SET-induced photorearrangement of 2-phenylallyl phosphites. Stereochemistry at phosphorus application to cyclic nucleotide derivatives

Article abstract of DOI:10.1021/jo9919557

The stereochemistry at phosphorus of the SET-induced photorearrangement of diastereomeric 4-tert-butyl-2-phenylallyl-1,3,2-dioxaphosphorinanes (8) to the corresponding 2-phenylallylphosphonates (9), which involves excited singlet 1,4-dicyanonaphthalene (1DCN*) as one-electron oxidant, was investigated. The rearrangement occurs with close to complete retention of configuration at phosphorus. The previously postulated mechanism for this photorearrangement is shown to be consistent with the stereochemical finding. Thus, one-electron reduction by DCN2.^- of the presumably stereospecifically formed distonic cyclic 1,3-cation radical intermediate 15, generated from cis-8 (Scheme 2), yields the thermodynamically stable diradical 16. β scission of 16 forms phosphonate cis-9. An alternative mechanism involving β scission of 15 to a styryl cation radical, prior to one-electron reduction to 15, is discounted on the basis of unpublished trapping studies using MeOH. The direct, kinetically controlled formation of diradical 16 rather than the thermodynamically less stable 21 with CH₂ bonded apically to phosphorus is argued to be consistent with the essentially equal values of the quantum yield for phosphonate formation (φp) on SET-induced rearrangement of the acyclic 2-phenylallyl phosphite 1 and phosphite 7 with phosphorus incorporated in a six-membered (1,3,2-dioxaphosphorinane) ring. This mechanism is contrasted to that for the previously reported triplet- sensitized photorearrangements of phosphites 1 and 7, which have greatly different φp values. For these reactions, kinetic formation of the triplet analogue of 21, but without the tertbutyl substituent, requires a permutation of substituents for conversion to diradical 16 prior to intersystem crossing and β scission to form the phosphonate corresponding to 7. The preparative- scale SET-induced photorearrangement of the thymidine-based 2-phenylallyl 3',5'-phosphite 10 gave both diastereomers of phosphonate 11 that were separated by HPLC. The 2-phenylallyl functionality provides an opportunity for further functionalization. As reported elsewhere, 11 was not formed in useful amounts via triplet-sensitized reaction of 10.

Full text of DOI:10.1021/jo9919557

2778
J . Org. Chem. 2000, 65, 2778-2785
SET-In d u ced P h otor ea r r a n gem en t of 2-P h en yla llyl P h osp h ites.
Ster eoch em istr y a t P h osp h or u s. Ap p lica tion to Cyclic Nu cleotid e
Der iva tives
David C. Hager, Alan E. Sopchik, and Wesley G. Bentrude*
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112
Received December 23, 1999
The stereochemistry at phosphorus of the SET-induced photorearrangement of diastereomeric 4-tert-
butyl-2-phenylallyl-1,3,2-dioxaphosphorinanes (8) to the corresponding 2-phenylallylphosphonates
(9), which involves excited singlet 1,4-dicyanonaphthalene (1DCN*) as one-electron oxidant, was
investigated. The rearrangement occurs with close to complete retention of configuration at
phosphorus. The previously postulated mechanism for this photorearrangement is shown to be
consistent with the stereochemical finding. Thus, one-electron reduction by DCN.- of the presumably
stereospecifically formed distonic cyclic 1,3-cation radical intermediate 15, generated from cis-8
(Scheme 2), yields the thermodynamically stable diradical 16. â scission of 16 forms phosphonate
cis-9. An alternative mechanism involving â scission of 15 to a styryl cation radical, prior to one-
electron reduction to 15, is discounted on the basis of unpublished trapping studies using MeOH.
The direct, kinetically controlled formation of diradical 16 rather than the thermodynamically less
stable 21 with CH2 bonded apically to phosphorus is argued to be consistent with the essentially
equal values of the quantum yield for phosphonate formation (φP) on SET-induced rearrangement
of the acyclic 2-phenylallyl phosphite 1 and phosphite 7 with phosphorus incorporated in a six-
membered (1,3,2-dioxaphosphorinane) ring. This mechanism is contrasted to that for the previously
reported triplet-sensitized photorearrangements of phosphites 1 and 7, which have greatly different
φP values. For these reactions, kinetic formation of the triplet analogue of 21, but without the tert-
butyl substituent, requires a permutation of substituents for conversion to diradical 16 prior to
intersystem crossing and â scission to form the phosphonate corresponding to 7. The preparative-
scale SET-induced photorearrangement of the thymidine-based 2-phenylallyl 3′,5′-phosphite 10
gave both diastereomers of phosphonate 11 that were separated by HPLC. The 2-phenylallyl
functionality provides an opportunity for further functionalization. As reported elsewhere, 11 was
not formed in useful amounts via triplet-sensitized reaction of 10.
In tr od u ction
radical cation, 5, prior to its reduction to 6 by electron
capture. In addition to unusual mechanistic consider-
ations, these photorearrangements are of interest for the
formation of allylphosphonates that can be further func-
tionalized and/or used in Horner-Emmons chemistry.
The same overall rearrangement including regiochem-
istry is effected by triplet sensitization4 of the styryl
functionality of 1 by benzophenone or triphenylene, as
previously reported.5 A triplet 1,3-diradical (triplet 4) was
invoked as the key intermediate. Product 6 presumably
arises from singlet 4 following triplet-singlet intersystem
crossing. The quantum yield for triplet-sensitized phos-
phonate 6 formation (φP) from 1 is relatively high (0.2-
0.3).5a,b Strikingly, when phosphorus is part of a six-
membered ring (7), the triplet-sensitized photorearrange-
ment is very inefficient (φP ) 0.002-0.003).5a,b A requisite
Induction of the rearrangement of dimethyl 2-phenyl-
allyl phosphite, 1, to the corresponding 2-phenylallyl-
phosphonate, 6, by electron transfer to excited singlet 9,-
10-dicyanoanthracene (1DCA*) was recently reported.1
The experimentally determined regiochemistry and two
potential mechanisms for the process are depicted in
Scheme 1. (In Scheme 1, photo-SET oxidant 1,4-dicy-
anonaphthalene, DCN, employed in the present study,
is depicted instead of DCA.) Although relative oxidation
potentials for removal of an electron from phosphorus2
and from the styryl3 system are too close to permit the
assignment of the position of the charge in cation radical
2, it was proposed that 2 cyclizes rapidly to generate the
distonic cyclic 1,3-cation radical 3. Product formation may
involve donation of an electron from the DCA radical
anion to 3 to afford 1,3-diradical 4 from which product
phosphonate 6 arises via C-O â scission to introduce the
two π bonds in 6. An alternative route to 6, set forth in
Scheme 1, is the ring opening of radical 3 to the styryl
(4) Measured triplet energies, ET, for: (a) R-Methylstyrene: 62 kcal/
mol (Crosby, P. M.; Dyke, J . M.; Metcalfe, J .; Rest, A. J .; Salisbury,
K.; Sodeau, J . R. J . Chem. Soc., Perkin Trans. 2 1977, 182. Tuqlang,
N. I.; Caldwell, R. A.; Melton, L. S. J . Am. Chem. Soc. 1989, 111, 457.)
(b) Benzophenone: 69.2 kcal/mol; triphenylene 67.0 kcal/mol (both
values from Murov, S. L.; Carmichael, I.; Hug, G. L. Handbook of
Photochemistry; Marcel Dekker: New York, NY, 1993.)
