Divergent regioselectivity in the synthesis of trisubstituted allylic alcohols by nickel- and ruthenium-catalyzed alkyne hydrohydroxymethylation with formaldehyde

Article abstract of DOI:10.1002/anie.201101496

Stoichiometric metals banned: Nonsymmetrically disubstituted alkynes were converted into primary trisubstituted allylic alcohols upon exposure to paraformaldehyde in the presence of nickel or ruthenium catalysts, which exhibit complementary regioselectivity and complete stereoselectivity in the absence of exogenous reducing agents (see scheme). Copyright

Full text of DOI:10.1002/anie.201101496

DOI: 10.1002/anie.201101496
Homogeneous Catalysis
Divergent Regioselectivity in the Synthesis of Trisubstituted Allylic
Alcohols by Nickel- and Ruthenium-Catalyzed Alkyne
Hydrohydroxymethylation with Formaldehyde**
Cory C. Bausch, Ryan L. Patman, Bernhard Breit,* and Michael J. Krische*
Dedicated to Professor Barry M. Trost on the occasion of his 70th birthday.
Trisubstituted allylic alcohols[1,2] are ubiquitous in natural
products and are readily converted into diverse chiral
building blocks by enantioselective epoxidation,[2a,b] cyclo-
propanation,[2a,c] hydrogenation,[2a,d] and allylic substitu-
tion.[2a,e] Among methods for the regio- and stereoselective
synthesis of trisubstituted primary allylic alcohols, alkyne
Scheme 1. Previously developed approaches requiring a stoichiometric
hydrometalation or carbometalation mediated by stoichio-
amount of a reducing agent, and the approach investigated in the
metric organometallic reagents has found broad use.[3–7] For
current study without exogenous reductants.
example, in seminal studies by Corey et al. (1967),[4c] the
regio- and stereoselective hydroalumination of propargyl
alcohols was used to construct vinyl iodides, which were
converted into trisubstituted allylic alcohols upon exposure to
lithium dialkyl cuprates. Similarly, alkyne hydromagnesiation
and carbomagnesiation with Grignard reagents delivered
trisubstituted allylic alcohols regio- and stereoselectively.[6,7]
Although alkyne functionalization through hydrometala-
tion and carbometalation remains at the forefront of
research,[3–7] the development of equivalent transformations
that avoid stoichiometric metal reagents is clearly desirable.
Conversely, whereas related nickel-catalyzed alkyne–carbon-
yl reductive couplings can be highly regioselective, such
processes require terminal reductants that are metallic,
pyrophoric, or highly mass intensive (e.g. ZnR2, BEt3,
HSiR3; Scheme 1),[8–10] although nickel-catalyzed alcohol-
mediated alkyne–enone couplings were recently disclosed.[11]
Hence, the discovery of alkyne–carbonyl (or alkyne–
imine) reductive couplings under hydrogenation conditions is
significant.[12,13] More recently, an alkyne–carbonyl reductive
coupling by ruthenium-catalyzed transfer hydrogenation was
developed; however, regioselectivity in such processes
remains largely unexplored.[14,15] Herein, we report the
regio- and stereoselective synthesis of trisubstituted primary
allylic alcohols from alkynes in the absence of stoichiometric
metallic reagents. In this reaction, paraformaldehyde is used
as a C1 feedstock and, more remarkably, as a reductant under
conditions of transfer hydrogenation with nickel and ruthe-
nium catalysts, which exhibit complementary regioselectivity
(Scheme 2).
In response to the lack of efficient methods for diene
hydroformylation,[16] we recently developed a process for
diene hydrohydroxymethylation under the conditions of
ruthenium-catalyzed transfer hydrogenation using parafor-
maldehyde as a C1 feedstock;[17] paraformaldehyde was itself
prepared from synthesis gas (via methanol). As the develop-
ment of efficient catalysts for alkyne hydroformylation
remains an unmet challenge,[18] we undertook the current
investigation into alkyne–paraformaldehyde reductive cou-
pling. Initial studies focused on the reductive coupling of 1-
phenylpropyne (1a) with paraformaldehyde. We explored the
nickel-catalyzed reductive coupling of 1a with paraformalde-
hyde in the absence of a reducing agent.[8–10] Remarkably,
conditions were identified under which the nickel catalyst
produced adduct 3a as a single regio- and stereoisomer, as
determined by 1H NMR spectroscopic analysis. Previously
determined conditions for ruthenium-catalyzed alkyne–car-
bonyl coupling with higher aldehydes[14] were further eval-
uated and meticulously adapted for the use of paraformalde-
hyde to enable formation of the isomeric primary trisubsti-
tuted allylic alcohol 2a in 85% yield as a single regio- and
[*] Dr. C. C. Bausch, Prof. B. Breit, Prof. M. J. Krische
Albert-Ludwigs-Universitꢀt Freiburg
Freiburg Institute for Advanced Studies (FRIAS)
Albertstrasse 21, 79104 Freiburg (Germany)
Fax: (+49)761-203-8715
E-mail: bernhard.breit@chemie.uni-freiburg.de
Dr. C. C. Bausch, Prof. B. Breit
Albert-Ludwigs-Universitꢀt Freiburg
Institut fꢁr Organische Chemie und Biochemie
Albertstrasse 21, 79104 Freiburg (Germany)
R. L. Patman, 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
[**] We acknowledge the Robert A. Welch Foundation (F-0038), the NSF-
ICC (CHE-1021640), the NSF-DFG (BR 1646/6-1), the University of
Texas at Austin, Center for Green Chemistry and Catalysis, and the
Freiburg Institute for Advanced Studies (FRIAS) for partial support
of this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101496.
Angew. Chem. Int. Ed. 2011, 50, 5687 –5690
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5687

