Iodine-catalyzed allylation of 1,3-dicarbonyl compounds with allylic alcohols at room temperature

Article abstract of DOI:10.1016/j.tetlet.2007.11.005

A highly efficient iodine-catalyzed allylation of 1,3-dicarbonyl compounds with a wide variety of allylic alcohols has been developed. The reaction is operationally straightforward and proceeds under very mild conditions at room temperature in good to exc

Full text of DOI:10.1016/j.tetlet.2007.11.005

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 122–126
Iodine-catalyzed allylation of 1,3-dicarbonyl compounds with
allylic alcohols at room temperature
Weidong Rao, Adeline Hui Ling Tay,ꢀ Pei Jing Goh,ꢀ Jessica Mun Ling Choy,ꢀ
Justin Kaijie Ke and Philip Wai Hong Chan*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371, Singapore
Received 6 August 2007; revised 22 October 2007; accepted 1 November 2007
Available online 6 November 2007
Abstract—A highly efficient iodine-catalyzed allylation of 1,3-dicarbonyl compounds with a wide variety of allylic alcohols has been
developed. The reaction is operationally straightforward and proceeds under very mild conditions at room temperature in good to
excellent yields (up to 99%) and regioselectivity.
Ó 2007 Elsevier Ltd. All rights reserved.
Carbon–carbon bond formation is a fundamental oper-
ation in organic synthesis. An important type of such
reactions involves allylation of 1,3-dicarbonyl com-
pounds.1 Among the myriad of works dedicated to this
reaction, those on developing new methods that make
use of inexpensive and readily available electrophiles,
mild reaction conditions, simple manipulation, atom-
economy, and environmentally friendly catalysts have
become very topical.2–13 Indeed, a recent example is
the establishment of new synthetic strategies that
employ allylic alcohols as the allylating reagent in the
presence of Pd, Co, and Cu salts and furnish H2O as
the only side product.4 Recently, Lewis and Brønsted
acids such as BF3ÆOEt2,5 InCl3,6 FeCl3,7 LnOTf
(Ln = La, Yb, Sc, Hf),8 Bi(OTf)3,9 p-toluenesulfonic
acid,10 and H-Montmorillonite11 have also been
reported to catalyze these reactions efficiently. Despite
these advances, it remains a challenge to develop a metal
catalyst-free and operationally simple version of this
useful carbon–carbon bond forming reaction that can
be accomplished under mild conditions. In this context,
we envisioned molecular iodine would hold promise as a
catalyst for allylation of 1,3-dicarbonyl compounds with
allylic alcohols. An inexpensive, commercially available
reagent that has a high tolerance to air and moisture,
molecular iodine has recently been shown to be versatile
in mediating a wide variety of organic transformations
in excellent yields and with high selectivity.12,13 To our
knowledge, while the iodine-catalyzed allylation of
indoles with allylic acetates has been reported by
Chen and co-workers,13 there are no examples of the
iodine-catalyzed allylation of 1,3-dicarbonyl compounds
with allylic alcohols. As part of an ongoing program in
our group on organic transformations mediated by
iodine-based reagents,14 we report herein the allylation
of a wide variety of 1,3-dicarbonyl compounds with
allylic alcohols catalyzed by molecular iodine that
proceeded in good to excellent yields (up to 99%) and
regioselectivity, at room temperature, and without the
need for inert and moisture-free reaction conditions
(Scheme 1).
Initially, we found that treating a solution of pentane-
2,4-dione 1a (1 equiv) and (E)-1,3-di-p-tolylprop-2-
en-1-ol 2a (1.2 equiv) in CH2Cl2 contained in an open
round bottom flask with 5 mol % of iodine as catalyst
at room temperature for 2.5 h gave 3-((E)-1,3-di-p-tolyl-
allyl)pentane-2,4-dione 3a in 88% yield (Table 1, entry
O
O
I2 (5 mol%)
O
O
OH
R4
R1
R2
+
R1
R2
R3
CH2Cl2, air
r.t., 1-18 h
R3
R4
1
2
3
*
Corresponding author. Tel.: +65 6316 8760; fax: +65 6791 1961;
e-mail: waihong@ntu.edu.sg
R1-R4 = alkyl, aryl
ꢀ Equal contributions to this work.
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.005