(5) (a) Bentrude, W. G.; Dockery, K. P.; Ganapathy, S.; Lee, S.-G.;
Tabet, M.; Wu, Y. W.; Cambron, R. T.; Harris, J . M. J . Am. Chem.
Soc. 1996, 118, 6192. (b) Ganapathy, S.; Cambron, R. T.; Dockery, K.
P.; Wu, Y. W.; Tetrahedron Lett. 1993, 34, 5987. (c) Bentrude, W. G.;
Lee, S.-G. J . Am. Chem. Soc. 1987, 109, 1577. (d) Bentrude, W. G.;
Lee, S.-G.; Akutagawa, K.; Ye, W.; Charbonnel, Y.; Omelanczuk, J .
Phosphorus Sulfur 1987, 30, 105.
(1) Ganapathy, S.; Dockery, K. P.; Sopchik, A. E.; Bentrude, W. G.
J . Am. Chem. Soc. 1993, 115, 8863.
(2) (a) Oxidation potential vs SCE for (MeO)3P, 1.64 eV (Ohmori,
H.; Nakai, S.; Masui, M. J . Chem. Soc., Perkin Trans. 1 1979, 2023).
(b) Reduction potention for DCA, -0.89 eV (Darmanyan, A. P. Chem.
Phys. Lett. 1984, 110, 89)
(3) Oxidation potential for R-methylstyrene vs SCE, is 1.76 eV (Katz,
M.; Riemenschneider, P.; Wendt, H. Electrochim. Acta 1972, 17, 1595).
10.1021/jo9919557 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/04/2000

Photorearrangement of 2-Phenylallyl Phosphites
J . Org. Chem., Vol. 65, No. 9, 2000 2779
Sch em e 1
Sch em e 2
thermodynamically favored 1,3-diradical, 16. Moreover,
we will show this mechanism to be in accord with the
constancy in the quantum yields for SET-induced rear-
rangements of 1 and 7.
We also report the successful application of the pho-
toinduced SET process for the preparation of cyclic
phosphonate 11 from phosphite 10 in reasonable yields
in a reaction that like 8 f 9 is retentive at phosphorus
but to a slightly lower degree. The diastereomers of 11
are separable by chromatography. Phosphonates, phos-
phates, and phosphoramidates, as neutral analogues of
cyclic 3′,5′-monophosphates, have been sought as poten-
tial agonists or antagonists of the action of the natural
cyclic nucleotides, in the mapping enzyme active sites,
and investigation of the potential chair-twist equilibrium
of the six-membered phosphate ring.6 The value of the
SET process for preparation of 11 is accented by the
reported7 failure of the triplet-sensitized preparation of
11 from 10.
Resu lts
permutation of the positions of the substituents on
phosphorus in the initial phosphoranyl 1,3-diradical, 22,
formed from triplet 1, to generate a thermodynamically
Ster eoch em istr y of SET-In du ced P h otor ear r an ge-
m en ts of cis- a n d tr a n s-8. Cyclic phosphites cis- and
trans-8 provide the opportunity to study the stereochem-
istry at phosphorus of the SET-induced photorearrange-
ments of 2-phenylallyl phosphites (8 f 9). As reported
elsewhere,7 the diastereomeric phosphites, 8, are easily
prepared from the phosphorochloridites on reaction with
2-phenylallyl alcohol under conditions of kinetic control
to give a configurationally stable, initial 8/92 cis/trans
ratio of diastereomers (see also the Supporting Informa-
tion). Two other ratios for stereochemical study were
obtained by thermal equilibration.
more stable structure, 23, has been proposed (eq 3).5a,b
For 22 this process is fast and competes readily with
reversal of 1,3-diradical formation back to triplet or
ground state of 1, and φP is relatively high. However, this
permutation is proposed to be slow for the 1,3-diradical
from 7 (analogous to 21) leading to inefficient phospho-
nate formation and low φP.5a,b (For tert-butyl-substituted
7, see 21 f 16, Scheme 3.)
The SET process gives phosphonate 6 from phosphite
1 relatively inefficiently (φP ) 0.03).1 However, by con-
trast to the triplet-sensitized reactions of 1 and 7, it has
been reported that placement of phosphorus in a six
membered ring has little effect on φP for the SET-induced
photorearrangement (φP ) 0.03).1 The low φP values
measured for 1 and 7 are not surprising considering the
typically observed predominance of back electron transfer
in the initial radical ion pair formed in SET processes.
In this paper, we report that the SET-induced photo-
rearrangement of cis/trans mixture of the cyclic phosphite
8 affords 9 in good yields with essentially complete
retention of configuration at phosphorus. This stereo-
chemistry is shown in Scheme 2 to be consistent with
the acceptance of an electron by the distonic 1,3-radical
cation intermediate 15 from 8 to give directly the
The designation cis or trans for the diastereomers of
phosphite 8 refers to the relationship of the tert-butyl and
2-phenylallyloxy groups. For phosphonate 9, the tert-butyl
and phosphoryl oxygen (PdO) are the priority groups.
This convention for phosphonates is opposite to what we
have used in other studies that involved closely related
(6) (a) Revenkar, G. R.; Robins, R. K. In Handbook of Experimental
Pharmacology; Nathanson, J . A., Kebabian, J . W., Eds.; Springer-
Verlag: Berlin and Heidelberg, West Germany, 1982; Vol. 58/I, pp 17-
151. (b) Van Haastert, P. J . M.; Kien, E. J . Biol. Chem. 1983, 258,
9636. (c) Nelson, K. A.; Bentrude, W. G. Carbohydr. Res. 1992, 234,
141.
(7) Hager, D. C.; Bentrude, W. G. J . Org. Chem. 2000, 65, 2786-
2791.

2780 J . Org. Chem., Vol. 65, No. 9, 2000
Hager et al.
cyclic phosphonates,8,9 but it follows the usual priority
rules for the substituents on rings: O > C on phosphorus
and C > H on carbon; i.e., the cis diastereomer of 9 has
the tert-butyl and PdO cis to one another.
Ta ble 1. Ster eoch em istr y of SET-In d u ced
P h otor ea r r a n gem en t of 8a
time,
h
% 8 % 9
cis/ trans-8 cis/ trans-9
cis/ trans-8 convnf formedg consumedh
formedi
0
2
4
6
0
2
4
6
0
2
4
6
20/80b,e
28/72
43/57
63/37
55/45c,e
61/39
72/23
83/17
82/18d,e
77/23
81/19
83/17
0
35
61
80
0
48
73
91
0
0
81
74
67
0
80
73
72
0
Assignments of absolute configuration to cis- and
trans-8 and -9 were readily made on the basis of the well-
established relationship between the 31P chemical shift
and the predominant axial or equatorial position of the
RO on phosphorus in phosphites and the R substituent
on phosphorus in phosphonates (δ31P (equatorial) > δ31P
(axial)).9 Previous work has shown the chair form 12 (2-
phenylallyloxy axial) to be totally populated for phosphi-
tes such as 8. Conformer 13 (PdO axial) is very predomi-
nantly populated for phosphonates similar to 9.9
3/97
5/95
8/92
3/97
6/95
11/89
49/51
48/52
50/50
47/53
46/54
48/52
37
56
78
76
64
64
89/11
80/20
83/17
91/9
80/20
79/21
Deoxygenated methylene chloride solutions, 0.01 or
0.08 M in phosphite 8, that contained approximately
twice the concentration of 1,4-dicyanonaphthalene and
a requisite amount of tri-n-propyl phosphate as internal
standard, were irradiated in Pyrex tubes with UV light
from a 450 W medium-pressure Hg lamp. Disappearance
of phosphite 8 and formation of phosphonate 9 were
monitored against the internal standard (n-PrO)3PO by
GC. Because the individual diastereomers of 8 are
thermally equilibrated during GC analysis, only the total
consumption of 8 can be determined in this way. The
configurationally stable product phosphonate diastereo-
mers, cis- and trans-9, could be readily quantitated by
GC analysis. Consumption of the individual diastereo-
mers of 8 was followed by two methods. Oxidation of
residual phosphite 8 with t-BuOOH gives the corre-
sponding phosphates that were quantitated by GC analy-
sis. Significantly, this near-quantitative oxidation occurs
with complete retention of configuration at phosphorus.10
Alternatively, the amounts of individual diastereomers
of both 8 and 9 were determined by 31P NMR, very
occasionally following careful concentration of the pho-
tolysate under argon. The GC and 31P NMR methods gave
closely similar results.
