Catalytic arylation of a C-H bond in pyridine and related six-membered N-heteroarenes using organozinc reagents

Article abstract of DOI:10.1002/asia.201100971

Despite significant advances in the catalytic direct arylation of heteroarenes, the application of this reaction to pyridines has been met with limited success. An oxidative nucleophilic arylation strategy has been developed to overcome this problem. Pyridine, pyrazine, quinolone, and related electron-deficient N-heteroarenes can be arylated at the most electrophilic site using the developed nickel-catalyzed reaction. This protocol serves as a complementary method to catalytic direct arylation reactions. Less is more: Pyridine, pyrazine, quinoline and related electron-deficient N-heteroarenes can be arylated at the most electrophilic site using organozinc reagents through nickel catalysis. This protocol serves as a complementary method to catalytic direct arylation reactions. Copyright

Full text of DOI:10.1002/asia.201100971

DOI: 10.1002/asia.201100971
À
Catalytic Arylation of a C H Bond in Pyridine and Related Six-Membered
N-Heteroarenes Using Organozinc Reagents
Isao Hyodo,[a] Mamoru Tobisu,*[a, b] and Naoto Chatani*[a]
Abstract: Despite significant advances in the catalytic direct arylation of heteroar-
enes, the application of this reaction to pyridines has been met with limited suc-
cess. An oxidative nucleophilic arylation strategy has been developed to overcome
this problem. Pyridine, pyrazine, quinolone, and related electron-deficient N-heter-
oarenes can be arylated at the most electrophilic site using the developed nickel-
catalyzed reaction. This protocol serves as a complementary method to catalytic
direct arylation reactions.
Keywords: cross-coupling · hetero-
cycles · homogeneous catalysis ·
nickel · zinc
Introduction
The catalytic direct arylation of heteroarenes has emerged
as an atom-economical alternative to the traditional cross-
coupling between organohalides and organometallic species
for constructing heteroaryl–aryl linkages, which constitute
an important class of substructures found in natural and
non-natural products.[1] Important studies in this area during
the last decade have delivered a number of catalytic proto-
cols that allow direct arylation of two classes of heteroar-
enes: electron-rich species (Figure 1a) and those bearing
[2]
À
a relatively acidic C H bond (Figure 1b). However, meth-
Figure 1. Classification of heteroarenes.
ods that are applicable to electron-deficient heteroarenes,
such as pyridine, pyrazine, and pyrimidine (Figure 1c),
which would produce heterobiaryls with widespread utility
(Figure 2), have been slower to develop.[3] The difficulty as-
sociated with arylation of these heteroarenes stems primari-
ly from the fact that the majority of direct arylation reac-
tions depend upon electrophilic aromatic substitution
(SEAr) or concerted metalation/deprotonation (CMD)
mechanisms.[4] These mechanisms are inherently unsuitable
for electron-deficient and non-acidic heteroarenes. A partial
solution to this issue has been provided by using pyridine N-
oxide[5a,b] and related N-activated analogues,[5c,d] directing
groups,[6] or intramolecular settings,[7] but a more straightfor-
ward and general method is desired.[8] At the time we began
this study in 2008, no catalytic methods for the direct aryla-
tion of pyridines were available, with the notable exception
of the work by Bergman and Ellman et al. using a rhodium
catalyst.[9,10] In 2011, Chang and co-workers reported RhII/
N-heterocyclic carbene catalyzed C4-arylation of quino-
lines.[11] Quite recently, palladium-catalyzed C3-arylation of
pyridines was reported by Yu and co-workers.[12]
Our approach to solving the problem of pyridine arylation
stems from the classical two-step procedure depicted in
Scheme 1a. Aryl lithium and magnesium reagents are
known to add across pyridines in a 1,2-fashion to form dihy-
dropyridines 1, which subsequently rearomatize to furnish 2-
aryl pyridines upon oxidation.[13] The overall sequence falls
in a general class of reaction known as oxidative nucleophil-
ic substitution of hydrogen.[14] The 1,2-dearomatizing addi-
tion/oxidative rearomatization approach would serve as
a versatile strategy for the arylation of electron-deficient
heteroarenes, and complement to the SEAr and CMD path-
ways, if the reaction could meet the following criteria:
1) use of less aggressive aryl nucleophiles, such as organo-
zinc or -boron compounds, and 2) the unstable dihydropyri-
[a] I. Hyodo, Dr. M. Tobisu, Prof. Dr. N. Chatani
Department of Applied Chemistry
Faculty of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
Fax : (+81)6-6879-7396
E-mail: chatani@chem.eng.osaka-u.ac.jp
[b] Dr. M. Tobisu
Center for Atomic and Molecular Technologies
Graduate School of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
Fax : (+81)6-6879-7395
E-mail: tobisu@chem.eng.osaka-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100971.
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(Scheme 1b). A mild arylating agent (Ar M) initially gener-
À
ates a more reactive aryl metal species 2 (Ar m, where m is
the catalytic metal center) by transmetalation. 1,2-Addition
of 2 across pyridine then forms dihydropyridine intermedi-
ate 3, which affords an aromatized product through b-hydro-
gen elimination. The addition of an external oxidant allows
for catalyst turnover by oxidizing metal hydride 4. In the
preliminary studies, this working catalytic reaction can be
realized by using organozinc reagents as aryl donor.[15] A no-
table feature of this methodology is that the organozinc re-
agent functions both as an aryl donor and oxidant, thus ob-
viating the need for additional external oxidants. Herein, we
describe this catalytic arylation of electron-deficient hetero-
arenes using organozinc reagents in detail, including prepa-
rative and mechanistic aspects.
Results and Discussion
Investigation based upon the working hypothesis outlined in
Scheme 1 identified diaryl zinc reagents as viable aryl donor
species.[16] For example, reaction of quinoline (5) with diphe-
nylzinc (6) in the presence of PdACHTNUTRGNEUNG(OAc)2/PCy3 catalyst af-
forded 2-phenylquinoline (7) in 15% yield (entry 2 in
Figure 2. Examples of biaryls containing six-membered N-heteroarenes.
