Umpolung of Carbonyl Groups as Alkyl Organometallic Reagent Surrogates for Palladium-Catalyzed Allylic Alkylation

Article abstract of DOI:10.1002/anie.201809112

Palladium-catalyzed allylic alkylation of nonstabilized carbon nucleophiles is difficult and remains a major challenge. Reported here is a highly chemo- and regioselective direct palladium-catalyzed C-allylation of hydrazones, generated from carbonyls, as a source of umpolung unstabilized alkyl carbanions and surrogates of alkyl organometallic reagents. Contrary to classical allylation techniques, this umpolung reaction utilizes hydrazones prepared not only from aryl aldehydes but also from alkyl aldehydes and ketones as renewable feedstocks. This strategy complements the palladium-catalyzed coupling of unstabilized nucleophiles with allylic electrophiles by providing an efficient and selective catalytic alternative to the traditional use of highly reactive alkyl organometallic reagents.

Full text of DOI:10.1002/anie.201809112

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Accepted Article
Title: Umpolung Carbonyl Groups as Alkyl Organometallic Reagent
Surrogates for Palladium Catalyzed Allylic Alkylation
Authors: Dianhu Zhu, Leiyang Lv, Chen-Chen Li, Sosthene Ung, Jian
Gao, and Chao-Jun Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809112
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10.1002/anie.201809112
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Umpolung of Carbonyl Groups as Alkyl Organometallic Reagent
Surrogates for Palladium-Catalyzed Allylic Alkylation
Dianhu Zhu, +[a] Leiyang Lv, +[a] Chen-Chen Li, [a] Sosthene Ung, [a] Jian Gao [a] and Chao-Jun Li*[a]
Carreira and others19 employed substituted hydrazones as formyl anion
Abstract: Palladium catalyzed allylic alkylation of non-stabilized carbon
equivalents or stabilized alkyl carbanion equivalents (α-carbanions of
carbonyl compounds) for allylic alkylation. However, the scope of both
reactions was limited to specific substrates generated from
formaldehyde or α-carbonyl aldehydes. Besides, these anion equivalents
nucleophiles is difficult and still remains a major challenge. We report a
direct palladium-catalyzed highly chemo- and regioselective C-allylation of
hydrazones generated from carbonyls as a source of umpolung unstabilized
alkyl carbanions and surrogates of alkyl organometallic reagents. Contrary
were relatively stable due to the presence of α-substituted imine or
to classical allylation techniques, this umpolung reaction utilizes hydrazones
prepared not only from aryl aldehydes but also from alkyl aldehydes and
ketones as renewable feedstocks. This strategy complements the palladium-
catalyzed coupling of unstabilized nucleophiles with allylic electrophiles by
providing an efficient and selective catalytic alternative to the traditional use
of highly reactive alkyl organometallic reagents.
carbonyls. A long-lasting challenge under such a context is if non-
substituted hydrazones can serve as the unstabilized alkyl carbanion
equivalents. In pursuit of this protocol, our group recently disclosed that
non-substituted hydrazones can serve as benzyl carbanion equivalents to
undergo the addition or cross coupling reactions under the ruthenium,
iron or nickel-catalyzed redox system.20 Nevertheless, many other
highly reactive alkyl organometallic reagent surrogates including alkyl
aldehydes or ketones were less efficient via these methods. Herein, we
report the umpolung of carbonyls21 as efficient alkyl organometallic
reagent surrogates for allylic alkylations via hydrazones intermediate
(Scheme 1B). Such a strategy involves prevalent carbonyls (aryl or alkyl
aldehydes and ketones) as renewable chemical feedstocks, and provides
a catalytic alternative to the traditional use of alkyl organometallic
reagents.
The Tsuji-Trost reaction has been one of the most important
achievements in modern synthetic chemistry by serving as a versatile
and powerful synthetic tool for the formation of C-C bonds with a wide
range of applications for the synthesis of biologically active molecules.1-
3
There has been a recent increase in the use of newly stabilized
nucleophiles4-5 in order to facilitate and extend the synthetic utility of
this reaction. Despite the success of those allylation methods, the use of
non-stabilized nucleophiles in palladium-catalyzed allylation is still
extremely limited.6 Traditional allylations of non-stabilized carbon
nucleophiles typically involve alkyl organometallic reagents (Scheme
1A). The introduction of the Grignard reagents as cross-coupling
partners with allylic substrates represented a major step forward,
enabling facile access to a diverse range of alkenes as shown by
Swierczewski7 and Goering.8 Later, Hoveyda,9 Feringa,10 and others.1
Since then, other alkyl organometallic reagents (such as organozinc,6a-
A. Previous work: allylations of non-stabilized carbon nucleophiles
(alkyl organometallic reagents or alkyl boron reagents)
X
+
R
[M]
R
[M]: [Mg], [Zn], [Li], [Al], [Zr], [B], etc.
