Synthesis of multifunctionalized building blocks via vinylogous addition of Chan's diene to carbonyl and carbonyl-related electrophiles, mediated by molecular iodine

Article abstract of DOI:10.1016/j.tet.2011.02.036

The synthesis of multifunctionalized β-ketoesters has been achieved by using molecular iodine as a catalyst under very mild conditions. The vinylogous addition of Chan's diene 1 to carbonyl and carbonyl-related compounds (aldehydes, ketones, imines and acetals) occurred with high efficiencies and with complete γ-selectivity, giving a useful method for the synthesis of interesting libraries of different δ-functionalized β-ketoesters.

Full text of DOI:10.1016/j.tet.2011.02.036

Tetrahedron 67 (2011) 2768e2772
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Tetrahedron
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Synthesis of multifunctionalized building blocks via vinylogous addition of Chan’s
diene to carbonyl and carbonyl-related electrophiles, mediated by molecular
iodine
,
b
b,
Rosaria Villano a , Maria R. Acocella , Arrigo Scettri
*
*
a Istituto di Chimica BiomolecolaredCNR, Trav. La Crucca 3, Reg. Baldinca, 07040 Li Punti, Sassari, Italy
Dipartimento di Chimica, Universita di Salerno, via Ponte don Melillo, 84084 Fisciano, Salerno, Italy
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of multifunctionalized b-ketoesters has been achieved by using molecular iodine as a catalyst
Received 22 October 2010
Received in revised form 26 January 2011
Accepted 14 February 2011
Available online 19 February 2011
under very mild conditions. The vinylogous addition of Chan’s diene 1 to carbonyl and carbonyl-related
compounds (aldehydes, ketones, imines and acetals) occurred with high efficiencies and with complete
g-selectivity, giving a useful method for the synthesis of interesting libraries of different
d-functionalized
b-ketoesters.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Chan’s diene
Vinylogous reaction
Iodine
d
g
-Functionalized
-Selectivity
Catalysis
b-ketoesters
1. Introduction
The vinylogous aldol addition of Chan’s diene 11 is one of the
H
X
O
O
OTMS
OTMS
X
+
most elegant and powerful methods for the synthesis of -hydroxy-
d
R
OMe
OMe
-ketoesters,2 molecules containing a C-5 highly functionalized
R
R
b
R
fragment (3 with R2¼H and X¼O, Scheme 1), which are useful key-
intermediates in the synthesis of many complex natural products.3
Consequently, the development of more efficient and competitive
methodologies for their synthesis is of great importance.4
3
1
2
R = aryl, alkyl; R = H, alkyl; X= O, NAr
Scheme 1. Synthesis of libraries of
tion of Chan’s diene 1.
d-functionalized b-ketoesters by vinylogous addi-
On the other hand, the number of known protocols of the re-
action that can be extended from aldehydes to other carbonyl and
carbonyl-related electrophiles with good results is very limit-
ed,1c,2c,5 so the development of more efficient and general condi-
tions for the synthesis of libraries of compounds 3, with different
R1, R2 and X (Scheme 1), is an extremely interesting research area.
Lewis acids, such as TiCl4 or BF3OEt2 were often used as pro-
moters in the vinylogous aldol addition but these methods always
require harsh and strictly controlled reaction conditions (dry sol-
vents and reagents, inert atmosphere, stoichiometric amounts of
Lewis acids, very low temperatures).2 Moreover, poor results were
often obtained by using these activators in the presence of elec-
trophiles other than aldehydes.
Recently, molecular iodine has been used in many organic trans-
formations6 and, even though its catalytic action has not been com-
pletely investigated from a mechanistic point of view,7 its mild Lewis
acidity makes this system compatible with a lot of different sub-
strates. In a recent paper,8 iodine was proposed as a very efficient
catalystfor Mukaiyama aldoladditionof2-(trimethylsilyloxy)furanto
several aromatic and aliphatic aldehydes. Compared to other cata-
lysts, iodine presents many advantages including that it is very in-
expensive, has low toxicity and is readily available; moreover, short
reaction times and operative simplicity (no special precautions in
order to exclude air and moisture from the system are required) make
iodine-mediated procedures particularly convenient.