Table 1). We initially expected that the addition of an oxi-
Table 1. Catalytic phenylation of quinoline (5) using diphenylzinc (6):
Catalyst screening.[a]
Entry
Catalyst
none
Yield of 7 [%][b]
1
0
2
3
4
Pd
Cu
[{RhCl
[Ni(cod)2]
[NiCl2A(PCy3)2]
G
15
16
38
99
33
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
5
ACHTUNGTRENNUNG
6[c]
E
CHTUNGTRENNUNG
[a] Reaction conditions:
(0.013 mmol), PCy3 (0.025 mmol), and toluene (1.0 mL) in
capped vial under N2 at 808C for 20 h. [b] Yield of isolated product
based on 5. [c] Run in the absence of PCy3.
5
(0.25 mmol),
6
(0.38 mmol), catalyst
Scheme 1. Dearomatizing 1,2-addition/oxidative rearomatization strategy
for arylation of pyridines.
a screw-
dine intermediate 1 should not need to be isolated, allowing
for a one-pot protocol. We postulated a simple catalytic
cycle that can accommodate the above requirements
dant may improve the yield of 7 by promoting the catalyst
À
regeneration process, as is the case for C H bond function-
alization reactions using organometallic reagents.[17] Howev-
er, addition of external oxidants gave no improvements. Fur-
ther catalyst screening identified that CuII and RhI com-
plexes exhibited promising levels of catalytic activity
(Table 1, entries 3 and 4). Finally, it was found that quantita-
Abstract in Japanese:
tive formation of 7 was achieved with [NiACHTUNTGRNEUNG(cod)2]/PCy3 cata-
lyst (Table 1, entry 5; cod=1,5-cyclooctadiene).[18] The reac-
tion mixture contained a precipitate of metallic zinc, indicat-
ing that zinc reagent 6 also acts as a stoichiometric oxidant
(see below for the discussion of a plausible mechanism).
The use of air-stable [NiCl2ACHTNUGTRNEUNG(PCy3)2] as a catalyst precursor
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Catalytic Arylation of a C H Bond in Pyridine Using Organozinc Reagents
resulted in a significant reduction in the yield of 7 (Table 1,
entry 6).
tained after protic quenching was 1,6-dihydro-2-methyl-6-
phenyl-pyrimidine (8), which is an addition product.[13e]
Unlike other heteroarenes, in situ oxidative rearomatization
did not proceed with pyrimidines, even at elevated tempera-
ture. The desired aromatized product was obtained quantita-
tively simply by treating the reaction mixture with 2,3-di-
Having an optimal catalyst in hand, we next explored the
scope of this direct arylation reaction. Initially, simple six-
membered N-heteroarenes and their benzo-fused analogues
were examined to identify the scaffolds suitable for this cat-
alytic direct arylation reaction (Table 2). Pyridine required
harsher reaction conditions (1308C, 3 equiv 6) than those
employed for quinoline (Table 2, entry 1 vs. entry 6). This
trend in reactivity is similar to those observed for 1,2-dearo-
matizing addition of Grignard or organolithium reagents.[13a]
Introducing another nitrogen atom into the pyridine ring led
to an significant increase in the reactivity toward this nickel-
catalyzed arylation. Pyrazine afforded a 2-phenylated prod-
uct in 81% yield at 1008C using 1.5 equiv 6 (Table 2,
entry 2). Although pyrimidine itself did not react, 2-methyl-
pyrimidine proved to be reactive. However, the product ob-
chloro-5,6-dicyano-1,4-benzoquinone
entry 3).[19] As observed for quinoline (Table 2, entry 4), six-
membered heteroarenes bearing fused benzene ring
(DDQ;
Table 2,
a
proved excellent substrates. Isoquinoline underwent aryla-
tion at the 1-position in a regioselective manner (Table 2,
entry 5).[13b] Quinoxaline is more reactive than pyrazine to
form mono- and diarylated products at 808C (Table 2,
entry 6). A diarylated product was formed exclusively by
using an excess amount of 6 (Table 2, entry 7). It should be
noted that selective monoarylation is possible using a less
reactive ArZnEt reagent (see below). Heteroarenes embed-
ded in an extended p system, such as in phenanthridine, can
be arylated under milder conditions (Table 2, entries 9 and
10). As revealed in Table 2, the reactivity and regioselectivi-
ty profiles are predictable on the basis of those observed in
1,2-dearomatizing addition using Grignard and organolithi-
um reagents.[13] Consistent with our working hypothesis,
electron-rich heteroarenes, such as indole and benzofuran,
Table 2. Nickel-catalyzed phenylation of heteroarenes using 2: Scope of het-
eroarenes.[a]
À
and those bearing an acidic C H bond, including azoles and
perfluorinated arenes, cannot be arylated under our catalytic
conditions, although these are excellent substrates under the
reported direct arylation reaction conditions (Figure 3).[2]
Entry Heteroarene
1[c]
T [8C] Product
Yield [%][b]
55
130
2
100
81
3
4
60
80
54[d]
99
5[e]
100
90
Figure 3. Inapplicable substrates.
6
80
100
66 (1:1)[f]
74 (0:1)[f]
7[c]
The regioselectivity observed with azine and azole fused sys-
tems further underscores the complementary nature of the
present methodology to direct arylation methods. Oxidative
8[e]
70
60
88
nucleophilic arylation of an imidazoACHTUNTRGNEUNG[1,2-a]pyrazine skeleton
9
>99
9 proceeded regioselectively at the most electrophilic 8-posi-
tion to form 10 (Scheme 2).[20] Interestingly, a rhodium cata-
lyst, rather than [NiACTHNUTRGNEUNG(cod)2]/PCy3 proved suitable for the ary-
10[c]
100
95
lation of this specific substrate.[21] In contrast, electrophilic
arylation using phenyl iodide under palladium catalysis de-
livered 3-phenylated product 11 in
a
regioselective
manner.[22]
Several common functional groups are compatible with
this nickel-catalyzed arylation reaction (Table 3). Chloro
(Table 3, entry 1), methoxy (Table 3, entry 2), and amino
(Table 3, entry 3) groups on the quinoline ring remained
intact under these conditions. Esters can also survive, which
is a notable advantage using organozinc reagents (Table 3,
[a] Reaction conditions: heteroarene (0.25 mmol), 6 (0.38 mmol), [NiACTHNUTRGNE(UNG cod)2]
(0.013 mmol), PCy3 (0.025 mmol), and toluene (1.0 mL) in a screw-capped
vial under N2 for 20 h. [b] Yield of isolated product based on heteroarene.
