Alkyne-aldehyde reductive C-C coupling through ruthenium-catalyzed transfer hydrogenation: Direct regio- and stereoselective carbonyl vinylation to form trisubstituted allylic alcohols in the absence of premetallated reagents

Article abstract of DOI:10.1002/chem.201101554

Nonsymmetric 1,2-disubstituted alkynes engage in reductive coupling to a variety of aldehydes under the conditions of ruthenium-catalyzed transfer hydrogenation by employing formic acid as the terminal reductant and delivering the products of carbonyl vinylation with good to excellent levels of regioselectivity and with complete control of olefin stereochemistry. As revealed in an assessment of the ruthenium counterion, iodide plays an essential role in directing the regioselectivity of C-C bond formation. Isotopic labeling studies corroborate reversible catalytic propargyl C-H oxidative addition in advance of the C-C coupling, and demonstrate that the C-C coupling products do not experience reversible dehydrogenation by way of enone intermediates. This transfer hydrogenation protocol enables carbonyl vinylation in the absence of stoichiometric metallic reagents. Fun with formate: Under the conditions of ruthenium-catalyzed transfer hydrogenation employing formic acid as the terminal reductant, nonsymmetric 1,2-disubstituted alkynes engage in reductive coupling to aldehydes, delivering the products of carbonyl vinylation with good to excellent levels of regioselectivity and with complete control of the olefin stereochemistry (see scheme). Copyright

Full text of DOI:10.1002/chem.201101554

FULL PAPER
DOI: 10.1002/chem.201101554
À
Alkyne–Aldehyde Reductive C C Coupling through Ruthenium-Catalyzed
Transfer Hydrogenation: Direct Regio- and Stereoselective Carbonyl
Vinylation to Form Trisubstituted Allylic Alcohols in the Absence of
Premetallated Reagents
Joyce C. Leung, Ryan L. Patman, Brannon Sam, and Michael J. Krische*[a]
Abstract: Nonsymmetric 1,2-disubsti-
tuted alkynes engage in reductive cou-
pling to a variety of aldehydes under
the conditions of ruthenium-catalyzed
transfer hydrogenation by employing
formic acid as the terminal reductant
and delivering the products of carbonyl
vinylation with good to excellent levels
of regioselectivity and with complete
control of olefin stereochemistry. As
revealed in an assessment of the ruthe-
nium counterion, iodide plays an essen-
tial role in directing the regioselectivity
ing studies corroborate reversible cata-
À
lytic propargyl C H oxidative addition
À
in advance of the C C coupling, and
À
À
of C C bond formation. Isotopic label-
demonstrate that the C C coupling
products do not experience reversible
dehydrogenation by way of enone in-
termediates. This transfer hydrogena-
tion protocol enables carbonyl vinyla-
tion in the absence of stoichiometric
metallic reagents.
Keywords: green chemistry · homo-
geneous catalysis · hydrogenation ·
ruthenium · transfer hydrogenation ·
vinylation
Introduction
hyde–vinylruthenium pairs en route to products of carbonyl
vinylation. In this way, carbonyl vinylation is achieved from
the alcohol or aldehyde oxidation level. The ability to
Under hydrogenation and transfer-hydrogenation condi-
À
tions, p-unsaturated reactants may serve as functional equiv-
engage alcohols directly in C C coupling bypasses discrete
À
alents to organometallic reagents in diverse C C bond-
alcohol oxidation and, hence, is reminiscent of related “hy-
drogen auto-transfer” or “borrowing hydrogen” processes.[15]
Whereas previous studies focused primarily on the reduc-
tive coupling of 2-butyne, a symmetrical alkyne,[12a,b] it was
forming processes.[1] In the specific case of C=X (X=O,
NR) vinylation,[1b] rhodium- or iridium-catalyzed hydrogena-
tion of alkynes in the presence of carbonyl compounds or
imines delivers allylic alcohols or allylic amines, respective-
