Cross-Coupling of Phenol Derivatives with Umpolung Aldehydes Catalyzed by Nickel

Article abstract of DOI:10.1021/acscatal.8b01224

A nickel-catalyzed cross-coupling to construct the C(sp²)-C(sp³) bond was developed from two sustainable biomass-based feedstocks: phenol derivatives with umpolung aldehydes. This strategy features the in situ generation of moisture/air-stable hydrazones from naturally abundant aldehydes, which act as alkyl nucleophiles under catalysis to couple with readily available phenol derivatives. The avoidance of using both halides as the electrophiles and organometallic or organoboron reagents (also derived from halides) as the nucleophiles makes this method more sustainable. Water tolerance, great functional group (ketone, ester, free amine, amide, etc.) compatibility, and late-stage elaboration of complex biological molecules exemplified its practicability and unique chemoselectivity over organometallic reagents.

Full text of DOI:10.1021/acscatal.8b01224

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Cross-Coupling of Phenol Derivatives with
Umpolung Aldehydes Catalyzed by Nickel
Leiyang Lv, Dianhu Zhu, Jianting Tang, Zihang Qiu, Chen-Chen Li, Jian Gao, and Chao-Jun Li
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 17 Apr 2018
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ACS Catalysis
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Cross-Coupling of Phenol Derivatives with Umpolung Aldehydes
Catalyzed by Nickel
Leiyang Lv,‡ [a,b] Dianhu Zhu,‡ [a] Jianting Tang,[a] Zihang Qiu,[a] Chen-Chen Li,[a] Jian Gao,[a] and Chao-
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Jun Li*[a,b]
[a] Department of Chemistry and FRQNT Center for Green Chemistry and Catalysis, McGill University, Montreal, QC, H3A
0B8, Canada
[b] State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Rd., Lanzhou, Gansu, 730000,
China
KEYWORDS: cross-coupling, hydrazone, phenol, alkyl nucleophile, nickel catalysis
ABSTRACT: A nickel-catalyzed cross-coupling to construct C(sp2)-C(sp3) bond was developed from two sustainable biomass-
based feedstocks: phenol derivatives with umpolung aldehydes. This strategy features the in situ generation of moisture/air stable
hydrazones from naturally abundant aldehydes, which act as alkyl nucleophiles under catalysis to couple with readily available
phenol derivatives. The avoidance of using both halides as the electrophiles and organometallic or organoboron regents (also de-
rived from halides) as the nucleophiles make this method more sustainable and renewable. Water tolerance, great functional group
(ketone, ester, free amine, amide etc) compatibility and late-stage elaboration of complex biological molecules exemplified its prac-
ticability, unique chemo-selectivity over organometallic reagents.
Transition-metal-catalyzed
cross-coupling
reactions
involving C(sp2)-O bond cleavage to construct C-C bond has
attracted considerable attention in synthetic chemistry over the
past decade,[1] especially the nickel-catalyzed cross-coupling
reactions of phenol derivatives with organometallic reagents.[2]
Compared to the traditional use of aryl halides, phenols and
their derivatives are naturally abundant, readily available and
often renewable from biomass. Representative excellent
examples are the nickel-catalyzed Kumada-Tamao-Corriu
(KTC) type reactions of phenolic electrophiles with Grignard
reagents, pioneered by Wenkert,[3] and developed by
Dankwardt,[4] Shi,[5] Chatani,[6] Martin,[7] Rueping[8] as well as
others[9] (Scheme 1a). However, due to the high
nucleophilicity and basicity, robust organometallic reagents
are typically moisture/air sensitive and display less functional
group compatibility, making them inferior candidates for late-
stage manipulation of complex molecules or direct use under
biocompatible conditions. In addition, the preparation of these
organometallic reagents requires pre-synthesized halides and
stoichiometric quantities of metals, thus producing copious
metal wastes. To address these challenges, air/moisture stable
organoboron reagents emerged as attractive coupling partners
Scheme 1. Representative Reagents in the Cross-Coupling
Reactions Involving C-O Bond Cleavage.
with O-based electrophiles (Scheme 1b). Chatani,[10] Garg[11]
,
As we know, tremendous efforts have been made by
Barluenga,[16] Wang[17] and others[18] employing electrophilic
carbene from N-tosylhydrazones, however, the reversal elec-
tronic characteristic of simple hydrazones (from aldehydes)
may offer new opportunities for chemical transformations.
