Switch in Selectivity for Formal Hydroalkylation of 1,3-Dienes and Enynes with Simple Hydrazones

Article abstract of DOI:10.1002/anie.201915875

Controlling reaction selectivity is a permanent pursuit for chemists. Regioselective catalysis, which exploits and/or overcomes innate steric and electronic bias to deliver diverse regio-enriched products from the same starting materials, represents a powerful tool for divergent synthesis. Recently, the 1,2-Markovnikov hydroalkylation of 1,3-dienes with simple hydrazones was reported to generate branched allylic compounds when a nickel catalyst was used. As part of the effort, shown here is that a complete switch of Markovnikov to anti-Markovnikov addition is obtained by changing to a ruthenium catalyst, thus providing direct and efficient access to homoallylic products exclusively. Isotopic substitution experiments indicate that no reversible hydro-metallation across the metal-π-allyl system occurred under ruthenium catalysis. Moreover, this protocol is applicable to the regiospecific hydroalkylation of the distal C=C bond of 1,3-enynes.

Full text of DOI:10.1002/anie.201915875

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Complete Switch of Directional Selectivity in the Formal
Hydroalkylation of 1,3-Dienes and Enynes with Simple
Hydrazones
Authors: Leiyang Lv, Lin Yu, Zihang Qiu, and Chao-Jun Li
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content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915875
Angew. Chem. 10.1002/ange.201915875
Link to VoR: http://dx.doi.org/10.1002/anie.201915875
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10.1002/anie.201915875
Angewandte Chemie International Edition
RESEARCH ARTICLE
Switch in Selectivity for the Formal Hydroalkylation of 1,3-Dienes and
Enynes with Simple Hydrazones
Leiyang Lv,‡[a] Lin Yu,‡[a] Zihang Qiu[a] and Chao-Jun Li*[a]
Dedication ((optional))
Selectivity challenge in
1,3-diene
(a)
hydrofunctionalization
Nu
Abstract: Controlling reaction selectivity is a permanent pursuit for chemists.
In particular, regio-selective catalysis, which exploits and/or overcomes
innate steric and electronic bias to deliver diverse regio-enriched products
from the same starting materials, represents a powerful tool for divergent
synthesis. Recently, our group reported the 1,2-Markovnikov
hydroalkylation of 1,3-dienes with simple hydrazones to generate branched
allylic compounds when a nickel catalyst was used. As part of the effort,
herein we show that a complete switch of Markovnikov to anti-Markovnikov
directionality is obtained by slightly changing to a ruthenium catalyst, thus
providing a direct and efficient access to the homoallylic products
exclusively. Isotopic substitution experiments indicate that no reversible
hydro-metallation across the metal-π-allyl system occurred under ruthenium
catalysis. Moreover, this protocol is also applicable to the regio-specific
hydro-alkylation of the distal C=C bond of 1,3-enynes.
H
1,2-terminal
3,4-internal
Nu
H
+
+
+
R1
R1
homoallylic
+
Nu
4
H
Nu
H
2
cat.
1
[M]
3
R1
R1
R1
H
Nu
Nu
H
1,4-conjugate
H
Nu
R1
R1
anti-Markovnikov
Markovnikov
work)
Selective
of
1,3-diene
1,2-terminal
(b)
(c)
hydroalkylation
(previous
R
NH2
N
R'
cat.
[Ni]
+
R1
H
branched
R1
R
R'
The design to switch the directional selectivity
Introduction
R'
H
R'
NH2
N
[Ru]
cat.
cat.
