High regiocontrol in the zinc-mediated crotylation of aldehydes and ketones: A straightforward and facile approach to linear homoallylic alcohols in DMPU

Article abstract of DOI:10.1002/ejoc.201101847

The α-regioselectivity of carbonyl crotylation is a long-standing problem in the realm of C-C bond formation reactions. We demonstrate that zinc-mediated crotylation of aldehydes and ketones can afford α-linear homoallylic alcohols exclusively to provide

Full text of DOI:10.1002/ejoc.201101847

FULL PAPER
DOI: 10.1002/ejoc.201101847
High Regiocontrol in the Zinc-Mediated Crotylation of Aldehydes and Ketones:
A Straightforward and Facile Approach to Linear Homoallylic Alcohols in
DMPU
[a]
[a]
[a]
[a]
Li-Ming Zhao,* Li-Jing Wan, Hai-Shan Jin, and Shu-Qing Zhang
Keywords: Aldehydes / Ketones / Reaction mechanisms / Regioselectivity
The α-regioselectivity of carbonyl crotylation is a long-stand-
ing problem in the realm of C–C bond formation reactions.
We demonstrate that zinc-mediated crotylation of aldehydes
ation of aldehydes and ketones by using an easily available
starting material, such as crotyl bromide, zinc dust, and the
less-toxic solvent DMPU. The reaction has broad substrate
and ketones can afford α-linear homoallylic alcohols exclu- scope and is highly efficient. Moreover, a metallo-[3,5]-sig-
sively to provide a simple solution for this problem. In this matropic rearrangement is proposed to account for the high
context, we describe a method for the α-regioselective crotyl- α-regioselectivity in the zinc-mediated crotylation.
Introduction
direct crotylation of carbonyls with crotyl halides is more
significant to prepare linear homoallylic alcohols. As far as
we know, only two highly α-regioselective crotylations of
α-Linear homoallylic alcohols are a class of useful com-
pounds in organic synthesis, being easily converted into
many important building blocks for natural product and
biologically important molecule synthesis.[ In principle,
the crotylation of aldehydes and ketones with crotylmetals
is the most straightforward approach to access this class of
valuable compounds. However, most current metal-medi-
ated or -catalyzed crotylation reactions of carbonyl com-
pounds are γ-regioselective to provide the γ-adducts pre-
dominantly (Scheme 1).[ α-Selectivity is difficult to achieve
because γ-allylations are dominant with direct organome-
limited aldehydes have been reported in the presence of In
[6]
or In(OTf) by Loh’s group and Ramachandram’s group.
3
1]
Furthermore, there are no examples of ketones provided in
these methods. Indeed, in some studies on indium, com-
pounds such as In(OTf) proved to be ineffective in ketone
3
[7]
allylborations. However, the α-regioselective crotylation
of ketones is also desirable due to the ability to prepare
tertiary linear homoallylic alcohols, which have proven to
2]
[8]
be important building blocks and versatile synthons.
Thus, the search continues for a more general and effective
solution with broad substrate scope for the direct synthesis
of linear homoallylic alcohols.
[
3]
tallic additions.
Recently, our group reported a highly α-regioselective
[
9]
zinc-mediated prenylation of carbonyls. In contrast with
[
10]
other methods, ketones are tolerated in this reaction. We
therefore considered whether we could expand this method
to the corresponding crotylation reaction. Herein, we report
a facile and general zinc-mediated method for the crotyl-
ation of aldehydes and ketones with high α-regioselec-
tivity in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone
Scheme 1. Current crotylation of aldehydes with crotyl bromide.
Only a few methods of α-crotylation of aldehyde have
been described, and they usually give mixtures containing
[
4]
variable amounts of undesired γ-addition products. At
present, linear homoallylic alcohols are usually obtained by
the reaction of other crotyl sources (such as the γ-adduct of
(DMPU) to afford linear homoallylic alcohols in good to
high yields.
The significant advantages offered by this method we
have developed are: (1) The high α-regioselectivity. (2) The
high generality with broad substrate scope that covers alde-
hydes and ketones compared to the previous reports that
were only limited to a rather limited range of aldehydes.
(3) The use of a simple and operationally convenient pro-
cedure. (4) The low toxicity of the DMPU solvent com-
pared to previous toxic hexamethylphosphoramide
[
1,5]
homoallylic alcohol as the crotyl donor) with aldehydes.
From a synthetic point of view, the methodology involving
[
a] School of Chemistry and Chemical Engineering, and Jiangsu
Key Laboratory of Green Synthetic Chemistry for Functional
Materials, Xuzhou Normal University,
Xuzhou 221116, Jiangsu, China
Fax: +86-516-83536977
E-mail: lmzhao@xznu.edu.cn
Supporting information for this article is available on the (HMPA). (5) The low price and convenience of zinc.
WWW under http://dx.doi.org/10.1002/ejoc.201101847.