The results of these experiments using 31P NMR to
quantitate both disappearance of the diastereomers of 8
and formation of those of 9 are given in Table 1. Three
initial cis/trans ratios of 8 were utilized. Each reaction
was monitored at several conversions of phosphite.
Notably, the thermodynamically less stable, higher en-
ergy trans-8 is consumed more rapidly. Total yields of
phosphonate (cis and trans) given are accountability
yields based on phosphite converted and are seen to be
quite good, especially at lower conversions. At each
reaction time, the ratio (cis/trans) of phosphite 8 con-
sumed is expressed in Table 1 as a ratio of percentages
(cis + trans ) 100%). The accountability yields of cis-9
(based on converted cis-8) and of trans-9 (based on
converted trans-8) were calculated and also are recorded
in the same manner (cis + trans ) 100%). The agreement
in ratios (cis/trans 8 consumed vs cis/trans 9 formed) in
Table 1 is very good and leads to the conclusion that the
a
b
By 31P NMR vs internal standard (n-PrO)3P(O). 0.42 mol of
8, 0.008 M. c 0.13 mol of 8, 0.001 M. 0.10 mol of 8, 0.008 M. e Each
d
solution contained approximately 2 equiv of DCN relative to initial
8. f Based on total moles of both cis and trans isomers of 8
g
consumed. Accountability yield of total 9 formed, based on total
moles of both cis and trans isomers of 8 consumed. Based on
moles of individual cis and trans isomers of 8 consumed. Based
on moles of individual cis and trans isomers of 9 formed.
h
i
photorearrangement occurs with retention of configuration
at phosphorus. This stereochemistry is clearly shown in
eq 1 for the cis diastereomers represented in their
predominate chair conformations (12 f 13).
However, the yields of these reactions are not quanti-
tative. Hence, the conclusion that they are essentially
stereospecific at phosphorus requires that the fraction
of byproducts formed from each diastereomer of 8 is the
same. That this requirement is met is supported by the
excellent correspondence observed between cis/trans
ratios of consumed 8 and cis/trans accountabilities of
product 9 seen at three initial ratios of 8, even with the
two diastereomers being consumed at different rates. In
addition, the results are internally consistent in each case
at several conversions of phosphate. Finally, the es-
sentially unchanged results noted over the period of the
photoreactions that employed phosphate very rich in the
thermodynamically less stable trans diastereomer (cis/
trans ) 8/92) is excellent evidence for the configurational
stability of 8 at phosphorus under the reaction conditions
(diastereomers of phosphate not interconverted). Fur-
thermore, this ratio was unchanged in a control sample
held at room temperature in the absence of UV light over
the period of photolysis. Independent control reactions
showed the phosphonate diastereomers to be configura-
tionally stable and not consumed on photoirradiation.
The conclusion concerning the retentive stereochemistry
at phosphorus of the SET-induced photorearrangements
of 8 to 9 clearly is soundly based.
(8) Bhanthumnavin, W.; Arif, A.; Bentrude, W. G. J . Org. Chem.
1998, 63, 7753.
SET-In itia ted P h otor ea r r a n gem en t of Th ym id in e
3′,5′-Cyclic 2-P h en yla llyl P h osp h ite, 10. As reported
elsewhere,7 the known 3′,5′-N,N-dimethylphosphoramid-
ite 10,11 derived from thymidine, is readily converted to
(9) Bentrude, W. G. In Conformational Behavior of Six-Membered
Rings; J uaristi, E., Ed.; VCH: New York, NY, 1995; Chapter 7.
Bentrude, W. G. In Phosphorus-31 NMR Spectral Properties in
Compound Characterization and Structural Analysis; Quin, L. D.,
Verkade, J . G., Eds.; VCH Publishers: New York, NY, 1994; pp 41-
53. Bentrude, W. G. In 31P NMR Spectroscopy; Verkade, J . G., Quin,
L., Eds.; VCH Publishers: New York, NY, 1987; Chapter 11. Mary-
anoff, B. A.; Hutchins, R. O.; Maryanoff, C. A. Top. Stereochem. 1979,
11, 187.
(10) Bentrude, W. G.; Hargis, J . H. J . Am. Chem. Soc. 1970, 92,
7136.
(11) Bentrude, W. G.; Khan, M. H.; Saadein, M. R.; Sopchik, A. E.
Nucleosides Nucleotides 1989, 8, 1359.

Photorearrangement of 2-Phenylallyl Phosphites
J . Org. Chem., Vol. 65, No. 9, 2000 2781
Ta ble 2. Ster eoch em istr y of SET-In d u ced
the 2-phenylallyl phosphite 10 and purified by chroma-
tography in 66% isolated yield. In the present study, the
thermodynamically less stable trans isomer predomi-
nated (cis/trans ) 36/64; relationship of nucleobase and
2-phenylallyoxy groups) in this mixture which was
configurationally stable at room temperature. The struc-
ture of phosphate 10 and the identity of its individual
P h otor ea r r a n gem en t of 10a in Meth ylen e Ch lor id e
time,
h
% 10
%11
cis/ trans-10 cis/ trans-11
cis/ trans-10 convne formedf consumedg
formedh
0
1
4
6
0
1
4
6
35/65b,d
40/60
55/45
61/39
36/64c,d
41/59
55/45
65/35
0
27
59
67
0
23
58
70
0
83
60
63
0
88
68
70
22/78
28/72
18/82
16/84
26/74
27/73
1
diastereomers were confirmed by comparison of 31P, H,
and 13C NMR spectra with those of the previously
reported, well-characterized methyl and phenyl phosphi-
tes12 analogous to 10. Photoreaction of 10 on a small
preparative scale (200-300 mg) in deoxygenated meth-
ylene chloride (250 mL) in an immersion well apparatus
under SET conditions, with excited singlet 1,4-dicyano-
naphthalene (1DCN*) as the electron acceptor, was
carried out with light from a 450 W medium-pressure
UV lamp filtered through Pyrex.
19/81
19/81
21/79
23/77
24/76
27/73
a
b
By 31P NMR vs internal standard (n-PrO)3PO. 0.218 mol of
d
10, 0.009 M. c 0.318 mol of 10, 0.012 M. Both reactions contained
approximately 1 equiv of DCN relative to initial 10. e Based on
total moles of both isomers of 10 consumed. f Accountability yield
of total 11, based on total moles of both isomers of 10 consumed.
g
Based on moles of individual cis and trans isomers of 10
h
consumed. Based on moles of individual cis and trans isomers
of 11 formed.
sluggish beyond about 70% conversion (4 h), after which
time the reaction is less stereochemically specific. Per-
haps, side products absorb UV light or are themselves
consumed by SET processes and interfere with the
photoreaction of 10. At higher conversions the yields in
the stereochemical studies are somewhat lower than that
in the preparative study.
