α- And β-Functionalized Ketones from 1,3-Dienes and Aldehydes: Control of Regio- And Enantioselectivity in Hydroacylation of 1,3-Dienes

Article abstract of DOI:10.1021/jacs.1c06245

Ketones are among the most widely used intermediates in organic synthesis, and their synthesis from inexpensive feedstocks could be quite impactful. Regio- and enantioselective hydroacylation reactions of dienes provide facile entry into useful ketone-bearing chiral motifs with an additional latent functionality (alkene) suitable for further elaboration. Three classes of dienes, 2- or 4-monosubstituted and 2,4-disubstituted 1,3-dienes, undergo cobalt(I)-catalyzed regio- and enantioselective hydroacylation, giving products with high enantiomeric ratios (er). These reactions are highly dependent on the ligands, and we have identified the most useful ligands and reaction conditions for each class of dienes. 2-Substituted and 2,4-disubstituted dienes predominantly undergo 1,2-addition, whereas 4-substituted terminal dienes give highly enantioselective 4,1- or 4,3-hydroacylation depending on the aldehyde, aliphatic aldehydes giving 4,1-addition and aromatic aldehydes giving 4,3-addition. Included among the substrates are feedstock dienes, isoprene (US$1.4/kg) and myrcene (US$129/kg), and several common aldehydes. We propose an oxidative dimerization mechanism that involves a Co(I)/Co(III) redox cycle that appears to be initiated by a cationic Co(I) intermediate. Studies of reactions using isolated neutral and cationic Co(I) complexes confirm the critical role of the cationic intermediates in these reactions. Enantioselective 1,2-hydroacylation of 2-trimethylsiloxy-1,3-diene reveals a hitherto undisclosed route to chiral siloxy-protected aldols. Finally, facile syntheses of the anti-inflammatory drug (S)-Flobufen (2 steps, 92% yield, >99:1 er) and the food additive (S)-Dihydrotagetone (1 step, 83% yield; 96:4 er) from isoprene illustrate the power of this method for the preparation of commercially relevant compounds.

Full text of DOI:10.1021/jacs.1c06245

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α- and β‑Functionalized Ketones from 1,3-Dienes and Aldehydes:
Control of Regio- and Enantioselectivity in Hydroacylation of 1,3-
Dienes
Mahesh M. Parsutkar and T. V. RajanBabu*
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ABSTRACT: Ketones are among the most widely used
intermediates in organic synthesis, and their synthesis from
inexpensive feedstocks could be quite impactful. Regio- and
enantioselective hydroacylation reactions of dienes provide facile
entry into useful ketone-bearing chiral motifs with an additional
latent functionality (alkene) suitable for further elaboration. Three
classes of dienes, 2- or 4-monosubstituted and 2,4-disubstituted
1,3-dienes, undergo cobalt(I)-catalyzed regio- and enantioselective
hydroacylation, giving products with high enantiomeric ratios (er).
These reactions are highly dependent on the ligands, and we have
identified the most useful ligands and reaction conditions for each
class of dienes. 2-Substituted and 2,4-disubstituted dienes
predominantly undergo 1,2-addition, whereas 4-substituted terminal dienes give highly enantioselective 4,1- or 4,3-hydroacylation
depending on the aldehyde, aliphatic aldehydes giving 4,1-addition and aromatic aldehydes giving 4,3-addition. Included among the
substrates are feedstock dienes, isoprene (US$1.4/kg) and myrcene (US$129/kg), and several common aldehydes. We propose an
oxidative dimerization mechanism that involves a Co(I)/Co(III) redox cycle that appears to be initiated by a cationic Co(I)
intermediate. Studies of reactions using isolated neutral and cationic Co(I) complexes confirm the critical role of the cationic
intermediates in these reactions. Enantioselective 1,2-hydroacylation of 2-trimethylsiloxy-1,3-diene reveals a hitherto undisclosed
route to chiral siloxy-protected aldols. Finally, facile syntheses of the anti-inflammatory drug (S)-Flobufen (2 steps, 92% yield, >99:1
er) and the food additive (S)-Dihydrotagetone (1 step, 83% yield; 96:4 er) from isoprene illustrate the power of this method for the
preparation of commercially relevant compounds.
