Radical addition reactions of chiral phosphorus hydrides

Article abstract of DOI:10.1016/j.tetasy.2003.04.001

Intermolecular radical addition of a (1R,2R,3S,5R)-(-)-pinanediol-derived thiophosphite leads to the diastereoselective formation of organophosphorus adducts. Addition of the intermediate phosphonothioyl radical to electron-rich alkenes or alkynes occurs

Full text of DOI:10.1016/j.tetasy.2003.04.001

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2849–2851
Radical addition reactions of chiral phosphorus hydrides
Christopher M. Jessop,a Andrew F. Parsons,a,* Anne Routledgea and Derek J. Irvineb
aDepartment of Chemistry, University of York, Heslington, York, YO10 5DD, UK
bUniqema, Wilton Centre, Wilton, Redcar, TS10 4RF, UK
Received 1 April 2003; accepted 14 April 2003
Abstract—Intermolecular radical addition of a (1R,2R,3S,5R)-(−)-pinanediol-derived thiophosphite leads to the diastereoselective
formation of organophosphorus adducts. Addition of the intermediate phosphonothioyl radical to electron-rich alkenes or alkynes
occurs with retention of configuration at phosphorus.
© 2003 Elsevier Ltd. All rights reserved.
The addition of phosphorus-centred radicals to alkenes
has long been utilised as an important method for
preparing organophosphorus adducts.1 Of particular
recent interest has been the addition of phosphonyl or
Our initial studies began with the synthesis of thiophos-
phite 2, which was prepared by coupling phosphonic
acid with (1R,2R,3S,5R)-(−)-pinanediol 18 in the pres-
ence of dicyclohexylcarbodiimide9 (Scheme 1).10 The
intermediate chiral phosphite (formed as a 1:1 mixture
of diastereoisomers) was then treated with Lawesson’s
reagent2f to afford the desired thiophosphite 2 as a 9:1
mixture of inseparable diastereoisomers (as indicated by
’
’
phosphonothioyl radicals, R2P(O) or R2P(S) , respec-
tively, to electron-rich alkenes.2 This work, particularly
that by Piettre et al., has shown that thiophosphites can
add more efficiently to alkenes than phosphites and this
has been attributed to the greater stability of the thio-
phosphonothioyl radical (compared to the phosphonyl
radical). The PꢀH bond in a thiophosphite is therefore
expected to be weaker and our studies on the cyclisa-
tion of dienes have recently supported the view that
diethyl thiophosphite is a more effective hydrogen-atom
donor than diethyl phosphite.3
1
the H NMR spectrum) in an overall yield of 45%. This
procedure was repeated a number of times and on each
occasion the ratio of diastereoisomers of 2 was found to
vary, although it was generally in the region of 4–9:1.11
It is unclear why different isomer ratios were observed
(under the same conditions) although the reaction tem-
perature is an important factor—heating an 8:1 mixture
of isomers of 2 in toluene for 3 days leads to epimerisa-
tion and the formation of a 2:1 mixture.
Following our initial studies using achiral thiophos-
phites,3 our attention turned towards the use of chiral
thiophosphites in radical addition reactions. Phospho-
nyl radicals have been shown to have a pyramidal
structure4 and studies by Mislow5 and Aaron6 showed
that addition of phosphonyl radicals to alkenes occurs
with complete retention of configuration at phospho-
rus. This suggested that the radical addition of chiral
thiophosphites to alkenes could afford a stereoselective
approach to synthetically useful organothiophospho-
nates. The synthesis of non-racemic organophosphorus
derivatives has attracted considerable recent attention
because of the biological activities associated with this
class of compound as well as their use in the prepara-
tion of catalytic antibodies.7
Scheme 1.
