Catalytic Enantioselective Hetero-dimerization of Acrylates and 1,3-Dienes

Article abstract of DOI:10.1021/jacs.7b10055

1,3-Dienes are ubiquitous and easily synthesized starting materials for organic synthesis, and alkyl acrylates are among the most abundant and cheapest feedstock carbon sources. A practical, highly enantioselective union of these two readily available pre

Full text of DOI:10.1021/jacs.7b10055

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Article
Catalytic Enantioselective Heterodimerization of Acrylates and 1,3-Dienes
Stanley M. Jing, Vagulejan Balasanthiran, vinayak pagar, Judith C. Gallucci, and T. V. RajanBabu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b10055 • Publication Date (Web): 09 Nov 2017
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Journal of the American Chemical Society
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Catalytic Enantioselective Heterodimerization of Acrylates and 1,3-
Dienes
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Stanley M. Jing, Vagulejan Balasanthiran, Vinayak Pagar, Judith C. Gallucci and T. V. RajanBabu*
Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OHIO 43210,
United States
ABSTRACT: 1,3-Dienes are ubiquitous and easily synthesized starting materials for organic synthesis and alkyl acrylates are
among the most abundant and cheap feedstock carbon sources. A practical, highly enantioselective union of these two readily
available precursors giving valuable, enantio-pure skipped 1,4-diene esters (with two configurationally defined double bonds) is
reported. The process uses commercially available cobalt salts and chiral ligands. As illustrated by the use of 20 different sub-
strates including 17 prochiral 1,3-dienes and 3 different acrylates, this heterodimerization reaction is tolerant of a number of com-
mon organic functional groups (e.g., aromatic substituents, halides, isolated mono- and di-substituted double bonds, esters, silyl
ethers and silyl enol ethers). The novel results including ligand, counter ion and solvent effects uncovered during the course of
these investigations show a unique role of a possible cationic Co(I) intermediate in these reactions. The rational evolution of a
mechanism-based strategy that led to the eventual successful outcome and the attendant support studies may have further implica-
tions for the expanding use of low-valent group 9 metal complexes in organic synthesis.
Nickel-catalyzed asymmetric hydrovinylation of alkenes
Introduction
H
(1 atmosphere)
Studies aimed at the development of highly efficient and enan-
R
R'
R
(1)
tioselective methods for the preparation of various classes of
organic compounds are among the most active areas of re-
search in modern organic synthesis.1 Successful outcome of
such research, especially when it involves catalytic reactions
between readily available starting materials and feedstock
carbon sources,2 can greatly impact the design, synthesis and
manufacture of molecules of interest from medicine to materi-
als.3 Development of enantioselective versions of coupling
reactions (heterodimerizations) between two different, stable
alkenes for the synthesis of chiral intermediates has huge po-
tential, yet presents significant challenges on two fronts, acti-
vation of the relatively unreactive molecules and selectivity
(chemo- regio- and enantioselectivity) in the reactions be-
tween them.4 In this context, we have reported highly enanti-
oselective heterodimerization between ethylene and activated
alkenes using nickel catalysts (Eq 1),5a and, between ethylene
and 1,3-dienes using cobalt catalysts (Eq 2).6a,b While the
reactions of ethylene are highly efficient and selective, and,
applicable for the syntheses of several biologically important
molecules (e. g., 2-arylpropionic acids,7a steroid analogs,7b
pseudopterosins,7c trikentrins7d) the utility of this reaction
would be vastly enhanced if instead of ethylene a functional-
ized alkene such as methyl acrylate can be used. Even though
acrylates are among the largest volume feedstocks (>
2,000,000 metric tons annual production), they are seldom
used in catalytic enantioselective reactions, and, for known
dimerization reactions involving acrylates and other alkenes,
the reported substrate scope, yields and selectivities are
somewhat limited.8 In the best example in the literature of an
enantioselective codimerization of an alkyl acrylate and a
diene, Hirano et al reported obtaining 31% yield and 58% ee
H
[L*]Ni(II)-catalyst
R'
(0.007-0.05 equiv)
vinylarenes
strained alkenes
yields >90%
ee's 90-99%
Cobalt-catalyzed asymmetric hydrovinylation of 1,3-dienes
H
(1 atmosphere)
R
H
[(P~ P)*]CoCl2/Me3Al or MAO
H
(2)
R'
*
R
0.01-05 equiv Co; Al/Co = 3
CH2Cl2, low temp.
R'
2
1
yields >90%
ee's 90-99%
Cobalt(I)-catalyzed heterodiemrization of 1,3-dienes and acrylates
variations of the
procedures in Eq 1, Eq 2
CO2R'
H
X
CO2R'
(3a)
H
R
3
4
*
5
R
+
(this work)
5
(3b)
[(P~P)Co–X or (P~N)Co–X
yields (70-90%)
ee's 95-99%
NaBARF, CH2Cl2, low temp
• Ligand and counter ion effects
• Isolation and characterization of intermediates
• Labeling studies in support of mechanism
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in the reaction between 1,2,3,4-tetramethylbutadiene and t-
Page 2 of 13
H
Z
I
1
2
3
4
5
6
7
8
P
P
butyl acrylate in the presence of 10 mol% of a Ru(0)-complex.
