Ferric chloride hexahydrate-catalyzed highly regio- And stereoselective conjugate addition reaction of 2,3-allenoates with grignard reagents: An efficient synthesis of β,γ-alkenoates

Article abstract of DOI:10.1002/adsc.200900091

Ferric chloride hexahydrate was shown to be an efficient catalyst for the conjugate addition of 2,3-allenoates with alkyl-, aryl-, or vinyl-Grignard reagents to synthesize polysubstituted β,γ-unsaturated alkenoates with high regio- and stereoselectivity.

Full text of DOI:10.1002/adsc.200900091

FULL PAPERS
DOI: 10.1002/adsc.200900091
Ferric Chloride Hexahydrate-Catalyzed Highly Regio- and
Stereoselective Conjugate Addition Reaction of 2,3-Allenoates
with Grignard Reagents: An Efficient Synthesis of
b,g-Alkenoates
Guobi Chai,a Zhan Lu,a Chunling Fu,a and Shengming Maa,*
a
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027,
Zhejiang, Peopleꢀs Republic of China
Fax : (+86)-21-6260-9305; e-mail: masm@mail.sioc.ac.cn
Received: February 10, 2009; Revised: May 2, 2009; Published online: July 7, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900091.
Abstract: Ferric chloride hexahydrate was shown to ferent reaction conditions with or without a catalyst
be an efficient catalyst for the conjugate addition of to construct an allylic quaternary carbon at the a-po-
2,3-allenoates with alkyl-, aryl-, or vinyl-Grignard re- sition of the ester group and a stereocontrollable re-
agents to synthesize polysubstituted b,g-unsaturated tention of the carbon-carbon double bond.
alkenoates with high regio- and stereoselectivity. The
in situ formed magnesium dienolate may readily Keywords: allenes; esters; Grignard reagents; iron;
react with different electrophilic reagents under dif- Michael addition
Introduction
action of an organolithium with 2,3-allenoates in the
presence of CuCN·2LiCl (0.5 equiv.)[4e,f] also affords
Substituted b,g-unsaturated alkenoates bearing a non- b,g-unsaturated alkenoates with good regio- and ste-
conjugated double bond are widely found in biologi- reoselectivity.
cally active natural products such as actiniarin A
However, these reactions are limited to the use of
methyl ester,[1a] 4-hydroxycinnamate derivatives,[1b] cy- stoichiometric or substoichiometric organocuprate re-
tochalasin Q,[1c] and, thus, they have caught the atten- agents; further improvements in this area are obvious-
tion of many synthetic organic and pharmaceutical ly desirable. Particularly, in the view of industrial ap-
chemists.[1] It is not so easy to synthesize this type of plications, an environmentally friendly and cheap cat-
compounds due to the possible migration of the C=C alytic system is important. In this context, iron is one
double bond to the conjugated a,b-position and the of the best choices.[5,6] In our previous work, we uti-
stereoselectivity referring to the formation of the C= lized the anhydrous iron salt FeACTHNUTRGENUGN(acac)3 to catalyze the
C double bond.[2] On the other hand, allenes, especial- conjugate addition reaction of 2,3-allenoates with
ly those with electron-withdrawing groups, have Grignard reagents, affording b,g-unsaturated alke-
become of great interest in synthetic organic chemis- noates with high regio- and stereoselectivity.[7]
try owing to the high reactivity of the allene moiety.[3]
Compared with FeACHTUNGTER(UNNG acac)3, FeCl3·6H2O is surely
In the past decades, the conjugate addition of organo- more readily available and extremely cheap. Howev-
metallic reagents to 2,3-allenoates has proven to be er, there are very limited reports concerning its appli-
an efficient way to synthesize b,g-unsaturated carbon- cations as a catalyst.[8] In this context, we present our
yl compounds via the a-protonation of the in situ recent surprising observation on the use of simple
formed metallic dienolates:[4] addition reactions of FeCl3·6H2O as an alternative catalyst for the conju-
lithium dialkylcuprates or dialkenylcuprate with gate addition reaction of 2,3-allenoates with various
simple 2,3-allenoates[4a] or 2,3-allenoates with func- Grignard reagents to afford b,g-unsaturated alke-
tional groups such as hydroxy,[4b] methoxycarbonyl,[4c] noates. Furthermore, highly stereocontrollable a-acy-
or ethylthio groups[4d] afford b,g-unsaturated alke- lation and allylation reactions of the in situ generated
noates with good regio- and stereoselectivity; the re- magnesium dienolate intermediate were achieved by
1946
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Ferric Chloride Hexahydrate-Catalyzed Highly Regio- and Stereoselective Conjugate Addition
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variations of the electrophiles and reaction condi-
tions.[9,10]
Results and Discussion
Synthesis of 2,3-Allenoates 3
2,3-Allenoates 3a and 3e–3o can be prepared from
the corresponding Wittig reagents with acyl chlorides
2 in the presence of Et3N (Scheme 1).[11]
2-Alkyl-4-phenyl-2,3-butadienoates 3b–3d can be
prepared from the esterification of corresponding 2,3-
allenoic acids 4 (Scheme 2).[12]
Scheme 2. Synthesis of 2,3-allenoates 3b–3d.