[c] Using 0.75 mmol 6. [d] The initial product was dihydropyrimidine 8. The
yield was determined after oxidation of 8 with DDQ. [e] Using 0.50 mmol 6.
[f] The ratio in the parentheses is that for mono- to diarylated products.
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entry 4). Although an electronically diverse array of quino-
lines efficiently afford 2-arylated products under optimized
conditions, their reactivities are significantly different. Elec-
tron-deficient substrates are generally arylated more rapidly
(Scheme 3).[23] This catalytic arylation is tolerant to steric
À
Scheme 2. Regioselective C H arylations of imidazo
N
Scheme 3. Electronic effect of N-heteroarenes.
Table 3. Nickel-catalyzed phenylation of heteroarenes using 6: Functional
group compatibility.[a]
hindrance. 3-Substituted quinolines successfully underwent
the arylation at the sterically congested C2-position to deliv-
er 2,3-disubstituted quinolines (Table 3, entries 6 and 7).
Moreover, introduction of a C8 substituent, which imposes
a steric demand around a ring nitrogen atom, did not inter-
fere the arylation (Table 3, entry 8). The present protocol
can be used not only to construct heterobiaryls, but also to
elaborate them (Table 3, entries 9–11). Of note is the high
reactivity of 2,2’-bipyridine, which successfully afforded
a monophenylated product in a selective manner, even in
the presence of excess 6.[13c] The reaction should be applica-
ble to the synthesis of a range of C1-symmetric 2,2’-bipyri-
dine ligands.
Entry Heteroarene
1
T [8C] Product
Yield [%][b]
94
130
2
3
160
160
94
70
In the course of our investigation, we noticed that the effi-
ciency of catalysis is highly dependent on the method used
to prepare the organozinc reagent. We used commercially
available solid Ph2Zn (6), which successfully participated in
the nickel-catalyzed arylation as described thus far. In con-
trast, no desired arylated product was obtained in the aryla-
tion of 5 when Ph2Zn solution prepared by the reaction of
ZnCl2 with two equivalents of PhMgBr or PhLi was used.
These results indicate that the presence of concomitant
metal salts such as MgX2 or LiX may have a detrimental
effect on the nickel-catalyzed process.[24,25] Indeed, the yield
of 7 was significantly improved (68%) by using salt-free
Ph2Zn solution prepared through the Charette and Cꢁtꢂꢃs
4
5
80
61
99
130
6
7
160
160
90
99
8
160
88
procedure (2PhMgBr+ZnACHTNUTGRNEUNG
(OMe)2; filtration).[26] As an alter-
native metal-free protocol for the preparation of diorgano-
zinc reagents, transmetalation from organoboron reagents
was next examined.[27] Among those examined, zinc reagents
prepared by the method of Fu and Smith, wherein aryl bor-
onic acids were treated with Et2Zn to generate ArZnEt,[27b]
proved the most effective aryl donors for arylation of elec-
tron-deficient heteroarenes using the developed reaction. As
shown in Table 4, a diverse range of aryl groups, which are
derived from readily available aryl boronic acids, can be in-
corporated into a quinoline core. Functional groups includ-
ing ethers (entries 3, 8, and 12), amines (entry 4), sulfides
(entry 5), fluorides (entry 6), esters (entry 10) and chlorides
(entry 12) are compatible with this arylation reaction. The
9[c]
10[c]
11
100
130
60
45
71
78[d]
[a] Reaction conditions: heteroarene (0.25 mmol), 6 (0.50 mmol), [NiACTHNUTRGNE(UNG cod)2]
(0.013 mmol), PCy3 (0.025 mmol), and toluene (1.0 mL) in a screw-capped
vial under N2 for 20 h. [b] Yield of an isolated product based on heteroarene.
[c] Using 0.75 mmol 6. [d] The initial product was dihydropyrimidine 8. The
yield was determined after oxidation of 8 with DDQ.
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Catalytic Arylation of a C H Bond in Pyridine Using Organozinc Reagents
Table 4. Scope of organozinc reagents.[a]
Entry Ar
1
Yield Entry Ar
[%][b]
Yield
[%][b]
75
8
86
Scheme 4. Sequential direct arylations of a quinoxaline scaffold.
2
97
9
71
3
4
97
93
10
11
31
90
5
56
12
13
51
65
6
7
56
63
Scheme 5. Cyclization/direct arylation tandem reaction.
[a] Reaction conditions: ArB(OH)2 (0.75 mmol) and ZnEt2 (1.1 mmol) in
dioxane (0.5 mL) at 608C for 12 h; (0.25 mmol), [Ni(cod)2]
5
ACHTUNGTRENNUNG
(0.013 mmol), and PCy3 (0.025 mmol) in toluene (1.0 mL) at 1308C for
20 h. [b] Yields of isolated product based on 5.
and Et2Zn did not react with pyridine and quinoline, iPr2Zn
(17) proved to be a potential nucleophile (Scheme 6). For
example, the reaction of 4-phenylpyridine (18) with 17 in
tolerance for a wide range of functionalities highlights the
advantage of using organozinc reagents in view of the po-
the presence of CuACHTGUNTERNNU(G OAc)/4,4’-di-tert-butylbipyridine catalyst
[28]
[29]
[30]
[31]
À
À
C S,
À
C F,
À
tential reactivity of C O,
and C Cl
bonds under Ni0 catalysis when more nucleophilic Grignard
reagents are employed. The electronic nature of the aryl
group on the zinc reagent has a significant impact: arylation
proceeds more efficiently with an electron-rich donor than
with an electron-deficient donor, as anticipated in our initial
reaction design.