ly.[2,3] Notably, these transformations do not generate stoi-
chiometric metallic by-products as they circumvent the use
of discrete vinylmetal reagents.[4–6] This atom economy dif-
ferentiates hydrogen-mediated C=X vinylation from the re-
lated rhodium-,[7] titanium-,[8] and nickel-catalyzed[9–11]
alkyne–carbonyl reductive couplings, which employ reduc-
tants that are more mass-intensive, such as silanes, or even
pyrophoric, such as borane and organozinc reagents.[7–11]
In recent studies from our laboratory, it was found that
direct alkyne–carbonyl reductive coupling is possible under
the conditions of ruthenium-catalyzed transfer hydrogena-
tion, employing formic acid as the terminal reductant.[12–14]
Notably, beyond alkyne–aldehyde reductive coupling medi-
ated by formic acid, primary alcohol dehydrogenation was
found to trigger alkyne hydrometallation to generate alde-
found that the catalyst prepared from [Ru
AHCUTNTGERG(NNUN PPh3)2] (TFA=O2CCF3) and Bu4NI enables the regioselec-
ACHTUNGRTENN(UNG TFA)2(CO)-
tive reductive coupling of nonsymmetric alkynes and paraf-
ormaldehyde.[12c] Based on this result, a survey of higher al-
dehydes was undertaken. Herein, we report that ruthenium
catalyzed transfer hydrogenation of nonsymmetric 1,2-disub-
stituted alkynes 1a–1 f in the presence of aldehydes 2a–2d
results in reductive coupling to furnish trisubstituted allylic
alcohols 3a–3 f, 4a–4 f, 5a–5 f, and 6a–6 f with good to excel-
lent levels of regioselectivity and with complete control of
olefin geometry.
[a] J. C. Leung, R. L. Patman, B. Sam, Prof. M. J. Krische
University of Texas at Austin
Department of Chemistry and Biochemistry
1 University Station, A5300, Austin
TX 78712-1167 (USA)
Fax : (+1)512-471-8696
E-mail: mkrische@mail.utexas.edu
Results and Discussion
In an initial experiment aimed at probing the feasibility of
developing a general regioselective process, phenylpropyne
(1a) was exposed to aldehyde 2b in the presence of formic
acid and substoichiometric quantities of [RuHCl(CO)-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101554.
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12437

A
form [RuCl
stoichiometric and catalytic reactions of [Ru
(PPh3)2] with alcohols are known to produce [RuH-
(TFA)(CO)
(PPh3)2] and an aldehyde or ketone [Eq. (3)].[17]
ACHUTGTNRNEUG(N TFA)(CO)ACHTGNUTRENNUNG
4a, iso-4a, and allyl-4a were isolated in low yield (Table 1,
entry 1). In parallel studies on the reductive coupling of par-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
Hence, the catalytic coupling of phenylpropyne (1a) to alde-
hyde 2b was attempted by using the ruthenium complexes
[RuHX(CO)ACTHNUGTRNEUNG(PPh3)3] (X=Cl, Br, and I) in the presence of
Table 1. The effect of the counterion on the regio- and stereoselectivity
of the catalytic reductive coupling reaction of phenylpropyne (1a) to al-
dehyde 2b through ruthenium-catalyzed transfer hydrogenation.[a]
C7F15CO2H. It was hypothesized that counterion exchange
would be rapid, and that different counterions might assist
different steps in the catalytic cycle.
Ru complex
Additive
–
Yield [%] 4a/iso-4a 4a/allyl-4a
1
2
3
4
5
6
23
31
40
2:1
2:1
5:1
6:1
2:1
7:1
8:1
8:1
–
–
17:1
1:1
C7F15CO2H 36
C7F15CO2H 35
C7F15CO2H 71
In the event, addition of C7F15CO2H promoted no signifi-
cant enhancement in regioselectivity in combination with
the ruthenium-chloride or -bromide complexes, nor was the
ratio of 4a/allyl-4a significantly improved (Table 1, entries 4
and 5). In contrast, the use of the ruthenium iodide complex
in the presence of C7F15CO2H delivered 4a as a single regio-
isomer in 71% isolated yield with an enhanced 8:1 ratio of
4a/allyl-4a (Table 1, entry 6). These data suggest that the
specific combination of iodide and carboxylate counterions
is necessary to promote high levels of regioselectivity and
conversion.