accomplished. Additional substituents on the diene, use of
difunctionalization reagents,3,8 and multicomponent additions
further exacerbate the situation. Among the reactions of 1,3-
dienes, there are examples of highly selective C−C bond-
forming reactions, even though enantioselective variations are
still rare. These include 3,4-additions of activated nucleophiles
such as involved in hydrocyanation,9 hydroalkynylation,10
hydroalkylation,11−15 hydroarylation,16−19 2,1- or 4,1-reductive
coupling,20−24 and hydrovinylation reactions.25−30 In addition,
several highly selective multicomponent additions involving
1,3-dienes have also been reported.31−36
INTRODUCTION
■
Acyclic 1,3-dienes and aldehydes are among the most readily
available precursors for organic synthesis, many of them
marketed in bulk as feedstock materials for chemical industry.1
Regio- and enantioselective union of easily accessible 1,3-
dienes and aldehydes (industrially produced by alkene
hydroformylation) is a reaction whose full potential has not
yet been realized and, like other similar reactions of dienes, can
provide valuable building blocks adorned with latent
functionalities for further synthetic elaboration.2−8 Unlike
reactions of simple alkenes, reactions of prochiral dienes
present additional challenges, since a multitude of primary
products can be formed, even for the simplest of these
compounds, such as a monosubstituted (E)-1,3-diene (Figure
1A, 1, R1 = R2 = R3 = H; R4 = alkyl). Thus, in a generic
hydrofunctionalization reaction, possibility exists for the
formation of 1,2/2,1-, 1,4/4,1-, and 3,4/4,3-adducts (regio-
selectivity defined by the number of the carbons of the diene to
which are attached the X and H, respectively), in addition to
geometrical isomers of the residual double bonds in some of
the products, even if an enantioselective reaction can be
Conspicuously absent among these reports on diene
functionalizations are the uses of regio- and enantioselective
hydroacylation, a versatile and potentially important C−C
Received: June 16, 2021
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A

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Figure 1. (A) Hydrofunctionalization of 1,3-dienes can lead to multiple chiral and achiral products. (B) Examples of medicinally relevant ketones
with α- or β-alkyl-bearing stereogenic centers. The alkene residue in the hydroacylation products can serve as a latent functionality for further
elaboration of the primary products. (C) Enantioselective intermolecular hydroacylations of alkenes are carried out with expensive Rh catalysts and
are limited to strained alkenes and/or aldehydes carrying heteroatoms capable of secondary coordination. (D) Lone reported example of Co-
catalyzed hydroacylation of 1,3-dienes (see text). (E) Judicious choice of ligands and activators enables highly selective hydroacylation of broad
classes of 1,3-dienes at room temperature (this work).
B
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a
Table 1. Hydroacylation of (E)-2-Methyl-1,3-octadiene: Optimization of Solvents and Activators
a
b
See eq 5 and Supporting Information, pp S11 and S16, for details of the procedures. No hydroacylation products. Only low yields of hetero-
Diels−Alder and oligomerization products of the diene were observed.
