Systematic survey of positive chlorine sources in the asymmetric Appel reaction: Oxalyl chloride as a new phosphine activator

Article abstract of DOI:10.1016/j.tetlet.2013.10.044

A wide selection of phosphine activators has been screened to improve the selection process in the asymmetric Appel reaction. Of the activators screened, hexachloroacetone (HCA) gave the highest selectivity with excellent yield, but at least one of its by

Full text of DOI:10.1016/j.tetlet.2013.10.044

Tetrahedron Letters 54 (2013) 7009–7012
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Tetrahedron Letters
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Systematic survey of positive chlorine sources in the asymmetric
Appel reaction: oxalyl chloride as a new phosphine activator
⇑
Kamalraj V. Rajendran, Lorna Kennedy, Cormac T. O’Connor, Enda Bergin, Declan G. Gilheany
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide selection of phosphine activators has been screened to improve the selection process in the asym-
metric Appel reaction. Of the activators screened, hexachloroacetone (HCA) gave the highest selectivity
with excellent yield, but at least one of its by-products, pentachloroacetone (PCA), can become involved
in the selection process. In addressing this, a new reaction of phosphines with oxalyl chloride was discov-
ered that can also generate the key intermediate chlorophosphonium salt (CPS), gives better enantiose-
lectivity and possesses significant advantages over other phosphine activators.
Received 17 August 2013
Revised 1 October 2013
Accepted 9 October 2013
Available online 17 October 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Asymmetric Appel conditions
P-Stereogenic/P-chiral
Chlorophosphonium salt
Hexachloroacetone
Pentachloroacetone
Oxalyl chloride
The use of enantiomerically pure phosphine ligands in asym-
metric catalysis is a popular strategy for asymmetric synthesis1
and much effort has been directed towards the design, synthesis
and testing of new enantiomerically pure phosphines.2 Many
methodologies have been developed for the synthesis of enantio-
merically pure P-stereogenic phosphines3 and a large number of
such ligands have been reported in the literature.3,4
Our own methodology for P-stereogenic phosphorus is based on
an asymmetric version of the Appel reaction system. This is an oxi-
dation/reduction/dehydration system in which a tertiary phos-
PCA
R*OH/ -78 °C
-PCA / fast
Ph
Cl
Cl
P
O
P
OR*
P
HCA/ -78 °C
very fast
Arbuzov
P
Ar
Ar -R*Cl / slow Ph
Ph
Ar
Ph
Ar
Racemic
Scalemic
CPS
DAPS
LAH
Ph
fast
(COCl)2
fast
NaBH4
P
Ar
BH3
O
P
Scalemic
Racemic
P
Ar
Ph
Ph
Ar
Scheme 1. Asymmetric Appel reaction: HCA = hexachloroacetone; PCA = penta-
chloroacetone; CPS = chlorophosphonium salt; DAPS = diastereomeric alkoxyphos-
phonium salt; blue: racemic; red: stereoenriched.
phine interacts initially with
a source of positively charged
chlorine, sometimes referred to as the phosphine activator.5 The
original Appel conditions utilized carbon tetrachloride for this pur-
pose but, later, the less toxic and more reactive hexachloroacetone
(HCA) was introduced.6 We found that this system could be used
for the asymmetric oxidation of racemic phosphines by interaction
with a chiral non-racemic alcohol giving a dynamic resolution of
racemic P-stereogenic phosphines in high yield with up to
82% ee.7,8 We have established the reaction sequence shown in
Scheme 1.9,10 Thus, the initially formed chlorophosphonium salt
(CPS) is captured stereoselectively by the chiral auxiliary (e.g.,
menthol) to form a pair of diastereomeric alkoxyphosphonium
salts (DAPS), which in turn undergo Arbuzov collapse to enantioen-
riched phosphine oxides.
Complementarily to this, we also showed9 that the key interme-
diate CPS could be generated from racemic phosphine oxide with
oxalyl chloride, allowing the oxide to be used as starting material
in lieu of phosphine. We also reported11 that the DAPS can be inter-
cepted by hydride reduction to give enantioenriched phosphine or
phosphine borane (Scheme 1).
