Polymer-mounted N3=P(MeNCH2CH2) 3N: A green, efficient and recyclable catalyst for room-temperature transesterifications and amidations of unactivated esters

Article abstract of DOI:10.1016/j.tetlet.2011.09.102

Merrifield resin-supported N₃P(MeNCH₂CH ₂)₃N shows excellent activity in the transesterification of higher esters such as glyceryl tribenzoate to methyl esters. The catalyst was successfully cycled 20 times (albeit with an increase in reaction time) without compromising yield up to the 20th cycle. The catalyst also showed good performance in amidation reactions of unactivated esters with amino alcohols.

Full text of DOI:10.1016/j.tetlet.2011.09.102

Tetrahedron Letters 52 (2011) 6523–6529
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Polymer-mounted N3@P(MeNCH2CH2)3N: a green, efficient and recyclable
catalyst for room-temperature transesterifications and amidations
of unactivated esters
⇑
Venkat Reddy Chintareddy, Hung-An Ho, Aaron D. Sadow, John G. Verkade
Department of Chemistry, 1275 Gilman Hall, Iowa State University, Ames, IA 50011, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Merrifield resin-supported N3@P(MeNCH2CH2)3N shows excellent activity in the transesterification of
higher esters such as glyceryl tribenzoate to methyl esters. The catalyst was successfully cycled 20 times
(albeit with an increase in reaction time) without compromising yield up to the 20th cycle. The catalyst
also showed good performance in amidation reactions of unactivated esters with amino alcohols.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 16 September 2011
Accepted 21 September 2011
Available online 25 September 2011
Keywords:
Merrifield resin
Solid-supported catalyst
Reusability
Transesterification
Amidation
Azidoproazaphosphatrane
In recent years the desirability of economical and environmen-
tally friendly syntheses has led to the generation of new methods
of catalyst immobilization aimed at facilitating product recovery,
catalyst re-use, reaction workup, and environmentally responsible
waste disposal.1 Anchoring a catalyst to a polymeric matrix is a
well known strategy to overcome these challenges1–3 and the liter-
ature contains numerous descriptions of polymer-bound catalysts
that have successfully replaced traditional homogeneous catalysts
in a variety of reactions.1d Transesterification is one such reaction
since it is a more advantageous process for ester synthesis than
reacting carboxylic acids with alcohols, owing to the poor solubil-
ity of many acids (in contrast to most esters) in common organic
solvents.4 Moreover, a variety of esters are readily prepared or
are commercially available as starting materials for transesterifica-
tions. These reactions are not only of interest in academic labora-
tories, but they also have applications in the paint industry for
the curing of alkyl resins,4 in polymerization processes,4 and in
the production of biodiesel from plant oils.5
Transesterification is an equilibrium process catalyzed by Lewis
acids (e.g., boron tribromide,6 tin-based compounds,4d and alumi-
num isopropoxide7), Bronsted acids (e.g., hydrochloric, phosphoric,
sulfonic, sulfuric, or p-toluenesulfonic acid),8 and bases (e.g., alkali
N3
Me
Me
1
NaN3, DMF
P
N
N
Me
N
toluene
N3
Cl
70 °C, 24 h
70 °C, 36 h
N
4 or 5
= Merrifield resinin 4, FibrCat resin in 5
Scheme 1. Synthesis of 4 or 5. FibreCat is commercially made by graft polymerization under electron beam conditions of functionalized monomers on to polypropylene fiber.
⇑
Corresponding author. Tel.: +1 515 2945023; fax: +1 515 2950105.
E-mail address: jverkade@iastate.edu (J.G. Verkade).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.102

6524
V. R. Chintareddy et al. / Tetrahedron Letters 52 (2011) 6523–6529
relatively small number of catalysts do catalyze this reaction [i.e.,
InI3 (9 reactions),12 dibutyltin oxide (9 reactions),13 fluoroalkyldis-
tannoxane (3 reactions),14a potassium dodecatungstocobaltate tri-
hydrate (1 reaction),14b and silicagel treated with thionyl chloride
O
O
4
r.t
+
R'OH
+ MeOH
OH
R
OR'
R
R
OMe
O
O
4
+
+ R'OH
OH
H2N
R
OR'
r.t.
