An electron-rich proazaphosphatrane for isocyanate trimerization to isocyanurates

Article abstract of DOI:10.1021/jo9023396

(Figure presented) A facile synthesis of the new electron-rich, sterically hindered proazaphosphatrane shown above is described herein. This proazaphosphatrane catalyzes the cyclotrimerization of a wide variety of isocyanates to isocyanurates under mild c

Full text of DOI:10.1021/jo9023396

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in the continuous anionic copolymerization of ε-caprolactam
An Electron-Rich Proazaphosphatrane for
Isocyanate Trimerization to Isocyanurates
to nylon-6,7 and triallyl isocyanurates are useful in the prepa-
ration of flame-retardant laminating materials for electrical
devices.1
Steven M. Raders and John G. Verkade*
The commercial importance of isocyanurates has generated
numerous efforts aimed at the development of more effective
methods for cyclotrimerizing isocyanates.8 Problems with some
of the known cyclotrimerization procedures include low cata-
lyst activity, diazetidine byproduct formation, lengthy reaction
times, product separation difficulties, and the use of toxic
solvents.1,9 Examples of Lewis base cyclotrimerization catalysts
that have been reported include phosphines,3,10 N-heterocyclic
carbenes,1 calcium carbene complexes,11 amines,12 NO,13 fluo-
ride anions,14 and alkoxyalkenes.15 Metal-containing cyclotri-
merization catalysts include organotin16 and zirconium17 com-
pounds, organozinc halides and alkoxides,18 copper and nickel
halides,13 and palladium(0) systems.19
Department of Chemistry, Iowa State University,
Ames, Iowa 50011
jverkade@iastate.edu
Received November 1, 2009
Proazaphosphatranes such as 1-5 are strong nonionic
bases owing to transannulation of the basal nitrogen to the
phosphorus atom upon protonation of the latter, and to the
donation of electron density from all three of the P-N
nitrogens.20 In terms of low catalyst loading, fast reaction
times, ease of product purification, and optional use of a
nontoxic solvent such as toluene, proazaphosphatranes have
thus far been shown to be the most effective catalysts so far
reported for the cyclotrimerization of isocyanates.10
A facile synthesis of the new electron-rich, sterically hindered
proazaphosphatrane shown above is described herein. This
proazaphosphatrane catalyzes the cyclotrimerization of a
wide variety of isocyanates to isocyanurates under mild
conditions with unprecedentedly fast reaction times, giving
moderate to high product yields. It is also shown that this
proazaphosphatrane can be recycled up to 5 times.
Isocyanurates (perhydro-1,3,5-triazine-2,4,6-triones), typi-
cally produced by cyclotrimerizing isocyanates, enhance the
physical properties of polyurethanes and coating materials.1
Incorporation of isocyanurates into the framework of polyur-
ethanes enhances their flame retardation and filming charac-
teristics, and commercial products containing polymeric iso-
cyanurates possess increased thermal and chemical resistance.2
Isocyanurates are also employed in the preparation of copoly-
mer resins which require water-resistance, transparency, and
impact resistance,3 and a novel optically active isocyanurate has
been used for chiral discrimination of enantiomeric amino acid
units.4 Selective bonding of chloride anions via a p-nitrophenyl-
sulfonamide group connected to an isocyanurate by an ethy-
lene moiety has been reported,5 and low-toxicity drug delivery
has been achieved by tethering drug molecules to an isocyanu-
rate backbone via an amide linker for facilitating subsequent
drug release.6 Triaryl isocyanurates are employed as activators
Previously, we showed that with no attempt at temperature
control of the reaction, proazaphosphatrane 1 at 0.3 mol %
(7) (a) Bukac, Z.; Sebenda, J. Chem. Prum. 1985, 35, 361. (b) Horsky, J.;
Kubanek, U.; Marick, J.; Kralicek, J. Chem. Prum. 1982, 32, 599.
(8) For additional information regarding isocyanate trimerization, see
the Supporting Information.
