Tetraarylphosphonium-supported carbodiimide reagents: Synthesis, structure optimization and applications

Article abstract of DOI:10.1021/jo702417v

(Chemical Equation Presented) New tetraarylphosphonium (TAP)-supported alkyl- and arylcarbodiimides were synthesized and used as coupling reagents for esterification reactions, amidation reactions and dehydration reactions of hydroxyesters. Taking advantage of the solubility properties imparted by the tetraarylphosphonium unit, a simple precipitation and filtration allowed complete separation of the urea by-products. This paper describes the structure optimization study of the various TAP-supported carbodiimide reagents to obtain the desired reactivity and solubility profile. Furthermore, we have demonstrated that the diimide reagent can be regenerated from the urea to recycle the reagents.

Full text of DOI:10.1021/jo702417v

Tetraarylphosphonium-Supported Carbodiimide Reagents:
Synthesis, Structure Optimization and Applications
Maryon Ginisty, Marie-Noelle Roy, and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, PO Box 6128, Station Downtown,
Montre´al, Canada QC H3C 3J7
andre.charette@umontreal.ca
ReceiVed NoVember 9, 2007
New tetraarylphosphonium (TAP)-supported alkyl- and arylcarbodiimides were synthesized and used as
coupling reagents for esterification reactions, amidation reactions and dehydration reactions of
hydroxyesters. Taking advantage of the solubility properties imparted by the tetraarylphosphonium unit,
a simple precipitation and filtration allowed complete separation of the urea by-products. This paper
describes the structure optimization study of the various TAP-supported carbodiimide reagents to obtain
the desired reactivity and solubility profile. Furthermore, we have demonstrated that the diimide reagent
can be regenerated from the urea to recycle the reagents.
Introduction
soluble derivatives such as 1-(3-(dimethylamino)-propyl-3-
ethylcarbodiimide hydrochloride (EDCI),7 which generates basic
urea byproducts that can be easily removed by an acidic aqueous
workup. Another process involves the use of polymer-bound
carbodiimide reagents, since removal of the resulting supported
urea byproducts can be achieved by filtration.8 This method
reduces the need for difficult work-ups and remove cumbersome
purification procedures. Furthermore, these reagents display
lower toxicity than DCC. The most popular supported carbo-
diimide reagents are generally synthesized on cross-linked
polystyrene beads, macroporous ion exchange resins or inorganic
supports.9 They include isopropylcarbodiimide (PS-DIC),10
Carbodiimides are versatile reagents that are widely used in
organic synthesis and bioorganic chemistry. These compounds
are capable of a variety of transformations including peptide
coupling,1 amide bond formation,2 esterification,3 anhydride
formation,4 oxidation5 and dehydrating reactions of â-hydroxy-
carbonyl derivatives.6 While there are many carbodiimides
available for these reactions, dicyclohexylcarbodiimide (DCC)
is the reagent most commonly used. However, the major
limitation of using DCC and its analogues is the formation of
the toxic N-alkylurea byproduct that may require demanding
purification steps for its complete removal.
In recent years, various approaches have been developed in
carbodiimide-mediated reactions to separate the desired product
from the urea byproduct. One method consists of using water-
(7) Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. L. J. Org. Chem.
1961, 26, 2525.
(8) For the recent reviews and uses of supported reagents in synthesis,
see: (a) Solinas, A.; Taddei, M. Synthesis 2007, 2409. (b) Baxendale, I.
R.; Ley, S. V. Curr. Org. Chem. 2005, 9, 1521. (c) Baxendale, I. R.; Ley,
S. V. Ind. Eng. Chem. Res. 2005, 44, 8588. (d) Storer, R. I.; Takemoto, T.;
Jackson, P. S.; Brown, D. S.; Baxendale, I. R.; Ley, S. V. Chem. Eur. J.
2004, 10, 2529. (e) Choi, M. K. W.; Toy, P. H. Tetrahedron 2004, 60,
2875. (f) Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. ReV. 2002,
102, 3325. (g) Bergbreiter, D. E. Chem. ReV. 2002, 102, 3345.
(9) (a) Parlow, J. J.; Mischke, D. A.; Woodard, S. S. J. Org. Chem. 1997,
62, 5908. (b) Flynn, D. L.; Devraj, R. V.; Naing, W.; Parlow, J. J.; Weidner,
J. J.; Yang, S. Med. Chem. Res. 1998, 8, 219. (c) Adamczyk, M.; Fishpaugh,
J. R.; Mattingly, P. G. Tetrahedron Lett. 1995, 36, 8345.
(1) Mikolajczyk, M.; Kiebalsinski, M. Tetrahedron 1981, 37, 233.
(2) (a) Bodanszki, M. Peptide Chemistry: A Practical Textbook;
Springer: New York, 1988. (b) Wang, S. S.; Tam, J. P.; Wang, B. S.;
Merrifield, R. B. Int. J. Pept. Protein Res. 1981, 19, 459.
(3) Neises, B.; Steglich, W. Org. Synth. 1985, 63, 183.
(4) (a) Chen, F. M. F.; Kuroda, K.; Benoiton, N. L. Synthesis 1978, 928.
(b) Rammler, D. H.; Khorana, H. G. J. Am. Chem. Soc. 1963, 85, 1997.
