Generation of α-phosphonovinyl radicals and development of a new route to highly functionalized vinylphosphonates and vinylphosphonate- incorporated carbocyclic or heterocyclic compounds via a radical trapping sequence

Article abstract of DOI:10.1039/b416394j

The first direct generation of synthetically useful α-phosphonovinyl radicals was achieved by treatment of α-phosphonovinyl halides with a tributyltin radical. The α-phosphonovinyl radicals 2a-d were trapped with electron-rich olefins and an electron-deficient olefin to produce α-functionalized vinylphosphonates 3a-f in 16-55% yields. The α-phosphonovinyl radicals 7e-g containing the YCH₂CH=CH ₂ (Y = O, CH₂, S) substituent at the β-position afforded mixtures of 5-exo and 6-endo cyclization products, 5e-g and 6e-g, in good yields. The 5-exo/6-endo product ratios increase in the following order of the β-substituent: OCH₂CH=CH₂ > CH ₂CH₂CH=CH₂ > SCH₂CH=CH ₂. The effects of the β-substituents upon the cyclization reaction were discussed. Radical cyclization of α-phosphonovinyl radicals bearing functional groups such as geranyloxy, geranylthio, and (2-cyclohexen-l-yl)thio groups at the β-position afforded 5-exo, 5-exo and 6-endo, and cis-fused-5,6-ring cyclization products incorporating an α,β-unsaturated phosphonate unit within the ring, respectively, in good yields. The β-phosphonovinyl radical 20 underwent tandem radical cyclization-radical cyclization to produce a mixture of two isomeric bicyclo[4.3.0]nonenes including a vinylphosphonate moiety in high yield. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b416394j

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A R T I C L E
Generation of a-phosphonovinyl radicals and development of a new
route to highly functionalized vinylphosphonates and
vinylphosphonate-incorporated carbocyclic or heterocyclic
compounds via a radical trapping sequence†
Takafumi Ageno,a Tatsuo Okauchi,a Toru Minami*a and Masaru Ishida*b
a Department of Applied Chemistry, Kyushu Institute of Technology, Sensui-cho, Tobata,
Kitakyushu, 804-8550, Japan. E-mail: minami@che.kyutech.ac.jp
b Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu, 501-1193,
Japan. E-mail: ishidam@apchem.gifu-u.ac.jp
Received 26th October 2004, Accepted 1st January 2005
First published as an Advance Article on the web 7th February 2005
The first direct generation of synthetically useful a-phosphonovinyl radicals was achieved by treatment of
a-phosphonovinyl halides with a tributyltin radical. The a-phosphonovinyl radicals 2a–d were trapped with
electron-rich olefins and an electron-deficient olefin to produce a-functionalized vinylphosphonates 3a–f in 16–55%
=
yields. The a-phosphonovinyl radicals 7e–g containing the YCH2CH CH2 (Y = O, CH2, S) substituent at the
b-position afforded mixtures of 5-exo and 6-endo cyclization products, 5e–g and 6e–g, in good yields. The
=
5-exo/6-endo product ratios increase in the following order of the b-substituent: OCH2CH CH2 >
=
=
CH2CH2CH CH2 > SCH2CH CH2. The effects of the b-substituents upon the cyclization reaction were discussed.
Radical cyclization of a-phosphonovinyl radicals bearing functional groups such as geranyloxy, geranylthio, and
(2-cyclohexen-1-yl)thio groups at the b-position afforded 5-exo, 5-exo and 6-endo, and cis-fused-5,6-ring cyclization
products incorporating an a,b-unsaturated phosphonate unit within the ring, respectively, in good yields. The
a-phosphonovinyl radical 20 underwent tandem radical cyclization–radical cyclization to produce a mixture of two
isomeric bicyclo[4.3.0]nonenes including a vinylphosphonate moiety in high yield.
Introduction
The synthesis and application of vinylphosphonates have re-
cently attracted much interest to synthetic organic chemists
and bioorganic chemists, since vinylphosphonates are of-
ten utilized as key intermediate reagents for the synthe-
sis of synthetically useful products and biologically active
compounds.1–3 Accordingly, development of new synthetic
methods of vinylphosphonates is one of the important sub-
application to the trapping reaction with various alkenes,
jects to organic chemists. Recently, a new synthesis of
intramolecular cyclization and tandem reaction. Furthermore,
vinylphosphonates by trapping vinyl radicals with (MeO)3P
we discuss the cyclization mode in the intramolecular reaction
has been developed by Jiao and Bentrude.4 Furthermore,
of a-phosphonovinyl radicals.
