.[3] Herein,we
report a novel four-component coupling of an alkyne,two
olefin molecules,and diphenyl diselenide,which proceeds
through selective bond formation to connect these four
molecules,and a subsequent 5- exo cyclization,as depicted in
Scheme 1.
Scheme 1. Sequential addition and cyclization strategy.
We started our study of this type of reaction by examining
the combination of alkynes that bear an electron-withdrawing
group with alkenes that bear an electron-donating group.[4]
When a mixture of ethyl propiolate (1), n-butyl vinyl ether
[*] Prof. A. Ogawa, K. Tsuchii
Department of Chemistry, Faculty of Science
Nara Women's University
Kitauoyanishi-machi, Nara 630–8506 (Japan)
Fax: (+81)742-20-3979
E-mail: a.ogawa@cc.nara-wu.ac.jp
M. Doi, Prof. T. Hirao
Department of Applied Chemistry, Faculty of Engineering
Osaka University
[**] This research was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (A) (No. 14044063) “Exploitation of
Multi-Element Cyclic Molecules” from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
Supporting information for this article, including full procedures
and characterization data, is available on the WWW under http://
www.angewandte.org or from the author.
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DOI: 10.1002/anie.200250790
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Chemie
(2),and diphenyl diselenide ( 3) was irradiated through pyrex
with a tungsten lamp (hn > 300 nm) in the absence of solvent,
none of the desired sequential addition and cyclization
product was formed,and instead the corresponding three-
component coupling product 4 was formed selectively,as
shown in Equation (1).[3]
carbon-radical-trapping ability of (PhSe)2 facilitates its selec-
tive sequential addition and cyclization with an alkyne and
two olefin molecules.[7]
Methyl acrylate,acrylonitrile,and methyl vinyl ketone can
be employed for this sequential addition and cyclization
reaction (Table 1). However,when alkynes without an
electron-withdrawing group were used in place of ethyl
propiolate,the desired product was obtained in very poor
yield. For example,the main products isolated from the
reactions of phenylacetylene and 1-octyne were the corre-
sponding three-component coupling products (7a and 7b,
respectively) and bisselenation products (8a and 8b,respec-
tively).
Surprisingly,however,when an electron-deficient alkene
was employed for this reaction instead of n-butyl vinyl ether,
the desired sequential addition and 5-exo radical cyclization
took place selectively. For example,the reaction of tert-butyl
acrylate (5a) under the same conditions provided 6a in 61%
[5]
yield (Scheme 2 and Table 1,entry 1),
along with small
A possible mechanistic pathway is shown in Scheme 3:
1) Upon irradiation with light of wavelength over 300 nm,
diphenyl diselenide (3; lmax = 330 nm) undergoes homolytic
Scheme 2. Synthesis of substituted cyclopentanes from ethyl propio-
late, an alkene, and (PhSe)2 through sequential radical addition and
cyclization.
Table 1: Sequential addition and cyclization reactions of ethyl propiolate,
alkenes, and (PhSe)2.[a]
Entry
6
R
Yield [%][b]
A/B/C/D
1
2
3
4
a
b
c
tBuO2C
MeO2C
NC
61
49
41
58
72:11:11:6
79:21:0:0
18:14:60:8
71:16:7:6
d
Me(O)C
Scheme 3. Proposed mechanism for the formation of cyclopentanes 6
(and by-products) through sequential radical addition and cyclization;
EWG=electron-withdrawing group.
[a] Reaction conditions: ethyl propiolate (0.20 mmol), (PhSe)2 (1 equiv),
alkene (40–60 equiv), 308C, hn: tungsten lamp(500 W, pyrex). [b] Yield
of isolated products.
amounts of by-products,such as the corresponding acyclic
three-component coupling product and the adduct of (PhSe)2
with 1. The use of (PhS)2 in place of (PhSe)2 under similar
reaction conditions led to the polymerization of the olefins
and did not provide the desired sequential addition and
cyclization product,which is probably a result of the poor
carbon-radical-capturing ability of (PhS)2. On the other hand,
when (PhTe)2 was used,most of the starting ethyl propiolate
(1) was recovered,which is probably a result of the lower
reactivity of the phenyltelluro radical (PhTe·) toward unsa-
turated bonds. When a similar reaction was conducted in the
presence of nBu3SnH as a mediator,most of the starting ethyl
propiolate (1) was also recovered.[6] Thus,the appropriate
dissociation to generate PhSe·,[8] which adds to ethyl propio-
late (1) selectively to form the b-phenylseleno-substituted
vinylic radical I;[9,10] 2) the vinylic radical I reacts with two
olefin molecules to produce the secondary alkyl radical II;
3) the radical intermediate II cyclizes in a 5-exo manner to
give the a-seleno radical III,which in turn undergoes an S H2
reaction with (PhSe)2 to provide 6.