[Ru]
R
N
+
[Ni]
via Ni-H
N
R'
R1
R
[Ni]
Engineering reaction selectivity rationally and predictably remains a
formidable challenge to synthetic chemists.1 Catalyst-controlled
selective transformation represents a promising tool for divergent
synthesis.2 The power of using catalysis to attain exquisitely selective
transformations is elegantly exploited by Nature, which can convert the
identical starting materials into a variety of diversified products by
enzymes. Inspired by the extraordinary selectivity of biocatalysis,
several strategies have been devoted to gain an analogous level of regio-
enriched products over facile innate reactivity.3 Examples include (a)
installation of different protecting or directing groups4 to overcome the
inherent steric and electronic biased factors, (b) modification of reaction
parameters, such as solvent5, temperature6, additives7, etc. and (c) design
and manipulation of the catalyst system.8 As Trost has asserted,
engineering a catalyst that completely overrides inherent regio- or
chemoselectivity to give exclusively the desired product requires
creativity and insight.9 To this end, transition metal-catalyzed selective
transformations have gained preferred attention due to their versatility,
broad applicability, and especially predictability.10 The appropriate
combination of metal catalysts and clever selection of ligands serve as
an ideal platform for designing and developing selective catalysis,
coordination
R1
H
R1
R
six-membered ring
work)
formal
hydroalkylation (this
Switched selectivity in
NH2
1,3-diene
(d)
(enyne)
H
R'
cat.
N
[Ru]
+
R1
R1
linear
R
R
R'
Scheme
1.
Selectivity
challenge
in
the
transition-metal-catalyzed
hydrofunctionalization of 1,3-dienes and strategy to switch the 1,2-terminal directional
selectivity.
1,3-Dienes represents an exceptionally attractive platform for
selective functionalization, because labile coordination and insertion
modes are accessible in the presence of transition metal.12 In other words,
at least six different isomers can be potentially formed during the
addition of Nu-H addition across a terminal diene, and the selectivity of
the newly formed bonds depends on the Markovnikov or anti-
Markovnikov directionality with internal, terminal 1,2-addition or
conjugate 1,4-addition (Scheme 1a).13-16 We17 and Zhou’s lab18 recently
independently communicated an nickel-catalyzed 1,2-Markovnikov
hydroalkylation19 of 1,3-dienes with umpolung carbonyls to generate
branched allylic compounds (Scheme 1b). In these reactions, the nickel
hydride species is generated, which reacts with the diene to generate an
electrophilic nickel-π-allyl intermediate (hydride adds preferentially to
the less steric hindered terminal olefinic carbon) (Scheme 1c, left).
Based on the literature report20 and our previous work21, instead of
generating metal hydride species, the ruthenium catalyst22 favors the
coordination of hydrazone and unsaturated partner and assists the inner-
sphere rearrangement of coordinated complexes to form a stable six-
membered ring intermediate. Inspired by this, we hypothesized that if
[a]
Dr. L. Lv‡, L. Yu‡, Z. Qiu, Prof. C.-J. Li
Department of Chemistry and FRQNT Center for Green Chemistry and
Catalysis, 801 Sherbrooke Street West, McGill University,
Montreal, Quebec, H3A 0B8, Canada
E-mail: cj.li@mcgill.ca
‡These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the
document.
especially from the same simple starting materials.11
This article is protected by copyright. All rights reserved.

10.1002/anie.201915875
Angewandte Chemie International Edition
RESEARCH ARTICLE
5
6
7
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
dppe
tBuOLi
tBuOLi
tBuOLi
trace
trace
7
1,3-diene was used as the unsaturated partner, the readily formed six-
membered ring system might allow for the anti-Markovnikov addition
directionality (Scheme 1c, right). Namely, outer-sphere addition gave
the branched Markovnikov product whereas inner-sphere
carboruthenation gave the linear anti-Markovnikov product. Besides,
this conformation controlled strategy might also help to prevent the
undesired allylic isomerization of the remaining C=C bond. With this
design in mind, herein we wish to report that changing the metal catalyst
from nickel to ruthenium, a complete switch of a Markovnikov to anti-
Markovnikov directionality was obtained from the same simple starting
materials (hydrazones and 1,3-dienes), thus affording the homoallylic
products exclusively (Scheme 1d). Moreover, the ruthenium catalysis is
applicable to the regio-specific formal hydro-alkylation of the distal
C=C bond of 1,3-enynes.23 The studies on simple hydrazone chemistry
also contribute to a departure from pre-metalated reagents in metal-
catalyzed C-C bond formation.24
dppf
2,2′-bipyridyl
1,10-phen-
anthrolinlone
8
[Ru(p-cymene)Cl2]2
tBuOLi
trace
9
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(C6Me6)Cl2]2
Cp*Ru(cod)Cl
IMes•HCl
SIMes•HCl
IPr•HCl
SIPr•HCl
dmpe
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
K3PO4
KOH
26
10
11
12
13
14
15
16
17
18
19
20
21
22
trace
11
trace
85
dmpe
84
Ru(PPh3)4Cl2
dmpe
84
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
-
dmpe
47
dmpe
78
Results and Discussion
dmpe
tBuOK
DBU
trace
N.D.
