Direct cobalt-catalyzed conjugate addition of functionalized aryl halides and triflates: A new strategy for the conjugate addition onto methyl vinyl ketone

Article abstract of DOI:10.1055/s-0028-1088117

An efficient cobalt-catalyzed method for the direct conjugate addition of functionalized aryl halides or triflates onto methyl vinyl ketone is described. The experimentally simple procedure relies on the use of a catalytic system consisting of CoBr₂(Bpy) and zinc and does not require the preformation of a stoichiometric organometallic species. The approach described herein displays considerable functional-group compatibility at good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088117

LETTER
1073
Direct Cobalt-Catalyzed Conjugate Addition of Functionalized Aryl Halides
and Triflates: A New Strategy for the Conjugate Addition onto Methyl Vinyl
Ketone
New
Strategy for the
C
u
onjugate Ad
r
dition on
i
to
M
et
e
hyl
V
inyl
K
l
etone Amatore, Corinne Gosmini*
Laboratoire Hétéroéléments et Coordination, Ecole Polytechnique, CNRS, 91128 Palaiseau Cedex, France
Fax +33(1)69334440; E-mail: corinne.gosmini@polytechnique.edu
Received 28 January 2009
aryl halides onto a,b-unsaturated acrylic ester derivatives4
as a starting point. However, under these conditions the
reaction of ethyl para-bromobenzoate with MVK afford-
ed the desired product only in poor yield (24% GC yield)
Abstract: An efficient cobalt-catalyzed method for the direct con-
jugate addition of functionalized aryl halides or triflates onto methyl
vinyl ketone is described. The experimentally simple procedure re-
lies on the use of a catalytic system consisting of CoBr2(Bpy) and
zinc and does not require the preformation of a stoichiometric orga- along with only partial consumption of the aryl bromide
nometallic species. The approach described herein displays consid-
(Table 1, entry 1).
erable functional-group compatibility at good to excellent yields.
Considering the insufficient reactivity of the low-valent
Key words: aryl halides, catalysis, cobalt, direct conjugate addi-
cobalt catalyst [Co(0) or Co(I)] under these conditions, we
tion, methyl vinyl ketone
anticipated that MVK – in contrast to acrylic esters –
might act as a reasonably strong chelating ligand for co-
balt.6 Such a scenario would account for the observed de-
The catalytic conjugate addition of carbon-based nucleo-
celerated oxidative addition of the cobalt catalyst to the
philes to electron-deficient olefins constitutes an attrac-
aryl bromide.7 The addition of various Lewis acids [AlCl3,
tive and widely used tool for C–C bond formation.1
CeCl3, Ti(Oi-Pr)4] intended to competitively bind to
Within this theme, the transition-metal-catalyzed addition
MVK and thus preventing a deactivation of the cobalt cat-
of organometallic species is extensively employed.2 How-
alyst remained unsuccessful. Although slight improve-
ever, traditional procedures typically include sophisticat-
ments could be observed at higher catalyst loadings up to
ed experimentation as the need for low temperatures and
50 mol% (Table 1, entries 2–4), or elevated temperatures
the handling of air- and/or moisture-sensitive organome-
(Table 1, entry 4), attainable yield did not exceed a mod-
tallic derivatives; with this in mind, limited functional-
erate level of 46% (GC yield, partial conversion of ArBr
group compatibility represents another critical issue. As
only). Unexpectedly, further investigations revealed the
opposed to these approaches, procedures involving the di-
beneficial effect of zinc as a stoichiometric reductant as
rect addition of readily available, inexpensive aryl halides
compared to manganese at equivalent catalyst loadings,
thus avoiding prior formation of sensitive organometallic
decreased to 20 mol% (Table 1, entries 2, 6, 7). Satisfy-
species have been developed.3 Following the latter idea,
ingly, in this case, by a small increase in temperature to
we previously reported a cobalt-catalyzed procedure facil-
80 °C, a fully consumption of the corresponding aryl bro-
itating the Michael addition of various functionalized aryl
mide was observed (Table 1, entry 7). For these experi-
bromides, chlorides, and triflates onto a,b-unsaturated
ments, we reasoned that an in situ generated arylzinc
esters and nitriles in the presence of a metal as stoichio-
reagent might be involved and thus the absence of water
metric reducing agent.4 In contrast to the generally high-
was required preventing a rapid hydrolysis of the latter in-
yielding addition to acrylic ester derivatives, the use of
termediate.8
a,b-enones remained problematic affording the respective
At this point, we questioned whether the postulated detri-
1,4-adducts in very low yields. Considering both, the syn-
mental catalyst deactivation by MVK could be resolved
thetic utility of this transformation and the inherent advan-
by changing the addition order of reactants (Table 2).