Eur. J. Org. Chem. 2012, 2579–2584
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2579

L.-M. Zhao, L.-J. Wan, H.-S. Jin, S.-Q. Zhang
FULL PAPER
Results and Discussion
Table 2, a variety of aromatic aldehydes underwent highly
α-regioselective crotylation and afforded the corresponding
α-addition products in good to high yield. The α-regioselec-
tive crotylation was effective for any substitution pattern at
the benzaldehyde. For example, 2-methoxybenzaldehyde
Initial experiments were carried out by using the reaction
between benzaldehyde and crotyl bromide as the model
(Table 1). To our delight, high α-regioselectivity was ob-
served in the crotylation with 71% of α-product 2a (Table 1,
(1b) gave the α-crotylation product in 79% yield (Table 2,
Entry 1), which is similar to the previous prenylation reac-
Entry 1), the α-crotylated alcohol from 3-methoxybenzalde-
[
9]
tion. Due to the carcinogenicity of HMPA, we explored
alternative solvents for the crotylation reaction based on
previous work on organozinc reagents,[ such as dimethyl
sulfoxide (DMSO), N,N-dimethylformamide (DMF), tetra-
methylurea (TMU), DMPU, and 1,3-dimethyl-2-imid-
azolidinone (DMI). The results showed that DMPU was
the most suitable solvent for the crotylation reaction to af-
ford α-adduct 2a exclusively in 68% yield (Table 1, Entry 5).
When using DMSO and DMF as the solvents, the reactions
gave low yields of the α-adduct together with variable
amounts of the γ-addition byproducts (Table 1, Entries 2
and 3). High α-regioselectivities were also acquired when
the crotylation was performed in TMU and DMI as sol-
vents, but the yields of the α-product were low (Table 1,
Entries 4 and 8). DMPU has a low toxicity and is almost
harmless to human beings.[ We thus chose to use DMPU
as the solvent for further investigation. To enable the ad-
dition to be carried out under much milder conditions, we
examined the reaction at a lower temperature. Unfortu-
nately, our attempts were not satisfactory. Decreasing the
reaction temperature from 130 to 110 °C caused the yield
hyde (1c) was obtained in 86% yield (Table 2, Entry 2), and
4
8
-methoxybenzaldehyde (1d) and piperonaldehyde (1e) gave
5 and 75% yield, respectively (Table 2, Entries 3 and 4).
11]
Also, the α-crotylation reaction proceeded effectively for
various benzaldehydes substituted with either electron-do-
nating or electron-withdrawing groups (Table 2, Entries 1–
5
and 6–9). Generally, benzaldehydes bearing electron-do-
nating substituents provided better yields (Table 2, En-
tries 2, 3, and 5). For those fluoro-substituted substrates,
the yields turned out to be slightly lower (Table 2, Entries 6
and 7). In addition to aromatic aldehydes, we also demon-
strated the crotylation of aliphatic aldehydes producing α-
adducts 2k and 2l in complete α-regioselectivity (Table 2,
Entries 10 and 11). It should be noted that α-adducts 2k
and 2l are volatile due to their relatively low molecular
weight, which did not allow efficient recovery of the ex-
pected compounds upon removal of the solvent. Conse-
quently, the actual yields of 2k and 2l are likely higher than
those of the isolated products.
12]
of the α-adduct to decrease and afforded an amount of γ- Table 2. α-Crotylation of various aldehydes and ketones.
adduct 3a, even though the reaction time was prolonged to
20 h (Table 1, Entry 6). These results highlighted the key
role of temperature in the regiocontrol of the reaction. A
high temperature was necessary to accelerate the α-crotyl-
ation reaction. Further optimization indicated that the reac-
tion temperature could be decreased to 120 °C with almost
no change in regioselectivity (Table 1, Entry 7).
[
a]
Entry
Substrate
Product Yield[%]
[b]
(
E/Z)
1
2
3
4
5
6
7
8
9
2-CH
3-CH
4-CH
3
OC
OC
OC
6
H
4
CHO (1b)
4
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
79 (70:30)
86 (70:30)
85 (58:42)
75 (58:42)
96 (67:33)
62 (66:34)
76 (67:33)
85 (63:37)
84 (75:25)
42 (61:39)
37 (71:29)
78 (53:47)
71 (67:33)
74 (55:45)
78 (73:27)
83 (74:26)
3
6
H
CHO (1c)
3
H CHO (1d)
6 4
Table 1. Optimization of reaction conditions.[a]
3,4-(OCH O)C H CHO (1e)
2
6
3
4-CH
4-FC
3-FC
4-ClC
4-BrC
3 6 4
C H CHO (1f)
6
H
H
4
CHO (1g)
CHO (1h)
CHO (1i)
CHO (1j)
6
4
6
H
4
6
H
4
10
11
12
13
14
15
16
cyclopropanecarbaldehyde (1k)
2-methylpropanal (1l)
Entry
Solvent
T [°C]
t [h]
2a [%][b]
3a [%][b]
C
6
H
5
COCH
OC COCH
4-CH COCH
3
(1m)
(1n)
(1o)
(1p)
(1q)
1
2
3
4
5
6
7
8
HMPA
DMSO
DMF
130
130
130
130
130
110
120
120
12
14
14
14
14
20
14
14
71
22
43
58
68
49
65
59
ND
3
5
ND
ND
12
trace
3
4-CH
3
6
H
4
3
3
C
6
H
4
3
2-ClC
4-ClC
6
H
H
4
COCH
COCH
3
TMU
DMPU
DMPU
DMPU
DMI
6
4
3
a] Isolated yield. [b] Determined by 1H NMR spectroscopy and
GC–MS.