X = Br, Cl, OAc, OCO2Me, OP(O)(OEt)2, OH, etc.
alkyl organometallic reagents:
alkyl boron reagents:
Highly basic and nucleophilic
Not readily available, difficult to prepare
Poor chemoselectivity and low functional group compatibility
B. This work: carbonyls as alkyl organometallic reagent surrogates for allylic alkylations
6b,12
lithium,13 aluminium14 or zirconium15 reagents) and alkyl boron
reagents6d-6e have also been used for allylations. Although these alkyl
organometallic reagents have numerous industrial applications, there are
still substantial drawbacks associated with them. The preparation of
these air/moisture sensitive organometallic reagents requires petroleum-
derived organic halides, which can be particularly problematic for large-
scale synthesis. Moreover, the high basicity and nucleophilicity of alkyl
organometallic reagents generally result in poor chemoselectivity and
low functional group compatibility, inhibiting their synthetic
applications. In addition, although alkyl boron reagents can achieve
valuable chemoselectivities and have excellent functional group
compatibility, they have been largely hampered by their challenging
preparation. Consequently, the development of new alternatives for
alkyl organometallic reagents in the allylation of alkyl carbanions is
desired.
NH2
O
OAc
-N2
N
R'
N2H4·H2
O
Selective C-Allylation (C:N > 98:1)
R
R'
R
R'
R
carbonyls
NH2
R'
N
O
unstabilized alkyl carbanion equivalents
alkyl organometallic reagent surrogates
R
R
R'
R
R'
Carbonyls not only from aryl aldehydes, but also from alkyl aldehydes or ketones
Broad substrate scope and good functional group compatibility
High yields, gram scale synthesis
Highly chemo- and regioselective allylation
A catalytic alternative to the traditional use of alkyl organometallic reagents
Scheme 1. Allylations of Non-Stabilized Alkyl Carbanions.
In recent years, hydrazones16 can not only serve as nitrogen
nucleophiles17 but also play the role of ligands18 in allylic alkylations.
Furthermore, the reversal of electronic characteristics from simple
hydrazones may facilitate the development of carbanion chemistry and
create new opportunities for chemical transformations. Recently,
We initially began our studies by evaluating the coupling of
benzaldehyde hydrazone 1ah with allyl acetates (see the Supporting
Information for more details). The base-free reaction did not lead to any
C-allylated product (4ah, but-3-en-1-ylbenzene), while 18% yield of N-
allylated product (5, N-allyl benzaldehyde hydrazone) and 80% yield of
N, N-diallylated product (6, N, N-diallyl benzaldehyde hydrazone) were
observed (entry 2), indicating that hydrazone 1ah is prone to N-
allylation in the absence of the base. Besides, no C-allylated or N-
allylated products were detected in the absence of catalyst/ligand,
suggesting that catalyst is indispensable for the allylation of hydrazones
in this system (entry 3). We postulated that the combination of both the
catalyst and the base mediates the deprotonation of hydrazones and
directs the reaction of 2,3-diazaallyl anions 3 with π-allylpalladium to
afford the C-allylated product 4ah, N-allylated product 5 and N, N-
diallylated product 6. In such a context, the key challenge is to control
the chemo- and regioselectivity to afford the C-allylation.
[a] Dr. D. Zhu,[+] Dr. L. Lv,[+] C.-C. Li, S. Ung, Dr. J. Gao,
Prof. Dr. C.-J. Li
Department of Chemistry and FRQNT Center for Green
Chemistry and Catalysis, McGill University,
Montreal, QC, H3A 0B8, Canada
E-mail: cj.li@mcgill.ca
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://doi.org/10.1002/anie.201809112R1.