A less substituted butadiene gave mixture of three products
(total yield 73%) in ee’s in the range of 10-29%.8f Since our
protocols for ethylene/1,3-diene heterodimerization that uses
cobalt/alkylaluminum (Eq 2) failed to work for the Lewis
basic acrylate, a new catalystsystem had to be developed. In
this article we report the development of a practical, and high-
ly regio- and enantioselective catalytic reaction that combines
H2C
3
Co
X
Z
+
R
6
R
5 Z = CO2R
4
X
X
P
CoIII
P
P
CoIII
H
P
R
o
a range of 1,3-dienes with alkyl acrylates (1:1.1 ratio, 23 C)
R
9
Z
Z
in the presence of 1-5 mol% of readily available bis-phosphine
cobalt halide complexes (Eq 3b) and an activator, sodium
tetrakis-3,5-bis-(trifluromethylphenyl)borate (NaBARF). The
products are nearly enantio-pure, conjugated 1,4-diene esters
(5) bearing a chiral center between the configurationally de-
fined double bonds. Since these double bonds have distinctly
different reactivities we expect these chiral synthons to be of
significant value for further synthetic applications. Reactions
of 20 different substrates including 17 different prochiral
dienes giving yields in the range of 70-90% and enantiomeric
excesses up to 99% are reported. Mechanistic studies includ-
ing isolation and characterization of intermediates (multi-
nuclear NMR, X-ray crystallography), solvent and counter-
anion effects, and isotopic labeling studies suggest the unique
role of cationic Co(I) intermediates in these reactions.
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Figure 1. Oxidative route to dimerization of alkenes
Results and Discussion
A mechanistic proposal
In detailed scouting studies (See Table S1 in Supporting In-
formation for details) we found that our broadly applicable
original procedures for hydrovinylation of dienes using vari-
ous bis-phosphine complexes (P~P)CoX2 and an activator
trimethylaluminum or methyl aluminoxane (MAO), led to
very low conversions to the desired adducts 5 (Eq 3a).
2
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Ph
Ph
1
2
3
4
5
6
7
8
9
P
Co
Ph2
P
Br
Ph
Ph
Ph
Ph
P
Ph
Ph
P
Ph
Ph
P
R
P
P
P
Ph
CoX2
Ph
Ph
Ph
Ph
P
Co
2
H
Ph
Ph
Br
(CH2)n
Co
P
Ph2
Co
X
Co Cl
Ph
P
P
P
P
Ph
Ph
R
Ph
Ph
Ph
Ph
(10a-c R = H; 10d R = Me)
9 (dppe)2Co-H
10a n = 1, X = Br
10b n = 1, X = Cl
10c n = 2, X = Cl
12a X = Br '(dppp)CoBr'
12b X = Cl '(dppp)CoCl'
11a [2(dppp)Co-Br].dppp
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13a '(dppb)CoCl'
(X-ray)
10d n = 1, X = Cl
[(S,S)-BDPP]CoCl2 (ref 15)
(P~P)
No
15a
15b
15c
15d
15e
DPPP
DPPB
(S,S)-DIOP
(S,S)-BDPP
(S,S)-BINAP (X-ray)
P
(P~P)
Co
Co
– (COD)
P
14 (COD)Co(COE–)
15e
10a
10d
11a
Figure 2. Cobalt(I) and cobalt (II) bis-phosphine complexes for heterodimerization of alkenes. See Supporting Information page S26 for
full structures of ligands.
3
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Page 4 of 13
We reasoned that the failure of this reaction involving vari-
recognized in the literature by others.12 Thus we decided to
1
2
3
4
5
6
7
8
ous alkyl aluminum promoters might be related to the in-
compatibility of these reagents with the reactive, Lewis basic
alkyl acrylate substrate (3), vis-à-vis ethylene that was used
in the successful reactions depicted in Eq 2. We wondered if
we could circumvent the use of aluminum alkyls in this pro-
tocol by exploiting a discrete and identifiable Co(I)/Co(III)-
redox cycle (Figure 1) as a possible pathway for this reaction
that maybe approached differently by modifying the reaction
conditions. This would involve an oxidative dimerization of
the two olefins assisted by the low-valent cobalt species (3 +
4 + 6 —> 7), a mechanistic possibility that has been ad-
vanced before in other ruthenium-9 and cobalt-10 catalyzed
heterodimerization reactions, but without much supporting
evidence. Even though low-valent cobalt phosphine com-
plexes have been used extensively in catalytic carbon-carbon
bond-forming reactions,11 these reagents are almost invaria-
bly generated in situ in the presence of excess reducing
agents and other metal salts, and the oxidation state of cobalt
and the nature of the intermediates (radicals or low-valent
organometallic C-Co species) in many of these reactions are
often open to speculation. A dearth of reports on well-
characterized phosphine-Co(I) complexes as it relates to its
catalytic properties and reaction chemistry has also been
examine the role of discrete well-characterized Co(I)-
complexes for the heterodimerization reactions of 1,3-dienes
with the goal of overcoming the limitations of our original
procedure.
Development of a modified protocol for the hydrovi-
nylation of 1,3-dienes
To test the viability of an oxidative route (Figure 1) for the
dimerization, we prepared and characterized several well-
defined Co(I)-complexes (Figure 2) and examined their utili-
ty in the catalyzed heterodimerization reactions between (E)-
1,3-dodecadiene and ethylene as a test reaction (Eq 4, Table
1). Details of the preparation and characterization of the
compounds listed in Figure 2 are described in the Supporting
Information.
9
10
11
12
13
14
15
16
17
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19
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60
H
( 1 atm)
H
+
H
(4)
[(P~P)Co(I) complex
activator, CH2Cl2
23 oC
C8H17
C8H17
C8H17
4a
16a
17a
Table 1. Codimerization of (E)-1,3-dodecadiene and ethylene using Co(I) complexesa
Co(I) source
(mol%)
temp (oC)
time
conv.
