Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction of Naphthyl and Quinolyl Alcohols with Boronic Acids

Article abstract of DOI:10.1021/acs.orglett.9b01669

A nickel-catalyzed C(sp³)-C(sp²) Suzuki cross-coupling of arylboronic acids and (hetero)naphthyl alcohols has been developed. A Ni(dppp)Cl₂ complex showed the highest efficiency and broadest substrate scope. High functiona

Full text of DOI:10.1021/acs.orglett.9b01669

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction of
Naphthyl and Quinolyl Alcohols with Boronic Acids
̀
Sunisa Akkarasamiyo, Jessica Margalef, and Joseph S. M. Samec*
Department of Organic Chemistry, Stockholm University, 106 91 Stockholm, Sweden
S Supporting Information
*
3
2
ABSTRACT: A nickel-catalyzed C(sp )−C(sp ) Suzuki cross-coupling of arylboronic acids and (hetero)naphthyl alcohols has
been developed. A Ni(dppp)Cl complex showed the highest efficiency and broadest substrate scope. High functional group
2
tolerance has been achieved where 35 compounds could be generated in good to excellent yields, including both primary and
secondary benzylic alcohols. Mechanistic studies using multiple NMR techniques as well as ESI-HRMS showed that the C−O
cleavage is facilitated by an activation of the benzylic alcohol through formation of a boronic ester intermediate.
1
1
he Suzuki reaction is one of the most reliable and
increasing the E-factor of the overall reaction. Very few
reports on Suzuki reactions of nonderivatized benzylic alcohols
can be found in the literature. In 2015, Shi and co-workers
pioneered the research field and reported a Pd(PPh3)4
catalyzed cross-coupling reaction with a broad scope of
2
T
widespread synthetic procedures to generate C(sp )−
2
1
C(sp ) bonds in organic synthesis. In 2010, Suzuki was
awarded the Nobel prize, together with Heck and Negishi, for
their pioneering work on palladium-catalyzed cross-coupling
reactions. Due to the usefulness of the methodology and also
stability, low toxicity, and high functional group tolerance of
organoboron compounds (in comparison to Grignard
reagent), the methodology has been well adopted by both
12
primary benzylic alcohols (Scheme 1a). In 2016, Roa and
co-worker showed that Cu(OTf) can catalyze the Suzuki
reaction of diarylmethanol to generate triarylmethanes in good
yields (Scheme 1b). Shi’s group has also successfully
performed nickel catalyzed cross-coupling reactions of benzylic
alcohols using a reactive Grignard reagent as a nucleophilic
2
1
3
1
academia and industry. Coupling reactions are traditionally
catalyzed by a palladium complex and performed between an
organoboron compound and an aryl halide. Variations of the
reaction have been developed such as utilizing other metals
than palladium and also several electrophilic partners.
Progressing the cross-coupling to more challenging benzylic
14
partner to the alcohol (Scheme 1c). Nickel catalyzed Suzuki
cross-coupling reactions of naphthyl and quinolyl alcohols have
never been reported. Herein, we report the first nickel
catalyzed Suzuki coupling reaction of both primary and
secondary naphthyl and quinolyl alcohols and simple boronic
acids to generate diarylmethanes (Scheme 1d). The
importance of naphthyl and quinolyl structures in the
pharmaceutical industry motivated us to develop this chemistry
(Figure 1).
-Quinolinemethanol 1a and 3-fluorophenyl boronic acid 2a
were chosen as coupling partners for the optimization of
reaction conditions (Table 1). The enhanced reactivity and
high atom-economy of boronic acids, prompted us to choose
3
electrophiles (C(sp )) is of great interest. However, this
2
−4
chemistry is less established.