Use of ArZnEt reagents allows for sequential diarylation
of heteroarenes containing two possible reaction centers.
For example, two different aryl groups can be introduced
onto a quinoxaline scaffold through two nickel-catalyzed ar-
ylations using different aryl zinc reagents (Scheme 4).[32]
More elaborate aryl zinc reagents can also be used in the
developed reaction. Nakamura et al. reported that treatment
of 2-alkynyl aniline derivatives, such as 15, with n-butyllithi-
um, followed by reaction with ZnCl2, generates 2-indolylzinc
reagents, which are amenable to various transformations, in-
cluding Negishi-type cross-coupling.[33] The nickel-catalyzed
reaction of the 2-indolylzinc generated from 15 with 5 suc-
cessfully delivered a cross-coupled product 16, further high-
lighting the synthetic utility of this methodology (Scheme 5).
Oxidative nucleophilic alkylation using the corresponding
alkyl zinc reagents was examined briefly. Although Me2Zn
Scheme 6. Catalytic alkylation of pyridines and quinolines.
afforded 2-alkylated product 19.[34] Interestingly, when an
analogous alkylation reaction was applied to a quinoline
ring system, an isopropyl group was selectively introduced
at the 4-position, a completely different regioselectivity to
that using Ph2Zn (see entry 3 in Table 1).[34]
To probe the intermediacy of 1,2-dearomatized adduct (3
in Scheme 1), the reaction of 2-phenyl-1,2-dihydroquinoline
(22) was examined under several conditions. It was found
that dehydrogenative aromatization of 22 occurs at ambient
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temperature upon treatment with 6, even in the absence of
a nickel catalyst (Scheme 7). Accordingly, after the forma-
tion of the postulated 1,2-dearomatized adduct, the hydro-
gen atom at the 2-position is eventually abstracted by an or-
to electrophilically activate pyridine substrates and strength-
en their interaction with electron-rich nickel species, 2) as
a mild aryl donor, and 3) as an oxidant to rearomatize the
1,2-addition product.
Conclusions
A catalytic variant of the classical two-step protocol for the
C2-functionalization of pyridines using Grignard or organo-
lithium reagents has been developed. The use of diorgano-
zinc reagents renders the reaction one-step, catalytic, and
functional-group-tolerant. [NiACHTNUTRGNEUNG(cod)2]/PCy3 proved the best
Scheme 7. Rearomatization of dihydroquinoline 22 with Ph2Zn (6).
catalyst, and zinc reagents prepared from aryl boronic acids
bearing an array of functional groups were successfully em-
ployed. The methodology allows straightforward access to
a range of arylated pyridines and related N-heteroarenes,
which are poor substrates for the catalytic direct arylation
reaction. The nucleophilic oxidative arylation reaction de-
ganozinc species like 23, rather than through b-hydrogen
elimination from a nickel-amide intermediate, as in 3 (m=
Ni). Indeed, NMR spectroscopy studies of a nickel-catalyzed
reaction of 2-deuteroquinoline with 6 indicates the forma-
tion of deuterobenzene.[35]
On the basis of the observations described above, a ration-
al mechanistic framework for the nickel-catalyzed direct ar-
ylation of pyridine using 6 is outlined in Scheme 8. Ni0 spe-
À
veloped here provides a strategy for C H functionalization
of heteroarenes that is complementary to the well-estab-
lished direct arylations by SEAr and CMD pathways in
terms of both applicable substrates and regioselectivity. Fur-
ther development of alternative strategies for the functional-
À
ization of C H bonds is in progress.
Experimental Section
General information
1H NMR and 13C NMR spectra were recorded on a JEOL JMN-270,
JEOL ECS-400, or JEOL ECP-400 spectrometer in CDCl3 with tetrame-
thylsilane as an internal standard. Data are reported as follows: chemical
shift in ppm (d), multiplicity (s=singlet, d=doublet, t=triplet, q=quar-
tet, sext=sextet, sept=septet, br=broad and m=multiplet), coupling
constant (Hz), integration, and interpretation. Infrared spectra (IR) were
obtained on a Horiba FT-720 spectrometer. Mass spectra were obtained
on a Shimadzu GCMS-QP 5000 or GCMS-QP 2010 instrument with ioni-
zation voltages of 70 eV. Melting points were determined on a Yamato
melting point apparatus and are uncorrected. Elemental analyses and
high-resolution mass spectra (HRMS) were performed by the Elemental
Analysis Section of Osaka University. Flash column chromatography was
performed with SiO2 (Silicycle Silica Flash F60 (230–400 mesh)). All cat-
alytic reactions were carried out in 10 mL sample vials with a Teflon-
sealed screw cap in a glovebox filled with N2.
Scheme 8. Possible mechanism.