(%)
activator
(mol%)
entry
16a/17a
1
9, 11a, 12a, 12b, 14, 15a
9 (dppe)2CoH (20)
none
variousa
<5
--
2
(C6F5)3B (20)
(C6F5)3B (60)
NaBARF (20)
(C6F5)3B (15)
NaBARF (30)
(C6F5)3B (30)
NaBARF (25)
ZnCl2 (50)
23, 4
100
100
>99
100
100
100
100
90
78/20
80/20
82/17
80/20
79/20
76/19
77/17
78/22
40/11
76/11
71/3
3
11a (dppp)3Co2Br2 (5)
11a (dppp)3Co2Br2 (5)
12ab ‘(dppp)CoBr’ (10)
12ab ‘(dppp)CoBr’ (10)
12bb ‘(dppp)CoCl’ (10)
12bb ‘(dppp)CoCl’ (10)
12bb ‘(dppp)CoCl’ (10)
12bb ‘(dppp)CoCl’ (10)
14 (COD)Co(COE-) (10)
15b (dppb)Co(COE-) (10)
15c (S,S)-DIOPCo(COE-) (5)
15d (S,S)-BDPPCo(COE-) (10)
23, 1
4
23, 1
5
23, 1
6
23, 1
7
23, 1.5
23, 1.5
23, 3
8
9
10
11
12
13
14
ZnI2 (30)
23, 6
55
(C6F5)3B (30)
(C6F5)3B (30)
(C6F5)3B (10)
(C6F5)3B (30)
23, 12
23, 1
100
100
25
-20, 12
0 to 23, 2
34c/5
77d/21
100
a See Eq 4 and Supporting Information for details. A more detailed list of cobalt(I) sources and corresponding reaction conditions are also
included there (Table S2). The conversion and composition of products 16 and 17 (Eq 4) were determined by gas chromatography and
confirmed by NMR spectroscopy. See Supporting Information for details. b Synthesized by reduction of the corresponding (P~P)CoX2 by
Zn. c 87% ee. d 80% ee.
The most significant findings from the initial scouting exper-
iments are shown in the Table 1. More extensive details
describing the effect of ligands and activators on this reac-
tion can be found in the Supporting Information (Table S2).
Not surprisingly, the coordinately saturated complex
(dppe)2CoH (9)13 or the Co(I) complexes 11a, 12a, 12b, 13a,
14, 15a do not catalyze the dimerization reaction under am-
bient conditions in the absence of an activator (entry 1).
However, in the presence of a Lewis acid, various Co(I)-
complexes become viable catalysts for this reaction (entries
(dppe)2CoH (9)13 and [(dppp)3Co2Br2] (11a), are an excellent
catalysts for this dimerization reaction in the presence of
(C6F5)3B (entries 2, 3).
Sodium tetrakis-3,5-(bis-3,5-
trifluromethylphenyl)borate (NaBARF) is also an excellent
activator of 11a (entry 4). This complex is readily prepared
by reduction of the corresponding (P~P)CoBr2 (10a) with
EtMgBr, activated Zn or Mn. The identity of the starting
(dppp)CoBr2 (10a) and the reduced species (11a) derived
from reactions of 10a with various reagents (EtMgBr, Zn)
were established by X-ray crystallography since NMR spec-
tra often resulted in broad peaks and generally not reliable,
2-14).
Thus fully characterized Co(I) complexes,
4
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Journal of the American Chemical Society
presumably because of the presence of traces amounts of and ZnI2 as activators for this reaction even though they are
1
2
3
4
5
6
7
8
Co(II) species and/or high-spin Co(I) species in the mixture.
The unit cell parameters of crystals obtained from reduction
of the (dppp)CoX2 with EtMgBr and Zn are identical. High-
resolution MALDI-mass spectra of the compounds 10a,
(used for the scouting experiments and the preparation of all
racemic products in Table 4), 10d (used to prepare the nearly
enantio-pure products described in Table 4), 11a and 12a
(mechanistically relevant, putative Co(I) complexes) are also
especially useful for further characterization of these key
compounds.16 The solid-state structure of a sample obtained
from reduction of 10a with EtMgBr revealed the presence of
an additional dppp ligand linking two cobalt centers (11a),
where each cobalt has 16-electrons. The Zn-reduced com-
plex, represented as ‘(dppp)CoBr’ (12a), when activated by
(C6F5)3B or NaBARF, catalyzed a quantitative heterodimeri-
zation of (E)-1,3-dodecadiene and ethylene to give products
not nearly as effective as NaBARF at comparable concentra-
tion levels. These activators are also moderately effective in
the use of (dppb)cobalt(I) chloride (13a) as a catalyst (not
shown). We recognized that the complex (COD)Co(η3-
cyclooctenyl) (14)14 is an excellent source of well-defined of
(P~P)Co(I)(η3-cyclooctenyl) complexes (15a-15e).
The
application of three such complexes (15b, 15c and 15d) for
the hydrovinylation reaction are shown in entries 12-14 in
Table 1. The enantioselectivity observed for the adduct 16a
using the chiral, enantiopure complexes 15c and 15d (entries
13 and 14) are comparable to what was previously observed
in our original reaction using Me3Al as the activator (Eq 2),15
validating the hypothesis that Co(I) intermediates may in-
deed be involved in these reactions carried out under dispar-
ate conditions. Most gratifyingly we find that this new pro-
tocol for heterodimerization that avoids the use of near stoi-
chiometric amounts of trimethylaluminum (Eq 2) has broader
scope for the alkenes, including for the use of alkyl acrylates
as reaction partners.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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59
60
16a and 17a (entries 5 and 6).