bond-forming reaction known for the synthesis of ketones from
aldehydes and alkenes (Figure 1C,D).37−39 Ketones with α-
and β-alkyl-bearing chiral centers are ubiquitous motifs in
many medicinally important natural products, especially
among polyketides exemplified by erythromycin, rapamycin,
and spongistatin and their analogs.40,41 They are also versatile
intermediates for synthesis of numerous pharmaceutical and
other fine chemicals, examples of which are shown in Figure
1B. Examples of enantioselective intramolecular hydroacylation
reactions for the synthesis of ketones have been reported, even
though developments in arguably the more broadly applicable
intermolecular reactions have lagged behind. Most successful of
these intermolecular reactions have been limited to the use of
rhodium (US$55,000−65,000/mol) as the catalytic metal and
involve substrates that are characterized by increased reactivity
due to strain (eq 2, Figure 1C),42−44 or those carrying
additional chelating groups to circumvent side reactions such
as decarbonylations (eq 3, Figure 1C).45−50 A lone example of
a non-enantioselective hydroacylation of 1,3-dienes catalyzed
by cobalt was reported by Dong in 2014 (Figure 1D).51 Even
though the scope of the reaction with respect to the precursors
was not fully explored, this seminal study provided useful hints
on the mechanism (oxidative heterodimerization) and viable
ligands (electron-rich) for this reaction. From our initial
studies, it appears that the published protocol for diene
hydroacylation (CoI2/In/InBr3/DCE/60 °C)51 may not be
suitable for enantioselective versions of several dienes,
especially for the more substituted ones that are sensitive to
Lewis acids (see later, Table 1 and Table S1 in the Supporting
Information). Yet another noteworthy example in the context
of cobalt catalysis is Brookhart’s Cp*Co(I)(vinylsilane)2-
catalyzed hydroacylation of vinylsilane.52,53 In addition, a 1,6-
enyne cycloisomerization terminating with a hydroacylation
has been reported,54 and an enantioselective version of this
reaction55 uses the catalyst system similar to what we first
reported in 2017.30 No examples of enantioselective hydro-
acylation of 1,3-dienes have been reported to date.56 In this
paper we disclose the first examples of highly regio- and
enantioselective hydroacylations of variously substituted 1,3-
dienes that can be accomplished at room temperature using
readily accessible cationic Co(I) complexes. Additionally, the
role of these cationic complexes in these reactions will be
clarified. The regioselectivity in the reactions of terminally
substituted 1,3-dienes is exquisitely controlled by the nature of
the aldehyde (aromatic vs aliphatic). A highly enantioselective
hydroacylation of 2-trimethylsiloxy-1,3-diene opens a new
route to nearly enantiopure silyl-protected aldols (Figure 1E,
R2 = OTMS, R4 = H). Applications for short enantioselective
syntheses of the flavoring agent (S)-Dihydrotagetone57 (er:
96:4) and anti-inflammatory 3-aroyl-2-methylpropionic acid
(R)-Flobufen58 (er: >99:1) from isoprene are also disclosed.
RESULTS AND DISCUSSION
■
Optimization Studies. For our initial studies (eq 5, Table
1), we chose an especially challenging substrate, (E)-2-methyl-
1,3-octadiene, a 2,4-disubstituted diene, and two prototypical
aliphatic aldehydes, n-heptanal and isobutyraldehyde, which
together represent a large set of precursors that would
considerably expand the scope of the intermolecular hydro-
acylation. The choice of methyl-substituted diene was inspired
C
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a
Table 2. Hydroacylation of (E)-2-Methyl-1,3-octadiene with Isobutyraldehyde: Selected Ligand Effects
a
For a more complete table (including ratio of E:Z isomer for [1,4]-adduct), see Supporting Information, Table S2; for procedure, see eq 5 in
b
Table 1; and for experimental details, see Supporting Information, p S11. For chart showing the structures of the ligands, see Supporting
Information, p S20. Conversion, regioselectivities, and enantioselectivities were determined by GC. nd = not determined. See experimental part in
the Supporting Information, pp S24, S34, S45, and S65, for absolute configuration of the products. Complete conversion of diene, and no low-
c
d
molecular-weight (hydroacylation) products were detected.
by the frequency of methyl-bearing chiral centers, which are
ubiquitous in propionate-derived natural products40,41,59 that
could be targeted via the products of the hydroacylation
reactions. In the intermolecular context, hydroacylation
reactions of aliphatic aldehydes are less developed in scope
and sometimes involve the use of excess of the diene and/or
elevated temperatures.51,53 The test substrates were subjected
to the reaction conditions established30 for the efficient
generation of cationic Co(I) species, following all products
(eq 5, Tables 1 and 2) formed in the reaction by GC and
GCMS.