Although the reaction manifold shown in Scheme 1 provides a
potentially powerful suite of methodologies for P-stereogenic
phosphorus, it is clearly limited by the moderate selectivities. As
part of our studies to raise selectivity and expand substrate scope,
we turned our attention to the influence of the phosphine activa-
tor. This can play a major role in determining the selectivity: for
example, we had noticed up to a 40% increase in selectivity on
switching from carbon tetrachloride to HCA.7a
⇑
Corresponding author. Tel.: +353 1 7162308; fax: +353 1 7162127.
E-mail address: declan.gilheany@ucd.ie (D.G. Gilheany).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.044

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K. V. Rajendran et al. / Tetrahedron Letters 54 (2013) 7009–7012
For our studies, we used model phosphines, the well-known
The lack of selectivity with bromine-based activators is also
noteworthy.
We then carried out a more systematic study of chlorine-based
activators with PAMP at low temperature and the results are
shown in Table 2.
Table 2 (entries 1–7) shows that at least three chlorines are re-
quired in the activator to induce both reactivity and stereoselectiv-
ity. That this is related to the stability of the anion produced on
chlorine abstraction seems to be confirmed by the reasonable re-
phenyl(o-anisyl)methylphosphine (PAMP) and, to a lesser extent,
phenyl(o-tolyl)methylphosphine (PTMP). We had previously
found7 that the latter gave the best selectivity with the cheap chi-
ral auxillary menthol (1), whereas the former was best with 8-phe-
nylmenthol (2). Using these systems, we screened initially a
variety of other known phosphine activators for comparison to
HCA, with the results shown in Table 1.
OH
OH
Ph
(-)-8-phenylmenthol 2
Table 2
Results of asymmetric Appel reactionsa using chlorine-based activators for PAMP
with (À)-menthol (1)b and (À)-8-phenylmenthol (2)c
(-)-menthol 1
It is plain that, although all these activators give moderate or
very good yields in the reaction, only HCA gives moderate stereose-
lectivity, approached only by N-chlorosuccinimide (entry 2). We
were surprised by the case of hexachloroethane (HCE, entry 4) be-
cause it is known to react with phosphines to form cleanly dichlo-
rophosphoranes, which are putative intermediates in our process.7
To check that this was the case, PAMP was treated with HCE in
CDCl3 at room temperature overnight, and indeed furnished a sin-
gle resonance at dP +70.5, consistent with literature precedent.12
However, treatment of the resulting solution with (À)-8-phenyl-
menthol still resulted in no selectivity in the resulting PAMPO.
R*OH
-78 ºC → r.t.
1 d
Cl-based
phosphine
activators
O
P
OMe
OMe
P
Ph
Ph
(
)-PAMP
(R)-PAMPO
Entry
1
Phosphine activator
R⁄OH = 1
R⁄OH = 2
Yield rangee (%)
12–19
eed (%)
eed (%)
O
0
0
Cl
EtO
O
2
3
0
0
0
0
10–13
12–17
Cl
Table 1
O
Results of asymmetric Appel reactionsa using common phosphine activators with
Cl
O
Cl
PAMP and PTMP
Cl
4
5
6
7
1
1
40–59
61–70
73–77
90–100
O
Cl
R*OH / r.t.
24 h
common
phosphine
activators
R
R
P
P
O
Ph
Ph
Cl
Cl
30
25
50f,g
42
—
Cl
O
c
Cl
Cl
Entry
Phosphine activator
R = Me
R = OMe
R⁄OH = 2
eeb (%)
Yield (%)
EtO
R⁄OH = 1
eeb (%)
Cl
O
Cl
Cl
Cl
Cl
Cl
77f
O
Cl
Cl
1
50
64
76/95
Cl
Cl
Cl
Cl
Cl
Cl
O
Cl
Cl
Cl
N
Cl
8
9
48g
28
74
50
63–72
47–59
2
3
4
35d
—
53d
5d
46/70
50
O
O
Cl
Cl3C
Cl
Cl
Cl
Br
N
Cl
O
O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CCl4
0e
84/95
10
11
—
66h
88
29
Cl
5
6
7
6f
<5
—
24d,g,h
<5
<5
60
60–80
75
CBr4 or Br2 or I2
SelectfluorÒ
O
25h,i
—
35–39
Cl
O
F
SO2NHPh
8
9
—
<2
—
34
40
Cl Cl
N
N
a
<1
S
S
Phosphine (0.11 mmol), alcohol (1.2 equiv), phosphine activator (1 equiv) at
À78 °C in toluene (0.11 M with respect to phosphine) unless noted otherwise,
a
Phosphine (0.11 mmol), alcohol (1.2 equiv), phosphine activator (1 equiv) at
rigorous drying of all materials; procedure as noted in the ESI.