The corresponding
(dppp)cobalt(I) chloride complex 12b is equally effective for
this reaction using either (C6F5)3B or NaBARF as an activa-
tor (entries 7, 8). Entries 9 and 10 illustrate the use of ZnCl2
Table 2. Optimization of 1,3-diene-acrylate dimerization (Ligand and counter ion effects)a
products (%)c
entry
Co(I) sourceb
(mol%)
activator
(mol%)
temp (oC)
time (h)
conv. (%)
18a
--
19a
1
12a (dppp)CoBr (10)
12a (dppp)CoBr (5)
12a (dppp)CoBr (5)
12a (dppp)CoBr (5)
12a (dppp)CoBr (10)
12a (dppp)CoBr (10)
12a (dppp)CoBr (10)
12b (dppp)CoCl (10)
13a (dppb)CoCl (10)
(dppe)CoBr (10)
none
23, 18
23, 12
23, 0.5
23, 12
23, 18
23, 20
23, 20
23, 12
23, 12
23, 12
23, 12 h
23, 12
0
--
2d
3e
4f
5
NaBARF (10)
NaBARF (15)
NaBARF (15)
ZnCl2 (100)
(C6F5)3B (30)
Me3Al (60)
100
100
0
80
85
--
12
10
--
100
9
79
-
15
-
6
7
<5
-
-
8
NaBARF (30)
NaBARF (30)
NaBARF (30)
NaBARF (30)
NaBARF (15)
100
100
100
56
79
78
86
54g
87h
13
13
7
9
10
11
12
[(S,S)-BDPP]CoBr (10)
[L3a]CoBr (5)
2
100
13
a See Eq 5 and Supporting Information for experimental details. More elaborate Tables (Tables S3a-S3e, Table S4a-S4b) describing effect
of various parameters used for the optimization of this reaction (activators, solvents, stoichiometries of NaBARF and methyl acrylate) are
also included in the Supporting Information. b The Co(I)-bromide complexes were prepared by reduction with activated zinc. See Sup-
c
d
f
porting information for details.
Up to 4% of a regioisomer 18a-α was also observed. 0.12 M in substrate. e 0.60 M in substrate. in
g
h
THF. 97% ee, See Scheme 1 below for the structure of the ligand. 60% ee, See Scheme 1 below for the structure of the ligand.
relatively inexpensive ZnCl2 is also found to be acceptable (en-
try 5) even though stoichiometric amounts of this reagent are
needed to complete the reaction. Surprisingly, Me3Al and
(C6F5)3B were found to be much less effective (entries 6, 7), as
were several others (AlCl3, Zn(OTf)2, AgOTf, methylaluminox-
ane, Et2Zn).16 Both AgSbF6 and ZnI2 were usable, but with low
conversions even at higher concentrations.16
Heterodimerization between (E)-1,3-diene and methyl
acrylate
Table 2 summarizes the results of optimization of a heterodi-
merization between methyl acrylate and a prototypical diene,
(E)-1,3-dodecadiene, using the new protocol (Eq 5). As ex-
pected none of Co(I)-complexes (Figure 1) catalyze the reaction
in the absence of activators under ambient conditions (e. g.,
entry 1). However, we find that several Co(I)-complexes,
among them, (dppp)CoBr (12a), (dppp)CoCl (12b), (dppb)CoCl
(13a) and (dppe)CoBr, efficiently catalyze this reaction in the
presence of various activators (entries 2-10). Among the activa-
H
H
CO2Me
CO2Me
(1.1 equiv.)
H
+
H
(5)
CO2Me
C8H17
+
CO2Me
[(P~P)Co(I)-X (cat)
C8H17
activator, CH2Cl2, 23 o
C
C8H17
18a (80%)
tors,
NaBARF
(BARF
=
terakis-[bis-(3,5-
C8H17
trifluromethylphenyl)borate] was found to be the most generally
applicable, facilitating the reactions of a wide range of Co(I)-
complexes. Among the other activators that were examined,
19a (12%)
18a-α (<4%)
4a
• [shown results with (dppb)CoBr (5 mol%) and activator NaBARF (10 mol%)]
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Page 6 of 13
Further optimizations (see Supporting Information Table plexes (Eq 5) helped to delineate novel aspects of this reac-
1
2
3
4
5
6
7
8
S3a-S3e) revealed that the reaction can be accomplished at
near 1:1 stoichiometry of the alkenes, with lower catalyst
loading (0.05 equiv), and, chlorinated solvents methylene
chloride and dichloroethane were the most optimal. In these
solvents for most substrates the reaction is best carried out at
0.5-0.6 M to effect complete conversion in 30 min with 5
mol% of the catalyst and 15 mol% of NaBARF (entry 3,
Table 2). Oxygenated solvents such as THF, ether or ethyl
acetate gave no conversion (entry 4). An important practical
consideration related to this solvent effect is that in the prep-
aration of the Co(I)-halide via Zn-reduction of the
(P~P)CoX2 complex, which is best carried out in THF, the
residual THF should be completely removed after reduction
for best results.16 Hydrocarbons, where the catalyst has low
solubility, showed very low conversion.
tion, including the role of various activators and solvent ef-
fects, the latter procedure (Scheme 1) is more convenient and
more efficient from a practical perspective. Therefore the
ligand effects in the enantioselective version of this reaction
were examined in greater detail using this protocol. The
results of these studies are documented in Table 3.
As is revealed by the entries in the Table 3, four classes of
cobalt complexes, those carrying DIOP (L1, entry 1), BDPP
(L2, entries 2, 3, 5, 6), 2-(2-diarylphosphino)phenyl oxa-
zolines (Helmchen’s ligands, entries 4, 7, 8, 9), and Josiphos
(L4, entry 10) ligands were found to be viable for this de-
manding reaction, with DIOP, BDPP and JOSIPHOS giving
outstanding regio- and enantioselectivities, the latter up to
97% ee. (For a complete list of ligands and their effect on
selectivities, see, Supporting Information Figures S1 and
S2). Entries 1-4 in Table 3 show applications of pre-reduced
Co(I)-complexes (Eq 5). The complex (DIOP)CoBr, while
giving high ee (entry 1), gave only modest chemical yields.