Communications
Table 1: Scope of the regio- and stereoselective ruthenium- and nickel-
catalyzed hydrohydroxymethylation of alkynes 1a–n.
Entry
Cond.[a]
Alkyne
R1
R2
Yield [%][b]
(2/3[c])
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1a
1b
1c
1d
1e
1 f
1j
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
85 (ꢀ20:1)
75 (ꢀ20:1)
74 (ꢀ20:1)
75 (10:1)
p-MeC6H4
p-MeOC6H4
p-ClC6H4
o-MeC6H4
m-MeOC6H4
p-BrC6H4
p-MeCOC6H4
p-EtCO2C6H4
2-thienyl
N-Boc-3-indoyl
BnOCH2CH2
Ph
p-MeC6H4
p-MeOC6H4
p-ClC6H4
o-MeC6H4
m-MeOC6H4
2-thienyl
Ph
63 (ꢀ20:1)
78 (12:1)
70 (9:1)
70 (8:1)
69 (9:1)
76 (11:1)
77 (ꢀ20:1)
64 (ꢀ20:1)
81 (1:ꢀ20)
65 (1:ꢀ20)
77 (1:ꢀ20)
67 (1:ꢀ20)
52 (1:ꢀ20)
50 (1:ꢀ20)
60 (1:ꢀ20)
60 (–)
Scheme 2. Complementary regioselectivity in ruthenium- and nickel-
catalyzed hydrohydroxymethylation reactions of alkynes 1a–d with
paraformaldehyde as a C1 feedstock. Cy=cyclohexyl, TBAI=tetra-
butylammonium iodide, tfa=trifluoroacetate.
1m
1n
Me
iPr
71 (1:2.3)
1
[a] Conditions A: alkyne (200 mol%), (CH2O)n (100 mol%), [Ru-
(tfa)2(CO)(PPh3)2] (5 mol%), Bu4NI (5 mol%), HCO2H (100 mol%),
THF (0.2m), 958C, 15 h. Conditions B: alkyne (100 mol%), (CH2O)n
(400 mol%), [Ni(cod)2] (10 mol%), PCy3 (10 mol%), Cs2CO3
(20 mol%), H2O (5 mol%), toluene (0.25m), 758C, 24 h. See the
Supporting Information for further details. [b] Yield of material isolated
by silica-gel chromatography. [c] Regio- and diastereoselectivity were
determined by 1H NMR spectroscopic analysis of the crude reaction
mixture. Bn=benzyl, Boc=tert-butoxycarbonyl.
stereoisomer, as determined by H NMR spectroscopic anal-
ysis. In both processes, paraformaldehyde may serve as the
electrophilic partner and the reductant. In fact, in the nickel-
catalyzed process, no reductant other than paraformaldehyde
is required. In the ruthenium-catalyzed process, an exogenous
reductant in the form of formic acid is required to enforce
complete conversion. These conditions were applicable to
aryl propynes 1a–d, which were converted into adducts 2a–d
and 3a–d using ruthenium and nickel catalysts, respectively,
with excellent partitioning of regioselectivity (Scheme 2).
To evaluate the scope of the nickel- and ruthenium-
catalyzed reductive alkyne coupling with paraformaldehyde,
we investigated a range of nonsymmetrical aryl–alkyl-sub-
stituted alkynes. The ruthenium catalyst tolerated both
electron-donating and electron-withdrawing substituents on
the aryl group (Table 1, entries 2–9); the nickel catalyst
showed compatibility with methoxy and chloro substituents
(Table 1, entries 15–18). Steric hindrance caused by an ortho
methyl substituent (Table 1, entries 5 and 17) diminished the
yield of the isolated product. Heteroaryl substituents, such as
a 2-thienyl or an N-Boc-protected 3-indolyl group, were
tolerated (Table 1, entries 10, 11, and 19). The ruthenium
catalyst showed remarkably high regioselectivity (ꢀ 20:1) in
the hydroxymethylation of a dialkyl-substituted alkyne, with
the discrimination of a CH2CH2OBn substituent and a methyl
group, whereas the nickel-catalyzed process enabled discrim-
ination between a methyl and an isopropyl substituent