N.D.
N.D.
N.D.
We started our study by evaluating the reaction between phenyl
hydrazone 2a (generated from benzaldehyde 1a and hydrazine, water
and solvent were removed before use without further purification) and
phenyl butadiene 3a in the presence of [Ru(p-cymene)Cl2]2, PMe3 and
tBuOLi in THF (tetrahydrofuran) at 80 oC for 12 h (Table 1).
Gratifyingly, the 1,2- and anti-Markovnikov addition product 3a was
formed in 23% yield exclusively (entry 1). Encouraged by this result and
given the vital role of ligands in transition-metal-catalyzed
transformations, we next interrogated a series of commercially available
ligands to improve the reaction efficiency. Notably, a 85% yield of the
desired product was obtained when bi-dentate and electron-rich
phosphine ligand dmpe [1,2-bis(dimethylphosphino)ethane] was used
(entry 4), while the other phosphine-, nitrogen-containing and/or NHC
ligands were found to be inferior for this transformation, leaving most
of the starting material 1,3-diene unreacted (entries 2-12). Further
investigation of several common ruthenium (II) catalysts showed that
comparative selectivity and yields could be achieved (entries 13-15).
Enquiry of bases revealed that tBuOLi gave the best results (entries 16-
19). The absence of reactivity with tBuOK was ascribed to the competing
Wolff–Kishner reduction of hydrazone under more basic conditions
(entry 18). As control experiments, no desired product was generated in
the absence of ruthenium catalyst, base or ligand (entries 20-22).
dmpe
dmpe
tBuOLi
tBuOLi
-
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
-
dmpe
R
P
PPh2
R
N
N
N
N
R
Cl
R
R
R
P
R
Fe
Cl
R
Ph2P
=
=
=
=
=
=
R
R
Me, dmpe IMes:
Ph,
2-mesityl)
SIMes:
6H3 SIPr:
)
2-mesityl)
(R
(R
(R
(R
-C
-C
IPr:
6H3
)
dppe
2,6-iPr2
2,6-iPr2
dppf
[a] Reaction conditions: phenyl butadiene 3a (0.2 mmol), phenyl
hydrazone 2a (0.6 mmol, generated from benzaldehyde and hydrazine),
[Ru(p-cymene)Cl2]2 (2.5 mol%), ligand (5 mol% for monodentate, 10
mol% for bidentate) and tBuOLi (0.4 mmol) in THF (0.3 mL) at 80 oC
for 12 h under N2 unless otherwise noted. [b] The yield of 4aa was
determined by 1H NMR using mesitylene as an internal standard
(isolated yield of 4aa in parenthesis). N. D. = not detected. DBU = 1,8-
diazabicyclo(5.4.0)undec-7-ene. Cp* = pentamethylcyclopentadiene.