* Corresponding authors. Tel.: þ39 079 2841204; fax: þ39 079 2841298 (R.V.);
tel.: þ39 089 969583; fax: þ39 089 969603 (A.S.). e-mail addresses: rosar-
ia.villano@icb.cnr.it (R. Villano), scettri@unisa.it (A. Scettri).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.036

R. Villano et al. / Tetrahedron 67 (2011) 2768e2772
2769
Here we report an efficient approach for the addition of Chan’s
diene to aldehydes by using molecular iodine as catalyst, under very
mild reaction conditions. The same reaction conditions, optimized
for aldehydes, were applied to other carbonyl and carbonyl-related
electrophiles with the production of a libraryof interesting scaffolds.
efficiency. Moreover, a 1/2 aldehyde/Chan’s diene ratio seemed to
be the key for high efficiency (compare entries 6 and 7, Table 1).
These results are particularly interesting also because, in the
absence of electrophiles and under the typical reaction conditions
(CH2Cl2, 0 ꢀC, 1 min), molecular iodine caused the complete de-
composition of Chan’s diene leading to a very complex mixture of
products, confirming that the addition to electrophiles is much
faster than other competing processes.
2. Results and discussion
The versatility of this methodology was demonstrated by evalu-
ating the reactivity of N-containing electrophiles, particularly imines,
under the same reaction conditions, leading to the achievement of
a new protocol for the vinylogous Mannich addition of Chan’s
diene.10,11
In a model study, benzaldehyde 2a and Chan’s diene 1 in CH2Cl2
solution were stirred at 0 ꢀC in the presence of a catalytic amount of
molecular iodine (10%) (Scheme 2). Quantitative conversion was
observed after only 1 min and, more importantly, after the desily-
lation procedure the vinylogous aldol 3a was isolated in 95% yield
(Table 1, entry 1), indicating that the process occurs with complete
In the initial phase, a one-pot approach was attempted by using
iminessynthesized insituaccordingto a knownprocedure10 (Scheme
3, Table 2, entries 1 and 3). Therefore, aldehydes 2a and 2b, chosen as
representative substrates, were submitted to reaction with aniline 5
for 1 h at room temperature in the presence of silica gel and anhy-
g
-selectivity in spite of the presence of two reactive nucleophilic
sites.9 No improvements were observed in the reaction outcome by
using increased catalyst loading (up to 25%) or more prolonged
reaction times (up to 3 h).
ꢁ
drous3A molecularsieves(MS).Then, inthesamevesseltheresulting
imines were directly reacted with Chan’s diene 1 under the usual
conditions, as reported in Scheme 3 and Table 2. Notably, the for-
mation of the expected adducts 6a,b was found to take place albeit in
moderate yields. However a control experiment, carried out on 2a by
omitting the addition of Chan’s diene 1, indicated the occurrence of
significant decomposition of the imine to the corresponding alde-
hyde, so that, after 1 min at 0 ꢀC a mixture 45/55 aldehyde/imine was
recovered. Therefore, bearing in mind that both the catalytic prop-
erties of I2 and the stability of Chan’s diene 1 could be negatively
influenced by the presence of molecular sieves/silica gel system, the
experiments of entries 1 and 3 (Table 2) were repeated, first removing
the solid phase by rapid filtration, and then adding 1 and I2. This
simplemodificationoftheoriginalprotocolallowedtheattainmentof
thecorresponding products6a,b insignificantlyhigher yields (entries
2 and 4). The procedure proved to be successful with other aromatic
Scheme 2. Vinylogous addition of Chan’s diene 1 to aldehydes 2.
