Diphenylphosphinoyl chloride as a chlorinating agent - The selective double activation of 1,2-diols

Article abstract of DOI:10.1039/b606881b

Treatment of 1,2-diols with diphenylphosphinoyl chloride in pyridine produces β-chloroethyl phosphinates which react with complete control of stereochemistry to give epoxides and azido-alcohols, useful intermediates in cyclopropane synthesis. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b606881b

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Diphenylphosphinoyl chloride as a chlorinating agent – the selective double
activation of 1,2-diols†
David J. Fox,* Daniel Sejer Pedersen, Asger B. Petersen and Stuart Warren
Received 15th May 2006, Accepted 21st June 2006
First published as an Advance Article on the web 6th July 2006
DOI: 10.1039/b606881b
Treatment of 1,2-diols with diphenylphosphinoyl chloride in pyridine produces b-chloroethyl
phosphinates which react with complete control of stereochemistry to give epoxides and azido-alcohols,
useful intermediates in cyclopropane synthesis.
Stereochemically pure 1,2-diols, derived either from the catalytic
asymmetric dihydroxylation of olefins1 or from other sources, are
important intermediates in asymmetric synthesis. The hydroxy
groups can be activated and differentially displaced by a variety of
nucleophiles, often with high levels of regiocontrol due to adjacent
electronic conjugating groups. Cyclic acylium ions, most often
generated by reaction of diols with orthoesters2–4 or equivalents,5
can be ring opened with fluoride,5 chloride2–4 and bromide to give
vicinial halo-acylates.3 Along with cyclic carbonates,6 sulfites7–9
and sulfates,10–12 chloro- and bromo-ethyl esters are valuable
intermediates in the stereoselective synthesis of epoxides,6,13 b-
Scheme 1 Reagents and conditions: i) Ph2POCl, pyridine, see Table 1.
Inset: X-ray crystal structure of chloro-phosphinate 6 with thermal
ellipsoids at 50% probability.
amino-alcohols8,9,14 diamines11 and amino-acids.7,10,15–17 In this
paper we describe a new and simple method that provides not
only the regioselective differentiation of 1,2-diols but also selective
bis-activation.
Table 1 Chloro-phosphinoylation of diols (see Scheme 1)
During synthesis of cyclopropane-containing c-amino ketones18
and esters19 the attempted bis-diphenylphosphinoylation of diols
1 and 2 with diphenylphosphinoyl chloride in pyridine resulted in
inclusion of only one phosphinoyl group. Initially it was assumed
that only one hydroxy group had reacted, but mass spectrometry
and X-ray crystallography indicated that chlorine had replaced the
hydroxy at the benzylic position with stereochemical inversion to
give chloro-phosphinates 5 and 6 (Scheme 1). Methyl and diphenyl
substituted diols13 3 and 4 also react selectively (Table 1). Only
the reaction of diol 1 produced a small amount (3%) of bis-
phosphinate product18 9. The reactions of diols 1, 2 and 3 produced
only single stereo- and regioisomers of chloro-phosphinates.
The reaction of methyl cinnamate-derived diol17 10 produced a
mixture of chloro-phosphinate regioisomers 11 and 12 along with
bis-phosphinate 13 (Scheme 2). This result indicated that esters
can also mediate the adjacent introduction of chlorine into 1,2-
diols. This was confirmed when non-aryl diol20 14 produced only
the 2-Cl isomer of chloro-phosphinate 15.
R
Diol
Chloro-phosphinate
Yield (%)a
(CH2)2COPh
(CH2)2CO2 Bu
Me
Ph
1
2
3
4
5
6
7
8
66b
83
60
71
t
a Isolated yield of chloro-phosphinate. b 3% biphosphinate 9 also isolated.
X-Ray crystallography of chloro-phosphinate 6 (Scheme 1)
showed that the introduction of chlorine occurred with inversion
of stereochemistry,21 probably by SN2 reaction of chloride ion
with the activated diol at the more activated position adjacent
to either the aryl or ester groups. Hydrobenzoin 4 was chosen as
a substrate to test the mechanism as it had substituted only once
Scheme 2 Reagents and conditions: i) Ph2POCl, pyridine, 11 : 12 : 13 =
52 : 17 : 31 (by 1H NMR); ii) Ph2POCl, pyridine, 45%.
despite containing two benzylic alcohols. Two possible reaction
pathways are either phosphinoylation of both alcohols followed
by displacement of one phosphinate by chloride, or alternatively,
reaction of the mono-phosphinate 16 with chloride, followed by a
second phosphinoylation (Scheme 3).