cies A initially reacts with diphenylzinc–pyridine adduct B
to form azanickelacyclopropane C. An analogous intermedi-
ate was proposed in the nickel(0)-mediated addition of
AlMe3 across imines.[36] An intramolecular phenyl transfer
(better described as intramolecular transmetalation between
nickel(II) amide and diphenylzincate) affords a nickel spe-
cies D,[37] which subsequently liberates a Ni0 catalyst A
along with zinc amide E by reductive elimination. In the
case of pyrimidine substrates, intermediate E was intercept-
ed by protonation to give 1,2-addition products (entry 3 in
Scheme 2). For other heteroarenes, zinc amide species such
as E underwent rapid oxidative rearomatization, leading to
arylated products (Scheme 7). In this step, a phenyl group
on the zinc center in E formally abstracts a hydrogen atom
at the C2 position to form an aromatized heteroarene F,
metallic zinc, and benzene,[38] which is in line with results
obtained in labeling experiments.[35] The organozinc reagent
plays three key roles in this mechanism: 1) as a Lewis acid
Materials
1,4-Dioxane and toluene were used after distillation over sodium benzo-
phenone and calcium hydride, respectively. [NiACTHNURGTNEUNG(cod)2] was purchased
from STREM chemicals, Inc. and used as received. Ph2Zn (6) was pur-
chased from Wako Chemicals and used as received. PCy3 was purchased
from Sigma–Aldrich and used as received. Pyridine was purchased from
Wako chemicals and used after distillation. Quinoline (5) was purchased
from Sigma–Aldrich and used after distillation. Isoquinoline, phen-
anthridine, 4-phenylpyridine, 4,4’-bipyridine, and pyrazine were pur-
chased from TCI laboratory chemicals and used as received. Phenylbor-
onic acid was purchased from TCI laboratory chemicals and used as re-
ceived. 3,5-Dimethylphenylboronic acid, 2-naphthylboronic acid, 4-me-
thoxyphenylboronic acid, 4-(N,N-dimethylamino) phenylboronic acid,
and 3-chloro-4-methoxyphenylboronic acid were purchased from Sigma–
Aldrich and used as received. Et2Zn was purchased from Sigma–Aldrich
and used as received. N-Benzyl-2-phenylethynyl aniline (15) was pre-
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Catalytic Arylation of a C H Bond in Pyridine Using Organozinc Reagents
pared by alkynylation of 2-iodoaniline under Sonogashira conditions, fol-
lowed by N-benzylation.[33] 2-Phenyl-1,2-dihydroquinoline (22) was pre-
pared by the reaction of quinoline with phenyllithium.[39] 2-Deuteroqui-
noline was prepared by the deuteration of 2-quinolyllithium, prepared
from the reaction of 2-bromoquinoline with nBuLi, using D2O. 2-(4-Tol-
yl)pyrimidine and 6-phenylquinoline (20) were prepared through the pro-
cedure reported by Fu et al.[40]
3-Phenylimidazo
ACHTUNGTREN[NUNG 1,2-a]pyrazine (11)
The procedure for the arylation of imidazoCATHNUGTREN[NUG 1,2-a]pyrimidine was fol-
lowed.[41] An oven-dried 10 mL screw-capped vial was charged with Pd-
(OAc)2 (2.8 mg, 0.013 mmol), PPh3 (6.6 mg, 0.025 mmol), iodobenzene
(102.0 mg, 0.50 mmol), Cs2CO3 (163 mg, 0.5 mmol), imodazo[1,2-a]pyra-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
zine (9, 30 mg, 0.25 mmol), and dioxane (2.0 mL) in a glovebox. The cap
was fastened, and the mixture was stirred at 1208C for 20 h. After the
volatiles were removed in vacuo, chromatography on silica gel (hexane/
General procedure for nickel-catalyzed phenylation of heteroarenes using
6 (entry 4 in Table 2).
EtOAc=1:1 to 0:1) furnished 3-phenylimidazoACTHNGUTERN[UNG 1,2-a]pyrazine (11,
48.3 mg, 99%) as a white solid.
An oven-dried 10 mL screw-capped vial was charged with [NiACTHNUTRGNEUNG(cod)2]
White solid; Rf =0.17 (hexane/EtOAc=5:1); m.p.=948C; 1H NMR
(CDCl3, 399.78 MHz): d=7.47–7.51 (m, 1H), 7.55–7.60 (m, 4H), 7.89 (s,
1H), 7.91 (d, J=4.4 Hz, 1H), 8.27 (dd, J=1.6, 4.4 Hz, 1H), 9.16 ppm (s,
1H); 13C NMR (CDCl3, 100.53 MHz): d=116.2, 126.9, 127.8, 127.9, 129.0,
129.4, 129.9, 134.5, 141.3, 144.5 ppm; HRMS (ESI): m/z calcd for
C12H9N3: 195.0796; found: 195.0803.
(3.4 mg, 0.013 mmol), PCy3 (7.0 mg, 0.025 mmol), 6 (84 mg, 0.38 mmol), 5
(32 mg, 0.25 mmol), and toluene (1.0 mL) in a glovebox. The cap was fas-
tened and the mixture was stirred at 808C for 20 h. After the volatiles
were removed in vacuo, chromatography on silica gel (hexane/EtOAc=
50:1 to 20:1) furnished 2-phenylquinoline (7, 50.8 mg, 99%) as a white
solid.
General procedure for nickel-catalyzed arylation of 5 using aryl zinc
reagents generated from aryl boronic acid and diethylzinc (entry 1 in
Table 4).
2-Phenylquinoline (7)
White solid; Rf =0.49 (hexane/EtOAc=5:1); m.p.=868C; 1H NMR
(CDCl3, 270 MHz): d=7.48–7.58 (m, 4H), 7.74 (t, J=5.9 Hz, 1H), 7.71–
7.90 (m, 2H), 8.17–8.23 ppm (m, 4H); 13C NMR (CDCl3, 67.80 MHz):
d=119.4, 126.7, 127.6, 127.9, 128.0, 129.2, 129.8, 130.1, 130.2, 137.2, 140.1,
148.7, 157.8 ppm; HRMS (ESI): m/z calcd for C15H11N: 205.0891; found:
205.0884.
An oven-dried 10 mL screw-capped vial was charged with Et2Zn
(130 mg, 1.1 mmol) and 1,4-dioxane (0.5 mL) in a glovebox, followed by
the addition of phenylboronic acid (91 mg, 0.75 mmol; most of the aryl
boronic acid examined dissolved exothermically with ethane generation).
The cap was fastened and the mixture was stirred at 608C for 12 h. After
2-Methyl-4-phenylpyrimidine
the mixture cooled to room temperature, [NiACTHNURGTNEUNG(cod)2] (3.4 mg,
0.013 mmol), PCy3 (7.0 mg, 0.025 mmol), quinoline (5, 32 mg, 25 mmol),
and toluene (1.0 mL) were added in a glovebox. The mixture was stirred
at 1308C for 20 h. After the volatiles were removed in vacuo, chromatog-
raphy on silica gel (hexane/EtOAc=50:1 to 20:1) furnished 2-phenylqui-
noline (7, 38.5 mg, 75%) as a white solid.