Initial experiments quickly confirmed that, like the other
[(L)Co(I)]+-catalyzed reactions we had reported,30,60,61 there
were strong solvent, counterion, and ligand effects in these
reactions (Table 1).62 While toluene and other hydrocarbons
lead to a sluggish reaction, oxygenated solvents such as THF,
ether, and ethyl acetate inhibit the reaction (entries 1−4).
Dichloromethane was found to be the optimum solvent.
Among the activators, NaBARF was found to be the best (and
a unique) choice, leading to nearly quantitative yield of the
product(s), with outstanding regioselectivity for the preferred
1,2-adduct with the proper choice of ligands (entries 1, 5, and
8). We found that ZnX2,54 InBr3,51 and various Ag salts which
have been previously used in related reactions lead to other
side reactions, including hetero-Diels−Alder reactions (espe-
cially with Ag salts).62
complete table with additional ligands and reaction conditions
included in the Supporting Information (see Table S2 for
details). Among the traditional 1,n-bis-diphenylphosphino-
alkane ligands (Ph2P-(CH2)n-PPh2, n = 1−4), only dppp (1,3-
bis-diphenylphosphinopropane) led to good yields of the
hydroacylation products, but giving a mixture of mostly 1,2-
and 1,4- (Z + E) adducts in a ratio of 43:54. Similar mixtures
of products were obtained with chiral bis-phosphines, (S,S)-
BDPP, (R,R)-QuinoxP*, and (S,S)-BenzP* (entries 2, 5, and
6). Other chiral bis-phosphines (see Supporting Information),
among them (R)-Prophos, (S,S)-Chiraphos, (R,R)-DIOP, Ph-
BIBOP, 2,2′-bis-phosphino-1,1-biaryls like (S)-BINAP, (S)-
SegPhos, and (R)-binaphane, and bis-phospholano ligands
(S,S)-Me-BPE, (R,R)-Et-BPE, and (R,R)-TangPhos, gave no
detectable amount of hydroacylation products (see Supporting
Information, Table S2 for details and p S20 for structures of
the ligands).62 A number of sterically and electronically
modified phosphinooxazoline (PHOX) ligands which were
successfully used elsewhere for Co(I)-catalyzed hydro-
boration60 and [2+2]-cycloaddition61 reactions also failed in
the hydroacylation. Most notably, catalysts from several ligands
completely consumed the starting 1,3-diene without producing
any of the hydroacylation products, presumably leading to
high-molecular-weight oligomers (entries 4, 8, and 10).63
The best ligands for 1,2-selective hydroacylation were found
to be bulky electron-rich phosphines such as 1,2-bis-dicyclo-
hexylphosphinoethane (Table 2, entry 1) and chiral ligands t-
Bu-BIBOP (entry 3), i-Pr-DUPHOS (entry 7), and Ph-BPE
(entry 9). The extreme sensitivity of the reaction to the ligand
structure is revealed by a pairwise comparison of the activities
Ligand Effects. Next we turned to an examination of the
ligand effects seeking the best activity and highest regio- and
enantioselectivity. The most important results obtained are
shown in an abbreviated form in Table 2, with a more
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a
Table 3. Selectivity in Hydroacylation of 2,4-Di- and 2-Monosubstituted 1,3-Dienes: Vicinal Additions Giving Linear Ketones
a
See eq 5 in Table 1 for procedure; (S,S)-Ph-BPE used as ligand. Cy = cyclohexyl. Isolated yields of combined product. rr = ratio of major product
b
c
to the other regioisomers. nd = not determined. Minimum value (estimated because of incomplete separation of enantiomers). (R,R)-i-Pr-
d
DUPHOS used as ligand instead of (S,S)-Ph-BPE. For the use of single-component [Co]+ catalysts for these reactions see eq 7 in Table 5. (R,R)-
Ph-BPE used as ligand instead of (S,S)-Ph-BPE.
of ligands shown in entries 3/4, 7/8, and 9/10. In each case, a
small change in alkyl substitution pattern of the ligand shows a
dramatic effect on the reaction. Among the active ligands, the
(S,S)-Ph-BPE gave the best overall yield and regio- and
enantioselectivity. This ligand was chosen for further studies to
explore the scope and limitations of the asymmetric hydro-
acylation.
