Iron-catalyzed regioselective transfer hydrogenative couplings of unactivated aldehydes with simple alkenes

Article abstract of DOI:10.1002/anie.201602130

An FeBr₃-catalyzed reductive coupling of various aldehydes with alkenes that proceeds through a direct hydride transfer pathway has been developed. With ⁱPrOH as the hydrogen donor under mild conditions, previously challenging coupling reactions of unactivated alkyl and aryl aldehydes with simple alkenes, such as styrene derivatives and α-olefins, proceeded smoothly to furnish a diverse range of functionalized alcohols with complete linear regioselectivity. The reductive coupling of various aldehydes and alkenes through a direct hydride transfer pathway can be catalyzed by FeBr₃. With isopropanol as the hydrogen donor, previously challenging coupling reactions of unactivated alkyl and aryl aldehydes with simple alkenes, such as styrene derivatives and α-olefins, proceeded smoothly to furnish a diverse range of functionalized alcohols with complete linear regioselectivity.

Full text of DOI:10.1002/anie.201602130

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201602130
German Edition: DOI: 10.1002/ange.201602130
Transfer Hydrogenative Couplings
Hot Paper
Iron-Catalyzed Regioselective Transfer Hydrogenative Couplings of
Unactivated Aldehydes with Simple Alkenes
Yan-Long Zheng+, Yan-Yao Liu+, Yi-Mei Wu, Yin-Xia Wang, Yu-Tong Lin, and Mengchun Ye*
Abstract: An FeBr3-catalyzed reductive coupling of various
aldehydes with alkenes that proceeds through a direct hydride
i
transfer pathway has been developed. With PrOH as the
hydrogen donor under mild conditions, previously challenging
coupling reactions of unactivated alkyl and aryl aldehydes with
simple alkenes, such as styrene derivatives and a-olefins,
proceeded smoothly to furnish a diverse range of functional-
ized alcohols with complete linear regioselectivity.
T
he catalytic hydrogenative or transfer hydrogenative cou-
pling of p-unsaturated reactants with carbonyl compounds
À
has recently emerged as one of the most attractive C C bond-
forming methods.[1] Unlike traditional catalytic reductive
[2]
À
C C couplings that employ alkyl metal reagents, metal
hydrides,[3] or elemental metals[4] as the reducing agents
(Scheme 1a), (transfer) hydrogenative couplings using hydro-
gen gas or hydrogen donors as greener terminal reductants
provide a much less expensive and more environmentally
À
benign C C bond-forming process without generating stoi-
chiometric amounts of metallic wastes. Following an isolated
report by Molander and Hoberg on the H2-mediated reduc-
tive cyclization of 1,5- and 1,6-dienes,[5] Krische and co-
workers pioneered the development of both hydrogenative
and transfer hydrogenative couplings of carbonyl compounds
with a variety of p-unsaturated compounds, including eno-
nes,[6a] alkynes,[6b] 1,3-dienes,[6c] enynes,[6d] allenes,[6e] and allyl
compounds.[6f] However, readily available simple alkenes,
such as styrenes and a-olefins, have always been challenging
substrates for intermolecular couplings with carbonyl com-
pounds owing to their low reactivity.[7] Although significant
progress has already been made to address this challenge, for
example, by introducing activated carbonyl compounds such
as carboxylic anhydride [Scheme 1b, Eq. (1)],[8] or by using
hydroxyoxindole as the pyruvamide precursor[9] [Eq. (2)] to
facilitate these couplings, a generally effective strategy to
achieve regioselective (transfer) hydrogenative couplings of
simple alkenes with abundant and accessible carbonyl com-
pounds such as aryl and alkyl aldehydes remains elusive.
Scheme 1. Catalytic intermolecular reductive couplings of p-unsatu-
rated reactants with carbonyl compounds.
On the other hand, catalysts based on noble metals such as
Rh, Ir, or Ru dominate these (transfer) hydrogenative
couplings of carbonyl compounds with various p-bonds.[1]
The replacement of these noble metals with less toxic,
inexpensive, and abundantly available metals is one of the
most important challenges in this field. A major breakthrough
was the nickel-catalyzed transfer hydrogenative coupling of
1,3-dienes with paraformaldehyde developed by Krische and
co-workers.[10] Iron as the second most abundant and gen-
erally non-toxic metal on Earth has become an increasingly
sought-after metal catalyst,[11] but iron-catalyzed (transfer)
hydrogenative couplings have not been developed thus far.
Herein, we report the first iron-catalyzed regioselective
transfer hydrogenative coupling of unactivated aldehydes
with simple alkenes, including styrene derivatives and a-
olefins, which is mediated by iPrOH [Eq. (3)].