[
[
a] Reactions were carried out with aldehyde (1.0 equiv.), crotyl
We next turned our attention to see whether this highly
bromide (2.5 equiv.), and zinc (3.0 equiv.). [b] Isolated yield.
α-regioselective zinc-mediated crotylation could be ex-
panded to ketones, which are generally less reactive than
On the basis of these results, we conducted the crotyl- aldehyde due to their poor electrophilicity and high steric
ation of benzaldehyde bearing various kinds of substituents hindrance. We were gratified to find that the α-crotylation
to investigate the generality of this method. As shown in was not limited to aldehydes. When reacting acetophenone
2580
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Eur. J. Org. Chem. 2012, 2579–2584

Regiocontrol in the Zn-Mediated Crotylation of Aldehydes and Ketones
Scheme 2. Proposed mechanism for the α-regioselective crotylation.
(1m) and substituted acetophenones 1n–q with crotylzinc
bromide in DMPU, desired α-adducts 2m–q were obtained
in good yields (Table 2, Entries 12–16). These results high-
lighted the generality and usefulness of our developed
method.
On the basis of the mechanistic proposal of prenylation
in our previous study,[ two possible pathways are proposed
to account for the high α-regioselectivity in the zinc-medi-
ated crotylation of aldehydes and ketones, as illustrated in
9]
Scheme 2, which are different from the conventional crotyl Scheme 3. Reaction of zinc alcoholate and benzaldehyde.
transfer mechanism.[
5d,13]
Both pathways involve the forma-
tion of γ-crotylation product A at the beginning. On the
one hand, zinc alcoholate A undergoes retro-allylation via reaction course, only aldehyde-derived γ-adduct 3a was ob-
a six-membered transition state first. The parent aldehyde served. The formation of keto-derived γ-adduct 3m was not
or ketone and primary crotylzinc are thus generated in situ. observed by TLC or GC–MS (Scheme 4). This result indi-
Then, a metallotropic equilibrium between primary and ter- cated that the relative order of reactivity of carbonyls to
tiary crotylzinc occurs in basic DMPU.[ Finally, the re- crotylzinc is aldehyde Ͼ ketone. Then, DMPU was intro-
sulting tertiary crotylzinc reacts again with the aldehyde or duced, and the mixture was heated at 120 °C for 14 h. The
ketone to afford zinc alcoholate F via a six-membered tran- reaction provided keto-derived α-adduct 2m in 75% yield
sition state (path A). On the other hand, the reaction ap- together with a small amount of aldehyde-derived α-adduct
pears to involve the coordination of DMPU by the zinc 2a (9% yield, Scheme 5). We speculate that major product
atom of initially formed zinc alcoholate A to form complex 2m probably results from the coordination of initially
B followed by a [3,5] sigmatropic shift[ via an eight-mem- formed zinc alcoholate to DMPU and acetophenone (1m)
bered transition state and elimination of carbonyl to afford followed by rearrangement to liberate benzaldehyde (1a).
intermediate E. Finally, elimination of DMPU from E re- Support for this conjecture derives from the fact that the
14]
15]
sults in the formation of zinc alcoholate F (path B).
aldehyde is more reactive toward the organozinc reagent
With the aim to demonstrate the proposed mechanism, than the ketone under our reaction conditions. If path-
we carried out the following experiment. First, α-adduct 3a way A is the preferred one, the major product should be
was synthesized and then treated with BuLi and zinc brom- aldehyde-derived α-adduct 2a, which results from the ad-
ide. The resulting zinc alcoholate reacted with benzaldehyde dition of the tertiary crotylzinc generated in situ to benzal-
(
7
1a) at 120 °C in DMPU to give desired α-adduct 2a in dehyde (1a). Thus, these data render an explanation of
2% isolated yield (Scheme 3). This result indicated that the pathway A for the regioselectivity less plausible. In path-
proposed mechanism appeared to be a reasonable assump- way B, it is quite probable that the Lewis acidity of zinc of
tion. initially formed γ-adduct A is enhanced by coordination
To further clarify the mechanism, we carried out a com- with DMPU. The metal zinc center in resulting complex B
petitive study by using an equimolar mixture of benzalde- maintains sufficient Lewis acidity and further coordinates
hyde (1a) and acetophenone (1m). The mixture was treated the carbonyl, which results in the formation of transition
with crotylzinc at room temperature for 0.5 h. During the state C.
Eur. J. Org. Chem. 2012, 2579–2584
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2581

L.-M. Zhao, L.-J. Wan, H.-S. Jin, S.-Q. Zhang
FULL PAPER
filtered through a Schlenk filter and kept under an atmosphere of
N
2
for the following reaction. A solution of carbonyl compound 1
(
1.5 mmol) in dry THF (3 mL) was added to a solution of crotyl-
zinc bromide prepared above. The solution was stirred for 1 h at
room temperature. Then, DMPU (2.0 mL) was added into the reac-
tion mixture, followed by removal of the initial reaction solvent
(
THF). The mixture was heated to 120 °C for 14 h. The residue
was purified by flash column chromatography to afford α-adduct
2
2
.