Discu ssion
After 8 h of irradiation, 31P NMR analysis showed
phosphite 10 to be 86% consumed. Phosphonate 11 was
formed in 79% accountability yield, based on consumed
10 (68% yield, based on total 10). 31P NMR showed less
than 5% of oxidation side product, the phosphate of 10,
to be present. Column chromatography afforded pure 11
as a mixture of cis and trans diastereomers in 63% overall
yield (cis/trans ) 33/67). The individual cis and trans
diastereomers from another preparation of 11 starting
with 120 mg of 10 were readily separated by HPLC (see
the Experimental Section). This product mixture was
considerably contaminated with the phosphate of 10.
Corrected for unreacted phosphite and phosphate byprod-
uct, the total yield of isolated pure cis and trans diaster-
eomers of 11 was 45%.
Qu a n tu m Yield s a n d Ster eoch em istr y of P h oto-
r ea r r a n gem en t: 1,3-Ca tion Ra d ica l Scission Mech -
a n ism , Dir ect Rin g Op en in g of 3 a n d 15. The ener-
getics of electron acceptance from phosphorus or the
2-phenylallyl moiety of 8 and 10 is about 4 kcal/mol more
favorable for excited singlet 1,4-dicyanonaphthalene than
it is for 9,10-dicyanoanthracene.14 Thus, the Weller
equation14b estimates electron removal from phosphorus
to be 14 kcal exergonic and from the π bond favorable by
11 kcal/mol. Nonetheless, the site of removal of the
electron cannot be predicted.
A very straightforward way to understand the essential
constancy of φP values for 1 and 7 (0.035a,b) is to propose
that the cyclic 1,3-cation radicals from both phosphites
ring open directly to yield a phosphonate styryl cation
radical (5 of Scheme 1 or the species from the ring
opening of the 1,3-cation radical analogous to 15 of
Scheme 2 but without the tert-butyl substituent). This
step is followed by electron transfer from the 1,4-
dicyanonaphthalene radical anion (DCN.-) to give the
product phosphonates (6 of Scheme 1 and the analogue
of 9, Scheme 2, without the tert-butyl substituent). The
cyclic 1,3-cation radical (3 of Scheme 1 or its spiro
counterpart, such as 15 of Scheme 2) is most likely
formed irreversibly and most certainly in competition
with back-electron transfer in the initial radical ion pair
(e.g., 2/DCN.-). Whether the phosphorus atom is part of
a spiro system should have little effect on this competi-
tion leading to comparable values of φP for 1 and 7.
The identities of the individual cis and trans isomers
of 11, like those of 9, were assigned from their relative
31P NMR chemical shifts.9 In addition the diagnostic 13
C
NMR parameters of the diastereomers of 11 were com-
pared to those known6c for the analogous phenyl- and
methylphosphonates (phenyl or methyl in place of the
2-phenylallyl substituent on phosphorus of 10). The
structure of the cis-thymidine methylphosphonate analo-
gous to 11 was determined by X-ray crystallography.13
The stereochemistry of the SET-initiated photorear-
rangement of 10, followed quantitatively by 31P NMR
spectroscopy with (n-PrO)3PO as internal standard, is
revealed by the results recorded in Table 2. Reaction
conditions were similar to those used for the stereochem-
ical studies of 8. As seen for the diastereomeric 8, the
configuration at phosphorus is largely retained in the
product phosphonates, 11, but with some increase in the
cis/trans ratio of phosphonate 11 formed. The SET-
induced photorearrangement of phosphite 10 is very
(14) (a) The reduction potential for DCN vs SCE is -1.28 eV while
that for DCA is -0.89 eV. The singlet energies, ES, for DCN and DCA
are 3.45 and 2.88 eV, respectively (Darmanyan, A. P. Chem. Phys. Lett.
1984, 110, 89). All oxidation and reduction potentials, unless otherwise
noted, are from Table 2 of: Photoinduced Electron Transfer; Fox, M.
A., Chanon, M., Eds.; Elsevier: New York, 1988; Part C, Chapter 4.1.
(b) For the Weller equation, see: Rehm, D.; Weller, A. Isr. J . Chem.
1970, 8, 259.
(12) Nelson, K. A.; Sopchik, A. E.; Bentrude, W. G. J . Am. Chem.
Soc. 1983, 105, 7752 and unpublished results.
(13) Bentrude, W. G.; Sopchik, A. E.; Bajwa, G. S.; Setzer, W. N.;
Sheldrick, W. S. Acta Crystallogr. 1986, C42, 1027.

2782 J . Org. Chem., Vol. 65, No. 9, 2000
Hager et al.
The stereochemistry of rearrangement by this mecha-
nism would clearly proceed with retention of configura-
tion at phosphorus on formation from cis-8, via 14, of the
phosphonium ion-like 1,3-cation radical (distonic) inter-
mediate 15 (Scheme 2). (See more detailed discussion in
the next section.) There should be a favorable thermo-
dynamic driving force for cleavage to the styryl cation
radical precursor of cis-9, analogous to 5 of Scheme 1, as
two π bonds are simultaneously introduced. Final reduc-
tion of the styryl-like radical cation analogous to 5,
formed from â scission of 15, is favorable energetically
by 11 kcal/mol, based on predictions of the Weller
equation and the measured oxidation potential for R-
methyl styrene (1.76 eV 14), the singlet energy of 1DCN*
(3.45 kcal/mol14), and oxidation potential of DCN.- (-1.28
eV14). Nonetheless, as set forth later, experimental
evidence against a mechanism involving intermediates
such as 5 exists.
In the alternative mechanism that we favor, depicted
in Scheme 2, the intermediate cyclic 1,3-cation radical
(3 in Scheme 1 and 15 in Scheme 2) is reduced by DCN.-
to the singlet diradical (4 in Scheme 1 and 16 in Scheme
3). The energetics of reduction of 3 or 15 by DCN.-, if
the parallel reduction by DCN.- of phosphonium salts
[RPPh3]+ is a good model, is calculated from redox
potentials to be endergonic by about 2 kcal/mol.15 How-
ever, within experimental error, this number may well
be energetically somewhat exergonic, allowing the reduc-
tion of 15 to 16 to occur readily.14b Nonetheless, DCA also
brings about these reactions, though the [RPPh3]+ model
predicts the trapping of 3 and 15 by DCA.- to be
endergonic by 11 kcal/mol.16 These estimates appear to
disfavor reaction via reduction of intermediates 3 and 15.
It should be noted, however, that other key reductions
in photoinduced SET reactions that involve 1DCA*/DCA.-
and that are estimated from redox potentials to be
energetically unfavorable, nonetheless, occur readily.17
Important experimental evidence against the forma-
tion of 6 via 3 f 5 f 6 comes from unpublished results
from this group of attempted trapping of 3 by methanol
in the SET rearrangement of phosphite 1 photoinduced
by DCA.18 The addition of methanol in significant amounts
to the DCA/SET-induced photorearrangement reaction
of 1 via 5 in the presence of MeOH should yield adduct
17 (eq 2). Indeed, adduct 17 is generated along with large
CPhdCH2,18,19 is formed from the outset of the reaction
in about 8% yield based on converted 1. Evidently, 17
results from SET-induced reaction of phosphonate 6 with
MeOH, rather than by trapping of 5. The conversion of
6 to 17 under the SET conditions with DCA was inde-
pendently verified.
