Aldol condensation of amides using phosphazene-based catalysis

Article abstract of DOI:10.1016/j.tetlet.2012.07.129

We have developed a new method for the direct aldol condensation of unactivated amides using 1,3,5-triazo-2,4,6-triphosphorine-2,2,4,4,6,6- hexachloride (TAPC)-based phosphorous/SO₄^2- catalysis. The SO₄^2- species in a reaction mixture enhances the reaction rate of the catalysis. In principle, no metal sources are required for the generation of the catalyst, and there is no requirement for the use of stoichiometric quantities of an acid or base. This catalyst system is operative under relatively acidic conditions. One major advantage of carrying out the reaction under acidic conditions is that both aldehydes and acetals are capable of undergoing carbon-carbon bond formation at the α-carbon of amide carbonyl groups through dehydration.

Full text of DOI:10.1016/j.tetlet.2012.07.129

Tetrahedron Letters 53 (2012) 5445–5448
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Aldol condensation of amides using phosphazene-based catalysis
Siong Wan Foo a, Shun Oishi a, Susumu Saito a,b,
⇑
a Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
b Institute for Advanced Research, Nagoya University, Chikusa, Nagoya 464-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a new method for the direct aldol condensation of unactivated amides using 1,3,5-
2À
Received 4 May 2012
Revised 23 July 2012
Accepted 30 July 2012
Available online 4 August 2012
triazo-2,4,6-triphosphorine-2,2,4,4,6,6-hexachloride (TAPC)-based phosphorous/SO4
catalysis. The
2À
SO4 species in a reaction mixture enhances the reaction rate of the catalysis. In principle, no metal
sources are required for the generation of the catalyst, and there is no requirement for the use of stoichi-
ometric quantities of an acid or base. This catalyst system is operative under relatively acidic conditions.
One major advantage of carrying out the reaction under acidic conditions is that both aldehydes and ace-
Keywords:
Amide
Aldol condensation
Non-metal-based catalysis
TAPC
tals are capable of undergoing carbon–carbon bond formation at the
through dehydration.
a-carbon of amide carbonyl groups
Ó 2012 Elsevier Ltd. All rights reserved.
Acidic conditions
Amides1a are abundant functional groups that are found in
many polymeric materials and their respective monomers (e.g.,
TAPC and H2SO4 could act synergistically to accelerate the reaction
rate. In comparison, examination of typical Brønsted acids such as
TfOH, TsOH, or HCl in place of H2SO4 brought a lower conversion of
2a (entries 19–21). A range of metal sulfates MnSO4 (n = 2 for
M = Li, Na, K, Cs; n = 1 for M = Cu) was also tested in place of
H2SO4 in order to explore more neutral pH conditions. Among
a
,b-unsaturated carboxamides, e-caprolactam). They also exist as
potent pharmacophores,1d,e,g–i as well as in repeating units of poly-
peptide macromolecules, and thus are accessible by many syn-
thetic methods.1b,c,f,j,k However, catalysis of amides2 is frequently
hampered and is of significant challenge, given a high thermody-
namic stability3 relevant to the least electrophilic carbonyl carbon
them,
a catalytic amount of Li2SO4 (20 mol %) or Na2SO4
(10 mol %) ensured the smoothest conversion (3aa: >80%) (entries
9 and 11). A series of MHSO4 more effectively promoted the catal-
ysis than M2SO4 (entries 8, 10, 12, and 14).
and the lowest acidity of the
a-CH of amide groups among car-
bon(x)yl functionalities.1a In particular, catalytic carbon elongation
via the corresponding enolate (enol) formation and subsequent al-
dol reaction with aldehydes has remained elusive.4–6 Indeed, poor
reactivity of amides represents one of the biggest issues in aldol
chemistry since its discovery in 1838,7 although an amide enolate
was previously formed through a Vilsmeier-Haack-type salt using
benzoyl chloride.5a Here, we report a new catalyst system based
on the use of 1,3,5-triazo-2,4,6-triphosphorine-2,2,4,4,6,6-hexa-
chloride8,9 (TAPC), which is effective for the aldol condensation
of unactivated amides (Scheme 1).