Impressive stereospecific/
selective Suzuki reactions of derivatives of benzylic alcohol
5
6
have been developed by the groups of Javo, Watson,
7
8
Tredwell, and Shen. An alternative to organohalides would
15
9
be the use of a nonderivatized alcohol as a coupling partner. If
6
this would be possible, it would unlock a plethora of easily
available compounds, including feedstocks from renewable
sources. Due to the poor leaving group ability of the OH group
and also the ability of the lone pair of the oxygen to coordinate
to the metal and promoting a β-hydride elimination, this is a
challenging task. Therefore, the alcohol is usually transformed
into a derivative such as ether, ester, or tosylate before being
16
these substrates over other boronic reagents. In addition,
they are cheap and a wide variety of them are commercially
10
subjected to the reaction. This adds a synthetic step usually
Received: May 11, 2019
with purification, thus lowering the atom economy and
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3
2
a
Scheme 1. C(sp )−C(sp ) Cross-Coupling Reaction of
Table 1. Screening for an Optimal Catalytic System
Benzylic Alcohols
temp
product
b
c
entry
1
2
3
4
5
[Ni] cat.
base
solvent
(°C)
(%)
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppe)Cl2
Ni(dppe)-
K P O
Toluene
Toluene
Toluene
Toluene
Toluene
100
100
80
100
100
98
78
9
93
94
4
2
7
7
7
7
7
d
K P O
4 2
K P O
4 2
K P O
4
2
K P O
4
2
(
o-tol)Cl
6
7
8
9
Ni(dppb)Cl2
Ni(dppf)Cl2
K P O
Toluene
Toluene
Toluene
Toluene
MeCN
THF
100
100
100
100
100
100
100
100
100
100
100
100
95
98
95
88
10
35
93
70
0
4
2
7
7
7
7
7
7
7
K P O
4
2
Ni(PPh) Cl2
K P O
4 2
3
Ni(PCy) Cl2
K P O
4 2
3
10
11
12
13
14
15
16
17
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(cod)2
K P O
4 2
K P O
4
2
K P O
TAA
4
2
K PO4
Toluene
Toluene
Toluene
Toluene
Toluene
3
K HPO4
2
−
0
29
0
e
e
K P O
4
2
7
7
K P O
4
2
a
6-Quinolinemethanol 1a (0.2 mmol), 3-fluorophenylboronic acid 2a
(
0.6 mmol), base (0.6 mmol), [Ni](10 mol %), toluene (1 mL), 80
b
°
C for 8 h and then 100 °C for 17 h. NMR yield using 1,3,5-
trimethoxybenzene as an internal standard. dppe: 1,2-bis(diphenyl-
phosphino)ethane. dppp: 1,3-bis(diphenylphosphino)propane. dppb:
c
1
,4-Bis(diphenylphosphino)butane. dppf : 1,1'-bis(diphenyl-
d
phosphino)ferrocene. TAA : tert-amyl alcohol. The reaction was
heated to 100 °C for 17 h (without prerunning at 80 °C for 8 h).
e
dppp (12 mol %) was added.
Figure 1. Examples of biologically active diarylmethane compounds.
entries 1, 10−12). The reaction required the addition of a base
(Table 1, entry 15). No cross-coupling product 3aa was
observed when the reaction was performed without addition of
base. K P O provided the best catalytic performance (Table 1,
available. Serendipitously, we found that stirring the reaction at
8
0 °C for 8 h and then at 100 °C, overnight gave the desired
product in an excellent yield (Table 1, entry 1). If the reaction
was heated to 100 °C from start, lower yield of the desired
product was obtained, where competing reactivities including:
homocoupling of the boronic acid (∼7−23% isolated yield),
homocoupling of the alcohols (4−14% isolated yield),
protodeboronation, and also reduction of the alcohols were
observed, vide infra (Table 1, entry 2). If the temperature was
not increased to 100 °C, we observed low conversion toward
the desired diarylmethane product (Table 1, entry 3). Details
about these observations will be discussed later. Next,
commercially available nickel-phosphine complexes were
screened. We found that the bite angle did not play an
important role in the reactivity, since 93−98% yield of
diarylmethane was observed in all cases (Table 1, entries 1,
4
2
7
entries 1, 13−14). A decrease in the reactivity was observed
when using an excess of phosphine ligand (Table 1, entry 16).