An oven-dried 10 mL screw-capped vial was charged with [Ni
ACHTUNGERTN(NUNG cod)2]
(3.4 mg, 0.0125 mmol), PCy3 (7.0 mg, 0.025 mmol), (83.5 mg,
6
0.38 mmol), 2-methylpyrimizine (23.5 mg, 0.25 mmol), and toluene
(1.0 mL) in a glovebox. The cap was fastened, and the mixture was
stirred for 20 h at 608C. The reaction mixture was quenched with MeOH
(0.5 mL). The reaction mixture was then filtered through a Celite pad,
and the pad was washed with Et2O. After removing the volatiles in
vacuo, 2-methyl-4-phenyl-3,4-dihydropyrimidine was obtained in quanti-
tative yield. This addition product was then treated with HOAc (12 mL),
DDQ (68.1 mg, 0.3 mmol), H2O (0.5 mL), and THF (3 mL), and the mix-
ture was stirred at room temperature in air for 20 h. The reaction mixture
was quenched with NaOH (1m, 0.3 mL, 0.3 mmol). The mixture was di-
luted with Et2O (5 mL), dried over MgSO4, and concentrated in vacuo.
Chromatography on silica gel (hexane/EtOAc=10:1) furnished 2-methyl-
4-phenylpyrimidine (23.0 mg, 54%).
White solid; Rf =0.11 (hexane/EtOAc=5:1); m.p.=438C; 1H NMR
(CDCl3, 399.78 MHz): d=2.81 (s, 3H), 7.49–7.50 (m, 3H), 7.51 (s, 1H),
8.06–8.09 (m, 2H), 8.67 ppm (d, J=5.2 Hz, 1H); 13C NMR (CDCl3,
100.53 MHz): d=26.3, 113.9, 127.1, 128.9, 130.8, 136.9, 157.4, 164.1,
168.4 ppm; HRMS (ESI): m/z calcd for C11H10N2: 170.0844; found:
170.0842.
A procedure for Scheme 52-(1-Benzyl-2-phenyl-1H-indol-3-yl)quinoline
(16)
An oven-dried 10 mL pressure-screw-capped vial was charged with N-
benzyl-2-phenylethynylaniline (180.3 mg, 0.63 mmol) and toluene
(0.75 mL). Then, nBuLi (1.6m in hexane, 0.39 mL, 0.63 mmol) was added
slowly at room temperature and heated at reflux for 2 h to afford 2-
phenyl-3-zincioindole.[33] [Ni
ACTHNUTRGEN(NUG cod)2] (3.5 mg, 0.0129 mmol), PCy3 (8.0 mg,
0.029 mmol), quinoline (32.7 mg, 0.25 mmol), and toluene (0.5 mL) were
added to this reaction mixture in a glovebox. The reaction mixture was
subjected to column chromatography on silica gel to give the N-benzyl-2-
phenyl-3-(2-quinolyl) indole as a colorless solid (84.9 mg, 83%).
White solid; Rf =0.43 (hexane/EtOAc=5:1); m.p.=1868C; 1H NMR
(CDCl3, 270.05 MHz): d=5.34 (s, 2H), 6.94–7.01 (m, 3H), 7.21–7.49 (m,
12H), 7.68–7.73 (m, 2H), 7.80 (d, J=8.6 Hz, 1H), 8.51 (d, J=8.6 Hz,
1H), 8.62 ppm (d, J=7.3 Hz, 1H); 13C NMR (CDCl3, 150.84 MHz): d=
47.5, 110.4, 115.2, 121.5, 121.8, 122.4, 123.0, 125.5, 126.0, 126.1, 127.2,
127.3, 127.4, 128.6, 128.8, 128.9, 129.1, 131.0, 131.7, 135.0, 137.2, 137.6,
140.6, 148.3, 155.5 ppm; HRMS (ESI): m/z calcd for C30H22N2: 410.1783;
found: 410.1781.
À
Regioselective C H arylations of imidazo
G
Phenylimidazo[1,2-a]pyrazine (10)
G
An oven-dried 10 mL screw-capped vial was charged with [{RhCl
(6.2 mg, 0.013 mmol), PCy3 (7.0 mg, 0.025 mmol), 6 (84 mg, 0.38 mmol),
imodazo[1,2-a]pyrazine (9, 30 mg, 0.25 mmol), and toluene (1.0 mL) in
ACHTUNGTNER(NUNG cod)}2]
Catalytic Alkylation of N-Heteroarenes Using iPr2Zn (17) (Scheme 6).2-
Isopropyl-4-phenylpyridine (19) [883566–21–0]
ACHTUNGTRENNUNG
a glovebox. The cap was fastened and the mixture was stirred at 1008C
for 20 h. After the volatiles were removed in vacuo, chromatography on
silica gel (hexane/EtOAc=5:1 to 1:1) furnished 8-phenylimidazoACTHNUTRGNE[NUG 1,2-
a]pyrazine (10, 20 mg, 40%) as a white solid. Analytically pure product
was obtained by GPC.
White solid; Rf =0.57 (EtOAc); m.p.=858C; 1H NMR (CDCl3,
399.78 MHz): d=7.49–7.58 (m, 3H), 7.72 (d, J=0.1 Hz, 1H), 7.86 (d, J=
0.8, 1H), 7.97 (d, J=4.4, 1H), 8.0 (d, J=4.4 Hz, 1H), 8.63–8.66 ppm (m,
2H); 13C NMR (CDCl3, 100.53 MHz): d=113.8, 117.9, 128.4, 129.1, 129.5,
130.3, 134.9, 136.0, 139.5, 150.4 ppm; HRMS (ESI): m/z calcd for
C12H9N3: 195.0796; found: 195.0799. The structure was confirmed by the
comparison of these spectra with those reported in the previous report.[20]
An oven-dried 10 mL screw-capped vial was charged with CuACHTUNGTRENNUNG(OAc)
(3.0 mg, 0.025 mmol), 4,4’-di-tert-butylbipyridine (6.7 mg, 0.025 mmol),
diisopropylzinc solution (1m in toluene, 0.5 mL, 0.50 mmol), 4-phenylpyr-
idine (18, 39 mg, 0.25 mmol), and toluene (0.5 mL) in a glovebox. The
cap was fastened, and the mixture was stirred at 1208C for 20 h. After
the volatiles were removed in vacuo, chromatography on silica gel
(hexane/EtOAc=50:1 to 30:1) furnished 2-isopropyl-4-phenylpyridine
(19, 27 mg, 55%) as a greenish oil. Analytically pure product was ob-
tained by GPC.
