Water opportunities: Catalyst and solvent in Mukaiyama aldol addition of Rawal's diene to carbonyl derivatives

Article abstract of DOI:10.1016/j.tet.2011.06.035

Addition reactions between Rawal's diene and different carbonyl compounds are rapidly and efficiently promoted by water. No catalyst or any other additive, water as an eco-friendly medium, clean reaction conditions, a simple work-up, and short reaction ti

Full text of DOI:10.1016/j.tet.2011.06.035

Tetrahedron 67 (2011) 5949e5955
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Water opportunities: catalyst and solvent in Mukaiyama aldol addition of Rawal’s
diene to carbonyl derivatives
*
Margherita De Rosa , Annunziata Soriente
ꢀ
Dipartimento di Chimica e Biologia, Universita degli Studi di Salerno, via Ponte don Melillo, 84084 Fisciano (SA), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Addition reactions between Rawal’s diene and different carbonyl compounds are rapidly and efficiently
promoted by water. No catalyst or any other additive, water as an eco-friendly medium, clean reaction
conditions, a simple work-up, and short reaction times are the salient features in this procedure. The
protocol is general, proceeding well with moderate to good yields for various aldehydes and activated
ketones. Based on the experimental 1H NMR results, a Mukaiyama aldol mechanism was proposed as the
reaction pathway, affording open chain products.
Received 31 March 2011
Received in revised form 23 May 2011
Accepted 13 June 2011
Available online 17 June 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Water chemistry
Mukaiyama aldol addition
Rawal’s diene
Catalyst-free
Siloxyaminobutadiene
1. Introduction
studies focused on finding new water-compatible and reusable
catalysts, strengthened by a growing development of catalyst-free
Traditionally, the use of water as a reaction medium in organic
processes has often been rejected. The idea that water had an ad-
verse effect on most organic reactions was mainly attributed to the
scant solubility of organic substrates in water, with the belief that
solubility was a prerequisite for reactivity, in addition to the in-
compatibility between water molecules and some functional
groups present in the reactants themselves. This belief was chal-
lenged by the studies done by Breslow1 and Grieco,2 which high-
lighted the positive effect of water on the rate and selectivity of
DielseAlder reactions. Further studies by Sharpless et al.3 greatly
increased the interest in water as a solvent, introducing the concept
of ‘on water’ conditions, which provide with a substantial reaction
rate acceleration for cases where the reactants are insoluble in
water. Since then, the list of organic processes performed efficiently
in water has been expanded including an increasing number of
different types of reactions.4
processes,5 with water used both as medium and as reaction pro-
moter, keeping in mind that ‘the best catalyst is no catalyst’6 in order
to accomplish clearer and cleaner synthesis.
Based on the above observations, and our interest in high-
lighting the potential of water in important CeC bond forming
processes,7 we investigated the reaction between electron-rich
diene, Rawal’s diene (1), and carbonyl compounds in water under
catalyst-free conditions (Scheme 1). The reaction is a powerful tool
in organic synthesis offering very convenient and rapid access to
highly functionalized frameworks. Rawal and Huang8 reported
a study on the solvent acceleration in the hetero DielseAlder (HDA)
reaction of diene 1 with a range of carbonyl derivatives in absence
Diel-Alder pathway
OTBS
Water is a unique solvent: inexpensive, readily available, and
environmentally acceptable, providing opportunities for clean pro-
cesses and simplicity of reaction conditions. Furthermore, reactions
performed in water can not only be faster and more selective than in
conventional organic solvents but also exhibit unique reactivity and
selectivity leading to novel assembly processes. In recent years,
R
O
TBSO
R1
N
O
O
A
R
+
R
R1
R1
O
3
R1
OTBS
O
R
N
2
1
N
B
Mukaiyama aldol pathway
* Corresponding author. Tel.: þ39 89969553; fax: þ39 89969603; e-mail address:
Scheme 1. Two possible pathways for HDA reaction of carbonyl compounds with
electron-rich dienes.
maderosa@unisa.it (M. De Rosa).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.035

5950
M. De Rosa, A. Soriente / Tetrahedron 67 (2011) 5949e5955
Table 2
of Lewis acid catalysts, demonstrating the positive role of the hy-
drogen bonding interactions on the observed rate acceleration in
protic solvents.
Catalyst-free aqueous reaction addition of Rawal’s diene 1 with aldehydes 2
TBSO
O
OH
O
There are two different reaction pathways for the reaction be-
tween an electron-rich diene, such as Rawal’s diene, and a carbonyl
compound depending on the catalyst used and reaction conditions
(Scheme 1). These paths are classified into two mechanisms; the
Mukaiyama aldol reaction and concerted [4þ2] cycloaddition. The
concerted DielseAlder pathway has been identified in the hydro-
gen bonding-promoted reactions reported by Rawal8 with tested
solvents.
To the best of our knowledge, a catalyst-free aqueous HDA re-
action between carbonyl compounds and electron-rich dienes has
not been reported to date, probably due to the stereotypical notion
of these dienes susceptibility to water.
water
rt
+
N
R
R
H
N
4a-s
2a-s
1
Entrya
1
RCHO
Reaction time (h)
1
Yield (%)b
90
O
H
2a
O
Encouraged by the reported favorable effect of a protic solvent
on the HDA reaction efficiency, we envisaged the feasibility of de-
veloping a convenient and alternative synthetic procedure in-
volving water molecules as the hydrogen-bond (HB) promoting.
Our goal was not only to use water as a simple substitute for con-
ventional organic solvents, but also to assess the influence of novel
reaction medium on the reaction both as efficiency of the process
and as feasible different mechanistic pathway (Scheme 1).
Herein, we report the first uncatalyzed addition reaction be-
tween Rawal’s diene 1 and various carbonyl compounds using
water as both reaction medium and as a hydrogen-bond donor
species to activate the carbonyl compound.
H
2
3
4
5
1
3
3
1
88
75
56
87
2b
O
H
H3CO
2c
OCH3
O
H
2d
2. Results and discussion
O
The coupling of the 1-amino-3-siloxybutadiene (Rawal’s diene)
1 with benzaldehyde 2a was conducted as a model screening re-
action and the results are summarized in Table 1.
H
O2N
2e
Table 1
Screening studies of catalyst-free aqueous reaction addition between Rawal’s diene
(1) and benzaldehyde (2a)
6
7
1
3
84
67
TBSO
O
OH
O
O
water
rt
+
N
H
H
N
NC
Br
4a
2a
1
2g
Entrya
1/2a (equiv)
Reaction time (min)
Volume (mL)
Yield (%)b
O
1
2
3
4
5
6
7
8c
1.0/1.0
1.0/1.2
1.2/1.0
1.2/1.0
1.2/1.0
1.2/1.0
1.2/1.0
1.2/1.0
60
60
60
30
90
60
60
60
1.5
1.5
1.5
1.5
1.5
0.5
10.8
6
64
65
90
61
92
90
68
83
H
8
9
0.5
89
93
2h
O
H
1
F3C
a
All reactions were run at atmospheric pressure in deionized water under
vigorous stirring on a 0.25 mmol scale. For details, see the Experimental section. The
use of tap water gives the same reaction yields.