(5) Moffatt, J. G. Oxidation 1971, 2, 1.
(6) L’Abbe, G.; Van Loock, E.; Albert, R.; Toppet, S.; Verhelst, G.;
Smets, G. J. Am. Chem. Soc. 1974, 96, 3973.
(10) Weinshenker, N. M.; Shen, C.-M. Tetrahedron Lett. 1972, 13, 3281.
10.1021/jo702417v CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/04/2008
2542
J. Org. Chem. 2008, 73, 2542-2547

Tetraarylphosphonium-Supported Carbodiimide Reagents
SCHEME 1
TAP-supported azide 4 bearing a biphenyl linker was prepared
in three steps from aldehyde 1.15 The solubility of TAP salts is
counterion-dependent; therefore, to simplify the purification
procedure, the bromide counterion was exchanged to generate
less soluble phosphonium salts. Subjecting 1 to potassium
hexafluorophosphate or lithium trifluoromethanesulfonate in
aqueous solution furnished the corresponding hexafluorophos-
phate 2a (X- ) PF6-) and triflate 2b (X- ) TfO-) salts,
respectively, in quantitative yields. The reduction of the
aldehydes 2 to alcohols 3 was achieved using sodium borohy-
dride in a mixture of ethanol and CH2Cl2 at -78 °C. It should
be emphasized that analytically pure phosphonium derivatives
2 and 3 were easily obtained by a selective precipitation of the
salt from a CH2Cl2 solution upon diethyl ether addition. Alcohols
3a and 3b were then converted into the corresponding primary
bromides that were directly transformed into azides 4a (97%)
and 4b (56%).
Subsequent condensation of the azides with various alkyl
isocyanates gave the corresponding supported carbodiimides
5-8 in good yields. The salts were either used crude or quickly
filtered through a pad of silica gel to remove any residual
impurities from the Staudinger reaction. The solubility properties
of the TAP-supported carbodiimides were consistent with those
of other tetraaryphosphonium salts in that all seven salts were
soluble in chlorinated solvents and could be precipitated upon
diethyl ether addition. The triflate salts were not as clean as the
hexafluorophosphate analogues, and all our attempts to increase
their purities by crystallization or chromatography failed.
Nevertheless, all seven salts were tested in the coupling and
dehydration reactions.
The first reaction that was studied was the amide formation
from a carboxylic acid and an amine (Table 1). The typical
procedure involved combining a slight excess of a carboxylic
acid (1.10 equiv) with the appropriate TAP-supported carbo-
diimide reagent (1.20 equiv) followed by the addition of an
amine (1.00 equiv). All reactions were complete within 3 h and,
after standard acidic and basic extractions to remove any
remaining starting material, the crude mixture was dissolved in
CH2Cl2. Et2O addition induced the precipitation of the TAP-
supported reagent’s byproduct. A subsequent filtration led to
the desired product free of the carbodimiide/urea.16
To determine the optimal structure of the supported carbo-
diimide reagent, two aspects were investigated. First, the
reactivity of the TAP-supported reagents was evaluated by
comparing the yields of the coupling product to that of DCC or
EDCI/HOBt.17 Second, the efficiency of the removal of the
byproducts by a precipitation/filtration sequence was assessed
by measuring the amount of phosphonium salt remaining in the
filtrate relative to the desired coupling product following the
precipitation/filtration sequence. The coupling reactions between
hexanoic acid or p-bromophenylacetic acid and phenethylamine
could be accomplished in excellent yields and purity using
supported carbodiimide reagent 5a and 6a (Table 1, entries 1
and 3). Furthermore, the purity of the coupling product between
alanine and glycine was excellent after the removal of the
phosphonium-supported byproducts by precipitation/filtration
(Table 1, entry 2), and no racemization was observed.17,18 In
N-benzyl-N′-cyclohexyl-carbodiimide (PS-BDDC)11 and polymer-
tethered-EDC.12 Although the use of these reagents is a
considerable improvement with regards to purification compared
to DCC, there still exist several limitations, including reaction-
scale restriction (quantity and loading capacity of the solid
supported reagent) and low reaction rates. Consequently, soluble
polymers have been developed that can combine advantages of
solid-phase and solution-phase reactions. For instance, reaction
progress can be easily monitored by standard techniques (LCMS,
TLC, HPLC, or NMR) and, as the reaction is carried out under
homogeneous conditions, the use of a large excess of reagents
is not necessary. To our knowledge, only Hanson and co-
workers have described the design of a high-load soluble
oligomeric variant of DCC (2GOACCn)18 via a ROM polymer-
ization step.13
Recently, our group has been interested in using tet-
raarylphosphonium (TAP) salts as new solubility control groups
(SCG) for reagents.14 We have previously shown that TAP salts
are usually soluble in polar solvents (CH2Cl2, CH3CN, DMSO,
PhCN, DMF) and can be precipitated upon addition of less polar
solvents such as hexane, Et2O or toluene. In this context, we
report herein the preparation of a series of novel and inexpensive
soluble supported carbodiimides, where the carbodiimide moiety
is covalently linked to the soluble TAP support. The loadings
of these supported reagents are quite high when compared to
their solid supported analogues. These reagents were success-
fully applied in esterification, amidation and dehydration
reactions and their structures were optimized to facilitate the
removal of byproducts by a precipitation/filtration sequence.