(9) (a) Wegener, G.; Brandt, M.; Duda, L.; Hofmann, J.; Klesczewski, B.;
Koch, D.; Kumpf, R.-J.; Orzesek, H.; Pirkl, H.-G.; Six, C.; Steinlein, C.;
Weisbeck, M. Appl. Catal. A 2001, 221, 303. (b) Silva, A. L.; Bordado, J. C.
Catal. Rev. 2004, 46, 31.
(10) (a) Tang, J.; Verkade, J. G. Angew. Chem., Int. Ed. Engl. 1993, 32,
896. (b) Liu, X.; Bai, Y.; Verkade, J. G. J. Organomet. Chem. 1999, 582, 16.
(11) Orzechowski, L.; Harder, S. Organometallics 2007, 26, 2144.
(12) (a) Tagachi, Y.; Shibaya, I.; Yasumoto, Y.; Ynoemoto, K. Bull.
Chem. Soc. Jpn. 1990, 63, 3486. (b) Moghaddam, F. M.; Dekamin, M. G.;
Koozehgari, G. R. Lett. Org. Chem. 2005, 2, 734.
(13) Villa, J. F.; Powell, H. B. Synth. React. Met.-Org. Chem. 1976, 6, 59.
(14) Nambu, Y.; Endo, T. J. Org. Chem. 1993, 58, 1932.
(15) Mizuya, J.; Yokozawa, T.; Endo, T. J. Polym. Sci., Polym. Chem.
1991, 29, 1544.
(1) Duong, H. A.; Cross, M. J.; Louie, J. Org. Lett. 2004, 6, 4679.
(2) (a) Wirpsza, Z. Polyurethanes: Chemistry, Technology and Application;
Ellis Horwood: London, UK, 1993. (b) Zitinkina, A. K.; Sibanova, N. A.;
Tarakanov, O. G. Russ. Chem. Rev. 1985, 54, 1866. (c) Nawata, T.; Kresta,
J. E.; Frisch, K. C. J. Cell. Plast. 1975, 267. (d) Nicholas, L.; Gmitter, G. R.
J. Cell. Plast. 1965, 85.
(3) Tang, J.; Mohan, T.; Verkade, J. G. J. Org. Chem. 1994, 59, 4931.
(4) Sugimoto, H.; Yamane, Y.; Inoue, S. Tetrahedron: Asymmetry 2000,
11, 2067.
(16) (a) Bloodworth, A. J.; Davies, A. G. J. Chem. Soc. 1965, 6858.
(b) Foley, S. R.; Yap, G. P. A.; Richeson, D. S. Organometallics 1999, 18, 4700.
(17) Li, Y.; Matsumura, H.; Yamanaka, M.; Takahashi, T. Tetrahedron
2004, 60, 1393.
(18) Noltes, J. G.; Boersma, J. J. Organomet. Chem. 1967, 7, 6.
(19) Paul, F.; Moulin, S.; Piechaczyk, O.; Le Floch, P.; Osborn, J. A.
J. Am. Chem. Soc. 2007, 129, 7294.
(20) (a) Verkade, J. G. New Aspects of Phosphorus Chemistry II, Majoral,
J. P., Ed., In Top. Curr. Chem. 2003, 223, 1-44. (b) Verkade, J. G.; Kisanga, P.
Tetrahedron 2003, 59, 7819–7858. (c) Verkade, J. G.; Kisanga, P. B. Aldrichim.
Acta 2004, 37, 3–14.
(5) Hettche, F.; Hoffman, R. W. New J. Chem. 2003, 27, 172.
(6) Murray, A. P.; Miller, M. J. J. Org. Chem. 2003, 68, 191.