As attempts to prepare the discrete complex [Ru-
ACHUTNERGNUN(G O2CR)2(I)(CO)HCAUTNTGNER(NUGN PPh3)2] (R=C7F15, CF3) were unsuccessful,
experiments conducted from this point onward employed
the catalyst generated in situ upon combination of [Ru-
ACHTUNGTRENNUG(TFA)2(CO)ACHTUNGTERNN(UGN PPh3)2] and Bu4NI. It was found that at lower
2:1
>20:1
[a] Yields are of combined isomeric materials. Regio- and stereoselectiv-
ity was determined by 1H NMR analysis of the crude reaction mixtures.
In general, low yields are due to incomplete conversion.
aformaldehyde with nonsymmetric disubstituted alkynes,[12c]
it was found that the use of tetrabutylammonium iodide as
an additive led to improved regioselectivities. Based on this
observation,
[RuHX(CO)
the
discrete
ruthenium
complexes
N
manner analogous to the corresponding chloride com-
plex.[16a] These complexes were assessed in the catalytic cou-
pling of phenylpropyne (1a) to aldehyde 2b under otherwise
identical conditions to those employed by using
concentrations, formation of allyl-4a was suppressed and
good regiocontrol was retained. A minimum of two equiva-
lents of the terminal reductant, formic acid, were necessary
to achieve optimal yields of 4a. At lower loadings of formic
acid, the yield of 4a and the ratio of 4a/allyl-4a deteriorate.
Finally, the precise loading of iodide is also crucial in terms
of suppressing the formation of both iso-4a and allyl-4a.
[RuHCl(CO)ACHTUNGTRENNUNG(PPh3)3]. Although no improvement in regiose-
lectivity was observed by using the bromide complex
(Table 1, entry 2), the iodide complex provided 4a and iso-
4a in a ratio of 17:1 but an increased proportion of allyl-4a
was observed (Table 1, entry 3). Thus, to promote formation
of a single isomeric product, use of the iodide complex
alone was insufficient, prompting consideration of additional
optimization strategies.
Thus, by using [RuACHTUNGTRNENG(U TFA)2(CO)ACHTUNGTNER(NUGN PPh3)2] (5 mol%), Bu4NI
(10 mol%), and formic acid (200 mol%) in THF at 658C,
the desired trisubstituted allylic alcohol product 4a was gen-
erated as a single regioisomer in 75% yield with complete
stereocontrol and in the absence of allyl-4a (Table 2).
It is known that [RuH2(CO)
acetic acid (HO2CCF3, TFAA) to form [RuH
(PPh3)3] and elemental hydrogen [Eq. (1)],[16a] as is the reac-
tion of [RuHCl(CO)(PPh3)3] with trifluoroacetic acid to
G
To evaluate the generality of these conditions, the catalyt-
ic vinylation of aldehydes 2a–2d was conducted by using
phenylpropyne (1a). The desired trisubstituted allylic alco-
hols 3a–6a were obtained in good yield with nearly exclu-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
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À
Alkyne–Aldehyde Reductive C C Coupling
FULL PAPER
Table 2. The regio- and stereoselective catalytic reductive coupling reaction of nonsymmetric alkynes 1a–1 f to aldehydes 2a–2d through ruthenium-cat-
alyzed transfer hydrogenation.[a]
74% yield 3a[b,c]
>20:1, 3a:iso-3a
>20:1, E:Z
77% yield 3b[b,c]
17:1, 3b:iso-3b
>20:1, E:Z
80% yield 3c[b,c]
17:1, 3c:iso-3c
>20:1, E:Z
55% yield 3 d[b,c]
5:1, 3d:iso-3d
>20:1, Z:E
76% yield 3e[b]
>20:1, 3e:iso-3e
>20:1, E:Z
61% yield 3 f[b]
>20:1, 3 f:iso-3 f
>20:1, E:Z
75% yield 4a
>20:1, 4a:iso-4a
>20:1, E:Z
63% yield 4b[e]
11:1, 4b:iso-4b
>20:1, E:Z