We next examined the four-component coupling reaction
in the presence of two types of olefin: an olefin with an
electron-withdrawing group and an olefin with an electron-
donating group. When the reaction of diphenyl diselenide (3)
with ethyl propiolate (1) and a large excess of both tert-butyl
acrylate (5a) and 2-methoxypropene (9) was performed in the
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absence of solvent,sequential addition of the
diselenide to the alkyne,of the resulting
intermediate to the electron-rich olefin 9,
and of the next intermediate to the electron-
poor olefin (5a),followed by a 5- exo radical
cyclization,took place to provide the corre-
sponding cyclic four-component coupling
product 10a in good yield (Scheme 4 and
[11]
Table 2,entry 1).
Small amounts of by-
products,such as the corresponding acyclic
three-component coupling product and the
adduct of (PhSe)2 with the alkyne,were also
formed. Similar conditions can be employed
with methyl acrylate,acrylonitrile,and methyl
vinyl ketone as the electron-deficient alkenes,
and the corresponding cyclic four-component
coupling products are obtained selectively in
good yields (Table 2,entries 2–4). In the case
of acrylonitrile,the desired four-component
Scheme 5. Proposed mechanism for the formation of cyclopentanes 10 through sequen-
tial radical addition and cyclization.
coupling reaction proceeds successfully to give the corre-
sponding five-membered-ring product in 76% yield (Table 2,
entry 3).
In summary,diphenyl diselenide has proved to be an
excellent mediator for highly selective sequential bond
formation between unsaturated compounds. The rate of
carbon-radical-capturing by (PhSe)2,appropriate for these
transformations,combined with the efficiency of the 5- exo
radical cyclization,prevent the undesired potential polymer-
ization and make it possible to carry out four-component
coupling reactions of unsaturated compounds and (PhSe)2.
Experimental Section
Scheme 4. Four-component coupling of ethyl propiolate, 2-methoxypro-
Representative procedure: Ethyl propiolate (19.6 mg,0.20 mmol),2-
methoxypropene (389 mg,5.4 mmol),and acrylonitrile (106 mg,
2.0 mmol) were placed in a pyrex glass tube (10 mm ” 75 mm)
under a N2 atmosphere. The mixture was irradiated with a tungsten
lamp (500 W) at 308C for 2 h,and diphenyl diselenide (62.4 mg,
0.20 mmol in total) was added in eight portions during the irradi-
ation.[12] When the reaction was complete,the purification of the
products was performed on a recycling preparative HPLC instrument
(Japan Analytical Industry Co. Ltd.,Model LC-908) equipped with
JAIGEL-1H and -2H columns,with CHCl 3 as the eluent,to yield 10c
(76%) as a stereoisomeric mixture (60:26:14). The stereochemistry of
pene, a second alkene, and (PhSe)2.
Table 2: Four-component coupling of ethyl propiolate, 2-methoxypro-
pene, a second alkene, and (PhSe)2.[a]
Entry
10
R
Yield [%][b]
A/B/C
1
2
3
4
a
b
c
tBuO2C
MeO2C
NC
47
47
76
41
81:19:0
43:37:20
60:14:26
72:24:4
the diastereoisomers of 10c was determined by NOE experiments.
d
Me(O)C
1
10c: Pale yellow oil; H NMR (major isomer; 300 MHz,CDCl ,
3
[a] Reaction conditions: ethyl propiolate (0.20 mmol), (PhSe)2 (1 equiv),
2-methoxypropene (10–30 equiv), RCH CH2 (10–30 equiv), hn: tung-
sten lamp (500 W, pyrex). [b] Yield of isolated products.