Recently, our group has disclosed novel and reliable rutheni-
um catalyzed nucleophilic additions to various π systems with
hydrazones as carbanion equivalents.[19] Earlier this year, we
exemplified the feasibility of cross-couplings of aryl halides
with hydrazones, albeit with very limited substrate scope, re-
quiring strictly anhydrous conditions and suffering from haz-
ardous halides.[20] To overcome such limitations as well as
towards the goal of green chemistry, herein, we wish to report
Shi[12] Snieckus[13] and others[14] have made great
,
contributions in the nickel-catalyzed Suzuki–Miyaura
couplings to prepare biaryls between polycyclic aromatic
phenol derivatives with aromatic boronic acids/esters.
However, C(sp2)-C(sp3) cross-coupling remains challenging
when phenol derivatives are employed as C−O
electrophiles..[5c,6a,8] Very recently, Rueping reported a practi-
cal alkylation of naphthol derivatives with B-alkyl-9-BBNs
via nickel catalysis.[15] Although organoboron reagents have
widespread applications in various cross-couplings, most of
them are obtained from organometallics or borylation of al-
kenes with expensive boron reagents.
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a sustainable and practical nickel-catalyzed C(sp2)-C(sp3)
Page 2 of 6
mation (see Table S1 in Supporting Information), probably
because nickel is more oxyphilic than palladium due to its
smaller size and increased hardness.[2] Ligand studies showed
that less sterically hindered monodentate (PMe3, PEt3) or bi-
dentate phosphine ligands (dmpe, dppf) facilitated this trans-
formation (entries 1-10), and the best result was obtained
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cross-coupling of phenol derivatives with umpolung aldehydes
via C-O bond cleavage. Highlighted features of this strategy
are: a) naturally abundant aldehydes as stable and environmen-
tally benign alkyl nucleophiles; b) easily available O-based
electrophiles from phenols; c) earth-abundant nickel as cata-
lyst; d) broad substrate scope and water tolerance; e) unique
chemo-selectivity; and f) great functional-group compatibility
and late-stage elaboration of complex biological molecules.
when using PMe3 as the ligand and DBU as the base (4aa, 80%
yield, entry 4). The combination of Ni(PPh3)4 with PMe3 gave
the desired product 4aa in 52% yield (entry 11), while it was
totally inactive in the absence of ligand PMe3 (entry 12). It is
noteworthy that more convenient Ni(II) pre-catalysts could
also facilitate this cross-coupling reaction, and moderate yields
of 4aa were obtained (entries 13-15). The efficiency of this
transformation was largely affected by the choice of base (en-
tries 16-19). In addition, decreasing the reaction temperature
to 80 oC resulted in no detection 4aa with all the starting mate-
rial 3a recovered (entry 20), which implies that the insertion of
nickel catalyst to C-O bond has a high activation energy.
Moreover, p-tolyl mesylate and p-tolyl triflate were also appli-
cable (entries 21-22), while aryl pivalate gave only trace
amount of cross-coupling product 4aa (entry 23).
Table 1. Optimization of the Reaction Conditionsa
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entry
1
catalyst
ligand
-
base
4aa (%)b
N.D.
trace
trace
80 (75)
38
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(PPh3)4
Ni(PPh3)4
NiCl2
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
tBuOK
K3PO4
Cs2CO3
-
2
PPh3
PCy3
PMe3
PEt3
3
4
Table 2. Scope of Aldehyde 1a,b
5
6
dmpe
dppf
53
7
71
8
dppe
Xantphos
bpy
trace
trace
7
9
10
11
12
13
14
15
16
17
18
19
20c
21d
22e
23f
PMe3
-
52
N.D.
52
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
Ni(acac)2
NiBr2•glyme
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
53
60
37
trace
trace
N.D.
N.D.