FeCl3·6H2O-Catalyzed Highly Regio- and
Stereoselective Conjugate Addition Reaction of 2,3-
Allenoates with Grignard Reagents
ACHTUNGTRENNUNG
of Z-5a was formed when no catalyst was used with
Initially, we accidentally attempted the reaction of 3a being recovered in 84% yield (entry 4, Table 1). In
ethyl 4-phenyl-2-propyl-2,3-butadienoate 3a with all cases, the formation of the E isomer of the conju-
methylmagnesium chloride under the catalysis of gate addition product was not observed; the a,b-unsa-
5 mol% of FeCl3·6H2O and the same conditions uti- turated conjugated isomer 3-methyl-4-phenyl-2-
lized in our previous work.[7] To our surprise, ethyl 3- propyl-2-butenoate 6a was formed to the extent of
methyl-4-phenyl-2-propyl-3(Z)-butenoate Z-5a was ꢀ1.2% (entries 1–4, Table 1). Obviously, compared
afforded in 93% yield highly selectively (entry 1, with the results from FeACHTNUTRGNEUNG(acac)3, although the forma-
Table 1). The stereochemistry was established by tion of a,b-unsaturated enoate 6a is slightly higher,[7]
NOE analysis (Figure 1). FeCl3·6H2O is more efficient and high yielding (com-
Next, 2 mol% of FeCl3·6H2O was used and a simi- pare entries 1 and 2 with entries 5 and 6, Table 1).
lar result was obtained (entry 2, Table 1). However, With the optimized reaction conditions in hand, we
when we reduced the loading of FeCl3·6H2O further explored the substrate scope of the FeCl3·6H2O-cata-
to 0.5 mol%, the reaction was quite slow, resulting in lyzed conjugate addition reaction of 2,3-allenoates
a very low yield of Z-5a (entry 3, Table 1). Only 13% with alkyl-Grignard reagents as shown in Table 2. R1
Scheme 1. Synthesis of 2,3-allenoates 3a and 3e–3o.
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Table 1. Effect of catalyst on the FeACTHUNTGRNEUNG(III)-catalyzed conjugate
addition of 2,3-allenoate 3a with methylmagnesium chlori-
de.[a]
Entry FeCl3·6H2O Yield of Z- Recovery of Yield of
[mol%]
5a [%][b]
3a [%][b]
6a [%][b]
1
2
3
4
5
5
2
93
98
46
13
81
–
–
46
84
–
0.7
0.7
1.2
0.9
0.8
0.5
–
Stereocontrollable a-Acylation and Allylation
Reactions of the in situ Generated Magnesium
Dienolate Intermediates with Electrophiles
5[c]
[a]
The reaction was conducted using 0.4 mmol of the 2,3-al-
lenoate, 3 equiv. of the Grignard reagent (3M solution in
THF) in 5 mL of toluene at À788C.
As a result, the magnesium 1,3-dienolate 7a may un-
dergo a coupling reaction with acetyl chloride to
afford Z-9a in 65% yield with an Z/E ratio of >99%
(conditions A, entry 1, Table 4). Similarly,[10] the reac-
tion of the in situ generated magnesium dienolate 7a
with allyl acetate at À788C followed by warming up
to room temperature afforded a-acylated 3(E)-alke-
noate E-9a in 50% yield with a reversed stereoselec-
tivity (E/Z=93/7) (conditions B, entry 1, Table 4).
