Regio- and Stereoselective Preparation of β,γ-Unsaturated Carboxylic Acids by One-Pot Sequential Double 1,6-Addition of Grignard Reagents to Methyl Coumalate

Article abstract of DOI:10.1002/adsc.201600212

An efficient regio- and stereoselective metal-catalyzed addition of two Grignard reagents (homo-coupling, 2 RMgX or hetero-coupling, R¹MgX+R²MgX) to methyl coumalate (methyl 2-oxo-2H-pyran-5-carboxylate) is described. This synthetic approach opens the access to a wide variety of functionalized β,γ-unsaturated carboxylic acids in a modular way. Control of the chemo- and stereoselectivity of this one-pot procedure is discussed. (Figure presented.).

Full text of DOI:10.1002/adsc.201600212

UPDATES
DOI: 10.1002/adsc.201600212
Regio- and Stereoselective Preparation of b,g-Unsaturated
Carboxylic Acids by One-Pot Sequential Double 1,6-Addition of
Grignard Reagents to Methyl Coumalate
Kristꢀna Plevovꢁ,a Liang Chang,a Emmeline Martin,a Quentin Llopis,a
Luc Dechoux,a,* and Serge Thorimberta,*
a
Sorbonne Universitꢂs, UPMC Univ Paris 06, UMR CNRS 8232, Institut Parisien de Chimie Molꢂculaire, 4 place Jussieu,
75005 Paris, France
E-mail: luc.dechoux@upmc.fr or serge.thorimbert@upmc.fr
Received: February 22, 2016; Revised: July 6, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600212.
Abstract: An efficient regio- and stereoselective
metal-catalyzed addition of two Grignard reagents
could explain the total stereoselectivity observed for
the reaction (Scheme 1).
(homo-coupling,
2
RMgX or hetero-coupling,
a-Pyrone derivatives[7] such as methyl coumalate
(methyl 2-oxo-2H-pyran-5-carboxylate, 1) can be con-
sidered as cyclic dienoate compounds.[8] We recently
reported the efficient and stereoselective synthesis of
conjugated (Z,Z) or (Z,E)-dienoic acids 2 by regiose-
lective 1,6-addition of Grignard reagents (1 equiv.) to
methyl coumalate 1 (Scheme 1).[9] Concomitantly to
our study, Fꢃrstner[7b] published the regio- and stereo-
selective 1,6-addition of Grignard reagents in excess
to substituted 1-pyrones in the presence of a catalytic
amount of [Fe(acac)3]. The reaction mechanism sug-
gested by Fꢃrstner involved the stepwise formation of
a h4-dienic iron complex followed by syn-selective
1,2-insertion of the p-system into the Fe–Me bond
and further anti-elimination (Scheme 1).
R1MgX+R2MgX) to methyl coumalate (methyl 2-
oxo-2H-pyran-5-carboxylate) is described. This syn-
thetic approach opens the access to a wide variety
of functionalized b,g-unsaturated carboxylic acids in
a modular way. Control of the chemo- and stereose-
lectivity of this one-pot procedure is discussed.
Keywords: double 1,6-conjugate addition; 6-p elec-
trocyclic ring opening; Grignard reagents; metal
catalysis; unsaturated acids
Introduction
Here we report a novel one-pot, three-step, double
1,6 conjugate addition[10] to methyl coumalate afford-
While numerous conjugate additions of Grignard re- ing a wide variety of functionalized b,g-unsaturated
agents to a,b-unsaturated carbonyl compounds have carboxylic acids
3
or
4
in
a
modular way
been described,[1] far less reports were devoted to the (Scheme 1).[11] The pivotal role of the catalyst
conjugate addition to a,b,g,d-di-unsaturated sys- {[Fe(acac)3] or Cu(OTf)2} in the regio- and stereo-
tems.[2,3] The reasons for this poor investigation are chemical control of the reaction, owing to the activa-
presumably based on the numerous issues to control tion of putative intermediate B, will be presented.
