Synergistic Relay Reactions To Achieve Redox-Neutral α-Alkylations of Olefinic Alcohols with Ruthenium(II) Catalysis

Article abstract of DOI:10.1002/anie.201915218

Herein, we report a ruthenium-catalyzed redox-neutral α-alkylation of unsaturated alcohols based on a synergistic relay process involving olefin isomerization (chain walking) and umpolung hydrazone addition, which takes advantage of the interaction between the two rather inefficient individual reaction steps to enable an efficient overall process. This transformation shows the compatibility of hydrazone-type “carbanions” and active protons in a one-pot reaction, and at the same time achieves the first Grignard-type nucleophilic addition using olefinic alcohols as latent carbonyl groups, providing a higher yield of the corresponding secondary alcohol than the classical hydrazone addition to aldehydes does. A broad scope of unsaturated alcohols and hydrazones, including some complex structures, can be successfully employed in this reaction, which shows the versatility of this approach and its suitability as an alternative, efficient means for the generation of secondary and tertiary alcohols.

Full text of DOI:10.1002/anie.201915218

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Accepted Article
Title: Synergistic Relay Reactions to Achieve Redox-Neutral α-
Alkylation of Olefinic Alcohols with Ruthenium(II)-Catalysis
Authors: Chen-Chen Li, Jian Kan, Zihang Qiu, Jianbin Li, Leiyang Lv,
and Chao-Jun Li
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10.1002/anie.201915218
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Synergistic Relay Reactions to Achieve Redox-Neutral α-
Alkylation of Olefinic Alcohols with Ruthenium(II)-Catalysis
Chen-Chen Li,[a] Jian Kan,[a],[b] Zihang Qiu,[a] Jianbin Li,[a] Leiyang Lv,[a] and Chao-Jun Li*[a]
Abstract: Here, we report a ruthenium-catalysed redox-neutral α-
alkylation of unsaturated alcohols through the synergistic relay of
olefin isomerization (chain-walking) and ’umpolung’ hydrazone
addition, which impeccably takes advantage of the interaction of the
two comparatively inefficient clause reactions to enable them to occur
in an efficient way. This transformation shows the compatibility of
hydrazone-type ‘carbanions’ and active protons in a one-pot reaction
and at the same time achieves the first case of a Grignard-type
nucleophilic addition using olefinic alcohols as latent carbonyls,
providing a higher yield of the corresponding secondary alcohol than
the classical hydrazone addition to aldehydes. A broad scope of
unsaturated alcohols and hydrazones, including some complex
structures, was successfully tested by this method which shows the
versatility of this approach and its suitability as an alternative efficient
way to build up secondary and tertiary alcohols.
place which opens up new avenues for organic synthesis and
other related fields.[7] For instance, Terada reported a transition-
metal and Brønsted acid binary catalyzed tandem olefin
isomerization and addition of an allyl amine.[7a] Moreover, Yang
applied the relay strategy onto phosphine chemistry and
successfully realized the formation of α-aminophosphonates.[7b]
On the other hand, at the end of the last century, ruthenium-
catalyzed isomerization of allylic alcohols to the corresponding
carbonyls was successfully developed.[6c, 6d, 8] However, to the
best of our knowledge, the relay of allylic alcohols
isomerization/carbanion addition has not been succeeded up to
now. The biggest challenge for this transformation is the
incompatibility of classic carbanion reagents and acidic proton on
allylic alcohol. The special tolerance of the ‘umpolung carbanion’
towards acidic proton and the similar ruthenium(II) catalyst in both
reactions inspired us to test the feasibility of relaying the
isomerization of allyl alcohol and the umpolung addition to
carbonyl to realize a redox-neutral α-alkylation of allyl alcohols.