The stereochemistry was also established by NOE
analysis. It should be noted that the formation of the
a-allylated product was not observed based on the
1H NMR analysis of the crude reaction mixture. The
in situ generated dienolates from the reactions of 3f,
3m and 3o also reacted with acetyl chloride or allyl
acetate affording the corresponding products Z-9 or
[b]
[c]
1
Determined by H NMR spectroscopy using 1,3,5-trime-
thylbenzene as the internal standard.
FeACHTUNGTRENNUNG
(acac)3 was used as catalyst instead of FeCl3·6H2O.[7]
Figure 1. NOE study of Z-5a.
could be aryl or alkyl groups; R2 could be H, Bn or E-9 with high stereoselectivity, respectively (condi-
alkyl groups; R3 could be alkyl, Bn or allyl groups. tions A and B, entries 3, 5 and 7, Table 4). In the Z-
The reaction may proceed with primary (entries 1–12, acylation reactions of the in situ generated magnesi-
Table 2), secondary, and tertiary Grignard reagents um dienolate 7, FeCl3·6H2O and FeACHTNUTRGENNG(U acac)3 both ex-
(entries 13–15, Table 2). However, in some cases such hibited very high stereoselectivity (>99/1) (conditions
as substrates 3g, 3i and 3j, the reaction requires A, compare entries 1, 3, 5 and 7 with 2, 4, 6 and 8,
5 mol% of FeCl3·6H2O for a complete conversion of Table 4). However, in the E-acylation reactions of the
the starting 2,3-allenoates (entries 7,
Table 2).
9
and 10, in situ generated magnesium dienolate 7, the results
obtained with Fe(acac)3 are better than those with
AHCTUNGTRENNUNG
The highly regio- and stereoselective addition reac- FeCl3·6H2O (conditions B, compare entries 1, 3, 5 and
tion of 2,3-allenoates with vinylmagnesium halides 7 with 2, 4, 6 and 8, Table 4).
(entries 1–3, Table 3) or phenylmagnesium chloride
(entries 4–7, Table 3) can also be performed to afford that under the catalysis of PdAHCNUTGTRENNUNG
Furthermore, we were again quite happy to observe
(PPh3)4, the reaction of
the conjugated dienes or 3-phenyl-substituted b,g-al- magnesium dienolate 7a with allyl acetate afforded
kenoates. 2-Thienylmagnesium bromide may also be the a-allylated 3(Z)-alkenoate Z-10a exclusively in
reacted with 3e to obtain the corresponding product 75% yield with high stereoselectivity (Z/E=98/2)
E-5w in 63% yield (entry 8, Table 3).
(conditions C, entry 1, Table 5). The configuration of
Treatment of the conjugate addition reaction mix- the C=C double bond in this compound was estab-
ture with D2O afforded 8 in 70% yield with 96% D lished again by NOE analysis. Likewise, under the
incorporation, indicating the intermediacy of the mag- catalysis of CuI, the reaction with allyl bromide af-
nesium 1,3(Z)-dienolate Z-7a [Eq. (1)].
forded the opposite stereoisomer E-10a in 52% yield
1948
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Ferric Chloride Hexahydrate-Catalyzed Highly Regio- and Stereoselective Conjugate Addition
FULL PAPERS
Table 2. FeCl3·6H2O-catalyzed conjugate addition of alkylmagnesium chlorides to 2,3-allenoates.[a]
Entry
R1
R2
R3
R4
Time [h]
Yield of 5 [%][b]
1
2
3
4
Ph
Ph
Ph
Ph
n-Pr
n-Pr
n-Pr
Me
Me
Me
n-Pr
Me
n-Pr
Bn
Me
H
Me
n-Pr
Me
Et (3a)
Me (3b)
Bn (3c)
allyl (3d)
Et (3e)
Et (3f)
Et (3g)
Et (3h)
Et (3i)
Et (3j)
Et (3k)
Et (3l)
Et (3e)
Et (3i)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
n-C5H11
c-Hex
s-Bu[d]
t-Bu
2.5
2.4
3.5
3
3.5
3
2.4
1
3
3
2
3.5
2
1.5
1.5
88 (Z-5a)
89 (Z-5b)
78 (Z-5c)
72 (Z-5d)
62 (Z-5e)
87 (Z-5f)
99 (Z-5g)
67 (Z-5h)
85 (Z-5i)
89 (Z-5j)
76 (Z-5k)
61 (Z-5l)
79 (Z-5m)
85 (Z-5n)
81 (E-5o)
5
Ph
6
p-BrC6H4
p-BrC6H4
p-MeOC6H4
n-C7H15
n-C4H9
n-C4H9
n-C4H9
Ph
7[c]
8
9[c]
10[c]
11
12
13
14
15
[d]
n-C7H15
Ph
Et (3e)
[a]
The reaction was conducted using 0.4 mmol of 2,3-allenoates, 3 equiv. of the Grignard reagents (solution in THF), and 2
mol% of FeCl3·6H2O in 5 mL of toluene at À788C, unless otherwise stated.