5308 J. Org. Chem. 2010, 75, 5308–5311
Published on Web 07/08/2010
DOI: 10.1021/jo9023396
r
2010 American Chemical Society

Raders and Verkade
JOCNote
TABLE 1. Comparison of Catalytic Activity of Various Lewis Bases for
the Cyclotrimerization of Phenyl Isocyanatea
entry
compd
R
pKa
timec yield (%)d
1
2
3
4
5
6
7
8
9
5
4
1
3
2
6
7
8
Bn
Piv
Me
iBu
iPr
31.60
169
97
97
95
99
97
99
98
96
4e,f
2f
32.84b 135
32.90b 121
33.53b 117
33.63b 110
2-MeOBn 33.70
2,4-DiMeOBn 34.16
2,4,6-TriMeOBn 34.25
96
92
84
5 d
24 h
5 d
P(NMe2)3
PtBu3
NEt3
10
11
3f
FIGURE 1. Computer drawing of the molecular structure of 6 at a
50% probability level. Hydrogen atoms are omitted for clarity.
aReaction conditions: 15 mmol of phenyl isocyanate, 2 mL of toluene,
rt. bReference 21. cSeconds except were noted. dAverage of three runs.
eHeated to 70 °C. f1 mol % of promoter used.
procedure was modified, however, by using NaHMDS for
the deprotonation step instead of K-OtBu, which has the
advantage of effecting full rather than partial conversion to
the desired deprotonated product. The syntheses of proaza-
phosphatranes 7 and 8 were carried out analogously. The
molecular structure of 6 (determined by X-ray means and
depicted in Figure 1) confirms its formulation as proposed in
Scheme 1. Following a procedure we developed earlier22 for
determining pKa values of proazaphosphatranes in aceto-
nitrile, these values in the same solvent are shown for the new
analogues 6, 7, and 8 in Table 1.
SCHEME 1. Synthesis of Proazaphosphatrane 6
For determining the catalytic activity of proazaphospha-
trane 6 for isocyanate cyclotrimerization relative to analo-
gues 1-5, 0.1 mol % of catalyst in toluene was used to
cyclotrimerize phenyl isocyanate in a water bath at room
temperature (Table 1). As shown in this table, excellent yields
of product were obtained for 1-8 in short times in these
exothermic reactions. There does not seem to be any straight-
forward correlation of reaction times with steric bulk or
electron inductive effects from the P-N nitrogen alkyl
substituents in 1-4.
There is an increasing trend in pKa values from 6 to 8,
however, suggesting that steric crowding of an axial proton
by the increasing number of methoxy groups is absent.
In fact, axial proton stabilization by hydrogen bonding
via six-membered-ring chelation by the oxygens of three
o-methoxy groups could occur, resulting in an increased
pKa value.
When tri-tert-butylphosphine was used in our protocol,
only a 2% yield of the desired product was achieved after 24 h
with a catalyst loading of 1 mol % (Table 1). Hexamethyl-
phosphorous triamide (HMPT) and triethylamine were also
used as catalysts (Table 1) but despite heating the HMPT
reaction at 70 °C for 5 days, only 4% of the desired product
was observed, and the use of triethylamine under the same
conditions led to only 3% of the desired product. The
contrasting catalyst performances of 1-4, for example,
compared with HMPT, demonstrate the advantageous
loading promoted the exothermic cyclotrimerization of phenyl
isocyanate to the corresponding isocyanurate in benzene to
give a product yield of 99% in 3 min,10a and that at a loading of
0.39 mol %, 2 catalyzes this reaction under the same conditions
in 1 min in 97% isolated product yield.10b The basicity (pKa) of
the phosphorus appears to rise as electron induction of the alkyl
substituent on the P-N nitrogens increases from 1 to 2, but this
trend in pKa values is apparently reversed in the series 2 to 4
(Table 1). Thus perhaps the size increase in the alkyl substitu-
ents on these proazaphosphatranes may be interfering with the
bonding of the apical proton and perhaps also with nucleophilic
attack of phosphorus on an isocyanate carbon. Proazaphos-
phatrane 5 is less basic than 321 presumably due to the electron
withdrawing nature of the phenyl rings. As expected, the
presence of electron donating groups on these rings in 6 to 8
(whose syntheses we report here) increases the pKa of these
compounds. Here we report the pKa values of 5 to 8 in aceto-
nitrile and the use of 6 as a superior catalyst for the cyclo-
trimerization of isocyanates to isocyanurates.
