Silica-supported tetramethylguanidine: An efficient solid base for aldol-type coupling of aldehydes with ethyl diazoacetate

Article abstract of DOI:10.1055/s-2008-1072769

Silica-supported tetramethylguanidine catalyst was prepared and effectively used in the aldol-type coupling of aldehydes with ethyl diazoacetate to afford the corresponding α-diazo-β-hydroxy esters in good to excellent yields. The catalyst was quantitatively recovered from the reaction by a simple filtration and reused for a number of cycles with almost consistent activity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072769

LETTER
1283
Silica-Supported Tetramethylguanidine: An Efficient Solid Base for
Aldol-Type Coupling of Aldehydes with Ethyl Diazoacetate
S
ilica-Support
r
ed Tetra
a
m
ethylguan
v
idine in R. Likhar,* Sarabindu Roy, Moumita Roy, M. S. Subhas, M. Lakshmi Kantam
Indian Institute of Chemical Technology, Inorganic & Physical Chemistry Division, Hyderabad 500007, India
Fax +91(40)27160921; E-mail: plikhar@iict.res.in
Received 31 January 2008
O
Abstract: Silica-supported tetramethylguanidine catalyst was pre-
pared and effectively used in the aldol-type coupling of aldehydes
with ethyl diazoacetate to afford the corresponding a-diazo-b-hy-
droxy esters in good to excellent yields. The catalyst was quantita-
tively recovered from the reaction by a simple filtration and reused
for a number of cycles with almost consistent activity.
O
HMDS
O Si
O
Cl
O Si
O
Cl
OSiMe3
OH
2
1
O
Key words: silica, tetramethylguanidine, aldol, a-hydroxy-b-di-
azoesters, reusable catalyst
N
TMG
Et3N
O Si
O
N
Et3NHCl
+
N
SiMe
O
3
a-Diazo carbonyl compounds1 are synthetically important
intermediates in the production of amino alcohols and ac-
ids. Diazo transfer reactions of carbonyl compounds are
usually used for the synthesis of a-diazo carbonyl com-
pounds.2 Condensation of acyldiazomethane with alde-
hydes is another route to obtain a-diazo carbonyl
compounds but it requires deprotonation of the acyldiazo-
methane. This is generally carried out by using strong
bases, such as butyllithium,3 lithium diisopropylamide
(LDA),4 sodium hydride,5 potassium hydroxide,6 1,8-di-
azabicyclo[5.4.0]undec-7-ene (DBU),7 quaternary ammo-
nium hydroxide,8 and potassium tert-butoxide (t-BuOK)9
etc. However, some of the methods require low tempera-
tures, absolute anhydrous conditions or expensive re-
SiO2-TMG
Scheme 1 Preparation of SiO2-TMG catalysts by stepwise functio-
nalization of chloropropyl-modified silica
of aldehydes with ethyl diazoacetate under mild condi-
tions. Guanidines are versatile strong bases and are good
candidates for immobilization. Among various supports
used to obtain heterogeneous catalysts, we have selected
silica as a support because silica displays many advanta-
geous properties: excellent stability (chemical and ther-
mal), high surface area, good accessibility, and organic
groups can be robustly anchored to the surface, to provide
catalytic centers.14
agents. More importantly all these homogeneous systems The preparation of tetramethylguanidine-functionalized
suffer from the nonreusability of the catalyst and waste silica involved the trimethylsilylation of the surface hy-
disposal problem.
droxyl groups of chloropropyl-modified silica 1 by hexa-
methyldisilazane (HMDS), a powerful silylating agent, to
form trimethylsilyl chloropropyl modified silica (SiO2-
TMS-Cl), 2. Subsequent treatment with 1,1,3,3-tetra-
methylguanidine (TMG) and triethylamine afforded the
final catalyst, SiO2-TMG and triethylammonium chloride.
