Synthesis of purine- and pyrimidine-substituted heptadienes. The stereochemistry of cyclization and cyclopolymerization products

Article abstract of DOI:10.1021/jo026379k

A series of 1,6-heptadienes, substituted in the 4 position with nucleic acid bases 1-6, have been synthesized via Mitsunobu condensations. Guanine, adenine, thymine, and uracil derivatives can be prepared directly by coupling the protected base with 1,6-heptadien-4-ol (7). However, coupling protected cytosine and 7 gives an O-alkylated product. Thus, the cytosine derivative must be prepared from the uracil-substituted heptadienes via the triazole. The free-radical addition of CCl₄ and BrCCl₃ to these adducts was investigated. In all cases, both 1:1 and 1:2 adducts were obtained. The 1:1 adduct was identified as the cyclized product of the initially formed 5-hexen-1-yl radical. The cyclization takes place in a stereospecific manner, with only one of the four possible diastereomers resulting. NMR studies indicate that all substituents are cis in this product. In the case of the addition of CCl₄ to the uracil-substituted heptadiene, this conclusion was confirmed by an X-ray structure determination of the isolated cyclized product. The free-radical-initiated cyclocopolymerizations of 1-6 with SO₂ gave 1:1 copolymers with cis-linked five-membered rings. Two-dimensional NMR studies on poly(2-SO₂) showed predominately the cis-syn isomer while poly(6-SO₂) has an approximately equal amount of cis-syn and cis-anti isomers.

Full text of DOI:10.1021/jo026379k

Syn th esis of P u r in e- a n d P yr im id in e-Su bstitu ted Hep ta d ien es. Th e
Ster eoch em istr y of Cycliza tion a n d Cyclop olym er iza tion P r od u cts
J ui-Yi Tsai,* Kamal Hani Bouhadir, J ing-Lan Zhou, Thomas R. Webb, Yahong Sun, and
Philip B. Shevlin
Department of Chemistry, Auburn University, Auburn, Alabama 36380
jytsai@ppg.com
Received August 31, 2002
A series of 1,6-heptadienes, substituted in the 4 position with nucleic acid bases 1-6, have been
synthesized via Mitsunobu condensations. Guanine, adenine, thymine, and uracil derivatives can
be prepared directly by coupling the protected base with 1,6-heptadien-4-ol (7). However, coupling
protected cytosine and 7 gives an O-alkylated product. Thus, the cytosine derivative must be
prepared from the uracil-substituted heptadienes via the triazole. The free-radical addition of CCl4
and BrCCl3 to these adducts was investigated. In all cases, both 1:1 and 1:2 adducts were obtained.
The 1:1 adduct was identified as the cyclized product of the initially formed 5-hexen-1-yl radical.
The cyclization takes place in a stereospecific manner, with only one of the four possible
diastereomers resulting. NMR studies indicate that all substituents are cis in this product. In the
case of the addition of CCl4 to the uracil-substituted heptadiene, this conclusion was confirmed by
an X-ray structure determination of the isolated cyclized product. The free-radical-initiated
cyclocopolymerizations of 1-6 with SO2 gave 1:1 copolymers with cis-linked five-membered rings.
Two-dimensional NMR studies on poly(2-SO2) showed predominately the cis-syn isomer while
poly(6-SO2) has an approximately equal amount of cis-syn and cis-anti isomers.
In tr od u ction
radical has the potential of generating a variety of
carbocyclic nucleotide analogues (eq 1). Although there
Interest in the chemistry of carbocyclic nucleotides and
polymeric nucleic acid analogues has increased the need
to develop synthetic routes to precursors of these species.1
The 1,6-heptadienes 1-6 with a nucleic acid base sub-
stituted in the 4 position represent an interesting set of
such molecules.
have been numerous studies of cyclizations of 5-hexenyl
radicals derived from 1,6-heptadiene and from other
sources,2 we know of none where a nucleic acid base is
substituted in the 4 position of the 1,6-heptadiene.
Modification of the process in eq 1 such that the
intermediate cyclopentylmethyl radical is allowed to
participate in a cyclocopolymerization may produce nu-
cleic acid analogues. Because it is well-known that 1,6-
heptadienes undergo a cyclocopolymerization with sulfur
dioxide,3 the reaction in eq 2 is a potential route to
polysulfone nucleic acid analogues.
(1) (a) Schuster, M. J .; Wu, G. Y. Drugs Today 1996, 32, 653-661.
(b) Sanghvi, Y. S.; Cook, P. D. In Nucleotides and Nucleosides as
Antitumor and Antiviral Agents; Chu, C. K., Baker, D. C., Eds.;
Plenum: New York, 1993; pp 311-324. (c) Huryn, D. M.; Okabe, M.
Chem. Rev. 1992, 92, 1745-1768. (d) Uhlmann, E.; Peyman, A. Chem.
Rev. 1990, 90, 544. (e) Smith, W. T. Prog. Polym. Sci. 1996, 21, 209-
253. (f) Takemoto, K.; Mochizuki, E.; Wada, T.; Inaki, Y. Biomimetic
Polym. 1990, 253.
(2) (a) Geise, B. Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds; Pergamon Press: Oxford, 1986. (b) De Riggi,
S. G.; Surzur, J . M.; Bertrand, M. P. J . Org. Chem. 1992, 57, 6118-
6125. (c) Brumwell, J . E.; Simpkins, N. S. Tetrahedron Lett. 1993, 34
(7), 1219-1222. (d) Naim, A.; Mills, G.; Shevlin, P. B. Tetrahedron Lett.
1992, 33 (45), 6779-6782.
In these compounds, free-radical addition to the diene
system followed by cyclization of the resultant 5-hexenyl
* To whom correspondence should be addressed. PPG Industries,
440 College Park Dr., Monroeville, PA 15146.
10.1021/jo026379k CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/23/2003
J . Org. Chem. 2003, 68, 1235-1241
1235

Tsai et al.
SCHEME 1. Syn th esis of Dien es by Mitsu n obu
Cou p lin g
Polysulfone DNA has generated considerable interest
recently.4 Sulfones are nonionic, achiral, isoelectric ana-
logues of phosphate diesters, which are stable to both
chemical and biochemical degradation. Crystal structures
have shown that dimethylene sulfone-bridged ribonucleo-
tides can form A-type, Watson-Crick-paired duplexes5
and, at elevated temperatures, extended single-stranded
structures with only three torsion angles significantly
different from A-type duplex RNA.6 Therefore, it would
be interesting to generate the polysulfone nucleic acid
analogues by polymerization.