Using Ni(0) as a catalyst precursor gave no reactivity in the
present system (Table 1, entry 17). Having the optimal
conditions in hand, the scope of arylboronic acids and benzylic
alcohols was explored considering these functional groups
(Scheme 2). There are numerous functional groups sensitive to
17
18
19
nickel catalysis. For instance, C−F, C−OMe, C−SMe,
20
and C−COR bonds have been reported to undergo cleavage
by nickel complexes. Gratifyingly, none of the mentioned
bonds were cleaved using the optimized reaction conditions
(Scheme 2, compounds 3aa−3ag, 3aj−3al, and 3an). Thus, a
wide range of diarylmethane compounds were obtained in
good to excellent yields. A wide range of boronic acids
containing both electron-donating (2j−2o) and electron-
withdrawing groups (2a−2g) were employed, and the
corresponding products were obtained in good to excellent
yields. However, we observed that strongly electron-deficient
boronic acids, such as 2d−2g, required a higher reaction
temperature to achieve high yields (125 °C). 3-Quinolineme-
thanol 1b and 5-quinolinemethanol 1c also performed well to
give products 3ba and 3ca in 90% yield. We were pleased to
see that we could expand the scope of alcohols to the
naphthalene systems 1d−1g. Hence, diarylmethane product
4
−8). The highest yields were obtained with a Ni-complex
with 1,3-bis(diphenylphosphino)propane (dppp) and 1,1′-
bis(diphenylphosphino)ferrocene (dppf) as ligands. However,
the dppp ligand showed a broader substrate scope and was
thus chosen for this study (vide infra, Supporting Information
(
SI) section 3). Electron-rich tricyclohexylphosphine provided
a lower yield than aromatic phosphines (Table 1, entry 9 vs 1,
4
−8). Using Ni(dppp)Cl as a catalyst precursor, we studied
2
other reaction parameters. Yields of desired product were
lower with more coordinating solvents; hence, toluene was
found to be the best solvent for this transformation (Table 1,
B
DOI: 10.1021/acs.orglett.9b01669
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Organic Letters
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3
2
Scheme 2. Nickel Catalyzed C(sp )−C(sp ) Suzuki Cross-
(66−94%) (Scheme 3). When alcohol 1a and arylboronic acid
2a (3 equiv) were mixed in toluene at 80 °C for 18 h (Scheme
a
Coupling of Primary Alcohols
3
2
Scheme 3. Nickel Catalyzed C(sp )−C(sp ) Suzuki Cross-
a
Coupling of Secondary Alcohols
a
Benzylic alcohol (0.2 mmol), ArB(OH) (0.6 mmol), K P O (0.6
2
4
2
7
mmol), Ni(dppp)Cl (10 mol %), toluene (1 mL), 80 °C for 8 h then
2
1
25 °C for 17 h. NMR yield using 1,3,5-trimethoxybenzene as an
internal standard.
A), boronic esters 6−8 were identified by H, 11B, and 19
F
1
4
NMR and HRMS analysis (SI, Figures 4−7). This shows that
the boronic esters are formed and may play a role in activating
the alcohol in the reaction. To further support this proposal,
additional experiments were performed. First, we generated
boronic ester 6 by mixing boronic acid 2a and quinolyl alcohol
1
(
a at 80 °C overnight, followed by adding another boronic acid
2k) together with a Ni-catalyst and base and increasing the
temperature. This gave a ratio of products 3aa/3ak of 2:1
Scheme 4B). This supports our proposal. This is in contrast
(
to the proposed activation in the palladium-catalyzed cross-
coupling reported by Shi and co-workers, where the boroxine
12
operates as a Lewis acid.