It indeed seems quite probable that the reduction
potentials for intermediates such as 3 and 15 are more
favorable than predicted by the [RPPh3]+ model. Thus,
the one-electron reduction potential for [(RO)4P]+, a closer
model for 3 and 15, should be less negative as a result of
the electronegative alkoxy substituents on phosphorus.
Furthermore, there may be a stabilizing interaction
between the single-electron-containing orbitals on phos-
phorus and carbon in 4 and 16. In fact, cyclopentane 1,3-
diradicals (diyls), though clearly different from 4 and 16,
are comparatively long-lived when their odd electron
bearing orbitals are properly oriented.20 In addition ring
opening of 3 and 15 to the styrene-like cation radicals
may involve unforeseen, relatively high activation bar-
riers such that reduction to the 1,3-diradical predomi-
nates.
St er eoch em ist r y a t P h osp h or u s: 1,3-Dir a d ica l
Mech a n ism . The stereochemistry of the SET-induced
photorearrangements of phosphites 8 and 10 is readily
understood in terms of the 1,3-diradical mechanism for
the photorearrangement process. This is shown for cis-8
in Scheme 2 presented earlier. The initial radical cation
14, formed by SET to1DCN*, undergoes cyclization to the
distonic 1,3-radical cation 15. As stated previously, the
stereochemistry at phosphorus is fixed initially by forma-
tion of 15. Reduction of 15 by electron transfer from the
DCN radical anion affords the phosphoranyl 1,3-diradi-
cal, 16, that undergoes â scission to yield product 9 with
predictably cis stereochemistry.
If 14 is in fact a styryl cation radical like 2b, formation
of 15 essentially involves the attack of the nucleophilic,
three-coordinate phosphorus lone pair on the electrophilic
carbon of 14. The anticipated charge/electron distribution
shown for 15 was demonstrated in the ESR spectrum of
the closely related adduct from reaction of the radical
cation of (MeO)3P with 1,1-di-tert-butylethene.21 The
formation of 15 then finds direct stereochemical analogy
in the retentive stereochemistry at phosphorus noted in
the formation of phosphonium salts from reaction of
optically active phosphines with benzyl bromide.22 Simi-
larly, the thermal Arbuzov reaction of phosphite 18 with
methyl iodide yields methylphosphonate 20 with reten-
tion of configuration at phosphorus.23 This process is
depicted in the sequence 18 f 19 f 20 in which 19 is
analogous to 15.
amounts of 6, but its formation lags behind that of
phosphonate 6. By contrast, the methyl ether, MeOCH2-
If instead 15 is the product of cyclization of a phos-
phorus cation radical ion, it is very significant that the
analogous radical cations derived from (MeO)3P and
(15) Based on the average of the one-electron reduction potentials
of [PhCMe2PPh3]+ (-1.51 eV) and [MeCPh2PPh3]+ (-1.24 eV) which
undergo rapid cleavage to Ph3P and the free radicals PhCMe2 and
MeCPh2, respectively (Saveant, J . M.; Binh, S. K. J . Org. Chem. 1977,
42, 1242 and the reduction potential for DCN (-1.28 eV15).
(16) Based on the averaged phosphonium salt reduction potential
of ref 16 and the reduction potential for DCA (-0.89 eV15).
(19) This ether could result from trapping of 2-phenylallyl cations
formed on cleavage of the initial radical cation (2b) or by addition of
MeOH to 2b followed by scission to yield 17 and the radical (MeO)2P-
(O).. Studies with deuterium-labeled 1 indicate the latter process
dominates.
(20) Adam, W.; Hoessel, P.; Huemmer, W.; Platsch, H.; Wilson, R.
M. J . Am. Chem. Soc. 1986, 108, 929.
(21) Gara, W. B.; Roberts, B. P. J . Chem. Soc., Perkin Trans. 2 1978,
150.
(22) Horner, L.; Fuchs, H.; Winkler, H.; Rapp, A. Tetrahedron Lett.
1963, 965.
(17) An example is found in the well-known DCA-promoted, anti-
Markovnikov addition of methanol to 1,1-diphenylethylene. The reac-
tion proceeds via the 1,1-diphenylethylene cation radical to give high
yields of methanol adduct, although the necessary reduction of
intermediate 1,1-diphenyl-2-methoxy radical is estimated from oxida-
tion half-wave potentials to be endergonic by about 9 kcal/mol. Thus,
for diphenylethyl radical, a valid model, the reduction potential vs SCE
is -1.34 eV (Wayner, D. D. M.; McPhee, D. J .; Griller, D. J . Am. Chem.
Soc. 1988, 110, 132) while that for DCA is only -0.89 eV.15
(23) Bentrude, W. G.; Hargis, J . H. J . Am. Chem. Soc. 1970, 92,
7136. Haque, M. U.; Caughlan, C. N.; Hargis, J . H.; Bentrude, W. G.
J . Chem. Soc. A 1970, 1786.
(18) Dockery, K. P. Ph.D. Thesis, University of Utah, 1995.

Photorearrangement of 2-Phenylallyl Phosphites
J . Org. Chem., Vol. 65, No. 9, 2000 2783
Sch em e 3
(EtO)3P are known from ESR measurements to be highly
pyramidal with a p/s ratio for the SOMO spin density
on phosphorus of approximately 3/1.24 The barrier to
inversion, though to our knowledge not measured, will
be relatively high because of the electronegativity of the
alkoxy groups attached to phosphorus.24 Sufficiently
rapid formation of 15, in competition with inversion of
cation radical 14 at phosphorus, would retain configu-
ration at phosphorus. By contrast, the stereochemistry
of oxidation of phosphorus-centered cation radicals from
Ph3P occurs with random stereochemistry.24
It should be noted that the triplet-sensitized photore-
arrangement of 8 to 9 also takes place with retention of
configuration at phosphorus.7 As shown in Scheme 3, the
proposed initial 1,3-diradical intermediate 21 isomerizes
to the same intermediate 16 that is postulated to be
formed directly by reduction of 15. The significance of
the initial formation of 16 rather than 21 in the SET
processes (Scheme 2) will be set forth in detail in the next
section. â scission of either 16 or 21 would afford
phosphonate 9 with the correct stereochemistry (cis-9 in
Scheme 3).
Similarly, 22 (eq 3) is the presumed initial 1,3-diradical
intermediate in the triplet-sensitized photorearrange-
ment of 1.5 To explain the efficient formation of phos-
phonate 2 (φP ) 0.2-0.3) from phosphate 1, it has been
postulated that there is rapid, though perhaps reversible,
conversion (eq 3) of the kinetically formed 1,3-diradical
22 to the thermodynamically more stable form, 23, from
which equatorial R-scission to reform phosphite 1 does
not occur. On â scission, 23 gives 6. Such an isomerization
Qu a n t u m Yield s for SE T-In d u ced P h ot or ea r -
r a n gem en ts of 1 a n d 7: 1,3-Dir a d ica l Mech a n ism .
The following arguments, set forth elsewhere,5 apply to
the formation, relative energies, and interconversions of
permutamers of the phosphoranyl 1,3-diradicals assumed
to be formed in the triplet-sensitized rearrangement of
phosphites 1, 7, and cis- and trans-8. (Phosphites 7 and
8 differ only in the presence of the tert-butyl substituent
on the six-membered ring). They serve as a necessary
background for understanding the consistency between
the stereochemistry of the SET-induced rearrangement
of 8, the constancy of quantum yields for the SET
rearrangement processes for 1 and 7 (φP ) 0.03), and the
quantum yields and stereochemistry of the triplet-
sensitized photorearrangements of 1, 7, and cis-8.