Scope of Aldehydes and 1,3-Dienes. Having established
a useful protocol for hydroacylation, the scope of coupling of
various aldehydes containing primary, secondary, and cyclo-
alkyl substituents with 2,4-di- and 2-monosubstituted 1,3-
dienes (including isoprene and myrcene) was explored using
the ligand (S,S)-Ph-BPE [and (R,R)-i-Pr-DUPHOS in selected
cases], and the results are shown in Table 3. 2-Methyl-1,3-
octadiene reacts with both primary (n-hepanal, n-pentanal, 3-
E
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a
Table 4. Hydroacylation of 1,3-Butadiene and Monosubstituted 1,3-Dienes
a
See eqs 5 and 6 and Tables 1 and 4. For procedure and experimental details, see Supporting Information, p S11. See Table S3 in the Supporting
b
Information for optimization of ligands. Ratio of major isomer ([4,1] or [4,3]) to the others. Ratio for Z:E can be found in the Supporting
Information. Determined by GC. (R,R)-i-Pr-DUPHOS used as ligand instead of (S,S)-Ph-BPE(for 14, 23, 24). Not determined. Using 15% by
c
d
e
f
weight 1,3-butadiene in hexanes.
methylbutanal) and secondary (isobutyraldehyde and
cyclopentanecarboxaldehyde) aldehydes, giving products in
good yields and excellent enantioselectivities (entry 1). Thus,
the isopropyl (1a), isobutyl (1d), and cyclopentyl (1e) ketones
are produced in an enantiomeric ratio of 96.5:3.5 or higher and
the corresponding n-hexyl and n-butyl derivatives in slightly
lower er. In general, the regioselectivity (regioisomeric ratio,
rr) for the 1,2-adduct, as measured by the ratio of the desired
1,2-adduct (1a−1e) to the sum of 1,4- and the other minor
adducts (eq 5), varies from 16:1 to 4:1. Replacing the 2-methyl
substituent in the diene with an isopropyl group (entry 2)
retains the high enantioselectivity in the formation of the
corresponding isobutyl ketone (er: 97:3). Enantioselectivities
in the reactions of a feedstock 1,3-diene, myrcene (entry 4),
depend on the aldehyde, with cyclopropylcarboxaldehyde
giving a product (4b) in an er of 99:1. Reactions of yet
another feedstock 1,3-diene, isoprene, are also noteworthy
because of the high regio- and enantioselectivities seen (er:
93.5:6.5 to 96:4, entries 5a−5e). The absolute configuration of
ketone 5a was established from the comparison of specific
rotation with that of (S)-Dihydrotagetone, a natural product of
known configuration (Figure 1B).57a The configurations of the
other aliphatic ketones (entries 1−6) were assigned by
analogy.
catalytic enantioselective route to aldol products, usually
derived from methyl ketones or equivalents, might offer an
attractive alternative (through a different disconnection) to
other more traditional chiral Lewis acid-catalyzed aldol
reactions starting with silyl enolates.65,66 A hydroacylation
route to aldol-like products has not been disclosed before.