We also performed the opposite reaction, generating the
ester of 2k and 1a at 80 °C, and then added 2a together with a
nickel catalyst and base. This gave a ratio of products 3aa:3ak
of 3:1 (Scheme 4C). Finally, a control reaction was performed
where 2a and 2k were mixed with 1a together with the Ni-
catalyst and base initially at 80 °C and then at 100 °C giving a
ratio of products 3aa:3ak of 3:1 (Scheme 4D). These
experiments clearly demonstrate that the formation of a
boronic ester intermediate is crucial for C−O bond cleavage of
benzylic alcohol Thus, at 80 °C a boronic ester is formed
between boronic acid and naphthyl/quinolyl alcohol, which
enables the C−O cleavage. For instance, the use of phenyl
boroxine gave a lower yield of the desired product than when
using boronic acid, whereas no reaction was observed when
phenylboronic pinacal ester was used (SI, Table 1). The
reaction mechanism was further examined by studying the
reaction mixture by ESI-HRMS. We mixed 1a, 2a, catalyst, and
base at 80 °C overnight and then increased the temperature to
100 °C for 1 h, before taking a sample and injecting it to the
mass detector. Interestingly, we identified several complexes
and intermediates as well as the product (Figure 2).
Ni(dppp)(OH) (D) was observed as a minor peak in the
spectrum with an m/z of 487 au. A large peak for
Ni(dppp)(C H F) (E) was observed with a mass of m/z of
a
Benzylic alcohol (0.2 mmol), ArB(OH) (0.6 mmol), K P O (0.6
2
4
2
7
mmol), Ni(dppp)Cl (10 mol %), toluene (1 mL), 80 °C for 8 h and
then 100 °C for 17 h; NMR yield using 1,3,5-trimethoxybenzene as an
internal standard. Isolated yield. Reactions performed at 80 °C for 8
h and then at 125 °C for 17 h.
2
b
c
3
da, 3e(a,h,p), 3f(a,h,p), and 3g(a,h) were obtained in good
to excellent yields (55−98%). Benzothiophenemethanol 1h−
1
i could be also used to provide compounds 3ha and 3ia in
6% and 50% yields, respectively. For these substrates a higher
7
reaction temperature (125 °C) was required in order to obtain
high yields.
To the best of our knowledge, Suzuki reaction of secondary
benzylic alcohols has only been reported for highly reactive
diarylmethanols. Secondary benzylic alcohols with an α-
methyl group are challenging substrates because a β-hydride
elimination could occur as a side reaction. Gratifyingly, we
could achieve diarylmethanes 5 from challenging substrates 4
and arylboronic acids 2a and 2p in good to excellent yields
1
3
6
4
565 au. Also, Ni(dppp)(C H F)(C H N)− (OH) (G) was
6
4
10
8
observed with a mass of m/z 724 au. In addition to these metal
complexes, product 3aa and boronic ester were observed in the
C
DOI: 10.1021/acs.orglett.9b01669
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Scheme 4. Control Experiments Using Quinoline Derivative 1a and Boronic Acids 2a and 2k
Scheme 5. Proposed Reaction Mechanism
Figure 2. ESI-HRMS of reaction of 1a and 2a.
mass spectrum. Based on the experimental data, we propose
the following reaction mechanism (Scheme 5). Boronic esters
are formed at 80 °C; however, the redox chemistry is very slow
at this temperature. If the reaction is performed without
preheating, the redox chemistry starts in the absence of
boronic esters resulting in homocouplings and disproportio-
nations/reductions. The catalyst precursor, Ni(dppp)Cl A, is
2
activated by 2 equiv of arylboronic acid and base to generate
Ni(dppp)(OH) D, which proceeds through formation of
catalytic amounts of diaryl coupling product, which is always
observed as a minor byproduct in the reaction mixture.
Transmetalation of D with arylboronic acid generates complex
E, which was also detected by ESI-HRMS. Next, intermediate
E undergoes oxidative addition of the preformed boronic ester
to give complex F. The reductive elimination is then promoted
by attack of a hydroxide ion generated from K P O and water,
via detected intermediate G, leading to the desired coupling
product and regeneration of Ni(dppp)(OH) D. Thus, boronic
4
2
7
D
DOI: 10.1021/acs.orglett.9b01669
Org. Lett. XXXX, XXX, XXX−XXX

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acid has three roles: (i) activation of catalyst precursor; (ii)
activation of alcohol; and (iii) as a coupling partner.