Diradical 21 (Scheme 3) has been proposed to be
formed kinetically via apical introduction of the terminal
(primary) end of the 1,2-diradical-like styryl unit of triplet
cis-8.5,7 The apical introduction of the methylene to yield
21 is in accord with conclusions from ESR work concern-
ing the formation of phosphoranyl monoradicals by
reversible oxidative addition of alkyl radicals to trialkyl
phosphites via the apical position.25 It has been pro-
posed5,7 that formation of 21 is highly reversible by
analogy to alkyl radical attack on phosphites.25 Phos-
phoranyl 1,3-diradical 21 is thermodynamically less
stable than its permutational isomer 16, which results
from a single mode 4 permutation of 21 (Scheme 3).
is of mode 4, and has been established by kinetic ESR
work to be relatively fast for phosphoranyl monoradicals
analogous to 22, e.g., 24 (24a / 24b), eq 4.26 The mode
4 permutation is operative rather than the mode 1
permutation defined for truly pentacovalent phosphorus
molecules. The isomerization 22 f 23, followed by â
scission to give 6, essentially traps 22 and prevents
reformation of triplet phosphite or, following intersystem
crossing, regeneration of ground state phosphate. The
result is a comparatively large value for φP (0.2-0.3).5a,b
By contrast, the analogous permutation process for
spiro phosphoranyl monoradicals is known to be unusu-
ally slow.27 Therefore, 1,3-diradical 21 (Scheme 3) from
cis-8 (and its analogue from 7) is presumed to isomerize
to 16 only very slowly leading to a low φP (for 7, φP
)
0.003), because 21 reopens primarily to the ground or
triplet state 7.5
(24) For the characterization of radical cations of phosphines (Ar3P
and R3P) and phosphites ((RO)3P, R ) Me, Et), see: (a) Tordo, P. In
The Chemistry of Organophosphorus Compounds; Hartley, F. R., Ed.;
Wiley and Sons: Chichester, 1990; Chapter 6. (b) Hasegawa, A.;
McConnachie, G. D. G.; Symons, M. C. R. J . Chem. Soc., Faraday
Trans. 1 1984, 80, 1005. (For effects of substituent electronegativity
on the pyramidal nature of these and related radicals, see: Symons,
M. C. R. Chemical and Biochemical Aspects of Electron Spin Resonance
Spectroscopy; Van Nostrand Reinhold: Wokingham, 1978.)
(25) Cooper, J . W.; Roberts, B. P. J . Chem. Soc., Perkin Trans. 2
1976, 808. Baban, J . A.; Roberts, B. P. J . Chem. Soc., Perkin Trans. 2
1980, 876. Dockery, K. P.; Bentrude, W.G. J . Am. Chem. Soc. 1994,
116, 10332. Dockery, K. P.; Bentrude, W.G. J . Am. Chem. Soc. 1997,
119, 1388.
Totally consistent with the above views and Schemes
2 and 3 is the fact that for SET-initiated photorearrange-
ment the quantum yields for phosphonate formation from
1 and 7, though inefficient, are the same (φP ) 0.03),1
(26) Cooper, J . W.; Parrot, M. J .; Roberts, B. P. J . Chem. Soc., Perkin
Trans. 2 1977, 730. Five-coordinate phosphorus modes of permutation,
applicable to trigonal bipyramidal phosphoranyl radicals, have been
defined (Musher, J . I. J . Chem. Educ. 1974, 51, 94).
(27) Griller, D.; Roberts, B. P. J . Chem. Soc., Perkin Trans. 2 1973,
1416.

2784 J . Org. Chem., Vol. 65, No. 9, 2000
Hager et al.
unlike those for the triplet-sensitized photorearrange-
ments of the same phosphites (0.3 and 0.003).5a,b As
shown in Scheme 2, reduction of the distonic cyclic 1,3-
radical cation 15, formed from cis-8, gives directly the
thermodynamically stable 1,3-diradical 16, which â scis-
sions to form product phosphonate cis-9 rather than
undergo equatorial P-CH2 R scission to triplet or ground
state cis-7. The opportunity for facile ring opening to
regenerate phosphate 8 is precluded because the thermo-
dynamically less stable form 21, initially formed in
reversible fashion in the triplet-sensitized rearrangement
of 7, would have to be formed from the thermodynami-
cally more stable, directly formed 16. As discussed earlier
in this paper, closure to 3, 15, and the 1,3-cation radical
analogue from 7 without tert-butyl substitution should
occur with the same efficiency. Likewise, their trapping
by electron donation by DCN.- to give 4 and 16 should
not be perturbed by phosphorus being part of a spiro
system (15 and its analogue from 7). The overall quantum
yield for phosphonate formation, φP, is then predicted to
be similar for 1 and 7, as is found experimentally.1
P r ep a r a tion of Cyclic Nu cleotid e-Ba sed P h os-
p h on a tes, 11. Phosphorothioate, methylphosphonate,
and phenyl and methyl phosphate analogues of nucleo-
side cyclic 3′,5′-monophosphates have been prepared as
potential mimics or antagonists of the interactions of the
natural cyclic nucleotides, cAMP and cGMP, with protein
kinases and phosphodiesterases.6 The photorearrange-
ment product phosphonate 11, isolated as the diastere-
omeric mixture in 63% yield, was separable into the
individual diastereomers. The SET-initiated process is
expected to be superior to the more classical alternative,
the Arbuzov reaction of the methyl phosphite analogous
to 10 with 2-phenyl-3-bromopropene. Thus, with 3′,5′-
cyclic methyl phosphites derived from nucleosides, e.g.,
adenosine and guanosine, featuring nucleobases with
strongly nucleophilic sites, alkylation at nitrogen is a
likely side reaction. Indeed, methyl iodide, utilized to
alkylate the phosphate oxygen of the salt of c-AMP to
form the methyl phosphate, was reported to also alkylate
the nucleobase.28 High concentrations of 2-phenyl-3-
bromopropene would be needed to alkylate phosphorus
in competition with product methyl bromide that will be
formed increasingly as the reaction progresses.
ration at phosphorus. Very significantly, in Scheme 2 the
thermodynamically stable 1,3-diradical 16, which has the
methylene carbon equatorial and ring oxygen apical on
trigonal bipyramidal phosphorus, is formed directly. By
analogy to what is known about phosphoranyl mono-
radicals, the equatorial position of the methylene pre-
cludes facile P-CH2 scission to reform cis-8 and reduce
the quantum yield for formation of phosphonate 9. The
rates of presumably irreversible formation of 1,3-cation
radicals 3 and 15 (and the non-tert-butyl-substituted
analogue from 7) should be similar and equally competi-
tive with back-electron transfer within the initial radical-
ion pair. The result is the experimentally observed
essentially identical quantum yields for phosphonate
formation (φP) for 1 and 7 (φP ) 0.03). By contrast,
electron donation to 15 (or its non-tert-butyl analogue
from 7) to give 21 (or the non-tert-butyl analog) directly
would lead to ring opening to reform the starting phos-
phite, cis-8, by R-scission of the apical CH2 (Scheme 3)
in competition with relatively slow rearrangement to
cis-9 (21 f 16 f cis-9). The result would be a decreased
quantum yield for phosphonate formation (φP) from 7
relative to that for 1, contrary to experimental observa-
tion. (The stereochemistry of the conversion of 8 to 9
would be unchanged by formation of 21 followed by its â
scission to afford 9.) An alternative mechanism, ring
cleavage of 3 to give styryl cation radical 5, is discounted
by the failure in an unpublished study18 of MeOH to trap
5.