N
H
Table 2
Transesterification of glyceryl tribenzoate at room temperature with methanol using
catalyst 420
Scheme 2. Transesterifications and amidations Using 4.
Cycle
t (min)
Ca (%)
IYb (%)
Cycle
t (min)
Ca (%)
IYb (%)
metal alkoxides,9 metal carbonates,9 amines,9 and NHCs4c,10) under
homogeneous conditions. Some heterogeneous/recyclable cata-
lysts11 are known for this transformation, including a polymer-
supported Zn-catalyst,11a Sn[N(SO2C8F17)2]4 and Hf[N(SO2C8F17)2]4
in a fluorous biphasic system,11b kaolinitic clays,11c hydrotal-
1
2
3
4
5
6
7
8
9
15
15
15
30
30
30
30
30
30
30
100
100
100
100
100
100
100
100
100
100
95.0
—
95.0
–
–
–
95.0
–
–
11
12
13
14
15
16
17
18
19
20
30
30
30
30
30
30
30
30
30
30
100
100
100
100
100
100
100
100
100
100
—
—
—
—
91.0
95.0
95.0
95.5
95.5
95.0
cites,11d hydroxyapatite-supported ZnCl2,11e phosphates,11f
a
Mn(III) (salen)-complex,11g and vanadyl(IV) acetate.11g However,
these catalysts are directed toward producing higher esters from
lower homologs. In the literature we found several Lewis acid cat-
alysts [Ti(OMe)4, AlCl3, and Ti(OPri)4] that fail to catalyze the for-
mation of methyl esters from their higher analogues.12,13 Only a
10
–
Values of 100 represent conversions based on 1H NMR spectroscopic
examination.
a
b
Isolated yield.
Table 1
Transesterifications with methanol catalyzed by 4 at room temperature20
Entry
1
Ester
Time (h)
Product
Yielda (%)
94
O
O
CH2CH3
CH3
3.0
5.0
5.0
O
O
O
O
O
O
H3CH2C
H3CH2C
CH2CH3
H3C
O
CH3
CH3
O
O
O
O
O
O
2
3
94
95
O
CH2CH3
H3C
O
O
O
O
O
O
CH3
O
O
4
5
Ethyl linoleate
2.0
6.0
Methyl linoleate
95
93
O
O
H3C(H2C)9H2C
O
OEt
H3C(H2C)9H2C
O
OMe
CH2CH3
CH3
O
O
O
O
6
7
8
2.5
0.2
2.5
81
95
70
CH2CH3
CH3
O
O
O
OCOPh
CH3
O
OCOPh
OCOPh
O
O
O
CH2CH3
CH3
CH3
O
O
O
O
CH2CH3
O
O
O
O
CH2CH3
CH3
O
82
9
6.0
90b
OCH3
OCH3
a
Isolated yields after column chromatography.
Using 150 mol % of indium triiodide12 in 25 h.
b

V. R. Chintareddy et al. / Tetrahedron Letters 52 (2011) 6523–6529
6525
Table 3
Amidations of unactivated esters with b-amino alcohols catalyzed by 2, 3, or 4 at room temperature20 in 24–36 h
Entry
Ester
Aminoalcohol
Product
Yielda (%)
O
O
OH
O
O
H2N
H2N
H2N
OH
OH
1
86 (7521
)
OMe
OBn
N
H
OH
OH
2
3
89
N
H
O
O
OH
OEt
N
H
84 (8721
)
O
O
OMe
OH
OH
H
H2N
H2N
N
4
5
95 (10021, 66b,24a
)
OH
O
O
O
O
OH
OH
54 (6621
)
N
H
O
CH2OH
O
OH
OH
O
H2N
HN
OMe
N
H
6
81
F
F
O
O
OH
NH
OEt
N
O
O
O
O
+
7b
74c (53/47)d
O
O
OH
O
H2N
OH
OMe
N
8
64
H
Cl
Cl
OMe
H
H2N
H2N
OH
N
OH
9
(95e)
74
O
O
O
O
OH
10
OCH3
N
H
OH
O
OH
O
H2N
H2N
OH
OMe
N
11
81f (8821, 8124b
)
H
F
F
O
O
OH
OH
OH
O
12
13
14
66 (9921
)
OCH3
N
H
O
H2N
H2N
68f (8821
)
HO
HO
OH
OH
N
O
H
OH
O
O
69f
( )
N
H
3
O
(continued on next page)

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V. R. Chintareddy et al. / Tetrahedron Letters 52 (2011) 6523–6529
Table 3 (continued)
Entry
Ester
Aminoalcohol
Product
Yielda (%)
O
O
H2N
OH
15
90g, 60f (16, 9621
)
OMe
N
H
OH
a
Isolated yields after chromatography on silica gel.
