Nickel-Catalyzed Coupling of Azoles with Aromatic Nitriles

Article abstract of DOI:10.1021/acs.orglett.7b01938

This manuscript describes the Ni-catalyzed coupling of azoles with aromatic nitriles. The use of BPh₃ promotes these arylations with electronically diverse azoles and benzonitriles. While the nickel catalyst is necessary for the arylations of phenyl oxazoles, arylation of benzoxazoles with some nitriles affords the arylated products even in the absence of the Ni catalyst albeit in lower yield than the catalyzed process. The Ni-catalyzed process exhibits higher rates and a broader scope than the uncatalyzed transformation.

Full text of DOI:10.1021/acs.orglett.7b01938

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Coupling of Azoles with Aromatic Nitriles
Mckenna G. Hanson, Noelle M. Olson, Zubaoyi Yi, Grace Wilson, and Dipannita Kalyani*
Department of Chemistry, St. Olaf College, 1520 St. Olaf Avenue, Northfield, Minnesota 55057, United States
S
* Supporting Information
ABSTRACT: This manuscript describes the Ni-catalyzed coupling of
azoles with aromatic nitriles. The use of BPh3 promotes these arylations
with electronically diverse azoles and benzonitriles. While the nickel catalyst
is necessary for the arylations of phenyl oxazoles, arylation of benzoxazoles
with some nitriles affords the arylated products even in the absence of the
Ni catalyst albeit in lower yield than the catalyzed process. The Ni-
catalyzed process exhibits higher rates and a broader scope than the uncatalyzed transformation.
Table 1. Optimization of Direct Arylation
iverse aromatic nitriles are relatively inexpensive, bench
1
Dstable, and commercially available.
Furthermore, the
robust CN group is retained in many transition-metal-catalyzed
reactions, thereby enabling the late-stage derivatization of this
functionality in a multistep synthesis.1 Despite these advan-
tages, only a few sporadic reports on biaryl synthesis using
aromatic nitriles have been published.2 These include Ni-
catalyzed cross-couplings of aryl nitriles with aryl magnesium,2b
boron,2c or manganese reagents.2d As part of our program on
transition-metal-catalyzed arylations,3 this paper describes the
hitherto unknown biaryl formation via Ni-catalyzed direct
arylation using aromatic nitriles. These arylations expand the
repertoire of electrophiles for Ni-catalyzed C−H arylations,
which are thus far limited to the use of aryl halides, phenolic,
and ester electrophiles.4−7 Importantly, previous reports on Ni-
catalyzed direct arylations demonstrate the preferential
functionalization of the pivalate, carbamate, or chloride leaving
groups in the presence of an aryl nitrile.5c,e Hence, the method
described herein may enable selective arylations of the pivalate
(or chloride and carbamate) and nitrile leaving groups at
different stages in a multistep synthesis. Furthermore, the
arylations detailed in this manuscript are a timely contribution
to the recent surge in interest for the development of
transformations using earth-abundant metal catalysts.4,8
i
entry
ligand
base
additive
yield of 1a (%)
1
dcype
dcype
dcype
dcype
dcype
dcype
dcype
none
Cs2CO3
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
none
none
none
none
none
none
KCN
none
none
BPh3
BPh3
BPh3
62
59
59
71
26
33
23
0
a
2
3
4
5
6
7
8
9
b
b
b
b
b
b
,
,
,
,
,
c
c
,
d
e
f
f
dcype
dcype
dcype
none
0
b
b
b
,
,
,
c
c
,
,
g
10
11
12
61
63
0
h
f,g
a
b
c
Conducted at 160 °C. 3.0 equiv of K3PO4 used. Ni(COD)2 (10
d
e
mol %) and dcype (11 mol %) used. Reaction time was 48 h. KCN
(1.0 equiv) added. General conditions, but with no Ni(COD)2. 40
mol % of BPh3 used. 60 mol % of BPh3 used. Calibrated GC yields
f
g
h
i
against hexadecane as the internal standard.