The reaction was accelerated when one of the counter-anions
2À
was SO4 rather than ClÀ in DMA. In contrast, partially modified
TAPC as phosphonate, 4a10 and 4b,10 also facilitated the reaction
but less effectively (entries 22 and 23). Stepwise replacement of
the Cl groups by bis(phenoxide) resulted in a steady reduction in
reaction rate. The effectiveness of the polymer analogue of TAPC,
poly(dichlorophosphazene)11 (4c), compares well with that of
TAPC (entry 24). A combined use of H2SO4 and a carbon analogue
of TAPC, 2,4,6-trichloro[1,3,5]triazine12 (TCT), resulted in a slower
reaction rate even with an elevated temperature and a higher load-
ing of the Brønsted acid (entry 26). No reaction was observed with
TCT alone (entry 25). It is known that TAPC or TCT in aqueous
Treatment of a N,N-dimethylacetamide (1a: DMA: ca. 11 equiv)
solution of benzaldehyde (2a) with TAPC (10 mol %; [TAPC]0 =
0.09 M) and concn H2SO4 (10 mol %: 99.999% purity) at 120 °C for
24 h under argon followed by column chromatography gave
a,b-
unsaturated amide 3aa in an isolated yield of 97% (Table 1, entry
7). The corresponding b-hydroxy amide was not detected. The
use of TAPC or H2SO4 alone gave 3aa in 40% and 4% (entries 1
and 4), respectively. This result suggests that a combination of
cat. TAPC
O
O
cat. M1M2SO4
120 200 °C
R1
R1
OHC
+
H2O
+
R4
N
N
R4
R2 R3
1a
R2 R3
M1, M2 = H or metal
c
2a l
3aa 3cb
⇑
Corresponding author. Tel./fax: +81 52 789 5945.
E-mail address: saito.susumu@f.mbox.nagoya-u.ac.jp (S. Saito).
Scheme 1. General scheme for the aldol condensation of amides.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.129

5446
S. W. Foo et al. / Tetrahedron Letters 53 (2012) 5445–5448
Table 1
Table 2
Aldol condensation of 1a with 2aa
Catalytic aldol condensation of DMA with various aldehydesa
Entry
1
Aldehyde 2
Product 3
Yieldb of 3 %
cat. Additive 1
cat. Additive 2
O
O
OHC
+
N
N
Ph
Conditions
99
H2O
1a
2a
3aa
X = p-Cl (2b)
X = p-Cl (3ab)
X = o-Cl (3ac)
X = p-MeO (3ad)
X = o-MeO (3ae)
X = p-Me (3af)
X = p-NO2 (3ag)
Entry Additive 1 Additive 2
Conditions (°C, h) Yieldb of 3aa (%)
2
3
4
5
6
X = o-Cl (2c)
77
70
51
71
50
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
TAPC
TAPC
None
None
None
None
TAPC
TAPC
TAPC
TAPC
TAPC
TAPC
TAPC
TAPC
TAPC
TAPC
TAPC
TAPC
TAPC
TAPC
TAPC
4a
None
None
HClc
H2SO4
H3PO4
120, 24
140, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
120, 24
140, 24
140, 24
40
76
14
4
<1
6
97
96
X = p-MeO (2d)
X = o-MeO (2e)
X = p-Me (2f)
X = p-NO2 (2g)
d
e
f
H2SO4 + H3PO4
H2SO4
Li2SO4 + H2SO4
Li2SO4
(3ah)
(3ai)
7
b-NaphCHO (2h)
70
71 (91)i
93
(2i)
42 (45)c
39d
NaHSO4ÁH2O
8
9
Na2SO4
82
70
64
85
69
60
58
80
59
48
47
74
KHSO4
K2SO4
(2j)
(3aj)
f
Cs2SO4 + H2SO4
Cs2SO4
CuSO4
Cu(OTf)2
(3ak)
10
c-HexCHO (2k)
58
f
CuSO4 + H2SO4
TfOHg
TsOHg
HClg
H2SO4
H2SO4
H2SO4
None
a
Unless otherwise specified, reactions were carried out using TAPC (10 mol %),
H2SO4 (10 mol %), 2 (1 mmol), and anhydrous DMA (1a: 1 mL) at 120 °C for 24 h
under Ar.
b
Of isolated, purified products.