Table 1
Vinylogous addition to aldehydes via Scheme 2
Entrya
Aldehyde
2
Product
Yield 3%b
1
2
3
4
PhCHO
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
95
99
90
95
89
41
99
79
97
70
pMeOeC6H4CHO
pNO2eC6H4CHO
oNO2eC6H4CHO
pCF3eC6H4CHO
pFeC6H4CHO
pFeC6H4CHO
2-FuCHO
5
6c
7
and a,b-unsaturated aldehydes (entries 5,6) while the aliphatic de-
rivative 2i was completely unreactive (entry 7).
2f
3f
8
9
10
2g
2h
2i
3g
3h
3i
PhCH]CHCHO
CH3(CH2)9CH2CHO
Table 2
Vinylogous addition to imines via Scheme 3
a
In all entries 1/2/0.1 aldehyde/diene/iodine ratio was used.
All the yields refer to isolated chromatographically pure compounds, whose
Yield 6%a
b
Entry
R-CHO
2
Product
structures were assigned by analytical and spectroscopic data.
1
Ph
Ph
2a
2a
2b
2b
2c
2h
2i
6a
6a
6b
6b
6c
6h
6i
59
80
66
84
90
96
ND
c
2b
3
In this entry 1/1.5 aldehyde/diene ratio was used.
pMeOeC6H4
pMeOeC6H4
pNO2eC6H4
PhCH]CH
CH3(CH2)9CH2
4b
5b
6b
7b
In order to demonstrate the generality of these reaction condi-
tions, a variety of aldehydes were reacted with Chan’s diene under
the optimized experimental conditions (Table 1, entries 2e10). It is
notable that high yields and no side products were obtained with
different classes of aldehydes. In fact, as shown in Table 1, variously
substituted aromatic aldehydes (entries 1e7) as well as hetero-ar-
a
All the yields refer to isolated chromatographically pure compounds, whose
structures were assigned by analytical and spectroscopic data.
b
In this entry molecular sieves and silica were removed before adding I2 and
Chan’s diene.
omatic (entry 8) and
react with Chan’s diene to give, after the desilylation procedure,
hydroxy- -ketoesters of type 3 in good to excellent yields. Fur-
thermore, the result reported in entry 10 is particularly intriguing
since the addition of masked acetoacetic esters to aliphatic alde-
hydes, according to known procedures, often takes place with low
a,b-unsaturated substrates (entry 9) could
In our opinion, these results are of particular synthetic value
because we have realized a very efficient methodology for the di-
rect synthesis of a series of d-amino-b-ketoesters, by using a one-
pot approach, which is particularly appropriate for the diversity-
oriented synthesis.
d-
b
OTMS OTMS
OMe
1
NH2
NH
O
O
MS / silica
RCHO
+
1. I2, 1 min / 0 °C
2. TFA
CH2Cl2, 1 h / rt
R
OMe
6
2
5
Scheme 3. Vinylogous addition of Chan’s diene 1 to imines synthesized in situ according to a known procedure.10

2770
R. Villano et al. / Tetrahedron 67 (2011) 2768e2772
Encouraged by these findings, we examined the behaviour of
conditions, the vinylogous addition of 1 to acetals 8 proved to be
much faster than other competing processes, allowing a very effi-
other two classes of milder electrophiles, that is, ketones and ace-
tals, which have often proven to be unreactive under the conditions
suitable for aldehydic substrates (Scheme 4).
cient approach to
d-alkoxy-b-ketoesters, while aldehydes 2a,b,
generated by the I2-mediated decomposition of the starting ma-
terials 8a,b, could afford the corresponding vinylogous aldols 3a,b
in rather poor yields.