2i
b
Yields refer to isolated, chromatographically pure product 4a and are the
H
average of two experiments.
10
11
3
3
70
66
O
c
The reaction was performed on 1 mmol scale.
O
2j
H
H
S
At the outset of this screening, equimolar amounts of 1 and 2a
were allowed to react using pure water (1.5 mL) as solvent and
under vigorous stirring at room temperature without the use of any
type of catalyst. Under these conditions, the reaction proceeded
cleanly giving the Mukaiyama-type aldol adduct 4a in a comforting
yield (entry 1, Table 1) along with a limited quantity of silyl-
protected aldol adduct (<8%) and of the diene solvolysis
O
O
2k
12
0.5
92
N
2l

M. De Rosa, A. Soriente / Tetrahedron 67 (2011) 5949e5955
5951
Table 2 (continued )
formation of the cycloadduct A from the concerted DielseAlder
pathway in low conversion (36%) and there was no evidence of the
formation of 4a, thereby highlighting the potential benefits from
water as a reaction medium in this process. Additional experiment
was performed on 1 mmol scale reaction demonstrating the val-
idity for scaling up the procedure (entry 8, Table 1).
Entrya
RCHO
Reaction time (h)
3
Yield (%)b
65
O
H
H
13
N
2m
Encouraged by these preliminary results, the scope and limita-
tions of this reaction with respect to the aldehyde component was
further investigated. A series of aromatic and aliphatic aldehydes
were reacted with Rawal’s diene 1 using the optimized conditions
in entry 3 of Table 1. In all cases the reactions were quite fast, they
smoothly proceeded to just reach the corresponding aldol products
4 in moderate to good yields together with a limited quantity of
silyl-protected aldol adduct (<10%) as summarized in Table 2.
The reaction worked well with aromatic aldehydes bearing either
electron-donating or electron-withdrawing groups, although the
conversion observed with these latter groups was inferior. The
expected aldol adduct 4 was obtained as only reaction product with
a yield ranging from 56 to 93% (entries 2e9, Table 2). Heteroaromatic
aldehydes also demonstrated to be viable substrates in this reaction,
giving the corresponding aldol from good (entry 12, Table 2) to
moderateyields (entries 10,11, and13, Table 2). Althoughthe reaction
of conjugated aldehydes proceeded in aqueous solvent, the yields of
desired product were more moderate (entries14 and19, Table 2). Our
protocol was then applied to aliphatic aldehydes. When n-octy-
laldehyde or cyclohexylcarboxyaldehyde were reacted, the corre-
sponding aldols 4p and 4q were obtained in good yield (entries 16
and 17, respectively, Table 2). When benzyloxyacetaldehyde 2o and
glyoxalate 2r were used, they were also suitable substrates for our
procedure but they provided the Mukaiyama aldol adduct with in-
creasing amount of silyl-protected product.
O
14
3
1
59
56
2n
H
O
15c
O
2o
H
H
5
16
17
1
1
84
88
O
O
2p
2q
O
H
d
18
1
3
69
44
O
2r
O
19
H
2s
a
Reaction conditions: 1 (0.30 mmol) and 2 (0.25 mmol) in pure deionized water
(1.5 mL) at room temperature. For details, see the Experimental section.
Table 3
b
All the yields refer to isolated chromatographically pure compounds, whose
Catalyst-free water-promoted Mukaiyama aldol reactions of Rawal’s diene 1 with
representative pyruvate esters 5aed
structures were confirmed by 1H and 13C NMR data, IR spectra, and mass spec-
trometry (see Experimental section). The yields are the average of two experiments.
c
TBSO
O
The silyl-protected aldol adduct was obtained in 22% yield.
The silyl-aldol adduct was obtained in 30% yield.
d
O
R
O
HO
OEt
water
rt
OEt
+
R
N
O
N
byproduct (13%). There was no evidence of the cycloaddition
product 3a. The rest of material is unreacted starting material.
Of special interest was the fact that the diene 1 was compatible
with the aqueous environment under our reaction conditions. In-
deed the competitive hydrolysis diene reaction didn’t surpass the
desired addition reaction in aqueous medium, and the water itself
could be a suitable protic solvent for pushing the reaction.
6a-d
5a-d
1
Entrya
1
Ketoester
Reaction time (h)
1
Yield (%)b
Quant.
O
OEt
O
5a
In hope to achieve higher conversion, the effects of molar ratio
of 1 to 2a were examined in detail. Whereas the reaction yield did
not appreciably vary increasing the amount of 2a (entry 2, Table 1),
changing to the molar ratio 1/2a in 1.2/1 significantly improved the
adduct yield (entry 3, Table 1). Therefore, only a modest excess of 1
was required for an efficient conversion. A variation of the reaction
times (entries 3e5, Table 1) revealed that 1 h proved to be the most
suitable reaction time (entry 5, Table 1) and indeed prolonging the
reaction time did not improve the yield (entry 5, Table 1). Next, the
influence of the solubility of reacting species in aqueous medium
on the reaction efficiency was investigated ranging from complete
(entry 7, Table 1) to partial (entry 3, Table 1) to almost no solubility
(entry 6, Table 1). The results demonstrated that when the reaction
mixture remained heterogeneous, the process appeared to benefit
from it (entry 3, Table 1). In order to investigate the role of water,
the reaction was performed neat under identical reaction condi-
tions, such as entry 3 of Table 1. Under these conditions, the 1H
NMR spectrum of the crude reaction mixture revealed the
O
OEt
2
3
1
91
O
5b
O
OEt
1
3
90
85
O
5c
O
OEt
4
O
NC
5d
a
Reaction conditions: 1 (0.30 mmol) and 5 (0.25 mmol) in pure deionized water
(1.5 mL) at room temperature. For details, see the Experimental section.
b
All the yields refer to isolated chromatographically pure compounds, whose
structures were confirmed by 1H and 13C NMR data, IR spectra, and mass spec-
trometry (see Experimental section). The yields are the average of two experiments.

5952
M. De Rosa, A. Soriente / Tetrahedron 67 (2011) 5949e5955
Fig. 1. 1H NMR spectra in CDCl3 of reaction addition of Rawal’s diene 1 with aldehyde 2l performed in different H-bonding solvents: (a) CDCl3; (b) D2O.
As a further aspect, we were curious to check if our procedure
compound through hydrogen bonding. The diene 1 then attacked
the activated carbonyl compound to form the new carbonecarbon
bond through a Mukaiyama-aldol pathway (Scheme 2) yielding the
aldol adduct 4.
could be extended to ketones, generally considered less reactive.