(i) the regioselectivity of addition (1,4- versus 1,6-),
(ii) the regioselectivity of reprotonation (giving access
to a,b- or b,g-unsaturated carbonyl derivatives), and Results and Discussion
(iii) the configuration of the newly formed double
bond. Only a handful of copper-catalyzed 1,6-addi- First, we investigated the conjugate addition of an
tions on dienoates[4] and dienones[5] have been report- excess of various Grignard reagents in the presence of
ed. For instance, the group of Urabe reported rare ex- TMSCl in THF at 08C (Table 1, entries 3, 6, and 13).
amples of 1,6-conjugate additions on unsaturated Interestingly, under these conditions, methyl Grignard
amides using an iron catalyst (FeCl2).[6] They observed reagent did not give the expected product 3 (see the
regio- and stereo-selective formation of b,g-unsaturat- Supporting Information for attribution) and when
ed carbonyl products. They proposed a mechanism in- sterically hindered nucleophiles such as i-PrMgBr or
volving h4-complexation of the iron complex that t-BuMgCl were used, the reaction stopped after the
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Table 1. One-pot metal-catalyzed double 1,6-addition of
Grignard reagents.
Entry
R
Catalyst
Products (yield [%]) E/Z ratio[c]
1
2
3
4
5
6
7
8
Me
Me
Et
Et
Et
Fe(acac)3 3a (76)
>95/5
>95/5
82/18
>95/5
>95/5
80/20
>95/5
>95/5
–
Cu(OTf)2 3a (90)
[a]
–
3b (30)
Fe(acac)3 3b (56)
Cu(OTf)2 3b (92)
[a]
n-Bu
–
3c (92)
n-Bu Fe(acac)3 3c/4c (70)[b]
n-Bu Cu(OTf)2 3c (98)
9
i-Pr
i-Pr
Fe(acac)3
–
10
11
12
13
14
15
Cu(OTf)2 3d/4d (60/40)[b]
–
t-Bu Fe(acac)3 4e (66)
t-Bu Cu(OTf)2 4e (72)
Ph
Ph
Ph
>95/5
>95/5
79/21
>95/5
>95/5
[a]
–
3f (90)
Fe(acac)3 3f (90)
Cu(OTf)2 3f (95)
[a]
No catalyst but 1 equiv. of Me3SiCl.
[b]
1
Total conversion, estimated yield based on H NMR of
the crude.
[c]
1
Determined by H NMR of the crude.
We surmised that the presence of Lewis acidic salts
could favor the 6-p electrocyclic opening of inter-
mediate A into B as well as activate both the nucleo-
philes and the electrophiles. We thus turned our at-
tention to the possible iron- or copper-catalyzed
double addition (Table 1).[12] In a typical experiment,
methyl coumalate 1 was treated with 4 equiv. of
Scheme 1. Stereoselective synthesis of unsaturated acids.
first addition. In these cases the a-Z/g-E-dienoic acids MeMgBr in Et2O at 08C in the presence of 5 mol%
2d, e were obtained as well as their corresponding lac- catalyst {Cu(OTf)2 or [Fe(acac)3]}. After 1.5 hours
tones 5 (see the Supporting Information for full de- and an acidic quench, the b,g-unsaturated acid (E)-3a
tails).[9] These first results indicate that in the absence was obtained in good yield and excellent regio- and
of a catalyst, bulky Grignard reagents do not add to stereoselectivity (Table 1, entries 1 and 2).
the putative 2,4-dienic magnesium carboxylate B
The data gathered in Table 1 highlight the scope
(Scheme 1). On the other hand, double addition of and limitations of this homo-double addition. Under
EtMgBr, n-BuMgBr and PhMgBr at the 6-position of
methyl coumalate occurred, giving the expected b,g-
unsaturated carboxylic acids 3b, c, and f in 30, 92, and
90% yields, respectively, with E/Z ratios close to 80/
20. Assignment of the configuration of the b,g-double
bond in (Z)-3b, c and (E)-3b, c was achieved by
NOESY experiments (strong correlation between Ha
and Hd in the E isomers). It is noteworthy that in all
1H NMR spectra, proton Hb of (E)-3 was deshielded
at around 7 ppm versus 6 ppm for (Z)-3 (Figure 1, for
full details see the Supporting Information).
Figure 1. Example of the assignment of configuration for
compound 3b.