Results and Discussion
Several structurally related carbodiimide derivatives were
prepared from readily available isocyanates via a Staudinger
reaction with a TAP-supported azide (Scheme 1). The desired
(11) Chou, T.-S.; Lee, S.-J.; Chang, L.-J. Bull. Inst. Chem., Acad. Sin.
1987, 34, 27.
(12) Desai, M. C.; Stramiello, L. M. Tetrahedron Lett. 1993, 34, 7685.
(13) Zhang, M.; Vedantham, P.; Flynn, D. L.; Hanson, P. R. J. Org.
Chem. 2004, 69, 8340.
(14) Poupon, J.-C.; Boezio, A.; Charette, A. B. Angew. Chem., Int. Ed.
2006, 45, 1415.
(15) Stazi, F.; Marcoux, D.; Poupon, J.-C.; Latassa, D.; Charette, A. B.
Angew. Chem., Int. Ed. 2007, 46, 5011.
(16) See Supporting Information for typical NMR spectra of crude
reaction products after the precipitation/filtration sequence.
(17) Nozaki, S.; Kimura, A.; Muramatsu, I. Chem. Lett. 1977, 18, 1057.
(18) Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447.
J. Org. Chem, Vol. 73, No. 7, 2008 2543

Ginisty et al.
TABLE 1. TAP-Supported Carbodiimide Amidation Reactions
a Isolated yield of the coupling product after precipitation and filtration of phosphonium-supported byproducts. b The purity is given by the [% expected
coupling product] - [% remaining phosphonium salt] measured by 1H NMR of the final product. c RCO2H (1.0 equiv), RNH2 (1.0 equiv), DCC (1.2 equiv),
HOBt (1.0 equiv), DMAP (0.10 equiv), CH2Cl2, 0 °C to rt. d The product is contaminated with ca. 5% of N,N-dicyclohexylurea that could not be completely
removed by the EtOAc precipitation.
TABLE 2. TAP-Supported Carbodiimide Esterification Reactions
a The yields were measured both by NMR and isolation of pure coupling product. b The purity is given by the [% expected coupling product] - [%
remaining phosphonium salt]. c Procedure B was followed, but DCC (1.2 equiv) was used instead of the phosphonium supported carbodiimide reagent.
general, the yields of the coupling products were higher when
using PF6 salts (5a-8a) than those observed with triflate salts
(5b-7b). We believe that the main reason for this observation
is the fact that the purity of the reagents 5a-8a are higher than
that of 5b-7b since all the reagents should display similar
reactivities. More importantly, the complete removal of the
phosphonium salts by a single precipitation/filtration procedure
was very effective with reagent 5a or 6a. This can be explained,
since the carbodiimide reagents possessing the smallest R group
had the most suitable solubility properties. This was expected
as the less lipophilic salts are more readily precipitated from
the solution by the addition of a less polar solvent. Similarly,
the coupling between alanine and valine proceeded well under
the same conditions when using 5a as the carbodiimide reagent
(Table 1, entry 4).19
that was used involved adding the TAP-supported reagent (1.10
equiv) to a mixture of a carboxylic acid (1.00 equiv), an alcohol
(1.00 equiv) or a phenol (3.00 equiv) and DMAP (0.10 equiv)
at 0 °C. All reactions were complete within 3 h at room
temperature, and the TAP-supported urea byproduct was
removed from the desired ester by precipitation upon ether
addition followed by filtration.
For the same reasons as those outlined for the amidation
reactions, reagents 5a and 6a provided excellent yields of the
corresponding esters. The reaction proceeded extremely well
for the esterification of phenylacetic acid and benzyl alcohol
(Table 2, entry 1) where a 97% yield of the ester was obtained
with carbodiimide 5a. Most supported carbodiimide reagents
were effective for this reaction and the byproducts formed with
almost all of the reagents could be removed by a single
precipitation/filtration sequence. The esterification using the
more sterically hindered isopropanol was almost as efficient as
when DCC was used (Table 2, entry 2). As before, supported
carbodiimide reagents 5a and 6a provided the highest yields
and the highest ester purity after the removal of the byproducts.
It was also possible to use the supported reagents to generate
Similar trends were observed for the carbodiimide-mediated
esterification reactions of carboxylic acids. The typical procedure
(19) Wonnemann, J.; Oberhoff, M.; Erker, G.; Fro¨hlich, R.; Bergander,
K. Eur. J. Inorg. Chem. 1999, 1111.
(20) Barbayianni, E.; Fotakopoulou, I.; Schmidt, M.; Constantinou-
Kokotou, V.; Bornsheuer, U. T.; Kokotos, G. J. Org. Chem. 2005, 70, 8730.
