Catalysis of phosphorus(V)-mediated transformations: Dichlorination reactions of epoxides under appel conditions

Article abstract of DOI:10.1021/ol102010h

A stereospecific triphenylphosphine oxide-catalyzed 1,2-dichlorination reaction of epoxides has been developed. The reaction is effective for a range of terminal and internal epoxides. In contrast to the classical Appel-type dichlorination of epoxides, oxalyl chloride is used as a stoichiometric reagent to generate the chlorophosphonium salt responsible for dichlorination from catalytic triphenylphosphine oxide.

Full text of DOI:10.1021/ol102010h

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4678-4681
Catalysis of Phosphorus(V)-Mediated
Transformations: Dichlorination
Reactions of Epoxides Under Appel
Conditions
Ross M. Denton,* Xiaoping Tang, and Adam Przeslak
School of Chemistry, UniVersity of Nottingham, UniVersity Park, Nottingham,
NG7 2RD, United Kingdom
ross.denton@nottingham.ac.uk
Received August 25, 2010
ABSTRACT
A stereospecific triphenylphosphine oxide-catalyzed 1,2-dichlorination reaction of epoxides has been developed. The reaction is effective for
a range of terminal and internal epoxides. In contrast to the classical Appel-type dichlorination of epoxides, oxalyl chloride is used as a
stoichiometric reagent to generate the chlorophosphonium salt responsible for dichlorination from catalytic triphenylphosphine oxide.
Alkyl chlorides are fundamentally important building blocks
in synthetic organic chemistry.1 They are also valuable end-
products in their own right; for example, a range of bioactive
naturally occurring polychlorinated hydrocarbons termed
chlorosulfolipids have been isolated from fresh water mi-
croalgae and toxic Adriatic mussels.2,3 These natural prod-
ucts, which contain numerous chlorine-bearing stereogenic
centers, have driven the development of new methods for
the stereocontrolled introduction of chlorine to functionalized
organic substrates. For example, asymmetric transformations
of carbonyl compounds,4 diastereoselective dichlorination of
alkenes5 and stereospecific dichlorination of epoxides6 have
all recently been reported, and total syntheses of chlorosul-
folipids have been disclosed exploiting these methods.7 In
contemplating the synthesis of polychlorinated target mol-
ecules, we were attracted to the chlorophosphonium salt-
mediated dichlorination of epoxides (Scheme 1a),6 a reaction
that has most recently been investigated by Tanaka and
Yoshimitsu,6g as a method to obtain vicinal dichloride
building blocks for chlorosulfolipid synthesis.7d
(2) (a) Elovson, J.; Vagelos, P. R. Proc. Natl. Acad. Sci. U.S.A. 1969,
62, 957. (b) Haines, T. H.; Pousada, M.; Stern, B.; Mayers, G. L. Biochem.
J. 1969, 113, 565. (c) Elovson, J.; Vagelos, P. R. Biochemistry 1970, 9,
3110. (d) Haines, T. H. In Lipids and Biomembranes of Eukaryotic
Microorganisms; Erwin, J. A., Ed; Academic Press: New York, 1973; p
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Chem. 2001, 66, 578. (g) Ciminiello, P.; Dell’Aversano, C.; Fattorusso, E.;
Forino, M.; Magno, S.; Di Rosa, M.; Iarno, A.; Poletti, R. J. Am. Chem.
Soc. 2002, 124, 13114. (h) Ciminiello, P.; Dell’Aversano, C.; Fattorusso,
E.; Forino, M.; Magno, S.; Di Meglio, P.; Ianaro, A.; Poletti, R. Tetrahedron
2004, 60, 7073.
(1) For reviews, see: (a) Chambers, R. D.; James, S. R. In ComprehensiVe
Organic Chemistry; Barton, D. H. R., Ollis, W. D., Eds.; Pergamon Press:
Oxford, 1979; Vol. 1, p 493. (b) Hudlicky, M., Hudlicky, T. In Compre-
hensiVe Chemistry of Functional Groups, Supplement, D.; Patai, S.,
Rappoport, Z., Eds.; Wiley: New York, 1983; p 1021. (c) Bohlmann, R. In
ComprehensiVe Organic Synthesis; Trost, B., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; pp 203. (d) Larock, R. C. ComprehensiVe Organic
Transformations; WILEY-VCH: Weinheim, 1999, p 689.
