Synthesis of phosphorus esters by transesterification mediated by N-heterocyclic carbenes (NHCs)

Article abstract of DOI:10.1039/b509783e

The versatile nucleophilic organic catalysts N-heterocyclic carbenes (NHCs) have been shown to effectively mediate the transesterification of phosphorus esters under mild conditions; user-friendly imidazolium salts can also be employed as pre-catalysts. T

Full text of DOI:10.1039/b509783e

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Synthesis of phosphorus esters by transesterification mediated by
N-heterocyclic carbenes (NHCs){
Rohit Singh and Steven P. Nolan*
Received (in Bloomington, IN, USA) 11th July 2005, Accepted 23rd August 2005
First published as an Advance Article on the web 3rd October 2005
DOI: 10.1039/b509783e
The versatile nucleophilic organic catalysts N-heterocyclic
carbenes (NHCs) have been shown to effectively mediate
the transesterification of phosphorus esters under mild condi-
tions; user-friendly imidazolium salts can also be employed as
pre-catalysts.
non-bonding electrons. Non-toxicity, a non-pyrophoric nature
and tunable sterics and electronics have helped establish NHCs
as versatile nucleophilic organic catalysts effectively mediating
15–23
organic transformations.
The screening of various NHCs
in the reaction involving dimethyl methylphosphonate (DMMP)
with benzyl alcohol showed the alkyl substituted NHCs, ICy
{1,3-bis(cyclohexyl)imidazol-2-ylidene}, IAd {1,3-bis(adamantyl)-
Phosphorus esters are important functional groups in organic
synthetic chemistry. They not only play an important role as
1
protective groups in pharmaceuticals but are also used as reagents
t
imidazol-2-ylidene} and I Bu {1,3-bis(tert-butyl)imidazol-2-
ylidene} are capable mediators in this transesterification reaction.
The cyclohexyl substituted NHC, ICy, was found to be the best
catalyst giving a good yield in only 2 hours (entry 1, Table 1).
Better yields can be obtained on increasing the reaction time
but this allows for an increase in formation of diesterified
product (entry 2, Table 1). Sterically demanding, alkyl
2
in organic transformations (e.g. Wadsworth–Emmons reaction)
3
or in the development of analytical tools. Moreover, on the
industrial scale, P-esters find applications in agrochemicals as
4
5
6
fertilizers, pesticides and insecticides. The major means of
preparation of P-esters involve alkyl dichlorophosphines or the
Michaelis–Arbuzov reaction. While the dichlorophosphines are
t
24
substituted NHCs, IAd and I Bu, provide moderate yields. The
7
usually expensive, the Michaelis–Arbuzov reaction suffers from
aryl substituted NHCs, which are less nucleophilic than the
14,25
alkyl substituted counterparts,
low yields when hindered substrates are used. Gagn e´ has reported
on the use of alkali metal alkoxide clusters as efficient catalysts for
8
the ester interchange reaction leading to phosphorus esters. A
did not show activity in
this transformation. Even on increasing the catalyst loading,
IPr {1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene} and IMes
{1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene} did not furnish
4
method relying on Ti(OR) /ROH catalyzed transesterification has
26
also been reported but suffers from long reaction times and a lack
9
of reactivity towards phosphonates. An inexpensive, metal-free,
the desired product.
To fully exploit the potential of this reaction, we examined a
wide array of conditions. The data presented in Table 2 illustrate
the effect of various parameters on the efficiency of this protocol.
Since transesterification is an equilibrium process, removal of
products from the reaction mixture drives the reaction in the
catalytic protocol for the synthesis of phosphorus esters via
transesterification would have a significant impact on the
accessibility of this class of compounds.
We previously reported on the use of N-heterocyclic carbenes
(
NHCs) as efficient transesterification catalysts for primary and
˚
forward direction. This is achieved by use of molecular sieves (4 A)
10
secondary alcohols. We have extended this methodology to now
include P-esters as substrates, achieving excellent yields using
mild conditions (Scheme 1). Phosphonate esters, which are usually
unreactive using the Michaelis–Arbuzov protocol, undergo
transesterification effectively with the use of various NHCs as
catalysts.
that absorb the methanol formed in the course of the reaction and
improve conversion. Initially similar conversions are observed in
a
Table 1 Screening of N-heterocyclic carbenes
11
12
13
Extensive works by Wanzlick, Bertrand, Arduengo and
1
4
others have shown that the singlet nucleophilic carbenes
are neutral compounds having a divalent carbon atom with two
Time Yield Product
(h)
Entry Catalyst
(%)
ratio (I:II)
1
2
3
4
5
6
a
R 5 Cyclohexyl
2
8
2
2
71
90
35
32
0
90:10
75:25
100:0
100:0
—
R 5 Cyclohexyl
R 5 Adamantyl
R 5 tert-Butyl
R 5 2,6-Diisopropylphenyl 18
R 5 2,4,6-Trimethylphenyl 18
Scheme 1 NHC catalyzed transesterification of P-esters.