The commonly proposed mechanism for nickel-catalyzed
direct arylation involves three key steps: oxidative addition, C−
H activation, and reductive elimination.4,9 Although biaryl
synthesis via C−H arylation using nitriles has remained elusive,
the three elementary steps in the mechanism are individually
documented using nickel complexes, thereby supporting the
feasibility of the proposed arylations.10
Our studies commenced with the investigation of reaction
parameters for the arylation of phenyl oxazole 1 with 3-
trifluoromethylbenzonitrile. These explorations began with the
use of catalyst/ligand combinations that have been previously
successful for Ni-catalyzed direct arylations.4,5 As shown in
Table 1, product 1a is obtained in moderate yield using the
Ni(COD)2/dcype catalyst combination in the presence of
Cs2CO3 as the base and diglyme as the solvent at 140 or 160
°C (entries 1 and 2). Ligands similar to dcype afford lower or
comparable yields of the desired product.11 Use of 1.5 equiv of
either Cs2CO3 or K3PO4 affords similar yields of 1a (entries 1
and 3). However, an increased amount of K3PO4 leads to
enhanced yields of 1a (entries 3 and 4). Lower catalyst loadings
result in diminished yields of 1a over 24 or 48 h (entries 5 and
6). Previous reports on Ni-catalyzed cross-couplings use Lewis
acids to accelerate the transformations involving aryl nitriles.12
Hence, a number of Lewis acids (CuF2, ZnCl2, AlMe2Cl, BPh3)
were evaluated for the formation of 1a.11 This study revealed
that the use of BPh3 (40 mol %) affords 1a with lower catalyst
loadings (10 mol % Ni(COD)2) in yields comparable to that
Received: June 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01938
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
obtained in the absence of BPh3 with 20 mol % Ni(COD)2 (cf.
entries 4 and 10). Use of 40 or 60 mol % BPh3 affords similar
yields of 1a (entries 10 and 11). No product is obtained in the
absence of Ni(COD)2 both in the presence and absence of
BPh3 (entries 8, 9, and 12). To obtain preliminary insight into
the role of BPh3, we monitored the reaction profile of arylations
with and without BPh3 using 10 mol % of Ni(COD)2.11 These
studies show that the reaction without BPh3 levels off at about
30% yield of 1a after 1 h. However, the arylation with BPh3
keeps progressing even after 3 h. Importantly, there is a very
small difference in the initial rates of the two transformations.
Taken together, these data suggest that BPh3 might be
suppressing catalyst deactivation possibly by sequestering the
cyanide anion. This hypothesis is consistent with the lower
yields of 1a from the Ni-catalyzed reaction in the presence of
KCN (entry 7).13
Table 2. Arylation of 5-Methylbenzoxazole
a
entry
ligand
base
time (h)
yield of 11a (%)
1
2
dcype
dcype
dcype
none
none
dcype
none
dcype
none
Cs2CO3
K3PO4
24
24
24
24
24
8
77
71
48
27
23
79
7
b
3
Cs2CO3
Cs2CO3
K3PO4
c
4
c
5
6
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
c
7
8
b,d
8
9
24
24
74
c,d
0
The optimal conditions for the formation of 1a with or
without BPh3 (Table 1, entries 4 and 10) can be applied to the
arylation of electronically varied oxazoles (Scheme 1). Electron-
a
b
Calibrated GC yields against hexadecane as the internal standard. 10
mol % of Ni(COD)2 and 11 mol % of dcype used. In the absence of
c
d
Ni(COD)2. 40 mol % of BPh3 was added.
a
Scheme 1. Scope of Oxazoles
These results suggest negligible contribution from the non-
catalyzed process to the formation of 11a in the presence of the
Ni(COD)2/dcype. Analogous to the arylations detailed in
Scheme 1, the use of BPh3 (40 mol %) enables the use of lower
catalyst loadings (cf. entries 1 and 8).11 Interestingly, however,
BPh3 suppresses the noncatalyzed arylation (cf. entries 4 and
9).17
These trends for the catalyzed and the noncatalyzed
arylations using 3-trifluoromethyl benzonitrile are observed
for electronically varied benzoxazoles (Scheme 2). Analogous
a
Scheme 2. Scope of Benzoxazoles
a
b
Isolated yields. Ni(COD)2 (10 mol %), dcype (11 mol %), and BPh3
(40 mol %) were used.
rich, electron-neutral, and electron-deficient oxazoles afford the
corresponding products in comparable yields (cf. 1a−3a).