(3) For reviews, see: (a) Ciminiello, P.; Dell’Aversano, C.; Fattorusso,
E.; Forino, M.; Magno, S. Pure Appl. Chem. 2003, 75, 325. (b) Ciminiello,
P.; Fattorusso, E. Eur. J. Org. Chem. 2004, 2533. (c) Dembitsky, V. M.;
Srebnik, M. Prog. Lipid Res. 2002, 41, 315.
10.1021/ol102010h  2010 American Chemical Society
Published on Web 09/16/2010

Scheme 1
.
(a) Stoichiometric and (b) Phosphine
Scheme 2. Proposed Catalytic Dichlorination of Epoxides
Oxide-Catalyzed Dichlorination of Epoxides
alcohols.10 Herein, we report the first examples of phosphorus-
mediated dichlorination reactions that are catalytic with
respect to triphenylphosphine oxide (Scheme 1b).
Our plan for the design of catalytic reactions of this type
is depicted in Scheme 2 and involves a catalytic cycle in
which the transformation of triphenylphosphine oxide into
chlorophosphonium salt 2,10,11 with concomitant loss of CO
and CO2, closes the catalytic cycle. This redox-neutral
strategy9a avoids the difficult stoichiometric reduction of the
strong phosphorus-oxygen double bond that would be neces-
sary for catalytic turnover in an alternative phosphorus(III)/
phosphorus(V) cycle. The increased atom efficiency12 as-
sociated with replacement of stoichiometric triphenylphos-
phine oxide with CO and CO2 as waste is also an appealing
aspect of this strategy.
Our interest in this reaction stemmed both from the
synthetic utility of the products7d,8 and from the more
fundamental challenge that it presented in terms of catalytic
reaction development: the reaction is stoichiometric in
phosphonium salt and therefore stoichiometric triphenylphos-
phine oxide is generated as waste. This impacts severely on
the atom efficiency of this and many other widely used
phosphorus(V)-mediated processes such as the Wittig, Mit-
sunobu and Appel reactions. Given the phosphorus waste
generated by these processess and the drive toward the
development of cleaner chemical reactions, the phosphine
oxide problem is a pressing issue that needs to be addressed
by catalysis.9 Our work involves the development of new
catalytic versions of important phosphorus(V)-mediated
transformations. For example, we recently reported a new
triphenylphosphine oxide-catalyzed chlorination reaction of
We began by establishing that the chlorophosphonium salt
2, generated in situ from triphenylphosphine oxide and oxalyl
chloride, was effective for the dichlorination of epoxide 3a
(eq 1).
(4) For key papers on the stereoselective introduction of chlorine, see:
(a) Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E. Tetrahedron
Lett. 1987, 28, 39. (b) Evans, D. A.; Ellman, J. A.; Dorow, R. L. Tetrahedron
Lett. 1987, 28, 1123. (c) Hu, S.; Jayaraman, S.; Oehlschlager, A. C. J. Org.
Chem. 1996, 61, 7513. (d) Hu, S.; Jayaraman, S.; Oehlschlager, A. C. J.
Org. Chem. 1996, 63, 8843. (e) Hintermann, L.; Tongi, A. HelV. Chim.
Acta 2000, 83, 2425. (f) Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury,
W. J.; Lectka, T. J. Am. Chem. Soc. 2001, 131, 1531. (g) Hafez, A. M.;
Taggi, A. E.; Wack, H.; Esterbrook, J.; Lectka, T. Org. Lett. 2001, 3, 2049.
(h) Brochu, M. P.; Brown, S. P.; Macmillan, D. W. C. J. Am. Chem. Soc.
2004, 126, 4108. (i) Halland, N.; Braunton, A.; Bachmann, S.; Marigo,
We next reacted epoxide 3a with oxalyl chloride (eq 2).
