Nickel-Catalyzed Addition of Arylboronic Acids to Alkyl Nitriles for Synthesis of Aryl Ketones in Fluorinated Solvent

Article abstract of DOI:10.1055/s-0036-1589137

A mild and efficient nickel-catalyzed addition of arylboronic acids to alkyl nitriles in a fluorinated solvent for the synthesis of various aryl ketones is described. A broad range of arylboronic acids and alkyl nitriles were investigated, and the desired products were obtained with good to excellent yields under the optimized conditions. This method provides an opportunity for the synthesis of aryl ketones from alkyl nitriles, especially acetonitrile, with a non-noble metal catalyst in one pot.

Full text of DOI:10.1055/s-0036-1589137

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
Synlett
D.-H. Tu et al.
Letter
Nickel-Catalyzed Addition of Arylboronic Acids to Alkyl Nitriles
for Synthesis of Aryl Ketones in Fluorinated Solvent
Dong-Huai Tua,b
Yang Lia,b
Bo Zhaoa,b
Yu-Jie Gua,b
O
NiBr2•diglyme, 1,10-phen
NaHCO3
Cl
F
B(OH)2
R2
R2
(R2 = alkyl)
R1
R1
+
N
CF3
HCFC-244bb, H2O
100 °C, 5 h
2
5 examples
63–95% yield
Bo Wanga,b
HCFC-244bb
Ju-You Lua,b
Jian Lu*a,b
a
State Key Laboratory of Fluorine and Nitrogen Chemicals,
Xi’an 710065, P. R. of China
Xi’an Modern Chemistry Research Institute, Xi’an 710065,
b
P. R. of China
lujian204@263.net
Received: 01.09.2017
Accepted after revision: 29.10.2017
Published online: 28.11.2017
nitriles to give aryl ketone derivatives. At almost the same
11
time, Miura and co-workers reported that this process can
12
DOI: 10.1055/s-0036-1589137; Art ID: st-2017-w0661-l
be realized by using a rhodium catalyst. Later, Cheng de-
veloped a nickel-catalyzed addition of arylboronic acids to
Abstract A mild and efficient nickel-catalyzed addition of arylboronic
acids to alkyl nitriles in a fluorinated solvent for the synthesis of various
aryl ketones is described. A broad range of arylboronic acids and alkyl
nitriles were investigated, and the desired products were obtained with
good to excellent yields under the optimized conditions. This method
provides an opportunity for the synthesis of aryl ketones from alkyl ni-
triles, especially acetonitrile, with a non-noble metal catalyst in one pot.
nitriles by using ZnCl as a Lewis acid; however, this meth-
2
od could not convert MeCN into the corresponding aryl ke-
tones. In 2013, Chen and co-workers13 reported that the ad-
dition of arylboronic acids to nitriles, especially MeCN,
could be accomplished by using a palladium catalyst. In ad-
dition, there are several reports of transition-metal-cata-
lyzed additions of arylboronic acids to nitriles to give aryl
ketones.14 However, to the best of our knowledge, there has
been no example of the use of low-cost metal complexes
Key words nickel catalysis, arylboronic acids, alkyl nitriles, aryl ke-
tones, fluorinated solvents
(such as those of Ni, Cu, or Fe) as catalysts for addition of
Aryl ketones form integral parts of various natural prod-
arylboronic acids to MeCN. Here, we report a mild and effi-
cient nickel-catalyzed method for the addition of arylbo-
ronic acids to alkyl nitriles, especially MeCN, to give aryl ke-
tones; the reaction is compatible with a wide variety of
substrates, and proceeds under mild conditions.