Greenish oil; Rf =0.26 (hexane/EtOAc=5:1); 1H NMR (CDCl3,
399.78 MHz): d=1.36 (d, J=6.8 Hz, 6H), 3.14 (sept, J=6.8 Hz, 1H),
7.32–7.33 (m, 1H), 7.38 (s, 1H), 7.41–7.51 (m, 3H), 7.63–7.65 (m, 2H),
8.59 ppm (d, J=5.2 Hz, 1H); 13C NMR (CDCl3, 100.53 MHz): d=22.6,
Chem. Asian J. 2012, 00, 0 – 0
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Mamoru Tobisu, Naoto Chatani et al.
FULL PAPERS
36.4, 118.7, 119.2, 127.1, 128.8, 129.0, 138.7, 148.9, 149.4, 167.8 ppm;
HRMS (ESI): m/z calcd for C14H15N: 197.1204; found: 197.1207.
[3] a) B. Shao, S. Victory, V. I. Ilyin, R. R. Goehring, Q. Sun, D. Hogen-
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[4] A comprehensive discussion on these two mechanisms: B. Liꢂgault,
D. Lapointe, L. Caron, A. Vlassova, K. Fagnou, J. Org. Chem. 2009,
74, 1826.
[5] Selected examples: a) S. H. Cho, S. J. Hwang, S. Chang, J. Am.
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4-Isopropyl-6-phenylquinoline (21)
An oven-dried 10 mL screw-capped vial was charged with CuACHTUNTRGNEUNG(OAc)
(1.5 mg, 0.013 mmol), PCy3 (7.0 mg, 0.025 mmol), diisopropylzinc solution
(1m in toluene, 0.5 mL, 0.50 mmol), 6-phenylquinoline (20, 51 mg,
0.25 mmol), and toluene (0.5 mL) in a glovebox. The cap was fastened
and the mixture was stirred at 808C for 20 h. After volatiles were re-
moved in vacuo, chromatography on silica gel (hexane/EtOAc=10:1 to
5:1) furnished 4-isopropyl-6-phenylquinoline (21, 25 mg, 41%) as a clear
oil. Analytically pure product was obtained by GPC.
Greenish-yellow oil; Rf =0.14 (hexane/EtOAc=5:1); 1H NMR (CDCl3,
399.78 MHz): d=1.44 (d, J=7.2 Hz, 6H), 3.83 (sept, J=7.2 Hz, 1H), 7.33
(d, J=4.4 Hz, 1H), 7.40–7.43 (m, 1H), 7.51 (t, J=7.6 Hz, 2H), 7.72 (d,
J=7.2 Hz, 2H), 7.95 (dd, J=2.0, 8.8 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H),
8.26 (d, J=2.0 Hz, 1H), 8.85 ppm (d, J=4.4 Hz, 1H); 13C NMR (CDCl3,
100.53 MHz): d=22.9, 28.3, 117.3, 121.1, 127.0, 127.6, 127.6, 128.6, 128.9,
130.7, 139.0, 140.9, 147.6, 150.3, 154.5 ppm; IR (neat): n˜ =3060 (m), 3028
(m), 2966 (s), 2931 (m), 2871 (m), 1926 (w), 1587 (s), 1492 (s), 1460 (m),
1388 (m), 1362 (s), 1279 (w), 1241 (m), 1215 (w), 1155 (m), 1105 (w),
1076 (w), 1051 (w), 1011 (w), 968 (w), 922 (w), 885 (m), 856 (s), 831 (m),
762 (s), 698 (s), 600 cmÀ1 (w); MS (70 eV): m/z (%): 248 (20), 247 (M+,
100), 246 (10), 233 (18), 232 (95), 230 (19), 217 (11), 115 (11), 88 (10);
HRMS (ESI): m/z calcd for C18H17N: 247.1361; found: 247.1366.
The reaction of 2-phenyl-1,2-dihydroquinoline (13) with Ph2Zn (Scheme
7).
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An oven-dried 10 mL pressure-screw-capped vial was charged with
Ph2Zn (83.6 mg, 0.38 mmol), 2-phenyl-1,2-dihydroquinoline[39] (13,
51.5 mg, 0.25 mmol), and toluene (1.0 mL) in a glovebox. The cap was
fastened and the mixture was stirred for 20 h at room temperature. The
reaction mixture was subjected to column chromatography on silica gel
to afford 2-phenylquinoline (38.5 mg, 75%). This result shows that the
oxidation process of 1,2-dihydroquinoline proceeds in the absence of
a nickel catalyst at room temperature.
À
[8] Several transformations other than arylation via catalytic C H bond
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Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific Re-
search on Innovative Areas “Molecular Activation Directed toward
Straightforward Synthesis” from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. I.H. thanks to JSPS for a Research
Fellowship for Young Scientists and the Global COE Program of Osaka
University. We also thank the Instrumental Analysis Center, Faculty of
Engineering, Osaka University, for assistance with the MS, HRMS, and
elemental analyses.
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À
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À
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[16] See the Supporting Information for the attempts to use other arylat-
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[2] Recent reviews on catalytic C H functionalization of heteroarenes:
a) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173; b) T.
Satoh, M. Miura, Chem. Lett. 2007, 36, 200; c) G. P. McGlacken,
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À
Catalytic Arylation of a C H Bond in Pyridine Using Organozinc Reagents
Yu, J. Am. Chem. Soc. 2006, 128, 12634; c) S. Yang, B. Li, X. Wan,
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[18] Other ligands, including PPh3, P(4-MeOC6H4)3, P(4-CF3C6H4)3, P-
8717; d) A. D. Sun, J. A. Love, Org. Lett. 2011, 13, 2750; e) M.
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A
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phosphino)ferrocene (dppf), 1,3-di(2,4,6-trimethylphenyl)imidazolin-
2-ylidene (IMes), and 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-yli-
dene (IPr) were less effective than PCy3. See the Supporting Infor-
mation for details.