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3
2
A simple and robust nickel (I/III)-catalyzed C(sp )−C(sp )
Suzuki cross-coupling of π-extended primary and secondary
benzylic alcohols to generate diarylmethanes has been
developed. The products were in most cases obtained in
good to excellent yields. This atom-efficient Suzuki cross-
coupling has a broad substrate scope in respect to quinolyl and
naphthyl alcohols and also boronic acids. In addition, although
a Ni-catalyst is used, the reaction is easy to perform without
requirement of glovebox conditions. Mechanistic studies
support that the C−O bond of the alcohol is activated via
formation of arylboronate esters which is then cleaved via
Ni(I) aryl species. Thus, the aryl boronic acid has several roles:
not only as both a coupling partner and an activating agent for
the alcohols but also to initiate the catalyst.
1
4
HBenzotriazoles with Arylboronic Acids. ChemCatChem 2015, 7,
156−4162. (e) Zhang, Y.; Feng, M.-T.; Lu, J.-M. N-Heterocyclic
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Air Atmosphere. ACS Omega 2017, 2, 7767−7771.
(3) (a) Wu, K.; Doyle, A. G. Parameterization of Phosphine Ligands
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Kinuta, H.; Nakamura, K.; Chatani, N. 1,3-Dicyclohexylimidazol-2-
ylidene as a Superior Ligand for the Nickel-Catalyzed Cross-
Couplings of Aryl and Benzyl Methyl Ethers with Organoboron
Reagents. Org. Lett. 2014, 16, 5572−5575. (c) Liao, J.; Guan, W.;
Boscoe, B. P.; Tucker, J. W.; Tomlin, J. W.; Garnsey, M. R.; Watson,
M. P. Transforming Benzylic Amines into Diarylmethanes: Cross-
Couplings of Benzylic Pyridinium Salts via C−N Bond Activation.
Org. Lett. 2018, 20, 3030−3033. (d) Chen, Q.; Fan, X.-H.; Zhang, L.-
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ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01669.
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(e) Ariki, Z. T.; Maekawa, Y.; Nambo, M.; Crudden, C. M.
*E-mail: joseph.samec@su.se.
Preparation of Quaternary Centers via Nickel-Catalyzed Suzuki−
Miyaura Cross-Coupling of Tertiary Sulfones. J. Am. Chem. Soc. 2018,
ORCID
1
(
40, 78−81.
Joseph S. M. Samec: 0000-0001-8735-5397
Notes
4) (a) Sun, Y.-Y.; Yi, J.; Lu, X.; Zhang, Z.-Q.; Xiao, B.; Fu, Y. Cu-
Catalyzed Suzuki−Miyaura Reactions of Primary and Secondary
Benzyl Halides with Arylboronates. Chem. Commun. 2014, 50,
The authors declare no competing financial interest.
11060−11062. (b) Procter, R. J.; Dunsford, J. J.; Rushworth, P. J.;
Hulcoop, D. G.; Layfield, R. A.; Ingleson, M. J. A Zinc Catalyzed
C(sp3)-C(sp2) Suzuki−Miyaura Cross-Coupling Reaction Mediated
by Aryl-Zincates. Chem. - Eur. J. 2017, 23, 15889−15893. (c) Bedford,
R. B.; Hall, M. A.; Hodges, G. R.; Huwe, M.; Wilkinson, M. C. Simple
Mixed Fe−Zn Catalysts for the Suzuki Couplings of Tetraarylborates
with Benzyl Halides and 2-Halopyridines. Chem. Commun. 2009,
ACKNOWLEDGMENTS
Formas and Stiftelsen Olle Engkvists Byggmas
■
̈
tare.
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DOI: 10.1021/acs.orglett.9b01669
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