With the optimized reaction conditions established, we first examined
the scope of the transformation with respect to the hydrazones. As shown
in Table 2, a series of aryl hydrazones bearing electron-donating and
electron-withdrawing substituents were amenable in this transformation,
providing the corresponding products 4ab-ap in moderate to good yields
(64-88%). Hydrazone derived from mesitaldehyde gave a lower yield
(4aq, 41%), indicating that the reaction efficiency was hampered by the
increased steric hindrance. Notably, substrates bearing ferrocene and
boronic ester underwent the reaction and afforded the desired products
4ar and 4as in 36% and 41% yields, respectively. Heterocyclic
hydrazones including furan, thiophene, pyridine and carbazole also
reacted smoothly (4av-ax) without any interference from the
coordinating hetero-atoms. Hydrazones derived from ketones and
aliphatic aldehydes were found to be a less effective substrate in this
protocol, owing to the rapid dimerization to form azines. To highlight
the practicability of this protocol, 3.0 mmol scale reaction was carried
out, giving the product 4ae in 76% yield (0.75 g). Subsequently, we
continued to explore the generality of this regioselective addition
Table 1. Optimization of the reaction conditions.a
4
2
3
1
Ph
3a
mol%)
-cymene)Cl
]
2 2 (2.5
p
[Ru(
NH2
O
N2H4 H2O
N
mol%)
ligand (5.0~10.0
tBuOLi
Ph
Ph
Ph
equiv)
(2.0
Ph
THF, 80 o 12 h
C,
1a
2a
4aa
entry catalyst
ligand
PMe3
PPh3
base
4aa (%)b
23
1
2
3
4
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
tBuOLi
tBuOLi
tBuOLi
tBuOLi
trace
PCy3
dmpe
trace
85 (81)
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10.1002/anie.201915875
Angewandte Chemie International Edition
RESEARCH ARTICLE
reaction towards 1,3-dienes under the standard reaction conditions. The
presence of an electron-withdrawing group on the aromatic moiety of
dienes appeared to be more beneficial than the presence of an electron-
donating group (4ba-bl). Dienes with polycyclic (hetero-) aromatic
substituents were also competent substrates, delivering the
corresponding products 4bj-bl in good to excellent yields (75-85%).
Buta-1,3-diene-1,1-diyldibenzene 3m was a suitable substrate in this
reaction, while substitution on other position were not accommodated.
Notably, this method could be readily extended to the functionalization
of pharmaceutically relevant α-Tocopherol derivative 3n.
to the alkene moiety were obtained, without any complication from the
alkyne part. The general applicability of this protocol was well
illustrated by the tolerance of an array of functional groups, such as
methyl, phenyl, methoxy, benzyloxy, trifluoromethoxy, methylthio,
N,N-dimethyl, trifluoromethyl, fluoride, chloride, bromide and
methylenedioxyl attached onto hydrazone (6aa-aaa, 49-99%). Various
hetero-aromatic hydrazones were evaluated and all worked efficiently,
giving the desired products (6aab-aak) in good yields. It is noteworthy
that hydrazones derived from aliphatic aldehydes and ketones could also
be used as suitable substrates, thus affording the desired products 6aal-
aaq in 21-94% yields.