University Chemical Laboratory, Lensfield Road, Cambridge, UK CB2
1EW. E-mail: djf34@cam.ac.uk
† Electronic supplementary information (ESI) available: experimental
procedures and analytical details for new compounds and crystallographic
data. See DOI: 10.1039/b606881b.
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Scheme 5 Reagents and conditions: i) Ph2POCl, pyridine.
Scheme 3 i) Phosphinoylation; ii) SN2 diplacement by chloride.
Independent synthesis of phosphonium ion 20 and reaction
with chloride ion was achieved via the reaction of diol 4 with
Ph2PCl3 in pyridine (Scheme 6).22 Along with unreacted diol, the
major product of the reaction is chloro-phosphinate 8. Peaks due
The mono- and bis-phosphinates 16 and 17 were therefore syn-
thesised from diol 4 to investigate their reactions with chloride ions
in pyridine. Interestingly, neither the mono- nor bis-phosphinate
reacts with pyridinium chloride, suggesting that these reactions do
not take place in the chloro-phosphination reaction (Scheme 4).
Unlike bis-phosphinate 17, the mono-phosphinate 16 does react
with diphenylphosphinoyl chloride to give chloro-phosphinate 8.
Finally, diol 4 does not react directly with pyridinium chloride.
1
to mono-phosphinate 16 can also be observed in the H NMR
spectrum of the crude reaction mixture. These products provide
good evidence for the participation of phosphonium ion 20 in
the chloro-phosphinoylation of diols with diphenylphosphinoyl
chloride according to the mechanism proposed in Scheme 5.
Scheme 6 Reagents and conditions: i) Ph2PCl3, pyridine (4 : 8 : 16 = 43 :
31 : 26, by 1H NMR).
Finally, the reactions of the chloro-phosphinates were studied
(Scheme 7). Displacement of the benzylic chlorides 5, 7 and 8
with azide produced mono-azide phosphinates 21–23 as single
diastereoisomers; the phosphinate neither acts as a leaving group
nor participates in the displacement of chloride. As with the
related anti-azido-phosphinate,18 syn-azido-phosphinate 21 could
be converted into mainly trans-cyclopropane 31. anti-Chloro-
phosphinates can also be converted into anti-epoxides 27 and
29: treatment with potassium carbonate in methanol13 results
in removal of the diphenylphosphinate group23 and ring closure.
The synthesis of cyclopropane24 30 results from the in situ base-
mediated reaction of epoxide 29. Overall, change in the order of
reagents in the conversion of chloro-phosphinate 8 into azido-
alcohols 26 and 28 reverses the stereochemistry of the final prod-
uct. Overall reaction occurs with maintenance of stereochemistry
via epoxide 27, but with inversion of stereochemistry at the
benzylic position if the diphenylphosphinate is removed as the
last step.
Scheme 4 Reagents and conditions: i) Ph2POCl, Et3N, DMAP, THF, 36%;
ii) Ph2POCl, Et3N, DMAP, CH2Cl2, 24%; iii) Ph2POCl, pyridine, >95%
1
(by H NMR); iv) pyridine·HCl, pyridine, or Ph2POCl, pyridine, 0%; v)
pyridine·HCl, pyridine, 0%; vi) pyridine·HCl, pyridine, 0%.
Given that mono-phosphinate 16 reacts with diphenylphos-
phinoyl chloride to give chloro-phosphinate 8, but that bis-
phosphinate 17 is not an intermediate, an alternative pathway
to those suggested above must be sought. In addition, as chloride
seems not to be nucleophilic enough to displace diphenylphosphi-
nate in these reaction conditions, a more electrophilic intermediate
must be involved. Cyclic phosphonium ion 20, formed via phos-
phinoylation of phosphorane 19, is suitably reactive (Scheme 5).
We hope to extend the simple chloro-phosphinoylation of 1,2-
diols to the synthesis of more complex and widely functionalised
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References and notes
1 H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Chem. Rev.,
1994, 94, 2483.