(Table 1, entries 12 and 21, respectively).
metalative and carbometalative (oxidative coupling) path-
ways.[19–21] In the case of ruthenium, the stoichiometric
reaction of [Ru(tfa)2(CO)(PPh3)2] with alcohols to generate
[RuH(tfa)(CO)(PPh3)2] along with an aldehyde or ketone is
known.[19] Furthermore, alkyne hydrometalation by [RuH-
(tfa)(CO)(PPh3)2], generated in situ from [Ru(tfa)2(CO)-
(PPh3)2] and ethanol, to furnish vinyl ruthenium complexes
has been established.[20] Finally, the resulting vinyl ruthenium
complexes were subjected to protonolysis by trifluoroacetic
acid to regenerate [Ru(tfa)2(CO)(PPh3)2].[20b] These reactions
support the feasibility of the proposed hydrometalative
mechanism for the ruthenium-catalyzed alkyne hydroxyme-
thylation mediated by formaldehyde (Scheme 3).
Similarly, in the case of nickel, the stoichiometric oxida-
tive coupling of butyne and benzaldehyde in the presence of
[Ni(cod)2] and tricyclohexylphosphane delivers isolable nick-
eladihydrofurans, which have been characterized by single-
crystal X-ray diffraction analysis.[21] At room temperature,
such metallacycles engage in b-hydride elimination to furnish
conjugated enones. These reactions support the feasibility of
the proposed carbometalative mechanism for nickel-cata-
lyzed alkyne hydroxymethylation mediated by formaldehyde.
As suggested by established stoichiometric reactions, the
mechanistic origins of regiodivergence with regard to the
nickel- and ruthenium-catalyzed hydroxymethylation reac-
tions appears to arise through the partitioning of hydro-
5688
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 5687 –5690

Received: March 1, 2011
Published online: May 9, 2011
Keywords: hydrohydroxymethylation · nickel ·
.
paraformaldehyde · reductive coupling · ruthenium
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An observation consistent with this proposal is that the
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are cleaved upon isolation (Scheme 4).
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Scheme 4. Proposed catalytic mechanism for nickel-catalyzed alkyne
hydrohydroxymethylation, as supported by established stoichiometric
transformations. (Details on the isolation of the formate ester can be
found in the Supporting Information.)
In summary, nonsymmetrical disubstituted alkynes were
converted into primary trisubstituted allylic alcohols upon
exposure to paraformaldehyde in the presence of ruthenium
or nickel catalysts, which exhibit complementary regioselec-
tivity and complete stereoselectivity. These procedures pro-
vide an alternative to alkyne hydroformylation, for which
efficient regioselective variants do not exist. Furthermore,
they serve as alternatives to established methods that rely on
the use of stoichiometric amounts of organometallic reagents,
and thus pave the way for more environmentally benign
organic synthesis. Related reductive carbon–carbon bond-
forming reactions are currently under investigation as alter-
natives to hydroformylation.
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Communications
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