As alluded to earlier, reactions with the (P~P)CoBr2 com-
plexes with zinc as a reducing agent is the most convenient
and practical way to effect this reaction (Scheme 1) and the
yields obtained for 18a using this procedure are substantially
higher (entries 5-10). Under these conditions nearly quanti-
tative conversion of the diene is observed giving the 1,4-(Z)-
adduct 18a along with varying amounts (1-5 %) of a linear
adduct (19a) and only traces, if any, of the isomeric 18a-α.
Thus, most gratifyingly, the enantioselective version of the
reaction offers significantly higher regioselectivity for the
reaction. Fine-tuning of the phosphinooxazoline (L3) leads
to slight improvements in ee’s (entries 7, 8 and 9), but even
the best of these ligands, the bis-cyclohexylphopsphino-
ligand L3f does not match the results obtained from the
BDPP (entries 5, 6), or, the JOSIPHOS (entry 10) ligand,
which gave >97% ee and yields in excess of 95% of the de-
sired 1,4-addition product 18a.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cobalt(I) complexes of chiral ligands, [(S,S)-BDPP]CoBr
and [L3a]CoBr (5) also are competent for the heterodimeri-
zation reaction, giving up to 97% ee in the former case (Ta-
ble 2, entry 11). However, in subsequent experiments we
realized that the in situ generation of the Co(I) complex (vide
infra, Scheme 1) provided an exceptionally facile way of
scouting the ligands for higher enantioselectivity for this
exacting reaction, and these efforts are described in the next
section. It should be noted that except for the counter ion,
this procedure resembles the original Hilt conditions for het-
erodimerization of 2,3-dimethylbutadiene and 1-alkenes.17
Scheme 1. Enantioselective heterodimerization between
(E)-1,3- dodecadiene and methyl acrylate
H
(P~P)CoBr2 (10 mol%)
NaBARF (20 mol%)
Zn (100 mol%)
CO2Me
C8H17
H
+
4a
+
CO2Me
CH2Cl2 (0.5 M), 23 oC, 12 h
C8H17
C8H17
CO2Me
H
18a (90-95%)
19a (<6%)
The absolute configuration of the major product 18b derived
from (E)-1,3-nonadiene and methyl acrylate using [(S,S)-
BDPP]CoBr2 has been established as (R) by the transfor-
mations shown in Scheme 2. Hydrovinylation of (E)-1,3-
nonadine using (S,S)-BDPP is known to give the (S) adduct,
20b.15 This adduct (20b) was transformed into a mixture of
epoxy esters [22a + 22b], by reaction with mCPBA, fol-
lowed by treatment of the product epoxide [21a+21b] with
Grubbs generation II metathesis catalyst in the presence of 5
equivalents of methyl acrylate. This diastereomeric pair is
identical (chiral stationary phase chromatography, NMR) to
the epoxides derived from the product of enantioselective
heterodimerization of (E)-1,3-nonadiene and methyl acrylate
using [(S,S)-BDPP]Co-complex. The assignments of the
configurations of the other structurally related products (Ta-
ble 4) were made by analogy. Retention behaviors of enan-
tiomers of the adducts in chiral stationary phase GC is also
consistent with the assignments across all products.16
O
PPh2
PPh2
P
O
P
O
Fe
R12P
N
L1 (R,R )-DIOP
R2
L3a R1 = Ph; R2 = Ph
PPh2
Ph2P
L4 (Josiphos-1)
L3b R1 = Ph; R2 = PhCH2-
L3c R1 = Ph; R2 = i-Pr
L3d R1 = 2,5-(CH3)2-phenyl; R2 = Ph
L3e R1 = 3,5-(CF3)2-phenyl; R2 = Ph
L3f R1 = Cyclohexyl; R2 = Ph
L2 (S,S )-BDPP
Enantioselective heterodimerization reactions
Next we turned our attention to enantioselective heterodi-
merization reactions. Following the optimizations described
thus far as
a guide, heterodimerization of (E)-1,3-
dodecadiene (4a) and methyl acrylate was carried out under
two slightly different protocols, either using the isolated
Co(I)-complexes (P~P)CoX (X = Br, Cl, COE-, COE- = η3-
cyclooctenyl) of various chiral ligands (Eq 5) or, by generat-
ing the Co(I) complexes in situ from the corresponding
Co(II)X2 complexes (Scheme 1). Most gratifyingly both
conditions for the reaction gave the expected branched prod-
uct 18a, with, typically, less than 6% of the achiral linear
product 19a, and only traces (<1%) of the branched product
18a-α. Even though the use of the isolated cobalt(I) com-
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1
2
3
Table 3. Ligand effects in enantioselective heterodimerization of (E)-1,3-dodecadiene and methyl acrylatea
4
5
6
7
18a
Co source (mol%), Zn (mol%)
activator (mol%)
time (h)
conv.(%)
Entry
ee (%)
yield (%)
Cobalt(I) [Eq 5]
8
9
93
97
93
60
(R,R)-DIOP(L1)CoBr (5), Zn (0), 20
NaBARF (7)
(S,S)-BDPP(L2)CoBr (10), Zn (0), 20
NaBARF (30)
(S,S)-BDPP(L2)Co(COE-) (5), Zn (0), 20
H(EtO)2BARF (5)
<10
56
<10
53
1
2
3
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
22
22
[L3a]CoBr (5), Zn (0), NaBARF (15)
12
100
87
Cobalt(II) [Scheme 1]
97
95
60
73
77
97
(S,S)-BDPP(L2) CoBr2 (10), Zn (100), 12
NaBARF (20)
(R,R)-BDPP(ent-L2) CoBr2 (10) Zn 12
(100) NaBARF (40)
[L3a]CoCl2 (10), Zn (100), NaBARF 12
(20)
(ent-L3b)CoBr2(10), Zn (100), NaB- 12
ARF (20)
(L3f) CoBr2(10), Zn (50), NaBARF 12
(40)
(L4) CoBr2(10), Zn (50), NaBARF 12
(40) Josiphos 1
100
100
100
100
100
99
95
94
88
68
80
97
5
6
7
8
9
10
a For entries 1-4, Eq 5, for entries 5-10 see Scheme 1. For a more complete list of ligands examined, see Supporting Information, Figures
S1 and S2.