Following a known procedure,21 6 was synthesized in
three steps in 61% overall yield (Scheme 1). The literature
(21) Laramay, M. A. H.; Verkade, J. G. J. Am. Chem. Soc. 1990, 112,
9421.
(22) Kisanga, P. B.; Verkade, J. G.; Schwesinger, R. J. Org. Chem. 2000,
65, 5431.
J. Org. Chem. Vol. 75, No. 15, 2010 5309

Raders and Verkade
JOCNote
TABLE 2. Substrate Scope of Aryl Isocyanates
TABLE 3. Recyclability of Proazaphosphatrane 6
entry
cycle
time (min)
yield (%)a,b
1
2
3
4
5
1
2
3
4
5
2
2
3.5
8
99
97
98
98
95
15
aReaction conditions: 15 mmol of phenyl isocyanate, 0.1 mol % of
proazaphosphatrane 6, 5 mL of toluene, rt. bAverage of two runs.
isocyanate required 30 min to cyclotrimerize in 53% isolated
product yield (Table 2, entry 7).
Previously, we proposed a mechanism in which a proaza-
phosphatrane attacks the isocyanate carbon atom on phenyl
isocyanate, producing an anionic charge on the isocyanate
nitrogen and a cationic charge on phosphorus. The anionic
site then similarly attacks a second phenyl isocyanate mole-
cule to generate an analogous zwitterion, which in turn
attacks a third isocyanate. This process is followed by
cyclotrimerization to form product and regenerated cata-
lyst.10b In the present work we demonstrate that the catalyst
is indeed regenerated for recycling. With use of 0.1 mol % of
proazaphosphatrane 6 in 5 mL of toluene for the cyclotri-
merization of phenyl isocyanate, the completion of the
reaction in 2 min was accompanied by the formation of a
white solid (Table 3, entry 1). After filtration of the solid
under inert atmosphere, the toluene filtrate (containing only
6) was subjected to a second cyclotrimerization cycle. Pleas-
ingly, the reaction completed in minutes with a 97% isolated
yield of the phenyl isocyanurate (Table 3, entry 2). The pro-
azaphosphatrane could then be recycled up to 3 more times
in which the phenyl isocyanurate was isolated in high yields,
but with longer formation times (Table 3, entries 3-5).
We suggest that adventitious moisture present in the
reaction mixture restricts the number of catalytic cycles of
6. Evidence for this suggestion was observed in the repetition
of the aforementioned recycling experiment with a larger
concentration (1 mol %) of 6. Under those conditions we
were able to observe a small peak in the 31P NMR at -10 ppm
in the filtrate corresponding to the phosphorus peak of the 6Hþ
cation (in addition to the þ128 ppm peak corresponding to
free 6). Subsequent recycling of 6 showed that the -10 ppm 31P
NMR peak grew in intensity. Attempts to remove the moisture
source by distilling phenyl isocyanate onto activated molecular
sieves and by using dry solvents under Schlenk techniques were
aReaction conditions: 15 mmol of isocyanate, 0.1 mol % of proaza-
phosphatrane 6, 2 mL of toluene, rt. bAverage of two runs.
stereoelectronic features20a of the proazaphosphatrane fra-
mework for the present catalytic objective.
With these results in hand, the scope of cyclotrimeriza-
tion using a variety of isocyanates was explored as shown in
Table 2. These reactions were carried out with 0.1 mol % of
proazaphosphatrane 6 as the promoter in toluene at room
temperature. The electron-rich aryl substrate 4-methoxy-
phenyl isocyanate was trimerized in 7 min in 96% isolated
yield (Table 2, entry 1). Such electron-rich substrates typically
show low reactivity toward cyclotrimerization with other cat-
alyst systems.15,23 4-Dimethylphenyl isocyanate was similarly
cyclotrimerized, providing a 97% isolated yield of a new
isocyanurate (Table 2, entry 2) in 6 min. Electron-deficient
4-nitrophenyl isocyanate was cyclotrimerized in 5 min in 93%
yield (entry 3). Isocyanates such as 4-chlorophenyl isocyanate
and 4-bromophenyl isocyanate also cyclotrimerized in fast
reaction times giving 91% and 95% isolated yields of product,
respectively (Table 2, entries 4 and 5). Our protocol is also
effective for sterically hindered isocyanates such as 1-naphthyl
isocyanate that provided a 94% isolated product yield (entry 6).