Initial approach showed that diene 1 was not reactive in the re-
action conditions with a simple ketone as cyclohexanone, but the
reaction with ethyl pyruvate 5a led to similar levels of success when
employed with benzaldehyde (entry 1, Table 3). The reaction went
to completion in just 1 h at room temperature under vigorous
stirring and gave the adduct of Mukaiyama-aldol pathway in
quantitative yield.
Similarly, other ketonic substrates 5 bearing a different acyl
moiety (isopropyl or phenyl instead of methyl) reacted smoothly
with 1, providing the aldol adduct 6 in good yield (entries 2e4,
Table 3).
O
H
Mukaiyama-aldol adduct
N
H
O
OH
O
R
+
N
R1
R
R1
Si
O
4
2
1
Finally to clarify whether water-mediated reaction proceeded
by Mukaiyama-aldol pathway or the DielseAlder pathway
(Scheme 1), we performed some experiments by monitoring the
reaction using 1H NMR analysis. Rawal and Huang8 have reported
that the reaction between carbonyl compounds and diene 1 in
hydrogen-bonding solvents proceeds by a rapid cycloaddition
resulting in clean formation of the expected cycloadduct A
(Scheme 1), which could then be transformed to a more stable
product, such as alcohol 4 or dihydro-4-pyrone 3 depending on
the work-up conditions. We carried out the addition reaction
between 2-pyridine carboxyaldehyde 2l and diene 1 as a model
reaction in, respectively, D2O and CDCl3 media, in order to di-
rectly examine the reaction mixture by NMR analysis without any
work-up procedure (Fig. 1).
Scheme 2. Proposed mechanism for the water-promoted addition reaction between
Rawal’s diene 1 and carbonyl compound 2.
3. Conclusion
Our study aims to add a further contribution to the fascinating
field of catalyst-free water-promoted organic reactions by including
a reaction traditionally carried out under strictly anhydrous con-
ditions. We have demonstrated the successful role played by neat
water both catalyst and reaction medium in a carbonecarbon bond
formation reaction as the addition reaction between Rawal’s diene,
notoriously water sensitive, and carbonyl compounds.
The reaction is, in general, very clean giving good to moderate
yields with excellent selectivity under mild reaction conditions
and short reaction times. In addition, the reaction scope is sub-
stantial and aromatic or aliphatic carbonyl compounds could be
successfully applied. It is interesting to observe the remarkable
difference between the protic solvents water and those reported
by Rawal8 as effective reaction promoters. Studies by 1H NMR
analysis indicate that the reaction solvent influences the reaction
pathway: using water as reaction medium the reaction follows
the Mukaiyama-aldol pathway affording the Mukaiyama aldol
adduct as only isolated product. On the other hand, with other H-
bonding solvents a rapid cycloaddition takes place following the
DielseAlder pathway. Therefore, water as novel reaction medium
is not only an alternative H-bonding promoter solvent for the
addition reaction between Rawal’s diene and a carbonyl com-
pound, but it also offers the opportunity for directly getting dif-
ferent reaction products.
The 1H NMR spectrum of the crude reaction mixture in D2O
showed the disappearance of the aldehyde after 30 min, but it
was not easy to analyze for examining the product structure.
Then, we decided to pour and shake the reaction mixture in
sufficient CDCl3 checking the 1H NMR spectrum of corresponding
organic phase (Fig. 1b). As shown in Fig. 1, a different behavior
was observed performing the reaction in the two different sol-
vents CDCl3 and D2O (compare a and b, Fig. 1). In the case of the
reaction carried out in CDCl3 (Fig. 1a), the 1H NMR spectrum
revealed the exclusive formation of the intermediate A pro-
ceeding through a concerted [4þ2] mechanism in complete
agreement with literature data.8 On the other hand, performing
the reaction in D2O under our reaction conditions (Fig. 1b), 1H
NMR spectrum clearly indicated the generation of a different
compound identified as the aldol product 4 without the obser-
vation of a detectable cyclization intermediate.
These results demonstrated that the aqueous addition reaction
followed the Mukaiyama-aldol pathway and the isolated product 4
did not come from a possible transformation of cycloadduct A fol-
lowing the work-up.
Then, under our reaction conditions, the water played a key role
as reaction promoter and activated the oxygen of the carbonyl
To the best of our knowledge, this is the first example of
Mukaiyama aldol reaction of Rawal’s diene with carbonyl com-
pounds using pure water as reaction medium and promoter with-
out the presence of any catalyst, additive or co-solvents. Currently,
studies are actively underway to expand the synthetic utility to the
optically active addition products.

M. De Rosa, A. Soriente / Tetrahedron 67 (2011) 5949e5955
5953
4. Experimental section
4.1. General method
(br s, 3H), 2.74 (dd, J¼3.3, 15.6 Hz, 1H), 2.65 (dd, J¼9.0, 15.6 Hz, 1H),
2.31 (s, 3H); 13C NMR (CDCl3, 75 MHz):
197.2, 153.2, 140.8, 136.4,
128.8 (ꢀ2), 125.7 (ꢀ2), 95.9, 71.0, 48.2, 44.8, 37.1, 20.7; IR (liquid
film, cmꢁ1) 3372, 2920, 1645, 1557, 1419, 1361, 1278, 1097; m/z 233
(Mþ).
d
Unless otherwise mentioned, all commercial reagents were
obtained from commercial suppliers and used without further
purification. Thin-layer chromatography was performed on Merck
Kieselgel 60 (0.25 mm) in appropriate solvent. Visualization was
accomplished with ultraviolet light (254 nm) and/or an alcoholic
p-anisaldehyde solution, followed by heating. Column chromatog-
raphy was carried out using silica gel 60 (70e230 mesh ASTM,
Merck). 1H and 13C NMR spectra were recorded on a Bruker AM 250
(250.13 MHz for 1H, 62.89 MHz for 13C), Bruker DRX 300 (300 MHz
for 1H; 75 MHz for 13C) and Bruker DRX 400 (400 MHz for 1H;
100 MHz for 13C). J values are given in hertz. The 1H chemical shifts
4.4.3. (E)-1-(Dimethylamino)-5-hydroxy-5-(4-methoxyphenyl) pent-
1-en-3-one 4c. Yellow oil; (found: C, 67.48; H, 7.70; N, 5.64.