Photoinduced SET rearrangement of the thymidine
cyclic 3′,5′-phosphite 10 gives reasonable yields of the
2-phenylallylphosphonate diastereomers of 11 that are
separable by HPLC. Chemical modification of the alkene
functionality of 11 may lead to increased bioapplications.
Exp er im en ta l Section
P r ep a r a tion of Com p ou n d s. Methylene chloride was
distilled from calcium hydride under argon. Reagents are from
Aldrich Chemical Co. Tri-n-propyl phosphate was distilled
prior to use. Thymidine (Sigma) was used as received. DCN
(1,4-dicyanonaphthalene) was prepared by standard proce-
dures.29 2-Phenylallyloxy 5-tert-butyl 1,3,2-dioxaphosphor-
inane, 8,7 2-oxo-2-phenylallyl-5-tert-butyl 1,3,2-dioxaphos-
phorinane, 9,7 and the thymidine 3′,5′-cyclic 2-phenylallyl
phosphite, 10,7 were made by procedures published elsewhere
and also are available in the Supporting Information.
P h otoch em ica l Rea ction s. The study of the stereochem-
istry of rearrangement of 8 with DCN as SET agent utilized
light from a 450-W medium-pressure Hg lamp, equipped with
a Pyrex glass sleeve in a water-cooled immersion photochemi-
cal apparatus. Samples were prepared in Pyrex tubes by
glovebox techniques under an argon atmosphere and placed
about 2.5 cm from the immersion tube apparatus. Preparative-
scale irradiations of 10 were carried out on argon-purged
solutions in a photochemical reaction vessel, fitted with a
quartz immersion tube, with Pyrex-filtered light from a 450-W
medium-pressure Hg lamp.
The 2-phenylstyryl moiety of phosphonate 11 is subject
to further chemical modification making it a potential
precursor to hitherto unknown cyclic nucleotide deriva-
tives. This lends further significance to the preparation
of these new cyclic nucleotide derivatives.
Con clu sion s
The SET-initiated photorearrangements of the cis- and
trans-2-phenylallyl phosphites, 8, to the corresponding
phosphonates, 9, take place with retention of configura-
tion at phosphorus. This result is consistent with, though
not proof of, the previously postulated rearrangement
mechanism for these processes illustrated for cis-8 in
Scheme 2. Electron donation to the stereospecifically
formed, cyclic, distonic 1,3-cation radical intermediate 15
gives rise directly to 1,3-phosphoranyl diradical 16 that
generates phosphonate cis-9 with retention of configu-
P h ysica l Meth od s. Melting points are uncorrected. J
values given in the 1H NMR spectral data refer to proton-
proton coupling unless otherwise stated. A 60 s repetition rate
was employed when the photoreactions were monitored by 31
P
NMR to ensure the accuracy of the integration. Microanalyses
were performed by Atlantic Microlab, Inc., Norcross, GA. GC-
EIMS (70 eV) analyses utilized a 30 m × 0.25 mm fused silica
capillary column. Reported intensities are percentages of the
base peak intensity. Other low resolution EIMS (70 eV) as well
as HRMS (EI, 70 eV) measurements utilized a standard inlet
(28) Attempted alkylation of both the potassium and silver salts of
cAMP with alkyl iodides led to alkylation at N1 of the nucleobase.
J arvest, R. L.; Lowe, G.; Potter, B. V. L.; J . Chem. Soc., Perkin Trans.
2 1981, 186. Beres, J .; Sandor, P.; Kalman, A.; Koritansnsky, T.; Otvos,
L. Tetrahedron 1984, 40, 2405.
(29) Kleigman, J . M.; Barnes, R. K. Tetrahedron 1970, 26, 2555.
Heiss, L.; Paulus, E. F.; Rehling, H. Leibigs Ann. Chem. 1980, 1583.

Photorearrangement of 2-Phenylallyl Phosphites
J . Org. Chem., Vol. 65, No. 9, 2000 2785
system. FABMS(LSIMS) spectra were obtained using a cesium
ion gun. The GLC yields were determined with a flame
ionization detector on a 20 m × 0.25 mm fused silica capillary
column (DB-1) with tri-n-propyl phosphate as internal stan-
dard.
P r ep a r a t ive Sca le P h ot oin d u ced Sin gle-E lect r on
Tr a n sfer In itia ted Rea r r a n gem en t of Th ym id in e Cyclic
2-P h en yla llyl-3′,5′-p h osp h ite (10). By glovebag techniques,
a photoreaction vessel was charged with thymidine cyclic
2-phenylallyl-3,5-phosphite 9 (237 mg, 0.587 mmol; cis/trans
) 34/66), 1,4-dicyanonaphthalene (112 mg, 0.49 mmol), and
methylene chloride (250 mL). An immersion well containing
a 450-W medium pressure Hg lamp (Pyrex sleeve) was fitted
to the vessel. The reaction solution, continuously purged with
a slow stream of argon, was irradiated for 8 h. The moles of
the individual diastereomers of 9 and 10 were determined by
31P NMR peak integration by reference to the internal stan-
dard. Samples for 31P NMR work were prepared by carefully
evaporating the solvent under argon and dissolving the residue
in CDCl3. The yield of 10 was determined to be 79%, based on
an 86% conversion of starting phosphite (overall yield 68%).
The crude product was purified by column chromatography
(eluting with 50% ethyl acetate/hexane) to give 149 mg (63%
isolated overall) yield of a mixture (cis/trans ) 33/67) of solid
phosphonate 10.
Ster eoch em istr y of th e P h otoin d u ced Sin gle-Electr on
Tr a n sfer In itia ted Rea r r a n gem en t of 5-ter t-Bu tyl-2-(2-
p h en yla llyloxy)-1,3,2-d ioxa p h osp h or in a n e (8). The fol-
lowing sample preparation procedure is typical. In a glovebag
under an argon atmosphere was added tri-n-propyl phosphate
to a preweighed 25.0 mL volumetric flask that contained 1,4-
dicyanonaphthalene (48.1 mg, 0.270 mmol). The flask was
removed from the glovebag and reweighed (tri-n-propyl phos-
phate, 73.9 mg, 0.330 mmol). In the glovebag, the contents
were dissolved and diluted to 25.0 mL with dry methylene
chloride. Similarly, 5-tert-butyl-2-(2-phenylallyloxy)-1,3,2-di-
oxaphosphorinane, 8 (37.6 mg, 0.128 mmol), was placed under
argon in a 10.0-mL volumetric flask and then diluted to 10.0
mL with the solution of internal standard. Three quartz test
tubes (13 mm × 80 mm) were flushed with argon, capped with
rubber septa, and transferred to the glovebag. To each tube
was transferred 2.5 mL of the reaction solution via syringe.
A less pure 34/66 trans/cis mixture of diastereomers of 10
from another preparation, based on 120 mg of starting phos-
phite 9, was chromatographed (HPLC) with 96:4 CHCl3/MeOH
on a Rainin Dynamax 21.4 mm i.d. silica gel column. By 31P
NMR peak area integration, 89% of the starting phosphite was
accounted for in the product mixture as unreacted phosphite
(7%), byproduct phosphate impurity (20%) from insufficient
deoxygenation, and 10 (51%, cis plus trans). HPLC gave 15
mg trans (95% pure, 31P NMR) and 27 mg cis (97% pure, 31P
NMR): trans/cis, 36/64 by weight. The accountability of
phosphite converted (corrected for phosphate formation) in
terms of the purified isomers of 10 was 45%. Further purifica-
tion by HPLC (CHCl3/MeOH) gave the individual isomers of
10 in >99% purity. trans-10: 31P NMR (121.4 MHz C6D6) δ
22.5; 1H NMR (499.8 MHz acetone-d6) δ 1.83 (d, J ) 1.3 Hz, 3
H, CH3), 2.36 (ddd, J ) 2.7, 8.3, 13.2 Hz, 1 H), 2.52 (ddd, J )
The samples were irradiated with light from
a medium
pressure 450-W Hg lamp, filtered through a Pyrex glass sleeve.