1
ucts, and are key intermediates for syntheses of drugs, per-
2
fumes, insecticides, and photoinitiators. Classical routes to
the synthesis of aryl ketones rely on Friedel–Crafts acyla-
3
tion reactions, which involve the use of stoichiometric
amounts of Lewis acids, or oxidations of the corresponding
secondary alcohols, which require stoichiometric amounts
We initially chose 4-methoxyphenylboronic acid (1a) as
a model substrate for the optimization of the transforma-
tion. A solution of 4-methoxyphenylboronic acid (1a; 1.0
mmol) and MeCN (2; 1.0 mL) in F CCO Et was stirred at
4
of oxidant. In addition, several methods, such as palladium-
catalyzed couplings of aldehydes with aryl bromides or
3
2
5
chlorides, noble- or non-noble-metal-catalyzed selective
100 °C in the presence of Ni(OAc) (5 mol%) as a catalyst,
2
6
oxidations of aralkanes, or reactions of carboxylic acid de-
2,2′-bipyridyl (bpy; 10 mol%) as a ligand, and NaHCO (2.0
3
7
rivatives have been frequently reported. Despite these
equiv) as a base. After five hours, 1-(4-methoxyphenyl)eth-
anone (3a) was formed in a low yield of 21% (Table 1, entry
1). Control experiments revealed that the metal, ligand, and
solvent were each indispensable for the reaction (entries 2–
4). Next, we examined the influence of the ligand and we
found that 1,10-phenanthroline (1,10-phen) is the best li-
gand for the reaction (entries 5–8). When the nickel source
great advances, the regioselectivity, functional-group toler-
ance, and costs of preparing catalysts are still less than sat-
isfactory. Consequently, there is still great demand for
more-efficient catalyst systems for the synthesis of aryl ke-
tones.
In recent years, several methods involving transition-
metal-catalyzed additions of arylboronic acids to nitriles to
was switched from NiCl2 to NiBr ·diglyme, a better yield
2
8
form aryl ketones have been reported. In 2006, Zhou and
was obtained (entries 9 and 10). Finally, we examined the
effect of the solvent and found that 2-chloro-1,1,1,2-tetra-
fluoropropane (HCFC-244bb) is the best solvent for the re-
9
10
Larock and Zhao and Lu separately developed palladium-
catalyzed methods for the addition of arylboronic acids to
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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Synlett
D.-H. Tu et al.
Letter
Table 1 Optimization of the Reaction Conditionsa
(Scheme 1). In general, arylboronic acids with electron-rich
aryl groups showed a higher reactivities than their elec-
tron-deficient analogues; for instance, the yield of 3a was
significantly higher than that of 3g. Substrates with meta-
or ortho-substituents also reacted, giving moderate yields
of products 3j–q. Interestingly, trifluoromethyl-substituted
arylboronic acids were well tolerated in this transformation
O
Ni (5 mol%)
B(OH)2
ligand (10 mol%)
+
H3C
N
base (2.0 equiv)
solvent (2.0 mL)
O
O
1a
2
3a
(
3i and 3m). Furthermore, 2-naphthylboronic acid could
b
Entry Catalyst
Ligand
Solvent
Yield (%)
also be converted into 1-(2-naphthyl)ethanone (3r) in a
moderate yield of 72% (3r).
1
2
3
4
5
6
7
8
9
Ni(OAc)
–
2
bpy
bpy
–
F
F
F
3
3
3
CCO
CCO
CCO
2
2
2
Et
Et
Et
21
n.d.c
n.d.
n.d.
5
NiBr2•diglyme (5 mol%)
O
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
2
2
2
2
2
2
1
,10-phen (10 mol%)
H2O (2.0 mmol)
B(OH)2
R2
bpy
–
R2
R1
+
N
R1
NaHCO3 (2.0 equiv)
HCFC-244bb (2.6 g)
100 °C, 5 h
(R2 = alkyl)
PCy
3
F
F
F
F
F
F
3
CCO
CCO
CCO
CCO
CCO
CCO
2
2
2
2
2
2
Et
Et
Et
Et
Et
Et
mbpyd
22
18
29
14
42
53
65
85
66
63
46
n.d.