The stepwise grafting of guanidine units onto chloropro-
pyl-modified silica is presented in Scheme 1. The grafting
of TMG onto silica support was characterized by FTIR
and chemical analysis. FTIR spectrum of SiO2-TMG
shows: (i) a broad band centered at 3420 cm–1 (assigned to
O–H stretching frequency of unprotected silanol groups
and adsorbed water), (ii) a band at 2957 cm–1 assigned to
tetrahedral carbon of the organic pendant group attached
to silica surface, (iii) a band at 1680 cm–1 assigned to an-
gular vibration of water molecules, (iv) a band at 1463
cm–1 assigned to C–N stretching of tetramethylguanidine,
(v) a band at 1099 cm–1 assigned to siloxane (Si–O–Si)
stretching, and a band at 955 cm–1 assigned to the stretch-
ing frequency of Si–O group. This is in agreement with
earlier studies of silica-guanidine composite.13a,b The
Owing to the increasing environmental pressure, current
interest is focused on the development of environmentally
friendly solid catalysts for clean processes to conform to
the concept of green technology. The development of het-
erogeneous catalysts for fine chemicals synthesis has be-
come a major area of research recently, as the potential
advantages of these materials (simplified recovery and re-
usability, the potential for incorporation in continuous re-
actors and microreactors) over homogeneous systems can
make a major impact on the environmental performance
of a synthesis.10 Recently we reported efficient synthesis
of a-diazo-b-hydroxy esters catalyzed by reusable nanoc-
rystalline magnesium oxide (Nano-MgO)11 and magne-
sium–lanthanum mixed oxide (Mg/LnO).12
We herein report the use of tetramethylguanidine-func-
tionalized silica (SiO2-TMG)13 for the aldol-type coupling
SYNLETT 2008, No. 9, pp 1283–1286
Advanced online publication: 07.05.2008
x
x.
x
x.
2
0
0
8
DOI: 10.1055/s-2008-1072769; Art ID: D03308ST
© Georg Thieme Verlag Stuttgart · New York

1284
P. R. Likhar et al.
LETTER
Table 1 Catalyst Screening for the Aldol-Type Coupling of 4-Bro-
mobenzaldehyde and EDAa,16
SiO2
SiO2
N
N
OH
NH2
CHO
CO2Et
CO2Et
catalyst
+
N2
N2
SiO2-NH2
SiO2-IMZ
solvent, r.t.
Br
Br
Entry
Catalyst (50 mg)
SiO2-NH2
SiO2-IMZ
SiO2-TMG
SiO2
Time (h)
Isolated yield (%)
N
SiO2
1
2
2
2
2
2
2
2
2
2
0
N
N
2
0
3
92
0
SiO2-TMG
4
Figure 1 Different silica-based basic catalysts
5
MgO
25
55
0
loading of TMG unit was ascertained by CHN analysis
(0.16 mmol/g).
6b
8
LDH-CO3
no catalyst
Et3N
Various silica-based catalysts (Figure 1)15 were then
screened for the condensation of 4-bromobenzaldehyde
and ethyl diazoacetate (EDA) at room temperature
(Table 1)16 and it was found that SiO2-TMG provided the
maximum yield of the product. 3-Aminopropyl-function-
alized silica (SiO2-NH2) and imidazole-functionalized sil-
ica (SiO2-IMZ) were found to completely inactive.
Commercially available magnesium oxide (MgO) and a
layered double hydroxides of Mg and Al (Mg/Al = 3:1)17
provided moderate yield of the product. In absence of any
catalyst no product formation was observed. When we
carried out the same reaction with Et3N (2 mol%) and
TMG (2 mol%), Et3N was found to be less effective (5%) Entry
whereas TMG afforded 95% product yield in two hours.
To verify whether the reaction was catalyzed by loosely
bound TMG or Et3N liberated in DMSO, we first stirred
SiO2-TMG in DMSO for one hour and filtered off the cat-
alyst. Then the filtrate was treated with 4-bromobenzalde-
hyde and EDA and stirred for one hour. No product
formation was observed, which rules out the possibility of
catalysis by loosely bound TMG or Et3N.
9c
10c
5
TMG
95
a Reaction conditions: aldehyde (0.5 mmol), EDA (1.2 equiv), cata-
lyst (50 mg), DMSO (1 mL), r.t.
b Layered double hydroxides of Mg and Al (Mg/Al = 3:1).
c Catalyst (2 mol%) was used.