The formation of two regioisomeric chlorooxalates 5a and
5b revealed a background reaction that could potentially
compete with the desired dichorination process.
M.; Jorgenson, K. A. J. Am. Chem. Soc. 2004, 126, 4790
.
(5) (a) Shibuya, G. M.; Kanady, J. S.; Vanderwal, C. D. J. Am. Chem.
Soc. 2008, 130, 12514. (b) Nilewski, C.; Geisser, R. W.; Ebert, M.-O.;
Carreira, E. M. J. Am. Chem. Soc. 2009, 131, 15866. (c) Kanady, J. S.;
Nguyen, J. D.; Ziller, J. W.; Vanderwal, C. D. J. Org. Chem. 2009, 74,
With this information in hand we began to investigate the
feasibility of catalytic dichlorination reactions (Table 1) on
substrate 3a. In the first instance (entry 1) chloroform
solutions of epoxide 3a and oxalyl chloride were added to a
solution of 20 mol % phosphonium salt 2 (formed from
oxalyl chloride and triphenylphosphine oxide). By using this
2175
.
(6) (a) Isaacs, N. S.; Kirkpatrick, D. Tetrahedron Lett. 1972, 13, 3869.
(b) Sonnet, P. E.; Oliver, J. E. J. Org. Chem. 1976, 41, 3279. (c) Echigo,
Y.; Watanabe, Y.; Mukaiyama, T. Chem. Lett. 1977, 1013. (d) Oliver, J. E.;
Sonnet, P. E. Org. Synth. 1978, 58, 64. (e) Croft, A. P.; Bartsch, R. A. J.
Org. Chem. 1983, 48, 3353. (f) Iranpoor, N.; Firouzabadi, H.; Azadi, R.;
Ebrahimzadeh, F. Can. J. Chem. 2006, 84, 69. (g) Yoshimitsu, T.;
Fukumoto, N.; Tanaka, T. J. Org. Chem. 2009, 74, 696
.
(7) For the total synthesis of (()-hexachlorosulfolipid, see: (a) Nilewski,
C.; Geisser, R. W.; Carreria, E. M. Nature 2009, 457, 573. For the total
synthesis of danicalipin A, see: (b) Bedke, D. K.; Shibuya, G. M.; Pereira,
A.; Gerwick, W. H.; Haines, T. H.; Vanderwal, C. D. J. Am. Chem. Soc.
2009, 131, 7570. For the total synthesis of malhamensilipin A, see: (c)
Bedke, D. K.; Shibuya, G. M.; Pereira, A. R.; Gerwick, W. H.; Vanderwal,
C. D. J. Am. Chem. Soc. 2010, 132, 2542. For the total synthesis of (+)-
hexachlorosulfolipid, see: . (d) Yoshimitsu, T.; Fukumoto, N.; Nakatani,
(9) Other research groups have been active in the development of
catalytic versions of phosphorus-mediated reactions; for the first phosphine
oxide-catalyzed aza-Wittig reaction, see: (a) McGonagle, A. E.; Marsden,
S. P.; McKever-Abbas, B. Org. Lett. 2008, 10, 2589. For the first phosphine
catalyzed Wittig reaction, see: (b) O’Brien, C. J.; Tellez, J. L.; Nixon, Z. S.;
Kang, L. J.; Carter, A. L.; Kunkel, S. R.; Przeworski, K. C.; Chass, G. C.
Angew. Chem., Int. Ed. 2009, 48, 6836. For Wittig reactions coupled with
phosphine oxide-promoted conjugate reduction and cyanosilylation, see:
(c) Cao, J.-J.; Zhou, F.; Zhou, J. Angew. Chem., Int. Ed. 2010, 49, 4976.
For a phosphine-catalyzed reduction of alkyl silyl peroxides, see: (d) Harris,
J. R.; Haynes, M. T., II; Thomas, A. M.; Woerpel, K. A. J. Org. Chem.
2010, 75, 5083.
R.; Kojima, N.; Tanaka, T. J. Org. Chem. 2010, 75, 5425
.