b
room temperature in toluene (0.11 M with respect to phosphine) unless noted
otherwise, procedure as noted in the ESI.
All (À)-menthol cases repeated with (+)-menthol with the same results—see ESI
Table 1.
b
c
Determined by CSP-HPLC, (R)-enantiomer in excess in all cases, see ESI for
Results also obtained for isomenthol, neomenthol and tert-butylcyclohexanol
details.
with similar conclusions—see ESI, Table 1.
Determined by CSP-HPLC, (R)-enantiomer in excess in all cases see ESI for
details.
c
d
As determined by 31P NMR, see ESI.
d
In benzene.
e
e
Repeated with a 1 day delay between initial addition of HCE and subsequent
As determined by 31P NMR, see ESI.
From Ref. 7a.
DAPS de = 50%.
At room temperature.
f
addition of the alcohol.
f
g
In carbon tetrachloride.
At reflux.
From Ref. 7a.
g
h
h
i
25% ee also with (+)-menthol and 2% ee with isopropanol.

K. V. Rajendran et al. / Tetrahedron Letters 54 (2013) 7009–7012
7011
Table 3
sults obtained with other systems that would result in stabilized
carbanions (entries 8–10), with hexachlorocyclopentadiene (entry
8) being competitive with HCA.
Results of asymmetric Appel reactionsa using the best phosphine activators for PTMP
with (À)-mentholb with measurement of the diastereoselectivity of DAPS formation
In the study with PAMP, we also briefly examined a chiral non-
racemic activator, menthyl trichloroacetate13 (Table 2, entry 11),
hoping to detect any intervention of exchange of anions in the
CPS, Scheme 2. On use of the chiral activator, no selectivity differ-
ence was detected between the enantiomers of menthol and al-
most no selectivity was obtained with an achiral alcohol
(isopropanol) suggesting little influence of the enolate salt
(Scheme 2). However, this is not conclusive because the actual
selectivity obtained (25% ee) is the same as that obtained with
the analogous achiral activator (entry 6), suggesting that the chi-
rality is too far from the phosphorus centre to be influential.
Returning to the use of hexachloroacetone (HCA), now that we
had established that multiple chlorinated ketones could act as acti-
vators, we were quite concerned that the pentachloroacetone
(PCA) produced in the reaction (Scheme 1) might itself react with
unreacted phosphine with different selectivity. With a synthesis
of PCA in hand,14 we were able to confirm that this was indeed
the case because when it was used to activate PTMP at low tem-
perature, it gave substantially lower selectivity (Table 3, entries 1
and 2), clearly signalling involvement of the CPS counter ion some-
how in the selection process.
By now it had become clear that that we required an activator
that did not give as by-product an alternative activator, and we
wished to examine both hexachlorocyclopentadiene (HCCP) and
hexachlorocyclohexadienone (HCCH). However, before doing so,
we had to consider another aspect of the measurement of the
selectivity, shown in Table 3. In our previous work,7b,9 we found
that the diastereomeric excess (de)15 in the DAPS was the better
measure of the stereoselective step of the reaction because the
enantiomeric excess (ee) in the product oxides is subject to a selec-
tivity eroding process that may occur during the Arbuzov collapse.
Therefore, to study the selectivity, we devised a consistent proce-
dure16 to measure the de of DAPS and these figures are also in-
cluded in Table 3. It can be seen that in the case of HCA and PCA,
these figures are the same. However this is not true for either HCCP
or HCCH (entries 3 and 4). The former gives the same de as HCA,
but ultimately lower ee of the oxide, while the latter gives lower
selectivity in general.