Thiophosphite 2 was then reacted with a series of
electron-rich alkenes (at rt in THF in the presence of
triethylborane) in order to give organophosphorus
adducts 5 via the intermediate radicals 3 and 4 as
shown in Scheme 2. When a 4:1 diastereomer mixture
of 2 was reacted with 1-octene, the desired regioselec-
tive radical addition reaction occurred to give 6a in
* Corresponding author. Tel.: +44-01904-432608; fax: +44-01904-
432516; e-mail: afp2@york.ac.uk
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.04.001

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C. M. Jessop et al. / Tetrahedron: Asymmetry 14 (2003) 2849–2851
equally well with either face of the intermediate carbon-
centred radical (of type 4). A similar result was obtained
when a 9:1 mixture of isomers of 2 was reacted with
ethylidenecyclohexane. This gave a 9:9:1:1 mixture of
diastereoisomers of 8 in a combined yield of 80%. It
therefore appears that the intermediate phosphorus-cen-
tred radical 3 (derived from 2) can equally well approach
either side of the double bond in ethylidenecyclohexane.
Scheme 2.
93% yield (Fig. 1).12 The 1H and 31P NMR spectra of 6a
showed the presence of two diastereoisomers in the ratio
of 4:1. As the product and starting material diastereoiso-
mer ratios were the same this suggested that the radical
addition had occurred with retention of configuration at
the phosphorus atom. A similar result was obtained
when 2 was reacted with methylenecyclohexane (under
the same reaction conditions as for 1-octene). Hence a
5:1 mixture of diastereoisomers of 2 gave rise to a 5:1
mixture of diastereomers of the organophosphorus
adduct 6b (as indicated by the NMR spectra) in 83%
yield.
Figure 2.
The organophosphorus adducts derived from these rad-
ical addition reactions are useful synthetic intermediates.
For example, a-alkylation reactions7,15 are possible and
this was investigated by deprotonation of 6b at −78°C
followed by treatment with benzyl bromide (Scheme 3).
This gives rise to 4 diastereoisomers of 9 in the ratio of
7.5:5.5:1.5:1 (as indicated by the NMR spectra) and so
there is little diastereoselectivity (1.5:1) in the alkylation.
Further deprotonation and alkylation of 9 (using MeI or
allyl bromide), in order to form a quaternary stereogenic
centre, was unsuccessful and only starting material was
recovered (as a 5:5:1:1 mixture of isomers).
Figure 1.
Scheme 3.
Radical addition to the alkyne bond of ethynylbenzene
is also possible and when a 9:1 mixture of isomers of 2
was reacted with this alkyne, a 9:1 mixture of
diastereoisomers of 6c was formed in 90% yield. Inter-
estingly, the 1H NMR spectrum of 6c suggested the
exclusive formation of the Z-isomer as indicated by a
coupling constant of 14 Hz between the alkenic hydro-
gens.13 The importance of using a thiophosphite rather
than a phosphite in these types of addition reactions
should be emphasised. Thus whereas reaction of
ethynylbenzene with diethyl thiophosphite produced the
expected Z-adduct in 67% yield, the corresponding
reaction using diethyl phosphite did not produce any of
the desired product.14
It should also be noted that the thiophosphonate deriva-
tives can be converted into phosphonates as shown in
Scheme 4. Thus, reaction of (a 9:9:1:1 mixture of isomers
of) 7 with m-CPBA16 resulted in the formation of
phosphonate 10 in good yield as a 9:9:1:1 mixture of
isomers. This result is consistent with previous work,
which has shown that oxidation of thiophosphonates
using m-CPBA occurs with overall retention of configu-
ration at phosphorus.17
Addition of 2 to prochiral alkenes was then investigated.
For example, reaction of a 9:1 mixture of diastereoiso-
mers of 2 with 2-methyl-2-propenyl phenyl ether gave 7
as an inseparable mixture of 4 diastereoisomers in 80%
Scheme 4.