3-(phosphonomethylene)oxacyclopentanes were derived from
intramolecular cyclization of a 6-phosphono-3-oxa-5-hexynyl
radical.5 This synthetic method of vinylphosphonates is, to our
knowledge, the first example via the a-phosphonovinyl radical
intermediate. Although various free radicals involving vinyl
radicals have been well studied and become useful intermediates
in organic synthesis,6 the studies on generation, synthetic
application, and ring formation mode in cyclization reaction
of the a-phosphonovinyl radical species have not been made
Results and discussion
Synthesis of the precursors, a-halovinylphosphonates 1a–g for
a-phosphonovinyl radicals
Abstraction of a halogen atom of a C–X (X = halogen)
bond with tri-n-butyltin radical has been known as the most
commonly used method for the generation of free radicals.6
To apply this method to the generation of a-phosphonovinyl
radicals, synthesis of their precursors, a-halovinylphosphonates
has been attempted first.
Of a-halovinylphosphonates, a-iodo- and a-bromophos-
phonoketene dithioacetals 1a,b and a-iodo-b-ethoxyvinyl-
phosphonate 1c were prepared according to the reported proce-
dures by us.8 As shown in Scheme 1, a-bromovinylphosphonate
so far, except for the above and a few related examples.5,7
2p,u,8
Accordingly, similar to a-phosphonovinyl carbanion
and a-
2y
phosphonovinyl carbocation equivalent species, generation of
a new type of reactive a-phosphonovinyl radical species and their
synthetic application are expected to open a new promising field
in the chemistry of vinylphosphonates.
We now report the first example of direct generation
of the a-phosphonovinyl radicals via abstraction of an a-
halogen atom from a wide variety of newly developed a-
halovinylphosphonates with the tri-n-butyltin radical, and their
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for all new compounds and
geometries and energies for all stationary points discussed in the paper.
See http://www.rsc.org/suppdata/ob/b4/b416394j/
Scheme 1 The synthesis of a-bromovinylphosphonate 1d. Reagents and
conditions: (a) Pd(PPh3)4, Bu3SnH, benzene, r.t.; (b) Br2, CCl4, −5 ◦C,
75% over two steps.
9 2 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 2 4 – 9 3 1
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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1d was synthesized by treatment of a-stannylvinylphosphonate,
which was produced by the palladium-catalyzed hydrostannyla-
tion of diethyl ethynylphosphonate with tri-n-butyltin hydride,
with bromine.
To examine the substituent effects on radical cyclization of
the a-phosphonovinyl radicals, various types of a-halovinyl-
phosphonates 1e–g containing unsaturated functional groups
such as allyloxy, homoallyl and allylthio at the b position
were developed. Thus, the synthesis of b-allyloxy-a-iodovinyl-
phosphonate 1e was realized by acid-catalyzed transacetaliza-
tion of diethylphosphonoacetaldehyde diethyl acetal with allyl
alcohol into the corresponding diallyl acetal, followed by the
similar procedures to those established in the preparation of 1c
(Scheme 2).
Scheme 4 The synthesis of b-allylthio-a-iodovinylphosphonate 1g.
Reagents and conditions: (a) nBuLi, allyl mercaptan, THF, −78 ◦C to
r.t., (E : Z = 76 : 24); (b) NaI, N-chlorosuccinimide, MeCN, r.t., 36%
over two steps.
radicals and the related application of vinyl radicals has
remained still unexplored except for a few examples.9 The
generation of a-phosphonovinyl radicals 2 and their appli-
cation to the intermolecular addition reaction with alkenes
are, therefore, expected to furnish an efficient synthetic
route to functionalized vinylphosphonates. When the reaction
of a-iodophosphonoketene dithioacetal 1a (0.2 M) with a-
methylstylene (10 equiv.) was performed in benzene at reflux by
addition of a benzene solution of Bu3SnH (0.22 M, 1.1 equiv.)
and AIBN (0.1 equiv.) over a period of 1 h, the desired addition
product 3a was obtained, albeit in low yield (28%), together with
the reduction product 4a (28%) (Scheme 5). To optimize the
product yield, we examined the influence of the concentration
and the addition time of Bu3SnH, and of the radical precursors
1 upon the yield (entries 2–4 in Table 1). The highest yield
(55%) of 3a was obtained by slow addition (5 h) of a solution of
Scheme 2 The synthesis of b-allyloxy-a-iodovinylphosphonate 1e.
Reagents and conditions: (a) allyl alcohol, TsOH, benzene, reflux; (b)
nBuLi, THF, −78 ◦C; (c) LDA, CuBrSMe2, I2, THF, −78 ◦C, 55% over
three steps.
In addition, diethyl 1-bromo-hexa-1,5-dienylphosphonate
(1f) was prepared by the Horner–Wadsworth reaction of
tetraethyl a-bromomethylenediphosphonate with 4-pentenal
(Scheme 3).
Scheme 3 The synthesis of a-bromo-1,5-hexadienylphosphonate 1f.
Reagents and conditions: (a) LDA, N-bromosuccinimide, THF, −78 ◦C
to r.t.; (b) 4-pentenal, THF, −78 ◦C to r.t., 70%.