Relay strategy was widely used in the organic methodology
development and total synthesis.[1] The utility of relay reactions
simplifies the synthetic steps and avoids the separation of
unstable intermediates to a certain extent.[2] Moreover, a relay of
two originally inefficient catalytic cycle in one-pot could
sometimes enable generation of the target product more
efficiently than the stepwise process. Taking these advantages,
several unique types of transformations have been designed,
which are not possible to easily achieve via classical methods.[1a,
1b]
Sp3 carbon-carbon bond formation is fundamental in organic
synthesis and has been an everlasting research topic in organic
chemistry. Our group recently developed a C-C bond formation
reaction using aldehydes as carbanion equivalent to undergo
ruthenium(II)-catalyzed Grignard-type nucleophilic addition to
carbonyls.[3] This newly developed ‘carbanion’ reagent not only
avoids the usage of stoichiometric amount of metals and alkyl
halides, but also is more stable to air and water. In addition, it can
tolerate various sensitive functional groups such as acidic protons,
esters, halogens, etc. In order to uncover the unique reactivities
of this new type of carbanion, we put our efforts into two aspects:
1) apply this new ‘carbanion’ towards other electrophiles beyond
aldehydes;[4] and 2) explore unprecedented transformations
concerning sp3 C-C bond formation by combining carbanion
addition with some other Ru-catalyzed reaction.[5]
Scheme 1. α-Alkylation of Allyl Alcohol via Olefin Isomerization/Addition
Strategy
Upon the analysis of the allyl alcohol isomerization literatures and
our recently developed hydrazone chemistry, [3-4, 9] a ruthenium
(II)-phosphine system was initially chosen to start our study.
Nevertheless, several factors were then taken into consideration:
1) To make the metal complex to favor the π-coordination,
insertion and de-insertion process, an electron-rich metal center
should be created,[10] and thus electron-rich phosphine ligands
were initially chosen; 2) To ensure the olefin isomerization and
hydrazone transformation to occur simultaneously, more flexible
coordinating sites should be provided, which implies the
importance of the ratio of metals and ligands in the catalytic
process; and 3) Base is a necessary component for the
hydrazone chemistry, and thus a suitable base should also be
chosen.
Redox allylic isomerization is
a unique transformation in
organometallic chemistry, and has been well studied since the
middle of the 20th century.[6] The advantage of this transformation
lies in its ability to translocate a non-polar C=C double bond to a polar
C=X (X =O, N, etc) double bond within a molecule without the
assistance of extra oxidant or reductant. Correspondingly, cascade
reactions using an olefin isomerization strategy such as remote
functionalization enable a host of unique transformations to take
[a]
[b]
C.-C. Li, Dr. J. Kan, Z. Qiu, J. Li, Dr. L. Lv and Prof. Dr. C.-J. Li
Department of Chemistry
McGill University
801 Sherbrook West, Montreal, QC, Canada. H3A 0B8
E-mail: cj.li@mail.mcgill.ca
State Key Laboratory of Structural Chemistry,
Fujian Institute of Research on the Structure of Matter,
Chinese Academy of Sciences,
Yangqiao West Road 155, Fuzhou, Fujian 350002 (China).
1
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10.1002/anie.201915218
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thermodynamic and kinetic points of view, lowering the
temperature might reduce the formation of these byproducts. To
our delight, decreasing the temperature to 40 oC indeed increased
the yield (77%) (scheme 2, entry 13). Additionally, another
bidentate phosphine ligand, bis-(dicyclohexylphosphino)-
ferrocene, which shares a similar bite angle but bears richer
electron density, worked also slightly better at 40 oC (scheme 2,
entry 14).[13]
A broad scope of allyl alcohols was then evaluated (scheme 3).
Alkyl
substituted
allylic
alcohols
underwent
the
isomerization/addition process in moderate to high yields,
including the ones with substituents on the β-position (3aa-3ae)
and γ-position (3af-3ah). The configuration of the double bond
has little influence on the reaction process, which gives the
desired product in similar yields (3ab). By replacing with bulkier
or longer chain substituents, the yield was slightly reduced (3ad-
3ae). Aryl (3ai-3al) and heteroaryl (3ak-3al) substituted allylic
alcohols could also be transformed to the final products smoothly,
albeit with slightly lower yields. Apart from these simple and non-
functional group-containing structures, those with reactive
functional groups also proceeded smoothly. For instance, with
substrates bearing multiple double bonds, only the double bond
closest to -OH is reactive and prone to isomerization/addition
while the further ones remain unchanged (3am). Besides, some
oxygen-containing compounds also showed high reactivity (3an).
More importantly, this method can tolerate comparatively
sensitive functional groups such as active protons (3ao) and
halogens (3aw). As one of the biggest problems of the classic
carbanion chemistry is its intolerance of active proton, the
success of the multi-OH substrate further sheds light on the
advantages of umpolung hydrazones as alkyl carbanion
surrogates.