In seeking a solution to this problem, we turned to oxalyl chlo-
ride, which had proven useful for the generation of the CPS from
phosphine oxide.9 The latter reaction of oxalyl chloride was well
known,17 but its reaction with a phosphine has, remarkably, appar-
ently never been studied. We therefore thought it was worth a test
reaction and we found that, most conveniently and gratifyingly,
oxalyl chloride reacted with the tertiary phosphine to produce
the identical CPC.18 On its employment in the asymmetric Appel
process for PTMP (Table 3, entry 5), it gave a notably improved
88% de, compared to HCA. Although there was still some erosion
of the selectivity, the isolation of the scalemic PTMPO was signifi-
cantly easier in the absence of by-product.19 One other advantage
is that the phosphine starting material now does not have to be rig-
orously oxide-free because both will now be converted into CPC.
Previously, contaminating racemic oxide resulted in a lowered ee
of the product scalemic oxide.
O
P
(-)-1
-78 ºC → r.t.
1 d
P
Ph
Ph
best
phosphine
activators
(
)-PTMP
(R)-PTMPO
Entry
1f
Phosphine activator
dec (%)
eed (%)
Yielde (%)
94
O
Cl
Cl
Cl
Cl
82g
70
82g
69
Cl
Cl
Cl
O
Cl
Cl
Cl
H
Cl
2
95
79
Cl
Cl
Cl
Cl
Cl
Cl
Cl
3f
82
75
O
Cl
Cl
Cl
Cl
4
76h
88
63i
82
94
88
Cl
O
O
Cl
5j
Cl
a
Phosphine (0.11 mmol), alcohol (1.2 equiv), phosphine activator (1 equiv) at
À78 °C in toluene (0.11 M with respect to phosphine), rigorous drying of all
materials, procedure as noted in the ESI.
b
All cases repeated with (+)-menthol with the same results, see ESI.Table 2.
c
Determined as described in the ESI.
d
Determined by CSP-HPLC, (R)-enantiomer in excess in all cases see ESI for
details.
As determined by 31P NMR, see ESI.
e
f
Other chiral alcohols gave comparable results, see ESI.Table 2.
g
From Ref. 9.
h
20% Phosphine oxide also produced.
i
65% ee with (À)-8-phenylmenthol.
j
See footnote 19 for reaction conditions.
the speed of counterion exchange, such as in Scheme 2, is signifi-
cant for the selectivity, with chloride perhaps allowing faster ex-
change. We will report kinetic investigations of that possibility at
a later date.
Finally, a mechanism for the newly discovered generation of
chlorophosphonium chloride from oxalyl chloride and phosphine
is proposed in Scheme 3. This is shown for the case of triphenyl-
phosphine, the progress of which reaction we monitored by 31P
NMR spectroscopy (spectra in ESI).
This mechanism is only one of several possibilities.20 Evidence
supporting it includes: (i) the 1:1 stoichiometry; (ii) the appear-
ance of transients in the 31P NMR spectra arguing against direct
formation via ethylene dione; (iii) the absence of phosphine oxide
in the 31P NMR spectra, and (iv) the presence of ketene traps has no
effect on the reaction. We note that it is ironic that we started out
seeking an alternative source of positive chlorine for our method
Together with our other work, this confirmation of the impor-
tance of the CPS counterion leads us towards the conclusion that
Cl
Cl
O
O
P
O
Cl
O
O
Cl
Cl
P
Cl
Cl
Cl
-2 x CO
Ph
Cl
Ph
O
Cl
Cl
Cl
Cl
Cl
Cl
P
Cl
P
Cl
Ar
P
Ph
Ph
Ph
Ph
Ph
Ph
Ar
Ph
Cl
Scheme 3. Proposed mechanism for the generation of CPS from phosphine.
Ph
Ph
Ph
O
O
P
Cl
Cl
Ph
Ph
Scheme 2. Possible exchange of counterions in the CPS intermediate.