[b]
[c]
[d]
Isolated yield.
5 mol% of FeCl3·6H2O was used.
Alkylmagnesium bromides were used.
Table 3. FeCl3·6H2O-catalyzed conjugate addition of aryl or vinyl magnesium halides with 2,3-allenoates.[a]
Entry
R1
R2
R4
Time [h]
Yield of 5 [%][b]
1[c]
2
3
4
5
Ph
n-Pr (3a)
Me (3m)
Me (3k)
Me (3h)
H (3l)
H (3n)
Me (3k)
Me (3e)
vinyl
vinyl[d]
vinyl
Ph
Ph
Ph
1.5
3
3
3
2.5
3
84 (Z-5p)
85 (Z-5q)
75 (Z-5r)
81 (E-5s)
64 (E-5t)
60 (E-5u)
70 (E-5v)
63 (E-5w)
p-ClC6H4
n-C4H9
p-MeOC6H4
n-C4H9
n-C7H15
n-C4H9
Ph
6
7
Ph
3
11
8[e]
2-thienyl[d]
[a]
The reaction was conducted using 0.4 mmol of 2,3-allenoates, 3 equiv. of the Grignard reagents (solution in THF), and
2 mol% of FeCl3·6H2O in 5 mL of toluene at À788C. Freshly prepared vinyl-Grignard reagent was needed.
Isolated yield.
5 mol% of FeCl3·6H2O was used.
Magnesium bromide was used.
[b]
[c]
[d]
[e]
This reaction was conducted at room temperature as no reaction occurred at À788C.
(E/Z=96/4) (conditions D, entry 1, Table 5). The con- PdACHTNUTRGNEUNG(PPh3)4 or allyl bromide under the catalysis of CuI
figuration of the C=C double bond in this compound affording the corresponding products Z-10 or E-10
was also established by NOE analysis. The in situ gen- with high stereoselectivity, respectively (conditions C
erated dienolates from the reaction of 3f, 3m and 3o and D, entries 3, 5 and 7, Table 5). In the a-allylation
also reacted with allyl acetate under the catalysis of of magnesium dienolate intermediates with allyl ace-
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Table 4. Reaction of in situ generated magnesium dienolate 7 with acetyl chloride or allyl acetate.[a]
Entry
R1
Conditions A
Yield of Z-9 [%][b]
Conditions B
Ratio (Z/E)[c]
Yield of E-9 [%][b]
Ratio [E/Z][c]
1
Ph (3e)
Ph (3e)
65 (Z-9a)
68 (Z-9a)
70 (Z-9b)
87 (Z-9b)
82 (Z-9c)
84 (Z-9c)
77 (Z-9d)
76 (Z-9d)
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
50 (E-9a)
50 (E-9a)
45 (E-9b)
62 (E-9b)
55 (E-9c)
50 (E-9c)
50 (E-9d)
69 (E-9d)
93/7
95/5
95/5
97/3
96/4
98/2
94/6
98/2
2[d]
3
p-BrC6H4 (3f)
p-BrC6H4 (3f)
p-ClC6H4 (3m)
p-ClC6H4 (3m)
p-FC6H4 (3o)
p-FC6H4 (3o)
4[d]
5
6[d]
7
8[d]
[a]
Conditions A: 2 mmol of acetyl chloride were added to 0.4 mmol of the in situ generated magnesium dienolate at À788C.
Conditions B: 2 mmol of allyl acetate were added to 0.4 mmol of the in situ generated magnesium dienolate at À788C fol-
lowed by warming up to room temperature naturally. The formation of 6–31% hydrolysis product was observed by
1H NMR analysis of the crude reaction mixture.
[b]
[c]
[d]
Isolated yield.
1
The ratio was determined by H NMR analysis of the crude products.