b
c
d
e
f
Using 30 mol % of TBD [1,5,7-triazabicyclo(4.4.0)dec-5-ene] catalyst under homogeneous conditions, see Ref. 1a.
Combined isolated yield of amide and ester.
Amide/ester ratio was determined by NMR spectroscopic integration.
Using 5 mol % of 3.
Using 5 mol % of 2.
Using 10 mol % of 2.
g
(1 reaction)].14c The quantities required for these catalysts were
150,12 10, 10 mol %, and 150 mg/mmol of ester, respectively.
Among the aforementioned catalysts, fluoroalkyldistannoxane,14a
and a cumbersome synthesis of the catalyst. Thus there is consid-
erable room for improvement in the catalytic conversion of higher
to lower esters with respect to catalyst efficiency and avoidance of
metals for environmental reasons.
potassium dodecatungstocobaltate trihydrate,14b and silicagel/
SOCl2
were recyclable, although the latter catalyst14c was se-
14c
verely deactivated in the second cycle (only 26–38% product
yields) and the potassium dodecatungstocobaltate trihydrate14b
was not recycled for the conversion of lower to higher esters.
Moreover, the fluoroalkyldistannoxane14a approach requires ele-
vated temperatures, expensive perfluorohexane as the solvent
R
R
P
N
N
N
R
N
R = methyl, 1
R = isopropyl, 2
R = isobutyl, 3
Table 4
Amidation of unactivated esters catalyzed by 3 or 4 or 5 at room temperature with chiral b-amino alcohols in 24–36 h20
Entry
1b
Ester
Aminoalcohol
Product
Yielda (%)
39
OCH3
HO
HO
N
O
O
HN
O
O
Ph
Ph
O
O
O
2b
75
61
OCH3
OCH3
OH
OH
O
S
H2N
H2N
N
H
3b
S
OH
OH
OH
Ph
N
H
BOC
OCH3
Ph
N
H
O
OH
4b
78
H2N
HO
HO
BOC
NH
N
H
O
O
O
BOC
BOC
BOC
OCH3
OCH3
OCH3
NH2
NH2
H
N
N
H
BOC
BOC
5c
6d
N
H
OH
OH
66
78
O
O
O
H
N
N
H
N
H
Ph
Ph
Ph
N
H
OH
OH
OH
OH
7c
34
41
H2N
H2N
BOC
BOC
NH
NH
N
H
O
O
BOC
OCH3
Ph
N
H
O
8d
N
H
a
b
c
Isolated yields after silicagel column chromatography.
Using 10 mol % proazaphosphatrane, 3.
Using 10 mol % proazaphosphatrane-Merrifield resin 4.
Using 10 mol % of proazaphosphatrane-Fibre Cat 5.
d

V. R. Chintareddy et al. / Tetrahedron Letters 52 (2011) 6523–6529
6527
Previously we reported that proazaphosphatranes15,16 1–3 are
exceedingly strong commercially available nonionic bases which
are useful as homogeneous catalysts and as stoichiometric re-
agents in a wide variety of important organic transformations,
including transesterifications.17 We have also demonstrated that
a dendrimer functionalized with azidoproazaphosphatrane moie-
ties is a good catalyst for C–C bond-forming reactions in Michael
and Henry reactions.18
As part of our effort to develop green chemical methods for or-
ganic synthesis, we focused our attention on converting one of our
homogeneous proazaphosphatranes (1) to a heterogeneous azido-
proazaphosphatrane analog. Herein we report that Merrifield re-
sin-bound N3@P(MeNCH2CH2)3N (4 in Scheme 1)17 is an efficient
catalyst with excellent reusabilty for transesterifications and ami-
dations at room temperature. Our protocol is operationally simple,
metal-free, low-energy, and eco-friendly (Scheme 2).