For the synthesis of the b-allylthio-a-iodovinylphosphonate
derivative 1g, a synthetic route via double transfunctional-
ization of b-ethoxy-a-(trimethylsilyl)vinylphosphonate8 at the
b- and a-positions was designed. On the basis of this
synthetic design, the Michael addition of an allylthiolate
anion to the vinylphosphonate expectedly resulted in b-
allylthio-a-(trimethylsilyl)vinylphosphonate in 60% yield as a
E- and Z-stereoisomeric mixture (E-isomer : Z-isomer =
76 : 24). Subsequent treatment of the E-isomer with NaI/N-
chlorosuccinimide in acetonitrile led to the desired b-allylthio-
a-iodovinylphosphonate 1g in a stereospecific manner in good
yield (Scheme 4).
Intermolecular additions of a-phosphonovinyl radicals to alkenes
The carbon radicals used in the intermolecular addition
reactions with alkenes have mostly been limited to alkyl
Scheme 5 Intermolecular additions of a-phosphonovinyl radicals 2a–d
with alkenes.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 2 4 – 9 3 1
9 2 5

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Table 1 Radical trapping reaction of a-phosphonovinyl radicals 2a–d with alkenes
Alkenes
Vinylphosphonates1 R3
Conditionsa
Entry
R4
Concentrationc/mol l−1
Addition time/h
Total time/d h
Productb (Yield, %)
1
2
3
4
5
6
7
8
9
1a
1b
1b
1b
1b
1b
1c
1d
1b
Me
Me
Me
Me
H
OSiMe3
H
Ph
Ph
Ph
Ph
SPh
Ph
SPh
SPh
CO2Et
0.2
1
1
5
5
2
5
2
2
2
5
2
6
8
4
12
3
5
3a (28)
3a (35)
3a (38)
3a (55)
3b (48)
3c (47)
3d (49)
3e (30)
3f (16)
4a (28)
4a (33)
4a (24)
4a (33)
4a (16)
4a (41)
4b (22)
—
0.07
0.07
0.025
0.07
0.025
0.07
0.07
0.1
H
H
7
4a (24)e
a Reactions were carried out by slow addition of a solution of Bu3SnH (0.22 mmol) and AIBN (0.02 mmol) in benzene (1 mL) for entries 1–3, 5, 7
and 8 and in benzene (2 mL) for entries 4, 6 and 9 through a syringe pump to a solution of 1 (0.2 mmol) in refluxing benzene (1–8 mL). b Isolated
yields. c Each concentration was determined on initial concentration of 1. d Total reaction time until starting material 1 was consumed completely.
e 1b was recovered unchanged in 44% yield.
Bu3SnH (0.11 M) and AIBN(0.01 M) in benzene to a solution
of a mixture of 1b (0.025 M) and a-methylstylene in benzene
(entry 4), while the addition of a benzene solution of Bu3SnH
(0.22 M) and AIBN (0.02M) to the mixture of 1b (0.07 M)
and a-methylstylene in benzene over 1 or 5 h improved slightly
the yield up to 35–38% (entries 2, 3). The similar tin-mediated
reaction of 1b with electron-rich olefins such as phenyl vinyl
sulfide and 1-phenyl-1-(trimethylsilyloxy)ethylene successfully
led to the corresponding radical adducts 3b,c in 48 and 47%
yields, respectively (entries 5 and 6).
Treatment of 1e (0.1 M) with Bu3SnH (1.1 equiv.) and AIBN
(0.1 equiv.) in benzene at reflux for 3.5 h led in high yield (90%) to
5-exo radical cyclization product 5e, along with a trace amount
of 6-endo cyclization product 6e, but no acyclic product was
observed (Scheme 6, entry 1 in Table 2).
To investigate the scope and limitations of this tin-mediated
a-phosphonovinyl radical coupling reaction with olefins, the re-
action of the radicals 2c,d, generated from a-iodo-b-ethoxyvinyl-
or a-bromovinylphosphonates 1c,d, with phenyl vinyl sulfide was
similarly conducted to give the corresponding coupling products
3d,e in 30–49% yields (entries 7 and 8). The stereochemistry
of 3d was assigned as the cis-isomer on the basis of the
coupling constant 3JP
= 10.5Hz between vinylic H and
–
H
phosphorus (see ESI†). The formation of the expected trans-
isomer was negligible. This result indicates that the radical
2d generated in the reaction system is configurationally stable
during the trapping reaction. Similar treatment of 1b with an
electron-deficient alkene, ethyl acrylate, also led to the radical
coupling product 3f albeit in low yield (16%) together with
recovered 1b (44%) (entry 9). These results showed that the
coupling reaction of a-phosphonovinyl radicals with olefins
is essentially substrate independent, although electron-rich
olefins are preferable to electron-deficient ones. Accordingly,
this synthetic method suggests a new promising possibility for
development of synthetically useful and biologically valuable
vinylphosphonates.