2544 J. Org. Chem., Vol. 73, No. 7, 2008

Tetraarylphosphonium-Supported Carbodiimide Reagents
SCHEME 2
Experimental Section
General Procedure for the Formation of (4′-Formyl-1,1′-
biphenyl-4-yl)(triphenyl)phosphonium Salts 2a and 2b. To a
solution of aldehyde 115 (7.64 mmol, 1.00 equiv) in DCM (10 mL)
and CH3CN (30 mL) was added a solution of corresponding metal
salt (KPF6 or LiOTf, 1.20 equiv) in H2O (10 mL). After 1 h of
stirring, TLC analysis (DCM/MeOH ) 95/5) showed that the anion
had completely exchanged. The mixture was then concentrated
under reduced pressure and diluted with DCM. The reaction mixture
was then washed with water and the resulting aqueous layer was
washed with DCM. The combined organic layers were washed twice
with water, dried over anhydrous MgSO4 and concentrated under
reduced pressure. The crude product was diluted with a minimum
of DCM and was precipitated upon Et2O addition (5 vol). The
heterogeneous solution was decanted and the solution was repre-
cipitated twice using the above procedure to afford pure 2a and 2b
as pale-yellow solid foams.
the phenol ester in high yield (Table 2, entry 3). The coupling
reaction between phenylacetic acid and a more sensitive alcohol
was accomplished successfully and in high yield (Table 2, entry
4).
We have also tested the TAP-supported carbodiimide reagents
in the dehydration reaction of a â-hydroxyester (eq 1).21 The
CuCl2-catalyzed dehydration of alcohol 17 with carbodiimide
5a or 6a was carried out in refluxing DCE and resulted in the
formation of diene 18 in a better yield than that obtained using
the parent unsupported reagents (86%).22 As above, the complete
removal of the urea byproduct was achieved by a single
precipitation/filtration sequence.
(4′-Formyl-1,1′-biphenyl-4-yl)(triphenyl)phosphonium Hexaflu-
orophosphate (2a). Pale yellow foam; yield 100%; mp 95-100
1
°C; H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.02-7.98 (m,
4H), 7.89-7.84 (m, 5H), 7.80-7.75 (m, 7H), 7.69-7.64 (m, 6H);
13C NMR (100 MHz, CDCl3) δ 191.8 (s, 1C), 146.6 (s, 1C), 144.0
(s, 1C), 136.2 (s, 1C), 135.6 (s, 3C), 134.9 (d, J ) 11.1 Hz, 2C),
134.2 (d, J ) 10.1 Hz, 6C), 130.6 (d, J ) 13.1 Hz, 6C), 130.3 (s,
2C), 129.3 (d, J ) 13.1 Hz, 2C), 128.2 (s, 2C), 117.3 (d, J ) 89.6
Hz, 3C), 116.8 (d, J ) 90.6 Hz, 1C); 31P NMR (162 MHz, CDCl3)
δ 23.3 (s, 1P), -144.0 (hept, J ) 712.7 Hz, 1P); IR (film) 1698,
1597, 1439, 1109, 832, 724 cm-1; MS (+ES) for C31H24OP: m/z
443.2 [M]+; MS (-ES) for 31PF6: m/z 145.1 [M]-. Anal. Calcd for
C31H24F6OP2: C 63.27, H 4.11. Found: C 63.24, H 3.93.
(4′-Formyl-1,1′-biphenyl-4-yl)(triphenyl)phosphonium Trif-
luoromethanesulfonate (2b). Pale yellow foam; yield 100%; mp
1
55-60 °C; H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 8.13-
8.00 (m, 4H), 7.89-7.84 (m, 5H), 7.80-7.75 (m, 7H), 7.69-7.64
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 191.8 (s, 1C), 146.5 (s,
1C), 143.9 (s, 1C), 136.1 (s, 1C), 135.6 (s, 3C), 135.0 (d, J ) 11.1
Hz, 2C), 134.2 (d, J ) 11.1 Hz, 6C), 130.6 (d, J ) 13.1 Hz, 6C),
130.3 (s, 2C), 129.3 (d, J ) 13.1 Hz, 2C), 128.1 (s, 2C), 117.2 (d,
J ) 90.6 Hz, 3C), 116.8 (d, J ) 90.9 Hz, 1C); 31P NMR (162
MHz, CDCl3) δ 23.3 (s, 1P); IR (film) 1698, 1597, 1439, 1261,
1109, 1030, 724, 636 cm-1; MS (+ES) for C31H24OP: m/z 443.2
[M]+; MS (-ES) for 32SO3CF3: m/z 149.1 Anal. Calcd for
C32H24F3O4PS: C 64.86, H 4.08, S 5.41. Found: C 64.66, H 3.94,
S 5.37.
The effectiveness of reagent 5a in many reactions prompted
us to improve its synthesis and recycling procedure (Scheme
2). Treatment of aldehyde 2c23 with N-ethylurea under Dube´’s
conditions24 led to the phosphonium-supported urea 19. This
compound, which is usually the byproduct of the phosphonium-
supported carbodiimide 5a, can be efficiently dehydrated into
5a upon treatment with triphenylphosphine/Br2/Et3N.
General Procedure for the Formation of {4′-(Hydroxy-
methyl)-1,1′-biphenyl-4-yl}(triphenyl)phosphonium Salt 3a and
3b. To a solution of aldehyde 2 (7.64 mmol, 1.00 equiv) in DCM
(0.20 M) at -78 °C was added dropwise a solution of NaBH4 (9.17
mmol, 1.20 equiv) in EtOH (30 mL). The solution was warmed to
0 °C for 1 h. A half-saturated NH4Cl aqueous solution (75 mL)
was carefully added. The combined organic layers were separated
and the aqueous layer was washed with DCM (2 × 100 mL). The
organic solution was washed with water (3 × 75 mL), dried over
MgSO4 and concentrated under reduced pressure. The crude product
was dissolved with DCM (10 mL) and was the phosphonium salt
was precipitated upon Et2O addition (50 mL). The ether layer was
decanted and the above isolation protocol was repeated twice to
afford pure alcohol 3a and 3b.