Scheme 2. Relating the absolute configuration of the heterodimerization product 18b to the known configuration of 20b
metathesis, Grubbs Gen 2 catalyst
H
H
[(S,S)-BDPP]CoBr2 (0.05 equiv.)
Zn-dust (1.0 equiv.)
m-CPBA (1.1 equiv.)
CH2Cl2, 23 oC, 4 h
(>95%)
CO2Me
( 5 equiv)
O
S
S
CH2Cl2, 40 o
C
NaBARF (0.075 equiv.)
CH2Cl2 (0.5 M), 23 oC, 2h
C5H11
H
C5H11
C5H11
(86% yield, 90% ee)
CO2Me
4b
20b
[21a+21b]
(major stereoisomers)
O
S
H
C5H11
CO2Me
CO2Me
[(S,S)-BDPP]CoBr2 (0.05 equiv.)
Zn-dust (1.0 equiv.)
m-CPBA ( 1 equiv.)
CH2Cl2, rt, 2 h
[22a+22b]
+
R
NaBARF (0.075 equiv.)
CH2Cl2 (0.5 M), 23 oC, 2h
C5H11
1.1 equiv.)
C5H11
18b (97% ee)
4b
Scope of the reaction
chain carrying a remote alkene, such as in β-myrcene (18t)
or even a trimethylsiloxy substituent (18n). Several exam-
ples show the use of methyl, ethyl and t-butyl acrylate.
The optimized conditions were applied to a variety of 1,3-
dienes and the results obtained are shown in Table 4. A full
Table listing all starting materials and product distribution is
included in the Supporting Information (Table S6). C4-
Substituted 1,3-dienes giving products 18a-18q are among
the best substrates for this reaction. This substituent can
bear a number of functional groups, among them, an aro-
matic moiety (18h and 18i), a chlorine (18j), a silyl ether
(18k), and, mono-, di or tri-substituted alkene (18l, 18m).
Substituents at the C2 and C3 positions are tolerated as ex-
emplified by products 18n-18t. The C2-substituent can be a
Even though we have not optimized the yield of all sub-
strates shown, especially for the synthesis of the racemic
series of products, the isolated yields of the branched product
(18x) are generally very good to excellent (70~85%). Vary-
ing amounts of the linear product (19x, Scheme 1) are also
observed in these reactions, especially for mono-substituted
1,3-dienes. Products from 1,3-disubstitued dienes including
a
trimethylsiloxy diene (18n) and from 2,3-
dimethylbutadiene (18s) generally constitute single
a
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Journal of the American Chemical Society
branched adduct. 2-Alkyl dienes, as expected, give two line-
Page 8 of 13
1
ar 1,4-adducts (e. g., 18r/19r and 18t/19t).
2
3
4
5
6
7
8
9
Most significantly, enantioselectivities in excess of 95 %ee
are obtained for most prochiral dienes. To our delight we
also find that the regioselectivities in the enantioselective
reactions are much superior to the achiral version of the reac-
tion. Thus, except for two substrates that carry a remote ar-
omatic ring (entries 18h and 18i) and one with a branching at
the allylic position (18f) less than 6% of the linear product
(19x) is formed in these reactions (For details, see Supple-
mentary Material, Table S6).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A chiral product 18m derived from citronellal-derived diene
gave a 1:1 diastereomeric ratio of the adducts upon reaction
with the achiral catalyst system, (dppp)CoBr2/NaBARF/Zn.
The reaction with either enantiomer of the BDPP-CoBr2
complex gives an unusually selective reaction, overcoming
the inherent selectivity of this chiral substrate. The two ex-
pected products (18m) are obtained in excellent diastereo-
meric ratios (>93:7 at C8) depending on which enantiomer of
the chiral catalyst is used.
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Journal of the American Chemical Society
Table 4. Scope of heterodimerization of 1,3-dienes and acrylatesa
1
2
3
4
Chiral Products
CO2Me
CO2t-Bu
CO2t-Bu
CO2Et
CO2Me
CO2t-Bu
CO2Me
CO2Et
CO2Et
5
6
7
8
CH3
C5H11
CH3
C5H11
C5H11
C8H17
C8H17
C8H17
CH3
9
18a-Me
18a-Et
18a-t-Bu
18b-Me
18f-Et
18f-t-Bu
18c-Me
18c-Et
18c-t-Bu
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
51
72
96
81
80
--
75
--
86
81
98
91
76
98
81
69
97
60
65
97
% yield (racemic)
% yield (non-racemic)
% ee
60
75
81
82
97
--
--
CO2t-Bu
CO2Me
CO2Me
CO2Me
CO2Me
CO2t-Bu
CO2t-Bu
CO2Me
CO2t-Bu
C6H13
C6H13
i-Bu
C7H15
i-Bu
CH2Ph
CH2Ph
18d-Me
18d-t-Bu
18e-Me
18e-t-Bu
18f-Me
18f-t-Bu
18g
18h-Me
18h-t-Bu
% yield (racemic)
% yield (nonracemic)
% ee
75
70
98
72
75
96
81
75
99
65
60
95
79
89
98
60
-
79
--
81
-
75
--
-
--
-
--
CO2t-Bu
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
TMSO
CO2Me
CH2CH2Ph
CH2CH2Ph
3
8
C8
C5H11
Cl
OSi(t-Bu)Me2
18k
18i-Me
18i-t-Bu
18j
18l
18mb
18n
62
--
85
--
% yield (racemic)
% yield (nonracemic)
% ee
85
79
76
72
98
92 (dr 1:1)
81, 75
78
87
98
78
87
98
--
--
>95
dr 95:5; 7:93
Products from 2 or 3-substituted 1,3-dienesc,d
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2t-Bu
CO2Me
CO2Me
CO2Me
+
+
C8H17
18q
C5H11
18o
C5H11
18p
18r
+
19r
18s-Me
18s-t-Bu
18t
+
19t
(% yield)
81
85
79
85 (1:1)
85
79
70 (1:1)
a See Scheme 1 and Supporting Information for details of the procedure and full characterization of products. The yield and proportion of
the major product (18x) is shown. The remaining material is the linear adduct 19x (see Eq 5). Selectivities were determined by chiral
stationary phase gas chromatography. Chromatograms for all products are included in the Supporting Information. For 18a, >96 % ee (S)
with (R,R)-BDPP CoBr2. b For 18m, diastereomeric ratio, [C8(R) : C8(S)], with (S,S)-BDPP = 95:5; with (R,R)-BDPP = 7:93. c For 18n-
18q the % ee was not determined. d Products 18r-18u are achiral.