94
3
3
3
3
3
1
2
3
IPr·HCle
O
O
O
O
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
NiCl
2
O
1
0
1
2
3
4
5
6
7
8k
NiBr
NiBr
NiBr
NiBr
NiBr
NiBr
NiBr
NiBr
NiBr
2
2
2
2
2
2
2
2
2
·diglyme
·diglyme
·diglyme
·diglyme
·diglyme
·diglyme
·diglyme
·diglyme
·diglyme
3a, 89%
3b, 95%
3c, 91%
3d, 83%
1
1
1
1
1
1
1
HCFO-1233xff
HFO-1234yfg
HCFC-244bbh
CFC-113ai
HFC-245faj
DMF
O
O
O
O
F
Cl
F
O2N
Cl
3
e, 79%
3f, 77%
3g, 73%
3h, 69%
O
O
O
O
O
DMSO
F3C
F3C
1
HCFC-244bb
3i, 76%
3j, 84%
3k, 73%
3l, 73%
a
Reaction conditions: 1a (1.0 mmol), MeCN (1.0 mL), catalyst (5 mol%), li-
(2.0 equiv), solvent (2.0 mL), 100 °C, 5 h.
O
O
O
O
F
O
gand (10 mol%), NaHCO
3
b
2
O N
Determined by GC using bromobenzene as internal reference.
n.d. = not determined.
c
d
e
f
4
,4′-Dimethoxy-2,2′-bipyridine.
,3-Bis(2,6-diisopropylphenyl)imidazolinium chloride.
CH =C(Cl)CF
=C(F)CF
MeC(Cl)(F)CF
Cl CCF
CCH
O (2.0 mmol) was added.
1
3m, 77%
3n, 70%
3o, 88%
3p, 89%
2
3
.
g
h
i
CH
2
3
.
O
Cl
O
O
O
3
.
3
3
.
j
F
3
2 2
CHF .
k
H
2
3q, 75%
3r, 72%
3s, 90%
3t, 89%
O
O
O
Cl
action (entries 11–17). Moreover, when 2.0 mmol of water
was added to the system, the target product 3a was ob-
tained with an excellent yield of 94% (entry 18). Therefore,
the best reaction conditions for this process are as follows:
Cl
3
u, 81%
3v, 72%
3w, 83%
3y, 63%
O
O
NiBr ·diglyme (5 mol%), 1,10-phenanthroline (1,10-phen)
2
(10 mol%), NaHCO3 (2.0 equiv), MeCN (1.0 mL) in HCFC-
2
44bb (2.0 mL, 2.6 g) as solvent at 100 °C for five hours.
By using the optimized reaction conditions, we ex-
HO
3x, 73%
plored the substrate scope of arylboronic acids and alkyl ni-
triles for this transformation. Initially, various arylboronic
acids were investigated (Scheme 1). Para-substituted ar-
ylboronic acids reacted smoothly with MeCN to afford good
to excellent yields of the corresponding products 3c–i
Scheme 1 Substrate scope of arylboronic acids and alkyl nitriles.
Reagents and conditions: arylboronic acid 1 (1.0 mmol), alkyl nitrile 2
15
(1.0 mL), NiBr ·diglyme (5 mol%), 1,10-phen (10 mol%), H O (2.0
2
2
mmol), NaHCO (2.0 equiv), HCFC-244bb (2.0 mL, 2.6 g), 100 °C, 5 h.
3
Isolated yields are given.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
Synlett
D.-H. Tu et al.
Letter
Subsequently, we evaluated other alkyl nitriles in this
reaction is compatible with a wide variety of substrates un-
der mild conditions. This method provides an opportunity
for the synthesis of aryl ketones from alkyl nitriles, espe-
cially MeCN, by using a non-noble metal catalyst in one pot.
16
transformation. As shown in Scheme 1, alkyl nitriles also
worked well for this reaction. For instance, propionitrile re-
acted smoothly with electron-rich or electron-deficient ar-
ylboronic acids to give good yields of the corresponding aryl
ketones 3t–v (Scheme 1). Similarly, butyronitrile and pen-
tanenitrile reacted with phenylboronic acids to provide the
expected aryl ketone derivatives 3w and 3x in 83 and 73%
yield, respectively. To our delight, heptanenitrile similarly
reacted with (4-hydroxyphenyl)boronic acid to give the
aryl ketone 3y in a moderate yield of 63%.
Funding Information
The authors gratefully acknowledge the financial support from the
National Natural Science Foundation of China (21327011, 21503610),
and the China Post-Doctoral Science Foundation (2016M592850).