Department of Chemistry, University of New Orleans, New Orleans,
LA-70148, USA. E-mail: snolan@uno.edu; Fax: +1 (504) 280-6860;
Tel: +1 (504) 280-6445
Electronic supplementary information (ESI) available: Experimental
details. See http://dx.doi.org/10.1039/b509783e
0
—
Reaction conditions: 5 mol% catalyst, 1 mmol of DMMP, 1 mmol
of BnOH, 0.5 g of molecular sieves, 1 mL of THF, NMR yields
average of two runs).
{
(
5
456 | Chem. Commun., 2005, 5456–5458
This journal is ß The Royal Society of Chemistry 2005

View Article Online
a
Table 2 Impact of variation of reaction parameters on NHC
catalyzed transesterification of P-esters
Table 3 In situ generation of catalyst
a
Product
Entry Catalyst precursor Time (h) Yield (%) ratio (I:II)
Product
Time (h) Yield (%) ratio (I:II)
1
2
3
4
5
a
bmim?HBF
4
6
3
3
3
12
84
71
46
58
72
81:19
70:30
85:15
63:37
60:40
Entry Conditions
ICy?HBF
ICy?HBF
4
b
4
1
2
3
4
5
6
7
8
9
a
No MS
No MS
With MS
With MS
T 5 40 uC
2 equiv. Bn–OH
2
8
2
8
2
2
67
70
71
90
87
75
100
100
72
100:0
100:0
90:10
75:25
60:40
100:0
45:55
36:64
—
IAd?HBF
4
t
I Bu?HBF
4
Reaction conditions: 5 mol% catalyst, 0.9 equiv. base, 1 mmol of
DMMP, 1 mmol of BnOH, 0.5 g of molecular sieves, 1 mL of THF,
NMR yields (average of two runs). No molecular sieves.
b
2 equiv. Bn–OH 36
2 equiv. Bn–OH 120
b
EDPP
6
An additional important use of phosphorus esters is in the
manufacture of chemical nerve agents. Chemical weapons such as
VX {S-2-(diisopropylamino)ethyl O-ethyl methylphosphonothio-
ate} and GB-Sarin are various forms of P-esters. These agents
inhibit the control of acetylcholinesterase over the central nervous
Standard reaction conditions:
5 mol% catalyst, 1 mmol of
˚
DMMP, 1 mmol of BnOH, 0.5 g of molecular sieves (4 A), 1 mL of
b
THF, NMR yields (average of two runs).
diphenylphosphonite: 0.5 g of molecular sieves (5 A).
EDPP 5 ethyl
˚
6,30
system by reacting with this enzyme in an irreversible fashion.
reactions with and without molecular sieves. However, on allowing
the reaction to stir for longer time periods, a significant difference
in conversion can be observed (entries 1–4, Table 2). Moreover,
formation of only mono-esterified product in the absence of
molecular sieves is indicative of the reaction being reversible
under equilibrium conditions, rather than undergoing a second
Recent developments have brought attention to chemical weapons,
especially methods for their detoxification/decommission. The
usual methods of detoxification of the nerve agent VX are
incineration and chemical neutralization. However, these methods
suffer from limitations making them unacceptable. Chemical
detoxification in particular suffers from the release of harmful side
31
27
products in yields as high as 15%. Moreover, the reagents have to
esterification. Not surprisingly, an increase in temperature has
a favorable effect on conversion. However, the selectivity suffers
in this case and an increase in formation of the diesterified product
is observed (entries 3 and 5, Table 2). The effect of excess
alcohol was also studied. On conducting the reaction over a longer
time period, quantitative conversion with loss of selectivity was
observed (entries 7 and 8, Table 2). To increase the scope of the
reaction, ethyl diphenylphosphonite was also tested. The reaction
proceeded to furnish the product in good yield (entry 9, Table 2).
Various reactions presented in Table 2 reveal simple and efficient
ways to alter the final outcome of the reaction, providing flexibility
be used in stoichiometric amounts. Metal catalyzed methods for
32
chemical detoxification of VX nerve agent have been proposed.
The NHC mediated transesterification of P-esters could be an
attractive alternative to the conventional methods of VX
detoxification. Since methyl and ethyl esters are more difficult to
2
7
cleave compared to benzyl esters, we propose that, using the
described methodology, the properties of P-esters can be altered to
33
render them innocuous.