[19] D. B. Harden, M. J. Mokrosz, L. Strekowski, J. Org. Chem. 1988, 53,
4137.
[20] The reaction of imidazo
À
[32] Elaboration of heteroarene cores through sequential C H aryla-
tions: a) K. Masui, A. Mori, K. Okano, K. Takamura, M. Kinoshita,
T. Ikeda, Org. Lett. 2004, 6, 2011; b) K. Itami, D. Yamazaki, J.-i.
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agent is reported to occur at the 8-position: A. Gueiffier, H. Viols, I.
Blache, O. Chavignon, J. C. Teulade, A. Aumelas, J.-P. Chapat, Het-
erocycles 1994, 38, 551.
[21] The [NiACHTUNGTRENNUNG(cod)2]/PCy3-catalyzed reaction of 9 with 6 resulted in a com-
plicated mixture, although 9 was completely consumed.
[22] Palladium-catalyzed direct arylation of a related imidazoACTHNUGRTNEUNG[1,2-a]pyri-
dine ring system is reported to occur at the 3-position; a) B. B.
Tourꢂ, B. S. Lane, D. Sames, Org. Lett. 2006, 8, 1979; b) J. Koubachi,
S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib, G. Guillaumet,
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[34] a) In the case of iPr2Zn (17) as a nucleophile, nickel and other metal
catalysts were ineffective. See the Supporting Information for de-
tails. b) The mechanism with copper-based catalyst is likely to be
different from that with a nickel catalyst. An alkyl copper(I) species
is a potential intermediate. See the Supporting Information.
[35] See the Supporting Information for details.
[23] C6 substituent affects the electrophilicity of C2 of a quiniline ring.
13C NMR chemical shifts of C2 of 6-substituted quinolines are as fol-
lows: R=CO2Me (152.9 ppm); R=H (150.3 ppm); R=OMe
(147.9 ppm).
[24] The detrimental effect of the metal halide salts could be attributed
to the coordination of halide anion(s) to Ph2Zn, which should de-
crease the Lewis acidity of Ph2Zn and inhibit the electrophilic acti-
vation of heteroarenes by Ph2Zn as in the proposed intermediate B
in Scheme 8.
[25] Negative salt effects in reactions using organozinc reagents: a) L.
Jin, C. Liu, J. Liu, F. Hu, Y. Lan, A. S. Batsanov, J. A. K. Howard,
T. B. Marder, A. Lei, J. Am. Chem. Soc. 2009, 131, 16656; b) L.
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1486; b) B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang, A.-
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1728; d) G. P. McGlacken, S. L. Clarke, ChemCatChem 2011, 3,
1260; e) M. Tobisu, N. Chatani, ChemCatChem 2011, 3, 1410.
[29] Selected examples: a) E. Wenkert, T. W. Ferreira, E. L. Michelotti,
J. Chem. Soc. Chem. Commun. 1979, 637; b) J. Srogl, W. Liu, D.
Marshall, L. S. Liebeskind, J. Am. Chem. Soc. 1999, 121, 9449; c) S.
Kanemura, A. Kondoh, H. Yorimitsu, K. Oshima, Synthesis 2008,
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2131; e) K. Ishizuka, H. Seike, T. Hatakeyama, M. Nakamura, J.
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[36] M. Ohashi, O. Kishizaki, H. Ikeda, S. Ogoshi, J. Am. Chem. Soc.
2009, 131, 9160.
[37] a) An alternative pathway to intermediate D involves an anionic
phenylnickelate species, which may be formed by the reaction of Ni0
with Ph2Zn. For a proposal of a similar nickelate intermediate, see:
J. Terao, S. Nii, F. A. Chowdhury, A. Nakamura, N. Kambe, Adv.
Synth. Catal. 2004, 346, 905; b) When CuI or RhI catalyst was used,
the phenylmetal complex is likely to serve as an active species to
form an intermeditate analogous to D. See the Supporting Informa-
tion for a possible catalytic cycle for CuI and RhI catalysis.
[38] a) Intermolecular hydrogen abstraction of E by an external Ph2Zn is
unlikely since the arylation proceeds in 62% yield when only
1 equiv Ph2Zn is used; b) When N-benzylideneaniline, in place of
quinoline, was used in a nickel-catalyzed reaction with Ph2Zn, a mix-
ture of an addition product (54%) and an oxidative arylation prod-
uct (39%) was obtained. These results indicate that aromatization is
the primary driving force for the reaction of E to F.
[39] T. P. Forrest, G. A. Dauphinee, S. A. Dreaniyagala, Can. J. Chem.
1985, 63, 412.
[40] N. Kudo, P. Mauro, G. C. Fu, Angew. Chem. 2006, 118, 1304; Angew.
Chem. Int. Ed. 2006, 45, 1282.
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Cai, R. D. Larsen, Org. Lett. 2003, 5, 4835.
[30] Reviews: a) H. Amii, K. Uneyama, Chem. Rev. 2009, 109, 2119;
b) A. D. Sun, J. A. Love, Dalton Trans. 2010, 39, 10362. Recent ex-
amples: c) M. Takachi, Y. Kita, M. Tobisu, Y. Fukumoto, N. Chatani,
Angew. Chem. 2010, 122, 8899; Angew. Chem. Int. Ed. 2010, 49,
Received: November 30, 2011
Revised: February 8, 2012
Published online: && &&, 0000
Chem. Asian J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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FULL PAPERS
Catalytic Arylation
Less is more: Pyridine, pyrazine, quin-
oline and related electron-deficient N-
heteroarenes can be arylated at the
most electrophilic site using organo-
zinc reagents through nickel catalysis.
This protocol serves as a complemen-
tary method to catalytic direct aryla-
tion reactions.
Isao Hyodo, Mamoru Tobisu,*
Naoto Chatani*
&&&& — &&&&
À
Catalytic Arylation of a C H Bond in
Pyridine and Related Six-Membered
N-Heteroarenes Using Organozinc
Reagents
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www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!