O
These latter results were particularly interesting; in fact,
a careful screening in the literature highlighted how the availability
of efficient methodologies for the vinylogous addition of dienoxy
silanes to acetals was very limited and usually very strong Lewis
acids (as TiCl4, SnCl4 or ZnCl2) and very controlled experimental
conditions were necessary in order to have good yields.2,13 In this
context, only a few examples concerned the employment of Chan’s
diene but generally the acetalic function was in a more complex
OH
O
O
R
R
7
R
OMe
R
9
OTMS
OTMS
I , CH Cl , 1 min / 0
C
OMe
OR
O
O
1
structure (
that, after the preliminary
a
-haloacetals, 2,5-dimethoxytetrahydrofuran, etc.), so
R
OMe
MeO
R
OMe
H
g-addition of the diene, a rapid in situ
10, R= Me
3, R= H
evolution of intermediates (usually by involving
a-position of 1)
was observed.1c,14
8
Scheme 4. Vinylogous addition of Chan’s diene 1 to ketones 7 and acetals 8.
3. Conclusion
In conclusion, molecular iodine was found to be an efficient cat-
alyst for the vinylogous addition of Chan’s diene to several carbonyl
and carbonyl-related electrophiles, under very mild conditions and
without side-products formation. This methodology is very com-
petitive because it is simple, fast, quite cheap and very efficient and
the reagents used have low toxicity. Moreover, thanks to iodine
properties, no particular operational precautions are necessary.
Finally, the generality of this method and the possibility to ex-
tend the experimental conditions from aldehydes to other car-
bonyl-related electrophiles (ketones, imines and acetals) make this
strategy potentially useful in order to access to a library of struc-
turally diversified compounds, which could be appropriate for drug
discovery.
As summarized in Fig. 1, both ketones and acetals exhibited high
reactivity under the typical conditions, resulting in the very effi-
cient and exclusive formation of g-vinylogous aldol-type products
and confirming the significant catalytic versatility of molecular
iodine.
OH
O
O
OH
O
O
OMe
OMe
9b (80%)
9a (89%)
OMe
OR
O
O
4. Experimental section
4.1. General
HO
O
OMe
O
All reactions were performed in oven-dried (140 ꢀC) vials. Thin-
layer chromatography was performed on Merck Kiesegel 60 F254
plates eluting with the solvents indicated, visualized by a 254 nm
UV lamp and aqueous ceric sulfate solution. Column chromato-
graphic purification of products was carried out using silica gel 60
(70e230 mesh, Merck). All reagents (Aldrich and Fluka) were used
without further purification. Infrared spectra were recorded on
a Bruker 22 series FT-IR spectrometer. NMR spectra were recorded
on a Varian 400 (400.135 MHz for 1H and 100.03 MHz for 13C)
spectrometer. ESI-mass spectra are reported in the form of m/z.
10a R = Me (82%)
3a R = H (8%)
9c (45%)
OR
O
O
OMe
O
10b R = Me (68%)
3b R = H (15%)
Fig. 1. Synthesis of products 9 and 10 by vinylogous addition of Chan’s diene 1 to
ketones and acetals. All the yields in parentheses refer to isolated chromatographically
pure compounds.
4.2. Typical procedure for the iodine-catalyzed vinylogous
addition to aldehydes
In particular, ketones seemed to be particularly intriguing
electrophiles for the possibility to introduce a quaternary carbon in
the scaffold (9aec, Fig. 1). It has to be noted that, in the case of
employment of cyclohexanone as starting material of type 7, the
modest yield (45%) can be attributed to a partial decomposition of
aldol 9c on silica gel via retro-aldol reaction.
To a solution of iodine (10 mol %, 0.025 mmol) in CH2Cl2 (1 mL),
aldehyde 2 (0.25 mmol) was added. The mixture was cooled at 0 ꢀC
and diene 1 (2 equiv, 0.50 mmol) was added. The mixture was stirred
at this temperature for 1 min, then the reaction was quenched with
aqueous sodium thiosulfate solution to remove iodine and extracted
with CH2Cl2. Evaporation of the solvent, followed by desilylation
according to Carreira’s protocol4k and purification on silica gel (ethyl
Furthermore, as regards acetals 8, the usual protocol proved to
be appropriate to circumvent the main difficulty represented by the
well-known instability of acetals in the presence of iodine.12 In fact,
a control experiment, carried out on p-methoxy-benzaldehyde di-
methyl acetal 8b in the absence of Chan’s diene, (CH2Cl2 solution,
acetate/hexane) afforded pure d-hydroxy-b-ketoesters 3. The spec-
troscopic data of aldols 3a,4f 3b,4f 3c,4f 3d,4c 3e,15 3f,4e 3g4e and 3h4f
matched the ones reported in the literature.