FeACHTUNGTRENNUNG(acac)3 was used instead of FeCl3·6H2O.
tate under the catalysis of PdACHTNURTGNEUNG(PPh3)4, the amounts of The coordination of the C=C bond in the allylic car-
a-acylated product 3(E)-alkenoate E-9 are in the boxylate or allylic bromide with the metal or the pres-
1
order of ꢀ0.9%, if any, based on the H NMR analy- ence of the more bulky Cu+ instead of Mg2+ would
sis of the crude reaction mixture. In all cases, further increase this steric effect leading to the iso-
FeCl3·6H2O exhibited better or similar stereoselectiv- merization of the in situ generated intermediate Z-7
ity (conditions C and D, compare entries 1, 3, 5 and 7 to the thermodynamically more stable E-7. Subse-
with 2, 4, 6 and 8, Table 5).
quent reaction with the allylic carboxylate or allylic
A possible mechanism has been proposed for the bromide leads to the formation of E-9 or E-10.[14]
inversion of the configuration of the C=C bond for
the formation of E-9 and E-10 (Scheme 3). The dieno-
late intermediate Z-7 may isomerize to the delocal- Conclusions
ized p-allylic intermediate, i.e., anti-allylic-MgCl,
which may isomerize to the more stable syn-allylic In summary, we have developed an efficient
metallic intermediate due to the steric effect between FeCl3·6H2O-catalyzed method to synthesize trisubsti-
the coordinated metal and the methyl/R1 groups.[10,13] tuted b,g-unsaturated Z-alkenoates with high regio-
Scheme 3. Possible mechanism for the formation of E-9 and E-10.
1950
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Ferric Chloride Hexahydrate-Catalyzed Highly Regio- and Stereoselective Conjugate Addition
Table 5. Transition metal-catalyzed allylation reactions of in situ generated dienolate 7 with different allyl reagents.[a]
FULL PAPERS
Entry
R1
Conditions C
Yield of Z-10 [%][b]
Conditions D
Yield of E-10 (%)[b]
Ratio (Z/E)[c]
Ratio (E/Z)[c]
1
Ph (3e)
Ph (3e)
76 (Z-10a)
67 (Z-10a)
70 (Z-10b)
80 (Z-10b)
72 (Z-10c)
66 (Z-10c)
69 (Z-10d)
74 (Z-10d)
98/2
96/4
97/3
93/7
97/3
96/4
96/4
94/6
52 (E-10a)
51 (E-10a)
71 (E-10b)
65 (E-10b)
63 (E-10c)
71 (E-10c)
69 (E-10d)
72 (E-10d)
96/4
96/4
>99/1
97/3
97/3
97/3
98/2
97/3
2[d]
3
p-BrC6H4 (3f)
p-BrC6H4 (3f)
p-ClC6H4 (3m)
p-ClC6H4 (3m)
p-FC6H4 (3o)
p-FC6H4 (3o)
4[d]
5
6[d]
7
8[d]
[a]
Conditions C: 5 mol% of PdACHTUNTRGNEUNG(PPh3)4 and 2 mmol of allyl acetate were added to 0.4 mmol of the in situ generated magnesi-
um dienolate at À788C followed by warming up to room temperature naturally. Conditions D: 10 mol% of CuI and
2 mmol of allyl bromide were added to 0.4 mmol of the in situ generated magnesium dienolate at room temperature.
Isolated yield (see the experimental section for the details). The formation of 1–13% hydrolysis product was observed by
1H NMR analysis of the crude reaction mixture.
The ratio was determined by H NMR analysis of the crude products.
FeACHTUNGTRENNUNG(acac)3 was used instead of FeCl3·6H2O.
[b]
[c]
[d]
1
and stereoselectivity. Primary, secondary and tertiary (>99/1) (conditions A, compare entries 1, 3, 5 and 7
alkyl, vinylic or aromatic groups may be introduced with 2, 4, 6 and 8, Table 4) while in the E-acylation re-
by using the readily available Grignard reagents to actions of the in situ generated magnesium dienolate
the 3-position of 2,3-allenonates. Good to excellent 7, the results obtained with Fe
yields were obtained with a catalytic loading of those with FeCl3·6H2O (conditions B, compare en-
FeCl3·6H2O. Compared with the results of Fe(acac)3, tries 1, 3, 5 and 7 with 2, 4, 6 and 8, Table 4). On the
ACHTUNGTERN(NUGN acac)3 are better than
AHCTUNGTRENNUNG
FeCl3·6H2O is more efficient and high yielding with other hand, FeCl3·6H2O exhibited better or similar
slightly higher yields for the formation of a,b-unsatu- stereoselectivity in the allylation reactions of the in
rated enoate (compare entries 1 and 2 with entries 5 situ generated magnesium dienolate 7 (conditions C
and 6, Table 1). Due to the cheap and easy handling and D, compare entries 1, 3, 5 and 7 with 2, 4, 6 and
nature of the catalyst, this catalytic system will have 8, Table 5). Further studies in this area are being con-
promising applications in organic synthesis. Further- ducted in our laboratory.