In this paper, we report the cyclization and copoly-
merization of SO2 with 1,6-heptadienes substituted in the
4 position (1-5) with nucleic acid bases to generate
carbocyclic analogues of nucleosides and polysulfone
nucleic acid analogues. Unlike previously reported poly-
sulfone nucleic acid analogues, those shown in eq 2 will
have the methylenes at the 3 and 4 positions cis to one
another.7 Although this weakens the analogy with nucleic
acids, these products are expected to have interesting
properties.
heptadien-4-ol (7) under Mitsunobu conditions and sub-
sequent deprotection. The guanine, adenine, thymine,
and uracil derivatives can be prepared directly by cou-
pling the protected base with 7. However, coupling the
protected cytosine, 8, and 7 gave predominantly the
O-alkylated product as shown in eq 3. The regiochemistry
Resu lt a n d Discu ssion
Syn th esis of Dien es. Mitsunobu conditions8 were
used to synthesize the 1,6-heptadienes 1-5 as shown in
Scheme 1. Thus, the protected guanine,9 adenine,10
thymine,11 uracil,11 and cytosine11 were coupled with 1,6-
of 13 was indicated by the downfield shift (75.1 ppm) of
the carbon attached to the O2 position of cytosine as
compared to the literature values of 50-60 ppm for
carbons on the N1 position in the corresponding N-
alkylated compounds.12,13 Cytosine protected at N4 usu-
ally acts as an ambient nucleophile in Mitsunobu reac-
tions with cyclopentanols, producing either the N- or
O-alkylated product or a mixture of both, depending on
the stereochemistry of the substituents on the carbocyclic
ring.14 Although the O-alkylated product is thermody-
namically stable, the N-alkylated product is often the
kinetically controlled product.15 The distribution of the
products in the Mitsunobu coupling of cytosines is usually
explained as arising from the inherent nucleophilicities
of the N1 and O2 in the attacking bases and the steric
hindrance in the competing SN2 transition states. This
steric hindrance is caused by an interaction either
between the incoming deprotonated base and the sub-
strate or between the oxyphosphonium leaving group and
the substituents on the substrate. In most cases, the N1
(3) (a) Butler, G. B. Cyclopolymerization and Cyclocopolymerization;
Marcel Dekker Inc.: New York, 1992; Chapter 2. (b) Amemiya, Y.;
Katayama, M.; Harada, S. Makromol. Chem. 1977, 178, 2499-2505.
(4) (a) Huang, Z.; Schneider, K. C.; Benner, S. A. J . Org. Chem. 1991,
56, 3869-3882. (b) Baseschlin, D. K.; Hyrup, B.; Benner, S. A.; Richert,
C. J . Org. Chem. 1996, 61, 7620-7626. (c) Schneider, K. C.; Benner,
S. A. Tetrahedron Lett. 1990, 31 (3), 335-338. (d) J enny, T. F.; Benner,
S. A. Helv. Chim. Acta 1993, 76, 826-841.
(5) Roughton, A. L.; Portmann, S.; Benner, S. A.; Egli, M. J . Am.
Chem. Soc. 1995, 117, 7249-7250.
(6) Hyrup, B.; Richert, C.; Schulte-Herbruggen, T.; Benner, S. A.;
Egli, M. Nucleic Acids Res. 1995, 117, 7249-7250.
(7) (a) Beckwith, A. L. J .; Blair, I.; Phillipou, G. J . Am. Chem. Soc.
1974, 96, 1613-1614. (b) Beckwith, A. L. J .; Lawrence, T.; Serelis, A.
K. J . Chem. Soc., Chem. Commun. 1980, 484-485. (c) Beckwith, A. L.
J .; Schiesser, C. H. Tetrahedron 1985, 41 (19), 3925-3941. (d) Kuehne,
M. E.; Damon, R. E. J . Org. Chem. 1977, 42, 1825-1832. (e) Beckwith,
A. L. J .; Schiesser, C. H. Tetrahedron Lett. 1985, 26 (3), 373-376. (f)
Beckwith, A. L. J .; Easton, C. J .; Lawrence, T.; Serelis, A. K. Aust. J .
Chem. 1983, 36, 545-556.
(8) (a) J enny, T. F.; Benner, S. A. Tetrahedron Lett. 1992, 33 (44),
6619-6620. (b) J enny, T. F.; Previsani, N.; Benner, S. A. Tetrahedron
Lett. 1991, 32 (48), 7029-7032.
(12) Perez-Perez, M. J .; Rozenski, J .; Busson, R.; Herdewijn, P. J .
Org. Chem. 1995, 60, 1531-1537.
(9) J enny, T. F.; Schneider, K. C.; Benner, S. A. Nucleosides
Nucleotides 1992, 11 (6), 1257-1261.
(13) Hossian, N.; Rozenski, J .; Clercq, E. D.; Herdewijn, P. Tetra-
hedron 1996, 43, 13655-13670.
(10) Schulhof, J . C.; Molko, D.; Teoule, R. Tetrahedron Lett. 1987,
28, 51-54.
(14) Bonnal, C.; Chavis, C.; Lucas, M. J . Chem. Soc., Perkin Trans.
1 1994, 11, 1401-1410.
(11) Brown, D. M.; Todd, A.; Varadarajan, S. J . Chem. Soc. 1956,
2384-2387.
(15) Zhou, J .-L. Ph.D. Thesis, Auburn University, Auburn, AL, 1997.
1236 J . Org. Chem., Vol. 68, No. 4, 2003

Purine- and Pyrimidine-Substituted Heptadienes
is more nucleophilic than the O2 and the kinetically
controlled product predominates. In the present case,
steric effects may favor the O-alkylation product.
Because 4 could not be generated directly by Mit-
sunobu coupling, we first prepared the uracil derivative
4-[(1H,3H)-pyrimidine-2,4-dion-1-yl]-1,6-heptadiene (5)
and converted it to 4 by established procedures (eq 4).16
F IGURE 1. 1H NMR chemical shifts of 22.