C14H19NO3 requires C, 67.45; H, 7.68; N, 5.62); 1H NMR (CDCl3,
400 MHz):
d
7.58 (d, J¼12.4 Hz, 1H), 7.31 (d, J¼8.0 Hz, 2H), 6.87 (d,
J¼8.0 Hz, 2H), 5.07e5.03 (m, 1H), 4.99 (d, J¼12.4 Hz, 1H), 3.79 (s,
3H), 3.09 (br s, 3H), 2.80 (br s, 3H), 2.73 (dd, 1H, J¼3.5, 15.7 Hz), 2.65
(dd, J¼9.0, 15.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
d 198.7, 160.1,
154.6, 133.4, 128.2 (ꢀ2), 115.0 (ꢀ2), 97.5, 72.3, 56.6, 50.0, 46.4, 38.5;
IR (liquid film, cmꢁ1) 3372, 2920, 1645, 1557, 1419, 1361, 1278, 1097;
m/z 272 (MþNa)þ.
were referenced to the solvent peak: CDCl3 (7.26 ppm), and the 13
C
chemical shifts were referenced to the solvent peak: CDCl3
(77.0 ppm). Melting points were determined in open capillary tubes
using an Electro Thermal 9100 series apparatus. Mass spectra were
recorded on a Micromass Quattro micro API mass spectrometer
using electrospray (ESþ) ionization technique. IR spectra were
recorded on an FT-IR instrument (Bruker Vector 22). Elemental
analyses were performed on the Flash EA 1112 Series with Thermal
Conductivity Detector (Thermo Electron Corporation).
4.4.4. (E)-1-(Dimethylamino)-5-hydroxy-5-(2-methoxyphenyl) pent-
1-en-3-one 4d. Yellow oil; (found: C, 67.47; H, 7.66; N, 5.64.
C14H19NO3 requires C, 67.45; H, 7.68; N, 5.62); 1H NMR (CDCl3,
400 MHz):
d 7.56e7.52 (m, 2H), 7.24e7.20 (m, 1H), 7.00e6.95 (m,
1H), 6.84 (d, J¼8.0 Hz, 1H), 5.40 (dd, J¼2.4, 9.3 Hz, 1H), 5.04 (d,
J¼12.6 Hz, 1H), 3.82 (s, 3H), 3.08 (br s, 3H), 2.91e2.80 (m, 4H), 2.59
(dd, J¼9.3, 15.9 Hz, 1H); 13C NMR (CDCl3, 62.89 MHz):
d 197.9, 156.0,
153.2,132.2,128.1,126.6,120.8,110.0, 96.6, 66.3, 55.2, 47.1, 45.1, 37.1;
IR (liquid film, cmꢁ1) 3372, 2937, 1645, 1568, 1418, 1239, 1095; m/z
272 (MþNa)þ.
4.2. Typical experimental procedure
A mixture of carbonyl compound (0.25 mmol) and diene 1
(0.30 mmol) was suspended in pure deionized water (1.5 mL) and
vigorously stirred at room temperature for the indicate time (Tables
1e3). After completion of the reaction, as indicated by TLC, the
water was simply removed by evaporation or alternatively EtOAc
(3ꢀ5 mL) could be used with, which to extract the organic material
from the aqueous layer. The collected organic phases were dried
with anhydrous magnesium sulfate, filtered, and the solvent
evaporated in vacuo. Purification was accomplished by column
chromatography on silica gel using chloroform/methanol mixture
as eluent.
4.4.5. (E)-1-(Dimethylamino)-5-hydroxy-5-(4-nitrophenyl) pent-1-
en-3-one 4e. Yellow solid, mp 129e131 ꢂC; (found: C, 59.11; H,
6.12; N, 10.62. C13H16N2O4 requires C, 59.08; H, 6.10; N, 10.60); 1H
NMR (CDCl3, 400 MHz):
d
8.20 (d, J¼9.0 Hz, 2H), 7.62e7.56 (m, 3H),
5.21 (dd, J¼3.3, 9.3 Hz, 1H), 4.99 (d, J¼12.0 Hz, 1H), 3.13 (br s, 3H),
2.83 (br s, 3H), 2.80e2.77 (m, 1H), 2.64 (dd, J¼9.3, 15.6 Hz, 1H); 13C
NMR (CDCl3, 62.89 MHz):
d
196.2, 153.5, 152.9, 151.4, 126.5 (ꢀ2),
123.6 (ꢀ2), 94.8, 70.6, 48.8, 45.2, 37.2; IR (liquid film, cmꢁ1) 3333,
2922, 1644, 1557, 1345, 1096; m/z 265 (Mþ1)þ.
4.4.6. (E)-1-(Dimethylamino)-5-hydroxy-5-(2-nitrophenyl) pent-1-
en-3-one 4f. Yellow solid, mp 119e121 ꢂC; (found: C, 59.05; H,
6.07; N, 10.58. C13H16N2O4 requires C, 59.08; H, 6.10; N, 10.60); 1H
4.3. NMR analysis of 4l
To a solution of 2-pyridine carboxyaldehyde 2l (0.125 mmol) in
D2O (0.75 mL) was added diene 1 (0.15 mmol) at room temperature.
After stirring for 30 min, the reaction mixture was extracted with
CDCl3 (1.0 mL) and organic phase was directly analyzed by 1H NMR
spectroscopy. The spectroscopic data showed exclusive formation
of 3l.
NMR (CDCl3, 400 MHz):
d
7.99 (d, J¼8.0 Hz, 1H), 7.93 (dd, J¼1.5,
8.0 Hz, 1H), 7.68e7.61 (m, 2H), 7.41 (dt, J¼1.5, 8.0 Hz, 1H) 5.59 (dd,
J¼2.0, 9.1 Hz, 1H), 5.00 (d, J¼12.8 Hz, 1H), 3.14 (br s, 3H), 3.13e3.04
(m, 1H), 2.85 (br s, 3H), 2.56 (dd, J¼9.1, 14.0 Hz, 1H); 13C NMR
(CDCl3, 62.89 MHz):
d 196.9, 153.7, 147.3, 139.4, 133.5, 128.5, 127.8,
124.1, 96.3, 67.5, 46.9, 45.1, 37.1; IR (liquid film, cmꢁ1) 3337, 2920,
1645, 1563, 1524, 1361, 1278; m/z 265 (Mþ1)þ, 287 (MþNa)þ.