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On the basis of known metal-catalyzed addition of aryl-
Supporting Information
12
boronic acids with nitriles, the plausible reaction pathway
shown in Scheme 2 is proposed to account for this nickel-
catalyzed addition reaction. The catalytic reaction is proba-
bly initiated by the formation of intermediate A through li-
gand exchange of 1,10-phen with the alkyl nitrile. Interme-
diate A then undergoes transmetalation with the arylbo-
ronic acid to give the aryl nickel(II) complex B. Next, 1,2-
addition of the coordinated aryl group to the alkyl nitrile
group gives intermediate C. Hydrolysis of intermediate C af-
fords the corresponding aryl ketone and nickel complex D.
Finally, intermediate D converts into intermediate A, and
the catalyst starts the next cycle.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589137.
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References and Notes
(1) (a) Surburg, H.; Panten, J. Common Fragrance and Flavor Materi-
als, 5th ed.; Wiley-VCH: Weinheim, 2006. (b) Battaglia, U.;
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Roskams, T.; Vandenheede, J. R.; Agostinis, P.; de Witte, P. A. Br.
J. Cancer. 2005, 92, 1406.
In conclusion, we have demonstrated a mild and effi-
cient nickel-catalyzed addition reaction of arylboronic ac-
ids to alkyl nitriles in a fluorinated solvent to give aryl ke-
tones. An investigation of substrates scope revealed that the
(2) (a) Franck, H. G.; Stadelhofer, J. W. Industrial Aromatic Chemis-
try: Raw Materials, Processes, Products; Springer: Berlin, 1987.
(
b) Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: Wein-
L
Br
Ni
heim, Germany, 2002. (c) Reux, B.; Nevalainen, T.; Raitio, K. H.;
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L
Br
(
d) Romines, K. R.; Freeman, G. A.; Schaller, L. T.; Cowan, J. R.;
R
R
ArB(OH)2
Gonzales, S. S.; Tidwell, J. H.; Andrews, C. W. III; Stammers, D.
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ecules 2013, 18, 9818.
N
R–C
N
Br
Br
Ni
N
Br–
A
Br–
(3) (a) Olah, G. A. Friedel–Crafts Chemistry; Wiley: New York, 1973.
(
b) Sartori, G.; Maggi, R. Advances in Friedel–Crafts Acylation
+
R
Reactions: Catalytic and Green Processes; CRC Press: Boca
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2000, 122, 12043. (d) Motiwala, H. F.; Vekariya, R. H.; Aubé, J.
Org. Lett. 2015, 17, 5484.
R
R
R
N
N
N
N
Ar
Br
N
Ni
Ni
Br
R
(4) (a) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem.
1
2
999, 64, 6750. (b) Dobereiner, G. E.; Crabtree, R. H. Chem. Rev.
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B
Gao, S. J. Org. Chem. 2016, 81, 2189.
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14800. (b) Ruan, J.; Saidi, O.; Iggo, J. A.; Xiao, J. J. Am. Chem. Soc.
O
Ar
Ar
2008, 130, 10510. (c) Colbon, P.; Ruan, J.; Purdie, M.; Xiao, J. Org.
Lett. 2010, 12, 3670. (d) Padmanaban, M.; Biju, A. T.; Glorius, F.
Org. Lett. 2011, 13, 98.
R
N
N
Ni
H2O
N
Br
(
6) (a) Shi, Z.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem. Int. Ed. 2009,
R
48, 7895. (b) Zhou, M.; Hintermair, U.; Hashiguchi, B. G.; Parent,
A. R.; Hashmi, S. M.; Elimelech, M.; Periana, R. A.; Brudvig, G.
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C
Scheme 2 A plausible reaction pathway for the addition of arylboronic
acids to alkyl nitriles
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
Synlett
D.-H. Tu et al.
Letter
(7) (a) Lindh, J.; Sjöberg, P. J. R.; Larhed, M. Angew. Chem. Int. Ed.
Teflon reaction tube. The tube was charged with arylboronic
2010, 49, 7733. (b) Genna, D. T.; Posner, G. H. Org. Lett. 2011, 13,
5358. (c) Rai, K. M. L.; Babu, M. S.; Byrappa, K. Asian. J. Chem.