Because this is a kinetically controlled reaction, there is
no reason to expect that these energies will reflect the
experimental product ratios.
Treatment of 5 with POCl3 and 1,2,4-triazole in aceto-
nitrile gave the triazole 14. The attempted ammonolysis
of the triazole with a methanolic ammonia solution at
room temperature gave 1-(1,6-heptadien-4-yl)-4-meth-
oxypyrimidin-2(1H)-one (15). Ammonolysis was achieved
by heating 15 with methanolic ammonia at 110 °C to give
4 in 51% overall yield from 5. A comparison of the13C
NMR spectra of 4 with that of 13 indicates the formation
of a C-O bond (O-alkylation) in the Mitsunobu reaction
of the latter. Thus, the signal of C4 in 13 is at 75.1 ppm,
while the corresponding carbon signal in 4 is at 54.9 ppm.
The water-soluble heptadiene derivative 6 was syn-
thesized by reacting 1-(2-bromoethyl)uracil (16)17 with
methyldiallylamine (17) in refluxing dioxane (eq 5).
The free-radical cyclization of 5 was investigated using
the redox-transfer reaction of Fe2+/Fe3+ and CCl4 to
generate the trichloromethyl radical (eq 6).19 The 13C
F r ee-Ra d ica l Cycliza tion of Nu cleic Acid Ba se-
Su bstitu ted Hep ta d ien es. To assess the potential of
these substituted heptadienes to undergo free-radical
cyclopolymerization, we have investigated the addition
of CCl4 to 5. This reaction has the possibility of generat-
ing diastereomers 18-21. Molecular mechanics calcula-
tions (MM2-calculated steric energies are shown with the
structures)18 gave the expected trends in energies with
the two trans 3,4 diastereomers, 20 and 21, more stable
products than the two cis 3,4 diastereomers, 18 and 19.
NMR spectrum of the product mixture showed only two
peaks for the CCl3 carbons, indicating the formation of
two major products. These were shown to be the cyclized
1:1 adduct 22 and the open-chain 1:2 adduct 23. 22
precipitated in 28% yield when the crude product was
triturated with chloroform. 23, contaminated with some
22, was collected in 61% yield. The fact that the 1:2
adduct was formed suggests that Cl abstraction from
CCl4 competes with cyclization in the 5-hexen-1-yl radical
24.
(16) Divakar, K. J .; Reese, C. B. J . Chem. Soc., Perkin Trans. 1 1982,
1171-1176.
(17) Inaki, Y.; Fukunaga, S.; Suda, Y.; Takemoto, K. J . Polym. Sci.,
Polym. Chem. Ed. 1985, 24, 119-132.
(18) Gajewski, J . J .; Gilbert, K. E.; McKelvey, J . In Advances in
Molecular Modelling; Liotta, D. A., Ed.; J AI Press: Greenwhich, CT,
1990; Vol. 2, p 65. The program used was PCWIN, version 5.1, from
Serena Software, Bloomington, IN.
Surprisingly, only one isomer of the cyclization product
22 was detected in this reaction. Decoupled 1H NMR
1
spectra were helpful in assigning the H NMR chemical
shifts of this isomer that are listed in Figure 1.
(19) Asscher, M.; Vofsi, D. Org. Synth. 1965, 45, 104-107.
J . Org. Chem, Vol. 68, No. 4, 2003 1237

Tsai et al.
TABLE 1. 1H a n d 13C NMR Sp ectr a of 25
Difference NOE (DNOE) was utilized to assign the
stereochemistry of 22. Thus, the irradiation of Hb resulted
in a 2% enhancement of Ha, indicating that the substit-
uents at C3 and C4 are cis to one another. The same
irradiation resulted in a 1% enhancement of Hj, indicat-
ing that the uracil ring is cis to the CH2Cl group. Other
DNOE enhancements included as Supporting Informa-
tion are consistent with an all-cis structure for 22. The
structure of 22 was confirmed by X-ray crystallography.
The generation of only one cyclized product in this
reaction may be rationalized by assuming a transition-
state geometry similar to that of 24 in which the uracil
assumes a pseudoequatorial position, as has been estab-
lished,7 leading to the all-cis product.
1H
δ (ppm)
13C
δ (ppm)
H2′
H2′′
H5 and H5′
H3′
H1′
H2
1.95
2.36
3.17
2.60
4.82
8.95
8.21
C2′
36.9
C5 and C5′
55.0
35.2
60.1
148.9
143.2
C3′
C2′
C1
H8
C8
copolymerized to generate copolymers with satisfactory
NMR spectral properties, only the copolymers of 2 and 6
were examined in detail, and these will be discussed.
In analogy with the well-known stereochemistry of
5-hexenyl radical cyclizations7 and with that of other
cyclopolymerizations,24,25 we believe that the two meth-
ylene groups linking the cyclopentane rings in the
copolymers are cis to one another as shown in eq 7 for
copolymer 25.
Preliminary studies of the AIBN-catalyzed addition of
BrCCl3 to 2 and 3 lead to the isolation of a single 1:1
adduct and a 1:2 adduct in each case. Although the gross
1
structure of these adducts was established by H NMR
and mass spectrometry, the stereochemistry has not been
determined.