1
3
a: Pale yellow oil. H NMR (400 MHz, CDCl , E isomer): δ =
Scheme 4. A competitive study of benzaldehyde and acetophenone
at room temperature.
7.34–7.27 (m, 5 H), 5.68–5.54 (m, 1 H), 5.46–5.39 (m, 1 H), 4.71
(dd, J = 8.0, 5.2 Hz, 1 H), 2.59–2.41 (m, 2 H), 2.08 (s, 1 H), 1.68
1
(
d, J = 6.8 Hz, 3 H) ppm. H NMR (400 MHz, CDCl
3
, Z isomer):
δ = 4.66 (dd, J = 8.0, 4.8 Hz, 1 H), 1.60 (d, J = 6.8 Hz, 3 H) ppm.
1
3
C NMR (100 MHz, CDCl
3
, E isomer): δ = 144.13, 128.39,
1
1
1
1
1
28.39, 127.61, 127.50, 125.86, 125.86, 125.71, 73.89, 36.90,
1
3
2.96 ppm. C NMR (100 MHz, CDCl
3
, Z isomer): δ = 144.08,
29.42, 128.36, 128.36, 127.42, 126.81, 125.82, 125.82, 73.52, 42.79,
+
8.04 ppm. HRMS (ESI): calcd. for C11
85.0943; found 185.0944.
H14ONa [M + Na]
1
2
b: Yellow oil. H NMR (400 MHz, CDCl
3
, E isomer): δ = 7.33
(dd, J = 7.6, 1.6 Hz, 1 H), 7.26–7.21 (m, 1 H), 6.96 (td, J = 7.6,
0
5
3
.8 Hz, 1 H), 6.87 (dd, J = 8.0, 0.8 Hz, 1 H), 5.63–5.54 (m, 1 H),
.51–5.44 (m, 1 H), 4.95–4.91 (m, 1 H), 3.86 (s, 3 H), 2.58–2.40 (m,
Scheme 5. A competitive study of benzaldehyde and acetophenone
at 120 °C.
1
H), 1.60 (d, J = 6.8 Hz, 3 H) ppm. H NMR (400 MHz, CDCl
3
,
Z isomer): δ = 3.84 (s, 3 H), 1.68 (d, J = 6.0 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl
3
, E isomer): δ = 156.49, 132.01, 128.26,
Conclusions
126.91, 126.75, 126.49, 120.69, 110.44, 70.41, 55.29, 34.89,
1
1
4
2.91 ppm. 13C NMR (100 MHz, CDCl
32.05, 128.49, 128.18, 127.56, 126.75, 120.69, 110.42, 69.79, 55.27,
0.73, 18.05 ppm. HRMS (ESI): calcd. for C12 Na [M +
3
, Z isomer): δ = 156.41,
In conclusion, we have developed a simple and direct
procedure for the α-crotylation of a wide range of aldehydes
and ketones mediated by inexpensive and convenient zinc Na] 215.1048; found 215.1050.
16 2
H O
+
in an environmentally benign solvent. This method, simple
to conduct and not requiring complex catalysts, is not only
mechanistically interesting but also represents a valuable ex-
1
2
7
5
3
c: Yellow oil. H NMR (400 MHz, CDCl , E isomer): δ = 7.28–
.24 (m, 1 H), 6.96–6.91 (m,2 H), 6.82 (dd, J = 8.0, 1.6 Hz, 1 H),
.68–5.58 (m, 1 H), 5.46–5.38 (m, 1 H), 4.70 (dd, J = 8.0, 5.2 Hz,
tension to the realm of ketones because the direct α-crotyl- 1 H), 3.82 (s, 3 H), 2.61–2.43 (m, 2 H), 2.06 (s, 1 H), 1.62 (d, J =
1
ation with crotylmetals is currently limited to aldehydes. On 6.8 Hz, 3 H) ppm. H NMR (400 MHz, CDCl
3
, Z isomer): δ =
1
3
the basis of the results of our reaction, we may conclude 4.65 (dd, J = 8.0, 5.2 Hz, 1 H), 1.70 (d, J = 6.4 Hz, 3 H) ppm.
C
NMR (100 MHz, CDCl
3
, E isomer): δ = 159.74, 145.92, 129.40,
that our method has higher α-regioselectivity and broader
substrate scope than existing carbonyl α-crotylation meth-
ods. Further studies to show the synthetic utility of the
highly α-regioselective crotylation is now in progress.
1
1
1
2
27.58, 125.71, 118.20, 112.95, 111.41, 73.79, 55.23, 36.86,
1
3
2.97 ppm. C NMR (100 MHz, CDCl
45.87, 129.37, 126.80, 125.71, 118.15, 112.95, 111.33, 73.41, 42.74,
9.70, 18.02 ppm. HRMS (ESI): calcd. for C12 Na [M +
3
, Z isomer): δ = 159.74,
16 2
H O
+
Na] 215.1048; found 215.1053.
1
2
d: Yellow oil. H NMR (400 MHz, CDCl
3
, E isomer): δ = 7.29
Experimental Section
(
d, J = 8.4 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 5.66–5.54 (m,1 H),
General: All aldehydes and ketones were commercially available.