80% yield 4 c[d]
8:1, 4c:iso-4c
>20:1, E:Z
67% yield 4d
11:1, 4d:iso-4d
>20:1, Z:E
77% yield 4e
>20:1, 4e:iso-4e
>20:1, E:Z
62% yield 4 f[d]
14:1, 4 f:iso-4 f
>20:1, E:Z
90% yield 5a[g]
18:1, 5a:iso-5a
>20:1, E:Z
88% yield 5b[g]
13:1, 5b:iso-5b
>20:1, E:Z
86% yield 5c[g]
8:1, 5c:iso-5c
>20:1, E:Z
78% yield 5d[g]
11:1, 5d:iso-5d
>20:1, Z:E
95% yield 5e[g]
>20:1, 5e:iso-5e
>20:1, E:Z
52% yield 5 f[f]
>20:1, 5 f:iso-5 f
>20:1, E:Z
85% yield 6a[h]
>20:1, 6a:iso-6a
>20:1, E:Z
84% yield 6b
9:1, 6b:iso-6b
>20:1, E:Z
79% yield 6c[i]
>20:1, 6c:iso-6c
>20:1, E:Z
40% yield 6d
8:1, 6d:iso-6d
>20:1, Z:E
1
63% yield 6e
>20:1, 6e:iso-6e
>20:1, E:Z
62% yield 6 f
>20:1, 6 f:iso-6 f
>20:1, E:Z
[a] Yields are of the isolated material. Regio- and stereoselectivity was determined through H NMR analysis of the crude reaction mixtures. [b] The re-
action was conducted for 16 h. [c] Bu4NI (5 mol%) was employed. [d] The reaction was conducted at a concentration of 1.0m. [e] The reaction was con-
ducted at a concentration of 0.5m. [f] The reaction was conducted for 15 h. [g] The reaction was conducted at a concentration of 2.0m for 24 h. [h] The re-
action was conducted at 458C for 48 h. [i] HCO2H (150 mol%) was employed. See the Supporting Information for further experimental details.
sive formation of a single isomeric adduct and with com-
plete stereocontrol. Encouraged by these results, 1,2-disub-
stituted alkynes 1b–1 f, which possess aryl, heteroaryl, or
alkyl substituents, were coupled to aldehydes 2a–2d. The
corresponding trisubstituted allylic alcohols 4a–4 f, 5a–5 f,
and 6a–6 f were formed in moderate to good yields, and in
most cases a single isomeric adduct predominates (Table 2).
The remarkable regioselectivity of this catalytic system is
underscored by the ability to differentiate the acetylenic ter-
mini of alkyne 1 f, which incorporates CH2CH2OBn and
CH3 groups, to form adducts 3 f–6 f in good yields and as
single regioisomers in all cases, notwithstanding adduct 4 f.
Finally, whereas the aforementioned transformations were
conducted by using 0.3 mmol of the aldehyde, the coupling
of phenylpropyne (1a) to aldehyde 2b on a 3.0 mmol scale
provided allylic alcohol 4a in a slightly higher 79% isolated
yield with a comparable level of selectivity.
In previous studies on the coupling of 2-butyne to alco-
hols and aldehydes under the conditions of ruthenium-cata-
À
lyzed C C bond-forming transfer hydrogenation, it was
found that dehydrogenation of the initially formed allylic al-
cohols could be induced to provide products of intermolecu-
lar alkyne hydroacylation from the alcohol or aldehyde oxi-
dation level [Eq. (4)].[12b] These products of alkyne hydro-
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M. J. Krische et al.
Table 3. Deuterium labeling and competition kinetics experiments.[a]
Reaction
acylation are not formed under the conditions used here. As
previously observed, dehydrogenation of the initially formed
allylic alcohol is suppressed by lower reaction temperatures
(65 vs. 1108C) and shorter reaction times (20 vs. 30 h). Also,
the presence of iodide and the use of formic acid, rather
than isopropanol, as the terminal reductant may be signifi-
cant, because these species may occupy a coordination site
on ruthenium that would be required for b-hydride elimina-
tion.