W. Rao et al. / Tetrahedron Letters 49 (2008) 122–126
Table 1. Optimization of reaction conditionsa
123
X-ray crystal structure determination of a closely related
product (see later). Under similar conditions, slightly
lower product yields of 63–70% were obtained on
decreasing the catalyst loading from 5 to 1, and
0.5 mol %, or with MeCN instead of CH2Cl2 as the sol-
vent (entries 2, 3 and 5). In contrast, the analogous reac-
tions conducted in other solvents were less effective and
lower product yields of 20–52% were obtained for reac-
tions in C6H6, PhMe, THF, or H2O as the solvent
(entries 6–9). As anticipated, no reaction was observed
in the absence of the iodine catalyst and both starting
materials were recovered in quantitative yields (entry 4).
O
O
Me
Me
O
O
1a
+
I2, solvent
r.t.
Me
Me
OH
Me
Me
3a
Me
Me
2a
Entry
Catalyst loading (mol %)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9e
5
1
0.5
—
5
5
5
5
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
PhMe
C6H6
88
67
63
To define the scope of the iodine-catalyzed reactions, we
applied this process to a series of substituted 1,3-dicar-
bonyl compounds 1a–e and allylic alcohols 2a–j.16 As
shown in Table 2, allylation of a variety of substituted
1,3-dicarbonyl compounds with allylic alcohols bearing
electron-withdrawing and electron-donating groups pro-
ceeded in good to excellent yields comparable to those
obtained in the analogous metal-catalyzed reactions.4–11
Notably, this included the allylation of less acidic b-
ketoesters 1c and 1d with 2a, which gave the adducts
3f and 3g in good yields (entries 5 and 6). The present
procedure was also shown to work well for the allylation
of cyclic 1,3-diketone 1e with 2a, giving 3h in good yield
as its enol ether (entry 7). Similarly, the 1,5-diene alco-
hols 2e and 2f were found to be good allylating reagents,
affording excellent product yields (entries 8–10). In
instances where it was envisaged that reactions with
c
d
—
70
20
45
37
52
THF
H2O
a All reactions were performed at room temperature for 2.5 h with an
I2:1a:2a ratio = 1:20:24 in solvent.
b Isolated yield.
c Reaction conducted in the absence of iodine catalyst.
d No reaction after 5 h based on TLC analysis.
e Reaction carried out with 1 equiv of Bu4NBr for 15 h.
1).15 The retention of trans-stereochemistry in the ally-
lated product was confirmed by H NMR analysis and
1
Table 2. Iodine-catalyzed allylation of 1,3-dicarbonyl compounds 1a–e with allylic alcohols 2a–ja
OH
OH
Me Me
O
O
R1
R2
R3
R4
F
F
O
O
1b, R1 = R2 = Ph
1c, R1 = Ph, R2 = OEt
1d, R1 = Me, R2 = OEt
2b, R3 = R4 = H
2c, R3 = R4 = Br
2d, R3 = Cl, R4 = Me
1e
2e
OH
OH
Me
OH
O
O
R3
R4
Me
2f, R3 = Ph, R4 = CH=CHPh
2g, R3 = Ph, R4 =CH2CH2Ph
2h, R3 = Ph, R4 = Me
2i
2j
Entry
Substrates
Time (h)
Product
Yield (%)b
1
2
3
1a + 2b
1a + 2c
1a + 2d
2.5
2.5
2
3b, R1 = R2 = Me, R3 = R4 = H
3c, R1 = R2 = Me, R3 = R4 = Br
3d0, R1 = R2 = R4 = Me, R3 = Cl
3d00, R1 = R2 = R3 = Me, R4 = Cl
3e, R1 = R2 = Ph, R3 = R4 = Me
3f, R1 = Ph, R2 = OEt, R3 = R4 = Me
3g, R1 = R3 = R4 = Me, R2 = OEt
99
68
91c
O
O
R1
R2
4
5
6
1b + 2a
1c + 2a
1d + 2a
1.5
18
15
90
76d
65d
R3
R4
Me Me
HO
O
7
1e + 2a
2
3h
80
Me
Me
(continued on next page)