Along these lines, we sought to decrease the concentration
of this reagent present in solution; a slow addition of
MVK to the reaction mixture was therefore assumed to se-
cure sufficient quantities of catalytically active reduced
cobalt. Yet, initially disappointing results were obtained
applying slow addition procedure A (Table 2, entry 2). In-
stead, aryl halide reduction and homocoupling products
(ArH and Ar–Ar) were observed as major products
present in the reaction mixture. This outcome indicated
the formation of arylcobalt intermediates, however, in too
high concentrations as opposed to available MVK. De-
creasing the concentration of CoBr2(Bpy) in solution by
tages of a direct approach using cobalt catalysis,5 we
focused our efforts towards the extension of our method-
ology to this substrate class. In this letter, we wish to re-
port a refined procedure suitable for the direct conjugate
addition of aromatic halides onto methyl vinyl ketone
(MVK) as a representative a,b-enone.
At the outset, we selected our previously developed con-
ditions being capable of facilitating the 1,4-addition of
SYNLETT 2009, No. 7, pp 1073–1076
x
x.
x
x.
2
0
0
9
Advanced online publication: 26.03.2009
DOI: 10.1055/s-0028-1088117; Art ID: G02109ST
© Georg Thieme Verlag Stuttgart · New York

1074
M. Amatore, C. Gosmini
LETTER
Table 1 Survey of Reaction Media for Cobalt-Catalyzed Conjugate Addition of Ethyl para-Bromobenzoate onto MVK
O
O
O
CoBr2(Bpy) cat.
O
Br
+
LiBr, H2O, reductant,
DMF, py
EtO
EtO
1.1 equiv
TFA cat., temp.
Entry
CoBr2(Bpy) (mol%)
Reductant
Mn
Temp (°C)
GC yield (%)a
1
2
3
4
5
6
7
10
20
50
50
10
20
20
50
50
50
80
50
50
80
24b
Mn
34b
Mn
37b
Mn
46b
Zn
28b,c
43b,c
50c,d
Zn
Zn
a Yield determined by GLC analysis using dodecane as internal standard.
b Only a partial conversion of ArBr was observed under these conditions.
c Without H2O as additive.
d Total conversion of ArBr was observed under these conditions.
slow addition of the catalyst in DMF to the reaction mix- facilitated not only a low but sufficient amount of MVK
ture prevented any productive consumption of the aryl in the reaction mixture but also a steady and moderate
bromide presumably due to complete catalyst deactiva- concentration of the low-valent cobalt complex. Thus the
tion at an adverse MVK–catalyst adduct (Table 2, proce- available active cobalt species might undergo oxidative
dure B, entry 3).
addition to the aryl bromide; subsequent conjugate addi-
tion would be favorable due to the constant addition small
amounts of MVK. Following this procedure, a constant
ratio of available active cobalt and MVK was secured.