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Page 10 of 13
overall selectivity (regioselectivity or enantioselectivity) of
Mechanism of heterodimerization
1
the reaction. An examination of the activators indicates that
a synergy between Lewis acidity of the metals and the prop-
erties of the counter ion is important. Significant variations
in the yield and selectivity of the reaction upon use of assort-
ed Zn and Ag salts support this contention (See Supporting
Information, Table S3f). Methyl aluminoxane and trimethyl
aluminum, which perform exceedingly well for simple co-
dimerization of dienes with ethylene, totally fail with methyl
acrylate. Diethylaluminum chloride leads to a number of
side-products including Diels-Alder reactions between the
diene and acrylate (Table S1). These observations suggest
that a cationic species is essential for success, and, simple
redox mechanism involving neutral Co(I)/Co(III)-cycle is
not operating under the reaction conditions. The role of the
cationic intermediates is further supported by the remarkable
solvent effect seen in this reaction (Supporting Information,
Table S3d). Coordinating solvents such as THF, ether, ethyl
acetate completely inhibit the reaction. Hydrocarbon sol-
vents are also not suitable, presumably because of insolubili-
ty of the putative cationic species. Finally, the configuration
of the diene-derived double bond in both major products 18
and 19 is Z, suggesting a strong η4-coordination of the 1,3-
diene or a metallacycle intermediate (vide infra, Figure 3).
All available evidence indicates that neither bis-phosphine
complexes derived from CoX2 (X = Br, Cl, I), (P~P)CoX2, or
the corresponding reduced species (P~P)CoX (X = Br, Cl or
η3-cyclooctenyl) in themselves are competent to effect this
reaction (Table 1, entry 1). Cobalt(I)-complexes, either iso-
lated, or in situ generated under conditions where no Lewis
acid is present, showed no reactivity. Activation by a Lewis
acid [typically NaBARF, (C6F5)3B or Zn salts] is essential
for the success of the reaction (Table 1, entries 2-14). The
most useful reactions (Table 1), especially the enantioselec-
tive versions (Tables 3 and 4), are best carried out using the
[BARF] counter ion. BARF is unique and a cationic Co(I)
complex cleanly generated from (S,S)-(BDPP)Co(η3-
octenyl) complex and [H(OEt)2]+[BARF]– is competent to
effect the reaction, albeit in only a modest 22% yield (Table
3, entry 3). However, the (Z)-selectivity of the internal dou-
ble bond derived from the 1,3-diene in the products 18a and
19a (Tables 2, 3), and the overall enantioselectivity of the
reaction are the same for a given ligand (e.g., (S,S)-BDPP,
L2) irrespective of which protocols is used (Table 3, entries
2, 3 or 5), strongly suggesting that the intermediates in-
volved in these reactions are identical. Reduction of the
Co(II)-salts either by Mn or Zn showed no effect on the
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
X
P
Co
P
X
X = Br, Cl, reducing
agent (Zn, Mn, Me3Al)
I
Co
P
P
X
6
Lewis acid
or NaBARF
H
Z
+
Z
R
+
R
I
Co Ln
1
2
P
P
P
P
Y–
+
CoIII
18
Z =
CO
2R
Z
R
4
23
3
Co-C1-insertion
L
27
+
+
Z
1
P
P
2
CoIII
P
Co
H
R
P
Z
+ 23
Z
4
3
H
26
R
24a
R
Co-C4-insertion
19 Z = CO2R
+
+
Z
P
P
1
CoIII
P
P
2
Co
R
Z
4
3
R
25
24b
Figure 3. A plausible mechanism of heterodimerization which accounts for the ligand, counter ion and solvent effects, the configuration
of double bonds in the products, and, labeling studies.
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To account for the experimental observations, we suggest the
cationic intermediates beyond 6 in the catalytic cycle. The
1H and 31P NMR spectra obtained upon treatment of 6 with
1,3-dienes in the presence of NaBARF or various Lewis
acids are largely unintelligible with broad peaks.