In summary, an organocatalytic approach for the synthesis of
phosphorus esters is described. Various parameters affecting the
transformation have been examined. Applications of this method
can range from synthesis of pharmaceutically important molecules
to detoxification of P-ester nerve agents. Efforts aimed at
expanding the scope of this user-friendly reaction and under-
standing its mechanism are presently underway.
28
to the protocol.
To render the protocol more user-friendly, various commercially
available, NHC pre-catalysts were also tested for activity. The use
4
of ionic liquid, bmim?HBF (N,N9-butylmethylimidazol-2-ylidene)
is of particular interest since it demonstrated good conversion, with
preferential formation of the mono-esterified product in .80%
yield (entry 1, Table 3). The imidazolium salts of ICy, IAd
Support of this work from the National Science Foundation is
gratefully acknowledged.
t
and I Bu also furnished moderate to good yields under similar
conditions with ICy?HBF proving to be the best pre-catalyst for
4
Notes and references
29
this transformation. To achieve better selectivity in the in situ
1
2
J. P. Krise and V. J. Stella, Adv. Drug Delivery Rev., 1996, 19, 287–310.
Comprehensive Organic Synthesis, ed. B. M. Trost, I. Fleming and
S. L. Schreiber, Pergamon, Oxford, 1991, pp. 761–773.
generated-carbene-protocol, experiments were performed with a
4
slight change in experimental conditions. ICy?HBF was employed
3
The phosphonite esters attached to macrocyclic scaffolds in metal
complexes have been used as anion sensors. For a recent example see:
O. Molt, D. Rubeling and T. Schrader, J. Am. Chem. Soc., 2003, 125,
12086–12087; N. Sabbatini, M. Guardigli, F. Bolletta, I. Manet and
R. Ziessel, Angew. Chem., Int. Ed. Engl., 1994, 33, 1501–1503.
G. F. Koopmans, W. J. Chardon, J. Dolfing, O. Oenema, P. Van der
Meer and W. H. Van Riemsdijk, J. Environ. Qual., 2003, 32, 287–295.
Y. Segall, G. B. Quistad, S. E. Sparks and J. E. Casida, Chem. Res.
Toxicol., 2003, 16, 350–356.
in the usual reaction conditions without the presence of molecular
sieves (entry 3, Table 3). Better selectivity was achieved under these
conditions. However, product conversion suffered because of
the absence of molecular sieves. The reaction did not proceed
further than 55% conversion after 24 h. Interestingly, no change
in selectivity was observed after allowing the reaction to proceed
for 24 h.
4
5
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 5456–5458 | 5457

View Article Online
6
7
H. Morales-Rojas and R. A. Moss, Chem. Rev., 2002, 102, 2497–2521.
N. Kurihara, J. Miyamoto, G. D. Paulson, B. Zeeh, M. W. Skidmore,
R. M. Hollingworth and H. A. Kuiper, Pure Appl. Chem., 1997, 69,
18 For NHC catalyzed preparation of c-butyrolactams see: S. S. Sohn,
E. L. Rosen and J. W. Bode, J. Am. Chem. Soc., 2004, 126, 14370–14371.
19 For NHC catalyzed kinetic resolution of secondary alcohols see:
Y. Suzuki, K. Yamauchi, K. Muramatsu and M. Sato, Chem.
Commun., 2004, 2770–2771; T. Kano, K. Sasaki and K. Maruoka,
Org. Lett., 2005, 7, 1347–1349.
2007–2025.
8
9
R. M. Kissling and M. R. Gagn e´ , J. Org. Chem., 1999, 64, 1585–1590;
R. M. Kissling and M. R. Gagn e´ , Org. Lett., 2000, 2, 4209–4212.
M. Froneman and T. A. Modro, Synthesis, 1991, 201–204.
2
0 For NHC catalyzed amidation of unactivated esters with amino
alcohols see: M. Movassaghi and M. A. Schmidt, Org. Lett., 2005, 7,
453–2456.
1 For NHC catalyzed trifluoromethylation of carbonyl compounds see:
10 G. A. Grasa, R. M. Kissling and S. P. Nolan, Org. Lett., 2002, 4,
3583–3586; G. W. Nyce, J. A. Lamboy, E. F. Connor, R. M. Waymouth
2
2
and J. L. Hedrick, Org. Lett., 2002, 4, 3587–3590; G. A. Grasa,
T. Guvelli, R. Singh and S. P. Nolan, J. Org. Chem., 2003, 68,
J. J. Song, Z. Tan, J. T. Reeves, F. Gallou, N. K. Yee and
C. H. Senanayake, Org. Lett., 2005, 7, 2193–2196.
2812–2819; R. Singh, R. M. Kissling, M.-A. Letellier and S. P. Nolan,
2
2 For conversion of a,b-unsaturated aldehydes into saturated esters via an
umpolung reaction catalyzed by NHCs see: A. Chan and K. A. Scheidt,
Org. Lett., 2005, 7, 905–908.