2012, 24, 1395. (d) Yu, A.; Shen, L.; Cui, X.; Peng, D.; Wu, Y. Tet-
acid 1i (1.0 mmol, 189.9 mg), MeCN (2; 1.0 mL), NaHCO3 (2.0
equiv, 168.0 mg), H O (2.0 mmol, 36.0 mg), and a magnetic
2
stirrer bar. NiBr ·diglyme (17.6 mg, 5 mol%) and 1,10-phen (18.0
2
rahedron 2012, 68, 2283. (e) Wu, H.; Xu, B.; Li, Y.; Hong, F.; Zhu,
D.; Jian, J.; Pu, X.; Zeng, Z. J. Org. Chem. 2016, 81, 2987.
mg, 10 mol%) were then added to the tube, the autoclave was
capped with a stopper and cooled with liquid N , and HCFC-
2
(
8) (a) Schiffer, M.; Scheer, M. Angew. Chem. Int. Ed. 2001, 40, 3413.
244bb (2.0 mL, 2.6 g) was added by self-suction. The mixture
was stirred at 100 °C for 5 h, then cooled to r.t. Excess HCFC-
(
6
b) Quntar, A. A. A.; Melman, A.; Srebnik, M. J. Org. Chem. 2002,
7, 3769.
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b) Zhou, C. X.; Larock, R. C. J. Org. Chem. 2006, 71, 3551.
244bb was carefully vented, and H O (30 mL) was added to the
2
(
mixture. The mixture was extracted with CH Cl (3 × 15 mL),
2
2
(
and the organic layers were combined, washed with brine,
dried (Na SO ), and concentrated under reduced pressure. The
(
(
(
(
(
10) (a) Zhao, B.; Lu, X. Org. Lett. 2006, 8, 5987. (b) Zhao, B.; Lu, X.
2
4
Tetrahedron Lett. 2006, 47, 6765.
11) Ueura, K.; Miyamura, S.; Satoh, T.; Miura, M. J. Organomet. Chem.
crude product was purified by column chromatography [silica
gel, hexane–EtOAc (20:1)] to give a colorless oil; yield: 142.9 mg
1
2
006, 691, 2821.
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736.
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016, 7, 5815.
(76%). H NMR (500 MHz, CDCl ): δ = 8.09 (d, J = 8.0 Hz, 2 H),
3
13
7.76 (d, J = 8.5 Hz, 2 H), 2.68 (s, 3 H). C NMR (125 MHz, CDCl ):
3
1
δ = 197.1, 139.8, 134.5 (q, JCF = 32.5 Hz), 128.7, 125.8 (q, J = 3.8
CF
Hz), 123.7 (q, JCF = 271.1 Hz), 26.9. 19F NMR (470 MHz, CDCl ):
3
2
δ = –63.1 (s, 3 F).
(16) 1-(4-Hydroxyphenyl)heptan-1-one (3i)
The reaction was carried as describe above with (4-hydroxy-
phenyl)boronic acid (1y; 1.0 mmol, 137.9 mg) and heptane-
(
2
nitrile (1.0 mL) to give a white solid; yield: 129.9 mg (63%); mp
1
62–63 °C. H NMR (500 MHz, CDCl ): δ = 7.91 (d, J = 8.5 Hz, 2 H),
3
2
6.91 (d, J = 9.0 Hz, 2 H), 6.67 (s, 1 H), 2.92 (t, J = 8.0 Hz, 2 H),
(
15) 1-[4-(Trifluoromethyl)phenyl]ethanone (3i); Typical Proce-
1.75–1.69 (m, 2 H), 1.40–1.35 (m, 2 H), 1.32–1.30 (m, 4 H), 0.88
13
dure
(t, J = 7.0 Hz, 3 H). C NMR (125 MHz, CDCl ): δ = 200.3, 160.5,
3
The reaction was carried out in an autoclave containing a 10 mL
130.8, 129.9, 115.4, 38.4, 31.7, 29.1, 24.8, 22.5, 14.0.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D