65
DBU
DBU
DBU
DBU
96
trace
[a] Reaction conditions: 3a (0.2 mmol), 1 (0.6 mmol), N2H4•H2O (0.72
mmol), [Ni] (10 mol%), PMe3 (40 mol%), DBU (0.6 mmol), THF (1.0
[a] Reaction conditions: 3a (0.1 mmol), 1a (0.3 mmol), N2H4•H2O (0.36
mL), 110 oC, 12 h under N2. [b] Reported yields are the isolated ones.
mmol), [Ni] (10 mol%), ligand (40 mol% for monodentate, 20 mol% for
o
bidentate), base (0.3 mmol), THF (0.5 mL), 110 C, 12 h under N2 unless
With the optimized conditions identified, the substrate
scope of aldehydes was investigated. As shown in Table 2,
variations of electronic effects of the nucleophiles did not re-
duce the efficiency of this coupling reaction. Aldehydes bear-
ing both electron-donating and electron-withdrawing substitu-
ents all reacted smoothly with phenyl tosylate 3a to give the
desired products 4ab-ap in good to excellent yields. Various
functional groups, such as methyl, methoxyl, chloro, fluoro,
trifluoromethyl and even ester, were all tolerated under the
optimized conditions. Hetero-aromatic aldehydes, such as
furan-2-carbaldehyde, thiophene-3-carbaldehyde, pyridine-3-
1
other noted. [b] NMR yields were determined by H NMR using mesity-
lene as an internal standard (isolated yield in parenthesis). [c] The reaction
o
was performed at 80 C. [d] p-Tolyl mesylate was used instead of 3a. [e]
p-Triflate was used instead of 3a. [f] p-Tolyl pivalate was used instead of
3a. N. D.= not detected.
Initially, the cross-coupling reaction of p-tolyl tosylate (3a)
and hydrazone generated in situ from benzaldehyde (1a) with
hydrazine was chosen as the model to explore the reaction
conditions (Table 1). Catalysts investigations revealed that
nickel was the only metal candidate to favor this transfor-
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carbaldehyde and benzothiophene-3-carbaldehyde were well
aw, 4ra). Moreover, the vinyl tosylates were also tested as
suitable coupling partners, thus expanding the electrophile
scopes to the cheap and natural abundant ketones (4sa, 4ta).
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applicable for the present transformation (4aq-at). Further-
more, the aldehydes bearing naphthyl or phenanthryl substitu-
ents afforded the corresponding products (4au-aw) in excel-
lent yields (> 90%). To our delight, the cross-coupling also
occurred with cinnamaldehyde and phenylacetaldehyde as
substrates, albeit with a slightly reduced reactivity (4ax, 4ay).
Unfortunately, only trace amount of desired products were
detected when simple aliphatic aldehydes were tested, proba-
bly due to the rapid competing formation of azines from the
hydrazone intermediates under high temperature.
Gratifyingly, the power and utility of this cross-coupling
reaction was further demonstrated by its application to
complex tosylate/triflate substrates. For example, the structural
elaboration of tyrosine 5, which is a non-essential amino acid
used by cells to synthesize proteins in biology, was readily
accomplished using our nickel-catalyzed cross-coupling
reaction with aldehydes as masked alkyl nucleophile (Scheme
2, Eq. 1). In addition, the alkylation of estrone proceeded
smoothly and efficiently while using the corresponding
tosylate 7 with the ketone moiety intact, impossible with
organometallic reagents (Scheme 2, Eq. 2). Furthermore, the
reaction of 1a with triflate of cholesterol was investigated
under the standard reaction conditions. The expected
alkylation product 10 was obtained in 82% yield (Scheme 2,
Eq. 3). These results indicated that this protocol would enrich
the tool box of chemists for the late-stage modification of
complex molecules.
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Table 3. Scope of Aryl/vinyl Tosylates 1a,b
Scheme 2. Alkylative Elaboration of Complex Tosyl-
ates/triflates Derived from Natural Products.
Then the chemo-selectivity of this nickel-catalyzed cross-
coupling reaction was explored. The chemo-specific alkylation
of C(sp2)-OTs with hydrazone 1a occurred with estradiol di-
tosylates 11 (Scheme 3, Eq. 1). To our delight, the chemo-
selective, sequential alkylation of substrate 13 was achieved
by the unique tunable reactivity between aryl iodide and tosyl-
ate, thus delivering the asymmetrical dibenzyl product 15 in
excellent yield (Scheme 3, Eq. 2).