Li2SO4 (20 mol %) in place of H2SO4; reaction time of 48 h.
Cs2SO4 (10 mol %) in place of H2SO4.
c
4b
32
4ch
86 (75)j
<1
d
TCT
TCT
g
H2SO4
78
a
Unless otherwise specified, the reaction was carried out using 2a (1 mmol),
additive 1 and 2 (10 mol % each, based on molar amount of 2a: [2a]0 = ca. 0.9 M) in
generally serve as building blocks of many synthetic intermediates,
UV absorbers for cosmetics, and anti-allergic agents.5l The 1,4-
addition was not observed using 2i, and the diene part of product
3ai was tolerated under less acidic conditions (entry 8); however,
prolonged reaction time diminished the yield due to product
decomposition. More neutral pH conditions displayed a greater
promise in terms of the reactions of an acid-labile aldehyde such
as 2j (entry 9).
DMA (1.0 mL) under Ar.
b
Of isolated, purified product based on 2a, determined by 1H NMR using 1,1,2,2-
tetrachloroethane as an internal standard.
c
60 mol %. A 2 M Et2O solution of HCl was used.
30 mol %.
10 + 30 mol %.
5 mol % each.
20 mol %. A 2 M Et2O solution of HCl was used.
Dichlorophosphazene units correspond to ca. 30 mol %.
20 mol % of Li2SO4.
Dichlorophosphazene units correspond to ca. 10 mol %.
d
e
f
g
h
i
a-Elongated amides should be potentially capable of undergo-
j
ing aldolization. When a higher reaction temperature (140 °C)
was applied for 1b, the corresponding aldol adduct 3bb was ob-
tained (Scheme 2). The catalysis was also compatible with primary
amine-derived amide 1c, giving 3cb a major product. Here we can
see an advantage of acidic conditions over the basic conditions pre-
viously used for the aldolization of activated amides,4 in which
abstraction of the CONH hydrogen (pKa = ꢀ25 in DMSO)3 may re-
tard or prevent a desirable aldol catalysis.
organic solvents was susceptible to undergo hydrolysis at 30 °C or
at higher temperatures.7a,13 In our case, however, catalytic species
remained active at 120 °C even in the presence of water, which
gradually accumulates as the reaction proceeds. Indeed, when
the fully hydrolyzed derivative H3PO4 (30 mol %) alone or in the
presence of H2SO4 (10 mol %) was used, almost no reaction took
place between 1a and 2a (entries 5 and 6).
TAPC (10 mol %)
O
O
H2SO4 (10 mol %)
R2
+
2b
Cl Cl
Cl
N
N
p-Cl(C6H4)
120–140 °C
24 h
O
O
O
O
R1
R1 R2
P
P
P
Cl
Cl
P
N
P
N
P
H2O
N
N
N
P
N
P
N
P
N
P
1
: R = Me; R2 = Me
3bb: 14%
Cl
Cl
Cl
Cl
N
O
1b
1c
Cl
Cl
Cl
Cl
Cl
Cl
n
N
Cl
N
Cl
: R1 = R2 = H
N
N
3cb: 57%
O
4c
TAPC
TCT
4a
4b
Scheme 2. Use of other amides.
TAPC (10 mol %)
O
O
H2SO4 (10 mol %)
Other examples of aldol reactions using various aldehydes are
Me
N
+
1a
listed in Table 2. In most cases the optimized experimental condi-
tions were used, with slight modification in others. The reaction
showed a broad substrate scope with respect to the aldehyde com-
ponent. In all runs, the corresponding b-hydroxy amides were not
detected by 1H NMR. N,N-Dimethylcinnamamides such as 3ah
O
O
200 °C, 6 h
Me
H2O
3al: 45%a
2l
Scheme 3. Synthesis of acrylamide derivative. aBased on one-third molar amount
of 2l.

S. W. Foo et al. / Tetrahedron Letters 53 (2012) 5445–5448
5447
Acrylamide 3al was readily produced upon reaction of 1,3,5-tri-
oxane (2l) with 1a albeit requiring an elevated temperature
(Scheme 3). Use of the polymer of formaldehyde, paraformalde-
hyde, also resulted in a comparable yield of 3al (40%, based on
the molar amount of CH2O) under otherwise identical conditions.