This asymmetric approach to organophosphorus deriva-
tives should be applicable to other chiral thiophos-
phites as chiral substituents can be easily introduced
on to phosphorus.7 This includes (−)-menthyl groups
and reaction of the known dimenthyl phosphite 11,18
with Lawesson’s reagent resulted in the formation of 12
(Fig. 3) in 95% yield (as a single diastereomer). Phos-
phite 11 can be prepared in ]95% yield by reaction
1
yield (Fig. 2). Analysis of the H and 31P NMR spectra
indicated a 9:9:1:1 ratio of the four diastereoisomers of
7. This suggests that although the configuration of the
phosphorus stereogenic centre is retained, there is no
control over the formation of the new carbon stereo-
genic centre in adduct 7. Hydride 2 can therefore react

C. M. Jessop et al. / Tetrahedron: Asymmetry 14 (2003) 2849–2851
2851
4. Roberts, B. P.; Singh, K. J. Organomet. Chem. 1978, 159,
31–35.
5. Farnham, W. B.; Murray, R. K.; Mislow, K. Chem.
Commun. 1971, 146–147.
6. Reiff, L. P.; Aaron, H. S. J. Am. Chem. Soc. 1970, 92,
5275–5276.
Figure 3.
7. Wiemer, D. F. Tetrahedron 1997, 53, 16609–16644.
8. For the use of pinanediols in asymmetric synthesis, see
for example: (a) Matteson, D. S. Acc. Chem. Res. 1988,
21, 294–300; (b) Matteson, D. S. Tetrahedron 1989, 45,
1859–1885.
of (−)-menthol with PCl3/Et3N followed by hydrolysis16
or alternatively, by coupling (−)-menthol with phospho-
nic acid in the presence of DCC.9
9. Munoz, A.; Hubert, C.; Luche, J.-L. J. Org. Chem. 1996,
61, 6015–6017.
10. All spectra were in accord with the structures assigned.
11. The configuration of the phosphorus chiral centre in the
major diastereoisomer of 2 was tentatively assigned as S.
This was based on a NOESY experiment, which showed
Reaction of thiophosphite 12 (3.5 equiv.) with 1-octene
(1 equiv.) in the presence of triethylborane (in cyclohex-
ane at rt) followed by oxidation using m-CPBA resulted
in the formation of phosphite 13 in an excellent 85% yield
s
(Fig. 4). On treatment with BuLi at −78°C followed by
benzyl bromide this afforded the expected alkylated
product 14 in 65% yield (as a 1:1 mixture of diastereoiso-
mers). In a similar manner, reaction of 12 with 2-methyl-
2-propenyl phenyl ether (1 equiv.) followed by m-CPBA
gave 15 in 47% yield as an equal mixture of two
diastereoisomers as indicated by the 1H NMR spectrum.
a correlation between the P–H6 and OC–CH6 3 groups.
12. 1-Octene (20 mg, 0.19 mmol) and a 1 M solution of
triethyl borane in hexanes (0.056 mL, 0.056 mmol) were
added to a stirred solution of thiophosphite 2 (110 mg,
0.46 mmol) as a 4:1 mixture of diastereoisomers in tetra-
hydrofuran (2 mL) under an atmosphere of nitrogen at
room temperature. After 6 h, further triethylborane
(0.056 mL, 0.056 mmol) was added and the mixture
stirred for 48 h while adding triethylborane portionwise
(3×0.056 mL, 0.056 mmol) over this period. The mixture
was then concentrated in vacuo. Purification by column
chromatography on silica (hexane:ethyl acetate; 8:2)
afforded (1R,2R,6S,8R)-2,9,9-trimethyl-4-octyl-3,5-dioxa-
4l5-phosphatricyclo[6.1.1.0.2,6]decane-4-thione 6a (60 mg,
93%) as a colourless oil as a 4:1 mixture of diastereoiso-
Figure 4.