There are two most commonly proposed pathways for
hydrogen transfer in metal-catalyzed (transfer) hydrogena-
tions of carbonyl compounds. The first one involves the initial
formation of a metal–hydride species and subsequent hydro-
gen transfer to the unsaturated bond.[12] The second one has
been proposed for Meerwein–Ponndorf–Verley (MPV) reac-
tions[13a] and alcohol dehydrogenase processes, which do not
[*] Y.-L. Zheng,[+] Y.-Y. Liu,[+] Y.-M. Wu, Y.-X. Wang, Y.-T. Lin, Prof. Dr. M. Ye
State Key Laboratory and Institute of Elemento-Organic Chemistry
Nankai University, Tianjin 300071 (China)
E-mail: mcye@nankai.edu.cn
Prof. Dr. M. Ye
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Tianjin 300071 (China)
[13b]
À
involve M H species;
direct hydride transfer from the
H donor to the unsaturated bond catalyzed by various non-
noble metal complexes is thus observed.[14] Currently, almost
all (transfer) hydrogenative couplings of carbonyl compounds
with p-unsaturated reactants have been developed on the
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201602130.
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basis of the former mechanism and involve metal–hydride
species,[1] whereas (transfer) hydrogenative couplings through
the latter direct H transfer mechanism have not been
reported to date. We envisaged that an alkene may be
introduced in the MPV reaction to form a transient carbo-
cation as the hydrogen trapping site instead of a carbonyl
group. On this basis, we envisaged the development of an
interrupted MPV-type transfer hydrogenative coupling of
carbonyl compounds with alkenes in the presence of a non-
noble-metal catalyst (Scheme 2).
optimal catalyst and provided the desired compound in 98%
yield (entry 14). Further reducing the catalyst loading
resulted in a significant decrease in yields (entries 15 and 16).
With optimized reaction conditions in hand, we first
explored a series of alkyl and aryl aldehydes to explore the
generality of the reaction (Scheme 4). Various alkyl alde-
Scheme 2. Proposed transfer hydrogenative coupling.
We commenced our studies by using isovaleraldehyde
(1a) and 1,1-diphenylethylene (2a) as the model substrates.
Using iPrOH as both the solvent and H donor, initial
investigations of a wide range of metal catalysts at various
temperatures failed to produce the expected product. For-
i
tunately, lowering the loading of PrOH to 10 equivalents in
DCE in the presence of Zn(OTf)2 as the catalyst led to a small
amount of the expected reductive-coupling product with
completely linear regiocontrol (Scheme 3, entry 1). Further
reducing the iPrOH loading to 2 equivalents greatly improved
the yield to 49% (entry 2). Many of the screened Lewis acids,
including Cu, Ag, Sc, In, and Ga salts, successfully catalyzed
this reaction with reasonable yields (entries 3–7). Notably,
Brønsted acids could also catalyze this reaction, but were less
efficient than Lewis acids (entry 8; see also the Supporting
Information, Table S3). To our great delight, inexpensive and
abundant Fe salts turned out to be an ideal choice for this
reaction (entries 9–14). Among them, FeBr3 proved to be the
Scheme 4. Aldehyde scope. [a] FeBr3 (1 mol%). [b] FeBr3 (10 mol%).
hydes with linear alkyl chains were highly reactive under
these conditions and afforded the corresponding products in
good to excellent yields in the presence of 1 or 5 mol% of
FeBr3 (3b–3d). Alkyl aldehydes with phenyl (3e and 3g) or
benzyloxy (3 f) moieties on the alkyl chain were also tolerated
and gave the desired products in moderate to excellent yields.
Impressively, various bulky alkyl aldehydes with large sub-
stituents in the a-position reacted well, providing compounds
3h–3m in moderate to good yields. Notably, sterically very
demanding pivaldehyde reacted smoothly to furnish the
desired alcohol in 39% yield (3j). Aside from alkyl aldehydes,
aryl aldehydes were also compatible with the reaction
conditions. Various aryl aldehydes bearing electron-with-
drawing groups, such as CF3 (3n, 3o, 3p, and 3q), NO2 (3r),
Ac (3s), and CN (3t), worked well and generated the
corresponding products in 36 to 91% yield, whereas benzal-
dehyde and aryl aldehydes bearing electron-donating groups
were found to be unsuitable for this reaction.
Next, the compatibility of a variety of alkenes with this
transfer hydrogenative coupling reaction was examined
(Scheme 5). 1,1-Diaryl alkenes proved to be excellent cou-
pling partners for this transformation and were converted into
the corresponding products in high yields (4a–4d). Styrene
(4e) and styrene derivatives with diverse substituents on the
aryl group reacted efficiently in the presence of 5 or 10 mol%
of FeBr3 to afford the corresponding products in satisfactory
Scheme 3. Optimization of the reaction conditions. [a] Determined by
1H NMR spectroscopy using CH2Br2 as the internal standard. Yields of
isolated products given in parentheses. [b] iPrOH (2 mmol, 10 equiv).
acac=acetylacetonate, DCE=1,2-dichloroethane, Tf =trifluorometha-
nesulfonyl.