Again the acidic conditions used here are more beneficial for the
activation of 2l than basic conditions, under which acetals are gen-
erally less reactive.
In order to get an insight into a likely reaction mechanism, ki-
netic experiments were carried out using TAPC/H2SO4 (10 mol %
each) and 2b in solvent 1a or 1a-d9 at 120 °C ([TAPC]0 = 0.09 M). Po-
sitive kinetic isotope effects (kH/kD ꢀ 1.2–1.5) were consistently ob-
served at all time in the periods of sampling (i.e., up to 24 h).14 This
observation suggests that deprotonation is one of the rate-deter-
mining steps of the reaction. A set of time-dependent 1H NMR spec-
required.17 Although at present the structure of a catalyst precur-
sor is not clear, elaboration of a new catalyst based on phosphorous
species and amine components for amide aldol reaction is now
underway.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Re-
search B (General) from JSPS and Scientific Research on Priority
Areas ‘Advanced Molecular Transformations of Carbon Resource’
from MEXT. S.W.F. was supported by the GCOE in chemistry, Na-
goya University (NU). The authors wish to thank Dr. K. Oyama
and Y. Maeda (Chemical Instrumentation Facility of RCMS) for
NMR and ESI-MS measurements and Professor R. Noyori (NU & RI-
KEN) for fruitful discussions.
tra of
a reaction mixture consistently showed the signals
corresponding to 1a, 2b, and product 3ab, along with a set of negli-
gible small signals. Hence an attempt to trace an amide enolate
intermediate in the absence of 2b by a set of NMR analyses was car-
ried out. When a 1:1 mixture of TAPC and DMA without any sol-
vents was heated at 120 °C for 1 h, 1H and 13C NMR showed
entire consumption of free DMA with a set of multiplied signals,
by which it was difficult to envision an enolate structure. In con-
trast, a similar procedure for aging enolate, in which a 1:1:1 mix-
ture of TAPC, DMA, and NaHSO4 was used, features a clear peak
set [in pyridine-d5 at 25 °C: 1H NMR (600 MHz) d 4.95 (d, 1H,
J = 3.5 Hz, C@CHH), 4.54 (d, 1H, J = 3.5 Hz, C@CHH), 2.51 (s, 6H,
N(CH3)2); 13C NMR (125 MHz) d 153.5 (O–C–NMe2, quaternary car-
bon), 91.0 (CH2@C), 39.4 (N(CH3)2)] (Fig. S2).15 An enolate-like
structure was also supported by the HSQC and HMBC measure-
ments (Fig. S3). This NMR sample was further subjected to an ESI-
MS analysis, which gave a set of intensive and relatively weak sig-
nals at m/z = [375.8823 (parent ion), 377.8803, 379.8755,
381.8697] and [459.9532 (parent ion), 461.9503, 463.9467,
465.9426], respectively (Fig. S4). The separation pattern of both sets
of signals highlights four chloro groups embedded in the enolate-
like species.16 One candidate to comply with these MS values is
the molecular formula of [(C4H8Cl4N5OP3) + H+] (Calcd: 375.8769)
and [(C4H8Cl4N5OP3)(C5D5NH)+] (Calcd: 459.9504). Based on these
data, enolate [(CH3)2N(CAO)@CH2]À [Cl4N4P3]+ could be an entity
responsible for aldol catalysis, although the exact molecular struc-
ture of the counter-cationic portion is still under scrutiny.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
07.129.
References and notes
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a
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2À
In summary, using TAPC-based phosphorous/SO4
catalysts
under rather acidic conditions, a new method for the amide aldol-
ization was realized. Some advantages of acidic over basic condi-
tions were also clarified. To the best of our knowledge, this is
essentially the first example of the catalytic aldol condensation
of unactivated amides under relatively acidic conditions, in which
the use of stoichiometric quantities of an acid or base is not
O
OH
conditionsa,b,c
3ab
N
Scheidt, K. A. J. Am. Chem. Soc. 2009, 131, 8805–8814; Synthesis of
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ˇ ˇ
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Scheme 4. Investigation of the dehydration process. Conditions a–c and yield% of
3ab: a: TAPC (10 mol %), 40%; b: H2SO4 (10 mol %), 5%; c: TAPC + H2SO4 (10 mol %
each), 78%.