Cyclocop olym er iza tion of Dien es w ith SO2. At-
tempts to carry out homocyclopolymerizations of dienes
1-5 were unsuccessful, probably as a result of the
termination by abstraction of allylic hydrogens on the
diene. Allylic monomers often exhibit such degradative
chain-transfer behavior.20 To circumvent this problem,
we have investigated the copolymerization of our substi-
tuted heptadienes with SO2. In this case, the cyclo-
pentylmethyl radical, rather than abstracting an allylic
hydrogen, will react with SO2 to generate a sulfinyl
radical. The weak S-H bond in sulfinic acids precludes
H abstraction, and the sulfinyl radical adds to another
diene to continue the copolymerization. Attempts to
copolymerize 1-5 with SO2 at 81 °C with AIBN as an
initiator were only successful in the presence of high
concentrations of the monomer (>0.3 M). We attribute
this concentration effect on the elevated-temperature
polymerizations to the fact that, as in many addition
polymerizations, there is a ceiling temperature at which
the rate of addition of the monomer to the growing
polymer chain is equal to the rate of the reverse reac-
tion.21 As this ceiling temperature is approached, high
concentrations of the monomer are required to drive the
polymerization. This effect has been observed in other
copolymerizations involving SO2.22
The 13C NMR spectrum of 25 in Table 1 shows six
signals for the proton-attached carbons that were as-
signed by a DEPT experiment. A 13C-1H heteroscalar
correlation (HETCOR) experiment was used to assign the
protons attached to these carbons (Table 1). To determine
the stereochemistry of the adenine ring with respect to
the two -CH2SO2- groups, the NOESY spectrum was
obtained (Supporting Information). This spectrum allows
us to identify H2′ by means of its large cross-peak with
the unresolved H5′ and H5′′. The fact that there is a large
NOE cross-peak between H1′ and H2′′ indicates that the
adenine ring is cis to H2′ and thus cis to H5′ and H5′′.26
Although these considerations clearly indicate that this
copolymer consists predominately of cis-linked rings in
which the adenine is cis to the backbone, the 13C
dimension in the HETCOR spectrum of 25 shows the
splitting of C1′ and C2′, indicating the presence of at least
one other isomer. The NOESY spectrum of 25 taken at
high sensitivity (Supporting Information) clearly shows
two other minor correlations for H1′, indicating the
presence of two additional stereoisomeric linkages. Al-
though the resolution of these NMR experiments does
not allow us to assign the stereochemistry of these
linkages, it is reasonable to assume that they correspond
to cis-linked rings with the base trans and to trans-linked
rings (eq 8). Integration of the H1′ protons for the three
linkages allows us to estimate that 65% of the linkages
in 25 are cis with the adenine cis and that the other
To avoid the complications associated with the elevated-
temperature polymerizations, we have used tert-butyl
hydroperoxide to initiate the copolymerizations at 20 °C
in acetonitrile.23 Although dienes 1-6 could all be
(20) (a) McLean, C. D.; Ong, A. K.; Solomon, D. H. J . Macromol.
Sci., Chem. 1976, 10, 857-873. (b) Dixon, W. T.; Norman, R. O. C.;
Buley, A. L. J . Chem. Soc. 1964, 3625-3634.
(21) Dainton, F. S.; Ivin, K. J . Trans. Faraday Soc. 1950, 46, 331-
348.
(24) Butler, G. B. Cyclopolymerization and Cyclocopolymerization;
Marcel Dekker: New York, 1992; Chapter 2, p 39.
(25) Lancaster, J .; Baccei, L.; Panzer, H. J . Polym. Sci., Polym. Lett.
Ed. 1976, 14, 549-554.
(26) Gambino, J .; Yang, T. F.; Wright, G. E. Tetrahedron 1994, 50
(39), 11363-11368.
(22) (a) Frey, F. E. J . Am. Chem. Soc. 1943, 65, 2417-2418. (b)
Bywater, S. Trans. Faraday Soc. 1955, 51, 1267-1272. (c) Ivin, K. J .
Trans. Faraday Soc. 1955, 51, 1273-1279.
(23) Mazzolini, C.; Patron, L.; Moretti, A.; Campanelli, M. Ind. Eng.
Chem. Prod. Res. Dev. 1970, 9 (4), 504-511.
1238 J . Org. Chem., Vol. 68, No. 4, 2003

Purine- and Pyrimidine-Substituted Heptadienes
TABLE 2. 1H a n d 13C NMR Sp ectr a of 26a a n d 26b
26a
δ (ppm)
26b
δ (ppm)
26a /26b
δ (ppm)
1H
13C
H2′ and H2′′
H5′ and H5′′
3.76, 4.18
3.86, 3.62
3.65
3.36
3.94
4.40
5.95
7.75
3.77, 4.31
3.86, 3.62
3.59
3.42
3.86
4.37
5.95
7.75
C2′
C5′
C3′
C1′
CR
Câ
C5
67.5 (br)
51.8 (br)
H3′
H1′
HR
Hâ
H5
32.3, 31.6
49.4, 51.7
59.5, 63.1
42.8, 43.1
102.6, 102.8
146.4, 146.3
H6
C6
Hâ, and H3′ signals correspond to those of the two
isomeric linkages. In principle, a NOESY study could
determine which of these signals corresponds to H2′ and
which to H2′′. However, resolution problems make this
determination problematic.
Although we are unable to assign NMR signals to a
particular linkage, the integration of the two signals for
H1′ gave a ratio of isomeric linkages of 1.2:1. Thus, 26 is
formed with less stereoselectivity than is 25. Possible
reasons for this reduced stereoselectivity include less
difference in the steric demand of the groups attached
to the 4 position on the heptadiene and the fact that the
polymerization of 6 is carried out at 81 °C as compared
to 20 °C for 2.
stereoisomeric linkages are 19.4 and 15.6%. The pre-
dominance of an all-cis link in copolymer 25 is analogous
with the free-radical cyclization of 5 in which the all-cis
product is isolated.
Unlike dienes 1-5, the copolymerization of 6 with SO2
can be conveniently carried out at 81 °C with AIBN
initiation to generate the copolymer 26 as shown in eq
9.27 If 26 has the expected cis-linked pyrrolidine rings
Con clu sion s
These studies demonstrate that 1,6-heptadienes sub-
stituted in the 4 position with a nucleic acid base can be
conveniently synthesized via Mitsunobo condensations.
The free-radical cyclization of the adenine-substituted
diene generates a carbocyclic nucleoside analogue in
which all three substitutents are cis. The copolymeriza-
tion of these dienes with SO2 generates copolymers with
cis-linked cyclopentanes in the backbone. Although the
fact that both the free-radical cyclization products and
the copolymers have cis links in the 3′,4′ position
diminishes the biological relevance of these species, they
may exhibit interesting self-binding and replication
properties. These possibilities are currently under study.
Exp er im en ta l Section
The NMR spectral measurements for poly(1-, 2-, 3-, 4-,
and 5-SO2) were determined in 85:15 D2O/D2SO4 with TMS
as the external standard. For poly(6-SO2), the solvent was
D2O with H2O as the internal standard.