Liquid aldehydes and ketones were freshly distilled before used and
solid aldehydes were used as purchased without further purifica-
tion. Solvents were treated prior to use according to the standard
methods. Other reagents were used as purchased without further
5.45–5.37 (m,1 H), 4.68–4.61 (m,1 H), 3.80 (s, 3 H), 2.61–2.38 (m,2
H), 2.01 (s, 1 H), 1.61 (d, J = 6.8 Hz, 3 H) ppm. H NMR
1
(400 MHz, CDCl , Z isomer): δ = 2.05 (s, 1 H), 1.68 (d, J = 6.4 Hz,
3
1
3
3 H) ppm. C NMR (100 MHz, CDCl , E isomer): δ = 159.03,
3
136.35, 127.38, 127.11, 127.11, 125.87, 113.77, 113.77, 73.52, 55.28,
1
13
13
purification. H NMR and C NMR spectra were recorded at 400
and 100 MHz, respectively, in CDCl with chemical shift (δ) given
36.82, 12.99 ppm. C NMR (100 MHz, CDCl , Z isomer): δ =
3
3
158.97, 136.30, 129.21, 127.07, 127.07, 126.98, 113.77, 113.77,
73.18, 55.28, 42.73, 18.06 ppm. HRMS (ESI): calcd. for
in ppm relative to TMS as an internal standard. Multiplicities are
indicated, s (singlet), d (doublet), t (triplet), q (quartet), br. s (broad
singlet), m (multiplet). High-resolution mass spectra (HRMS) were
recorded by using electrospray ionization (ESI) with a micrOTOF-
Q II instrument (Bruker).
+
C H O Na [M + Na] 215.1048; found 215.1049.
1
2
16
2
1
2
1
5
3
e: Yellow oil. H NMR (400 MHz, CDCl , E isomer): δ = 6.89 (s,
H), 6.83–6.76 (m, 2 H), 5.95 (s, 2 H), 5.68–5.55 (m, 1 H), 5.44–
.37 (m, 1 H), 4.64–4.57 (m, 1 H), 2.59–2.32 (m, 2 H), 1.98 (d, J
= 2.4 Hz, 1 H), 1.62 (d, J = 6.8 Hz, 3 H) ppm. H NMR (400 MHz,
1
General Procedure for the Synthesis of α-Adducts 2: Crotyl bromide
(
0.4 mL, 3.8 mmol) was added to a suspension of activated zinc
CDCl
(d, J = 6.0 Hz, 3 H) ppm. C NMR (100 MHz, CDCl
δ = 147.73, 146.89, 138.27, 127.57, 126.76, 119.24, 108.03, 106.43,
3
, Z isomer): δ = 6.87 (s, 1 H), 2.04 (d, J = 2.0 Hz, 1 H), 1.69
[
16]
13
powder
(300 mg, 4.6 mmol) in dry THF (10 mL); the reaction
3
, E isomer):
mixture was stirred for 1 h at room temperature. The solution was
582
2
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Eur. J. Org. Chem. 2012, 2579–2584

Regiocontrol in the Zn-Mediated Crotylation of Aldehydes and Ketones
1
00.97, 73.74, 36.92, 12.98 ppm. 13C NMR (100 MHz, CDCl
isomer): δ = 147.72, 146.82, 138.22, 129.40, 125.66, 119.18, 108.03,
06.43, 100.95, 73.38, 42.81, 18.03 ppm. HRMS (ESI): calcd. for
3
, Z 121.12, 72.77, 42.78, 18.03 ppm. HRMS (ESI): calcd. for
+
C
11
H13BrONa [M + Na] 263.0048; found 263.0047.
1
C
1
2
k: Colorless oil. H NMR (400 MHz, CDCl
3
, E isomer): δ = 5.97–
+
12
H
14
O
3
Na [M + Na] 229.0841; found 229.0842.
5.81 (m, 1 H), 5.15–5.09 (m, 2 H), 2.68 (t, J = 5.6 Hz, 1 H), 2.39–
1
2
f: Colorless oil. H NMR (400 MHz, CDCl
3
, E isomer): δ = 7.24
2.36 (m, 1 H), 1.76 (s, 1 H), 1.11 (d, J = 6.4 Hz, 3 H), 0.94–0.91
1
(d, J = 8.8 Hz, 2 H), 7.16 (d, J = 8.0 Hz, 2 H), 5.67–5.57 (m, 1 H),
(m, 1 H), 0.51–0.49 (m, 2 H), 0.28 (s, 2 H) ppm. H NMR
5
.46–5.38 (m, 1 H), 4.69–4.62 (m, 1 H), 2.60–2.34 (m, 2 H), 2.34
(400 MHz, CDCl , Z isomer): δ = 2.79 (t, J = 5.6 Hz, 1 H), 2.45–
3
1
13
(
(
6
1
7
s, 3 H), 1.98 (s, 1 H), 1.61 (d, J = 6.8 Hz, 3 H) ppm. H NMR 2.42 (m,1 H), 1.85 (s, 1 H), 0.56–0.53 (m, 2 H) ppm. C NMR
400 MHz, CDCl
3
, Z isomer): δ = 2.03 (s, 1 H), 1.68 (dd, J = (100 MHz, CDCl , E isomer): δ = 138.87, 113.62, 77.73, 43.03,
3
.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl
, E isomer): δ = 14.42, 13.49, 1.44, 0.01 ppm. C NMR (100 MHz, CDCl , Z iso-
13
3
3
41.20, 137.17, 129.09, 129.09, 127.47, 125.88, 125.82, 125.82,
mer): δ = 138.84, 112.83, 77.59, 41.83, 12.98, 12.58, 1.38, 0.16 ppm.