Conclusion
In summary, new soluble TAP-supported carbodiimide
reagents have been prepared and shown to be excellent coupling
reagents for the preparation of amides and esters and for the
dehydration of â-hydroxy-esters. The urea byproducts were
easily removed following simple workup procedures involving
a precipitation/filtration sequence. Among the various SCG-
carbodiimides that were prepared, the hexafluorophosphate
tetraarylphosphonium salts 5a and 6a are the best supported
reagents in terms of efficiency, and their byproducts are less
soluble and more easily removed. Finally, the high reagent
loadings (1.42-1.55 mmol/g), high reactivity and the possibility
of recycling make them attractive alternatives to non-supported
carbodiimide reagents.
{4′-(Hydroxymethyl)-1,1′-biphenyl-4-yl}(triphenyl)phos-
phonium Hexafluorophosphate (3a). White foam; yield 99%; mp
1
97-99 °C; H NMR (400 MHz, CDCl3) δ 7.94-7.83 (m, 5H),
7.79-7.74 (m, 6H), 7.70-7.62 (m, 10H), 7.47 (d, J ) 7.9 Hz,
2H), 4.72 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 148.1 (s, 1C),
142.3 (s, 1C), 137.0 (s, 1C), 135.5 (d, J ) 2.9 Hz, 3C), 134.8 (d,
J ) 11.6 Hz, 2C), 134.2 (d, J ) 10.4 Hz, 6C), 130.6 (d, J ) 12.8
Hz, 6C), 128.8 (d, J ) 13.3 Hz, 2C), 127.6 (s, 2C), 127.4 (s, 2C),
117.9 (s, 1C), 117.0 (s, 1C), 64.3 (s, 1C); 31P NMR (162 MHz,
CDCl3) δ 23.3 (s, 1P), -144.0 (hept, J ) 712.7 Hz, 1P); IR (film)
(21) (a) Corey, E. J.; Andersen, N. H.; Carlson, R. M.; Paust, J.; Vedejs,
E.; Vlatas, I.; Winter, R. E. K. J. Am. Chem. Soc. 1968, 90, 3245. (b) Corey,
E. J.; Letavic, M. J. Am. Chem. Soc. 1995, 117, 9616.
(22) Moreau, B.; Ginisty, M.; Alberico, D.; Charette, A. B. J. Org. Chem.
2007, 72, 1235.
(23) Aldehyde 2c was prepared by washing the bromide 1 with LiClO4
in acetonitrile (see ref 15 for details).
(24) Dube´, D.; Scholte, A. A. Tetrahedron Lett. 1999, 40, 2295.
J. Org. Chem, Vol. 73, No. 7, 2008 2545

Ginisty et al.
3063, 1596, 1439, 1393, 1109, 831 cm-1; MS (+ES) for C31H24O1P1:
m/z 445.2 [M]+; MS (-ES) for 31PF6: m/z 145.1 [M]- Anal. Calcd
for C31H26F6OP2: C 63.06, H 4.44. Found: C 63.79, H 4.37.
{4′-(Hydroxymethyl)-1,1′-biphenyl-4-yl}(triphenyl)phos-
phonium Trifluoromethanesulfonate (3b). White foam; yield
dissolved in DCM (10 mL). Addition of ether induced the
phosphonium salt precipitation. Filtration over Celite led to the solid
that was further submitted to the dissolution/precipitation protocol
described above three times to afford the expected carbodiimides
5 and 6. The solid was further purified by flash chromatography in
the case of hexafluorophosphate salts.
1
88%; mp 80-85 °C; H NMR (400 MHz, CDCl3) δ 7.91-7.87
(m, 4H), 7.80-7.75 (m, 6H), 7.68-7.61 (m, 9H), 7.57 (d, J ) 8.0
Hz, 2H), 7.45 (d, J ) 8.4 Hz, 2H), 4.69 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 148.1 (s, 1C), 143.2 (s, 1C), 136.4 (s, 1C), 135.6
(s 3C), 134.7 (d, J ) 10.6 Hz, 2C), 134.2 (d, J ) 10.3 Hz, 6C),
130.6 (d, J ) 12.9 Hz, 6C), 128.7 (d, J ) 13.3 Hz, 2C), 127.6 (s,
2C), 127.1 (s, 2C), 117.9 (s, 1C), 117.0 (s 1C), 63.8 (s, 1C); 31P
NMR (162 MHz, CDCl3) δ 23.3 (s, 1P); IR (film) 3062, 1595,
1438, 1392, 1262, 1154, 1111, 1030, 724, 636 cm-1; HRMS (+ES)
calcd for C31H26O1P1 [M]+: 445.1716, found 445.1727; MS (-ES)
for 32SO3CF3 [M]-: m/z 149.1.