Reactions of Isoprene. Since isoprene (US$1.40/kg) is
one of the cheapest feedstock dienes, we have examined the
full scope of aldehydes (in addition to the examples in entry 5
in Table 3) that would engage this precursor in an
enantioselective 1,2-hydroacylation, and the additional results
are shown in entries 7−13 in Table 3. Aromatic aldehydes
including various substituted benzaldehydes with electron-
withdrawing and electron-donating groups (7a−7e), heteroaryl
aldehydes (2-furan- and 2-thiophene-carboxaldehyde, 8a and
8b), naphthalene-2-carboxaldehyde (9), and ferrocene-
carboxaldehyde (10) underwent enantioselective hydro-
acylation with isoprene, giving excellent er’s, several in the
range of 98.5:1.5 or higher. Products from α,β-unsaturated
aldehydes, (E)-cinnamaldehyde (12a) and (E)-2-octenal
(12b), are highly functionalized ketones carrying two different
alkenyl substituents, useful for further elaboration of these
nearly enantiomerically pure building blocks.
Hydroacylation of Terminally Monosubstituted 1,3-
Diene. These dienes (Table 4) belong to yet another
important class of readily available precursors, whose enantio-
selective hydroacylation yields α-chiral ketones, important
precursors in their own right for further synthesis. These
substrates revealed a striking dependence of the regioselectivity
on the nature of the aldehyde. Details of the optimization of
the reaction are included in the Supporting Information (Table
S3). Thus, commercially available (E)-1,3-pentadiene gave a
One of the most useful substrates is 2-trimethylsiloxy-1,3-
butadiene (entry 6), which gives protected aldol products 6a
and 6b with a latent alkene suitable for further elaboration of
the carbon chain. Excellent enantioselectivities are observed for
the protected aldol products from cyclohexanecarboxaldehyde
(er = 94:6 er) and benzaldehyde (er = 99:1). Configuration of
the desilylated aldol 6a was confirmed by comparison of
optical rotation with that of a closely related analog.64 This
F
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Figure 2. Two-step, gram-scale synthesis of (S)-Flobufen from isoprene. Flobufen represents an example of the synthesis of an α-substituted γ-keto
acid, a widely used pharmacophore in medicinal chemistry.
good yield of the [4,1]-adduct (rr [(4,1):(4,3)] = 93:7, er =
97.5:2.5) upon reaction with isovaleraldehyde (14, Table 4),
while giving almost exclusively a [4,3]-adduct (20, rr [(4,3):
(4,1)] = 97:3, er = 98.5:1.5) with benzaldehyde. Similar
regiodivergent selectivity was observed for the other dienes
with aliphatic and aromatic aldehydes listed in Table 4. The
absolute configuration of the product 20 was ascertained by
comparison of its specific rotation with those of authentic
samples previously reported in the literature,67 and other
configurations were assigned by analogy. Finally, 1,3-butadiene
itself undergoes almost exclusive 1,2-hydroacylation, irrespec-
tive of the nature of the aldehyde, giving γ,δ-unsaturated
ketones 23 and 24 (Table 4).
Gram-Scale, Two-Step Synthesis of (S)-(−)-Flobufen
from Isoprene. In addition to the previously described
synthesis of the flavoring agent (S)-Dihydrotagetone (Table 3,
5a), a gram-scale synthesis of the anti-inflammatory agent, (S)-
(−)-Flobufen (a representative example of α-substituted γ-keto
Figure 3. An oxidative dimerization mechanism initiated by a cationic
acids, a large class of medicinally important compounds that
Co(I) species explains the various solvent counterion effects and the
include metalloproteinases, renin, and angiotensin-converting
inhibitors, Figure 1, B), was carried out starting from the
predominant (Z)-stereoselectivity seen in 4,1/1,4-additions.
isoprene-derived alkene 13a (Table 3, entry 13) by oxidation
gives some support to an oxidative pathway for reactions of
with aqueous NaIO4 and RuCl3 (Figure 2). The absolute
configuration of the product was deduced by comparison with
the known specific rotations of authentic enantiomers.58b,62
Role of Cationic Co(I) Intermediates in Hydro-
acylation. Two distinct mechanisms have been invoked for
the cobalt-catalyzed hydroacylation of alkenes, involving
activation of the aldehyde hydrogen such as by a Co(I)
these species. The regioselectivity, the Z-configuration for the
4,1/1,4-adducts, the lack of decarbonylation, and the counter-
ion and solvent effects on the reaction (Table 1) all suggest a
key role for a cationic cobalt(I) intermediate in this highly
effective hydroacylation protocol that proceeds at room
temperature. Several experiments based on isolated cationic
Co(I) complexes (Figure 4) which support this conjecture are
shown in Table 5.