4.4. Analytical data for new compounds among the products
4.4.7. 4-((E)-5-(Dimethylamino)-1-hydroxy-3-oxo pent-4-enyl)ben-
zonitrile 4g. Pale yellow solid, mp 130e132 ꢂC; (found: C, 68.81; H,
6.58; N, 11.44. C14H16N2O2 requires C, 68.83; H, 6.60; N, 11.47); 1H
4.4.1. (E)-1-(Dimethylamino)-5-hydroxy-5-phenylpent-1-en-3-one
4a. Pale yellow oil; (found: C, 71.23; H, 7.84; N, 6.37. C13H17NO2
requires C, 71.21; H, 7.81; N, 6.39); 1H NMR (CDCl3, 400 MHz):
d
7.58
NMR (CDCl3, 300 MHz):
d
7.61e7.55 (m, 3H), 7.50 (d, J¼9.0 Hz, 2H),
(d, J¼11.3 Hz, 1H), 7.41e7.38 (m, 2H), 7.37e7.33 (m, 2H), 7.28e7.18
(m, 1H), 5.13 (dd, J¼3.2, 11.3 Hz, 1H), 3.10 (br s, 3H), 2.82 (br s, 3H),
2.77 (dd, J¼2.8, 13.3 Hz, 1H), 2.72e2.65 (m, 1H); 13C NMR (CDCl3,
5.14 (dd, J¼3.0, 9.0 Hz, 1H), 4.96 (d, J¼12.0 Hz, 1H), 3.10 (br s, 3H),
2.82 (br s, 3H), 2.76 (dd, J¼2.7, 16.0 Hz, 1H), 2.61 (dd, J¼9.1, 16.0 Hz,
1H); 13C NMR (CDCl3, 75 MHz):
d
196.2, 153.4, 149.3, 132.0 (ꢀ2),
75 MHz):
d
197.1, 153.3, 143.7, 128.2 (ꢀ2), 127.1, 125.7 (ꢀ2), 96.3,
126.6 (ꢀ2), 118.9, 110.7, 94.9, 70.8, 47.7, 45.0, 37.1; IR (liquid film,
cmꢁ1) 3322, 2918, 2226, 1644, 1557, 1418, 1361, 1278, 1097; m/z 245
(Mþ1)þ, 267 (MþNa)þ.
71.2, 49.1, 44.9, 37.0; IR (liquid film, cmꢁ1) 3370, 2916, 2809, 1645,
1558, 1418, 1362, 1276, 1101, 762, 702; m/z 220 (Mþ1)þ, 242
(MþNa)þ.
4.4.8. (E)-5-(4-Bromophenyl)-1-(dimethylamino)-5-hydroxypent-1-
en-3-one 4h. Yellow solid, mp 87e89 ꢂC; (found: C, 52.34; H, 5.40;
N, 4.72. C13H16BrNO2 requires C, 52.36; H, 5.41; N, 4.70); 1H NMR
4.4.2. (E)-1-(Dimethylamino)-5-hydroxy-5-p-tolylpent-1-en-3-one
4b. Yellow oil; (found: C, 72.04; H, 8.19; N, 6.03. C14H19NO2 requires
C, 72.07; H, 8.21; N, 6.00); 1H NMR (CDCl3, 300 MHz):
d
7.55 (d,
(CDCl3, 400 MHz):
7.25 (d, J¼8.0 Hz, 2H), 5.04 (dd, J¼2.8, 9.6 Hz,1H), 4.97 (d, J¼12.4 Hz,
1H), 3.08 (br s, 3H), 2.79 (br s, 3H), 2.72 (dd, J¼2.9, 16.0 Hz, 1H), 2.60
d
7.56 (d, J¼12.4 Hz, 1H), 7.43 (d, J¼8.0 Hz, 2H),
J¼12.3 Hz, 1H), 7.27 (d, J¼8.7 Hz, 2H), 7.13 (d, J¼8.7 Hz, 2H), 5.06
(dd, J¼2.7, 9.0 Hz, 1H), 4.99 (d, J¼12.3 Hz, 1H), 3.07 (br s, 3H), 2.79

5954
M. De Rosa, A. Soriente / Tetrahedron 67 (2011) 5949e5955
(dd, J¼9.2, 16.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
d
196.7, 153.2,
127.3, 126.4(ꢀ2), 95.9, 69.8, 46.7, 45.0, 37.1; IR (liquid film, cmꢁ1
3330, 2911, 1644, 1557, 1418, 1361, 1274, 1111; m/z 245 (M)þ.
)
142.9, 131.2 (ꢀ2), 127.5 (ꢀ2), 120.7, 95.4, 70.6, 48.4, 45.0, 37.0; IR
(liquid film, cmꢁ1) 3344, 2923, 1643, 1560, 1419, 1362, 1277, 1094;
m/z 320 (MþNa)þ.
4.4.15. (E)-6-(Benzyloxy)-1-(dimethylamino)-5-hydroxyhex-1-en-3-
one 4o. Yellow oil; (found: C, 68.40; H, 8.01; N, 5.30. C15H21NO3
requires C, 68.42; H, 8.04; N, 5.32); 1H NMR (CDCl3, 400 MHz):
4.4.9. (E)-1-(Dimethylamino)-5-(4-(trifluoromethyl)phenyl)-5-
hydroxypent-1-en-3-one 4i. Yellow solid, mp 79e81 ꢂC; (found: C,
58.55; H, 5.63; N, 4.91. C14H16F3NO2 requires C, 58.53; H, 5.61; N,
d
7.57 (d, J¼13.2 Hz, 1H), 7.36e7.28 (m, 5H), 5.04 (d, J¼13.2 Hz, 1H),
4.58 (s, 2H), 4.27e4.21 (m, 1H), 3.52 (dd, J¼6, 9.6 Hz, 1H), 3.49 (dd,
J¼6, 9.6 Hz, 1H), 3.09 (br s, 3H), 2.82 (br s, 3H), 2.62 (dd, J¼3.6,
15.6 Hz, 1H), 2.55 (dd, J¼8.4, 15.6 Hz, 1H); 13C NMR (CDCl3,
4.88); 1H NMR (CDCl3, 300 MHz):
d 7.59e7.54 (m, 3H), 7.49 (d,
J¼7.8 Hz, 2H), 5.14 (dd, J¼3.3, 9.6 Hz, 1H), 4.97 (d, J¼12.0 Hz, 1H),
3.08 (br s, 3H), 2.80 (br s, 3H), 2.78e2.73 (m, 1H), 2.63 (dd, J¼9.3,
100 MHz):
d
197.0, 153.1, 138.2, 128.3(ꢀ2), 127.7 (ꢀ2), 127.6, 96.3,
15.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
d
196.5, 153.3, 147.8, 129.8,
73.8, 73.7, 68.2, 45.0, 43.4, 37.2; IR (liquid film, cmꢁ1) 3386, 2919,
1646, 1557, 1420, 1361, 1275, 1112; m/z 264 (Mþ1)þ, 286 (MþNa)þ.
125.9(ꢀ2), 125.1(ꢀ2), 122.3, 95.1, 70.8, 48.2, 45.0, 37.3; IR (liquid
film, cmꢁ1) 3343, 2919, 1645, 1563, 1420, 1326, 1277, 1118; m/z 288
(Mþ1)þ.