Table 2 Solvent Effect on the Aldol-Type Coupling of 4-Bro-
mobenzaldehyde with EDA using SiO2-TMG Catalysta,16
Solvent (1 mL)
MeCN
THF
Isolated yield (%)
1
20
10
35
45
40
42
92
78
2
3
4
5
6
7
8
dioxane
MeOH
toluene
H2O
The effect of solvents in the SiO2-TMG-catalyzed con-
densation of 4-bromobenzaldehyde and EDA was investi-
gated to optimize the reaction conditions. The
condensation of 4-bromobenzaldehyde and EDA was car-
ried out using 1.6 mol% of catalyst relative to substrate
(aldehyde) in various solvents at room temperature. From
Table 2, it is evident that DMSO was the most effective
solvent in terms of yield (Table 2, entry 7). DMF also af-
forded good yields of the product. Toluene, water, metha-
nol and dioxane gave moderate yields whereas poor yields
were observed in THF and acetonitrile.
DMSO
DMF
a Reaction conditions: Aldehyde (0.5 mmol), EDA (1.2 equiv), sol-
vent (1.0 mL), SiO2-TMG (50 mg, 1.6 mol%), r.t., 1 h.
the para position reacted at a slower rate compared to ar-
omatic aldehydes containing electron-donating groups in
a meta position (Table 3, entries 5–7). Highly electron-
rich 4-benzyloxy-3-methoxybenzaldehyde afforded high
yield of the product albeit in long reaction time (Table 3,
entry 8). Sterically hindered 2-bromobenzaldehyde was
found to be less reactive (Table 3, entry 9) and the 2-meth-
oxybenzaldehyde was found to be completely unreactive
(Table 3, entry 10). Excellent yields were obtained in the
reactions of N-heterocyclic aldehydes (Table 3, entries 11
and 12). Aliphatic aldehydes also afforded the corre-
To expand the scope of the current protocol, a variety of
aldehydes were treated with EDA under the optimized re-
action conditions and the results are summarized in
Table 3. Aromatic aldehydes with electron-withdrawing
moieties in the para position afforded excellent yields of
the products in very short times (Table 3, entry 4). Aro-
matic aldehydes containing electron-donating groups in
Synlett 2008, No. 9, 1283–1286 © Thieme Stuttgart · New York

LETTER
Silica-Supported Tetramethylguanidine
1285
observed. This observation clearly proves that the cou-
pling of aldehydes and EDA is catalyzed by heteroge-
neous SiO2-TMG catalyst.
Table 3 Aldol-Type Coupling of Aldehydes and EDA in the Pres-
ence of SiO2-TMG Catalysta,16
OH
EtO2C
SiO2-TMG (50 mg)
EtO2C
In conclusion, we have developed an efficient heteroge-
neous protocol for the coupling of aldehydes and ethyl di-
azoacetate to afford the corresponding a-diazo-b-hydroxy
esters using silica-immobilized tetramethylguanidine cat-
alyst, which can be easily separated from the reaction
mixture and reused with consistent activity.
RCHO
+
R
N2
DMSO, r.t.
N2
Entry
1
R
Time (h)
Isolated yield (%)
Ph
2
90
92
92
92
88
85
95
82
60
n.r.b
90
92
92
90
67
2
4-BrC6H4
4-ClC6H4
4-NO2C6H4
4-MeC6H4
2
Acknowledgment
3
2
S.R. and M.S.S. thank CSIR and M.R. thanks UGC for providing
research fellowships.
4
1.5
6
5
6
4-MeOC6H4
3-PhOC6H4
3-MeO-4-BnOC6H3
2-BrC6H4
6
References and Notes
(1) Doyle, M. P.; McKervey, M. A. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley-
Interscience: New York, 1998.
(2) (a) Regitz, M.; Maas, G. Diazo Compounds, Properties and
Synthesis; Academic Press: Orlando, FL, 1986.
(b) Kruglaya, O. A.; Vyazankin, N. S. Russ. Chem. Rev.
(Engl. Transl.) 1980, 49, 357. (c) Moody, C. J.; Mortt, C. N.
Synthesis 1998, 1039. (d) Wang, J.; Yao, W. Org. Lett.
2003, 5, 1527.
(3) (a) Schöllkopf, U.; Frasnelli, H.; Hoppe, D. Angew. Chem.,
Int. Ed. Engl. 1970, 9, 300. (b) Schöllkopf, U.; Banhidai,
B.; Frasnelli, H.; Meyer, R.; Beckhaus, H. Justus Liebigs
Ann. Chem. 1974, 1767.
(4) (a) Pellicciari, R.; Natalini, B. J. Chem. Soc., Perkin Trans.