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Table 2. Selective one-pot copper-catalyzed hetero double
1,6-addition.
these new conditions, using either copper or iron cat-
alysis, the expected double 1,6-addition was more
general and gave better stereoselectivity. In the case
of primary (Me, Et, and n-Bu) or phenyl Grignard re-
agents and using Cu(OTf)2 as catalyst, the expected
b,g-unsaturated carboxylic acids 3a–c and f were now
isolated in high yields and excellent stereoselectivity
(Table 1, entries 2, 5, and 8). The iron catalyst was
slightly less efficient than the copper one, since it re-
sulted the formation of by-products or in one case for-
mation of product 4c arising from 1,6-addition of hy-
dride (Table 1, entries 4, 7, and 9). Secondary and ter-
tiary Grignard reagents afforded the a,b-unsaturated
acids 4d, e using both catalysts (Table 1, entries 10–
12).[13]
The presence of the ester moiety on the carbon-5
of methyl coumalate seems to be essential for the
double addition on carbon-6 to occur. Indeed, a-
pyrone reacted with PhMgBr in the presence of
[Fe(acac)3] or Cu(OTf)2 to give mixture of 1,4- and
1,6-addition products in low yields. Starting from
methyl 2-pyrone-3-carboxylate, the reaction with
Entry R1
R2
Ph
Products (yield [%]) E/Z ratio[b]
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
3i (71)
93/7
94/6
86/14
79/21
–
n-Bu 3k (74)
i-Pr
vinyl
Me
n-Bu 3n (68)
i-Pr
3l (90)
3m (61)
degrad.
93/7
>95/5
>95/5
80/20
–
91/9
–
–
3o (59)
3p (76)
3q (67)
3k (30)
3r (89)
–
3n (25)
3s (29)
degrad.
t-Bu
vinyl
[a]
[a]
PhMgBr provided the 1,4-addition product no matter 10
n-Bu Me
n-Bu i-Pr
n-Bu t-Bu
n-Bu Ph
n-Bu vinyl
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
t-Bu
11
12
13
14
15
16
17
18
19
20
what catalyst was used (8f–10f, for full details see the
Supporting Information).
Next we examined the outcome of the copper-cata-
lyzed one-pot reaction by using successively two dif-
ferent Grignard reagents (Table 2). We focused our
attention on the use of Cu(OTf)2, as we initially ob-
served lower yields with [Fe(acac)3] (vide supra,
Table 1). Due to obvious chemoselectivity issues, one
equivalent of the first Grignard reagent was added
89/11
–
Me
n-Bu 3r (98)
t-Bu
Ph
>95/5
–
[b]
3t/4d (52/48)
3o (31)
3u (52)
>95/5
>95/5
>95/5
>95/5
>95/5
>95/5
vinyl
n-Bu 4e (19)[a]
before addition of catalyst (in order to ensure effi- 21
i-Pr
Ph
vinyl
4e (82)
3p (76)
3w (39)
22
23
cient formation of the mono-adduct (carboxylate B)
and to avoid formation of the homo-coupling adduct.
The new conditions were as follows: 1.1 equiv. of the
first Grignard reagent was added without catalyst,
then 5 mol% of Cu(OTf)2, followed by addition of
4 equiv. of the second Grignard reagent.
[a]
1
Total conversion, estimated yield based on H NMR of
the crude product.
[b]
1
Determined by H NMR of the crude product.
The data in Table 2 illustrate the scope and limita-
tions of the hetero-coupling method. In almost all moderate to good yields (Table 2, entries 1, 4, 9, 13,
cases, good yields and good to excellent stereoselec- 14, 18, 19, 22, and 23).