4.4.16. (E)-1-(Dimethylamino)-5-hydroxydodec-1-en-3-one
4p. Yellow oil; (found: C, 69.69; H, 11.30; N, 5.82. C14H27NO2 requires
4.4.10. (E)-1-(Dimethylamino)-5-(furan-2-yl)-5-hydroxypent-1-en-
C, 69.66; H, 11.27; N, 5.80); 1H NMR (CDCl3, 300 MHz):
d 7.59 (d,
3-one 4j. Yellow oil; (found: C, 63.17; H, 7.26; N, 6.71. C11H15NO3
J¼13.5 Hz, 1H), 5.02 (d, J¼13.5 Hz, 1H), 4.02e3.94 (m, 1H), 3.10 (br s,
3H), 2.83 (br s, 3H), 2.57 (dd, J¼2.7, 16.2 Hz, 1H), 2.38 (dd, J¼9.3,
16.2 Hz, 1H), 1.65e1.38 (m, 13H), 0.99 (t, J¼6.6 Hz, 3H); 13C NMR
requires C, 63.14; H, 7.23; N, 6.69); 1H NMR (CDCl3, 300 MHz):
d 7.56
(d, J¼12.5 Hz, 1H), 7.33 (d, J¼0.84 Hz, 1H), 6.29e6.27 (m, 1H),
6.24e6.22 (m, 1H), 5.09 (dd, J¼4.0, 8.1 Hz, 1H), 5.00 (d, J¼12.5 Hz,
1H), 3.07 (br s, 3H), 3.03e2.77 (m, 5H); 13C NMR (CDCl3, 100 MHz):
(CDCl3, 62.89MHz): d 198.1,152.9, 95.9, 68.9, 46.9, 45.0, 37.2, 37.0, 31.9,
29.7, 29.3, 25.7, 22.7,14.2; IR (liquid film, cmꢁ1)3390,2926,2855,1645,
1627, 1558, 1418, 1361, 1278, 1096; m/z 242 (Mþ1)þ, 264 (MþNa)þ.
d
196.4, 156.2, 153.2, 141.7, 110.2, 106.0, 95.1, 65.3, 45.3, 45.0, 37.3; IR
(liquid film, cmꢁ1) 3361, 2927, 1647,1560,1420,1362, 1276, 1100; m/
z 232 (MþNa)þ.
4.4.17. (E)-5-Cyclohexyl-1-(dimethylamino)-5-hydroxypent-1-en-3-
one 4q. Yellow oil; (found: C, 69.26; H, 10.31; N, 6.25. C13H23NO2
requires C, 69.29; H, 10.29; N, 6.22); 1H NMR (CDCl3, 400 MHz):
4.4.11. (E)-1-(Dimethylamino)-5-hydroxy-5-(thiophen-2-yl) pent-1-
en-3-one 4k. Yellow oil; (found: C, 58.62; H, 6.68; N, 6.20.
C11H15NO2S requires C, 58.64; H, 6.71; N, 6.22); 1H NMR (CDCl3,
d
7.57 (d, J¼12.0 Hz, 1H), 5.02 (d, J¼12.6 Hz, 1H), 3.76e3.72 (m, 1H),
3.09 (br s, 3H), 2.82 (br s, 3H), 2.56 (dd, J¼2.6, 15.6 Hz, 1H), 2.39 (dd,
250 MHz):
d
7.57 (d, J¼12.7 Hz, 1H), 7.19 (dd, J¼1.6, 4.8 Hz, 1H),
J¼9.5, 15.6 Hz, 1H), 1.9e1.6 (m, 5H), 1.40e0.97 (m, 6H); 13C NMR
6.94e6.86 (m, 2H), 5.33 (dd, J¼3.9, 8.0 Hz, 1H), 5.00 (d, J¼12.7 Hz,
(CDCl3, 100 MHz): d 198.4, 152.8, 96.0, 73.1, 44.9, 43.6, 43.2, 37.0,
1H), 3.07 (br s, 3H), 2.85e2.78 (m, 5H); 13C NMR (CDCl3,
28.8, 28.4, 26.5, 26.2, 26.1; IR (liquid film, cmꢁ1) 3399, 2924, 2851,
1651, 1558, 1418, 1361, 1275, 1110; m/z 226 (Mþ1)þ, 248 (MþNa)þ.
62.89 MHz): d 196.7, 153.4, 147.9, 126.3, 124.1, 122.8, 95.4, 67.8, 48.1,
45.2, 37.0; IR (liquid film, cmꢁ1) 3350, 2926, 1645, 1568, 1418, 1360,
1274, 1097; m/z 226 (Mþ1)þ, 248 (MþNa)þ.
4.4.18. (E)-6-(Dimethylamino)-2-hydroxy-1-phenylhex-5-ene-1,4-
dione 4r. Brown oil; (found: C, 67.98; H, 6.90; N, 5.65. C14H17NO3
4.4.12. (E)-1-(Dimethylamino)-5-hydroxy-5-(pyridin-2-yl) pent-1-
en-3-one 4l. Yellow oil; (found: C, 65.41; H, 7.31; N, 12.69.
C12H16N2O2 requires C, 65.43; H, 7.32; N, 12.72); 1H NMR (CDCl3,
requires C, 68.00; H, 6.93; N, 5.66); 1H NMR (CDCl3, 400 MHz):
d 8.03
(d, J¼7.6 Hz, 2H), 7.64 (d, J¼12.4 Hz,1H), 7.59 (m,1H), 7.49 (t, J¼7.6 Hz,
2H), 5.48 (dd, J¼3.6, 8.0 Hz,1H), 5.08 (d, J¼12.4 Hz,1H), 3.11 (br s, 3H),
2.89e2.81 (m, 4H), 2.73 (dd, J¼8.0, 15.6 Hz, 1H); 13C NMR (CDCl3,
300 MHz):
d
8.50 (d, J¼4.5 Hz, 1H), 7.70e7.62 (m, 1H), 7.58e7.44 (m,
2H), 7.17e7.10 (m, 1H), 5.15 (dd, J¼3.6, 8.4 Hz, 1H), 5.03 (d,
100 MHz):
d
201.2, 193.9, 153.3, 134.0, 133.4, 128.8 (ꢀ2), 128.7 (ꢀ2),
J¼12.9 Hz, 1H), 3.07 (br s, 3H), 2.99 (dd, J¼3.6, 15.6 Hz, 1H),
95.7, 71.5, 44.9, 42.2, 37.1; IR (liquid film, cmꢁ1) 3356, 2925, 2459,
2.79e2.68 (m, 4H); 13C NMR (CDCl3, 75 MHz):
d 197.3, 162.7, 153.4,
1645, 1568, 1419, 1364, 1275, 1112; m/z 248 (Mþ1)þ, 270 (MþNa)þ.
148.3, 136.9, 122.1, 120.4, 97.0, 71.7, 47.2, 44.8, 36.9; IR (liquid film,
cmꢁ1) 3359, 2953, 2927, 2809,1645, 1568,1471, 1418, 1275, 1108; m/
z 221 (Mþ1)þ.