[4′-{((Ethylimino)methyleneamino)methyl}biphenyl-4-yl]-
(triphenyl)phosphonium Hexafluorophosphate (5a). White foam;
yield 92% (ca. 90% pure). The purity of the product could be
improved by doing a flash chromatography on a small pad of silica
using CHCl3/EtOAc/iPrOH/Et3N (97/2/1/3 to 95/4/1/3) as eluent.
However, the overall recovery was low (30%) due to the carbo-
1
diimide sensitivity on silica gel; H NMR (400 MHz, CDCl3) δ
7.96 (dd, J ) 2.8 Hz, J ) 8.4 Hz, 2H), 7.89-7.86 (m, 3H), 7.78-
7.74 (m, 7H), 7.71-7.62 (m, 9H), 7.44 (d, J ) 8.0 Hz, 2H), 4.42
(s, 2H), 3.20 (q, J ) 7.2 Hz, 2H), 1.15 (t, J ) 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 147.3 (s, 1C), 137.2 (s, 1C), 135.6 (s,
3C), 134.8 (d, J ) 10.1 Hz, 2C), 134.2 (d, J ) 10.1 Hz, 6C), 130.6
(d, J ) 10.1 Hz, 6C), 128.9 (s, 2C), 128.8 (s, 2C), 128.2 (s, 3C),
127.6 (s, 3C), 117.9 (d, J ) 89.6 Hz, 1C), 115.8 (d, J ) 91.6 Hz,
1C), 49.9 (s, 1C), 41.2 (s, 1C), 16.5 (s, 1C); 31P NMR (162 MHz,
CDCl3) δ 23.3 (s, 1P), -144.0 (hept, J ) 712.5 Hz, 1P); IR (film)
3063, 2121, 1596, 1438, 1109, 829, 723, 690 cm-1; HRMS (+ES)
calcd for C34H30N2P1 [M]+: 497.2141, found 497.2142; HRMS
(-ES) calcd for 31PF6 [M]-: 144.9647, found 144.9650.
General Procedure for the Formation of {4′-(Azidomethyl)-
1,1′-biphenyl-4-yl}(triphenyl)phosphonium Salt 4. To a solution
of alcohol 3 (7.62 mmol, 1.00 equiv), PPh3 (11.4 mmol, 1.50 equiv)
and CBr4 (11.4 mmol, 1.60 equiv) in anhydrous DMF (40 mL)
was added NaN3 (22.9 mmol, 3.00 equiv). After stirring for 10
min, the reaction was warmed to 60 °C for 4 h. The solution was
then cooled to room temperature and DCM and water were added.
The aqueous layer was then washed twice with DCM, and the
combined organic phases were washed five times with water, dried
over anhydrous MgSO4 and concentrated under reduced pressure.
The crude product was diluted with DCM, precipitated upon Et2O
addition and the mixutre was decanted. The crude solid was
resubmitted twice to this dissolution/precipitation sequence. Finally,
the solid was dissolved in DMF (5 mL) at 85 °C and precipitated
from a mixture of hexane/iPrOH (100 mL, 1/1) to afford the azido
compound 4 with (4b) or without (4a) further purification.
{4′-(Azidomethyl)-1,1′-biphenyl-4-yl}(triphenyl)phos-
phonium Hexafluorophosphate (4a). For analytical data, a
sample has been purified by flash chromatography (DCM ) 100%).
White foam; yield 97%; mp 70-75 °C; 1H NMR (400 MHz,
CDCl3) δ 7.97-7.95 (m, 2H), 7.91-7.87 (m, 3H), 7.78-7.75 (m,
7H), 7.73-7.63 (m, 9H), 7.46 (d, J ) 7.9 Hz, 2H), 4.42 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 147.3 (d, J ) 3.0 Hz, 1C), 137.8
(s, 1C), 136.2 (s, 1C), 135.4 (d, J ) 2.0 Hz, 3C), 134.6 (d, J )
11.1 Hz, 2C), 134.0 (d, J ) 10.1 Hz, 6C), 130.4 (d, J ) 12.1 Hz,
6C), 128.8 (s, 2C), 128.7 (s, 4C), 127.6 (s, 2C), 117.2 (d, J ) 89.6
Hz, 1C), 115.4 (d, J ) 91.6 Hz, 1C), 53.9 (s, 1C); 31P NMR (162
MHz, CDCl3) δ 23.3 (s, 1P), -144.0 (hept, J ) 712.7 Hz, 1P); IR
(film) 3064, 2098, 1597, 1439, 1110, 833 cm-1; HRMS (+ES) calcd
for C31H25N3P1 [M]+: 470.1781, found 470.1795; HRMS (-ES)
calcd for 31PF6 [M]-: 144.9647, found 144.9650.