Ma ter ia ls. 1,6-Heptadien-4-ol (7),29 N6-isobutyrylcytosine
(8),11 N-benzoyluracil (9),11 3N-benzoylthymine (10),11 N2-
3
as do the homopolymers of diallylammonium salts,28 we
may expect that the steric demands of the groups
attached to the quaternary nitrogen (methylene and
methyl) would be similar and that the linkages 26a and
26b would be present in the copolymer. The 13C NMR
spectra of 26, listed in Table 2, confirm this expectation,
showing two signals for C1′, CR, Câ, C3′, C5, and C6. A
1H-detected heteronuclear multiple-quantum coherence
experiment allows us to assign the protons in 26, whose
chemical shifts are listed in Table 2. The two H1′, HR,
isobutyryl-O6-[2-(p-nitrophenyl)ethyl]guanine (11),9 N6-iso-
butyryladenine (12),10 and 1-(2-bromoethyl)uracil (16)17 were
prepared according to literature procedures.
Gen er a l P r oced u r e for Mitsu n obu Con d en sa tion s. A
500-mL flask was charged with protected base (1 equiv), 7 (1.2
equiv), triphenylphosphine (1 equiv), and dioxane (300 mL).
A solution of diethyldiazodicarboxylate (1 equiv) in dioxane
(100 mL) was added dropwise under a nitrogen stream over
0.5 h. The reaction was stirred at room temperature overnight
to yield a clear solution. The solvent was removed, and the
residue was purified by column chromatography (9:1 CH2Cl2/
CH3COCH3) to give a white solid. For the condensation
products of 9, 10, and 12 with 7, the deprotection was carried
out with sodium methoxide. For the condensation product of
(27) For an explanation for the lack of degradative chain transfer
on the monomer 6, see: Kabanov, V. A.; Topchiev, D. A.; Nazhmetdi-
nova, G. T. Vysokomol. Soedin., Ser. B 1984, 26 (1), 51-53.
(28) Lancaster, J .; Baccei, L.; Panzer, H. J . Polym. Sci., Polym. Lett.
Ed. 1976, 14, 549-554.
(29) Barbot, F. J . Organomet. Chem. 1977, 132, 445-454.
J . Org. Chem, Vol. 68, No. 4, 2003 1239

Tsai et al.
11, the 2-(p-nitrophenyl)ethyl group was first removed by
DBU,8 followed by ammonolysis to remove the isobutyl group.
4-(Gu a n in -9-yl)-1,6-h ep ta d ien e (1): 1H NMR (250 MHz)
δ 2.57 (m, 4 H), 4.37 (p, 1 H), 4.96 (m, 4 H), 5.58 (m, 2 H), 7.75
(s, 1 H), 10.55 (NH2, br); 13C NMR (250 MHz) δ 38.01, 53.45,
116.50, 117.93, 134.16, 136.13, 151.24, 153.23, 156.86; MS (EI)
m/z (relative intensity) 245 (M+, 29.16), 204 (57.83), 151 (100),
109 (59.85), 41 (55.75). HRMS calcd for C12H15N5O1, 245.1277;
found, 245.1271. 36.5% from 11 and 7.
4-(6-Am in o-9H-p u r in -9-yl)-1,6-h ep ta d ien e (2): 1H NMR
(250 MHz, CDCl3) δ 2.73 (m, 4 H), 4.65 (m, 1 H), 5.0 (m, 4 H),
5.6 (m, 2 H), 6.6 (br s, 2 H), 7.79 (s, 1 H), 8.35 (s, 1 H); 13C
NMR (250 MHz, CDCl3) δ 38.4, 55.4, 118.0, 119.9, 133.0, 139.2,
150.1, 152.7, 155.9; MS (VG 7070E, CI) m/z (relative intensity)
230 (M+, 100), 215 (6.9), 204 (22.3). HRMS (CI, M+) calcd for
2.56 (m, 4 H), 4.04 (s, 3 H), 5.04 (m, 1 H), 5.19 (m, 4 H), 5.74
(m, 2 H), 5.99 (d, 2 H), 7.43 (d, 2 H); 13C NMR (250 MHz) δ
37.79, 54.27, 55.59, 95.30, 118.93, 133.10, 143.79, 156.95,
170.80; MS (EI) m/z (relative intensity) 220 (M+, 6.85), 179
(48.98), 147 (22.70), 127 (100), 79 (75.31), 41 (44.37). HRMS
calcd for C12H16N2O2, 220.1211; found, 220.1206.
4-(Cytosin -1-yl)-1,6-h ep ta d ien e (4). A 50-mL high-pres-
sure reaction vessel was charged with 15 (0.7 g, 3.18 mmol)
and 30 mL of a saturated methanolic ammonia solution. The
vessel was sealed and heated at 110 °C for 48 h. The solvent
was removed and the residue purified by column chromatog-
raphy (8:2 CH2Cl2/acetone) to give 4 (0.58 g, 90%): 1H NMR
(250 MHz) δ 2.43 (m, 4 H), 4.82 (m, 1 H), 5.04 (m, 2 H), 5.65
(m, 4 H), 5.93 (d, 1 H), 7.15 (d, 1 H); 13C NMR (250 MHz) δ
37.85, 54.97 (br), 95.14, 118.47, 133.48, 141.71, 157.20, 165.46;
MS (EI) m/z (relative intensity) 205 (M+, 5.41), 164 (54.92),
121 (19.59), 112 (100), 94 (43.78), 79 (61.83), 41 (30.38). HRMS
calcd for C11H15O1N3, 205.1215; found, 205.1217.
[2-(Ur acil-1-yl)eth yl]m eth yldiallylam m on iu m Br om ide
(6). A mixture of 16 (2.2 g, 0.01 mol) and 17 (2.8 g, 0.025 mol)
in dioxane (40 mL) was refluxed overnight. After the removal
of the solvent, the residue was washed with diethyl ether and
recrystallized from ethanol to give 2.88 g (87%) of 6 as colorless
crystals: 1H NMR (D2O/dioxane, 250 MHz) δ 2.92 (s, 3 H),
3.35-3.41 (m, 2 H), 3.81 (d, J ) 7.2 Hz, 4 H), 4.07-4.13 (m, 2
H), 5.52-5.66 (m, 5 H), 5.69-5.95 (m, 2 H), 7.43 (d, J ) 7.9
Hz, 1 H); 13C NMR (D2O/dioxane, 62.9 MHz) δ 42.1, 47.8, 57.0,
64.6, 102.6, 123.8, 129.7, 146.6, 151.9, 166.5; MS (ES) m/z
(relative intensity) 250 (M - Br, 100).