1 1977, 1882. (b) Pellicciari, R.; Natalini, B.; Sadeghpour,
B. M.; Marinozzi, M.; Snyder, J. P.; Williamson, B. L.;
Kuethe, J. T.; Padwa, A. J. Am. Chem. Soc. 1996, 118, 1.
(c) Moody, C. J.; Taylor, R. J. Tetrahedron Lett. 1987, 28,
5351.
7
2
8
12
24
24
2
9
10
11
12
13
14
15
2-MeOC6H4
2-pyridine
4-pyridine
2.5
1.5
2
cyclohexyl
Me(CH2)3
PhCH=CH
6
a Reaction conditions: aldehyde (0.5 mmol), EDA (1.2 equiv), DMSO
(1.0 mL), SiO2-TMG (50 mg, 1.6 mol%), r.t.
b No reaction.
(5) Jiang, N.; Qu, Z.; Wang, J. Org. Lett. 2001, 3, 2989.
(6) (a) Wenkert, E.; Pherson, A. A. M. J. Am. Chem. Soc. 1972,
94, 8084. (b) Burkoth, T. L. Tetrahedron Lett. 1969, 57,
5049. (c) Woolsey, N. F.; Khalil, M. H. J. Org. Chem. 1972,
37, 2405.
Table 4 Reusability Study of SiO2-TMG Catalysta
Run
1
2
3
4
5
6
(7) (a) Jiang, N.; Wang, J. Tetrahedron Lett. 2002, 43, 1285.
(b) Xiao, F.; Liu, Y.; Wang, J. Tetrahedron Lett. 2007, 48,
1147.
(8) Varala, R.; Ramu, E.; Nuvula, S.; Adapa, S. R. Tetrahedron
Lett. 2006, 47, 877.
Yield (%)
92
92
90
91
90
89
a Reaction conditions: 4-bromobenzaldehyde (0.5 mmol), EDA (1.2
equiv), SiO2-TMG (50 mg, 1.6 mol%), DMSO (1 mL), r.t., 2 h.
(9) Sreebdhar, B.; Balasubrahmanyam, V.; Sridhar, C.; Prasad,
M. N. Catal. Commun. 2005, 6, 517.
sponding a-diazo-b-hydroxy esters in excellent yields in
short durations (Table 3, entries 13 and 14). a,b-Unsatur-
ated aldehydes such as cinnamaldehyde gave good yields
of the product (Table 3, entry 15).
(10) (a) Mizuno, N.; Misono, M. Chem. Rev. 1998, 98, 199.
(b) Sartori, G.; Ballini, R.; Bigi, F.; Bosica, G.; Maggi, R.;
Righi, P. Chem. Rev. 2004, 104, 199.
(11) Kantam, M. L.; Chakrapani, L.; Ramani, T. Tetrahedron
Lett. 2007, 48, 6121.
The recovery and reusability of catalyst was demonstrated
by using simple workup procedure. The catalyst was sep-
arated by simple filtration and washed with ethyl acetate
followed by water and finally with acetone and air-dried.
The recovered catalyst was used in the next run and al-
most consistent activity was noticed for six consecutive
cycles (Table 4). To check the nature of heterogeneity of
the catalysis we filtered off the catalyst from the reaction
of 4-bromobenzaldehyde and EDA after 20 minutes (43%
conversion) and continued the reaction for an additional
two hours. No further enhancement in the conversion was
(12) Kantam, M. L.; Balasubrahmanyam, V.; Kumar, K. B. S.;
Venkanna, G. T.; Figueras, F. Adv. Synth. Catal. 2007, 349,
1887.
(13) (a) Faria, E. A.; Ramalho, H. F.; Marques, J. S.; Suarez, P.
A. Z.; Prado, A. G. S. Appl. Catal. A: Gen. 2008, 338, 72.
(b) DeOliveira, E.; Torres, J. D.; Silva, C. C.; Luz, A. A. M.;
Bakuzis, P.; Prado, A. G. S. J. Braz. Chem. Soc. 2006, 17,
994. (c) Blanc, A. C.; Macquarrie, D. J.; Valle, S.; Renard,
G.; Quinn, C. R.; Brunel, D. Green Chem. 2000, 2, 283.
(14) Corma, A.; Garcia, H. Adv. Synth. Catal. 2006, 348, 1391.