J. Org. Chem., 2004, 69, 209–212; G. A. Grasa, R. Singh and S. P. Nolan,
Synthesis, 2004, 971–985.
1 H.-W. Wanzlick and E. Schikora, Angew. Chem., 1960, 72, 494;
1
2
3 For one-step assembly of functionalized c-butyrolactones from benzoins
or benzaldehydes via an NHC-mediated tandem reaction see: W. Ye,
G. Cai, Z. Zhuang, X. Jia and H. Zhai, Org. Lett., 2005, 7, 3769–3771.
H.-W. Wanzlick and H.-J. Kleiner, Angew. Chem., 1961, 73, 493;
H.-W. Wanzlick, Angew. Chem., 1962, 74, 129–134.
1
2 A. Igau, H. Gruetzmacher, A. Baceiredo and G. Bertrand, J. Am.
Chem. Soc., 1988, 110, 6463–6466; A. Igau, A. Baceiredo, G. Trinquier
and G. Bertrand, Angew. Chem., Int. Ed. Engl., 1989, 28, 621–622.
t
4 Free carbenes, IAd and I Bu are now commercially available from
Strem Chemicals, Inc.
2
2
5 A. M. Magill, K. J. Cavell and B. F. Yates, J. Am. Chem. Soc., 2004,
26, 8717–8724.
6 No product formation was observed on increasing the catalyst loading
to 10 mol% for IPr and IMes.
7 J. Otera, Chem. Rev., 1993, 93, 1449–1470.
1
3 A. J. Arduengo, III, R. L. Harlow and M. Kline, J. Am. Chem. Soc.,
991, 113, 361–365; A. J. Arduengo, III, H. V. R. Dias, R. L. Harlow
and M. Kline, J. Am. Chem. Soc., 1992, 114, 5530–5534.
1
1
2
1
4 For comprehensive reviews on NHC see: M. Regitz, Angew. Chem., Int.
Ed. Engl., 1996, 35, 725–728; A. J. Arduengo, III and R. Krafczyk,
Chemie en Unserer Zeit, 1998, 32, 6–14; D. Bourissou, O. Guerret,
F. P. Gabbai and G. Bertrand, Chem. Rev., 2000, 100, 39–92;
W. A. Herrmann, Angew. Chem. Int. Ed., 2002, 41, 1290–1309.
2
2
8 On the suggestion of a reviewer, we wish to report a limitation of this
protocol. The NHCs are not compatible with acidic alcohols hence the
reaction fails to proceed when phenols, trifluoroethanol or binol are
used. These alcohols deactivate the carbene by protonating it. We thank
15 For triazole-2-ylidene catalyzed benzoin condensations see: D. Enders
and U. Kallfass, Angew. Chem. Int. Ed., 2002, 41, 1743–1745.
the reviewer for his suggestion.
9 Imidazolium salts of ICy, IAd and I Bu are now available commercially
from Ryan, Strem and Acros Chemicals.
t
2
1
6 For carbenes as catalysts in the ring opening polymerization of
lactones see: E. F. Connor, G. W. Nyce, M. Meyers, A. M o¨ ck and
J. L. Hedrick, J. Am. Chem. Soc., 2002, 124, 914–915; G. W. Nyce,
T. Glauser, E. F. Connor, A. M o¨ ck, R. M. Waymouth and J. L. Hedrick,
J. Am. Chem. Soc., 2003, 125, 3046–3056; S. Csihony, D. A. Culkin,
A. C. Sentman, A. P. Dove, R. M. Waymouth and J. L. Hedrick, J. Am.
Chem. Soc., 2005, 127, 9079–9084.
30 Macmillan Encyclopedia of Chemistry, ed. C. A. Bunton and
J. J. Lagowski, Macmillan Reference USA, Simon and Schuster
Macmillan, New York, 1997, vol. 1, pp. 343–346.
31 Y.-C. Yang, Acc. Chem. Res., 1999, 32, 109–115.
32 W. Y. Mills, R. M. Kissling and M. R. Gagn e´ , Chem. Commun., 1999,
1713–1714.
17 For NHC catalyzed cyclotrimerization of isocyanates see: H. A. Duong,
M. J. Cross and J. Louie, Org. Lett., 2004, 6, 4679–4681.
33 EDPP and DMMP are used as VX-model compounds in studies
relating to the nerve agents (see reference 31).
5
458 | Chem. Commun., 2005, 5456–5458
This journal is ß The Royal Society of Chemistry 2005