Notably, since the combined addition of Co(II) and MVK
led to satisfactory results, this experiment substantiates
If, in turn, a solution of CoBr2(Bpy) and MVK in DMF
was added slowly over a period of 15 minutes, the reac-
tion proceeded in unprecedented efficiency to afford the
corresponding 1,4-adduct in 66% yield as determined by
GC (Table 2, procedure C, entry 4). This addition mode
Table 2 Effect of Reaction Parameters on Cobalt-Catalyzed Conjugate Addition of Ethyl para-Bromobenzoate onto MVK Using
CoBr2(Bpy)/Zn System
O
O
O
CoBr2(Bpy) (20 mol%)
Br
+
O
LiBr, Zn, DMF, py,
TFA cat., 80 °C
EtO
EtO
1.1 equiv
"standard conditions"
Entry Variation from ‘standard conditions’
GC yield (%)a
1
2
3
4
5
none
50
<5
0
procedure A: slow addition of MVK to medium containing all reagents at 80 °C (15 min)
procedure B: slow addition of CoBr2(Bpy) to medium containing all reagents at 80 °C (15 min)
procedure C: slow addition of CoBr2(Bpy) and MVK to medium containing all reagents at 80 °C (15 min)
66
procedure D: slow addition of CoBr2(Bpy), MVK, and H2O (0.50 equiv) to medium containing all reagents at 80 °C 86b,c
(15 min)
6
7
procedure E: slow addition of CoBr2(Bpy), MVK, and H2O (0.50 equiv) to medium containing all reagents at 80 °C
with Mn instead of Zn (15 min)
0
procedure F: slow addition of CoBr2(Bpy), MVK, and H2O (0.50 equiv) to medium containing all reagents at 80 °C
without LiBr (15 min)
0
a Yield determined by GLC analysis using dodecane as internal standard.
b Isolated yield 83%.
c Optimized amount of H2O: 74% and 72% (GC yield) were observed with 0.25 and 1.00 equiv of H2O, respectively.
Synlett 2009, No. 7, 1073–1076 © Thieme Stuttgart · New York

LETTER
New Strategy for the Conjugate Addition onto Methyl Vinyl Ketone
1075
our hypothesis of a strong and detrimental effect of an ex-
cess MVK on low-valent cobalt yet not on cobalt(II). Hav-
ing established this experimentally convenient procedure,
a survey of reaction parameters revealed the beneficial ef-
fect of water as an additive, avoiding product evolution in
the medium [H2O (0.50 equiv), 86% GC yield, 83% iso-
lated yield, Table 2, entry 5]. It is of particular interest that
the presence of water dispels the possible in situ formation
of an arylzinc intermediate as a productive reaction path-
way. Interestingly, reconsidering manganese as a stoichio-
metric reductant under optimized conditions remained
unsuccessful leading only to an unproductive consump-
tion of starting material (Table 2, procedure E, entry 6).
We also established the essential impact of lithium bro-
mide; without this additive no reaction was observed
(Table 2, procedure F, entry 7). In the latter case, the deh-
alogenation was detected, implying a slow formation of
ArZnX under these conditions. Analogously to palladium
or copper catalysis,9 LiBr might increase the oxidative ad-
dition rate of cobalt by in situ generation of more reactive
and soluble arylcobalt species and possibly also prevent
the transmetalation from cobalt to zinc.
Table 3 Cobalt-Catalyzed Conjugate Addition onto MVK: Aryl
Bromide Substrate Scope
CoBr2(Bpy) (20 mol%)
Br
MVK (1.1 equiv)
O
FG
FG
H2O, DMF
+ Zn, LiBr, TFA cat.,
DMF, py, 80 °C
slow addition
Entry
FG
Addition
Isolated yield (%)
time (min)a (GC yield, %)b
1
2
4-CO2Et
3-CO2Et
4-COMe
3-COMe
4-CN
15
83
15
10
15
10
15
10
15
15
20
20
75
3
70
4
42 (58)
79
5
6
3-CN
46 (64)
53 (86)
75
7
4-SO2Me
4-CF3
8
9
3-CF3
62
Having established the optimal reaction conditions, we
next examined the substrate scope.10 As outlined in
Table 3, para-substituted aryl bromides bearing an elec-
tron-withdrawing group furnished the corresponding 1,4-
adducts in consistently good results (Table 3, entries 1, 3,
5, 7, and 8). Variation of the substituent position to meta
was typically associated with a slight loss in reaction effi-
ciency (Table 3, entries 2, 4, 6, and 9). Along these lines,
ortho-functionalized aromatic bromides remained prob-
lematic. Less reactive electron-rich aryl bromides were
associated with lower yields and higher catalyst loading
up to 30 mol% was required (Table 3, entries 10–12). Al-
beit with a moderate yield, this method proved effective
for a one-step synthesis of Nabumeton (Table 3, entry
12).11
10
11
H
55c
4-OMe
45c
Br
12
20
50c
MeO
a Optimized addition times in each case.
b Yield determined by GLC analysis using dodecane as internal stan-
dard.
c With 30 mol% CoBr2(Bpy).