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K. V. Rajendran et al. / Tetrahedron Letters 54 (2013) 7009–7012
4. For reviews of P-stereogenic compounds, see: Grabulosa, A.; Granell, J.; Muller,
G. Coord. Chem. Rev. 2007, 251, 25–90; Glueck, D. S. Synlett 2007, 2627–2634;
Johansson, M. J.; Kann, N. C. Mini Rev. Org. Chem. 2004, 1, 233–247;
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Stereogenic Ligands in Enantioselective Catalysis; Grabulosa, A., Ed.; Royal
Society of Chemistry: Cambridge: UK, 2011; Kolodiazhnyi, O. I. Tetrahedron:
Asymmetry 2012, 23, 1–46.
5. Appel, R.; Halstenberg, M. Tertiary Phosphane Halogenoalkane Reagents. In
Organophosphorus Reagents in Organic Synthesis; Cadogan, J. I. G., Ed.; Academic
Press: London, 1979; p 387. Chapter 9; Downie, I. M.; Holmes, J. B.; Lee, J. B.
Chem. Ind. (London) 1966, 900; (c) Weiss, R. G.; Snyder, E. I. J. Org. Chem. 1971,
36, 403–406; (d) Jones, L. A.; Sumner, C. E., Jr.; Franzus, B.; Huang, T. T. S.;
Snyder, E. I. J. Org. Chem. 1978, 2821–2827; (e) Dabbagh, H. A.; Franzus, B.;
Huang, T. T. S.; Davis, B. H. Tetrahedron 1991, 47, 949–960.
6. Magid, M. R.; Fruchey, S.; Johnson, W. L.; Allen, T. G. J. Org. Chem. 1979, 44, 359–
363.
7. Bergin, E.; O’Connor, C. T.; Robinson, S. B.; McGarrigle, E. M.; O’Mahony, C. P.;
Gilheany, D. G. J. Am. Chem. Soc. 2007, 129, 9566–9567; Rajendran, K. V.;
Kennedy, L.; Gilheany, D. G. Eur. J. Org. Chem. 2010, 5642–5649.
8. Gilheany, D. G.; Robinson, S. B.; O’Mahony, C. P.; O’Connor, C. T.; Bergin, E.;
Walsh, D. M.; Clarke, E. F.; Kelly B. G.; McGarrigle, E. M. Int. Patent, WO
2005118603, 2005; Chem. Abstr. 2005, 144, 36428. This method has been
successfully run on a multi-kilogram scale in an industrial process.
9. Rajendran, K. V.; Gilheany, D. G. Chem. Commun. 2012, 10040–10042.
10. Carr, D. J.; Kudavalli, J. S.; Dunne, K. S.; Müller-Bunz, H.; Gilheany, D. G., J. Org.
Chem., Accepted for, publication, http://dx.doi.org/10.1021/jo401318g.
11. Rajendran, K. V.; Kudavalli, J. S.; Dunne, K. S.; Gilheany, D. G. Eur. J. Org. Chem.
2012, 2720–2723.
and have now settled on a phosphine activator that we propose
does not work as an electrophilic chlorine source.
In conclusion, a systematic study of phosphine activators in the
asymmetric Appel reaction has been carried out. Although HCA
gave high selectivity, along with excellent yield, it has the disad-
vantage that its by-product can become involved in the process
leading to erosion of selectivity. In searching for a replacement
we discovered an interesting new reaction of oxalyl chloride with
tertiary phosphine that allows us to run our process with higher
selectivity, without complicating by-products and without the
need for extensive purification of the starting material. We are
now positioned to study the asymmetric Appel reaction to improve
its scope and selectivity by screening various chiral non-racemic
alcohols and phosphines, which will be the subject of future
reports.
Acknowledgments
We sincerely thank Science Foundation Ireland (SFI) for funding
this chemistry under Grants RFP/08/CHE1251 and 09/IN.1/B2627.
We are also grateful to UCD Centre for Synthesis and Chemical
Biology (CSCB) and the UCD School of Chemistry and Chemical
Biology for access to their extensive analysis facilities.
12. For example, dichloroethyldiphenylphosphorane has dP +74.3: Appel, R.;
Schöler, H. Chem. Ber. 1977, 110, 2382–2384.