124
W. Rao et al. / Tetrahedron Letters 49 (2008) 122–126
Table 2 (continued)
Entry
Substrates
Time (h)
3.5
Product
Yield (%)b
O
O
Ph
Ph
8
1b + 2e
3i
85
F
F
O
O
9
10
1a + 2f
1b + 2f
2.5
1.5
3j, R = Me
3k, R = Ph
99
80
R
R
Ph
Ph
O
O
3l, R1 = R2 = R3 = Ph, R4 = CH2Bn
73
R1
R2
11
12
1b + 2g
1a + 2h
15
15
3m0, R1 = R2 = R3 = Me, R4 = Ph
3m00, R1 = R2 = R4 = Me, R3 = Ph
89e
R3
R4
O
O
Ph
Ph
Me
13
1b + 2i
2
3n
56
O
O
O
O
R
R
14
15
1a + 2j
1b + 2j
17
2
3o, R = Me
3p, R = Ph
51
54
Me
a All reactions were performed at room temperature with I2:1:2 ratio = 1:20:24 in a solution of CH2Cl2.
b Isolated yield.
c Isolated as an inseparable mixture of regioisomers in a ratio = 3:1.
d Isolated as an inseparable mixture of diastereomers in a ratio = 1:1.
e Isolated as an inseparable mixture of regioisomers in a ratio = 7:1.
allylic alcohols containing two different substituents
such as an aryl and alkyl group as in 2f–j would lead
to a mixture of regioisomeric products, the exclusive for-
mation of only one product indicates that the present
procedure is regioselective (entries 11 and 13–15). This
was further confirmed by X-ray structure analysis of
3n, as shown in Figure 1.17 The allylations of 1a with
either 2d or 2h were the only examples where the prod-
ucts 3d and 3m were furnished as a mixture of insepara-
ble regioisomers in ratios of 3:1 and 7:1, respectively
(entries 3 and 12). Moreover, in all the above reactions,
a side product that we initially presumed to be due to
dimerization of 2 was found to form competitively,
but disappears on consumption of the starting materials
(TLC analysis); this suggested that the dimer itself also
readily underwent reaction in the presence of 1. Indeed,
this was confirmed by isolating dimer 4a18 as the sole
product as a mixture of diastereomers in 97% yield from
the reaction of 2a with 5 mol % of iodine under the
Me
Me
Me
Me
I2 (10 mol%)
1a (2.4 equiv)
I2 (5 mol%)
2a
3a
O
CH2Cl2, r.t.
2.5 h
CH2Cl2, r.t.
16 h
95% yield
4a
97% yield
Figure 1. ORTEP drawing of 3n with thermal ellipsoids at 50%
probability levels.17
Scheme 2.