Analogous to the formation of 1a (Table 1), the use of BPh3
with 10 mol % of Ni(COD)2 affords the arylated products in
yields comparable to that obtained using 20 mol % of
Ni(COD)2 regardless of azole electronics. Importantly, no
product is obtained in the absence of Ni(COD)2/dcype
regardless of the oxazole substrate.
a
b
Isolated yields Yields for reactions in the absence of Ni(COD)2 and
c
dcype. Yields using BPh3 (40 mol %) as additive, Ni(COD)2 (10 mol
%), and dcype (11 mol %). Calibrated GC yields against hexadecane
as the standard. dcypt was used in place of dcype.
d
e
We next investigated the use of benzoxazoles in these
arylations. Not surprisingly, the Ni-catalyzed coupling of 5-
methyl benzoxazole with 3-trifluoromethyl benzonitrile affords
11a in good yield using Cs2CO3 or K3PO4 (Table 2, entries 1
and 2). Unlike the coupling of phenyl oxazoles (Scheme 1),
product 11a is formed in significant amounts (23−27%
yield)14,15 in the absence of the nickel catalyst possibly via a
SNAr pathway (entries 4−5).16 The catalyzed arylation is
significantly faster, affording 11a in 79% yield over 8 h (versus
7% yield from the noncatalyzed process, cf. entries 6 and 7).
to arylations in Scheme 1, BPh3 promotes these arylations
regardless of benzoxazole electronics. The noncatalyzed
arylation affords the arylated products in yields ranging
between 14 and 68%. In the absence of Ni(COD)2/dcype,
the highest yield (68%) of the arylated product (17a) is
observed for the electron-deficient, fluoro-substituted benzox-
azole substrate. The extent of the background reaction is
diminished for electron-rich and electron-neutral azoles. The
B
DOI: 10.1021/acs.orglett.7b01938
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
nickel catalyst is essential for the formation of product 18a
from the arylation of the less acidic benzothiazole substrate.18
Electronically diverse aryl and heteroaryl nitriles couple with
5-methylbenzoxazole and aryl oxazoles to afford the products in
modest to good yields (Scheme 3). The lowest yield was
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01938.
■
S
a
Experimental procedures (PDF)
1H and 13CNMR spectra (PDF)
Scheme 3. Scope of Nitriles
AUTHOR INFORMATION
■
Corresponding Author
*Tel: 507 786 3740. E-mail: kalyani@stolaf.edu.
ORCID
Dipannita Kalyani: 0000-0003-4349-8016
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NIH NIGMS (R15
GM107892), NSF (CHE-1554630), and St. Olaf College.
The authors acknowledge St. Olaf College undergraduate
students Deborah Steinberg and Ryan Walser-Kuntz for
assisting with synthesis of oxazole substrates and rate studies.
REFERENCES
a
b
c
■
Isolated yields dcypt used instead of dcype. Yields for reactions in
d
(1) (a) Wen, Q.; Lu, P.; Wang, Y. RSC Adv. 2014, 4, 47806−47826.
(b) Wang, R.; Falck, J. R. RSC Adv. 2014, 4, 1062−1066. (c) Souillart,
L.; Cramer, N. Chem. Rev. 2015, 115, 9410−9464. (d) Chen, F.;
Wang, T.; Jiao, N. Chem. Rev. 2014, 114, 8613−8661. (e) Ruhland, K.
Eur. J. Org. Chem. 2012, 2012, 2683−2706. (f) Blaser, H. − U.;
Indolese, A.; Naud, F.; Nettekoven, U.; Schnyder, A. Adv. Synth. Catal.
2004, 346, 1583−1598.
the absence of Ni(COD)2 and dcype. Yields using BPh3 (40 mol %)
as additive, Ni(COD)2 (10 mol %), ligand (11 mol %). Calibrated
GC yields against hexadecane as the standard. K3PO4 (3.0 equiv) used
as the base.
e
f
(2) (a) Tobisu, M.; Kita, Y.; Ano, Y.; Chatani, N. J. Am. Chem. Soc.
2008, 130, 15982−15989. (b) Miller, J. A. Tetrahedron Lett. 2001, 42,
6991−6993. (c) Yu, D.-G.; Yu, M.; Guan, B.-T.; Li, B.-J.; Zheng, Y.;
Wu, Z.-H.; Shi, Z.-J. Org. Lett. 2009, 11, 3374−3377. (d) Liu, N.;
Wang, Z. Adv. Synth. Catal. 2012, 354, 1641−1645.