F r ee-Ra d ica l Cycliza tion of 4-(6-Am in o-9H-p u r in -9-yl)-
1,6-h ep ta d ien e (2) w ith Br CCl3 a n d AIBN. A 50-mL round-
bottom flask was charged with 2 (0.5 g, 2.18 mmol), AIBN
(0.043 g, 0.217 mmol), and bromotrichloromethane (8.84 mL,
108.89 mmol). The flask was purged with nitrogen gas and
heated at 70 °C for 16 h. The solvent was evaporated under
reduced pressure, and diethyl ether was added to dissolve the
brownish residue. Upon standing overnight, a white powder
precipitated and was identified as the 1:1 adduct (0.1 g, 13%):
1H NMR (250 MHz, DMSO-d6) δ 2-3.3 (m, 8 H), 4.28 (d, 1 H),
4.89 (d, 1 H), 5.22 (m, 1 H), 8.4 (s, 1 H), 8.72 (s, 1 H), 9.2 (br
d, 2 H); 13C NMR (250 MHz, DMSO-d6) δ 35.97 (d), 37.3 (t),
54.3 (d), 54.7 (d), 58.9 (t), 100.5 (d), 120.4 (d), 139.8 (s), 141.1
(s), 148.8 (d), 156.6 (s); MS (CI) m/z (relative intensity) 348
(M + 2 - Br, 2.5), 346 (M - Br, 1.9), 312 (15.3), 310 (17.8),
244 (15.9), 242 (19.6), 136 (100); MS (EI) m/z (relative
intensity) 393 (M + 4 - HBr, 0.41), 391 (M + 2 - HBr, 1.08),
389 (M - HBr, 0.61), 136 (59.86), 135 (100). The mother liquor
was evaporated under reduced pressure to give 0.72 g of crude
mixture (71%), where the major product was identified as the
1:2 adduct: MS (CI) m/z (relative intensity) 635 (M + 14, 0.4),
633 (M + 12, 0.8), 631 (M + 10, 3.9), 629 (M + 8, 12.6), 627
(M + 6, 22.8), 625 (M + 4, 26.7), 623 (M + 2, 15.7), 621 (M+,
4.1), 188 (5.4), 162 (16), 136 (100), 135 (26.4).
C
12H15N5, 230.1405; found, 230.1407. 33.2% from 12 and 7.
4-[(1H,3H)-5-Meth ylp yr im id in e-2,4-d ion -1-yl]-1,6-h ep -
1
ta d ien e (3): H NMR (250 MHz, CDCl3) δ 1.93 (s, 3 H), 2.43
(m, 4 H), 4.72 (m, 1 H), 5.06 (m, 4 H), 5.7 (m, 2 H), 6.92 (s, 1
H), 9.3 (br s, 1 H); 13C NMR (250 MHz, DMSO-d6) δ 12.6, 37.8,
54.7, 110.6, 118.9, 133, 136.6, 151.5, 163.7; MS (EI) m/z
(relative intensity) 220 (M+, 4.18), 179 (66.64), 136 (100), 127
(15.29), 109 (7.35). HRMS calcd for C12H16N2O2, 220.1212;
found, 220.1216. 22.5% from 10 and 7.
4-[(1H,3H)-P yr im idin e-2,4-dion -1-yl]-1,6-h eptadien e (5):
1H NMR (250 MHz, CDCl3) δ 2.3-2.5 (m, 4 H), 4.75 (p, 1 H),
5.0-5.12 (m, 4 H), 5.6-5.75 (m, 2 H), 5.72 (d, 1 H), 7.12 (d, 1
H), 7.79 (s, 1 H), 8.35 (s, 1 H); 13C NMR (250 MHz, CDCl3) δ
37.75, 54.96, 102.15, 119.2, 132.7, 141.1, 151.4, 163.4; MS (EI)
m/z (relative intensity) 206 (M+, 5), 165 (76), 122 (100), 113
(13), 95 (41.5). HRMS (EI, M+) m/e calcd for C11H14N2O2,
206.1055; found, 206.1056. 46% from 9 and 7.
2-(1,6-Hep ta d ien -4-yl)-O2-isobu tyr ylcytosin e (13): 1H
NMR (250 MHz, CDCl3) δ 1.20 (d, 6 H), 2.41 (m, 4 H), 2.58
(m, 1 H), 4.98 (m, 2 H), 5.16 (m, 1 H), 5.76 (m, 4 H), 7.72 (d,
1 H), 8.26 (br s, 1 H), 8.31 (d, 1 H); 13C NMR (250 MHz, CDCl3)
δ 19.1, 36.3, 37.5, 75.1, 103.9, 117.6, 133.5, 159.9, 160.4, 164.2,
176.4; MS (EI) m/z (relative intensity) 276 (M+, 6.47), 235
(53.26), 181 (100), 165 (42.22), 150 (63.03). HRMS calcd for
C
15H21O2N5, 275.1634; found, 275.1631.
4-(1,2,4-Tr ia zol-1-yl)-1-(1,6-h ep t a d ien -4-yl)p yr im id in -
2(1H)-on e (14). Triethylamine (1.16 mL, 8.36 mmol) was
added dropwise to a stirred, cooled (ice-water bath) mixture
of 1,2,4-triazole (603.4 mg, 8.74 mmol), phosphoryl chloride
(0.17 mL, 1.87 mmol), and acetonitrile (20 mL). To the
resulting mixture was added a solution of 5 (0.2 g, 0.97 mmol)
in acetonitrile (30 mL), and the reaction mixture was stirred
at room temperature overnight. Triethylamine (0.74 mL, 5.26
mmol) and water (0.19 mL, 10.5 mmol) were then added. After
10 min, the solvent was evaporated under reduced pressure.