The photolysis solutions were sampled at 0, 2, 4, and 6 h. At
each conversion, the moles of each diastereomer of unreacted
8 were determined by 31P NMR, by reference to the internal
standard, on aliquots of reaction solution transferred to an
NMR tube in a glovebag under argon. Moles of the individual
diastereomers of 9 formed were determined in the same way.
Very rarely, it was necessary to concentrate the samples under
a slow stream of argon prior to quantitation by 31P NMR. The
yields of the individual diastereomers of 9 (tri-n-propyl phos-
phate internal standard) also could be determined by GLC on
a sample carefully concentrated under argon, using a 20 m ×
0.32 mm RSL-150 capillary column. The individual diastere-
omers of remaining phosphite 8 were quantitated by GC in
those cases by slow syringe addition under argon to the
concentrate of approximately 1.1 equiv of a t-BuOOH in an
organic solvent to convert 8 to the phosphate. The data of Table
1 are based on the 31P NMR method. Yields of 9 at t ) 6 h,
based on converted starting dioxaphosphorinane, were in the
range of 64-72%. Product phosphonate structures were con-
firmed by 31P NMR and GC-EIMS comparisons to authentic
phosphonates prepared independently.
St er eoch em ist r y of P h ot oin d u ced Sin gle-E lect r on
Tr a n sfer In itia ted Rea r r a n gem en t of Th ym id in e 3′,5′-
Cyclic 2-P h en yla llyl P h osp h ite (10). Via the above glovebag
techniques, preweighed phosphite (88.9 mg, 0.218 mmol) 10
in a 25.0-mL volumetric flask was diluted to volume with a
50.0-mL methylene chloride stock solution of 1,4-dicyano-
naphthalene (43.7 mg, 0.245 mmol) and tri-n-propyl phosphate
(88.7 mg, 0.396 mmol). To each of four rubber septa capped,
argon-flushed NMR tubes (5 mm) that had been fitted with
10/30 ground glass joints was transferred 1.5 mL of the above
solution via syringe. The tubes were degassed by four freeze-
pump-thaw cycles on a vacuum line (0.02 mmHg) and flame
sealed. The reaction mixture was checked by 31P NMR at time
zero. The tubes were irradiated with Pyrex sleeve filtered light
from a medium-pressure 450-W Hg UV lamp. The photolysis
solutions were monitored at periods over the time of the
reaction by 31P NMR without opening the tubes. The final
yields (at t ) 6 h) of phosphonate 11 ranged from 63 to 70%,
based on converted starting phosphite (Table 2). By utilizing
the 31P NMR peak area of the internal standard, along with
those of remaining phosphite and phosphonate diastereomers
formed, the moles of consumption and formation of each was
determined and reported on a percentage basis (Table 2). It
was shown that the reactions also could be quantitated
accurately to give comparable results by opening the tubes
under argon, oxidizing the remaining phosphite to the phos-
phate with tert-butyl hydroperoxide and then concentrating
the mixture under vacuum before 31P NMR analysis. The
results of Table 1 were obtained by the direct 31P NMR
procedures without invasion of the NMR tubes.
2
9.3, 9.6, 13.2 Hz, 1 H), 3.36 (d, J HP ) 21.0 Hz, 1 H), 3.44 (d,
4
2J HP ) 21.0 Hz, 1 H), 3.96 (dddd, J ) 9.2, 5.0, 10.3 Hz, J HP
)
3
0.4 Hz, 1 H), 4.39 (ddd, J ) 5.0, 9.5 Hz, J HP ) 14.9 Hz, 1 H),
3
4.56 (ddd, J ) 10.3, 9.5 Hz, J HP ) 4.0 Hz, 1 H), 4.79 (dddd, J
3
2
) 9.6, 8.3, 9.2 Hz, J HP ) 1.0 Hz, 1 H), 5.41 (d, J ) 5.5 Hz, 1
2
H), 5.54 (d, J ) 5.5 Hz, 1 H), 6.31 (dd, J ) 9.3, 2.7 Hz, 1 H),
7.22-7.62 (m, 6 H), 10.0 (bs, 1 H, NH); 13C NMR (125.7 MHz
1
3
CDCl3) δ 12.57, 33.14 (d, J CP ) 134.8 Hz), 35.25 (d, J CP
)
2
3
5.9 Hz), 70.18 (d, J CP ) 10.4 Hz), 73.65 (d, J CP ) 12.1 Hz),
2
3
76.47 (d, J CP ) 5.4 Hz), 86.36, 111.77, 118.22 (d, J CP ) 12.3
Hz), 126.32, 128.27, 128.60, 136.15, 138.02 (d, 2J CP ) 11.3 Hz),
139.78 (d, J CP ) 3.7, 149.40, 162.89 Hz). cis-10: 31P NMR
2
(121.4 MHz CHCl3) δ 27.3; 1H NMR (499.8 MHz acetone-d6) δ
1.82 (d, J ) 1.3 Hz, 3 H), 2.32 (ddd, J ) 9.2, 10.3, 13.2 Hz),
2
2.49 (ddd, J ) 2.6, 8.2, 13.2 Hz, 1 H), 3.26 (d, J HP ) 22.2 Hz,
4
2 H), 3.70 (dddd, J ) 9.2, 10.7, 5.2 Hz, J HP ) 0.8 Hz, 1 H),
3
4.33 (ddd, J ) 5.2, 9.2 Hz, J HP ) 16.3 Hz, 1 H), 4.40 (ddd, J
3
) 10.7, 9.2 Hz, J HP ) 3.5 Hz, 1 H), 4.84 (dddd, J ) 8.2, 10.3,
9.2 Hz, 3J HP ) 1.6 Hz, 1 H), 5.36 (d, 2J ) 5.7 Hz, 1 H), 5.55 (d,
2J ) 5.7 Hz, 1 H), 6.29 (dd, J ) 9.3, 2.6 Hz, 1 H), 7.22-7.62
(m, 6 H), 10.0 (bs, 1 H); 13C NMR (125.7 MHz CDCl3) δ 12.58
1
3
(CH3), 32.58 (d, J CP ) 137.5 Hz), 35.44 (d, J CP ) 6.9 Hz),
2
3
68.56 (d, J CP ) 9.6 Hz), 73.87 (d, J CP ) 5.2 Hz), 74.07 (d,
2J CP ) 5.0 Hz), 83.50, 112.51, 117.99 (d, J CP ) 11.9 Hz),
3
126.28, 128.21, 128.43, 134.49, 137.85 (d, J CP ) 11.5 Hz),
2
139.64 (d, J CP ) 3.5), 149.75, 162.73; FAB LRMS, m/z 405
(M+). Anal. Calcd for C19H21N2O6P: C, 56.47; H, 5.23. Found:
C, 56.45; H, 5.19. (Determined on a mixture of isomers, cis/
trans ) 33/67).
Ack n ow led gm en t. Support of this research by
grants from the National Science Foundation and Public
Health Service (GM) is gratefully acknowledged.
Su ppor tin g In for m ation Available: Procedures for prepa-
ration of 8-10. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O9919557