0
ꢀC, I2) indicated the fast and quantitative regeneration of the al-
dehydic functionality after 1 min. Nevertheless, under the typical
4.2.1. Methyl 5-hydroxy-3-oxohexadecanoate (3i). Pale yellow oil. Rf
0.5 (Et2O/CHCl3 1/9); HRMS (ESI) calcd for C17H33O4 [MþH]þ:

R. Villano et al. / Tetrahedron 67 (2011) 2768e2772
2771
301.2379, found: 301.2368; nmax (liquid film) 1740, 1616, 1514, 1378,
1106 cmꢁ1; 1H NMR (400 MHz, CDCl3)
4.09e4.03 (m, 1H), 3.75 (s,
13C NMR
d 204.2, 167.3, 70.9, 52.8, 52.4, 50.6, 37.5, 25.6, 21.9 (NMR
d
data matched the ones reported in the literature).16
3H), 3.49 (s, 2H), 2.73 (dd, 1H, J¼3.3, 17.4 Hz), 2.64 (dd, 1H, J¼8.8,
17.4 Hz), 1.51e1.25 (m, 20H), 0.88 (t, 3H, J¼6.8 Hz). 13C NMR
d
203.6,
4.4.4. Methyl 5-methoxy-3-oxo-5-phenylpentanoate (10a). Slightly
yellowishoil. Rf 0.5 (petroleum ether/AcOEt 8/2); HRMS (ESI) calcd for
C13H17O4 [MþH]þ: 237.1127, found: 237.1115; nmax (liquid film) 3032,
167.4, 67.5, 52.4, 49.6, 36.5, 31.9, 29.62, 29.59, 29.55, 29.53, 29.47,
29.3, 25.4, 22.6, 14.1.
2951, 1745, 1716, 1330 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.38e7.28
4.3. Typical procedure for the iodine-catalyzed vinylogous
addition to imines
(m, 5H), 4.64 (dd, J¼4.0, 9.4 Hz, 1H), 3.72 (s, 3H), 3.49 (s, 2H), 3.20 (s,
3H), 3.05(dd, J¼9.4,16.0 Hz,1H), 2.70 (dd, J¼4.0,16.0 Hz,1H).13C NMR
d
200.7, 167.4, 140.5, 128.6, 128.0, 126.5, 79.5, 56.8, 52.3, 51.2, 50.0.
ꢁ
In a dry vial silica gel (90 mg), 3 A molecular sieves (89 mg,
activated by heating under the atmosphere at 120 ꢀC for at least
48 h), CH2Cl2 (0.2 mL), aldehyde 2 (1 equiv, 0.125 mmol) and aniline
(1 equiv, 0.125 mmol) were added. The resulting mixture was
stirred for 1 h at room temperature, then it was cooled at 0 ꢀC and
after few minutes a solution of iodine (10 mol %, 0.012 mmol) in
CH2Cl2 (0.8 mL) and Chan’s diene 1 (2 equiv, 0.25 mmol) were
added.
4.4.5. Methyl
5-methoxy-5-(4-methoxyphenyl)-3-oxopentanoate
(10b). Yellow oil. Rf 0.5 (petroleum ether/AcOEt 8/2); HRMS (ESI)
calcd for C14H19O5 [MþH]þ: 267.1232, found: 267.1239; nmax (liquid
film) 3033, 2945, 1740, 1708, 1330 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.23 (d, J¼8.4 Hz, 2H), 6.88 (d, J¼8.4 Hz, 2H), 4.57 (dd, J¼4.0, 9.0 Hz,
1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.48 (br s, 2H), 3.16 (s, 3H), 3.04 (dd,
J¼9.0, 15.6 Hz, 1H), 2.68 (dd, J¼4.0, 15.6 Hz, 1H). 13C NMR
d 200.8,
The resulting mixture was stirred for 1 min at 0 ꢀC, then it was
quenched by the addition of aqueous sodium thiosulfate solution.