Scheme 2. Examination of Reaction Conditions: 1a (0.25 mmol), 2a (0.2
mmol), catalyst (3 mol %), ligand (3 mol %), base (1.1 equiv), solvent (0.2 mL)
under N2 atmosphere. See Supporting Information (SI) for details. 1H NMR yield
was determined using mesitylene as an internal standard. ‘Trace’ amount of
product was noted when the desired product was not clearly detected.
With the considerations above, we used 2-pentene-1-ol and
benzaldehyde hydrazone as the model substrates with
Ru(PPh3)4Cl2 as catalyst, K3PO4 as base, 2-Me-THF as solvent
o
and examined several electron-rich phosphine ligands at 80 C
(Table 1, entries 1-6). Unfortunately, no or trace amount of the
desired product was observed with some non-bulky or electron
poor bi-dentate and mono-dentate phosphine ligands. For our
propose, apart from electronic effect, the failure of these ligands
is due to the formation of M(P)4 type stable complex which blocks
the necessary free-coordinating site. To solve this problem, we
turned to bulkier electron-rich bidentate phosphine ligands with
larger bite angles, such as bis-(dicyclohexylphosphino)-butane
(dcypb), which would disfavor the formation of ML2 and provide
more free-coordinating site.[11] To our satisfaction, the desired
product was observed in moderate yield with dcypb (scheme 2,
entry 7). Another key factor for the success of this cascade
reaction is to synchronize the rates of the hydrazone
transformation and the olefin isomerization. As shown in our
previous work, the initiation of the hydrazone transformation
involves base. Generally, a stronger base is more favorable than
a weaker one.[3-4, 9a] As the olefin isomerization process is likely
the slower step, controlling the rate of the hydrazone
transformation might favor this reaction. The study of different
bases confirmed this hypothesis (scheme 2, entries 7-10).
Regarding the catalyst, a ruthenium triphenylphosphine complex
seemed to be the proper choice, among which Ru(PPh3)3Cl2
worked the best. Some other types of ruthenium precursors, such
as the Grubbs’ catalysts, could also give the desired products, but
with much lower efficiency (scheme 2, entry 7, entries 10-12). We
then analyzed the type of side products formed. Wolff-Kishner
reduction[12] (self-reduction of hydrazones) and alkene formation
(from the dehydrative condensation of hydrazone and allylic
alcohol) turned out to be two main side reactions. From both a
Secondary allylic alcohols were then examined to expand the
scope of this process. Initial testing of secondary allylic alcohols
under the standard conditions gave us a very poor and
disappointing result with only trace amounts of the desired
product being observed. However, the isomerization intermediate
(ketone) was observed in a significant amount while the
hydrazone counterpart was completely consumed, mainly to form
the Wolff-Kishner reduction product. This result suggests that for
secondary allylic alcohols, both the isomerization and the
nucleophilic addition process of hydrazone might be much slower
than for primary allylic alcohols. As a result, the Wolff-Kishner
reduction was faster than the isomerization/addition process.
Consequently, we increased both the hydrazone substrate to 4
equiv and the temperature in order to: 1) maintain a high
concentration of hydrazone to accelerate the hydrazone addition
even towards the end of the reaction; and 2) shorten the time to
minimize the Wolff-Kishner reduction for the hydrazone.
Fortunately, with all these efforts, a moderate to high yield of the
desired product was realized for various secondary allylic
alcohols (3ap-3at, 3ax). It is noteworthy that the substrate with a
sensitive ester group can still give the desired product in moderate
yield (3ax). However, the one with nitro group would not generate
the desired product (3ay). To illustrate its potentials in synthetic
applications, we then studied the reaction on selected complex
molecules. Thanks to the broad functional group tolerance,
several types of allylic alcohol-bearing complex structures,
2
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10.1002/anie.201915218
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including steroids (3au) and protected sugars (3av), could also
undergo this reaction. These results showed a promising
application of this reaction in late-stage functionalizations.
heterocyclic substrates, can also proceed by increasing the
equivalents of hydrazone substrate (3ja).