Table 4 Cobalt-Catalyzed Conjugate Addition onto MVK: Aryl
Chloride Substrate Scope
CoBr2(Bpy) (20 mol%)
Cl
The present approach also showed the remarkable reactiv-
ity towards functionalized aryl chlorides. At slightly ele-
vated temperatures, a selection of aryl chlorides bearing
electron-withdrawing groups proved to be equally effi-
cient when subjected to the direct cobalt-catalyzed conju-
gate-addition protocol (Table 4, entries1–4).
MVK (1.1 equiv)
FG
O
+ Zn, LiBr, TFA cat.,
DMF, py, 110 °C
H2O, DMF
FG
slow addition
Entry
FG
Addition time
Isolated yield (%)
(GC yield, %)b
(min)a
Exemplarily, we also examined the reactivity of aryl tri-
flates. Gratifyingly, slightly modified conditions facilitat-
ed the coupling with MVK (Scheme 1). Similar to the
conjugate addition of electron-rich, deactivated aryl bro-
mides, the reaction of an activated aryl triflate with MVK
required higher catalyst loading to furnish the 1,4-adduct
in moderate yield.
1
2
3
4
4-CO2Me
4-COMe
4-CN
20
70
15
71
15
80
4-SO2Me
15
52 (80)
a Optimized addition times in each case.
b Yield determined by GLC analysis using dodecane as internal stan-
dard.
O
CoBr2(Bpy) (30 mol%)
O
OTf
MVK (1.1 equiv)
O
EtO
H2O, DMF, 15 min
slow addition
EtO
In summary, we developed a novel approach for the direct
cobalt-catalyzed conjugate addition of functionalized aryl
halides onto a,b-unsaturated enones such as methyl vinyl
ketone. While complementing our previous cobalt-
+ Zn, LiBr, TFA cat.,
DMF, py, 80 °C
62%
Scheme 1 Cobalt-catalyzed conjugate addition of an activated aryl
triflate onto MVK
Synlett 2009, No. 7, 1073–1076 © Thieme Stuttgart · New York

1076
M. Amatore, C. Gosmini
LETTER
Nagashima, T.; Curran, D. P. Org. Lett. 2003, 5, 419.
(o) Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54,
3321. (p) Bazin, S.; Feray, L.; Siri, D.; Naubron, J.-V.;
Bertrand, M. P. Chem Commun. 2002, 2506.
catalyzed conjugate-addition protocol of aromatic halides
onto acrylic ester derivatives, this method represents an
interesting alternative to more traditional methods that
rely on the use of preformed organometallic coupling re-
agents. Michael adducts are readily available in good
yields from inexpensive, commercially available re-
agents. Most notably, previous formation of sensitive or-
ganometallic species is avoided. Extension of the
substrate scope of this reaction to other enones, and the in-
vestigation of the crucial role of zinc are currently under
way in our laboratory.
(4) (a) Amatore, M.; Gosmini, C.; Périchon, J. J. Org. Chem.
2006, 71, 6130. (b) Amatore, M.; Gosmini, C.; Périchon, J.
FR 2865203, 2005.
(5) Selected references: (a) Gosmini, C.; Bégouin, J.-M.;
Moncomble, A. Chem. Commun. 2008, 3221. (b) Amatore,
M.; Gosmini, C. Angew. Chem. Int. Ed. 2008, 47, 2089.
(c) Fillon, H.; Gosmini, C.; Périchon, J. J. Am. Chem. Soc.
2003, 125, 3867. (d) Hess, W.; Treutwein, J.; Hilt, G.
Synthesis 2008, 3537. (e) Cahiez, G.; Chaboche, C.;
Duplais, C.; Moyeux, A. Org. Lett. 2009, 11, 277.