tivities were attained. When MeMgBr or PhMgBr
Concerning the chemoselective C- versus H- addi-
were added first, the expected b,g-unsaturated acids tion during the second step, Me-, Ph- and vinyl-
3i–q were obtained as the E-isomers with good diaste- Grignard reagents afforded the expected double alky-
reoselectivity (Table 2, entries 1–9). With primary, lated products 3 (obviously, there is no possible b-hy-
secondary and tertiary Grignard reagents as first nu- dride elimination). In the case of Grignard reagents
cleophile, the outcome of the reaction depended on bearing a b-hydride, the course of the reaction
the structure of the second nucleophile (Table 2, en- changed and depended on the bulkiness of the first
tries 10–21). When MeMgBr was used as second nu- introduced alkyl group. Indeed, inversion of the order
cleophile, the reaction gave the expected product 3 in of addition of i-PrMgBr and t-BuMgCl led to inver-
low yield (Table 2, entries 5, 10, and 15, see also the sion of the chemoselectivity (Table 2, entries 17 and
Supporting Information, Table S1 for more data). In 21). More generally, introduction of a first bulky alkyl
contrast, the addition of phenyl and vinyl Grignards group favored the hydride addition except when b-hy-
as second nucleophiles was successfully achieved af- dride elimination of the second Grignard reagent was
fording compounds 3i, m, n, o, p, q, s, u, and w in impossible (Table 2, entries 21 vs. 22).
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ing from methyl coumalate. This is a valuable method
for the preparation of b,g-unsaturated carboxylic
acids in a highly regio-, chemo- and stereoselective
manner.[11] We also elucidated the pivotal role of the
Grignard reagent as regards the stereoselectivity out-
come of the reaction. The later could be rationalized
by invoking a constrained chair-like transition state
with the formation of a stable bimetallic intermediate.
Experimental Section
General Method for Homocoupling
Scheme 2. Proposed mechanism for copper-catalyzed stereo-
selective addition leading to acids 3 and 4.
To a solution of methyl coumalate (308 mg, 2 mmol) in dry
Et2O (25 mL) at 08C, under an argon atmosphere, Cu(OTf)2
(36 mg, 0.1 mmol) or Fe(acac)3 (35 mg, 0.1 mmol) was
added, followed by R1MgX (8 mmol) by dropwise addition
(5–10 min). The mixture was stirred for 1.5 h, then quenched
at 08C with saturated aqueous NH4Cl solution and washed
with dichloromethane (2ꢅ20 mL). The aqueous layer, was
then acidified with 1M HCl (until pH 1–2) and extracted
with CH2Cl2 (3ꢅ20 mL). The combined organic layers were
dried over anhydrous MgSO4, filtered and evaporated under
reduced pressure to afford the target product.
Concerning the mechanism of this multi-step reac-
tion, the stereoselectivity of the process should give
us some clues.[14] Notably, we should take into account
the difference of stereo outcome observed between
the reactions with or without metal catalysis (Table 1,
for more details see the Supporting Information, spec-
tra of compound 3b page S9). Furthermore, the occur-
rence of a thermodynamic equilibrium between the
stereoisomers during acid treatment of the reactions
was ruled out. Indeed, even when the reaction mix-
ture was hydrolyzed overnight (entry 6 in Table 2)
with 1M HCl or when the reaction was quenched
with higher concentrations of aqueous HCl, no
change of the stereoisomeric ratio was observed (E/
Z=97/3). We propose the involvement of a highly
chelated transition state D in the second step of the
reaction (Scheme 2).
(E/Z)-4-(Methoxycarbonyl)-5-methylhex-3-enoic
acid
1
(3a): Colorless oil; H NMR (400 MHz, CDCl3): E-isomer:
d=6.70 (t, J=7.2 Hz, 1H, Hb), 3.71 (s, 3H, OMe), 3.31 (d,
J=7.2 Hz, 2H, 2ꢅHa), 2.86–2.79 (m, 1H, Hd), 1.20 (s, 3H,
CH3), 1.18 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): E-
isomer: d=176.1, 167.5, 141.1, 130.3, 51.6, 33.1, 28.1, 20.7;
IR (film): n=3500–2400 (br);, 2970, 2877, 1712, 1643, 1436,
1257, 1199, 1045, 985, 877, 767 cmÀ1; HR-MS (ESI-MS):
m/z=209.0796, calcd. for C9H14O4Na [M+Na]+: 209.0790.