(3) (a) Nervig, C. S.; Waller, P. J.; Kalyani, D. Org. Lett. 2012, 14,
4838−4841. (b) Wang, J.; Ferguson, D.; Kalyani, D. Tetrahedron 2013,
69, 5780−5790. (c) Ferguson, D.; Rudolph, S. R.; Kalyani, D. ACS
Catal. 2014, 4, 2395−2401. (d) Steinberg, D. F.; Turk, M. C.; Kalyani,
D. Tetrahedron 2017, 73, 2196−2209.
(4) (a) Yamaguchi, J.; Muto, K.; Itami, K. Eur. J. Org. Chem. 2013,
2013, 19−30. (b) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Nature
2014, 509, 299−309. (c) Cai, X.; Xie, B. ARKIVOC 2015, 184−211.
(d) Khan, M. S.; Haque, A.; Al-Suti, M. K.; Raithby, P. R. J. Organomet.
Chem. 2015, 793, 114−133. (e) Johnson, S. A. Dalton Trans. 2015, 44,
10905−10913. (f) Ananikov, V. P. ACS Catal. 2015, 5, 1964−1971.
(g) Hyster, T. K. Catal. Lett. 2015, 145, 458−467.
(5) (a) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009,
11, 1737−1740. (b) Amaike, K.; Muto, K.; Yamaguchi, J.; Itami, K. J.
Am. Chem. Soc. 2012, 134, 13573−13576. (c) Muto, K.; Yamaguchi, J.;
Itami, K. J. Am. Chem. Soc. 2012, 134, 169−172. (d) Meng, L.;
Kamada, Y.; Muto, K.; Yamaguchi, J.; Itami, K. Angew. Chem., Int. Ed.
2013, 52, 10048−10051. (e) Muto, K.; Hatakeyama, T.; Yamaguchi, J.;
Itami, K. Chem. Sci. 2015, 6, 6792−67. (f) Muto, K.; Yamaguchi, J.;
Musaev, D. G.; Itami, K. Nat. Commun. 2015, 6, 7508. (g) Wang, Y.;
Wu, S. − B.; Shi, W. − J.; Shi, Z. − J. Org. Lett. 2016, 18, 2548−2551.
(6) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,
174−238. (b) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009,
38, 2447−2464. (c) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew.
Chem., Int. Ed. 2009, 48, 9792−9826. (d) Kuhl, N.; Hopkinson, M. N.;
Wencel-Delord, J.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 10236−
10254. (e) Segawa, Y.; Maekawa, T.; Itami, K. Angew. Chem., Int. Ed.
2015, 54, 66−81.
obtained for the reaction using the o-methyl benzonitrile to
afford 11j. Interestingly, the identity of the ortho substituent on
the nitrile is important since 11h and 11i were obtained in
significantly higher yields. Akin to the coupling of benzoxazoles
with 3-trifluoromethyl benzonitrile (Scheme 2), the non-
catalyzed arylation of benzoxazoles affords significant yields of
the biaryls with a few nitriles (Scheme 3). While no clear trends
emerge, the nickel catalyst is necessary for the formation of
biaryls using nitriles containing an ester (11f) or bearing a
methoxy group at the ortho- (11i) or para-positions (11g−h)
relative to the CN functionality. Furthermore, analogous to
results in Scheme 1, no product (1b−d,i,k) is obtained in the
absence of Ni(COD)2/dcype for arylations with phenyl oxazole
regardless of the nitrile substrate. Finally, BPh3 promotes the
arylations of oxazoles and benzoxazoles with electron-rich and
electron-deficient benzonitriles.
In summary, this paper describes the first example of Ni-
catalyzed arylation using electronically diverse azole and
benzonitriles. The use of BPh3 for these transformations
enables the use of lower catalyst loading regardless of the azole
or nitrile substrates. While the nickel catalyst is necessary for
the arylation of oxazoles, oxadiazole, and benzothiazole
subtrates, arylations of benzoxazoles can proceed in the
absence of Ni(COD)2/dcype. The extent of the noncatalyzed
process is dependent on the acidity of the azole and electronic
nature of the benzonitrile substrates. Furthermore, the
catalyzed process is significantly faster than the noncatalyzed
reaction. Overall, the scope and efficiencies of the Ni-catalyzed
arylation are higher than the noncatalyzed process.