Ring formation in radical cyclization of a-phosphonovinyl
radicals
The synthesis of biologically active compounds and naturally
occurring compounds10 by radical cyclization of alkenyl and
vinyl radicals as well as alkyl radicals has recently attracted
great attention of synthetic organic chemists, due to various
advantages such as high regio- and/or stereoselectivity,11 simple
procedures, good yield, etc. In contrast to alkenyl radicals
which usually cyclize in the 5-exo-mode, the cyclization of
vinyl radicals often affords 6-endo-mode products in substantial
yields in addition to 5-exo-mode products.12 Since the role that
the a-phosphono group and b-heteroatom may play in the
vinyl radical cyclization mode was not known, we examined
the substituent effect of a-phosphonovinyl radicals with a
Scheme 6 Intramolecular cyclization of a-phosphonovinyl radicals
7e–g.
We next examined the Bu3SnH concentration dependence
on the products.13 Similar treatment of 1e (0.025 M) by slow
addition of a solution of Bu3SnH (ca. 0.11 M, 1.1 equiv.)
and AIBN (0.1 equiv.) in benzene over 5 h resulted in a
77 : 23 mixture of 5e and 6e in 79% yield (entry 2). The a-
bromovinylphosphonate 1f was similarly treated under the same
conditions as above to produce 66 : 34 and 8 : 92 mixtures of
5-exo and 6-endo cyclization products, 5f and 6f, in 73% and
83% yields, respectively (entries 3 and 4). These results indicate
=
YCH2CH CH2 (Y = O, CH2, S) substituent at the b-position
on ring formation reaction and also aimed at developing a new
synthetic method of hard-to-prepare heterocyclic or carbocyclic
systems incorporating the vinylphosphonate unit.
9 2 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 2 4 – 9 3 1

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Table 2 Radical cyclization of a-halovinylphosphonates 1e–g
Conditionsa
Entry
Vinylphosphonates1
Concentration/mol l−1
Addition time/h
Timeb/h
Yieldc (%) (5 + 6)
Ratiod of 5 : 6
1
1e
1e
1f
0.1
0.025
0.1
0.025
0.1
0.025
0
5
0
5
0
5
3.5
7.0
4.0
8.0
3.5
8.0
90
79
73
83
76
77
5e : 6e = 99 : 1
5e : 6e = 77 : 23
5f : 6f = 66 : 34
5f : 6f = 8 : 92
5g : 6g = 20 : 80
5g : 6g = 5 : 95
2e
3
4e
5
1f
1g
1g
6e
a The reaction was carried out by using 1 (0.2 mmol), Bu3SnH (0.22 mmol) and AIBN (0.02 mmol), unless otherwise noted. b Total reaction time
until starting material 1 was consumed completely. c Isolated yields. d Based on 1H NMR yield. e To a solution of 1 (0.2 mmol) in refluxing benzene
(8 mL) was added a benzene solution (2 mL) of Bu3SnH (0.22 mmol) and AIBN (0.02 mmol) through a syringe pump.
that, as observed in other vinyl radicals,13 cyclization of a-
phosphonovinyl radicals 7e,f at higher concentration of Bu3SnH
predominantly gave kinetically controlled 5-exo products 5e,f.
However, it is of great interest that the a-iodovinylphosphonate
1g on treatment with Bu3SnH/AIBN under identical conditions
with entry 1 afforded 5-exo and 6-endo products, 5g and 6g, in a
20 : 80 ratio, which is the reversed ratio when 1e,f were used as
substrates (entry 5). Application of trans-1g isomer to cyclization
reaction was not attempted.
Treatment with slow addition of Bu3SnH/AIBN increased
the ratio of 6g to 5g up to 95 : 5 (entry 6). Thus, even at higher
concentration of stannane, b-allylthio-a-phosphonovinyl radical
7g strongly favored 6-endo cyclization over 5-exo cyclization.
This data might not rule out the possibility that the product 6g
was formed via both of two different pathways, a direct 6-endo
radical cyclization of 7g to 10g and a 5-exo radical cyclization
to 8g, followed by rearrangement into thermodynamically
favorable 6-endo radical intermediate 10g through 9g, that is,
via “formal 6-endo cyclization” (Scheme 6).
were performed using the GAUSSIAN 98 program packages,
employing standard basis sets and theoretical methods as
14a
defined in these programs. Geometries were optimized at the
14b–d
Becke3LYP/6-31G* level of theory.
All structures were
characterized as minima (number of imaginary frequencies,
NIMAG = 0) or transition structures (NIMAG = 1) by analytic
energy second-derivative calculations of harmonic vibrational
frequencies. The same method was used to establish the connec-
tion of saddle points with minima on both sides by intrinsic
reaction coordinate (IRC) calculations. Relative energies are
given in kJ mol−1. Absolute energies and structures are provided
as ESI.†
A: Cyclization reaction
Cyclization reactions of vinyl radicals 7ꢀe–g with 5-exo and
6-endo fashion resulted in the formation of product radicals,
8ꢀe–g and 10ꢀe–g, respectively. The relative activation energies,
DDErxn‡, in cyclization reactions show that transition structures
of 5-exo cyclization reactions, 7ꢀe/8ꢀe, 7ꢀf/8ꢀf and 7ꢀg/8ꢀg, are
more stable than transition structures of 6-endo cyclization
reactions, 7ꢀe/10ꢀe, 7ꢀf/10ꢀf and 7ꢀg/10ꢀg, by −19.3, −12.1 and
−5.0 kJ mol−1, respectively. The cyclization reactions are all
highly exothermic and the reaction energies DErxn are in the
range between −112.6 and −152.4 kJ mol−1 (Fig. 1, Table 3).