1
2
3
4
5
6
7
8
mechanism shown in Figure 3 based on literature precedents
and our initial hypothesis (Figure 1), but slightly modified to
accommodate the effects of the Lewis acids, solvents and the
counter ions. Thus the cobalt (I)-complex (P~P)CoX (6),
which is readily formed from the corresponding Co(II) pre-
cursor under the reduction conditions, reacts with the Lewis
acid or NaBARF to produce the highly reactive cationic spe-
cies 23. Subsequent oxidative dimerization (via insertion of
the acrylate into the Co-C4 bond of 24a/24b) gives 25, which
undergoes β-hydride elimination to give 26. Reductive elim-
ination from the Co(III) species 26 leads to the major prod-
uct 18 with regeneration of the catalyst 23. Such elimination
could be assisted by other ligands such as the diene or the
acrylate giving a less coordinately unsaturated species for-
mally represented as 23. Similar insertion of acrylate into
Co-C1, would lead to the minor product 19 via 27.
To gain further insight into the mechanism of the reaction,
we have carried out the heterodimerization reaction using
(2,3,3)-d3 methyl acrylate and (E)-1,3-dodecadiene (Eq 6a)
and examined the incorporation of deuterium atoms in the
product(s). The products of the reaction 18a-d3 and 19a-d3
1
2
are readily identified by H, H and 13C NMR spectroscopy.
The incorporation of D can be estimated quantitatively by
13C[1H,2H] NMR spectroscopy employing inverse-gated
decoupling experiments since substitution by D for H moves
the chemical shifts of the Csp2-CH3-group in 18 to slightly
higher field (in this case by ~ 0.3 δ).18 Exceptionally high
fidelity in the transfer of D from the methyl acrylate-d3 to the
product provides strong support for the mechanism pro-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
While we have identified and fully characterized several
catalytically active Co(I) species (Figure 2) including
(dppp)3Co2Br2 (11a) and (S,S-BINAP)Co(η3-cyclooctenyl)
(15e), we were unsuccessful in characterizing any of the
posed.
A
corresponding experiment with (1,1)-d2-
dodecadiene and methyl acrylate (Eq 6b) further supports the
mechanistic conclusions.
.
CO2Me
D
D
[(dppp)CoBr2 (5 mol%)
CH2D
D
MeO2C
D
D
Zn (50 mol%), NaBARF (7.5 mol%)
+
+
CO2Me
(6a)
D
CH2Cl2 (0.5 M), 23 oC, 2 h
(100% conv. >90% yield)
D
D
C8H17
C8H17
C8H17
4a
19a-d3 (14%)
18a-d3 (81%)
(>97% D retention)
D D
D
D
[(S,S)-BDPP)CoBr2 (5 mol%
CD2H
MeO2C
H
(6b)
CO2Me
C8H17
19a-d2 (7%)
Zn (50 mol%), NaBARF (7.5 mol%)
+
CO2Me
+
CH2Cl2 (0.5 M), 23 oC, 2 h
(100% conv. >90% yield)
H
H
C8H17
18a-d2 (93%)
(>95% D retention)
C8H17
4a-d2
cations with further implications beyond the synthetic reac-
tions described in this paper.
Conclusions
1,3-Dienes are ubiquitous and easily synthesized starting
materials for organic synthesis and alkyl acrylates are among
the most abundant and cheap feedstock carbon sources. A
practical, highly enantioselective union of these two readily
available precursors giving valuable, nearly enantio-pure
skipped 1,4-diene esters (with two configurationally defined
double bonds) contributes significantly to our repertoire of
powerful synthetic methods, especially since the process also
uses commercially available cobalt salts and chiral ligands.
This atom-economical heterodimerization reaction is tolerant
of a number of common organic functional groups as illus-
trated by the use of 20 different substrates including 17
prochiral 1,3-dienes and 3 different acrylates. The novel
results including ligand, counter ion and solvent effects we
have uncovered during the course of these investigations
show a unique role of a possible cationic Co(I)- intermediate
in these reactions. We hope that the rational evolution of a
mechanism-based strategy that led to the eventual successful
outcome and the attendant support studies will add to the
burgeoning organometallic chemistry of cobalt and its appli-
ASSOCIATED CONTENT
SUPPORTING INFORMATION
Experimental procedures for the scouting experiments, synthe-
ses and isolation of the heterodimerization products. Spectro-
scopic and gas chromatographic data showing compositions of
products under various reaction conditions. Crystallographic
Information Files (.cif) for compounds 10a, 11a, 15e whose
structures were determined by X-ray crystallography. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
*rajanbabu.1@osu.edu.
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Hilt, G. Org. Lett., 2011, 13, 5700-5703. (f) Hiroi, Y.; Komine, N.;
Notes
Komiya, S.; Hirano, M. Organometallics, 2014, 33, 6604-6613.
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(10) (a) Hilt, G.; Treutwein, J. Chem. Commun., 2009, 1395-1397.
For a theoretical study of related intermeidiates in cobalt-catalyzed
Diels-Alder reactions, see: (b) Mörschel, P.; Janikowski, J.; Hilt, G.;
Frenking, G. J. Am. Chem. Soc., 2008, 130, 8952–8966.
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The authors declare no financial interest.
ACKNOWLEDGEMENTS
Financial assistance for this research provided by the US Na-
tional Institutes of Health (R01 GM108762) and the National
Science Foundation (CHE-1362095) is gratefully acknowl-
edged. We thank Dr. Arpad Somogyi and Mahesh Parsutkar for
the MALDI-MS experiemnets.
(11) Reviews: (a) Usman, M.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-
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H(D)
R'
(P~P)CoBr2 (5 mol%)
NaBARF (7.5 mol%)
Zn (50-100 mol%)
R'
CO2R
R
*
CH2Cl2 (0.5 M), 23 oC, 12 h
+
CO2R
R
R = functionalized alkyl
R' = H, alkyl, OSiMe3
H(D)
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yield: 70-95%
ee 94-99%
(1.0:1.1)
• Ligand and counter ion effects
• Isolation and characterization of intermediates
• Labeling studies in support of mechanism
• [(P~P)Co(I)]+ intermediate?
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