(15) Preparation of Silica-Based Catalysts; SiO2-TMG: 3-
Chloropropyl-modified silica, 1 (5 g, 2.5% loading, Aldrich)
Synlett 2008, No. 9, 1283–1286 © Thieme Stuttgart · New York

1286
P. R. Likhar et al.
LETTER
was dispersed in dry hexane (50 mL) under nitrogen and
then hexamethyldisilazane (HMDS, 5 mL) was added to the
dispersion and refluxed for 8 h, cooled to r.t., filtered and
washed with copious amount of hexane to get the
compounds are as follows:
2-Diazo-3-hydroxy-3-(3-phenoxyphenyl)propionic Acid
Ethyl Ester (Table 3, entry 7): FTIR (neat): 3441, 2982,
2099, 1680, 1586, 1483, 1291, 1243, 1113, 756 cm–1. 1H
NMR (300 MHz, CDCl3): d = 7.20–7.37 (m, 3 H), 7.00–7.15
(m, 3 H), 6.84–6.99 (m, 3 H), 5.82 (s, 1 H), 4.23 (q, J = 6.8
Hz, 2 H), 3.72 (br s, 1 H), 1.28 (t, J = 6.8 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): d = 166.2, 157.7, 157.0, 141.0, 130.0,
129.8, 123.4, 120.5, 118.9, 118.5, 116.2, 68.4, 61.2, 14.37
(one quaternary C was not observed). MS–ESI: m/z = 335
[M + Na]. Anal Calcd for C17H16N2O4: C, 65.38; H, 5.16; N,
8.97. Found: C, 65.32; H, 5.19; N, 8.94.
3-(4-Benzyloxy-3-methoxyphenyl)-2-diazo-3-hydroxy-
propionic Acid Ethyl Ester (Table 3, entry 8): FTIR (KBr):
3446, 2932, 2104, 1674, 1513, 1394, 1229, 1114, 740 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.19–7.50 (m, 5 H), 6.95
(s, 1 H), 6.83 (s, 2 H), 5.79 (s, 1 H), 5.13 (s, 2 H), 4.29 (q,
J = 6.8 Hz, 2 H), 3.91 (s, 3 H), 3.1 (br s, 1 H), 1.34 (t, J = 6.8
Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 166.4, 150.0,
148.2, 137.0, 131.8, 128.5, 127.7, 127.2, 117.9, 114.1,
109.4, 71.0, 68.5, 61.1, 56.1, 14.4 (one quaternary C was not
observed). MS–ESI: m/z = 357 [M + 1]. Anal. Calcd for
C19H20N2O5: C, 64.04; H, 5.66; N, 7.86. Found: C, 64.01; H,
5.68; N, 7.90.
trimethylsilylated chloropropyl modified silica 2.
Trimethylsilylated chloropropyl modified silica, 2 (1 g) was
stirred with tetramethylguanidine (TMG, 2 mmol) and Et3N
(1 mmol) in MeOH (20 mL) under nitrogen at 110 °C for 24
h. Afterwards the solid was separated by filtration and once
again washed with toluene using Sohxlet for 24 h to afford
SiO2-TMG (loading of TMG: 0.16 mmol/g, calculated from
elemental analysis). SiO2-IMZ was prepared in a similar
fashion using imidazole (loading of IMZ: 0.14 mmol/g,
calculated from elemental analysis). SiO2-NH2 (loading 1
mmol/g) was purchased from Aldrich.
(16) General Procedure for Aldol-Type Coupling of
Aldehydes with EDA: A mixture of aldehyde (0.5 mmol),
EDA (1.2 equiv), and SiO2-TMG (50 mg) in DMSO (1 mL)
was stirred in a round-bottom flask at r.t. After completion
of the reaction, as monitored by TLC, the mixture was
diluted with EtOAc (10 mL) and the catalyst was filtered off.
The filtrate was washed with sat. aq NH4Cl solution,
followed by brine. The organic layer was dried over
anhydrous Na2SO4 and the solvent was evaporated under
reduced pressure to get the crude product. The crude product
was purified by chromatography on silica gel using hexane–
EtOAc mixture as eluent to afford the corresponding a-
diazo-b-hydroxy esters. Spectroscopic data of the new
(17) Fujita, N.; Motokura, K.; Mori, K.; Mizugaki, T.; Ebitani,
K.; Jitsukawa, K.; Kaneda, K. Tetrahedron Lett. 2006, 47,
5083.
Synlett 2008, No. 9, 1283–1286 © Thieme Stuttgart · New York

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