Relative reaction energies, DDErxn, show that 5-exo radicals
8ꢀe–g are less stable than 6-endo radicals 10ꢀe–g by 26.0, 28.5
and 25.1 kJ mol−1, respectively. From these results it can be
concluded that cyclization reactions of 7ꢀe–g almost exclusively
(or predominantly in the case of 7ꢀg) take place with 5-exo
In order to investigate the reason which caused such high 6-
endo selectivity in the competition between 5-exo and 6-endo
cyclization, we next calculated the energy level diagram relevant
to the two competing mechanism in the radical cyclization of
simple vinyl radicals as model systems.
Theoretical calculations
The reactions were examined briefly by theoretical calculations
to disclose the origin of highly dependent selectivity (5-exo vs.
6-endo) upon the substrates, 7e–g, and reaction conditions,
since there was no report of such a calculation to the best of
our knowledge. The potential energy surfaces associated with
cyclization and rearrangement reactions of vinyl radicals 7ꢀe–
g were calculated as model systems (Scheme 7). Calculations
Table 3 Activation energies (DErxn‡) and reaction energies (DErxn) of
the intramolecular cyclizations of 7ꢀe–g into 5-exo and 6-endo radicals,
8ꢀe–g and 10ꢀe–g, and the rearrangement between the radicals 8ꢀe–g and
10ꢀe–g via the bicyclic radical 9ꢀe–ga,b
Cyclization
Rearrangement
‡
‡
Reaction
DErxn
DErxn
Reaction
DErxn
DErxn
7ꢀe → 8ꢀe
4.2
23.4
−126.4 8ꢀe → 9ꢀe
−152.4 9ꢀe → 10ꢀe
45.6
45.2
4.6
−30.6
7ꢀe→10ꢀe
DDErxn = −19.3c
‡
DDErxn = 26.0d
7ꢀf→8ꢀf
16.3
28.5
−112.6 8ꢀf → 9ꢀf
−141.1 9ꢀf → 10ꢀf
43.5
40.6
10.0
−38.5
7ꢀf→10ꢀf
‡
DDErxn = −12.1c
DDErxn = 28.5d
7ꢀg → 8ꢀg
16.3
21.4
−119.3 8ꢀg → 9ꢀg
33.1
−9.6
7ꢀg → 10ꢀg
−144.4 9ꢀg → 10ꢀg 39.4
−15.5
‡
DDErxn = −5.0c
DDErxn = 25.1d
‡
‡
a Becke3LYP/6-31G*. b kJ mol−1
.
c DDErxn
=
DErxn (7ꢀ→ 8ꢀ)
−DErxn‡(7ꢀ→ 10ꢀ). d DDErxn = DErxn (7ꢀ → 8ꢀ) −DErxn(7ꢀ → 10ꢀ).
Scheme 7 Model systems for theoretical calculation cyclization/
rearrangement reaction of vinyl radicals 7ꢀe–g.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 2 4 – 9 3 1
9 2 7

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fashion to give radicals 8ꢀe–g. The possibility of the formation of
8ꢀe–g via equilibrium between 8ꢀe–g and 10ꢀe–g can be excluded
because of higher thermodynamic stability of 10ꢀe–g than 8ꢀe–g.
The possibility of direct formation of 10ꢀg from 7ꢀg to some
extent can not be ruled out because of a lower energy gap
between 5-exo and 6-endo transition structures 7ꢀg/8ꢀg and
(or predominantly in the case of 7g). (ii) The radicals 8e–g are
thermodynamically less stable than 6-endo radicals 10e–g. (iii)
Rearrangement reactions of 8e–g take place with considerable
rate to give 10e–g and is competitive with radical trapping
reaction by Bu3SnH. Relative kinetic stabilities of the radicals
8e–g in the rearrangement reactions are in the order of 8e > 8f ꢁ
8g. It is proposed that cyclization of 7g takes place to form
kinetically favored 5-exo 8g, predominantly, which rearranges
so rapidly to give 6g in high yield even at higher concentrations
of Bu3SnH. Needless to say, at lower concentrations, the more
rearrangement product 10g would be formed. The possibility of
some contribution of direct formation of 10g can not be ruled
out from the model calculations as already mentioned.
7ꢀg/10ꢀg (DDErxn = −5.0 kJ mol−1).