more, stereocontrollable a-acylation and allylation re-
actions of the in situ generated magnesium dienolate
intermediates 7 were achieved with the use of differ-
Experimental Section
ent electrophiles and conditions: 2-acylated 3(Z)- and
3(E)-alkenotes 9 were formed when we used acetyl
chloride or allyl acetate as the electrophiles; 2-allylat-
ed 3(Z)- and 3(E)-alkenotes 10 were formed when we
Ethyl 3-Methyl-4-phenyl-2-propyl-3(Z)-butenoate
(Z-5a); Typical Procedure for the Synthesis of
ComACTHNUTRGNEpUNG ounds 5
used allyl acetate in the presence of PdACHTNURTGNEUNG(PPh3)4 or allyl
bromide in the presence of CuI as the electrophiles,
respectively. In the Z-acylation reactions of the in situ
generated magnesium dienolates 7, FeCl3·6H2O and
To a dried Schlenk tube were added FeCl3·6H2O (2.2 mg,
2 mol%, 0.008 mmol), 3a (91.7 mg, 0.4 mmol), and toluene
(5 mL) sequentially under a nitrogen atmosphere at room
FeACHTUNGTRENNUNG(acac)3 both exhibited very high stereoselectivity temperature. A solution of CH3MgCl in THF (0.4 mL, 3M,
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Guobi Chai et al.
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1.2 mmol, 3 equiv.) was then added with a syringe to the re-
action mixture within 3 min at À788C. After the reaction
was over as monitored by TLC, the reaction mixture was
quenched slowly with a saturated aqueous solution of
NH4Cl (1 mL) at À788C, followed by warming up to room
temperature naturally and the addition of water (5 mL).
After extraction with diethyl ether (30ꢂ3 mL), the organic
layer was washed sequentially with diluted HCl (5%, aque-
ous), a saturated aqueous solution of NaHCO3, and brine,
and dried over anhydrous Na2SO4. Filtration, evaporation,
and column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate=100/1) afforded the desired product Z-
ether (30ꢂ3 mL), the organic layer was washed sequentially
with diluted HCl (5%, aqueous), a saturated aqueous solu-
tion of NaHCO3, and brine, and dried over anhydrous
Na2SO4. Filtration, evaporation, and column chromatogra-
phy on silica gel (eluent: petroleum ether/ethyl acetate=
100/1~20/1) afforded E-9a as a liquid;[10] yield: 51.8 mg
1
(50%); H NMR (300 MHz, CDCl3): d=7.35 (t, J=7.5 Hz,
2H), 7.25 (t, J=7.5 Hz, 3H), 6.41 (s, 1H), 4.26 (q, J=
7.1 Hz, 2H), 2.30 (s, 3H), 1.88 (d, J=1.2 Hz, 3H), 1.61 (s,
3H), 1.31 (t, J=7.1 Hz, 3H).