6. A part of the results herein was primarily presented in the 90th Annual
Meeting of Japan Chemical Society, March 2010, Abstract IV, #1F7-42. In a

5448
S. W. Foo et al. / Tetrahedron Letters 53 (2012) 5445–5448
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Weinheim, 2004.
8. Reviews: (a) Allcock, H. R. Chem. Rev. 1972, 72, 315–356; (b) Allcock, H. R. Acc.
Chem. Res. 1978, 11, 81–87; (c) Allcock, H. R. Acc. Chem. Res. 1979, 351–358; (d)
Chandrasekhar, V.; Thomas, K. R. J. Appl. Organomet. Chem. 1993, 7, 1–31.
9. Catalytic application of TAPC: (a) Hashimoto, M.; Obora, Y.; Sakaguchi, S.; Ishii,
Y. J. Org. Chem. 2008, 73, 2894–2897; (b) Bahrami, K.; Khodaei, M. M.; Arabi, M.
S. J. Org. Chem. 2010, 75, 6208–6213; (c) Du, Y.; Oishi, S.; Saito, S. Chem. Eur. J.
2011, 17, 12262–12267.
13. Yan, Z.; Xue, W.-L.; Zeng, Z.-X.; Gu, M.-R. Ind. Eng. Chem. Res 2008, 47, 5318–
5322.
14. See Figure S1 in the Supplementary data for detail.
15. NMR data of the lithium enolate of DMA in pyridine: 1H NMR d 3.16 (d, 1H),
2.93 (d, 1H), 2.63 (s, 6H); 13C NMR d 169.39, 55.99, 39.53. See: (a) Woodbury, R.
P.; Rathke, M. W. J. Org. Chem. 1978, 43, 1947–1949; (b) Woodbury, R. P.;
Rathke, M. W. J. Org. Chem. 1977, 42, 1688–1690.
16. Silverstein, R. M.; Webster, F. X.; Kiamla, D. J. Spectrometric Identification of
Organic Compounds, 7th ed.; John Wiley & Sons, Inc.: USA, 2005.
17. Typical procedure: The direct aldol reaction of amide with aldehyde using TAPC. To
a DMA (1a) (1 mL) solution of TAPC (34.7 mg, 0.1 mmol) was added sulfuric
acid (5.3 lL, 0.1 mmol), and the mixture was stirred for 1 h under Ar at
10. (a) Brandt, K.; Jedlinski, Z. J. Org. Chem. 1980, 45, 1672–1675; (b) Carriedo, G. A.;
Fernández-Catuxo, L.; Alonso, F. J. G.; Gómez-Elipe, P.; González, P. A.
Macromolecules 1996, 29, 5320–5325.
ambient temperature. To the mixture was added aldehyde 2 (1 mmol) and the
mixture was allowed to warm to 120 °C and stirred for 24 h. The mixture was
poured into a separation funnel containing water and extracted with ethyl
acetate. The organic layer was dried over Na2SO4, filtered, and concentrated.
The residue was monitored by 1H NMR measurement before purification.
Product yield of 3 was doubly checked. It was calculated based on the ratio of 3
to the internal standard (1,1,2,2-tetrachloroethane) after determination of an
isolated yield by purifying with column chromatography on silica gel (EtOAc/
hexane 1:10–1:2). Spectral and analytical data of all new compounds are in the
Supplementary data.
11. Commercially available from Aldrich. See also: Honeyman, C. H.; Manners, I.;
Morrissey, C. T.; Allcock, H. R. J. Am. Chem. Soc 1995, 117, 7035–7036.
12. Selected examples of TCT-based catalysis in organic synthesis: (a) Forbes, D. C.;
Barrett, E. J.; Lewis, D. L.; Smith, M. C. Tetrahedron Lett. 2000, 41, 9943–9947;
(b) Luca, L. D.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2001, 66, 7907–7909;
(c) Bandgar, B. P.; Pandit, S. S. Tetrahedron Lett. 2002, 43, 3413–3414; (d) Luca,
L. D.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67, 6272–6274; (e)
Giacomelli, G.; Porcheddu, A.; Salaris, M. Org. Lett. 2003, 5, 2715–2717; (f)