[4′-{((Isopropylimino)methyleneamino)methyl}biphenyl-4-yl]-
(triphenyl)phosphonium Hexafluorophosphate (6a). White foam;
yield 93% (ca. 90% pure). The purity of the product could be
improved by doing a flash chromatography on a small pad of silica
using CHCl3/EtOAc/iPrOH/Et3N (95/4/1/3) as eluent. However, the
overall recovery was low (57%) due to the carbodiimide sensitivity
on silica gel. 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J ) 3.2 Hz,
J ) 8.4 Hz, 2H), 7.89-7.86 (m, 3H), 7.78-7.74 (m, 7H), 7.71-
7.62 (m, 9H), 7.44 (d, J ) 8.0 Hz, 2H), 4.40 (s, 2H), 3.52 (hept,
J ) 6.4 Hz, 1H), 1.12 (d, J ) 6.4 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 147.7 (s, 1C), 139.8 (s, 1C), 137.7 (s, 1C), 135.6 (s,
3C), 134.8 (d, J ) 11.1 Hz, 2C), 134.2 (d, J ) 10.1 Hz, 6C), 130.6
(d, J ) 13.1 Hz, 6C), 128.9 (s, 2C), 128.8 (s, 2C), 128.3 (s, 3C),
127.6 (s, 3C), 117.4 (d, J ) 89.6 Hz, 1C), 115.4 (d, J ) 91.6 Hz,
1C), 50.1 (s, 1C), 49.0 (s, 1C), 24.4 (s, 1C); 31P NMR (162 MHz,
CDCl3) δ 23.3 (s, 1P), -144.0 (hept, J ) 712.5 Hz, 1P); IR (film)
3062, 2970, 2114, 1596, 1438, 1108, 829, 723, 689 cm-1; HRMS
(+ES) calcd for C35H32N2P1 [M]+: 511.2298, found 511.2302;
HRMS (-ES) calcd for 31PF6 [M]-: 144.9647, found 144.9650.
Improved Synthesis of Phosphonium Supported Carbodi-
imide 5a. To a solution of aldehyde 2c15 (25.00 g, 46.04 mmol,
1.00 equiv) and N-ethylurea (12.17 g, 138.13 mmol, 3.00 equiv)
in MeCN (230 mL, 0.20 M) at room temperature was added TFA
(10.26 mL, 138.13 mmol, 3.00 equiv), followed by Et3SiH (22.06
mL, 138.13 mmol, 3.00 equiv). The reaction mixture was stirred
for 18 h. The solution was diluted with CH2Cl2 (500 mL) and
washed with water (3 × 50 mL), 10% (w/v) aqueous K2CO3 (2 ×
50 mL) and water (50 mL). The organic layer was transferred to a
2-L round-bottom flask and an aqueous solution of KPF6 (12.71 g,
69.06 mmol, 1.50 equiv, 0.69 M) was added. The biphasic solution
was vigorously stirred for 30 min. The layers were separated and
the organic layer was washed with water (50 mL), brine (50 mL),
dried over anhydrous MgSO4 and concentrated under reduced
pressure. The slow addition of Et2O (250 mL) to the resultant oil
with vigorous stirring gave a solid product that was collected by
filtration. The solid was washed with Et2O (100 mL). The crude
phosphonium supported urea 19 (27.44 g) was obtained as a yellow
solid and was used directly in the next step. To a solution of PPh3
(11.98 g, 45.69 mmol, 1.10 equiv) at 0 °C in CH2Cl2 (105 mL,
0.40 M) was slowly added Br2 (2.55 mL, 49.84 mmol, 1.20 equiv),
followed by Et3N (14.4 mL, 103.8 mmol, 2.50 equiv). After 10
min, a solution of crude phosphonium 19 (27.44 g, 41.54 mmol,
1.00 equiv) in CH2Cl2 (105 mL, 0.40 M) was slowly added. The
reaction mixture was warmed to room temperature and stirred for
{4′-(Azidomethyl)-1,1′-biphenyl-4-yl}(triphenyl)phos-
phonium Trifluoromethanesulfonate (4b). White foam; yield
56% (flash chromatography CHCl3/EtOAc/iPrOH ) 95/4/1 to 80/
1
15/5); mp 48-53 °C; H NMR (400 MHz, CDCl3) δ 7.97-7.94
(m, 2H), 7.90-7.86 (m, 3H), 7.79-7.74 (m, 7H), 7.72-7.61 (m,
9H), 7.44 (d, J ) 7.9 Hz, 2H), 4.39 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 147.3 (d, J ) 3.0 Hz, 1C), 137.8 (s, 1C), 136.2 (s, 1C),
135.4 (d, J ) 2.0 Hz, 3C), 134.6 (d, J ) 11.1 Hz, 2C), 134.0 (d,
J ) 10.1 Hz, 6C), 130.4 (d, J ) 12.1 Hz, 6C), 128.8 (s, 2C), 128.7
(s, 4C), 127.6 (s, 2C), 117.2 (d, J ) 89.6 Hz, 1C), 115.4 (d, J )
91.6 Hz, 1C), 53.9 (s, 1C); 31P NMR (162 MHz, CDCl3) δ 23.1 (s,
1P); IR (film) 3062, 2096 1596, 1439, 1261, 1151, 1109, 1030,
725, 636 cm-1; HRMS (+ES) calcd for C31H25N3P1 [M]+: 470.1781,
found 470.1795; MS (-ES) for 32SO3CF3 [M]-: m/z 149.1.