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10.1002/anie.201809112
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Table 2. Scope of Carbonylsa,b
Table 1. Impact of Different Parameters on the Allylation of Hydrazonesa
[a] Reaction conditions: hydrazones (0.75 mmol, 1.25 M generated in situ from
aldehydes or ketones and hydrazine), allyl acetate (0.6 mmol), [Pd(allyl)Cl]2 (5 mol%),
Ptol3 (20 mol%), tBuOLi (2.0 equiv) in 3.0 mL THF at 45 oC for 24 h. [b] Isolated yield.
[c] hydrazones (0.75 mmol), allyl acetate (0.6 mmol), [Pd(allyl)Cl]2 (5 mol%), IPr·HCl
(10 mol%), tBuOLi (2.2 equiv) in 3.0 mL THF at 45 oC for 24 h.
[a] Standard conditions: hydrazones (0.25 mmol, 1.25 M generated in situ from
benzaldehyde and hydrazine), allyl acetate (0.20 mmol), [Pd(allyl)Cl]2 (5 mol%), Ptol3
(20 mol%), tBuOLi (2.0 equiv) in 1.0 mL THF at 45 oC for 24 h.
t
Surprisingly, reaction in the presence of 2.0 equiv of BuOLi using a
With the optimized conditions in hand, the substrate scope of
allylation of hydrazones with allyl acetate was investigated in Table 2.
In general, hydrazones bearing both electron-withdrawing and electron-
donating substituted groups gave good to excellent yields, with the
former giving higher yields. The reaction showed good functional group
compatibility as well, as many functional groups such as trifluoromethyl,
fluoro, chloro, cyano, methyl, ethyl, phenyl, methoxy and alkoxy
substituents were all tolerated to give the corresponding products in high
yields (4aa-4ac, 4af, 4ah-4ay). Some groups (such as bromo and ester
substituents), which were not compatible with the traditional allylations
of alkyl organometallic reagents, also worked well with our conditions
(4ad-4ae). However, no desired product was observed for hydrazones
bearing a strongly oxidizing nitro group (4ag). In addition to the good
functional-group compatibility, para-, meta-, ortho-, or multi-
substituted aromatic hydrazones were all tolerated in this system (4aa-
4ay). Moreover, hydrazones prepared from polycyclic aromatic
aldehydes such as 1-naphthaldehyde, 2-naphthaldehyde or
phenanthrene-9-carbaldehyde delivered high yields of C-allylated
products (4az-4bb). Hydrazones generated from heterocyclic aldehydes
were then investigated under the standard conditions. Hydrazones
prepared from benzo[b]thiophene-3-carbaldehyde, picolinaldehyde, or
isonicotinaldehyde were all compatible with this system, affording the
allylic product in 66%-75% yields (4bc-4be). To emphasize the
synthetic potential of our methodology, a gram scale allylation of
hydrazones was performed, giving products 4ac and 4as in 89% (1.18 g)
and 94% yields (1.13 g), respectively.
[Pd(allyl)Cl]2/Ptol3 (tri-p-tolylphosphine) catalytic system in THF
(tetrahydrofuran) at 45 °C for 24 h provided the C-allylated product 4ah
in quantitative yield (98%), along with a high selectivity over the N-
allylated product (4ah:5 = 98:1) (entry 1). Other palladium catalysts
including Pd2(dba)3 (dba: dibenzylideneacetone), PdCl2(PPh3)2 gave
moderate yields of 4ah and a lower selectivity of allylic products (entry
4). Parallel experiments showed that with PPh3 the reaction proceeded to
afford 90% yield of C-allylated product 4ah with a 90:1 selectivity over
N-allylated product (entry 5); while reactions delivered unsatisfactory
yields of 4ah when dmpe, dppe, trismesitylphosphine, tri(p-
methoxyphenyl) phosphine, dppf, BINAP and Xantphos were used as
ligands (entry 6). It is also interesting to note that the carbene ligand
SIPr·HCl could deliver similar results to Ptol3 (entry 7). The choice of
base was found to be crucial to the denitrogenation as well as the chemo-
and regioselectivity: weak bases cannot trigger denitrogenation
explaining why N-allylation or N, N-diallylation were the only products,
while relatively strong bases could deliver satisfactory yields of C-
allylated product 4ah with a high selectivity over N-allylated product.