52
reagent CpCo(I)L2 in an intermolecular reaction or by a
Co(0) reagent as in (P∼P)Co(0) in the context of an
enantioselective intramolecular reaction.68,69 Alternatively, an
oxidative cyclization involving the (P∼P)Co(I) catalyst
followed by a β-hydride elimination and subsequent reductive
elimination has been proposed for an intermolecular hydro-
acylation of 1,3-dienes.51,70 Based on several anecdotal
observations during our previous investigations30 on the
applications of cationic complexes [(P∼P)Co(I)]+[X]−, and
a detailed mechanistic investigation of the heterodimerization
of 1,3-dienes and methyl acrylate,71 we believe that the
oxidative addition route (Figure 3) is the preferred pathway for
the hydroacylation reaction. Our recently completed mecha-
nistic study of cycloisomerization/hydroalkenylation of 1,6-
enynes catalyzed by similar cationic Co(I) complexes72 also
In order to clarify the role of such a cationic intermediate
and to rule out a mechanism involving a Co(0)/Co(II) redox
cycle, we prepared a number of discrete Co(I) complexes (free
of any reducing agents or other residual metal salts), including
cationic ones, and examined them for catalytic activity. The
most extensive among these studies were conducted using
(R,R)-[i-Pr-DUPHOS]CoX2 [X = Cl, Br, (25a, 25b)], which
served as a source of several catalytically viable cationic Co(I)
complexes (Figure 4). (R,R)-i-Pr-DUPHOS complexes were
used in this study (Table 5) even though they gave less
selective reactions compared to (S,S)-Ph-BPE ligands (Table
3) because the former set gave highly crystalline intermediates.
The Co(I) complex 26, a known compound previously
prepared by Chirik by an alternate route from 25a,73 is most
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Figure 4. New synthesis of a neutral Co(I) complex and its use for the generation of cationic complexes useful as single-component catalysts for
hydroacylation. BARF counterions are omitted for clarity in representations of the solid-state structures.
Table 5. Role of Cationic Complex [P∼P]Co(I)]+[BARF]−
conveniently prepared by reduction of 25a by 1,4-bis-
a
in Hydroacylation
trimethylsilylpyrazine.74 Unlike the corresponding (S,S)-
BDPP Co(I) complex,75 which forms a ligand-bridged
dimer,60 the DUPHOS complex is formed as a chloride-
bridged dimer (26). This dimer 26 itself is not a catalyst for
the reaction (Table 5, entry 1), but upon addition of NaBARF,
a reaction ensues (entry 2) giving the same products as with
our in situ-generated catalyst (Table 3, entry 7, product 7a).
The role of the BARF counterion is also obvious from the in
situ procedure shown in entry 4, but devoid of NaBARF, there
was no reaction. The cationic 2,3-dimethylbutadiene complex
27 is a viable catalyst, albeit a less efficient one (entry 5).
Attempts to isolate a possible intermediate (28) in the
hydroacylation led to a Tishchenko reaction product, which
made a stable complex (29) with the [(P∼P)Co(I)]+
fragment. This complex (29) is also a catalyst for hydro-
acylation reactions, especially for the reactions of the more
reactive 2-trimethylsiloxy-1,3-butadiene (entry 6), where the
isolated single-component catalysts have a distinct advantage
in that the competitive Mukaiyama aldol reaction between the
2-siloxy-1,3-diene and the aldehyde is significantly slowed
down. Finally, a model complex (31), prepared from a dienyl
aldehyde (30), complex 26, and NaBARF, offers further
support for the ability of [(L)Co(I)]+ to assemble the reacting
components in its coordination sphere. This complex (31) is
also a competent catalyst for the hydroacylation of the more
reactive 2-trimethylsiloxy-1,3-diene (entry 7).