(8) For the functional group interconversion of chlorides, see: (a) Larock,
R. C. ComprehensiVe Organic Transformations; WILEY-VCH: Weinheim,
1999; p 667. (b) For elimination reactions of 1,2-dichlorides, see: (c) Larock,
R. C. ComprehensiVe Organic Transformations; WILEY-VCH: Weinheim,
(10) Denton, R. M.; Jie, A.; Adeniran, B. Chem. Commun. 2010, 46,
1999; p 259
.
3025.
Org. Lett., Vol. 12, No. 20, 2010
4679

Table 2. Substrate Scope of the Dichlorination Reactiona
Table 1. Optimisation of Triphenylphosphine Oxide-Catalyzed
Dichlorination Reactiona
Ph3PO,
mol %
(COCl)2,
mol %
2,6-tBuPy,
mol %
time,
h
yield
4a, %
entry
1
2
3
4
5
6
20
20
20
15
15
0
100
100
100
100
130
130
0
0
150
150
150
150
6
16
6
16
6
58b
73b
78c, 69b
56c
entry
product
solvent
temp. °C
yield %
1
2
3
4
5
6
7
8
4a
4a
4b
4c
4d
4e
4f
4g
4g
4h
4i
CHCl3
EtOAc
CHCl3
CHCl3
CHCl3
CHCl3
C6H6
C6H6
C6H6
C6H6
C6H6
23
23
23
23
23
23
80
80
80
80
80
91c
91c
94c 81b
84c 78b
66c 57b
75c 66b
72c 62b
56c 44b
0b
6
0b
a Addition protocol: To solution of Ph3PO (0.15 equiv) in chloroform
(1.0 mL) was added (COCl)2 (0.15 equiv). To this solution was simulta-
neously added a solution of epoxide (1 mmol, 1.0 equiv) and 2,6-
ditertbutylpyridine (1.5 equiv) in chloroform (0.80 mL) and a solution of
(COCl)2 (0.75 or 1.15 equiv) in chloroform (0.80 mL) over the time
indicated at room temperature. b Isolated yield after flash column
chromatography. c Yield determined using 1H NMR spectroscopy with
tetrachloroethane as an internal standard.
9
10
11
58c 46b
57c
66c
a Addition protocol for reagents: see Table 1 footnote a. b Isolated yield
after flash column chromatography. c Yield determined using 1H NMR
spectroscopy with tetrachloroethane as an internal standard.
addition protocol, we hoped to minimize the unwanted
background reaction observed previously. An isolated yield
of 58% was encouraging and was improved to 73% by
extending the addition time to 16 h. The remainder of the
mass balance in both cases consisted of oxalates 5a and 5b.
At this point, we were conscious that HCl present in the
oxalyl chloride could react with the substrate to afford
chlorohydrins e.g. 6a that would then be converted into
oxalate esters. Therefore, we sought a non-nucleophilic base
to use as an additive. We found that 2,6-di-tert-butylpyridine
did not react with oxalyl chloride and was effective as an
additive in this regard (Entry 3). A decrease in catalyst
loading in the presence of the additive resulted in a lower
yield (Entry 4). However, this was improved to an excellent
91% when 1.3 equivalents of oxalyl chloride was used (Entry
5). A control experiment conducted under the optimal
conditions, in the absence of triphenylphosphine oxide,
afforded no dichloride product (Entry 6). Having identified
conditions for the catalytic dichlorination of a terminal
epoxide, we examined the scope of the reaction (Table 2).
The reaction was effective for a range of epoxides with yields
ranging from moderate to excellent. Terminal epoxides
underwent efficient catalytic dichlorination at room temper-
ature and alkenyl (Entry 3), aryl (Entries 4 and 5) as well as
silyl-protected hydroxyl functionalities (Entry 6) were toler-
ated. Attempts to chlorinate epoxides derived from 1,2-
disubstituted alkenes under analogous conditions failed.