[a] Reaction conditions: 3 (0.2 mmol), 1a (0.6 mmol), N2H4•H2O (0.72
mmol), [Ni] (10 mol%), PMe3 (40 mol%), DBU (0.6 mmol), THF (1.0
mL), 110 oC, 12 h under N2. [b] Reported yields are the isolated ones.
Subsequently, the scope of phenyl/vinyl tosylates was
investigated, as summarized in Table 3. In general, substrate 3
with electron-donating (-OMe, -OPh, -Me, -iPr, -tBu, -Ph, etc.)
on the para- and/or meta-position of phenyl ring all worked
well to give the desired diarymethanes 4ac, 4ba-da, 4fa-ia,
albeit with moderate yields observed when electron-
withdrawing groups (-CN, -Cl, -F, -CF3) attached (4ja, 4am,
4ai, 4al, 4ka). Product 4ea was obtained in 51% yield due to
the ortho-steric hindrance of methyl group. When the tosylate
of isoeugenol perfume was tested, the desired product 4la was
obtained in 81% yield with olefin moiety untouched (E/Z de-
rived from substrate). It is worth mentioning that other func-
tional groups such as ester, amine and amide, which are fragile
in the presence of Grignard reagents, were well tolerated under
our conditions (4ma-oa). In addition, the N-heterocyclic (pyr-
idine, indole and carbazole) tosylates, as important motifs in
alkaloids, underwent efficient cross-couplings with benzalde-
hyde hydrazone (4as, 4pa, 4qa). As expected, the polycyclic
(naphthyl or phenanthryl) tosylates were well applicable (4au-
Scheme 3. Chemo-Selectivity Tests.
Moreover, the efficiency of this transformation was not af-
fected in the presence of H2O, thus showing its distinct mois-
ture tolerant character than organometallic reagents (Scheme
4).
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Leiyang Lv: 0000-0002-2850-8952
Page 4 of 6
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Chao-Jun Li: 0000-0002-3859-8824
Author Contributions
‡(L. Lv, D. Zhu) These authors contributed equally.
Scheme 4. Water Tolerance Tests.
Notes
Although exact mechanism was still not clear at this stage,
The authors declare no competing financial interest.
according to our previous works[19] and literature reports,[2]
a
plausible reaction pathway was depicted in Scheme 5. Similar
to the Ni-catalyzed KTC type and Suzuki coupling reaction
intensive studied by Chatani,[21] Itami[22] and Martin,[23] the
coordination of Ni (0) with π system and oxygen allowing the
oxidative addition to give intermediate B, which underwent
transmetallation with carbon-nucleophile D derived from
deprotonation of hydrazone 2 to form intermediate E. Reduc-
tive elimination gave the diimide F[24] and regenerated Ni (0)
catalyst. Finally, the desired product 4 was formed by denitro-
genation assisted with base.
ACKNOWLEDGMENT
9
We are grateful to the Canada Research Chair Foundation (to C.-J.
L.), the Canadian Foundation for Innovation, FRQNT Centre in
Green Chemistry and Catalysis, and the Natural Science and En-
gineering Research Council of Canada for support of our research.
Dr. L. Lv is grateful for the support from National Postdoctoral
Program for Innovative Talents (No. BX201700110) and China
Postdoctoral Science Foundation Funded Project (No.
2017M623270).
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Scheme 5. Proposed Mechanism.
In summary, we have developed a sustainable nickel-
catalyzed cross-coupling of phenol-based electrophiles with
aldehydes umpolung to construct C(sp2)-C(sp3) bonds. This
strategy features the in situ generation of moisture/air stable
hydrazones from naturally abundant aldehydes, which act as
alkyl nucleophiles under catalysis to couple with easily availa-
ble phenol derivatives. The avoidance of using organometallic
or organoboron regents derived from halides make this method
more sustainable and renewable. Water tolerance, great func-
tional group (ketone, ester, free amine, amide etc) compatibil-
ity and late-stage elaboration of complex biological molecules
exemplified its practicability, unique chemo- selectivity over
organometallic reagents. Further applications of aldehydes as
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge
via the Internet at http://pubs.acs.org.
Screening data, experimental details, characterization of
new compounds and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: cj.li@mcgill.ca (C.-J. Li)
ORCID:
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