The Merrifield resin catalyst 4 was synthesized as shown in
Scheme 1.19 Our results for the use of catalyst 4 in room-tempera-
ture transesterifications of ethyl, glyceryl, and benzyl esters to
their corresponding methyl esters are summarized in Table 1.20
In this table only 6.7 mol % of catalyst was required, in contrast
to InI3 and dibutyltin oxide which require 15012 and 10 mol %,13
respectively, for catalyzing the conversions of higher esters to low-
er analogues. Although (E)-methyl 3-methoxycinnamate has been
obtained from its corresponding ethyl ester in 90% yield in 25 h
using indium triiodide,12 catalyst 4 facilitated the same reaction
in 6 h, although the yield (82%) was lower (entry 9). To the best
of our knowledge, however, ours is the first metal-free protocol
for the transformation of higher esters to lower analogs.
reported14a a method for transesterifying Ph(CH2)2COOEt to the
corresponding methyl ester in perfluorohexanes using fluor-
oalkyldistannoxane as a catalyst which was recycled 20 times un-
der biphasic conditions at 150 °C for 16 h. By contrast, the same
transesterification by our protocol in Table 2 occurs at room
temperature in 15–30 min and requires no metal-containing cata-
lyst or expensive solvent.
The recently-published novel catalytic amidation of unactivated
esters with amino alcohols using homogeneous nitrogen-contain-
ing heterocyclic carbene (NHC)21 catalysts prompted us to test
the efficacy of our heterogeneous catalyst 4 in such amidations.
The b-hydroxyamide products of the reactions of this type are use-
ful in the synthesis of peptides,22 polymers,22 biologically active
natural products,23 and other complex molecules.22,23
Interestingly, good to excellent yields of amidation products are
achieved using 6.7 mol % of 4 at room temperature (Table 3). From
this table it is seen that functional group tolerance is good and that
our yields are comparable to the literature yields in the cases of en-
tries 3 and 4. The product yield in entry 1 is higher than that re-
ported with a homogeneous NHC catalyst, but lower than that
achieved with such a catalyst for the product in entry 5. Not sur-
prisingly, a secondary amino alcohol (entry 7) resulted in an insep-
arable mixture resulting from competing transesterification and
amidation. The transformations in entries 11–15 were carried out
using catalyst 2 at room temperature. Interestingly, we obtained
a 90% yield for the reaction in entry 15 (a transformation promoted
in 16% yield by an NHC and in 96% in the presence of LiCl as an
additive21). The scope of amidation couplings using 2–5 are re-
ported in Tables 3–5.
Catalyst 4 was successfully cycled 20 times in the case of glyc-
eryl tribenzoate (Table 2). It is noteworthy that there was no reac-
tion observed in the absence of catalyst 4 under the same reaction
conditions (see foot note a of Table 2). The recyclability experi-
ments presented in this table were carried out twice with very
similar results.19b It is interesting to note here that Otera et al. have
It is interesting to note here that the product in entry 4 of Table
3 was isolated in 95% yield as a 1H NMR-pure white solid without
column chromatography. Simple filtration of the polymer catalyst
4 followed by the evaporation of solvent sufficed.
As can be seen from Table 4, a variety of esters have been exam-
ined, including BOC-protected esters, all of which underwent clean
Table 5
Double amidation of unactivated esters catalyzed by 3 or 4 at room temperature with chiral b-amino alcohols20
Entry
1a,b
Ester
Aminoalcohol
Product
Yielda (%)
49
H3CO
OCH3
OCH3
H
N
H
N
N
H
HO
N
H
OH
OH
OH
O
O
O
O
H2N
O
O
O
O
H3CO
H
N
H
N
N
H
HO
N
H
2c
93
OH
OH
H2N
H2N
H3CO
H3CO
OCH3
OCH3
H
N
H
N
N
H
3d
HO
HO
N
H
OH
OH
46
75
O
O
O
O
O
O
O
O
H
N
H
N
N
H
N
H
4e
OH
OH
H2N
H3CO
OCH3
H
H
N
H
N
N
HO
N
OH
O
O
5f
90
H
O
O
H2N
a
b
c
d
e
f
Using 10 mol % of catalyst 4.