As previously demonstrated,[9] addition of the first
Grignard reagent gives intermediate B resulting in
General Method for Heterocoupling
To a solution of methyl coumalate (308 mg, 2 mmol) in dry
complex C by reaction with the organocopper com- Et2O (25 mL) at 08C, under an argon atmosphere, R1MgX
plex (R2CuOTf). Addition of the second Grignard re-
(2.2 mmol) was added dropwise (5–10 min) and the mixture
stirred for 0.5 h. Then Cu(OTf)2 (36 mg, 0.1 mmol) was
agent leads to a chair-like bicyclic transition state D
added and mixture was further stirred for 5 min. R2MgX
locking the overall stereoselectivity. Axial positioning
(8 mmol) was added dropwise (5 min) and the solution
of the alkyl chain and equatorial positioning of the
stirred for 1.5 h at 08C. The reaction mixture was quenched
methyl ester group could be rationalized by the pres-
at 08C with 1M HCl (until pH 1–2), diluted with ethyl ace-
ence of a stabilizing electronic interaction through the
tate (20 mL) and separated. The organic layer was washed
formation of an 8-membered pseudo-cycle. Further
once with 1M HCl (6 mL) and filtered through celite. The
transmetallation may give access to a stabilized bimet-
allic cyclic intermediate E. In this stabilized inter-
mediate, the non-planarity of the two C=C double
bonds explains both the kinetic control (no change in
the stereoselectivity with time) and the total regiocon-
trol of the reprotonation (a versus g) giving the b,g
unsaturated acids 3 or 7 as unique regioisomers.
combined organic layers were evaporated under reduced
pressure to afford the target acid.
(E/Z)-4-(Methoxycarbonyl)-5-phenylhex-3-enoic
acid
1
(3i): Yellow oil; H NMR (400 MHz, CDCl3): E-isomer: d=
7.25 (s, 5H, Ph), 6.92 (t, J=7.2 Hz, 1H, Hb), 4.17 (q, J=
7.2 Hz, 1H, Hd), 3.67 (s, 3H, OMe), 3.26 (dd, J=18.5 Hz,
J=7.2 Hz, 1H, Ha), 3.16 (dd, J=18.4 Hz, J=7.1 Hz, 1H,
Haꢆ), 1.57 (d, J=7.2 Hz, 3H, CH3); Z-isomer (significant sig-
nals): d=6.14 (t, J=7.9 Hz, 1H, Hb); 13C NMR (100 MHz,
CDCl3): E-isomer: d=175.7, 167.3, 143.1, 139.7, 132.5, 128.4,
127.3, 126.2, 51.9, 37.0, 33.4, 31.0, 17.8; IR (film): n=3600–
2500 (br); 2970, 1708, 1645, 1435, 1390, 1247, 1130,1026, 991,
796, 748 cmÀ1; HR-MS (ESI-MS): m/z=255.1213, calcd. for
Conclusions
In summary, we have developed a one-pot sequential
double alkyl-alkyl or alkyl-hydride 1,6-addition start- C14H16O4Li [M+Li]+: 255.1203.
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b) C. L. Sun, A. Fꢃrstner, Angew. Chem. 2013, 125,
13309–13313; Angew. Chem. Int. Ed. 2013, 52, 13071–
13075.
Acknowledgements
We thank the University P. et M. Curie (UPMC) and CNRS
for funding. The Fꢀdꢀration de Recherche (FR2769) provided
technical access for analysis. K. P. gratefully acknowledges
the French Embassy in Slovakia for financial support and L.
C. the China Scholarship Council (CSC) for a PhD fellow-
ship.
[8] For publications concerning the 1,6-addition of soft nu-
cleophiles on a-pyrones, see: a) W. T. Caldwell, F. T.
Tyson, L. Lauer, J. Am. Chem. Soc. 1944, 66, 1479–
1484; b) R. H. Wiley, L. H. Knabeschuh, A. L. Duck-
wall, N. R. Smith, J. Am. Chem. Soc. 1954, 76, 625–627;
c) V. Kvita, H. Sauter, G. Rihs, Helv. Chem. Acta 1983,
66, 2769–2777; d) V. Kvita, H. Sauter, G. Rihs, Helv.
Chem. Acta 1988, 71, 1467–1473; e) M. H. Nantz, P. L.