The residue was partitioned between chloroform (50 mL) and
saturated aqueous sodium hydrogen carbonate (30 mL). The
organic layer was separated and the aqueous layer extracted
with chloroform (2 × 30 mL). The combined organic layers
were dried (MgSO4), and the residue was purified by column
chromatography (9:1 CH2Cl2/acetone) to yield a white solid
(0.189 g, 76%): 1H NMR (250 MHz) δ 2.56 (m, 4 H), 5.04-
5.13 (m, 5 H), 5.69 (m, 2 H), 7.05 (d, 1 H), 7.89 (d, 1 H), 8.14
(s, 1 H), 9.28 (s, 1 H); 13C NMR (250 MHz) δ 37.69, 57.31, 94.43,
119.7, 132.48, 143.1, 147.98, 154.04, 155.53, 158.46; MS (ES)
m/z (relative intensity) 257 (M+, 3.81), 94 (75.63), 79 (100), 53
(54.12), 39 (45.46), 28 (31.22). HRMS calcd for C13H15N5O1,
257.1277; found, 257.1283.
1-(1,6-H e p t a d ie n -4-yl)-4-m e t h oxyp yr im id in -2(1H )-
on e (15). Aqueous ammonia (0.30 g) was added to a solution
of 14 (0.14 g, 0.55 mmol) in dioxane (10 mL) at room
temperature. After 6 h, the reaction mixture was concentrated
under reduced pressure and the residue dissolved in metha-
nolic ammonia (half-saturated at 0 °C, 16.5 mL). After 16 h,
the solution was evaporated to dryness. The residue was
purified by column chromatography (9:1 CH2Cl2/acetone) and
gave 15 as a white solid (78 mg, 75%): 1H NMR (250 MHz) δ
F r ee-Ra d ica l Cycliza tion of 4-[(1H,3H)-P yr im id in e-2,4-
d ion -1-yl]-1,6-h ep ta d ien e (5) w ith CCl4 by Red ox Tr a n s-
fer . A 10-mL round-bottom flask was charged with 5 (1.0 g,
4.85 mmol), benzoin (0.1 g, 0.47 mmol), FeCl3‚6H2O (0.1 g, 0.37
mmol), CCl4 (2.5 mL, 25.8 mmol), acetonitrile (1.0 mL, 18.9
mmol), and Et2NH2Cl (0.05 g, 0.46 mmol). The flask was freeze
thawed, degassed twice, purged with nitrogen gas, and heated
at 80 °C for 22 h. Chloroform (10 mL) was added, and the
mixture was washed with aqueous HCl (10%, 10 mL), dried
over anhydrous MgSO4, and filtered. The solvent was evapo-
rated under reduced pressure to give a mixture of products.
One isomer was crystallized from methanol (0.5 g, 28.6%), and
the mother liquor was evaporated under reduced pressure to
give 1.07 g of crude mixture (61%). The crystalline product
was identified as the 1:1 adduct 22: 1H NMR (250 MHz,
DMSO-d6) δ 1.84 (m, 1 H), 1.99 (q, 1 H), 2.36 (m, 2 H), 2.59
(m, 1 H), 2.68 (m, 1 H), 3.04 (m, 1 H), 3.78 (m, 2 H), 4.82 (p,
1 H), 5.65 (d, 1 H), 7.48 (d, 1 H), 11.11 (br s, 1 H); 13C NMR
(250 MHz, DMSO-d6) δ 33.19 (d), 36.47 (t), 33.59 (d), 40.8 (d),
1240 J . Org. Chem., Vol. 68, No. 4, 2003

Purine- and Pyrimidine-Substituted Heptadienes
47 (t), 54.37 (t), 55 (d), 100 (s), 102.4 (d), 141.34 (d), 151.2 (s),
163.5 (s); MS (EI) m/z (relative intensity) 360 (M + 2, 0.85),
358 (M+, 0.69), 325 (0.82), 323 (M - Cl, 0.83), 113 (100), 112
(56.89); HRMS (EI, M+) m/e calcd for C12H14N2O2Cl4, 357.9809;
found, 357.9808. Crystals were obtained by crystallizing the
1:1 adduct from dioxane. The major product in the crude
mixture was identified as the 1:2 adduct 23: 1H NMR (250
MHz, DMSO-d6) δ 1.84 (m, 1 H), 1.99 (q, 1 H), 2.4 (m, 4 H),
3.76 (m, 2 H), 4.38 (m, 1 H), 5.18 (d, 1 H), 8.5 (d, 1 H); 13C
NMR (250 MHz, DMSO-d6) δ 39.4, 41.3, 54.1, 59.2, 96.2, 101.4,
142.6.
P oly[4-(a d en in -9-yl)-1,6-h ep ta d ien e-SO2] (25): 1H NMR
(400 MHz, 85:15 D2O/D2SO4) δ 1.95, 2.36, 2.60, 3.17, 4.82, 8.21,
8.95; 13C NMR (400 MHz, 85:15 D2O/D2SO4) δ 35.2, 36.9, 55.0,
60.1, 143.2, 148.9; IR (KBr) 3101, 1699, 1284, 1137 cm-1. 70%
yield.
P oly[4-(gu an in -9-yl)-1,6-h eptadien e-SO2]: 1H NMR (400
MHz, 85:15 D2O/D2SO4) δ 1.23, 1.77, 2.43, 2.82, 2.94, 3.17, 3.65,
4.45, 7.75, 8.49; IR (KBr) 1140, 1290, 1403, 1690, 3143 cm-1
.
40% yield. Because poly(5-SO2) has a very low solubility in
any common organic solvent or acidic or basic aqueous
solution, the 13C NMR spectrum was not measured.