Average of two runs was carried out for 3 days. Product was prepared on a 6.02 g scale of ester.
2.06 g of product was isolated, using 10 mol % of catalyst 3, THF (100 mL) 3 days.
2.03 g of product was isolated, using 10 mol % of catalyst 3, THF (100 mL) 3 days.
Using 10 mol % of catalyst 3, THF (100 mL), 3 days.
3.26 g of product was isolated, using 10 mol % of catalyst 3, THF (100 mL) 3 days.

6528
V. R. Chintareddy et al. / Tetrahedron Letters 52 (2011) 6523–6529
1059–1070; (c) Lotero, E.; Liu, Y.; Lopez, D. E.; Suwannakaran, A.; Bruce, D. A.;
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amidation reactions providing good yields of products with reten-
tion of the chirality of the aminoalcohols. It is interesting that in
both of the cases wherein the FibreCat catalyst 5 was used (entries
6 and 8) the product yields were substantially higher than were
realized with 4 (entries 5 and 7, respectively). This result can be as-
cribed to the fibrous structure of FibreCat in which the catalyst
functional groups are concentrated on the surface of the fiber for
good substrate interaction. This contrasts with the structure of re-
sin beads which require solvent swelling and substrate diffusion
into bead interiors for contact with catalytic sites.
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In Table 5, the usefulness of our protocol was successfully dem-
onstrated for the double amidation of esters using chiral amino
alcohols at room temperature in good to excellent yields using cat-
alyst 3 or 4.
The high reactivity of amino alcohols also allows their selective
coupling with unactivated esters in the presence of amines (Eq 1).
As in Table 4, the reactions in Table 5 proceeded with retention of
chirality of the aminoalcohols.
BuNH2
H
+
N
4
OH
PhCH2CO2Me
+ H2N 2OH
O
THF, r.t.
+
81%
BnNH2
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ð1Þ
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346, 1093–1096.
In conclusion, Merrifield resin-bound N3@P(MeNCH2CH2)3N (4)
is a highly efficient, recyclable, metal-free green catalyst for transe-
sterifications of higher esters to lower esters at room temperature.
The robustness of 4 for recycling was demonstrated with triglyce-
ryl benzoate which sucessfully allowed 20 cycles albeit with an in-
crease in the time required for excellent yields. Separation of esters
from the reaction mixture is readily effected by the filtration of cat-
alyst 4 or 5 followed by evaporation of excess methanol to obtain
products in acceptable purity. To the best of our knowledge, 4 and
5 are the first heterogeneous catalysts reported for the amidation
of unactivated esters with amino alcohols, and it appears to be
quite general for this purpose. Our catalytic amidation protocol
does not require the use of excess coupling component, heat,
molecular sieves, or activated esters.
19. (a) Ilankumaran, P.; Verkade, J. G. J. Org. Chem. 1999, 64, 9063–9066. in which 4
was erroneously reported as the corresponding imine; The polymer catalyst 4
was prepared according to our previous method19a except that the
temperature employed was 70 °C rather than 130 °C, See (b) Venkat Reddy,
C.; Fetterly, B. M.; Verkade, J. G. Energy Fuels 2007, 21, 2466–2472. This
manuscript also reports the crystal structure of small molecule analogs of
polymer catalyst 4; The precursor (1) for the synthesis of polymer catalyst 4
was synthesized using our modified procedure (c) Venkat Reddy, C.; Verkade, J.
G. J. Org. Chem. 2007, 72, 3092–3096. The polymer catalyst 5 was prepared
analogously to 4 except that FibreCat was used as the starting material in stead
of Merrifield resin.