1
2
3
4
5
6
7
8
To gain further insight into the reaction mechanism a
series of deuterium labeling experiments were performed.
Exposure of phenylpropyne (1a) to deuterated aldehyde
[D1]-2b under the standard conditions results in the forma-
tion of allylic alcohol [Dn]-4a with essentially complete re-
tention of deuterium at the carbinol position (>98% D;
Table 3, entry 1). This result suggests that 4a does not expe-
rience significant reversible oxidation–reduction by way of
enone intermediates, which is important with regard to the
potential development of related enantioselective processes.
In a kinetic competition experiment, phenylpropyne (1a)
reacts with [D1]-2b (50% D) under standard conditions to
deliver [Dn]-4a (48% D), revealing no significant kinetic
effect within the error limits of this experiment (Table 3,
entry 2).
[a] The extent of
D
incorporation was evaluated by using 1H and
Interestingly, exposure of phenylpropyne (1a) to 2b
under standard conditions employing [D2]-formic acid re-
sults in partial deuterium incorporation of [Dn]-4a at the vi-
nylic position (21% D) and, remarkably, at the vinylic
methyl group (50% D with respect to all three hydrogen
atoms; Table 3, entry 3). Given the likelihood that adventi-
tious water compromises the extent of deuterium incorpora-
tion, results arising from the use of [D2]-formic acid and
[D1]-formic acid were compared. Indeed, by using [D1]-
formic acid, substantially less deuterium incorporation is ob-
served at the vinylic position (1% D) and at the vinylic
methyl group (8% D; Table 3, entry 4). This result suggests
that it is primarily the acidic OD deuterium atom in [D2]-
formic acid that is incorporated at the vinylic position of the
product.
Reaction of the deuterated alkyne, [D3]-1a, and aldehyde
2b under the standard conditions delivers [Dn]-4a, which re-
tains approximately half of the isotopic label at the vinylic
methyl group (56% D with respect to all three hydrogen
atoms) without significant transfer of deuterium to any
other position (Table 3, entry 5). As anticipated in view of
the initial labeling experiment (Table 3, entry 1), exposure
of [D3]-1a to [D1]-2b under the standard conditions does
D NMR spectroscopy. The indicated values represent the average of two
runs. [D2]-formic acid in D2O (95 wt%); [D1]-formic acid in H2O
(95 wt%).
not reduce the loss of deuterium at the vinylic methyl group
(53% D with respect to all three hydrogen atoms) and deu-
terium is retained at the carbinol position (>99% D;
Table 3, entry 6). Coupling of the deuterated alkyne, [D3]-
1a, and aldehyde 2b by using [D1]-formic acid does little to
mitigate the loss of deuterium at the vinylic methyl group
(60% D; Table 3, entry 7). In contrast, the use of [D2]-
formic acid significantly suppresses the loss of deuterium at
the vinylic methyl group (83% D; Table 3, entry 8).
The accumulation of deuterium at the vinylic methyl
group in [Dn]-4a (Table 3, entries 3 and 4) and the loss of
deuterium at the vinylic methyl observed in the conversion
of [D3]-1a into [Dn]-4a (Table 3, entries 5 and 6) may be ac-
counted for on the basis of the indicated catalytic mecha-
À
nism for H D exchange (Scheme 1, right). Therein, a ruthe-
À
nium(0) complex, generated upon H I reductive elimina-
À
À
tion, engages alkyne 1a in C H or C D oxidative addition
to the propargylic C H or C D bond, which results in the
À
À
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À
Alkyne–Aldehyde Reductive C C Coupling
FULL PAPER
À
À
Scheme 1. A plausible catalytic mechanism for the C C coupling and the catalytic mechanism accounting for H D exchange at the propargylic position
of alkyne [D3]-1a in the specific case of deuterium loss.