3.75, 36.86, 21.14, 18.09 ppm. 13C NMR (100 MHz, CDCl
, Z HRMS (ESI): calcd. for C H ONa [M + Na] 149.0942; found
+
3
8
14
isomer): δ = 141.15, 137.06, 129.30, 129.06, 129.06, 126.97, 125.78,
25.78, 73.38, 42.77, 21.14, 13.02 ppm. HRMS (ESI): calcd. for
149.0942.
1
1
2l: Colorless oil. H NMR (400 MHz, CDCl
3
, E isomer): δ = 5.83–
+
C
12
H16ONa [M + Na] 199.1099; found 199.1098.
5.74 (m, 1 H), 5.12 (d, J = 12.8 Hz, 2 H), 3.10 (s, 1 H), 2.38–2.31
1
2
7
5
2
g: Yellow oil. H NMR (400 MHz, CDCl
3
, E isomer): δ = 7.35–
(
m, 1 H), 1.78–1.73 (m, 1 H), 1.46 (s, 1 H), 1.03 (d, J = 6.4 Hz, 3
.24 (m, 2 H), 7.02 (t, J = 8.6 Hz, 2 H), 5.68–5.56 (m, 1 H), 5.42–
.36 (m, 1 H), 4.69 (dd, J = 7.2, 6.0 Hz, 1 H), 2.58–2.32 (m, 2 H),
.09 (s, 1 H), 1.59 (d, J = 6.8 Hz, 3 H) ppm. H NMR (400 MHz,
1
H), 0.97 (d, J = 6.4 Hz, 3 H), 0.92 (d, J = 6.4 Hz, 3 H) ppm. H
NMR (400 MHz, CDCl , Z isomer): δ = 5.07 (d, J = 6.4 Hz, 2 H),
.18 (s, 1 H), 1.38 (s, 1 H) ppm. C NMR (100 MHz, CDCl
isomer): δ = 140.53, 116.09, 79.42, 41.41, 30.36, 19.87, 17.10,
3
1
13
3
3
, E
CDCl
6.4 Hz, 3 H) ppm. C NMR (100 MHz, CDCl
62.16 (d, J = 244.0 Hz), 139.82 (d, J = 3.6 Hz), 127.87, 127.53,
3
, Z isomer): δ = 4.65 (dd, J = 8.0, 5.2 Hz, 1 H), 1.69 (d, J
1
3
=
3
, E isomer): δ =
13
1
1
3
6.41 ppm. C NMR (100 MHz, CDCl , Z isomer): δ = 141.91,
14.60, 79.52, 40.62, 30.50, 19.64, 16.96, 13.54 ppm. HRMS (ESI):
1
1
1
3
27.44, 125.38, 115.26, 115.04, 73.22, 37.00, 12.94 ppm. C NMR
, Z isomer): δ = 162.12 (d, J = 243.4 Hz), 139.77
d, J = 3.5 Hz), 129.72, 127.48, 127.39, 126.51, 115.23, 115.03,
2.84, 42.89, 18.03 ppm. HRMS (ESI): calcd. for C11 13FONa [M
16ONa [M + Na]+ 151.1099; found 151.1098.
calcd. for C
8
H
(100 MHz, CDCl
3
1
2m: Yellow oil. H NMR (400 MHz, CDCl
3
, E isomer): δ = 7.47–
(
7
+
7.42 (m, 2 H), 7.36–7.31 (m, 2 H), 7.25–7.22 (m, 1 H), 5.68–5.54
H
+
(m, 1 H), 5.30–5.19 (m, 1 H), 2.65–2.59 (m, 2 H), 2.12 (s, 1 H),
Na] 203.0848; found 203.0841.
1
1
.64 (d, J = 8.0 Hz, 3 H), 1.51 (s, 3 H) ppm. H NMR (400 MHz,
CDCl , Z isomer): δ = 2.45–2.39 (m, 2 H), 2.02 (s, 1 H), 1.61 (d, J
6.8 Hz, 3 H), 1.56 (s, 3 H) ppm. C NMR (100 MHz, CDCl
isomer): δ = 147.99, 130.57, 128.12, 128.12, 126.49, 125.86, 124.82,
1
2
7
5
h: Yellow oil. H NMR (400 MHz, CDCl
3
, E isomer): δ = 7.33–
3
.27 (m, 1 H), 7.14–7.06 (m, 2 H), 6.95 (t, J = 8.4 Hz, 1 H), 5.71–
.56 (m, 1 H), 5.44–5.37 (m, 1 H), 4.72 (dd, J = 7.2, 5.8 Hz, 1 H),
.58–2.29 (m, 2 H), 2.14 (s, 1 H), 1.60 (d, J = 6.8 Hz, 3 H) ppm.