20. General procedure for room-temperature transesterifications and amidations: A
round bottom centrifuge tube containing catalyst 4 (6.7 mol % based on the
percent phosphorus determined by elemental analysis or as otherwise stated
in the footnotes of the corresponding Tables) was equipped with a rubber
septum and two magnetic stir bars for extra stirring efficiency. After flushing
the tube with argon, it was charged via syringe with a higher ester (5 mmol)
and MeOH (5 mL) for transesterifications. For amidations, the tube was
similarly charged with an ester (2 mmol), amino alcohol (2 mmol), and THF
(3 mL). The reaction mixture was vigorously stirred at room temperature (23–
25 °C) and progress of the reaction was monitored by thin layer
chromatography. Upon completion of the reaction, the reaction mixture was
filtered through Whatman No. 1 filter paper and washed with 3 ꢀ 10 mL of
THF. The combined organics were subjected to short-path silica gel
chromatography (0–20% ethyl acetate in hexanes v/v) to obtain an
analytically pure product. In the case of amides, products were purified
using a short-path silica gel column eluted with dichloromethane/methanol
(95:5, v/v).
Acknowledgment
The authors are grateful to the National Science Foundation for
grant support.
Supplementary data
Supplementary data (general considerations, references to
known compounds and 1H, 13C NMR spectra and HRMS reports
of all compounds prepared) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.09.102.
References and notes
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Spectral data for selected products: 3-fluoro-N-(2-hydroxyethyl)-benzamide
(Table 3, entry 6): 1H NMR (CDCl3, 300 MHz): d 7.46–7.53 (m, 2H), 7.34–7.41
(m, 1H), 7.15–7.21 (m, 1H), 6.80 (br s, 1H), 3.82 (m, 2H), 3.60 (m, 2H), 2.91 (br
s, 1H) ppm; 13C NMR (CD3OD, 100.6 MHz): d 170.4, 166.7, 164.2, 139.5, 139.4,

V. R. Chintareddy et al. / Tetrahedron Letters 52 (2011) 6523–6529
6529
132.9, 132.9, 125.6, 120.9, 120.7, 116.8, 116.6, 62.9, 45.1 ppm; FTIR (in CHCl3):
removed from the separated supernatant liquid via a rotavapor apparatus. The
methyl benzoate remaining was purified using a short-path silica gel column
eluted with hexanes (1.94 g, 95%). The centrifuged catalyst, which was still
submerged under a minimal volume of methanol/methyl benzoate solution,
was used for recycling by charging fresh reactants.
1639 (C@O) cmꢁ1
; HRMS m/z Calcd for C9H10FNO2: 183.06956. Found:
183.06977. 4-Chloro-N-(2-hydroxyethyl)-benzamide (Table 3, entry 8): 1H
NMR (CDCl3, 400 MHz, 40 °C): d 7.71 (d, J = 8.0 Hz), 7.41 (d, J = 8.0 Hz), 6.58 (br
s, 1H), 3.82 (m, 2H), 3.62 (m, 2H), 2.43 (br s, 1H) ppm; 13C NMR (CDCl3,
100.6 MHz):
d
167.8, 138.2, 132.7, 129.1, 128.7, 62.1, 43.0 ppm; FTIR (in
21. Movassaghi, M.; Schmidt, M. A. Org. Lett. 2005, 7, 2453–2456. and references
cited therein.
CHCl3): 1639 (C@O) cmꢁ1; HRMS m/z Calcd for C9H10ClNO2: 199.04001. Found:
199.04039. Mp: 116–117 °C (lit. 118–119 °C).25
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25. Phillips, A. P. J. Am. Chem. Soc. 1951, 73, 5557–5559.
Procedure for transesterification of glyceryl tribenzoate and recyclability protocol:
A centrifuge tube containing catalyst 4 (20 mol %) was equipped with a rubber
septum and two magnetic stirring bars for increased stirring efficiency. After
flushing the tube with argon, 2.02 g (5 mmol) of glyceryl tribenzoate and
15 mL of MeOH were charged to the tube separately via syringe. The progress
of the reaction was monitored by TLC. Upon completion of the reaction, the
reaction mixture was centrifuged and the vast majority of the supernatant was
carefully removed via syringe to avoid disturbing the catalyst. The catalyst was
further washed with 15 mL of methanol and the combined solvents were