258C,TMS): d = 1.29 (s,3H; CH 3),1.34 (t, 3J(H,H) = 7.2 Hz,3H;
CH3CH2O2C),1.95 (dd, 3J(H,H) = 12.6 Hz, 2J(H,H) = 13.2 Hz,1H;
CCH2CH),2.30 (ddd, 4J(H,H) = 2.1 Hz, 3J(H,H) = 6.3 Hz, 2J(H,H) =
¼
13.2 Hz,1H; CC H2CH),2.32 (dd, 4J(H,H) = 2.1 Hz, 2J(H,H)
=
14.7 Hz,1H; CCH 2C),2.42 (d, 2J(H,H) = 14.7 Hz,1H; CCH 2C),
The formation of 10 may be explained by the following
proposed mechanism (see Scheme 5): 1) PhSe·,generated
from (PhSe)2 by irradiation with light of wavelength over
300 nm,adds to ethyl propiolate ( 1) selectively to form the b-
phenylseleno-substituted vinylic radical I; 2) the vinylic
radical I reacts with an electron-rich olefin preferentially to
produce the a-methoxyl radical IV; 3) the radical intermedi-
ate IV reacts with an electron-poor olefin and then cyclizes to
provide the a-seleno radical V,which is trapped with (PhSe) 2
to yield the cyclic four-component coupling product 10,with
regeneration of PhSe·.
2.90 (s,3H; CH O),3.50 (dd, 3J(H,H) = 6.3,12.6 Hz,1H; NCCH),
3
4.16–4.34 (m,2H; CH 3CH2O2C),4.58 (s,1H; (PhSe) 2CH),7.15–7.31
(m,6H; Ph),7.43–7.46 ppm (m,4H; Ph); 13C NMR (major isomer;
75 MHz,CDCl 3,25 8C,TMS): d = 13.9,21.0,38.6,42.4,45.6,49.1,54.7,
62.5,64.6,82.3,119.6,128.2,128.3,129.3,134.2,134.8,172.2 ppm;
ꢀ
¼
IR (NaCl): n˜ = 2977,2245 (C N),1718 (C O),1578,1478,1439,1369,
860,746,690 cm ꢁ1; HRMS (m/z): calcd for C24H27NO3Se2: 537.0322;
found: 537.0311; elemental analysis: calcd for C24H27NO3Se2: C 53.84,
H 5.08,N 2.62; found: C 53.50,H 5.00,N 2.85.
Received: December 17,2002
Revised: April 11,2003 [Z50790]
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Keywords: alkenes · alkynes · cyclizations · domino reactions ·
.
radicals
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M. P. Sibi),VCH,Weinheim, 2001.
[2] The rate constant for the SH2 reaction of the 5-hexenyl radical
with (PhSe)2 is 1.2 ” 107 mꢁ1 sꢁ1: a) G. A. Russell,H. Tashtoush, J.
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[5] The stereochemistry of the sequential addition and cyclization
products was determined by NOE experiments (see Supporting
Information).
[6] E. Lee,C. U. Hur,Y. H. Rhee,Y. C. Park,S. Y. Kim,
J. Chem.
Soc. Chem. Commun. 1993,1466 – 1468.
[7] The use of (p-CF3-C6H4Se)2 and (MeSe)2 in place of (PhSe)2 led
to the successful formation of the corresponding four-compo-
nent coupling products. However,when (PhCH Se)2 was used
2
none of the desired four-component coupling products were
ꢁ
obtained,probably because of
(PhCH2Se)2.
C
Se bond cleavage in
[8] U. Schmidt,A. Mꢀller,K. Markau, Chem. Ber. 1964, 97,405 –
414.
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Sonoda, Chem. Lett. 1991,2241 – 2242.
[10] In general,vinyl radicals are believed to be a stereoisomeric
mixture of s radicals that are in rapid equilibrium: a) R. W.
Fessenden,R. H. Schuler, J. Chem. Phys. 1963, 39,2147 – 2195.
In contrast, a-aryl-substituted vinylic radicals are thought to be
p radicals: b) L. A. Singer,J. Chen, Tetrahedron Lett. 1969, 10,
4849 – 4854. The corresponding radical species derived from
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A. Guarnieri,H. Koch,P. Mencarelli,Z. Rappoport,
Chem. 1997, 62,4072 – 4077; d) H. Rubin,H. Fischer,
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[11] The stereochemistry of the four-component coupling products
was determined by NOE experiments (see Supporting Informa-
tion).
[12] The four-component coupling of ethyl propiolate (1) with olefins
5 and 9 and (PhSe)2 described requires the use of excess amounts
of the olefins. When the molar ratio of 5 to 1 or 9 to 1 was
decreased,the yield of the four-component coupling product
also decreased,and the adduct of (PhSe) 2 with 1 was formed as a
by-product.
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