13. Synthesised from (À)-menthol and trichloroacetyl chloride: Akiyama, F.;
Tokura, N. Bull. Chem. Soc. Jpn. 1968, 41, 2690–2695.
Supplementary data
14. We have previously published a simple synthesis of PCA using an achiral Appel
process: Rajendran, K. V.; Carr, D. J.; Gilheany, D. G. Tetrahedron Lett. 2011, 52,
7113–7115.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
10.044.
15. Diastereomeric excess (de) is used rather than diastereomeric ratio (dr) to
facilitate comparison with the enantiomeric excess (ee) of the ultimate oxide
products of the reactions.
16. In a parallel experiment by 31P NMR spectroscopy.
17. Masaki, M.; Fukui, K. Chem. Lett. 1977, 151–152; Yano, T.; Hoshino, M.;
Kuroboshi, M.; Tanaka, H. Synlett 2010, 801–803; Yano, T.; Kuroboshi, M.;
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B. Chem. Commun. 2010, 3025–3027; Denton, R. M.; An, J.; Adeniran, B.; Blake,
A. J.; Lewis, W.; Poulton, A. M. J. Org. Chem. 2011, 76, 6749–6767; Rajendran, K.
V.; Gilheany, D. G. Chem. Commun. 2011, 817–819.
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temperature to a solution of PTMP (10.0 mL, 0.11 M, 1.0 mmol in dry toluene,
1 equiv), which was taken in a flame-dried degassed Young’s tube. The reaction
was allowed to stir for 30 min. 31P NMR was taken to identify the intermediate
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(CPS) 70.5 ppm. Excess oxalyl chloride was completely removed through a
dedicated cold trap connected to a Schlenk manifold for 60 min. Dry CH2Cl2
(10 mL) was added to dissolve CPS again and the mixture was cooled to À82 °C
using an EtOAc/N2 mixture and (À)-menthol (15 mL, 0.132 M, in dry toluene,
2.0 equiv) was added dropwise to the mixture over 30 min. The reaction was
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neomenthyl chloride and menthol oxalate followed by (MeOH—CH2Cl2)
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Marsden, S. P. J. Org. Chem. 2007, 72, 7185–7189; Catalytic asymmetric
synthesis: Scriban, C.; Glueck, D. S. J. Am. Chem. Soc. 2006, 128, 2788–2789;
Chan, V. S.; Bergman, R. G.; Toste, F. D.; Korff, C.; Helmchen, G. Chem. Commun.
2004, 530–531; Cedric, G.; Canipa, S. J.; O’Brien, P.; Taylor, S. J. Am. Chem. Soc.
2006, 128, 9336–9377; designed, highly efficient diastereoselective synthesis
via chiral benzoxazaphosphinine oxide relay: Han, Z. S.; Goyal, N.; Herbage, M.
A.; Sieber, J. D.; Qu, B.; Xu, Y.; Li, Z.; Reeves, J. T.; Desrosiers, J. N.; Ma, S.;
Grinberg, N.; Lee, H.; Mangunuru, H. P. R.; Zhang, Y.; Krishnamurthy, D.; Lu, B.
Z.; Song, J. J.; Wang, G.; Senanayake, C. H. J. Am. Chem. Soc. 2013, 135, 2474–
2477.
yielding (R)-PTMPO as
a
white solid; 31P NMR 32.2 ppm (lit. 32.5 ppm)
(0.22 g 88%). A portion of the sample (ꢀ3 mg) was dissolved in 2 mL of HPLC
solvent (HPLC grade solvents purchased from Aldrich were used as supplied)
and filtered through a PTFE syringe filter into a HPLC vial. High-performance
liquid chromatography was performed on an Agilent Technologies 1200 series
connected to
a
6-column switcher. HPLC (CHIRALPAKÒ IA column, 80:20
heptane/EtOH, 1 mL/min): 81.4% ee Rt = 6.8 (S), 7.6 (R) min.
20. For example: via transient formation of ethylene dione or phosphine oxide/
ketene. Some of these mechanisms are shown in the ESI along with the spectra
resulting from 31P NMR spectroscopic monitoring of the reaction mixture.