t
While quantitative yield of 4ah was observed with BuOLi (entry 1),
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), K3PO4 or CsF could not
give any of this product. It should be noted that 94%-95% yield of N, N-
diallylated products 6 was formed in the presence of K3PO4 or
K3PO4/CsF (entry 8). Other lithium salts such as Li2CO3 and LiOH, were
also tested and no C-allylated product was detected, albeit with 30%-
38% yield of N-allylated products and 36-60% yield of N, N-diallylated
products. Moreover,
a
few green solvents, such as 2-
To expand the scope of this methodology, we also studied the
palladium-catalyzed allylation of hydrazones originated from alkyl
aldehydes and ketones. Alkyl hydrazones generated from 2-
phenylacetaldehyde and 3-phenylpropanal gave the desired products in
78%-80% yields using Ptol3 as the ligand (4bf-4bg). However, this
methyltetrahydrofuran and cyclopentyl methyl ether, and other regular
ether solvents such as 1,4-dioxane and diglyme, were also effective and
delivered 37%-86% yields of C-allylated products (entry 9). Finally, the
reaction could be performed at room temperature, with only a slightly
decreased yield for the expected product (90%) (entry 10).
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system was unsuccessful with other alkyl aldehydes or ketones. After a
quick screening of the reaction conditions, hydrazones prepared from
alkyl aldehydes and ketones with allyl acetates occurred smoothly at
45 °C in THF, affording selectively C-allylated products in high to
palladium-catalyzed allylation of hydrazones is proposed in Scheme 2.
Initially, allyl acetates 2 and Pd (0)/phosphine complex, derived from
[Pd(allyl)Cl]2 and tri-p-tolylphosphine, generate the π-allylpalladium
complex A via oxidative addition. Then, after deprotonation in the
presence of the base (tBuOLi), hydrazones 1 ligates to complex A
forming 2,3-diazaallyl anions of benzaldehyde hydrazone (complex B).
Subsequently, 2,3-diazaallyl anions attack the π-allylpalladium complex
to afford the corresponding allylic products (C-allylated product 4 or N-
allylated product 5 or 6) through reductive elimination in the presence
of base and regenerates the Pd (0)/phosphine. High yields of 4 and high
chemo- and regioselectivity towards C-allylated products 4 can only be
obtained in the presence of 2.0 equiv of tBuOLi.
quantitative
yield
when
IPr·HCl
(1,3-bis(2,6-
diisopropylphenyl)imidazolium chloride) was used as the ligand.
Cyclohexanecarboxaldehyde hydrazone or 2-ethylbutanal hydrazone
could afford 84%-92% yield of the desired products (4bh-4bi).
Hydrazones originated from acetophenone and its derivatives also
delivered high yields of the corresponding products (4bj, 4bm-4bn).
Besides, propiophenone hydrazone and 1-phenylbutan-1-one hydrazone
were also effective in this system (4bk-4bl). In addition to aryl ketones,
hydrazones elaborated from alkyl ketones including heptan-3-one,
undecan-6-one, 5-methylhex-4-en-2-one and cyclohexanone, could
successfully give the C-allylated products in 84%-96% yields with a
high selectivity (4bo-4br). Other hydrazones generated from ketones
with ring strain such as adamantan-2-one, 2,3-dihydro-1H-inden-1-one
or 3,4-dihydronaphthalen-1(2H)-one reacted efficiently to give the
desired allylic products in >95% yields (4bs-4bu).
Table 3. Scope of Allylic Acetatesa,b
Scheme 2. A Tentative Mechanism.
Finally, preliminary asymmetric allylation studies were carried out.
When the chiral carbene ligand generated from a sulfonate-bearing
imidazolinium salt with a 3,5-diaryl-substituted phenyl moiety (L*) was
used, 4bz was obtained in 45% yield with 78:22 enantiomeric ratio (e.r.)
at room temperature (Scheme 3). The preliminary investigations thus
show a potential for enantioselective allylation of hydrazones.
[a] Reaction conditions: hydrazones (0.75 mmol), allyl acetate (0.6 mmol),
t
[Pd(allyl)Cl]2 (5 mol%), Ptol3 (20 mol%), BuOLi (2.0 equiv) in 3.0 mL THF at 45 oC
for 24 h. [b] Isolated yield. [c] hydrazones (0.75 mmol), allyl acetate (0.6 mmol),
[Pd(allyl)Cl]2 (5 mol%), SIPr·HCl (10 mol%), tBuOLi (2.2 equiv) in 3.0 mL THF at 45
oC for 24 h.