4.4.19. (1E,6E)-1-(Dimethylamino)-5-hydroxocta-1,6-dien-3-one
4s. Brown oil; (found: C, 65.56; H, 9.38; N, 7.66. C10H17NO2 requires C,
65.54;H, 9.35;N, 7.64);1HNMR(CDCl3, 400 MHz):
d
7.56 (d, J¼13.2 Hz,
4.4.13. (E)-1-(Dimethylamino)-5-hydroxy-5-(quinolin-2-yl) pent-1-
en-3-one 4m. Brown oil; (found: C, 71.07; H, 6.69; N, 10.38.
C16H18N2O2 requires C, 71.09; H, 6.71; N, 10.36); 1H NMR (CDCl3,
1H), 5.75e5.65(m,1H), 5.50(dd, J¼5.6,15.2 Hz,1H), 5.00 (d, J¼13.2 Hz,
1H), 4.48e4.42 (m, 1H), 3.08 (br s, 3H), 2.82 (br s, 3H), 2.71e2.44 (m,
2H), 1.68 (d, J¼5.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d 197.5, 153.0,
250 MHz):
d
8.16 (d, J¼8.4 Hz, 1H), 8.09 (d, J¼8.4 Hz, 1H), 7.82 (d,
132.8,126.3, 96.7, 70.0, 46.7, 45.4, 37.1,17.9; IR (liquid film, cmꢁ1) 3396,
2919, 1628, 1568, 1422, 1361, 1264, 1115; m/z 184 (Mþ1)þ.
J¼8.0 Hz, 1H), 7.75e7.68 (m, 2H), 7.62e7.50 (m, 2H), 5.38 (dd, J¼3.7,
8.5 Hz, 1H), 5.08 (d, J¼12.6 Hz, 1H), 3.09e3.01 (m, 1H), 3.08 (br s,
3H), 2.86 (dd, J¼8.5, 15.3 Hz, 1H), 2.80 (br s, 3H); 13C NMR (CDCl3,
4.4.20. (E)-Ethyl-6-(dimethylamino)-2-hydroxy-2-methyl-4-oxohex-
5-enoate 6a. Pale yellow oil; (found: C, 57.65; H, 8.37; N, 6.09.
C11H19NO4 requires C, 57.62; H, 8.35; N, 6.11); 1H NMR (CDCl3,
100 MHz):
d 196.5, 162.9, 153.4, 146.6, 137.1, 129.6, 128.5, 127.6,
127.4, 126.2, 118.6, 96.1, 71.9, 48.0, 44.9, 37.0; IR (liquid film, cmꢁ1
3367, 2917, 1645, 1558, 1418, 1360, 1276, 1101; m/z 271 (Mþ1)þ.
)
300 MHz):
d
7.53 (d, J¼12.3 Hz, 1H), 4.97 (d, J¼12.3 Hz, 1H), 4.18 (q,
J¼6.6 Hz, 2H), 3.07 (br s, 3H), 3.04 (d, J¼15.9 Hz, 1H), 2.80 (br s, 3H),
4.4.14. (1E,6E)-1-(Dimethylamino)-5-hydroxy-7-phenylhepta-1,6-
dien-3-one 4n. Pale orange oil; (found: C, 73.41; H, 7.79; N, 5.74.
C15H19NO2 requires C, 73.44; H, 7.81; N, 5.71); 1H NMR (CDCl3,
2.60 (d, J¼15.9 Hz, 1H), 1.38 (s, 3H), 1.25 (t, J¼7.5 Hz, 3H); 13C NMR
(CDCl3, 75 MHz):
d 195.8, 176.0, 153.1, 95.6, 73.6, 61.3, 48.8, 45.2,
37.0, 25.9, 14.2; IR (liquid film, cmꢁ1) 3412, 2981, 1738, 1645, 1628,
1574, 1421, 1365, 1228, 1110; m/z 230 (Mþ1)þ, 252 (MþNa)þ.
400 MHz):
d
7.62 (d, J¼12.4 Hz, 1H), 7.39 (d, J¼8.0 Hz, 2H), 7.31 (m,
2H), 7.22 (m, 1H), 6.65 (d, J¼15.6 Hz, 1H), 6.26 (dd, J¼6.4, 15.6 Hz,
1H), 5.05 (d, J¼12.4 Hz, 1H), 4.72 (m, 1H), 3.12 (br s, 3H), 2.84 (br s,
3H), 2.72 (dd, J¼2.4, 16.0 Hz, 1H), 2.59 (dd, J¼8.8, 16.0 Hz, 1H); 13C
4.4.21. (E)-Ethyl-6-(dimethylamino)-2-hydroxy-2-isoproyl-4-
oxohex-5-enoate 6b. Orange oil; (found: C, 60.65; H, 8.98; N, 5.42.
C13H23NO4 requires C, 60.68; H, 9.01; N, 5.44); 1H NMR (CDCl3,
NMR (CDCl3, 75 MHz):
d
197.1, 153.1, 136.9, 131.2, 129.5, 128.4(ꢀ2),

M. De Rosa, A. Soriente / Tetrahedron 67 (2011) 5949e5955
5955
300 MHz):
d
7.54 (d, J¼12.9 Hz, 1H), 5.01 (d, J¼12.9 Hz, 1H), 4.20 (q,
References and notes
J¼7.5 Hz, 2H), 3.05 (br s, 3H), 2.93 (d, J¼15.9 Hz, 1H), 2.80 (br s, 3H),
2.66 (d, J¼15.9 Hz, 1H), 1.98e1.85 (m, 1H), 1.26 (t, J¼7.5 Hz, 3H), 0.95
(d, J¼7.2 Hz, 3H), 0.91 (d, J¼7.0 Hz, 3H); 13C NMR (CDCl3,
1. (a) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816e7817; (b) Breslow,
R.; Maitra, U. Tetrahedron Lett. 1983, 24, 1901e1904; (c) Breslow, R.; Maitra, U.
Tetrahedron Lett. 1984, 25, 1239e1240; (d) Breslow, R. Acc. Chem. Res. 1991, 24,
159e164; (e) Breslow, R. Acc. Chem. Res. 2004, 37, 471e478.
2. (a) Grieco, P. A.; Garner, P.; He, Z. Tetrahedron Lett. 1983, 24, 1897e1900; (b)
Grieco, P. A.; Yoshida, K.; Garner, P. J. Org. Chem. 1983, 48, 3137e3139.
3. Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2005, 44, 3275e3279.
62.89 MHz):
d 196.2, 175.8, 153.1, 96.1, 78.9, 61.4, 46.3, 45.1, 37.2,
36.0, 17.0, 16.5, 14.2; IR (liquid film, cmꢁ1) 3451, 2968, 2879, 1723,
1646, 1568, 1421, 1362, 1278, 1093; m/z 258 (Mþ1)þ, 280 (MþNa)þ.