Ethyl 2-Allyl-2,3-dimethyl-4-phenyl-3(Z)-butenoate
(Z-10a); Typical Procedure for the Synthesis of
ComACTHNUTRGNEUpGN ounds Z-10
1
5a as a liquid;[7] yield: 86.2 mg (88%); H NMR (300 MHz,
CDCl3): d=7.36–7.24 (m, 4H), 7.24–7.15 (m, 1H), 6.49 (s,
1H), 4.17 (q, J=7.2 Hz, 2H), 3.70 (t, J=7.7 Hz, 1H), 1.84
(s, 3H), 1.80–1.65 (m, 1H), 1.65–1.25 (m, 1H), 1.28 (t, J=
7.2 Hz, 3H), 1.23–1.01 (m, 2H), 0.76 (t, J=7.4 Hz, 3H).
To a dried Schlenk tube were added FeCl3·6H2O (1.9 mg,
1.8 mol%, 0.008 mmol), 3e (81.8 mg, 0.4 mmol), and toluene
(5 mL) sequentially under a nitrogen atmosphere at room
temperature. Then a solution of CH3MgCl in THF (0.4 mL,
3M, 1.2 mmol, 3 equiv.) was added with a syringe to the re-
action mixture within 3 min at À788C. After the reaction
was over (3 h) as monitored by TLC, to the resulting reac-
Ethyl 2-Acetyl-2,3-dimethyl-4-phenyl-3(Z)-butenoate
(Z-9a); Typical Procedure for the Synthesis of
Compounds Z-9
To a dried Schlenk tube were added FeCl3·6H2O (2.6 mg,
2.4 mol%, 0.010 mmol), 3e (81.8 mg, 0.4 mmol), and toluene
(5 mL) sequentially under a nitrogen atmosphere at room
temperature. Then a solution of CH3MgCl in THF (0.4 mL,
3M, 1.2 mmol, 3 equiv.) was added with a syringe to the re-
action mixture within 3 min at À788C. After the reaction
was over as monitored by TLC, acetyl chloride (0.14 mL,
d=1.104 gmLÀ1, 154.6 mg, 2 mmol, 5 equiv.) was slowly
added dropwise at À788C. After the reaction was over
(1.5 h) as monitored by TLC, the reaction mixture was
quenched slowly with a saturated aqueous solution of
NH4Cl (1 mL) at À788C, followed by warming up to room
temperature naturally. After extraction with diethyl ether
(30ꢂ3 mL), the organic layer was washed sequentially with
diluted HCl (5%, aqueous), a saturated aqueous solution of
NaHCO3, and brine, and dried over anhydrous Na2SO4. Fil-
tration, evaporation, and column chromatography on silica
gel (eluent: petroleum ether/ethyl acetate=100/1~20/1) af-
tion mixture were added sequentially PdACHTNUGTERN(NUG PPh3)4 (22.4 mg,
0.02 mmol, 5 mol%) and allyl acetate (0.22 mL, d=
0.928 gmLÀ1, 204.2 mg, 2 mmol, 5 equiv., dropwise) at
À788C, followed by warming up to room temperature natu-
rally. After the reaction was over as monitored by TLC, it
was quenched with a saturated aqueous solution of NH4Cl
(1 mL) at 08C, followed by warming up to room tempera-
ture naturally. After extraction with diethyl ether (30ꢂ
3 mL), the organic layer was washed sequentially with dilut-
ed HCl (5%, aqueous), a saturated aqueous solution of
NaHCO3, and brine, and dried over anhydrous Na2SO4. Fil-
tration, evaporation, and column chromatography on silica
gel (eluent: petroleum ether/CH2Cl2 =8/1~petroleum ether/
ethyl acetate=100/1) afforded Z-10a as a liquid;[10] yield:
79.1 mg (76%); 1H NMR (300 MHz, CDCl3): d=7.29–7.22
(m, 2H), 7.21–7.14 (m, 1H), 7.13–7.08 (m, 2H), 6.49 (s, 1H),
5.77–5.61 (m, 1H), 5.07–4.97 (m, 2H), 3.61 (dq, J1 =10.8 Hz,
J2 =7.2 Hz, 1H), 3.50 (dq, J1 =10.8 Hz, J2 =7.2 Hz, 1H),
2.52–2.35 (m, 2H), 1.92 (d, J=1.8 Hz, 3H), 1.28 (s, 3H),
1.06 (t, J=7.2 Hz, 3H).
1
forded Z-9a as a liquid;[10] yield: 68.7 mg (65%); H NMR
(300 MHz, CDCl3): d=7.28–7.08 (m, 5H), 6.65 (s, 1H),
3.90–3.68 (m, 2H), 2.04 (s, 3H), 1.91 (s, 3H), 1.50 (s, 3H),
1.15 (t, J=7.1 Hz, 3H).