‡
Synthetic application of a-phosphonovinyl radicals
On the basis of above results, we expected that the synthe-
sis of functionalized carbocyclic or heterocyclic compounds
incorporating an a,b-unsaturated phosphonate moiety can be
similarly realized by radical cyclization of functionalized a-
phosphonovinyl radicals. So, we investigated radical cyclization
of the terpenoid group-containing a-phosphonovinyl radicals
to give the terpenoid-functionalized carbocyclic or heterocyclic
compounds incorporating the vinylphosphonate moiety, which
are expected to act as versatile building blocks for the synthesis
of naturally occurring compounds and related derivatives or
to exhibit useful biological activity. The synthesis of a-iodo-
b-(geranyloxy)vinyl-11a and b-(geranylthio)vinylphosphonates
11b as radical precursors was achieved in a similar manner as
1g via double transfunctionalization of b-ethoxy-a-(trimethyl-
silyl)vinylphosphonates8 (Scheme 8). Diethyl 1-bromo-4,8-di-
methyl-4-vinylnona-1,7-dienylphosphonate (12) was prepared
by the Horner–Wadsworth reaction of tetraethyl a-bromo-
methylenediphosphonate with 3,7-dimethyl-3-vinyl-6-octenal.
Fig. 1 Potential energy surfaces of the intramolecular cyclization of
the model radicals 7ꢀe–g and of the rearrangement between the 5-exo
and 6-endo radicals, 8ꢀe–g and 10ꢀe–g calculated at the B3LYP/6-31G*
level of the theory (kJ mol−1).
B: Rearrangement
Calculation of the rearrangement reactions of 8ꢀe–g to 10ꢀe–g
via intermediate radicals 9ꢀe–g showed interesting features in
‡
activation and reaction energies, DErxn and DErxn (Table 3).
The activation energy DErxn in rearrangement 8ꢀe → 9ꢀe is
‡
Scheme 8 Preparation of terpenoid group-containing a-bromovinyl-
phosphonates 11a,b and 12. Reagents and conditions: (a) nBuLi, RH,
−78 ◦C to r.t.; (b) NaI, N-chlorosuccinimide, MeCN, r.t.; (c) tetraethyl
methylenediphosphonate, LDA, THF, −78 ◦C to r.t., and then NBS,
THF, −78 ◦C to r.t.
45.6 kJ mol−1 and slightly larger than those of 8ꢀf → 9ꢀf
(43.5 kJ mol−1) and 8ꢀg → 9ꢀg (33.1 kJ mol−1). The successive
rearrangements 9ꢀe → 10ꢀe, 9ꢀf → 10ꢀf and 9ꢀg → 10ꢀg again
show a similar trend indicating that the activation energies,
DErxn‡, are 45.2, 40.6 and 39.4 kJ mol−1, respectively. From these
results, it can be concluded that 5-exo radical 8ꢀg is considerably
kinetically less stable in rearrangement reactions than 8ꢀe and
8ꢀf. It is noteworthy that reaction 8ꢀg → 9ꢀg is exothermic by
−9.6 kJ mol−1, although the reactions 8ꢀe → 9ꢀe and 8ꢀf → 9ꢀf,
are slightly endothermic by 4.6 and 10.0 kJ mol−1, respectively.
These calculations supported the following assumptions. (i)
Cyclization reactions of intermediate radicals 7e–g irreversibly
take place with 5-exo fashion to give radicals 8e–g, exclusively
As expected, the tin-mediated reaction of a-iodo-b-(gera-
nyloxy)vinylphosphonate 11a produced exclusively 3-diethyl-
phosphono-4-(6ꢀ-methyl-5ꢀ-hepten-2ꢀ-yl)-4,5-dihydrofuran (14)
(74% yield), which is the 5-exo radical cyclization product of
a-phosphonovinyl radical 13 (Scheme 9).
Neither product via 6-endo radical cyclization or via
tandem cyclization was found. On the other hand, a-iodo-b-
(geranylthio)vinylphosphonate 11b on similar treatment led to
9 2 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 2 4 – 9 3 1

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Scheme 9 Cyclization of a-phosphonovinyl radicals.
Scheme 10 Tandem radical cyclization of a-phosphonovinyl radicals.
a 80 : 20 mixture of the 5-exo cyclization product, 3-diethyl-
phosphono-4-(6ꢀ-methyl-5ꢀ-hepten-2ꢀ-yl)-4,5-dihydrothiophene
(15) and the 6-endo cyclization product, 3-diethylphosphono-4-
methyl-4-(4ꢀ-methyl-3ꢀ-penten-1ꢀ-yl)-4,5-dihydro-6H-thiopyran
(16) in 97% yield. This tin-mediated radical cyclization
reaction was applied to homologous a-iodo-b-(2-cyclohexenyl-
thio)vinylphosphonate 17 to result in 3-phosphono-hexahydro-
benzothiophene 18 (eqn. (1)).
Conclusion
We note the following results from this investigation: (1) the first
direct generation of a-phosphonovinyl radicals was achieved by
treatment of a-halovinylphosphonates with Bu3SnH/AIBN. (2)
A new synthetic method of highly functionalized vinylphos-
phonates and vinylphosphonate-incorporated carbocyclic or
heterocyclic compounds, which are not easily accessible by the
established methods, was developed. (3) The influence of b-
substituents upon radical cyclization mode of a-phosphonovinyl
radicals was discussed on the basis of theoretical calculation of
vinyl radicals as model compounds.