(f) Cahiez, G.; Chaboche, C.; Duplais, C.; Giulliani, A.;
Moyeux, A. Adv. Synth. Catal. 2008, 350, 1484.
(g) Jeganmohan, M.; Cheng, C.-H. Chem. Eur. J. 2008, 14,
10876. (h) Shukla, P.; Hsu, Y.-C.; Cheng, C.-H. J. Org.
Chem. 2006, 71, 655. (i) Kobayashi, T.; Ohmiya, H.;
Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2008, 130,
11276. (j) Kawatsura, M.; Komatsu, Y.; Yamamoto, M.;
Hayase, S.; Itoh, T. Tetrahedron 2008, 64, 3488.
(k) Shirakawa, E.; Imazaki, Y.; Hayashi, T. Chem. Lett.
2008, 37, 654. (l) Korn, T. J.; Knochel, P. Angew. Chem. Int.
Ed. 2005, 44, 2947.
(6) Buriez, O.; Nédélec, J.-Y.; Périchon, J. J. Electroanal.
Chem. 2001, 506, 162.
(7) The same effect have been reported in palladium catalysis:
(a) Amatore, C.; Carré, E.; Jutand, A.; Medjour, Y.
Organometallics 2002, 21, 4540. (b) Amatore, C.;
Bensalem, S.; Ghalem, S.; Jutand, A.; Medjour, Y.
Eur. J. Org. Chem. 2004, 366.
(8) Under the conditions in Table 1, in the absence of water,
slow formation of ArZnX was detected by GLC analysis
after iodolysis. In presence of water, no ArZnX is
observable.
(9) (a) Alexakis, A.; Berlan, J.; Besace, Y. Tetrahedron Lett.
1986, 27, 1047. (b) Yuguchi, M.; Tokuda, M.; Orito, K.
J. Org. Chem. 2004, 69, 908. (c) Amatore, C.; Jutand, A.
Acc. Chem. Res. 2000, 33, 314. (d) Amatore, C.; Azzabi,
M.; Jutand, A. J. Am. Chem. Soc. 1991, 113, 8375.
(e) Negishi, E.-I.; Takahashi, T.; Akiyoshi, K. J. Chem. Soc.,
Chem. Commun. 1986, 1338. (f) Scott, W. J.; Stille, J. K.
J. Am. Chem. Soc. 1986, 108, 3033.
References and Notes
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis, Vol. 9; Baldwin, J. E.; Magnus, P. D., Eds.;
Tetrahedron Organic Chemistry Series, Pergamon Press:
Oxford, 1992. (b) Yamamoto, Y. In Houben-Weyl, 4th ed.,
Vol. 4 E21; Helmchen, G.; Hoffmann, R. W.; Mulzer, J.;
Schaumann, E., Eds.; Thieme: Stuttgart, 1996, Chap.
1.5.2.1. (c) Tomioka, K.; Nagaoka, Y. In Comprehensive
Asymmetric Catalysis, Vol. 3; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer Verlag: Berlin, Heidelberg,
1999, Chap. 31.1.
(2) Selected references: (a) Taylor, R. J. K. In Organocopper
Reagents, A Practical Approach; Harwood, L. M.; Moody,
C. J., Eds.; Oxford University Press: Oxford, 1994.
(b) Breit, B.; Schmidt, Y. Chem. Rev. 2008, 108, 2928.
(c) Alexakis, A.; Bäckvall, J. E.; Krause, N.; Pàmies, O.;
Diéguez, M. Chem. Rev. 2008, 108, 2796. (d) Harutyunyan,
S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa,
B. L. Chem. Rev. 2008, 108, 2824. (e) Gutnov, A. Eur. J.
Org. Chem. 2008, 4547. (f) Knochel, P.; Singer, D. Chem.
Rev. 1993, 93, 2117. (g) Westermann, J.; Imberg, U.;
Nguyen, A. T.; Nickisch, K. Eur. J. Inorg. Chem. 1998, 295.
(h) Nishikata, T.; Yamamoto, Y.; Miyaura, N.