Ethyl 2-Allyl-2,3-dimethyl-4-phenyl-3(E)-butenoate
(E-10a); Typical Procedure for the Synthesis of
ComACTHNUTRGNEUpGN ounds E-10
Ethyl 2-Acetyl-2,3-dimethyl-4-phenyl-3(E)-butenoate
(E-9a); Typical Procedure for the Synthesis of
To a dried Schlenk tube were added FeCl3·6H2O (2.1 mg,
1.9 mol%, 0.008 mmol), 3e (80.2 mg, 0.4 mmol), and toluene
(5 mL) sequentially under a nitrogen atmosphere at room
temperature. Then a solution of CH3MgCl in THF (0.4 mL,
3M, 1.2 mmol, 3 equiv.) was added with a syringe to the re-
action mixture within 3 min at À788C. After the reaction
was over as monitored by TLC, the cooling bath was re-
moved and the reaction mixture was stirred at room temper-
ature for 2 h followed by sequential addition of CuI (7.9 mg,
0.04 mmol, 10 mol%) and allyl bromide (0.17 mL, d=
1.390 gmLÀ1, 236.3 mg, 2 mmol, 5 equiv., dropwise). After
the reaction was over as monitored by TLC, it was
quenched with a saturated aqueous solution of NH4Cl
(1 mL) at 08C, followed by warming up to room tempera-
ture naturally. After extraction with diethyl ether (30ꢂ
ComACHTUNGTRENNUNGpounds E-9
To a dried Schlenk tube were added FeCl3·6H2O (2.2 mg,
2 mol%, 0.008 mmol), 3e (80.9 mg, 0.4 mmol), and toluene
(5 mL) sequentially under a nitrogen atmosphere at room
temperature. Then a solution of CH3MgCl in THF (0.4 mL,
3M, 1.2 mmol, 3 equiv.) was added with a syringe to the re-
action mixture within 3 min at À788C. After the reaction
was over as monitored by TLC, allyl acetate (0.22 mL, d=
0.928 gmLÀ1, 204.2 mg, 2 mmol, 5 equiv.) was slowly added
dropwise at À788C followed by warming up to room tem-
perature naturally. After the reaction was over as monitored
by TLC, the reaction mixture was quenched with a saturated
solution of NH4Cl (1 mL) at 08C, followed by warming up
to room temperature naturally. After extraction with diethyl
1952
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ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1946 – 1954

Ferric Chloride Hexahydrate-Catalyzed Highly Regio- and Stereoselective Conjugate Addition
FULL PAPERS
3 mL), the organic layer was washed sequentially with dilut-
ed HCl (5%, aqueous), a saturated aqueous solution of
NaHCO3, and brine, and dried over anhydrous Na2SO4. Fil-
tration, evaporation, and column chromatography on silica
gel (eluent: petroleum ether/CH2Cl2 =8/1) afforded E-10a[10]
(yield: 42.5 mg) as a mixture of E-10a and ethyl 2,3-dimeth-
yl-4-phenyl-3(Z)-butenoate Z-5e in a molar ratio by NMR
of 94/6, content of E-10a: 95% by weight and a mixture of
E-10a, Z-5e and E-5e, molar ratio by NMR: 86/6/8 (yield:
0.0141 g), content of E-10a: 88% by weight; combined
yield: 52% as a liquid; 1H NMR (300 MHz, CDCl3): d=
7.36–7.28 (m, 2H), 7.27–7.17 (m, 3H), 6.40 (s, 1H), 5.79–
5.63 (m, 1H), 5.15–5.04 (m, 2H), 4.16 (q, J=7.1 Hz, 2H),
2.67–2.52 (m, 2H), 1.80 (d, J=1.2 Hz, 3H), 1.37 (s, 3H),
1.25 (t, J=7.1 Hz, 3H).
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Acknowledgements
Financial support from National Natural Science Foundation
of China (20732005) and the Major State Basic Research De-
velopment Program (2006CB806105) is greatly appreciated.
Shengming Ma is a Qiu Shi Adjunct Professor at Zhejiang
University. We thank Mr. W. Kong in this group for repro-
ducing the results presented in entries 3, 13, and 15 of
Table 2, entries 2 and 8 of Table 3, entry 4 of Table 4 and
entry 3 of Table 5.
[7] Z. Lu, G. Chai, S. Ma, J. Am. Chem. Soc. 2007, 129,
14546.
[8] For some recent examples of reactions utilizing
FeCl3·6H2O as catalyst, see: a) K. Komeyama, T. Mori-
moto, K. Takaki, Angew. Chem. 2006, 118, 3004;
Angew. Chem. Int. Ed. 2006, 45, 2938; b) G. Anilkumar,
B. Bitterlich, F. G. Gelalcha, M. K. Tse, M. Beller,
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ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1946 – 1954