Experimental
General methods
1
1H and 13C NMR spectra were obtained in CDCl3, H NMR
at 400.13 MHz, 500.00 MHz and 13C NMR at 100.62 MHz,
125.65 MHz with Me4Si as an internal standard. IR spectra
were recorded on a JEOL JIR-WINSPEC50 spectrometer. Mass
spectra were measured on a JEOL JMS-SX102A system.
(1)
General procedure for intermolecular additions of a-phosphono-
vinyl radicals derived from a-halovinylphosphonates 1a–d to
We are, furthermore, interested in development of a synthetic
route of fused bicyclic systems incorporating a vinylphospho-
nate moiety via a tandem radical cyclization process.15,16 Similar
treatment of the bromovinylphosphonate 12 with tin hydride
led to 92% of a 18 : 82 mixture of desired two isomeric
vinylphosphonate-incorporating bicyclo[4.3.0]nonene systems
21 and 22, which are produced via tandem 5-exo-cyclization-
6-exo-cyclization and 6-endo-cyclization-5-exo-cyclization pro-
cesses, respectively (Scheme 10).
Thus, we revealed that a-phosphonovinyl radical species can
be utilized for the synthesis of poly-functionalized vinylphos-
phonates and a wide variety of ring-size controlled carbocyclic
or heterocyclic compounds incorporating an a,b-unsaturated
phosphonate group within their rings.
alkenes. To
a solution of a-halovinylphosphonate 1a–d
(0.2 mmol) and an alkene (2.0 mmol) in benzene (1–8 mL) at
reflux was added Bu3SnH (0.22 mmol) and AIBN (0.02 mmol)
in benzene (1–2 mL) through a cannula using syringe pump
for 1–5 h. After addition, the reaction mixture was heated at
reflux for additional 1–7 h until starting material 1a–d was
completely consumed. After removal of the solvent, the residue
was chromatographed on preparative TLC (AcOEt–hexane =
2 : 1 or 1 : 1) to give 3a–f. The reaction conditions and yields
of 3a–f are summarized in Table 1. Representative spectral data
are given for 3b below.
Diethyl 3-(phenylthio)-1-(1,3-dithiolan-2-ylidene)propylphos-
phonate (3b). IR (neat) 792, 1041, 1390, 1243, 1438, 1538,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 2 4 – 9 3 1
9 2 9

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1
2981, 3451 cm−1; H NMR d 1.31 (6H, t, J = 7.1 Hz), 2.64–
3-(Diethylphosphono)-3a,4,5,6,7,7a-hexahydrobenzothiophene
2.73 (2H, m), 3.05–3.09 (2H, m), 3.36 (2H, t, J = 6.1 Hz), 3.41
(2H, m), 4.03–4.13 (4H, m), 7.17 (1H, t, J = 7.4 Hz), 7.29 (2H,
t, J = 7.5 Hz), 7.40 (2H, d, J = 7.5 Hz); 13C NMR ( 16.3 (d,
3JP C = 6.4 Hz), 30.67, 35.9 (d, 2JP = 8.4 Hz), 36.8, 39.1, 61.6
(18). IR (neat) 863, 960, 1238, 1392, 1448, 1540, 2933,
1
3486 cm−1; H NMR d 1.33 (6H, t, J = 7.1 Hz), 1.53–1.54
(1H, m), 1.57–1.63 (4H, m), 1.75–1.80 (2H, m), 1.89–1.98 (1H,
m), 2.88–2.91 (1H, m), 4.02–4.15 {[P(OCH2CH3)2, 4H, m],
(d, JP = 5.2 Hz), 110.2 (d, JP C= 190.0 Hz), 125.7, 128.7,
[SCH(CH2)(CH), 1H, m]}, 7.16 (1H, d, 3JP
= 11.8 Hz);
–
–
2
1
–
C
–
C
–
H
128.9, 136.0, 159.9 (d, JP = 15.4 Hz); MS m/z 390 (M+).
13C NMR d 16.3, 21.7, 22.8, 25.9, 27.2, 47.2, 54.3 (d, JP
=
2
3
–C
–
C
Anal. Calc. for C16H23PO3S3: H, 5.94; C, 49.21. Found: H, 6.03;
C, 49.17%.
12.7 Hz), 61.7 (d, 2JP = 5.4 Hz), 128.7 (d, 1JP = 190.7 Hz),
–
C
–
C
145.2 (d, JP = 17.5 Hz); MS (FAB+) m/z 277 (M+ + H);
2
–C
HRMS: calc. for C12H21O3PS 276.0949, Found 276.0959.