Subsequently, the allyl acetate substrate scope was investigated in
Table 3. The transformations delivered the branched allylic products
with excellent yields (4bv-4cd) and high B/L ratio (branched : linear up
to > 20:1) (4bw-4by), likely due to the steric effect associated with the
3,3’-elimination in the regiochemistry-determining step analogous to
Morken’s work6d-6e (see the Supporting Information for more details).
Besides, coupling of hydrazones with 2-cyclohexenyl acetate could also
deliver the corresponding products in 72%-81% yields (4cb-4cd).
Scheme 3. Preliminary Investigations on Asymmetric Allylation of Hydrazones
In summary, we have developed a direct highly chemo- and
regioselective C-allylation of non-substituted hydrazones enabled by
palladium catalyst. Highlighted features of this methodology are: (a)
effective for a wide variety of hydrazones originated not only from aryl
aldehydes, but also alkyl aldehydes and ketones, (b) umpolung of
carbonyls as highly reactive alkyl organometallic reagent surrogates for
allylic alkylation, (c) the use of only a catalytic amount of both metal
and ligand, (d) the high yields and ease to scale up, (e) the compatibility
with a wide range of functional groups while maintaining a high chemo-
and regioselectivity of C-allylation. With all those characteristics, this
umpolung reaction is expected to complement the palladium-catalyzed
methods using stabilized nucleophiles and it provides with a novel
catalytic alternative to the traditional use of highly reactive alkyl
organometallic reagents. It is very likely that more strategies using
hydrazones as unstabilized alkyl carbanion equivalents for other cross-
coupling reactions will emerge in the future.
The excellent functional group tolerance highlights the great potential
of this reaction for the transformation of natural aldehydes and their
derivatives (see the Supporting Information for more details). Under the
standard conditions, hydrazones originated from 4-hydroxyaldehyde
derivatives (methyl, benzyl or allyl 4-hydroxyaldehyde) gave C-
allylated products in 84%, 86% and 84% yields, respectively (4ce-4cg).
Besides, Veratraldehyde (methyl Vanillin) could efficiently afford the
C-allylated product (4-(but-3-en-1-yl)-1,2-dimethoxybenzene) in high
yield (4ch). Likewise, the conjugation of azaallyl anions with an olefin
was also tolerated and gave the C-allylated product. Allylation of the
hydrazone elaborated from cinnamaldehyde afforded a 68% yield with
a mixture of branched and linear products (B:L (4ci:4ci’) = 1.7:1).
Based on the mechanistic studies (see the Supporting Information for
more details) and previous literatures,22 a tentative mechanism of the
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10.1002/anie.201809112
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The authors acknowledge the Canada Research Chair Foundation, the
CFI, FQRNT Center for Green Chemistry and Catalysis, NSERC, and
McGill University for the support of our research. The authors also thank
Shanghai Institute of Organic Chemistry (SIOC) for supporting a
postdoctoral fellowship to D. Zhu.
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Keywords: carbonyl • hydrazone • alkyl organometallic reagent •
allylic alklation • palladium catalysis
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10.1002/anie.201809112
Angewandte Chemie International Edition
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Title
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COMMUNICATION
NH2
Dianhu Zhu, Leiyang Lv, Chen-Chen Li,
Sosthene Ung, Jian Gao and Chao-Jun Li*
N
O
unstabilized alkyl carbanion equivalents
alkyl organometallic reagent surrogates
R
R'
R
R'
R
R'
OAc
Page No. – Page No.
NH2
R'
O
N
R'
N2H4·H2O
cat.[Pd]/L
-N2
Selective C-Allylation (C:N > 98:1)
R
R'
carbonyls
(aryl or alkyl aldehydes and ketones)
R
R
Umpolung of Carbonyl Groups as Alkyl
Organometallic Reagent Surrogates for
Palladium-Catalyzed Allylic Alkylation
hydrazones
Umpolung of Carbonyls in Allylic Alklation: A direct palladium-catalyzed highly chemo-
and regioselective C-allylation of hydrazones was developed using umpolung carbonyls as a
source of unstabilized alkyl carbanions and surrogates of highly reactive alkyl organometallic
reagents, with a catalytic amount of both metal and ligand, high yields, ease to scale up, wide
substrate scopes and great functional group compatibility.
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