1
mers as indicated by the H and 31P NMR spectra. Rf 0.4
(hexane:ethyl acetate; 8:2): wmax (CH2Cl2) 2929 (s), 2856
(s), 1267 (s), 943 (s) cm−1. The major diastereoisomer was
indicated by: lH (300 MHz, CDCl3) 4.48 (1H, m, OCH),
2.45–1.25 (20H, m, 9×CH2 and 2×CH), 1.54 (3H, s,
CH3), 1.32 (3H, s, CH3), 0.88 (3H, t, J=6 Hz, CH3), 0.85
(3H, s, CH3); lC (75.0 MHz, CDCl3) 91.6 (d, JCP=4 Hz,
This work has shown for the first time that radical
addition of chiral thiophosphites to alkenes occurs with
retention of configuration at phosphorus. Addition to a
variety of electron-rich alkene double bonds is possible
and this offers a mild, efficient and selective approach to
asymmetric organothiophosphonates, which are useful
intermediates in organic synthesis.
OCCH), 80.5 (d, JCP=2.7 Hz, OCHCH2), 52.2 (d, JCP
=
4 Hz, OC(CH3)CH), 39.9 (CH), 38.6 (d, JCP=92 Hz,
PCH2), 35.3 (CH2), 32.2 (CH2), 30.7, 30.5, 29.5, 29.4
(4×CH2), 28.9 (POCCH3), 27.6 (CH2), 27.5, 24.6 (2×
CH3), 23.0 (CH2), 14.5 (CH2CH2CH3); lP (97.4 MHz,
CDCl3) 121.0; m/z (CI, NH3) 345 (M+H+, 100%); HRMS
found 345.2018. C18H34O2PS requires for MH, 345.2017).
The presence of the minor diastereoisomer was indicated
by: lH (300 MHz, CDCl3) 4.25 (1H, m, OCH); lP (97.4
MHz, CDCl3) 121.1.
Acknowledgements
We thank Uniqema and the BBSRC for funding.
References
13. (a) Semenzin, D.; Etemad-Moghadam, G.; Albouy, D.;
Diallo, O.; Koenig, M. J. Org. Chem. 1997, 62, 2414–
2422; (b) Mitchell, T. N.; Heesche, K. J. Organomet.
Chem. 1991, 409, 163–170.
14. The corresponding reaction using diphenylphosphine
oxide gave a 1.8:1 mixture of the Z- and E-isomers,
respectively, in a combined yield of 50%.
15. (a) Molt, O.; Schrader, T. Synthesis 2002, 2633–2670; (b)
Afarinkia, K.; Jones, C. L.; Yu, H.-W. Synlett 2003,
509–512.
16. Yokomatsu, T.; Sada, T.; Shimizu, T.; Shibuya, S. Tetra-
hedron Lett. 1998, 39, 6299–6302.
1. Depre`le, S.; Montchamp, J.-L. J. Org. Chem. 2001, 66,
6745–6755.
2. See for example: (a) Herpin, T. F.; Motherwell, W. B.;
Roberts, B. P.; Roland, S.; Weibel, J.-M. Tetrahedron
1997, 53, 15085–15100; (b) Lopin, C.; Gautier, A.;
Gouhier, G.; Piettre, S. R. Tetrahedron Lett. 2000, 41,
10195–10200; (c) Dubert, O.; Gautier, A.; Condamine,
E.; Piettre, S. R. Org. Lett. 2002, 4, 359–362; (d) Gautier,
A.; Garipova, G.; Dubert, O.; Oulyadi, H.; Piettre, S. R.
Tetrahedron Lett. 2001, 42, 5673–5676; (e) Piettre, S. R.
Tetrahedron Lett. 1996, 37, 2233–2236; (f) Piettre, S. R.
Tetrahedron Lett. 1996, 37, 4707–4710.
17. Herriott, A. W. J. Am. Chem. Soc. 1971, 93, 3304–3305.
18. Gulea-Purcarescu, M.; About-Jaude´t, E.; Collignon, N.
Tetrahedron Lett. 1995, 36, 6635–6638.
3. Jessop, C. M.; Parsons, A. F.; Routledge, A.; Irvine, D.
Tetrahedron Lett. 2003, 44, 479–483.