In the presence of catalyst 6, sterically bulky 2,6-dimethylphenyl
1
to no avail. P NMR monitoring of a toluene solution of a
mixture of 6 and phenyl isocyanate in a flame-sealed NMR
tube over a period of 1 month revealed that the small 1P peak
corresponding to 6Hþ that formed initially remained constant
in intensity, thus confirming the likelihood of contamination by
moisture during workup procedures.
In conclusion, we have demonstrated that the new proaza-
phosphatrane 6 is a superior catalyst for the synthesis of
isocyanurates from a wide variety of aryl isocyanates. It
should be noted that alkyl isocyanates (such as cyclo-
hexylisocyanate) did not form the corresponding isocyanurate
(23) Endo, T.; Suike, J. Chem. Abstr. 1990, 112, 77236.
5310 J. Org. Chem. Vol. 75, No. 15, 2010

Raders and Verkade
JOCNote
with our protocol. We have also shown that catalyst 6 can be
recycled up to 5 times with high product yields but with
successively slower reaction times owing to continuous deacti-
vation by moisture. Exploration of additional catalytic applica-
tions of 6 is underway.
(28.6 g, 2 equiv) was added to the slurry and then the reaction
mixture was stirred overnight. The THF was then evaporated
under inert atmosphere and then ether (100 mL) was added to
extract 6. After filtration of the extract, the ether was evaporated
under reduced pressure and 10 mL of toluene was added
followed by 40 mL of pentane, resulting in precipitation of 6.
Evaporation of the solvent under reduced pressure left 30.46 g of
6 (73% isolated yield). Crystals of 6 suitable for X-ray analysis
were obtained by placing a concentrated solution of MeCN in a
freezer for 2 days. 1H NMR (400 MHz, C6D6) δ 2.69-2.70 (m,
6H), 2.86 (br, 6H), 3.35 (s, 9H), 4.52-4.54 (d, 6H, J = 10 Hz),
6.57-6.59 (d, 3H, J = 8 Hz), 6.93-6.97 (t, 3H, J = 14.8 Hz),
7.11-7.16 (t, 3H, J=14 Hz), and 7.65-7.67 (d, 3H, J=7.2 Hz).
13C NMR (100 MHz, C6D6) δ 158.3, 130.2 (d, J=5.7 Hz), 130.0,
128.1, 55.1, 51.9, 48.0 (d, J=41.1 Hz), and 46.8 (d, J=6.6 Hz).
31P NMR (186 MHz, C6D6) δ 127.90 ppm. HRMS m/z
534.27714 (calcd for C30H39N4O3P 534.27596).
General Procedure for the Synthesis of Isocyanurates with 6 as
a Catalyst. To a 100 mL round-bottomed flask with a side arm
was added 8 mg (0.1 mol %) of proazaphosphatrane 6 in a
glovebox. The flask was capped with a rubber septum and then it
was taken out of the glovebox and charged with 2 mL of toluene.
The isocyanate (1.78 g, 15 mmol) was added with stirring for the
allotted time indicated, using a stopwatch, until the isocyanu-
rate had precipitated. The solids were washed with 5 mL of
toluene to extract any impurities and the mixture was then
filtered. The solids were dried under reduced pressure and
weighed.