2 M. S. Newman and D. R. Olson, J. Org. Chem., 1973, 38, 4203.
3 M. S. Newman and C. H. Chen, J. Org. Chem., 1973, 38, 1173.
4 M. S. Newman and C. H. Chen, J. Am. Chem. Soc., 1973, 95, 278.
5 S. Hara and T. Fukuhara, US Pat. 2006/0014972, 2006.
6 H. T. Chang and K. B. Sharpless, J. Org. Chem., 1996, 61, 6456.
7 I. A. Sayyed and A. Sudalai, Tetrahedron: Asymmetry, 2004, 15,
3111.
8 M. Braun, R. Fleischer, B. Mai, M. A. Schneider and S. Lachenicht,
Adv. Synth. Catal., 2004, 346, 474.
9 K. Sahasrabudhe, V. Gracias, K. Furness, B. T. Smith, C. E. Katz, D. S.
Reddy and J. Aube, J. Am. Chem. Soc., 2003, 125, 7914.
10 C. Y. Xiong, W. Wang and V. J. Hruby, J. Org. Chem., 2002, 67,
3514.
11 P. F. Richardson, L. T. J. Nelson and K. B. Sharpless, Tetrahedron Lett.,
1995, 36, 9241.
12 B. B. Lohray, Y. Gao and K. B. Sharpless, Tetrahedron Lett., 1989, 30,
2623.
13 H. C. Kolb and K. B. Sharpless, Tetrahedron, 1992, 48, 10515.
14 H. T. Chang and K. B. Sharpless, Tetrahedron Lett., 1996, 37, 3219.
15 F. Soucy, L. Grenier, M. L. Behnke, A. T. Destree, T. A. McCormack,
J. Adams and L. Plamondon, J. Am. Chem. Soc., 1999, 121, 9967.
16 J. G. Deng, Y. Hamada and T. Shioiri, J. Am. Chem. Soc., 1995, 117,
7824.
17 Z. M. Wang, H. C. Kolb and K. B. Sharpless, J. Org. Chem., 1994, 59,
5104.
18 D. J. Fox, S. Parris, D. S. Pedersen, C. R. Tyzack and S. Warren, Org.
Biomol. Chem., 2006, DOI: 10.1039/b606874j.
19 D. J. Fox, D. S. Pedersen and S. Warren, Org. Biomol. Chem., 2006,
DOI: 10.1039/b606879k.
20 W. H. Pearson and M.-C. Cheng, J. Org. Chem., 1987, 52, 3176.
Scheme 7 Reagents and conditions: i) NaN3, DMF; ii) K2CO3, MeOH;
iii) K2CO3, MeOH, 86%; iv) NaN3, DMF, 75%; v) K2CO3, MeOH, 79%;
vi) LDA, THF, 47% (31 : 32 = 9 : 1).
21 Crystal data for 6. C27H30ClO4P, M = 484.93, orthorhombic, space
˚
group P212121, a = 5.8203(10), b = 11.4038(2), c = 37.8022(9) A, a =
◦
3
−1
˚
90, b = 90, c = 90 , U = 2509.1(4) A , Z = 4, l(Mo-Ka) = 0.247 mm
,
molecules where the introduction of two different leaving groups
with defined stereochemistry will have significant use.
10165 reflections collected at 180(2) K using an Oxford Cryosystems
Cryostream cooling apparatus, 4316 unique (Rint = 0.056); R1 = 0.053,
wR2 = 0.127 [I > 2r(I)], absolute structure parameter 0.02(10). CCDC
reference number 600429. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b606881b.
Acknowledgements
22 V. Chandrasekhar, T. Chivers, S. S. Kumaravel, A. Meetsma and J. C.
van de Grampel, Inorg. Chem., 1991, 30, 3402.
We thank Dr John Davies for crystallography and the EPSRC
for financial assistance towards the purchase of the Nonius CCD
diffractometer. D. S. P. thanks the Alfred Benzon Foundation for
financial support.
23 D. J. Fox, D. S. Pedersen and S. Warren, Org. Biomol. Chem., 2006,
DOI: 10.1039/b606873a.
24 T. Boesen, D. J. Fox, W. Galloway, D. S. Pedersen, C. R. Tyzack and S.
Warren, Org. Biomol. Chem., 2005, 3, 630.
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 3117–3119 | 3119
©