However, changing the solvent from chloroform to benzene
and heating to 80 °C afforded reasonable results for these
less reactive internal epoxides. In these cases alkenes were
observed with dichlorides 4f and 4g as minor inseparable
byproducts.6g
For example, trans-epoxide 3f afforded syn-dichloride 4f
as the only diastereoisomer in reasonable yield. Likewise
cis-epoxide 3g gave rise to anti-dichoride 4g. The stereo-
chemistry of the products is consistent inversion with at both
stereogenic centers. Products 4f and 4g, which contain a
protected hydroxyl group are noteworthy since similar
building blocks have been used by Tanaka and Yoshimitsu
in their synthesis of chlorosulfolipids6d,7d and now they are
available Via a method that is catalytic in phosphorus.
We next applied the catalytic reaction to the synthesis of
a biologically active naturally occurring dichlorinated fatty
acid.3c To this end, 8,9-epoxyeliadic acid13 was dichlorinated
in 66% yield to afford 4i (Entry 11). Subsequent saponifica-
tion (LiOH, THF/CH3OH, 6 h, 71%) afforded the natural
product. Finally, subjecting cis-epoxide 3g to the reaction
conditions, in the absence of catalyst, afforded no chloride
product (Entry 8).
(11) (a) Masaki, M.; Fukui, K. Chem. Lett. 1977, 151. For recent
applications of the reaction, see: (b) Yano, T.; Hoshino, M.; Kuroboshi,
M.; Tanaka, H. Synlett 2010, 5, 801. (c) Yano, T.; Kuroboshi, M.; Tanaka,
H. Tetrahedron Lett. 2010, 51, 698.
(12) (a) Trost, B. M. Science 1991, 254, 1471. (b) Sheldon, R. A. Pure
Appl. Chem. 2000, 72, 1233. (c) Anastas, P.; Eghbali, N. Chem. Soc. ReV.
2010, 39, 301.
(13) See the Supporting Information for full details.
4680
Org. Lett., Vol. 12, No. 20, 2010

Having established that dichloride products of type 4 were
not formed in the absence of phosphine oxide we further
examined the role of the catalyst. Specifically, we sought to
establish the feasibility of the intervention of a second
catalytic cycle in which triphenylphosphine oxide functions
as a nucleophilic catalyst (e.g., 5f8f4 Scheme 3, cycle 2).
obtained. A similar experiment was conducted with 5c and
5d under the more vigorous conditions used for internal
epoxides; again, no vicinal dichloride products were obtained.
Finally, a reaction between 5a and one equivalent of Ph3PO
also afforded no product. These results, which are in
agreement with our earlier findings on the reactivity of
chlorooxalates10 and those of others,14 are consistent with
an Appel-type chlorination process (cycle 1, Scheme 3).
In summary, we have developed the first chlorophospho-
nium salt-mediated dichlorination reactions of epoxides that
are catalytic in phosphorus. The new chemistry provides
access to useful building blocks and naturally occurring
biologically active chlorinated fatty acids. Significantly, the
usual stoichiometric triphenylphosphine oxide waste product
has been replaced with CO and CO2. Specifically, this work
further validates the concept of redox-neutral catalysis for
phosphorus(V)-mediated transformations9a,10 and the use of
oxalyl chloride to induce phosphine oxide turnover in such
processes. The application of this catalysis strategy to several
other phosphorus(V)-mediated transformations is underway.
Scheme 3. Potential Catalytic Cycles
The relevant chlorooxalates were prepared from epoxides
3a and 3g via the corresponding chlorohydrins13 to inves-
tigate their reactivity with triphenylphosphine oxide (eq 3).13
Acknowledgment. Funding from The University of Not-
tingham (New Researcher’s Fund NRF5012), The Royal
Society (Research Grant RG090319) and the EPRSC (First
Grant EP/H018034/1) is gratefully acknowledged.
Note Added after ASAP Publication. This paper pub-
lished ASAP September 16, 2010. References 5b and c were
added in the version reposted September 21, 2010.
Supporting Information Available: Full experimental
procedures and spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL102010H
Chlorooxalates 5a and 5b were added to a solution of
Ph3PO under conditions identical to those used in the
catalytic reactions; no dichloride products of type 4 were
(14) Rhoads, S. J.; Michel, R. E. J. Am. Chem. Soc. 1963, 85, 585.
Org. Lett., Vol. 12, No. 20, 2010
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