t
er for 7a
or 6b
entry
1
Z
catalyst (mol%)
(h)
conv (%)
b
Me
{[i-Pr-DUPHOS]
24
0 (0)
−
CoICl}2 (2.5)
b
2
3
4
5
Me
Me
Me
Me
{[i-Pr-DUPHOS]
24
60 (100)
98:2
CoICl}2 (2.5)
NaBARF (7.5)
[i-Pr-DUPHOS]CoBr2
(5)
Zn (50), NaBARF (7.5)
[i-Pr-DUPHOS]CoBr2
(5)
24
24
40
93
<5
60
98:2
−
Zn (50), NaBARF (0)
[i-Pr-DUPHOS]
[CoI(2,3-Me2BD)]+
(27)
98:2
6
7
TMSO [CoI]+ catalyst 29 (5)
TMSO [CoI]+ catalyst 31 (5)
30
48
95
73
99:1
99:1
a
For a more complete table, see Table S4 in the Supporting
Information; procedure F (Supporting Information, p S14) gives
details. In ether, where the cationic species appears to be more
b
stable.
H
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J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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CONCLUSIONS
ACKNOWLEDGMENTS
■
■
We disclose a general procedure for the regio- and enantio-
selective addition of the hydrogen and the acyl group of an
aldehyde (hydroacylation) to three classes of substituted 1,3-
dienes to produce a wide variety of functionalized ketones with
α- or β-alkyl/alkenyl-bearing chiral centers in enantiomeric
ratios up to >99:1. In this cobalt-catalyzed reaction,
inexpensive feedstock dienes and aldehydes that are used
include 1,3-butadiene, isoprene, myrcene, piperylene, butyr-
aldehyde, benzaldehyde, and furfural. While reactions of most
diene substrates can be carried out using very practical, in situ-
generated [(L)Co(I)]+ catalysts, use of single-component
catalysts that were prepared to establish the intermediacy of
such species in these reactions may have significant advantages
in reactions of highly sensitive substrates such as trimethyl-
siloxydienes, where these catalysts preclude a competitive
Mukaiyama aldol reaction yet promote very efficient hydro-
acylation. This reaction provides a new, hitherto undisclosed
enantioselective route to aldols. Application of this chemistry
for a two-step, gram-scale synthesis of (S)-Flobufen from
isoprene (92% yield and enantiomeric ratio >99:1) illustrates
the power of the new protocols for the preparation of
pharmaceutically relevant compounds.
We like to thank Dr. Curtis Moore for the determination of the
solid-state structures by X-ray crystallography. Financial
assistance for this research provided by the U.S. National
Institutes of Health (1 R35 GM139545-01) and the U.S.
National Science Foundation (CHE-1900141) is gratefully
acknowledged. M.M.P. acknowledges an Ohio State University
Presidential Fellowship. We acknowledge Professor David
Nagib for the use of a CSP HPLC instrument.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c06245.
Full experimental details for the preparation of all new
compounds, and their spectroscopic and chromato-
graphic data, including Tables S1−S8 with details of
several optimization studies and Figure S1 showing
names, structures, and sources of all chiral ligands
(PDF)
Accession Codes
CCDC 2016106 and 2074144−2074147 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
T. V. RajanBabu − Department of Chemistry and
Biochemistry, The Ohio State University, Columbus, Ohio
43210, United States; orcid.org/0000-0001-8515-3740;
Email: rajanbabu.1@osu.edu
Author
Mahesh M. Parsutkar − Department of Chemistry and
Biochemistry, The Ohio State University, Columbus, Ohio
43210, United States; orcid.org/0000-0001-6320-2345
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c06245
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Notes
The authors declare no competing financial interest.
I
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