The reaction mixture was extracted with CH2Cl2 and the com-
bined organic phase was dried (MgSO4) and concentrated.
The desilylation of the residue according to Carreira’s protocol4k
followed by purification on silica gel (petroleum ether/AcOEt 9/1)
gave the products 6 (entries 1 and 3 in Table 2). For entries 2, 4, 5, 6
and 7 (Table 2) a variation of this procedure was realized. In par-
ticular, after the synthesis of the imine, molecular sieves and silica
gel were removed by filtration (by using a Pasteur pipette plugged
with a bit of cotton wool) before cooling at 0 ꢀC and before adding
iodine solution and 1, but no isolation of the imine was required.
The spectroscopic data of imino-aldols 6 matched the ones repor-
ted in the literature.10
167.4, 159.4, 132.4, 127.8, 114.0, 79.1, 56.5, 55.2, 52.3, 51.2, 50.0.
Acknowledgements
ꢀ
We are grateful to MIUR, Universita di Salerno and Regione
Autonoma della Sardegna (L.R. 7 agosto 2007, n. 7) for the financial
support.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.02.036.
References and notes
4.4. Typical procedure for the iodine-catalyzed vinylogous
addition to ketones or acetals
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1337e1339; (e) Phukan, P. J. Org. Chem. 2004, 69, 4005e4006; (f) Banik, B. K.;
Samajdar, S.; Banik, I. J. Org. Chem. 2004, 69, 213e219; (g) Ji, S. J.; Wang, S. Y.;
4.4.1. Methyl 5-hydroxy-3-oxo-5-phenylhexanoate (9a). Pale yellow
oil. Rf 0.2 (petroleum ether/AcOEt 9/1); 1H NMR (400 MHz, CDCl3)
d
7.44e7.40 (m, 2H), 7.36e7.31 (m, 2H), 7.25e7.21 (m, 1H), 3.69 (s,
3H), 3.36 (s, 2H), 3.30 (d, J¼16.8 Hz, 1H), 2.97 (d, J¼16.8 Hz, 1H), 1.55
(s, 3H). 13C NMR
d 203.9, 167.0, 146.8, 128.3, 126.9, 124.2, 73.3, 53.8,
52.4, 50.3, 30.5 (NMR data in the literature16 were recorded in CCl4).
4.4.2. Methyl 5-hydroxy-3-oxo-5-phenylheptanoate (9b). Pale yel-
low oil. Rf 0.2 (petroleum ether/AcOEt 9/1); HRMS (ESI) calcd for
C14H19O4 [MþH]þ: 251.1283, found: 251.1291; nmax (liquid film)
2560, 1740, 1700 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.39e7.30 (m,
4H), 7.25e7.20 (m,1H), 3.69 (s, 3H), 3.33 (s, 2H), 3.32 (d, J¼16.8,1H),
2.96 (d, J¼16.8, 1H), 1.89e1.73 (m, 2H), 0.74 (t, J¼7.6 Hz, 3H). 13C
NMR
d 204.2, 167.0, 145.0, 128.2, 126.8, 124.9, 75.8, 52.5, 52.4, 50.5,
35.8, 7.6.
4.4.3. Methyl 4-(1-hydroxycyclohexyl)-3-oxobutanoate (9c). Pale
yellow oil. Rf 0.2 (petroleum ether/AcOEt 9/1); 1H NMR (400 MHz,
CDCl3)
d 3.74 (s, 3H), 3.49 (s, 2H), 2.70 (s, 2H), 1.68e1.25 (m, 10H).

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R. Villano et al. / Tetrahedron 67 (2011) 2768e2772
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