Experimental Section
Synthesis of Compound 9. To 1.0 equiv of freshly distilled
tris(2-aminoethyl)amine in 100 mL of MeOH was added 3.1
equiv of o-anisaldehyde. The mixture was allowed to stir at
room temperature overnight and then another 100 mL of
MeOH was added. The reaction mixture was cooled 0 °C in
an ice bath and then NaBH4 (1.5 equiv) was added slowly and
portion-wise over 1 h. The reaction mixture was stirred over-
night and then the MeOH was removed via rotovap. The
addition of 50 mL of water was followed by extraction with
3 ꢀ 100 mL of toluene. The toluene extracts were combined and
dried over Na2SO4 and then the toluene extract was filtered and
removed via rotovap. The crude dark yellow oil was purified by
column chromatography (1% MeOH in CH2Cl2) to obtain 92%
1
of the desired product as a yellow oil. H NMR (400 MHz,
CDCl3) δ 2.57-2.58 (d, 6H, J=5.2 Hz), 2.62-2.63 (d, 6H, J=
4.8 Hz), 3.71 (s, 15H), 4.39 (br, 3H), 6.76-6.78 (d, 3H, J=8 Hz),
6.80-6.84 (t, 3H, J=14.8 Hz), and 7.15-7.27 ppm (m, 6H). 13
C
NMR (100 MHz, CDCl3) δ 157.4, 130.1, 128.6, 126.3, 120.4,
110.1, 55.1, 53.5, 47.9, and 46.5 ppm. HRMS m/z 506.32700
(calcd for C30H42N4O3 506.32569).
Synthesis of (6H)Cl. Dry CH3CN (50 mL) was charged to a
round-bottomed Schlenk flask, which was then cooled to 0-5 °C.
HMPT [P(NMe2)3, 10.05 g, 2.0 equiv] was added under argon
followed by slow addition of PCl3 (4.19 g, 1 equiv) via syringe.
After the reaction mixture was stirred at 0-5 °C for 15 min,
9 (46.53 g, 3.0 equiv) dissolved in 50 mL of dry CH3CN was added.
The reaction mixture was stirred overnight at rt and then solvent
was removed via rotovap, leaving a sticky yellow solid. Addition of
5-10 mL of THF to this solid formed a free-flowing solid and
addition of ethyl ether (250 mL) to this mixture led to the
formation of additional solids. Placing the flask in a freezer for
3 days caused more solids to form. Filtration of the solids followed
by drying under reduced pressure produced a light yellow powder
(85% isolated yield). 1H NMR (400 MHz, CD3CN) δ 3.04-3.10
(m, 6H), 3.20-3.25 (m, 6H), 3.76 (s, 9H), 4.07-4.11 (d, 6H, J =
16.8 Hz), 5.09-6.37 (d, 1H, J = 509.2 Hz), 6.9-6.95 (m, 6H),
7.16-7.18 (d, 3H, J = 7.2 Hz), and 7.25-7.29 ppm (t, 3H, J =
15.6 Hz). 13C NMR (400 MHz, CD3CN) δ 125.4, 129.7, 129.5,
127.0, 121.3, 118.3, 111.6, 56.0, 47.9, 46.8, and 40.0 ppm. 31P NMR
(168 MHz, CD3CN) δ -9.97 ppm.
Procedure for Recycling 6. To a 100 mL round-bottomed flask
with a side arm was added 8 mg (0.1 mol %) of 6 in a glovebox.
The flask was capped with a rubber septum and then it was
removed from the glovebox and charged with 2 mL of toluene.
Phenyl isocyanate (1.78 g, 15 mmol) was added to the flask
under an argon flow and then the mixture was stirred for the
allotted time. After completion of the reaction, 5 mL of toluene
was added followed by stirring for an additional 30 min, after
which the solution was filtered under an inert atmosphere
through a glass fritted filter tube and then the solution was
dried under reduced pressure. This procedure was repeated 4
more times.
Acknowledgment. The authors thank the National
Science Foundation for supporting this work through a
grant (0750463).
Supporting Information Available: References to known
1
compounds, copies of H and 13C NMR spectra for all isocya-
Synthesis of 6. To a 25 mL round-bottomed flask containing
compound (6H)Cl (44.54 g, 1 equiv) was added 150 mL of THF
followed by stirring for 10 min at room temperature. NaHMDS
nurate products, data for unknown compounds, and 31P NMR
spectra for proazaphosphatranes 6, 7, and 8. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 15, 2010 5311