Scheme 4. Further optimization of hydrazone scope under PCP-Ru system:
General reaction conditions A: 1a (0.3 mmol), 2a (0.2 mmol), catalyst (2.5
mol %), ligand (5 mol %), base (1.1 equiv), solvent (0.3 mL) under N2
atmosphere. See SI for details. Yield of isolated product was reported otherwise
noted. [a] The ratio of major product A and minor product B after initial
separation by column chromatography without further work up. See SI for
details; [b] The ratio of major product A and minor product B after further work
up with Pd/C and H2 gas. See SI for details; [c] Those products are volatile. The
NMR yield was determined with mesitylene as internal standard.
To further extend the nucleophile scope to aliphatic ones, being
unreactive possibly due to the lack of stabilization of certain
intermediate by aromatic ring under the original reaction
conditions, we turned to select some special ligand due to its vital
role in this transformation. Both allylic isomerization and
nucleophilic addition of hydrazones require electron rich ligands.
As a result, carbene-type ligand was considered, since it showed
special reactivity on aliphatic aldehyde hydrazones in our
previous studies.[4e] Furthermore, for aliphatic aldehyde
hydrazone reaction, alkene product (olefination) is more favored
than the corresponding alcohol product (1,2-addition) owing to the
possibility of forming ruthenium-oxide intermediate. Thus,
restricting the empty site of active ruthenium-complex species will
disfavor the formation of ruthenium oxide and favor the 1,2-
addition. Taking all these into consideration, we replaced dcypf
with a PCP-type pincer ligand (PCP-1) under the standard
conditions and performed the reaction at room temperature.
Under this protocol, various aliphatic aldehyde hydrazones were
reacted with 1-phenyl-2-propene-1-ol (2p), and moderate to high
yield of the desired products were obtained (3kp-3qp).
Sometimes, a small amount of Shapiro-type vinylation product
due to the active α-position of aliphatic hydrazones was formed,
which can be converted to the product readily by treating the
crude mixture with Pd/C and H2 gas under ambient temperature
without further purification (scheme 4).
Scheme 3. Substrate Scope of Allyl Alcohols and Hydrazones: General
reaction conditions A: 1a (0.25 mmol), 2a (0.2 mmol), catalyst (3 mol %), ligand
(3 mol %), base (1.1 equiv), solvent (0.2 mL) under N2 atmosphere under 40 oC.
General reaction conditions B: 1a (0.8 mmol), 2a (0.2 mmol), catalyst (3 mol %),
ligand (3 mol %), base (1.1 equiv), solvent (0.2 mL) under N2 atmosphere under
70 oC. See SI for details. Yield of isolated product was reported otherwise
noted.*catalyst (5 mol %) and ligand (5 mol %) was used. **This product is
volatile, and the yield of this product was determined by 1HNMR with mesitylene
as standard (this reaction requires 0.375 equiv 1a).
Apart from allylic alcohols, the scope of nucleophiles was also
studied. Aromatic aldehyde hydrazones including some
heterocycles were the first series of candidates being tested.
Among these substrates, having substituents at the ortho-position
to some extent lowered the reactivity due to steric effect. Thus,
with a small fluoro substituent, the reaction gave the desired
product in slightly higher yield (3ba). All meta-substituted
benzaldehyde hydrazones tested can tolerate this reaction
regardless of the electronic nature of the substituent (3ca-3ea).
With para-substituted aldehyde hydrazones, most of the
substrates also gave good results (3fa-3ga, 3ia). In addition to
substituted benzaldehyde hydrazones, hydrazones bearing other
aromatic rings could also act as proper substrates. Notably,
3
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10.1002/anie.201915218
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experiment (Eq. 5), strongly suggests β-hydride elimination / 1,4
hydride insertion for the isomerization step.
Scheme 5. Reactivity with remote-unsaturated alcohols: General reaction
conditions: 1a (0.8 mmol), 2a (0.2 mmol), catalyst (5 mol %), ligand (5 mol %),
base (1.1 equiv), solvent (0.2 mL) under N2 atmosphere. Yield of isolated
product was reported.
Scheme 6. Comparison of efficiency of relay reactions and the
corresponding separate reactions
After the successful exploration of allyl alcohols, we tuned our
attention to alcohols bearing olefins at a longer range (scheme 5).
As ‘chain-walking’ is a powerful strategy to realize remote
functionalization, we tested the possibility of longer chain olefinic
alcohols to undergo this synergistic relay reaction. We used 4-
pentene-2-ol as a testing substrate for homoallylic-type alcohols.