C
DOI: 10.1021/acs.orglett.7b01938
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(7) (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2009, 48, 5094−5115. (b) Lyons, T. W.; Sanford, M. S. Chem.
Rev. 2010, 110, 1147−1169. (c) Gorelsky, S.; Lapointe, D.; Fagnou, K.
J. Org. Chem. 2012, 77, 658−668. (d) Kozhushkov, S. I.; Potukuchi, H.
K.; Ackermann, L. Catal. Sci. Technol. 2013, 3, 562−571.
(8) (a) Cahiez, G.; Moyeux, A. Chem. Rev. 2010, 110, 1435−1462.
(b) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.;
Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346−
1416. (c) Nakamura, E.; Hatakeyama, T.; Ito, S.; Ishizuka, K.; Ilies, L.;
Nakamura, M. Organic Reactions 2013, 83, 1−209. (d) Tekale, S. U.;
Jadhav, V. B.; Pagore, V. P.; Kauthale, S. S.; Gaikwad, D. D.; Pawar, R.
P. Mini-Rev. Org. Chem. 2013, 10, 281−301. (e) Mesganaw, T.; Garg,
N. K. Org. Process Res. Dev. 2013, 17, 29−39.
(9) (a) Muto, K.; Yamaguchi, J.; Lei, A.; Itami, K. J. Am. Chem. Soc.
2013, 135, 16384−16387. (b) Xu, H.; Muto, K.; Yamaguchi, J.; Zhao,
C.; Itami, K. J. Am. Chem. Soc. 2014, 136, 14834−14844. (c) Lu, Q.;
Yu, H.; Fu, Y. J. Am. Chem. Soc. 2014, 136, 8252−8260. (d) Li, Z.; Liu,
L. Chin. J. Catal. 2015, 36, 3−14.
(10) (a) Garcia, J. J.; Brunkan, N. M.; Jones, W. D. J. Am. Chem. Soc.
2002, 124, 9547−955. (b) Schaub, T.; Doring, C.; Radius, U. Dalton
̈
Trans. 2007, 1993−2002. (c) Abla, M.; Yamamoto, T. J. Organomet.
Chem. 1997, 532, 267−270. (d) Garcia, J. J.; Jones, W. D.
Organometallics 2000, 19, 5544−5545. (e) Garcia-Ventura, I.; Flores-
Alamo, M.; Garcia, J. J. RSC Adv. 2016, 6, 101259−10126.
(11) See the SI for detailed optimization. See Scheme S1 in the SI for
reaction profiles for arylations with and without BPh3.
(12) (a) Nakao, Y.; Yada, A.; Ebata, S.; Hiyama, T. J. Am. Chem. Soc.
2007, 129, 2428−2429. (b) Yada, A.; Yukawa, T.; Idei, H.; Nakao, Y.;
Hiyama, T. Bull. Chem. Soc. Jpn. 2010, 83, 619−634. (c) Yada, A.;
Ebata, S.; Idei, H.; Zhang, D.; Nakao, Y.; Hiyama, T. Bull. Chem. Soc.
Jpn. 2010, 83, 1170−1184.
(13) Alternatively, BPh3 might also be promoting the oxidative
addition and C-H activation steps.
(14) The noncatalyzed reaction proceeds to the same extent when
commercial 5-methyl benzoxazole is used with or without further
recrystallization. Anhydrous Cs2CO3 (99.995%) and K3PO4 (97%)
were used for these reactions. The low yield of 11a from the
noncatalyzed reaction is due to low conversions.
(15) Use of stronger bases (MOtBu, M = Li, Na or K) affords 11a in
at most 4% yield from the noncatalyzed arylation (Table S2 , SI).
(16) Thompson, A. D.; Huestis, M. P. J. Org. Chem. 2013, 78, 762−
769.
(17) BPh3 may inhibit the uncatalyzed reaction by complexing with
the deprotonated azole. However, further studies are needed to
support this hypothesis.
(18) Shen, K.; Fu, Y.; Li, J. − N.; Liu, L.; Guo, Q. − X. Tetrahedron
2007, 63, 1568−1576.
D
DOI: 10.1021/acs.orglett.7b01938
Org. Lett. XXXX, XXX, XXX−XXX