General Procedure for the Formation of [4′-{((Alkylimino)-
methyleneamino)methyl}biphenyl-4-yl]triphenylphosphonium
Salt (5, 6). To a solution of azide 4 (1.62 mmol, 1.00 equiv) in
DCM (10 mL) at room temperature was added dropwise n-Bu3P
(1.94 mmol, 1.50 equiv) to produce a green solution. The corre-
sponding isocyanate (1.94 mmol, 1.50 equiv) was then slowly added
and the mixture was stirred for an additional 90 min. The solution
was concentrated under reduced pressure and the residue was
2546 J. Org. Chem., Vol. 73, No. 7, 2008

Tetraarylphosphonium-Supported Carbodiimide Reagents
90 min. The solution was diluted with CH2Cl2 (500 mL) and washed
with water (2 × 75 mL), with saturated aqueous Na2S2O3 (75 mL)
and with saturated aqueous NaHCO3 (75 mL), dried over Na2SO4
and concentrated under reduced pressure. The resulting oil was
triturated with Et2O (250 mL) followed by decantation. The oily
crude product was then dissolved in a mixture of CH2Cl2/hexane/
Et3N (400 mL, 80/19.8/0.2). The solution was filtered through a
2.5 cm high/10 cm diameter pack of silica gel (prewashed with
0.2% triethylamine/hexanes) and washed with CH2Cl2/Et3N (1.60
L, 99.8/0.2). The organic layer was concentrated under reduced
pressure to half of its volume and washed with water (75 mL) and
saturated aqueous NaHCO3 (75 mL), dried over Na2SO4 and
concentrated under reduced pressure. The slow addition of Et2O
(250 mL) to the resultant oil with vigorous stirring gave a solid
that was collected by filtration and further washed with Et2O (100
mL). The phosphonium salt 5a (20.57 g, 70% for two steps) was
obtained as a beige solid.
General Procedure A: Amide Bond Formation. To a solution
of the carboxylic acid (0.22 mmol, 1.10 equiv) in DCM (2 mL)
was added at room temperature TAP-carbodiimide (0.23 mmol, 1.20
equiv) followed by the amine (0.20 mmol, 1.00 equiv). For entries
2 and 4, triethylamine (0.20-0.40 mmol, 1.00-2.00 equiv) was
also added. The reaction mixture was stirred until TLC analysis
indicated complete consumption of the starting materials. DCM was
then added and the organic layer was washed with saturated aqueous
NaHCO3, dried over anhydrous MgSO4 and concentrated under
reduced pressure. The resulting residue was then dissolved in a
minimum volume of DCM; Celite was added followed by Et2O to
induce the complete precipitation of the phosphonium salt (or with
a mixture of Et2O/DCM ) 2.5/1 for entry 3). The mixture was
filtered through a 1-cm-high micropack of silica gel and concen-
trated under reduced pressure to afford the expected pure coupling
product.
added. The ice bath was then removed and the mixture was stirred
at room temperature until TLC analysis indicated complete
consumption of the starting materials. After dilution with DCM,
the organic layer was washed successively with brine, 10% aqueous
HCl, brine, saturated aqueous NaHCO3, brine, dried over anhydrous
MgSO4 and concentrated under reduced pressure. The resulting
residue was then dissolved in a minimum of DCM; Celite was added
followed by Et2O (5 volumes) to induce the complete precipitation
of the phosphonium salt. The mixture was filtered through a 1-cm-
high micropack of silica gel and concentrated under reduced
pressure to afford the expected pure coupling product. A sample
was purified by flash chromatography for complete characterization.
Ethyl 6-Acetoxy-2-[(1E)-but-1-enyl]octa-2,7-dienoate (18). To
the (2R,E)-ethyl-6-acetoxy-2-(but-1-enyl)-3R-hydroxyoct-7-enoate
(17) (45 mg, 0.15 mmol, 1.00 equiv) dissolved in DCE (3 mL)
were added molecular sieves 4 Å (around 250 mg), CuCl2 (2 mg,
0.015 mmol, 0.10 equiv), and finally the corresponding TAP-
carbodiimide 5a (148 mg, 0.23 mmol, 1.50 equiv). The reaction
was stirred at 85 °C for 6 h. After cooling to room temperature,
the reaction mixture was diluted with DCM (10 mL) and filtered.
The resulting organic layer was washed successively with water
(20 mL), with 15% (w/v) aqueous NH4Cl (20 mL) and with brine
(20 mL). After drying over anhydrous Na2SO4 and concentration
under reduced pressure, the crude product was diluted with DCM
(5 mL) and precipitated upon Et2O (25 mL) addition. Filtration
through a 1-cm-high micropack of silicagel afforded the desired
diene 18.
Acknowledgment. This work was supported by NSERC
(I2I), the Canada Research Chair Program, the Canadian
Foundation for Innovation and the Universite´ de Montre´al.
Supporting Information Available: Experimental procedures
for the preparation of all reagents and compounds as well as
characterization data for each reaction and detailed structural
assignment. This material is available free of charge via the Internet
at http://pubs.acs.org.
General Procedure B: Esterification. To a stirred solution of
the carboxylic acid (0.20 mmol, 1.00-1.10 equiv) in DCM at room
temperature was added, DMAP (0.10-0.20 equiv) followed by the
corresponding alcohol (1.00-3.00 equiv). After the reaction mixture
was cooled to 0 °C, TAP-carbodiimide reagent (1.20 equiv) was
JO702417V
J. Org. Chem, Vol. 73, No. 7, 2008 2547