4. For reviews about the state of the art of water as solvent in organic reactions: (a)
Lubineau, A.; Auge, J.; Queneau, Y. Synthesis 1994, 8, 741e760; (b) Li, C.-J.; Chang,
4.4.22. (E)-Ethyl-6-(dimethylamino)-2-hydroxy-4-oxo-2-phenylhex-
5-enoate 6c. Yellow oil; (found: C, 65.94; H, 7.24; N, 4.79.
C16H21NO4 requires C, 65.96; H, 7.27; N, 4.81); 1H NMR (CDCl3,
ꢁ
T. H. Organic Reactions in Aqueous Media; Wiley: New York, NY, 1997; (c) Grieco,
P. A. Organic Synthesis in Water; Blackie Academic and Professional: London,
1998; (d) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945e7950; (e)
250 MHz):
d 7.57e7.45 (m, 3H), 7.31e7.20 (m, 3H), 4.98 (d,
€
Lindstrom, U. M. Chem. Rev. 2002, 102, 2751e2771; (f) Reichardt, C. Solvent and
J¼12.5 Hz, 1H), 4.12 (q, J¼7.5 Hz, 2H), 3.42 (d, J¼16.5 Hz, 1H), 3.01
Solvent Effects in Organic Chemistry, 3rd ed.; Wiley-VCH: Weinheim, 2002; (g) Li,
C.-J. Chem. Rev. 2005, 105, 3095e3166; (h) Pirrung, M. C. Chem.dEur. J. 2006, 12,
1312e1317; (i) Li, C.-J.; Chang, T. H. Comprehensive Organic Reactions in Aqueous
Media, 2nd ed.; Wiley: New York, NY, 2007; (j) Raj, M.; Singh, V. K. Chem.
Commun. 2009, 6687e6703; (k) Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109,
725e748; (l) Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302e6337; (m)
Rueping, M.; Theissmann, T. Chem. Sci. 2010, 1, 473e476.
(br s, 3H), 2.80 (d, J¼16.5 Hz, 1H), 2.75 (br s, 3H), 1.15 (t, J¼7.5 Hz,
3H); 13C NMR (CDCl3, 62.89 MHz):
d 196.0, 174.4, 153.4, 141.3, 128.1
(ꢀ2), 127.5, 124.9 (ꢀ2), 95.2, 77.4, 61.6, 49.7, 44.9, 36.9, 13.8; IR
(liquid film, cmꢁ1) 3374, 2980, 1728, 1645, 1568, 1421, 1365, 1267,
1093; m/z 292 (Mþ1)þ, 314 (MþNa)þ.
5. Selected examples: (a) Loh, T.-P.; Feng, L.-C.; Wei, L.-L. Tetrahedron 2000, 56,
7309e7312; (b) Naik, S.; Bhattacharjya, G.; Talukdar, B.; Patel, B. K. Eur. J. Org.
Chem. 2004, 6, 1254e1260; (c) Deb, M. L.; Bhuyan, P. J. Tetrahedron Lett. 2006,
47, 1441e1443; (d) Habib, P. M.; Kavala, V.; Kuo, C.-W.; Yao, C.-F. Tetrahedron
Lett. 2008, 49, 7005e7007; (e) Halimehjani, Z. A.; Saidi, M. R. Tetrahedron Lett.
2008, 49, 1244e1248; (f) Habib, P. M.; Kavala, V.; Raju, B. R.; Kuo, C.-W.; Huang,
W.-C.; Yao, C.-F. Eur. J. Org. Chem. 2009, 26, 4503e4514; (g) Halimehjani, Z. A.;
Aryanasab, F.; Saidi, M. R. Tetrahedron Lett. 2009, 50, 1441e1443; (h) Sreedhar,
B.; Reddy, P. S.; Reddy, M. A. Synthesis 2009, 10, 1732e1738; (i) Williams, D. B.
G.; Cullen, A.; Fourie, A.; Henning, H.; Lawton, M.; Mommsen, W.; Nangu, P.;
Parker, J.; Renison, A. Green Chem. 2010, 12, 1919e1921; (j) Alam, J.; Keller, T.
H.; Loh, T.-P. J. Am. Chem. Soc. 2010, 132, 9546e9548; (k) Jung, E. J.; Park, B. H.;
Lee, Y. R. Green Chem. 2010, 12, 2003e2011; (l) Curti, C.; Battistini, L.; Zanardi,
F.; Rassu, G.; Zambrano, V.; Pinna, L.; Casiraghi, G. J. Org. Chem. 2010, 75,
8681e8684; (m) Zhang, X.; Jia, X.; Wang, J.; Fan, X. Green Chem. 2011, 13,
413e418.
4.4.23. (E)-Ethyl-2-(4-cyanophenyl)-6-(dimethylamino)-2-hydroxy-
4-oxohex-5-enoate 6d. Yellow solid, mp 107e109 ꢂC; (found: C,
64.51; H, 6.35; N, 8.84. C17H20N2O4 requires C, 64.54; H, 6.37; N, 8.86);
1H NMR (CDCl3, 250 MHz):
d
7.73 (d, J¼8.3 Hz, 2H), 7.64e7.56 (m, 3H),
5.00 (d, J¼12.5 Hz, 1H), 4.19 (q, J¼7.1 Hz, 2H), 3.4 (d, J¼16.3 Hz, 1H),
3.09 (br s, 3H), 2.82 (d, J¼16.3 Hz,1H), 2.82 (br s, 3H),1.21 (t, J¼7.1 Hz,
3H); 13C NMR (CDCl3, 62.89 MHz):
d 194.9, 173.3, 162.1, 153.6, 146.5,
132.0 (ꢀ2),125.9 (ꢀ2),118.9,111.4, 95.3, 77.4, 62.0, 49.9, 45.6, 36.8; IR
(liquid film, cmꢁ1) 3414, 2983, 2931, 228.8, 1732, 1644, 1557, 1417,
1366, 1217, 1093, 1019; m/z 317 (Mþ1)þ, 339 (MþNa)þ.
6. Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazzacani, A.; Sartori, G. Tetrahedron
Lett. 2001, 42, 5203e5205.
Acknowledgements
7. (a) De Rosa, M.; Soriente, A. Eur. J. Org. Chem. 2010, 6, 1029e1032; (b) De Rosa,
M.; Soriente, A. Tetrahedron 2010, 66, 2981e2986.
8. (a) Huang, Y.; Rawal, V. H. Org. Lett. 2010, 2, 3321e3323; (b) Huang, Y.; Rawal, V.
H. J. Am. Chem. Soc. 2002, 124, 9662e9663.
The authors thank Dr. Patrizia Oliva and Dr. Patrizia Iannece of
the University of Salerno for experimental support in the charac-
terization of new products.