13
=
3
, E
2
13
1
24.82, 73.66, 47.23, 29.90, 18.05 ppm. C NMR (100 MHz,
CDCl , Z isomer): δ = 147.88, 128.33, 128.33, 126.57, 125.86,
24.96, 124.96, 124.84, 74.41, 41.22, 29.74, 13.01 ppm. HRMS
1
H NMR (400 MHz, CDCl
3
, Z isomer): δ = 4.67 (dd, J = 8.0,
3
4
.8 Hz, 1 H), 1.69 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz,
1
CDCl
3
, E isomer): δ = 162.96 (d, J = 243.8 Hz), 146.83 (d, J =
+
(
ESI): calcd. for C12
H
16ONa [M + Na] 199.1099; found 199.1101.
6
2
.3 Hz), 129.84 (d, J = 8.6 Hz), 128.12, 125.17, 121.40 (d, J =
.7 Hz), 114.24 (d, J = 21.1 Hz), 112.77 (d, J = 22.0 Hz), 73.17 (d,
1
2n: Yellow oil. H NMR (400 MHz, CDCl
3
, E isomer): δ = 7.35
13
(d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 2 H), 5.66–5.54 (m,1 H),
J = 1.8 Hz), 36.89, 12.95 ppm. C NMR (100 MHz, CDCl
isomer): δ = 162.96 (d, J = 243.8 Hz), 146.78 (d, J = 6.1 Hz),
29.98, 129.81 (d, J = 8.5 Hz), 126.28, 121.36 (d, J = 3.0 Hz), 114.2
d, J = 21.3 Hz), 112.74 (d, J = 21.9 Hz), 72.75 (d, J = 1.6 Hz),
2.77, 18.03 ppm. HRMS (ESI): calcd. for C11 13FONa [M +
3
, Z
5
1
.31–5.20 (m,1 H), 3.81 (s, 3 H), 2.62–2.37 (m,2 H), 2.01 (s, 1 H),
.64 (d, J = 6.0 Hz, 3 H), 1.50 (s, 3 H) ppm. H NMR (400 MHz,
1
1
(
4
CDCl
s, 3 H) ppm. 1 C NMR (100 MHz, CDCl
139.19, 129.37, 124.97, 124.97, 124.11, 112.39, 112.39, 72.34, 54.20,
3
, Z isomer): δ = 2.01 (s, 1 H), 1.61 (d, J = 6.8 Hz, 3 H), 1.54
3
(
3
, E isomer): δ = 157.25,
H
+
Na] 203.0848; found 203.0836.
1
3
46.26, 28.93, 17.05 ppm. C NMR (100 MHz, CDCl
3
, Z isomer):
1
2
i: Colorless oil. H NMR (400 MHz, CDCl
3
, E isomer): δ = 7.33–
δ = 157.18, 139.05, 129.58, 127.11, 125.00, 125.00, 112.68, 112.68,
7.27 (m, 4 H), 5.70–5.56 (m, 1 H), 5.43–5.36 (m, 1 H), 4.72–4.68
7
3.10, 54.44, 40.24, 28.77, 12.01 ppm. HRMS (ESI): calcd. for
(
m, 1 H), 2.58–2.31 (m, 2 H), 2.05 (s, 1 H), 1.60 (d, J = 6.0 Hz, 3
Na [M + Na]+ 229.1205; found 229.1208.
13 18 2
C H O
1
3
H) ppm. H NMR (400 MHz, CDCl , Z isomer). δ = 4.67–4.64 (m,
1
H), 2.10 (s, 1 H), 1.69 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR 2o: Pale yellow oil. H NMR (400 MHz, CDCl
1
, E isomer): δ =
3
(
1
100 MHz, CDCl
3
, E isomer): δ = 142.57, 133.11, 128.49, 128.49,
7.33 (t, J = 8.0 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 5.67–5.53 (m,
1 H), 5.30–5.20 (m, 1 H), 2.59 (d, J = 7.2 Hz, 1 H), 2.38 (d, J =
1
3
28.05, 127.24, 127.24, 125.21, 73.14, 36.95, 12.96 ppm. C NMR
, Z isomer): δ = 142.53, 133.02, 129.91, 128.47,
28.47, 127.20, 127.20, 126.31, 72.74, 42.81, 18.02 ppm. HRMS
(100 MHz, CDCl
3
8.4 Hz, 1 H), 2.34 (s, 3 H), 2.10 (s, 1 H), 1.64 (d, J = 6.4 Hz, 3 H),
1
1
(
2
1.49 (s, 3 H) ppm. H NMR (400 MHz, CDCl
3
, Z isomer): δ =
+
ESI): calcd. for C11
19.0563.
H
13ClONa [M + Na] 219.0553; found
2.62 (d, J = 6.4 Hz, 1 H), 2.42 (d, J = 8.4 Hz, 1 H), 2.01 (s, 1 H),
1
3
1.61 (d, J = 7.2 Hz, 3 H), 1.54 (s, 3 H) ppm. C NMR (100 MHz,
CDCl , E isomer): δ = 145.08, 136.10, 130.44, 128.82, 128.82,
25.11, 124.75, 124.75, 73.52, 47.20, 29.99, 20.95, 18.06 ppm.