Fuchs, Synth. Commun 1987, 17, 761–771; f) V. Kvita,
H. Sauter, G. Rihs, Helv. Chem. Acta 1989, 72, 457–
463; g) V. Kvita, Synthesis 1991, 883–884; h) V. Kvita,
H. Sauter, G. Rihs, Helv. Chem. Acta 1991, 74, 407–
416; i) Y. K. Ko, S. C. Lee, D. W. Koo, M. Jung, D. W.
Kim, Bull. Korean. Chem. Soc. 2001, 22, 234–239. For
papers concerning the addition of hard nucleophiles,
see: j) R. Gompper, O. Christmann, Chem. Ber. 1961,
94, 1784–1794; k) R. Gompper, O. Christmann, Chem.
Ber. 1961, 94, 1795–1799; l) G. Vogel, J. Org. Chem.
1965, 30, 203–207; m) A. R. Frisbee, M. H. Nantz,
G. W. Kramer, P. L. Fuchs, J. Am. Chem. Soc. 1984,
106, 7143–7145.
References
[1] P. Perlmutter, in: Conjugate Addition Reactions in Or-
ganic Synthesis, Pergamon, Oxford, 1992.
[2] For recent reviews dealing with 1,6-conjugate additions,
see: a) S. R. Harutyunyan, T. den Hartog, K. Geurts,
A. J. Minnaard, B. L. Feringa, Chem. Rev. 2008, 108,
2824–2852; b) A. Alexakis, J. E. Bꢇckvall, N. Krause,
O. Pamies, M. Dieguez, Chem. Rev. 2008, 108, 2796–
2823; c) A. G. Csꢈkꢉ, G. de La Herran, M. C. Murcia,
Chem. Soc. Rev. 2010, 39, 4080–4102; d) E. M. P. Silva,
A. M. S. Silva, Synthesis 2012, 44, 3109–3128.
[3] Some organocatalyzed approaches have been reported
since 2014, see: a) B. S. Donslund, T. K. Johansen, P. H.
Poulsen, K. S. Halskov, K. A. Jørgensen, Angew. Chem.
2015, 127, 14066–14081; Angew. Chem. Int. Ed. 2015,
54, 13860–13875; b) J. Stiller, P. H. Poulsen, D. C. Cruz,
J. Dourado, R. L. Davis, K. A. Jørgensen, Chem. Sci.
2014, 5, 2052–2056; c) Q.-Q. Zhou, Y.-C. Xiao, X.
Yuan, Y.-C. Chen, Asian J. Org. Chem. 2014, 3, 545–
549.
[4] a) E. J. Corey, C. U. Kim, R. H. K. Chen, M. Takeda, J.
Am. Chem. Soc. 1972, 94, 4395–4396; b) E. J. Corey,
R. H. K. Chen, Tetrahedron Lett. 1973, 14, 1611–1614;
c) Y. Yamamoto, S. Yamamoto, H. Yatagai, Y. Ishihara,
K. Maruyama, J. Org. Chem. 1982, 47, 119–126; d) K.
Fukuhara, H. Urabe, Tetrahedron Lett. 2005, 46, 603–
606; e) T. den Hartog, S. R. Harutyunyan, D. Font, A. J.
Minnaard, B. L. Feringa, Angew. Chem. 2008, 120, 404–
407; Angew. Chem. Int. Ed. 2008, 47, 398–401; f) T.
Hata, H. Goto, T. Yokomizo, H. Urabe, Org. Synth.
2014, 91, 307–321. For some silyl cuprations, see: g) K.-
S. Lee, H. Wu, F. Haeffner, A. H. Hoveyda, Organome-
tallics 2012, 31, 7823–7826; h) K.-S. Lee, A. H. Hovey-
da, J. Am. Chem. Soc. 2010, 132, 2898–2900.
[5] a) F. Barbot, A. Kadib Elban, P. Miginiac, J. Organo-
met. Chem. 1983, 255, 1–9; b) E. J. Corey, N. W. Boaz,
Tetrahedron Lett. 1985, 26, 6019–6022; c) S. P. Modi,
J. O. Gardner, A. Milowsky, M. Wierzba, L. Forgione,
P. Mazur, A. J. Solo, W. L. Duax, Z. Galdecki, P. Gro-
chulski, Z. Wawrzak, J. Org. Chem. 1989, 54, 2317–
2321; d) H. Liu, L. M. Gayo, R. W. Sullivan, A. Y. H.