General procedure for cyclization reaction of a-phosphonovinyl
radicals derived from a-halovinylphosphonates 1e–g (Table 2,
entries 1, 3, 5). A solution of a-halovinylphosphonate 1
(0.2 mmol), Bu3SnH (0.22 mmol) and AIBN (0.02 mmol) in
benzene (2 mL) was heated under reflux for 3.5–4.0 h, until
starting material 1 was consumed completely. After removal of
the solvent, the residue was chromatographed on preparative
TLC (silica gel; AcOEt–hexane = 1 : 1) to give a difficultly
separable mixture of 5 and 6. The reaction conditions, and yields
and ratios of the mixtures of 5e–g and 6e–g are summarized in
Table 2.
Acknowledgements
We thank Professor Yong Hae Kim, Korea Advanced Institute
of Science and Technology, for support of this work, the Center
for Instrumental Analysis KIT for the use of their facilities. We
are grateful for financial support of this work by a Grant-in-Aid
for Scientific Research from the Ministry of Education, Science
and Culture of Japan.
References
General procedure for cyclization reaction of a-phosphonovinyl
radicals derived from a-halovinylphosphonates 1e–g (Table 2,
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Bu3SnH (0.22 mmol) and AIBN (0.02 mmol) in benzene (2 mL)
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The reaction conditions, and yields and ratios of the mixtures of
5e–g and 6e–g are summarized in Table 2. The mixtures of 5e–g
and 6e–g had the following properties.
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2H-furan (5e) and 3-(diethylphosphono)-4,5-dihydro-2H-pyran
(6e) (entry 2, Table 2). IR (neat) 794, 1025, 1259, 1608, 2964,
3471 cm−1; 1H NMR d 1.14 (3H, d, J = 6.8 Hz, for 5e), 1.24–1.30
[(6 + 11/50 × 6)H, m, for 5e and 6e], 1.80–1.89 (11/50 × 2H,
m, for 6e), 2.04–2.05 (11/50 × 2H, m, for 6e), 3.12–3.15 (1 H,
m, for 5e), 3.96–4.05 {[P(O)(OCH2CH3)2 (4 + 11/50 × 4)H,
m, for 5e and 6e], [OCHHCHMe, 1H, m, for 5e], [OCH2CH2,
11/50 × 2H, m, for 6e]}, 4.52 (OCHHCHMe, 1H, t, J = 9.8 Hz,
for 5e), 6.87 (1H, d, 3JP = 3.6 Hz, for 5e), 7.10 (11/50 × 1 H,
–H
d, 3JP H = 10.7 Hz, for 6e); MS m/z 220 (M+); HRMS: calc. for
–
C9H17O4P 220.0864; found 220.0860.
The mixture of 1-(diethylphosphono)-5-methylcyclopentene (5f)
and 1-(diethylphosphono)cyclohexene (6f) (entry 3, Table 2). 1H
NMR d 1.09 (3H, d, J = 6.9 Hz, for 5f), 1.23–1.28 [(6 + 1/2 ×
6)H, m, for 5f and 6f], 1.47–1.50 (1/2 × 2H, m, for 6f), 1.56–
1.60 (2H, m, for 6f), 2.1–2.15 [(2 + 1/2 × 2)H, m, for 5f and
6f], 2.39–2.44 (1/2 × 2H, m, for 6f), 2.45–2.46 (1/2 × 2H, m,
for 6f), 2.80–2.90 (1H, m, for 5f), 3.96–4.05 [(4 + 1/2 × 4)H, m,
for 5f and 6f], 6.57 (1H, ddd, 3JP H = 11.4 Hz, for 5f), 6.69 (1/2
–
3
H, ddd, JP = 22.2 Hz, for 6f); HRMS: calc. for C10H19O3P
–H
218.1072; found 218.1072.
The mixture of 3-(diethylphosphono)-4,5-dihydro-4-methyl-
2H-thiophene (5g) and 3-(diethylphosphono)-4,5-dihydro-2H-
thiopyran (6g) (entry 5, Table 2). IR (neat) 786, 962, 1024,
1
1232, 1571, 2931, 3453 cm−1; H NMR d 1.24 (6/25 × 3H, d,
J = 6.8 Hz, for 5g), 1.30–1.37 [(6 + 6/25 × 6)H, m, for 5g and
6g], 2.01–2.05 (2H, m, for 6g), 2.26–2.31 (2H, m, for 6g), 2.88–
2.91 (2H, m, for 6g), 3.53–3.58 (6/25 H, dd, J = 11.0 Hz, for
5g), 4.01–4.11 {[P(O)(OCH2CH3)2 (4 + 6/25 × 4)H, m, for 5g
and 6g], (SCHHCHMe, 6/25 H, m, for 5g)}, 7.11 (6/25 H, d,
3JP = 11.4 Hz, for 5g), 7.22 (1H, d, 3JP = 21.6 Hz, for 6g);
–
H
–
H
MS m/z 236 (M+); Anal. (as a mixture). Calc. for C9H17O3PS:
C, 45.75; H, 7.25. Found: C, 45.76; H, 7.15%.
9 3 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 2 4 – 9 3 1

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