Encouraged by these results, we speculated the possibility to extend
the method to the hydrofunctionalization of 1,3-enynes (Table 3). To our
delight, the regio-specific 1,2- and anti-Markovnikov addition activity
Table 2. Scope of hydrazones and 1,3-dienes.a
Ar
3
p
mol%)
]
2 2 (2.5
dmpe (5.0
-cymene)Cl
[Ru(
NH2
H
O
N2H4 H2O
N
mol%)
Ar
R
tBuOLi
(2.0
R
H
equiv)
R
THF, 80 o 12 h
C,
1
2
4
Scope of
(a)
hydrazones
OCF3
Me
Ph
F
OMe
OBn
b
4ab
4ag
4ac
4ad
4ai
4ae
4aj
4af
,
82%
82%
88%
81%
87%
83%
84%
80%
64%
,
,
,
,
,
(76%)
CF3
SMe
Cl
Br
Br
4ah
4ak
,
84%
,
,
,
OMe
OMe
Br
OMe
Cl
OMe
4al
4am
4an 74%
4ao 75%
4ap
78%
81%
85%
,
,
,
,
,
Me
S
O
B
Fe
O
Me
Me
4aq 41%
4ar
4as 41%
4at 77%
4au
4az
36%
76%
,
,
,
,
,
O
N
N
Et
4av
64%
,
4aw
4ax
81%
,
4ay
,
52%
10%c
23%c
,
,
Scope of
1,3-dienes
(b)
Me
Ph
MeO
F
Cl
4ba
4bb
4bg
4bc
4bd
4be
83%
,
78%
83%
84%
79%
62%
82%
,
,
,
,
,
Me
Cl
Cl
Cl
F3C
4bf
4bh
4bi
4bj 75%
,
80%
78%
82%
,
,
,
O
O
O
3
3
90%
85%
86%d
4bn
,
4bk
4bl
4bm
,
,
,
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10.1002/anie.201915875
Angewandte Chemie International Edition
RESEARCH ARTICLE
[a] Reaction conditions: 1,3-diene 3 (0.2 mmol), hydrazone 2 (0.6 mmol, generated from aldehyde and hydrazine), [Ru(p-cymene)Cl2]2 (2.5 mol%),
dmpe (5 mol%) and tBuOLi (0.4 mmol) in THF (0.3 mL) at 80 oC for 12 h under N2. Reported yields were the isolated ones unless otherwise noted.
1
[b] The yield in parenthesis was obtained in 3.0 mmol scale based on 1,3-diene. [c] The yield was determined by H NMR analysis of the crude
mixtures. [d] The reaction was performed on 0.1 mmol scale.
Table 3. Scope of hydrazones with 1,3-enynes.a
R2
5a
p
mol%)
]
2 2 (2.5
dmpe (5.0
-cymene)Cl
NH2
R1
[Ru(
O
N2H4 H2O
mol%)
N
tBuOLi
(2.0
R1 R2
1
equiv)
R1 R2
2
THF, 80 o 12 h
C,
6
Aromatic
(a)
hydrazones
Me
Ph
OMe
OBn
6aa
,
6ab
6ac
,
6ad
6ae
94%
,
99%
94%
96%
96%
,
,
Me
N
OCF3
SMe
Br
Cl
Me
6af,
6ag
6ah
6ai
6aj
95%
93%
91%
90%
88%
,
,
,
,
Me
X
OMe
O
B
CF3
O
=
=
=
X
X
X
6ao 89%
,
F,
6ak
,
6al
6am
6an
6ap
87%
,
89%
76%
85%
88%
Cl,
,
,
,
Br, 6aq 88%
,
Me
CF3
Cl
F
Cl
Cl
Me
Cl
6ar
6as
,
6at
6au
6av
92%
,
85%
87%
85%
82%
,
,
,
Me
OMe
OMe
OMe
O
O
Me
Me
OMe
OMe
6aw
6ax
,
6ay
,
6az
6aaa
95%
,
93%
80%
49%
94%
,
,
Hetero-aromatic
(b)
hydrazones
O
O
S
S
S
6aab
6aac
6aad
6aae
6aaf
84%
,
78%
81%
82%
92%
89%
,
,
,
,
Me
N
N
N
Fe
N
Et
6aag
6aah
6aai
6aaj
87%
,
6aak 47%
,
92%
87%
,
,
,
and
from aldehydes
ketones
(c) Aliphatic hydrazones
Me
n
n =
n =
6aal
28%
,
,
1,
2, 6aam 47%
6aap
6aaq
86%
,
94%
,
6aan 21%
6aao
64%
,
MeO
,
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10.1002/anie.201915875
Angewandte Chemie International Edition
RESEARCH ARTICLE
[a] Reaction conditions: 1,3-enyne 5a (0.2 mmol), hydrazone 2 (0.4 mmol, generated from aldehyde/ketone and hydrazine), [Ru(p-cymene)Cl2]2 (2.5
mol%), dmpe (5 mol%) and tBuOLi (0.4 mmol) in THF (0.6 mL) at 80 oC for 12 h under N2. Reported yields were the isolated ones.
aromatic enynes, alkyl enynes, such as cyclohexyl and octyl substituted
The potential of the present regioselective catalysis was demonstrated
by further elaboration of the enyne partners. As illustrated in Table 4, a
broad range of structurally diverse enynes bearing either electron-
donating or electron-withdrawing functional groups at the para-, meta-,
and ortho- positions of the phenyl moiety were all converted into the
desired products (7a-j) smoothly. In addition, hetero-aromatic such as
thienyl and/or pyridyl substituted enynes could be applied in the
transformation with very good efficiency (7k-m, 87-92%).