Choi, H. W. Moore, J. Org. Chem. 1994, 59, 3284–3288.
[6] a) S. Okada, K. Arayama, R. Murayama, T. Ishizuka,
K. Hara, N. Hirone, T Hata, H. Urabe, Angew. Chem.
2008, 120, 6966—6970; Angew. Chem. Int. Ed. 2008, 47,
6860–6864. For addition on 2,4-unsaturated sulfones,
see: b) T. Hata, T. Nakada, Y. T. Oh, N. Hirone, H.
Urabe, Adv. Synth. Catal. 2013, 355, 1736–1740.
[9] J. Agarwal, O. Bayounes, S. Thorimbert, L. Dechoux,
RSC Adv. 2014, 4, 2772–2775.
[10] For 1,6-1,4 double addition on a dienic system see:
a) M. Magrez-Chiquet, M. S. T. Morin, J. Wencel-
Delord, S. D. Amraoui, O. Basle, A. Alexakis, C. Crevi-
sy, M. Mauduit, Chem. Eur. J. 2013, 19, 13663–13667;
see also: b) T. E. Schmid, S. Drissi-Amraoui, C. Crꢂvisy,
O. Baslꢂ, M. Mauduit, Beilstein J. Org. Chem. 2015, 11,
2418–2434.
[11] a) Y. Gao, S. Iijima, H. Urabe, F. Sato, Inorg. Chim.
Acta 1994, 222, 145–153; for several others attractive
methods based on carboxylation with metal complexes
of dienes or allenes see: b) M. Takimoto, M. Mori, J.
Am. Chem. Soc. 2001, 123, 2895–2896; c) M. Takimoto,
Y. Nakamura, K. Kimura, M. Mori, J. Am. Chem. Soc.
2004, 126, 5956–5957; d) J. Takaya, N. Iwasawa, J. Am.
Chem. Soc. 2008, 130, 15254–15255; e) M. North,
Angew. Chem. 2009, 121, 4166–4168; Angew. Chem.
Int. Ed. 2009, 48, 4104–4105; f) J. Takaya, K. Sasano, N.
Iwasawa, Org. Lett. 2011, 13, 1698–1701; g) S. Song, S.-
F. Zhu, S. Yang, S. Li, Q.-L. Zhou, Angew. Chem. 2012,
124, 2762–2765; Angew. Chem. Int. Ed. 2012, 51, 2708–
2711; h) K. Kiyokawa, T. Kojima, Y. Hishikawa, S. Min-
akata, Chem. Eur. J. 2015, 21, 15548–11552.
[12] For two recent reviews on iron-catalyzed reactions, see:
a) I. Bauer, H.-J. Knçlker, Chem. Rev. 2015, 115, 3170–
3387; b) R. B. Bedford, Acc. Chem. Res. 2015, 48, 1485–
1493. c) See also a special issue on “copper organome-
tallic chemistry”, in: Organometallics 2012, 31, 7631–
7633.
[13] Fe-H intermediate, see: a) A. Fꢃrstner, R. Martin, H.
Krause, G. Seidel, R. Goddard, C. W. Lehmann, J. Am.
Chem. Soc. 2008, 130, 8773–8787; b) J. A. Labinger,
J. E. Bercaw, Organometallics 1988, 7, 926–928.
[14] For a recent perspective related to one-pot synthesis,
[7] a) For a review on the reactivity of a-pyrones, see: A.
Goel, V. J. Ram, Tetrahedron 2009, 65, 7865–7913;
see: Y. Hayashi, Chem. Sci. 2016, 7, 866–880.
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UPDATES
6 Regio- and Stereoselective Preparation of b,g-Unsaturated
Carboxylic Acids by One-Pot Sequential Double 1,6-
Addition of Grignard Reagents to Methyl Coumalate
Adv. Synth. Catal. 2016, 358, 1 – 6
Kristꢀna Plevovꢁ, Liang Chang, Emmeline Martin,
Quentin Llopis, Luc Dechoux,* Serge Thorimbert*
Adv. Synth. Catal. 0000, 000, 0 – 0
6
ꢄ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!