formation of a propargylruthenium hydride. Hydrogen–deu-
terium exchange then occurs with formic acid through dis-
crete reversible protonation–deprotonation (equivalent to
pated on the basis of previous observations (Table 3,
entry 4), the extent of deuterium incorporation at the vinylic
À
positions (25% D) is higher than that observed in the C C
À
O H oxidative addition/reductive elimination) or by way of
coupling product [Dn]-4a under the same conditions. This is
due to the fact that deuterium incorporation at the vinylic
positions occurs after the initial reduction of 1a. Consistent
with this interpretation, cis-b-methylstyrene is the major re-
duction product at low conversion. Thus, it would appear
that the initially formed cis-olefin engages in hydrometalla-
tion to generate alkyl ruthenium species, which upon b-hy-
dride elimination delivers trans-b-methylstyrene as the sole
reduction product. Reversible hydrometallation–b-hydride
elimination accounts for the increase in deuterium incorpo-
ration at the vinylic positions [Eq. (5)].
À
À
six-centered transition state A. Subsequent C H or C D re-
ductive elimination of the propargylruthenium hydride or
deuteride releases the alkyne, which can enter the catalytic
À
cycle for C C coupling (see below).
This interpretation suggests that any accumulation or loss
of deuterium at the propargylic position of alkyne 1a occurs
À
prior to C C coupling. To challenge this hypothesis, cou-
pling product 4a was resubjected to the standard reaction
conditions employing [D1]-formic acid or [D2]-formic acid.
1
Analysis of the recovered 4a by H and D NMR spectrosco-
py revealed no incorporation of deuterium [Eq. (5)]. Addi-
tionally, alkyne 1a was exposed to the standard reaction
conditions by using [D1]-formic acid in the absence of alde-
hyde 2b. The product of alkyne reduction, trans-b-methyl-
styrene, was formed in 70% isolated yield in this reaction
[Eq. (6)].
The collective results on isotopic labeling (Table 3, en-
tries 4 and 5) are consistent with the indicated catalytic
mechanism for aldehyde vinylation (Scheme 1). Therein,
[Ru
ACHUTGTNREN(NUG TFA)(I)(CO)ACHTNUGTRENNUNG
terion exchange between [Ru
N
ACHTUNGTRENNUNG
Bu4NI, engages in carboxylate exchange with formic acid to
release trifluoroacetic acid and generate a ruthenium for-
mate (not shown), which eliminates carbon dioxide to fur-
nish [RuH(I)(CO)ACHTNUGTRNEG(UN PPh3)2]. This species may eliminate HI
À
to generate zero-valent ruthenium, which catalyzes the H D
exchange at the propargylic position, as previously de-
scribed. Alternatively, regioselective alkyne hydrometalla-
tion occurs to deliver a vinylruthenium intermediate that,
upon carbonyl addition, provides the indicated ruthenium
alkoxide. Trifluoroacetic acid mediated protonolysis of the
ruthenium alkoxide releases the product of carbonyl vinyla-
tion and regenerates [RuACTHNUTRGENN(GU TFA)(I)(CO)AHCTUNGTRENN(NGU PPh3)2] (Scheme 1).
The proposed hydrometallative mechanism for alkyne–
carbonyl reductive coupling is corroborated by the stoichio-
metric conversion of [Ru
(TFA)(H)(CO)(PPh3)2] under transfer hydrogenation condi-
tions employing ethanol as the terminal reductant,[17b] and
the subsequent reaction of [Ru(TFA)(H)(CO)(PPh3)2] with
ACHTUNGTRENUN(G TFA)2(CO)AHCTUNGTRENN(GUN PPh3)2] into [Ru-
Although the extent of deuterium incorporation at the vi-
nylic methyl group in trans-b-methylstyrene (4% D with re-
spect to all three hydrogen atoms; Table 3, entry 5) is antici-
N
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
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12441

M. J. Krische et al.
c) R. L. Patman, J. F. Bower, I. S.
Kim, M. J. Krische, Aldrichimica
Acta 2008, 41, 95–104; d) F. Shi-
bahara, M. J. Krische, Chem. Lett.
2008, 37, 1102–1107; e) J. F.
Bower, I. S. Kim, R. L. Patman,
M. J. Krische, Angew. Chem.
2008, 121, 36–48; Angew. Chem.