Functionalities assembled onto the substrates, such as ester and nitrile,
were well tolerated, enabling further functionalization of the generated
products (7n and 7o). More importantly, the scope is not restricted to
ones, were also exemplified as suitable substrates for this catalytic
system (7p and 7q). The steric bias onto the alkene moiety resulted in
reduced reactivity of enynes, as previously observed in the dienes
functionalization. The yield was decreased to 48% (7r) when 2-methyl
group was installed onto the olefinic part, while only trace amount of
desired product 7s was observed when internal enyne tested.
Interestingly, the diyne product 7t was obtained exclusively in 93% yield
in the case of bis-enyne tested. Moreover, relatively complicated enynes,
derived from L-menthol and cholesterol, were accommodated as well in
this reaction (7u and 7v).
Table 4. Scope of 1,3-enynes with hydrazones.a
R3
R2
5
R3
p
mol%)
]
2 2 (2.5
mol%)
-cymene)Cl
dmpe (5.0
[Ru(
NH2
H
O
N2H4 H2O
R1
N
R2
tBuOLi
(2.0
R1
H
equiv)
R1
THF, 80 o 12 h
C,
1
2
7
Aromatic
enynes
(a)
n
F3CO
-Bu
Ph
MeO
F
7a
7b
7g
7c
7d
7e
87%
,
90%
93%
82%
92%
92%
,
,
,
,
,
Me
Me
Cl
Me
F3C
Br
MeO
Cl
7f
7h
7i
7j
89%
88%
92%
94%
95%
,
,
,
,
OMe
OMe
S
S
MeO2C
N
NC
OMe
7k
91%
87%
96%b
77%b
7o
,
7l
7m
7n
,
,
,
,
Steric bias
enynes
(b) Aliphatic
(c)
Me
Me
OBn
OBn
7p
7q
7r
7s
trace
,
68%
71%
48%
,
,
,
Bis-enyne
enynes
(e) Complicated
(d)
H
H
H
O
O
MeO
H
OMe
93%c
91%d
88%d
7v
,
7t
7u
,
,
[a] Reaction conditions: 1,3-enyne 5 (0.2 mmol), hydrazone 2 (0.4 mmol, generated from aldehyde and hydrazine), [Ru(p-cymene)Cl2]2 (2.5 mol%),
dmpe (5 mol%) and tBuOLi (0.4 mmol) in THF (0.6 mL) at 80 oC for 12 h under N2 unless otherwise noted. Reported yields were the isolated ones.
[b] K3PO4 was used instead of tBuOLi. [c] Bis-enyne (0.1 mmol), phenyl hydrazone 2a (0.5 mmol), other reaction conditions were similar. [d] The
reaction was performed on 0.1 mmol scale.
In order to gain some information about this transformation,
deuterium-labeled substrates d2-3a and d-3a were reacted under the
standard conditions. We found that the formed products d2-4ad and d-
4ad with deuteration solely at the 1- and 2-position, respectively
(Scheme 2, Eqs a and b). These results indicated that there were no
reversible hydro-metallation across the metal-π-allyl system, since we
would observe deuterium scrambling at the 3- or 4- position, which was
detected in our previously recorded nickel-catalyzed Markovnikov
hydroalkylation. To examine this hypothesis further, d2-2d was
employed under standard reaction conditions, in which product d2-4ad′
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10.1002/anie.201915875
Angewandte Chemie International Edition
RESEARCH ARTICLE
was obtained while no deuterium migration was detected (Scheme 2, Eq
c).