F r ee-Ra d ica l Cycliza tion of 4-[(1H,3H)-5-Meth ylp yr im -
id in e-2,4-d ion -1-yl]-1,6-h ep ta d ien e (3) w ith Br CCl3 by
Red ox Tr a n sfer . A 50-mL round-bottom flask was charged
with 3 (6.35 g, 28.8 mmol), benzoin (0.127 g, 0.6 mmol), FeCl3‚
6H2O (0.18 g, 0.67 mmol), BrCCl3 (4.5 mL, 45.7 mmol),
acetonitrile (3.0 mL, 56.7 mmol), and Et2NH2Cl (0.1 g, 45.7
mmol). The flask was freeze thawed, degassed twice, purged
with nitrogen gas, and heated at 80 °C for 4 days. Chloroform
(5 mL) was added, and the mixture was washed with aqueous
hydrochloric acid (10%, 3 mL), dried with anhydrous magne-
sium sulfate, and filtered. The solvent was evaporated under
reduced pressure to give a mixture of products. One isomer
was crystallized from methanol (2.72 g, 23%) and was identi-
fied as the 1:1 cyclized product: 1H NMR (250 MHz, DMSO-
d6) δ 1.7 (m, 1 H), 1.79 (s, 3 H), 1.96 (q, 1 H), 2.2 (m, 2 H), 2.5
(m, 1 H), 2.6 (m, 1 H), 2.9-3.2 (m, 2 H), 3.7 (d, 2 H), 4.73 (p,
1 H), 7.6 (s, 1 H), 11.2 (br s, 1 H); 13C NMR (250 MHz, DMSO-
d6) δ 11.97 (q), 34.6 (t), 35.4 (t), 37.25 (t), 37.5 (d), 41.5 (d),
53.7 (t), 54.4 (d), 99.95 (s), 109.0 (d), 137.8 (s), 150.76 (s), 163.6
(s); MS (EI) m/z (relative intensity) 422 (M + 6, 0.14), 420 (M
+ 4, 0.61), 418 (M + 2, 0.88), 416 (M+, 0.42), 127 (27.89), 126
(100). The mother liquor was evaporated under reduced
pressure to yield the 1:2 adduct contaminated with some 1:1
adduct: 1H NMR (250 MHz, DMSO-d6) δ 1.72 (s, 3 H), 2.3-
2.5 (m, 2 H), 3.3-3.5 (m, 1 H), 4.0 (m, 1 H), 4.3 (m, 2 H), 7.25
(s, 1 H), 11.0 (br s, 1 H); 13C NMR (250 MHz, DMSO-d6) δ
11.67 (q), 97.3 (s), 107.5 (d), 137.6 (s), 151.3 (s), 164.8 (s); MS
(EI) m/z (relative intensity) 620 (M+8, 0.12), 618 (M+6, 0.18),
616 (M+4, 0.24), 614 (M+2, 0.13), 126 (100), 55 (83.79).
Gen er al P r ocedu r e for th e Copolym er ization of Dien es
1-5 w ith SO2. The monomers 1-5 (0.873 mmol) and the
initiator (TBHP, 4.74 mg, 0.043 mmol) were placed in a long-
stemmed glass tube. Acetonitrile was added as the solvent to
maintain the monomer concentration at 0.1 M. The tube was
attached to a vacuum line, and sulfur dioxide (55.87 mg, 0.873
mmol) was distilled in at 77 K. The tube was then degassed
and sealed off. The reaction vessel was placed at -23 °C
(CCl4-liquid N2 slurry) for 24 h. The solvent was evaporated
and the residue washed with methanol to remove the mono-
mer, giving the polymer as an insoluble residue. The molecular
weight of the polymer was not measured. The poly(1-, 2-,
3-, 4-, and 5-SO2) were slightly soluble in DMSO and soluble
in H2SO4.
P oly[4-(th ym in -1-yl)-1,6-h eptadien e-SO2]: 1H NMR (400
MHz, 85:15 D2O/D2SO4) δ 1.80, 2.27, 2.62, 3.12, 4.05, 4.42, 7.74;
13C NMR (400 MHz, 85:15 D2O/D2SO4) δ 11.9, 35.2, 36.9, 55.0,
60.1, 109, 137.9, 150.7, 163.3; IR (KBr) 1137, 1284, 1403, 1684,
3143 cm-1. 64% yield.
P oly[4-(cytosin -1-yl)-1,6-h eptadien e-SO2]: 1H NMR (400
MHz, 85:15 D2O/D2SO4) δ 1.60, 2.05, 2.53, 3.06, 4.35, 5.88, 7.44;
13C NMR (400 MHz, 85:15 D2O/D2SO4) δ 31.1, 32.25, 52.4, 58.7,
95.1, 146.1; IR (KBr) 1120, 1280, 1542, 1679, 2350, 3103 cm-1
74% yield.
.
P oly[4-(u r a cil-1-yl)-1,6-h ep ta d ien e-SO2]: 1H NMR (400
MHz, 85:15 D2O/D2SO4) δ 1.70, 2.28, 2.60, 3.24, 3.66, 4.43, 6.23,
7.88; 13C NMR (400 MHz, 85:15 D2O/D2SO4) δ 36.7, 38.15, 52.3,
55.38, 105.5, 146.20, 161.2, 176.9; IR (KBr) 1137, 1284, 1403,
1684, 3143 cm-1. 48% yield.
P oly{[2-(u r a cil-1-yl)et h yl]m et h yld ia llyla m m on iu m -
SO2} Br om id e (26). A solution of 6 (0.11 g, 0.33 mmol), AIBN
(1.64 mg, 0.01 mmol), and 3.3 mL of methanol was placed in
the long-stemmed glass tube, which was attached to a vacuum
line, and sulfur dioxide (21.1 mg, 0.33 mmol) was distilled in
at 77 K. The tube was degassed, sealed off under vacuum, and
heated at 81 °C (the boiling point of acetonitrile) for 5 h. At
the conclusion of the reaction, the volatiles were removed
under reduced pressure. A small amount of water was added,
and the mixture was dialyzed against water (cellulose mem-
brane, MW cutoff 1000) for 48 h to give 105 mg (80%) of 26
after evaporation of the water: 1H NMR (400 MHz, D2O) δ
1.43, 3.15, 3.23, 3.36, 3.42, 3.59, 3.62, 3.65, 3.76, 3.86, 3.94,
4.13, 4.31, 4.37, 4.40, 5.95, 7.75; 13C NMR (400 MHz, D2O) δ
31.6, 32.3, 42.8, 43.1, 49.4, 51.7, 51.8 (br), 59.5, 63.1, 67.5 (br),
102.6, 102.8, 146.3, 146.4, 152.0, 166.5; IR (KBr) 495, 515,
1126, 1261, 1684, 3040, 3427 cm-1
.
Su p p or tin g In for m a tion Ava ila ble: DNOE results and
the ORTEP figure for the adduct 22, and two-dimensional
NOESY NMR spectrum of copolymer 25 in high and low
contour levels. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O026379K
J . Org. Chem, Vol. 68, No. 4, 2003 1241