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Scheme 6. Gram-scale reaction and synthesis of two pharmaceutically
active compounds.
First, no aldehyde or alkene hydrogenation was observed in
the reactions of either the aldehyde or alkene itself under the
optimized reaction conditions (see the Supporting Informa-
tion). This result ruled out a possible iron-catalyzed alcohol–
alkene direct coupling process.[16] Second, a deuterium-label-
ing experiment with isovaleraldehyde and 1,1-diphenylethy-
i
lene (2a) in the presence of PrOH-d8 under our optimized
conditions showed complete deuterium incorporation at the
former alkene C2 position (Scheme 7a). Third, an obvious
kinetic isotope effect (kH/kD = 2.5) was observed in a compe-
tition experiment with iPrOH and an equal amount of iPrOH-
d8, and a radical trapping experiment showed that neither 0.2
nor 0.5 equivalents of the radical scavenger BHT (butylated
hydroxytoluene) have an apparent inhibiting effect on this
coupling reaction (see the Supporting Information). These
results suggest that a radical pathway can be ruled out. Finally,
an intramolecular coupling reaction of olefinic aldehydes (see
the Supporting Information) did not provide the reductive
coupling product, which suggests that a cationic intermediate
could be formed, but that the geometric constraints of the
substrate prevent the hydride transfer. Based on these results,
two possible pathways were proposed. The first one corre-
Scheme 5. Alkene scope. [a] FeBr3 (1 mol%). [b] FeBr3 (10 mol%).
[c] 2,3-Dimethylbut-1-ene (0.6 mmol).
yields (4 f–4m). Vinyl-substituted naphthalenes (4n and 4o)
were also suitable coupling partners (76–91%). More impor-
tantly, styrene derivatives bearing a 2-substituted alkyl group
(4p, 4q, and 4r) reacted well in this coupling reaction, and the
possible olefinated side product was not observed. Among
them, a highly hindered trisubstituted alkene worked effi-
ciently to provide the corresponding product with very high
diastereoselectivity (4r; characterized by single crystal X-ray
diffraction analysis, see the Supporting Information). Pleas-
ingly, branched a-olefins (4s and 4t) also reacted smoothly to
deliver the expected products in reasonable yields.
This transfer hydrogenative coupling of isovaleraldehyde
1a with styrene could easily be scaled up to gram scale
without an apparent decrease in yield (1.5 g of product 4e;
Scheme 6). To further study the synthetic utility of our
method, two pharmaceutically active compounds were syn-
thesized. Two 1,1-diaryl alkenes were coupled with parafor-
maldehyde under the optimized reaction conditions but with
i
only 1.2 equiv of PrOH to form the corresponding primary
alcohols 5a and 5b, which were then transformed into
tosylates 6a and 6b. Further amination of 6a with 1-phenyl-
ethanamine afforded compound 7 (fendiline) in 93% yield,
and amination of 6b with diisopropylamine followed by
demethylation furnished compound 8 (tolterodine). Com-
pared with the industrial process, which requires six steps and
air- and moisture-sensitive metallic hydrides for the synthesis
of racemic tolterodine, our method could provide a promising
alternative.[15]
To understand the mechanism of this hydrogenative
coupling reaction, additional experiments were conducted.
Scheme 7. Mechanistic studies.
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À
which both the C C coupling and the hydride transfer are
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alternative is based on an iron-catalyzed Prins/hydride-trans-
À
fer process, in which C C coupling occurs via an oxocarbe-
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reductive-coupling product (Scheme 7c). Although the
results with the Brønsted acids suggest that the latter pathway
involving a precedented 1,5-H shift could be preferred,[17] the
former pathway cannot be excluded at this stage because of
the superior reactivity of iron.
In summary, we have successfully developed an iron-
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À
under mild conditions. This new C C bond-formation method
enables the coupling of unactivated aldehydes, such as alkyl
and aryl aldehydes, with simple alkenes, such styrene
derivatives and branched a-olefins, for the first time and is
based on the use of catalytic amounts of FeBr3. Preliminary
mechanistic studies suggest that the reaction could proceed
through a Prins/hydride-transfer pathway. We are currently
working towards obtaining further evidence for our proposed
mechanism and towards expanding the applicability of our
method to various transfer hydrogenative couplings.
Acknowledgements
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We thank the National Natural Science Foundation of China
(21402096, 21421062), the Tianjin Applied Basic Research
Project and Cutting-Edge Technology Research Plan
(14JCYBJC41400), and the “1000-Youth Talents Plan” for
financial support.
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Keywords: aldehydes · alkenes · hydride transfer · iron ·
transfer hydrogenative couplings
How to cite: Angew. Chem. Int. Ed. 2016, 55, 6315–6318
Angew. Chem. 2016, 128, 6423–6426
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Received: March 1, 2016
Published online: April 13, 2016
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