Organometallics 2004, 23, 4317. (i) Hayashi, T.; Yamasaki,
K. Chem. Rev. 2003, 103, 2829. (j) Fagnou, K.; Lautens, M.
Chem. Rev. 2003, 103, 169. (k) Thaler, T.; Knochel, P.
Angew. Chem. Int. Ed. 2009, 48, 645. (l) Henon, H.;
Mauduit, M.; Alexakis, A. Angew. Chem. Int. Ed. 2008, 47,
9122. (m) Hawner, C.; Li, K.; Cirriez, V.; Alexakis, A.
Angew. Chem. Int. Ed. 2008, 47, 8211. (n) Robert, T.;
Velder, J.; Schmalz, H.-G. Angew. Chem. Int. Ed. 2008, 47,
7718.
(10) General Procedure for Conjugate Addition of Aryl
Halides or Triflates onto MVK
A flask was charged with aryl halide or triflate (7.5 mmol),
LiBr (7.5 mmol, 651 mg), zinc powder (15 mmol, 981 mg),
DMF (9 mL), and pyridine (2 mL). A solution of CoBr2 (20
mol%, 1.5 mmol, 328 mg), 2,2¢-bipyridine (20 mol%, 1.5
mmol, 234 mg), MVK (1.1 equiv, 8 mmol) and H2O (0.5
equiv, 3.75 mmol, 68 mL) in DMF (10 mL), first stirred at r.t.
for 10 min, was added dropwise to the resulting solution
(ArX, LiBr, Zn in DMF–pyridine) stirred at 80 °C or 110 °C.
After addition, the amount of the corresponding coupling
product was measured by GC using an internal reference
(dodecane, 200 mL). The reaction mixture was poured into a
soln of 2 N HCl and extracted with Et2O or CH2Cl2. The
organic layer was washed with a sat. soln of NaCl and dried
over MgSO4. Evaporation of solvent and purification by
column chromatography on SiO2 (pentane– Et2O) afforded
the conjugate adducts characterized by NMR (1H, 13C, 19F)
and mass spectrometry.
(3) (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000,
100, 3009. (b) Boldrini, G. P.; Savoia, D.; Tagliavini, E.;
Trombini, C.; Umani Ronchi, A. J. Organomet. Chem. 1986,
301, C62. (c) Lebedev, S.; Lopatina, V. S.; Petrov, E. S.;
Beletskaya, I. P. J. Organomet. Chem. 1988, 344, 253.
(d) Sustmann, R.; Hopp, P.; Holl, P. Tetrahedron Lett. 1989,
30, 689. (e) Bontempelli, G.; Magno, F.; Daniele, S.;
Schavion, G. J. Electroanal. Chem. 1983, 159, 117.
(f) Bonjoch, J.; Solé, D.; Carcía-Rubio, S.; Bosch, J. J. Am.
Chem. Soc. 1997, 119, 7230. (g) Yu, S.; Berner, M.; Cook,
J. M. J. Am. Chem. Soc. 2000, 122, 7827. (h) Nicolaou,
K. C.; Roecker, A. J.; Follmann, M.; Baati, R. Angew. Chem.
Int. Ed. 2002, 41, 2107. (i) Subburaj, K.; Montgomery, J.
J. Am. Chem. Soc. 2003, 125, 11210. (j) Condon, S.;
Nédélec, J.-Y. Synthesis 2004, 3070. (k) Gomes, P.;
Gosmini, C.; Nédélec, J.-Y.; Périchon, J. Tetrahedron Lett.
2002, 43, 5901. (l) Gomes, P.; Gosmini, C.; Nédélec, J.-Y.;
Périchon, J. Tetrahedron Lett. 2000, 41, 3385. (m) Curran,
D. P.; Wolin, R. L. Synlett 1991, 317. (n) Rivkin, A.;
(11) (a) Goudie, A. C.; Gaster, L. M.; Lake, A. W.; Rose, C. J.;
Freeman, P. C.; Hughes, B. O.; Miller, D. J. Med. Chem.
1978, 21, 1260. (b) Valero, M.; Costa, S. M. B.; Santos,
M. A. J. Photochem. Photobiol A: Chem. 2000, 132, 67.
Synlett 2009, No. 7, 1073–1076 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.