Int. Ed. 2008, 48, 34–46; f) S. B.
Han, I. S. Kim, M. J. Krische,
Chem. Commun. 2009, 7278–
7287.
[2] For hydrogen-mediated coupling
of nonconjugated alkynes to car-
bonyl compounds and imines,
see: a) J.-U. Rhee, M. J. Krische,
J. Am. Chem. Soc. 2006, 128,
Scheme 2. Established stoichiometric transformations that corroborate the proposed hydrometallative mecha-
nism for alkyne–carbonyl reductive coupling.
ꢀ
10674–10675; b) E. Skucas, J. R. Kong, M. J. Krische, J. Am. Chem.
Soc. 2007, 129, 7242–7743; c) A. Barchuk, M.-Y. Ngai, M. J. Krische,
J. Am. Chem. Soc. 2007, 129, 8432–8433; d) M.-Y. Ngai, A. Barch-
uk, M. J. Krische, J. Am. Chem. Soc. 2007, 129, 12644–12645;
e) S. B. Han, J.-R. Kong, M. J. Krische, Org. Lett. 2008, 10, 4133–
4135; f) V. M. Williams, J.-R. Kong, B.-J. Ko, Y. Mantri, J. S. Brod-
belt, M.-H. Baik, M. J. Krische, J. Am. Chem. Soc. 2009, 131, 16054–
16062.
PhC CPh to provide the corresponding vinylruthenium
complex (Scheme 2).[18b] The regioselectivity of hydrometal-
lation, which favors placement of ruthenium adjacent to the
aryl substituent in alkynes 1a–1e, may be driven by addi-
tional stabilization associated with the p-benzyl character of
this intermediate. For alkyne 1 f, the Lewis basic benzyl
ether moiety is anticipated to direct the regioselectivity of
the hydrometallation.[19] It should be noted that oxidative
coupling pathways cannot be excluded on the basis of the
available data and may account for contra-steric regiocon-
[3] For hydrogen-mediated coupling of 1,3-enynes to carbonyl com-
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À
trol in the C C coupling event.
Conclusion
[4] For selected reviews on alkyne hydrometallation and carbometalla-
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[5] Enantioselective aldehyde vinylation has been accomplished by
using organozinc reagents, which are prepared by alkyne hydrome-
tallation (R2BH or Cp2ZrHCl) with subsequent transmetallation to
zinc by using ZnMe2. For reviews, see: a) P. Wipf, C. Kendall, Chem.
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A highly regio- and stereoselective alkyne–aldehyde reduc-
tive coupling protocol for the synthesis of trisubstituted al-
lylic alcohols has been developed. Iodide counterions were
shown to play an essential role in directing the regioselectiv-
À
ity of the C C bond formation. Isotopic labeling studies cor-
À
roborate the reversible catalytic propargyl C H oxidative
À
addition in advance of C C coupling, and demonstrate that
the C C coupling products do not experience reversible de-
hydrogenation by way of enone intermediates. Based on
these findings, asymmetric variants of this vinylation process
appear feasible.
À
Experimental Section
[6] Isolated examples of rhodium-catalyzed addition reactions of vinyl-
metal reagents to aldehydes have been reported. References [a] and
[f] report asymmetric transformations, however only modest enan-
tioselectivities are observed: a) M. Sakai, M. Ueda, N. Miyaura,
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See the Supporting Information for full experimental details.
Acknowledgements
Acknowledgement is made to the Robert A. Welch Foundation (F-0038),
the NIH-NIGMS (RO1-GM069445) and the University of Texas at
Austin Center for Green Chemistry and Catalysis.
À
[1] For selected reviews on C C bond-forming hydrogenation and
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12442
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 12437 – 12443

À
Alkyne–Aldehyde Reductive C C Coupling
FULL PAPER
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À
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ACHTUNGRTENN(UNG TFA)2(CO)-
A
R
ACHTUNGTRENNUNG
À
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À
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Received: May 19, 2011
Revised: August 11, 2011
Published online: September 27, 2011
Chem. Eur. J. 2011, 17, 12437 – 12443
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12443