W. Rao et al. / Tetrahedron Letters 49 (2008) 122–126
125
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conditions described in Scheme 2. Dimer 4a could be
converted to 3a in 95% yield on treatment with 2.4 equiv
of 1a and 10 mol % of iodine catalyst in CH2Cl2 for 16 h
at room temperature.
Although the above experimental results do not provide
a clear perspective on the mechanism of the present pro-
cedure, we tentatively propose that the reaction pro-
ceeds via formation of an allylic carbocation species
from reaction of the allylic alcohol 2 with HI generated
in situ. The regioselectivities obtained in these reactions
could be due to subsequent attack at the sterically less
hindered carbon of this presumed allylic carbocation
intermediate by 1 or another molecule of 2 to produce
the reactive dimer 4, which, as mentioned earlier, reacts
further in the presence of 1 to give the allylated product
3. The role of iodine in facilitating the in situ generation
of HI is supported by the fact that 3b was obtained in a
comparable yield of 93% for the analogous reaction of
1a with 2b under the same conditions to those described
in Table 2, entry 1 but with NaI (5 mol %) and trifluoro-
acetic acid (5 mol %) in place of iodine as catalyst.
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In summary, we have demonstrated a practical and
operationally simplistic method for the allylation of
1,3-dicarbonyl compounds under atmospheric condi-
tions at room temperature that proceeded in good to
excellent yields. The present protocol is applicable to a
variety of 1,3-dicarbonyl compounds and allylic
alcohols containing electron-withdrawing and electron-
donating, and sterically demanding substrate combina-
tions. Efforts are currently underway to examine the
scope and mechanism of this reaction and will be
reported in due course as part of a full paper.
14. Rao, W.; Chan, P. W. H. Tetrahedron Lett. 2007, 48, 3789.
15. Typical experimental procedure: To a CH2Cl2 (2 mL)
solution of 1 (0.3 mmol, 1 equiv) and 2 (0.36 mmol,
1.2 equiv) contained in a round bottom flask open to air
at room temperature was added molecular iodine
(15 lmol, 5 mol %). The reaction was stirred until com-
pletion (TLC analysis). The reaction mixture was
quenched with aqueous Na2S2O3 (10 mL) and extracted
with CH2Cl2 (10 mL). The organic layer was washed with
brine (10 mL), dried over anhydrous MgSO4, concen-
trated, and purified by flash silica gel column chromato-
graphy (n-hexane/EtOAc as eluent) to give 3.
Acknowledgement
This work was supported by a College of Science Start-
Up Grant from Nanyang Technological University.
References and notes
1
16. Representative data for 3c: white solid; H NMR (CDCl3,
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400 MHz) d 7.44 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.4 Hz,
2H), 7.11–7.14 (m, 4H), 6.33 (d, 1H, J = 15.8 Hz), 6.12
(ddd, 1H, J = 15.7, 6.2, 1.3 Hz), 4.13–4.47 (m, 2H), 2.23
(s, 3H), 1.95 (s, 3H); 13C NMR (CDCl3, 100 MHz) d
202.3, 202.1, 138.9, 135.2, 132.2, 131.0, 129.7, 129.4, 127.9,
121.7, 121.3, 74.3, 48.3, 30.0, 29.7; IR (film, cmꢀ1) 1728,
1697, 1487, 1356, 1072; Anal. Calcd for C20H18Br2O2: C,
53.36; H, 4.03. Found: C, 53.27; H, 4.29. Compound 3k:
2. (a) Trost, B. M. Acc. Chem. Res. 2002, 35, 695; (b) Trost,
B. M. Science 1991, 254, 1471.
1
white solid; H NMR (CDCl3, 400 MHz) d 8.03 (d, 2H,
J = 7.4 Hz), 7.80 (d, 2H, J = 7.5 Hz), 7.08–7.56 (m, 16H),
6.54 (dd, 1H, J = 15.6, 10.3 Hz), 6.34 (d, 1H, J = 15.6 Hz),
6.14 (dd, 1H, J = 15.0, 10.4 Hz), 5.90–5.98 (m, 2H), 4.75
(t, 1H, J = 9.0 Hz); 13C NMR (CDCl3, 100 MHz) d 194.3,
193.8, 140.8, 137.2, 136.9, 133.9, 133.5, 133.3, 132.6, 132.2,
128.9, 128.8, 128.7, 128.6, 128.6, 128.5, 128.4, 127.4, 126.9,
126.3, 62.8, 50.0; IR (film, cmꢀ1) 1695, 1663, 1447, 1261,
989, 691; Anal. Calcd for C32H26O2: C, 86.85; H, 5.92.
Found: C, 86.51; H, 6.52.
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126
W. Rao et al. / Tetrahedron Letters 49 (2008) 122–126
17. CCDC 655561 contains the supplementary crystallo-
graphic data for this Letter. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
5.03 (dd, 2H, J = 10.2, 7.1 Hz), 2.35 (s, 3H), 2.34
(s, 3H), 2.31 (s, 3H), 2.30 (s, 3H); 13C NMR (CDCl3,
100 MHz) d 138.5, 137.5, 137.3, 134.0, 131.3, 131.1, 129.8,
129.5, 129.2, 127.1, 126.7, 79.0, 78.9, 21.3; IR (film, cmꢀ1
)
18. Dimer 4a: 1H NMR (CDCl3, 400 MHz) d 7.07–7.32
(m, 16H), 6.53 (dd, 2H, J = 15.9, 6.7 Hz), 6.28 (m, 2H),
3051, 1608, 1512, 1265, 968, 739; MS(EI): m/z 221
[M–C17H17O]+.