4
2
p
mol%)
]
2 2 (2.5
dmpe (5.0
-cymene)Cl
[Ru(
3
1
D
N
NH2
mol%)
+
MeO
D
D
D
D
tBuOLi
(2.0
equiv)
OMe
THF, 80 o 12 h
C,
0
92%
d2-3a
d2-4ad
92%
2d
D
D
99%
0
D
99%
p
p
mol%)
mol%)
-cymene)Cl
dmpe (5.0
[Ru(
[Ru(
]
2 2 (2.5
N
N
NH2
mol%)
+
+
MeO
MeO
H
tBuOLi
(2.0
equiv)
OMe
OMe
THF, 80 o 12 h
2d
d-3a
d-4ad
C,
82%
ND2
82%
82%
D
H
D
-cymene)Cl
dmpe (5.0
]
2 2 (2.5
mol%)
H
tBuOLi
equiv)
(2.0
C,
THF, 80 o 12 h
d2-2d
d2-4ad'
3a
Scheme 2. Isotope-labeling experiments
Based on these results and previous studies17,18,20-22, the following
reaction mechanism was proposed (Scheme 3). The catalytic active
species A is generated from precatalyst [Ru(p-cymene)Cl2]2 upon ligand
dissociation/association with dmpe. Then hydrazone 2 and 1,3-diene 3
coordinates to the metal center to form intermediate C, which undergoes
inner-sphere rearrangement to form a new carbon-carbon bond and the
six-memebered ring intermediate D in the meantime. Subsequently,
decomposition of this species by N2 extrusion and protodemetalation
releases product 4, and completes the catalytic cycle.
straightforward and efficient access to a variety of valuable homoallylic
alkenes and alkynes (> 100 examples), which were versatile
intermediates in chemical synthesis. The conformation (six-membered
ring) controlled strategy might account for the regio-specific 1,2-anti-
Markovnikov addition selectivity. Our study contributes to the art of
tuning metal catalyst to engineer the reaction selectivity from the same
starting materials to construct different products and also a departure
from pre-metalated reagents in metal-catalyzed C-C bond formation.
p
-cymene)Cl2 2
]
[Ru(
Acknowledgements
dmpe
P
We are grateful to the Canada Research Chair Foundation (to C.-J. Li),
the Canadian Foundation for Innovation, FRQNT Centre in Green
Chemistry and Catalysis, the Natural Science and Engineering Research
Council of Canada and Killam Research Fellow of the Canadian Council
of Arts for support of our research. We are also indebted to Dr. Haining
Wang for constructive discussion on the mechanism.
[RuΙΙ]
R'
R
H
H
+
B-
H2N
N2
N
P
+
R1
R'
A
2
R
4
BH
BH
P
P
P
[RuΙΙ]
P
H
[RuΙΙ]
N
R'
N
R'
R1
Keywords: directional selectivity • 1,3-diene • hydrazone •
N
N
B
H
R
D
hydroalkylation • ruthenium catalysis
R
[1]
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[RuΙΙ]
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10954-10990.
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H
N
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10.1002/anie.201915875
Angewandte Chemie International Edition
RESEARCH ARTICLE
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R
R'
Leiyang Lv,‡ Lin Yu,‡ Zihang Qiu and Chao-
Jun Li*
cat.
[Ni]
H
R1
R1
NH2
R'
branched
Page No. – Page No.
N
+
R1
H
R'
Title: Switch in Selectivity for the Formal
Hydroalkylation of 1,3-Dienes and Enynes
with Simple Hydrazones
R
cat.
[Ru]
linear
R
Rodeo ruthenium: Different directional selectivity can be obtained from the same starting
materials by using different catalytic systems. The nickel-catalyzed hydroalkylation of
hydrazones with 1,3-dienes yielded 1,2-Markovnikov products, whereas the ruthenium-
catalyzed version led to 1,2-anti-Markovnikov directionality.
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