Delightfully, under the standard reaction conditions with 5 mol %
catalyst at 80 oC. the relay chain-walking and nucleophilic addition
proceeded efficiently (6aa). Such an efficiency could also be
observed with other substituted homoallylic alcohols (6ab) and
even longer-chain unsaturated alcohols (6ac).
To verify the synergistic enhancement nature of the cascade
reaction, as is shown in Scheme 4, we performed the
isomerization and nucleophilic addition of hydrazone
independently. The results clearly showed that neither of them
could happen efficiently under the standard conditions. The
inefficiency of 1,2-addition is likely due to several side reactions
of aldehydes such as azine condensation and aldol condensation
while the inefficiency of allylic isomerization lies in its huge energy
barrier. However, in the cascade reaction, the aldehyde
(electrophile) was generated in-situ via the relay of allylic alcohol
isomerization so that low concentration of aldehyde would largely
inhibit the side reactions. Moreover, as the two catalytic cycles
share the same catalytic system, the ruthenium aldehyde adduct
would directly go through the next C-C formation cycle. On the
other hand, the quick consumption of aldehyde intermediate to
form C-C bond would accelerate the allylic alcohol isomerization.
In order to gain a better understanding of the reaction, several
mechanistic experiments were conducted (Scheme 5). First,
when secondary allylic alcohols were reacted with 1.25 equiv of
hydrazones, we obtained both ketones and 1,2 carbonyl addition
products, indicating carbonyl intermediate formation and
supporting the proposed isomerization/nucleophilic addition
process (Scheme 5, Eq. 4). Then, the absence of either olefin
isomerization or C-C bond formation product from methyl-
protected allylic alcohols is consistent with the hypothesis that the
formation of reactive carbonyl intermediate being the driving force
of the isomerization step (Eq. 5). Finally, the isotopic labelling
experiment with α-deuterated allylic alcohol showed nearly
quantitative 1,3-deuteride shift (Eq. 6). This result, together with
carbonyl capture experiment (Eq. 4) and alcohol protection
Scheme 7. Mechanistic study of relay allyl isomerization/carbanion
addition
Based on the experimental data and analysis above, a tentative
mechanism for the reaction is proposed involving a ruthenium-
catalyzed olefin isomerization cycle and hydrazone addition cycle
(Scheme 8). For the isomerization, the reaction likely proceeds
via
a β-H elimination-hydride insertion according to the
corresponding experiments (Scheme 5) and previous
literatures.[6c, 14] The ruthenium complex A coordinates with allyl
alcohol to form complex B. Then, a β-hydride elimination occurs
to generate a ruthenium hydride complex C. At this stage, the so-
formed Ru-H undergoes
a 1,4-hydride insertion to the
unsaturated carbonyl to complete the olefin isomerization and
generate complex D. With the formation of D, hydrazone addition
occurs via a 6-membered ring transition state as we reported
before to give the desired product.
In conclusion, a relay of allyl alcohols isomerization and Grignard-
type nucleophilic addition of 'umpolung’ hydrazone was
developed by utilizing a Ru(II) catalytic system. This reaction
allows the chemoselective redox isomerization process to occur
with nucleophilic addition of ‘carbanion’ in one-pot, and can
tolerate various functional groups (e.g. -OH, -Halo, etc). At the
same time, this synergistic ‘relay’ of reactivity makes two originally
4
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Scheme 8. Proposed mechanism for relay nucleophilic addition of
hydrazones
Acknowledgements
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The authors acknowledge the Canada Research Chair
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Chemistry and Catalysis, NSERC, and McGill University for
support of our research. J. K. thanks China Scholarship Council
for a visiting scholarship.
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Keywords: relay • alkylation • allylic alcohol • ruthenium •
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10.1002/anie.201915218
Angewandte Chemie International Edition
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A redox-neutral α-alkylation of olefinic alcohol was realized by synergistic relay of isomerization of olefinic alcohol and nucleophilic
addition of hydrazone with carbonyls. This relay takes advantage of mutual influence of two inefficient reactions to let the desired
product be generated in a more efficient way than stepwise generation. A broad scope of substrates including steroids and protected
sugars derivatives can efficiently suit this reaction.
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