1
3
2
j: Yellow oil. H NMR (400 MHz, CDCl , E isomer): δ = 7.46 (d,
3
1
3
1
C
J = 8.0 Hz, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 5.69–5.56 (m, 1 H),
5
2
NMR (100 MHz, CDCl
3
, Z isomer): δ = 144.97, 135.99, 128.82,
.42–5.35 (m, 1 H), 4.68 (dd, J = 7.2, 5.8 Hz, 1 H), 2.57–2.31 (m,
H), 2.11 (s, 1 H), 1.59 (d, J = 6.8 Hz, 3 H) ppm. H NMR
1
1
2
28.82, 128.20, 125.99, 124.77, 124.77, 74.29, 41.18, 29.82, 20.95,
1
+
3.05 ppm. HRMS (ESI): calcd. for C13
13.1256; found 213.1256.
H18ONa [M + Na]
3
(400 MHz, CDCl , Z isomer): δ = 4.63 (dd, J = 8.0, 6.4 Hz, 1 H),
13
1
3
.69 (d, J = 6.4 Hz, 3 H) ppm. C NMR (100 MHz, CDCl , E iso-
1
mer): δ = 143.09, 131.44, 131.44, 128.09, 127.60, 127.60, 125.17,
21.21, 73.18, 36.90, 12.97 ppm. 13C NMR (100 MHz, CDCl
isomer): δ = 143.05, 131.42, 131.42, 129.96, 127.57, 127.57, 126.27,
2p: Yellow oil. H NMR (400 MHz, CDCl
3
, E isomer): δ = 7.68
1
3
, Z (d, J = 7.6 Hz, 1 H), 7.35 (d, J = 7.6 Hz, 1 H), 7.27–7.16 (m, 2 H),
5.66–5.53 (m, 1 H), 5.22–5.10 (m, 1 H), 3.07–2.77 (m, 2 H), 2.80
Eur. J. Org. Chem. 2012, 2579–2584
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2583

L.-M. Zhao, L.-J. Wan, H.-S. Jin, S.-Q. Zhang
FULL PAPER
(
dd, J = 14.4, J = 8.4 Hz, 1 H), 2.55 (s, 1 H), 1.71 (s, 3 H), 1.63
Robles, J. M. Cuerva, J. Justicia, J. Org. Chem. 2011, 76, 732–
735; k) A. V. Malkov, M. Barlog, Y. Jewkes, J. Mikusek, P. Ko-
covsky, J. Am. Chem. Soc. 2011, 133, 4800–4804; l) A. Millan,
A. G. Campana, B. Bazdi, D. Miguel, L. Alvarez de Cien-
fuegos, A. M. Echavarren, J. M. Cuerva, Chem. Eur. J. 2011,
1
3
(d, J = 6.0 Hz, 3 H) ppm. H NMR (400 MHz, CDCl , Z isomer):
δ = 3.18–3.13 (m, 1 H), 2.57–2.51 (m, 1 H), 2.59 (s, 1 H), 1.67 (s,
H) ppm. 1 C NMR (100 MHz, CDCl
3
3
1
2
1
7
3
, E isomer): δ = 143.84,
31.34, 130.93, 128.38, 128.24, 128.02, 126.81, 124.88, 75.02, 38.04,
7.24, 13.02 ppm. 13C NMR (100 MHz, CDCl
, Z isomer): δ =
17, 3985–3994.
3
[
3] a) Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207–2293; b)
44.01, 131.30, 130.78, 130.55, 128.19, 128.05, 126.81, 125.82,
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+
C
12
H
15ClONa [M + Na] 233.0709; found 233.0719.
1
2
q: Yellow oil. H NMR (400 MHz, CDCl
3
, E isomer): δ = 7.38 (t,
J = 8.4 Hz, 2 H), 7.30 (d, J = 8.4 Hz, 2 H), 5.69–5.53 (m, 1 H),
5
6
isomer): δ = 2.42–2.32 (m, 1 H), 2.12 (s, 1 H), 1.65 (d, J = 6.8 Hz,
3
.27–5.16 (m, 1 H), 2.65–2.52 (m, 2 H), 2.02 (s, 1 H), 1.60 (d, J =
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3
.8 Hz, 3 H), 1.54 (s, 3 H) ppm. H NMR (400 MHz, CDCl , Z
13
H), 1.49 (s, 3 H) ppm. C NMR (100 MHz, CDCl
3
, E isomer):
δ = 146.37, 132.38, 128.78, 128.20, 128.20, 126.42, 126.42, 124.49,
4.15, 41.14, 29.80, 13.03 ppm. 1 C NMR (100 MHz, CDCl
isomer): δ = 146.50, 132.29, 131.06, 128.20, 128.20, 126.40, 126.40,
25.40, 73.38, 47.14, 29.92, 18.07 ppm. HRMS (ESI): calcd. for
3
7
3
, Z
1
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C
+
12
H
15ClONa [M + Na] 233.0709; found 233.0689.
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13
cle): Copies of the H NMR and C NMR spectra for compounds
a–q.
2
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stirring for 20 min, the metal was filtered, washed and dried
under high vacuum for 3 h.
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2
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Received: December 23, 2011
Published Online: March 13, 2012
R. E. Estevez, J. L. Oller-Lopez, E. Alvarez-Manzaneda, R.
2584
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2579–2584