Cobalt-catalyzed ortho-C-H alkylation of 2-arylpyridines via ring-opening of aziridines

Article abstract of DOI:10.1002/adsc.201400049

A cobalt-N-heterocyclic carbene catalyst, in combination with neopentylmagnesium bromide, was found to promote ortho-C-H functionalization of 2-arylpyridines with 1,2-diarylaziridines through ring-opening alkylation. The reaction affords 1,1-diarylethanes bearing 2-amino functional groups in moderate to good yields under mild room-temperature conditions.

Full text of DOI:10.1002/adsc.201400049

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DOI: 10.1002/adsc.201400049
À
Cobalt-Catalyzed ortho-C H Alkylation of 2-Arylpyridines via
Ring-Opening of Aziridines
Ke Gao,a Rupankar Paira,a and Naohiko Yoshikaia,*
a
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371, Singapore
Fax : (+65)-6791-1961; e-mail: nyoshikai@ntu.edu.sg
Received: January 13, 2014; Revised: February 18, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400049.
[8]
À
Abstract: A cobalt–N-heterocyclic carbene catalyst,
C H bond, and the other involves formal deproto-
À
in combination with neopentylmagnesium bromide,
nation of the ortho-C H bond followed by electro-
À
was found to promote ortho-C H functionalization
philic trapping. The feasibility of the latter type of re-
action has been demonstrated for electrophiles such
as aldimines,[9] aryl chlorides,[10] and alkyl chlorides/
bromides.[11–13] Here, we report that aziridines also
serve as viable electrophiles for this reaction manifold
(Scheme 1). Thus, a cobalt–N-heterocyclic carbene
catalyst, in combination with neopentyl-Grignard re-
agent, allows ortho-functionalization of 2-arylpyri-
of 2-arylpyridines with 1,2-diarylaziridines through
ring-opening alkylation. The reaction affords 1,1-di-
arylethanes bearing 2-amino functional groups in
moderate to good yields under mild room-tempera-
ture conditions.
À
À
Keywords: aziridines; C C bond formation; C H
functionalization; cobalt
À
dines with 1,2-diarylaziridines via regioselective C N
bond cleavage, affording 1,1-diarylethanes bearing 2-
amino groups.
We chose 2-phenylpyridine 1a and 1,2-diphenylazir-
idine 2a as model substrates for a screening of the re-
À
Transition metal-catalyzed chelation-assisted C H action conditions (Table 1). A catalytic system consist-
bond activation has attracted considerable attention ing of CoCl2 (10 mol%), IPr·HCl (10 mol%), and t-
as an atom- and step-economical approach to regiose- BuCH2MgBr (1.8 equiv.), which we previously used
lective functionalization of aromatic compounds.[1] for the reaction of 2-arylpyridines and aldimines,[9]
À
While C H alkylation, alkenylation, and arylation re- promoted the reaction of 1a and 2a (2 equiv.) at room
actions using alkenes, alkynes, and arylating agents temperature to afford a 1,1-diarylethane derivative
(e.g., aryl halides, arylmetals, and arenes) have been 3aa in 70% yield (entry 1). Thus, the ring-opening of
extensively developed, exploration of other types of the aziridine 2a took place regioselectively at the
coupling partners is crucial for further expansion of more hindered C-2 position. Upon brief examination
the synthetic scope of this approach. In this context, of the catalyst loading, the reaction stoichiometry,
recent years have witnessed remarkable progress in
À
ortho-C H functionalization reactions using carbon-
based electrophiles such as alkyl halides[2,3] and those
containing polar p-bonds (e.g, aldimines, aldehydes,
isocyanates).[4,5] Recently, Li, Wan and co-workers
added N-sulfonylaziridines to the repertoire of elec-
trophiles, which served as coupling partners for
À
RhACHTUNGTRENNUNG(III)-catalyzed ortho-C H functionalization of 2-
arylpyridines.[6]
Over the past several years, our group has devel-
oped mild and cost-effective cobalt catalysts for
À
a series of chelation-assisted C H bond functionaliza-
tion reactions, which can be classified into two
types.[7] One involves insertion of unsaturated hydro-
Scheme 1. Cobalt–NHC-catalyzed ortho-functionalization of
carbons such as alkynes and alkenes into the ortho- arenes with electrophiles.
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Table 1. Cobalt-catalyzed ortho-alkylation of 2-phenylpyri-
dine 1a with 1,2-diphenylaziridine 2a.[a]
Table 2. Reaction of various 2-arylpyridines with aziridine
2a.
Entry
x
Ligand (y)
RMgX
Yield [%][b]
1
2
3
4
5
6
7
8
9
10 IPr·HCl (10)
t-BuCH2MgBr
t-BuCH2MgBr
t-BuCH2MgBr
70
72[c]
29
11
0
0
0
6
0
5
5
5
5
5
5
5
5
IPr·HCl (5)
SIPr·HCl (5)
IMes·HCl (5) t-BuCH2MgBr
PPh3 (10)
t-BuCH2MgBr
t-BuCH2MgBr
Me3SiCH2MgCl
CyMgBr
PCy3 (10)
IPr·HCl (5)
IPr·HCl (5)
IPr·HCl (5)
PhMgBr
[a]
The reaction was performed on a 0.3 mmol scale.
Determined by H NMR using 1,1,2,2-tetrachloroethane
[b]
1
as an internal standard.
Isolated yield.
[c]
and the temperature, we found that the reaction
smoothly proceeded with 5 mol% each of CoCl2 and
IPr·HCl and 1.8 equiv. of t-BuCH2MgBr, affording
3aa in 72% isolated yield (entry 2). Reduction of the
amount of either 2a or t-BuCH2MgBr resulted in
a substantial decrease in the product yield, and lower
or higher temperature (08C or 608C) did not improve
the reaction.
The reaction was very sensitive to the ligand and
the Grignard reagent. Thus, the use of other NHC
preligands such as SIPr·HCl and IMes·HCl resulted in
much lower yields of 3aa (entries 3 and 4), while PPh3
[a]
A mixture of regioisomers (4:1) was obtained. The major
isomer is shown.
and PCy3 were entirely ineffective (entries 5 and 6). while the regioselectivity was perfect for a substrate
The catalytic activity was totally or significantly lost bearing a meta-trifluoromethyl group (see 3ia). In
when t-BuCH2MgBr was replaced with other contrast, 2-(naphthalen-2-yl)pyridine reacted at the
Grignard reagents such as Me3SiCH2MgCl, CyMgBr, more hindered 1-position to afford the product 3ja as
or PhMgBr (entries 7–9).
a pure regioisomer. The C-3 position of 2-(thiophen-
With the reaction conditions in entry 2 of Table 1, 2-yl)pyridine was also alkylated albeit in a modest
we explored the scope of the present ring-opening al- yield (see 3ka). The reaction proved to be rather sen-
kylation reaction. First, various 2-arylpyrdine deriva- sitive to steric congestion of 2-arylpyridines, because
tives were subjected to the reaction with 2a (Table 2). those substituted at the ortho-position of the benzene
2-Arylpyridines bearing para-substituents such as me- ring (1l, 1m) or the 3-position of the pyridine ring
thoxy, fluoro, and trifluoromethyl groups on the ben- (1n) afforded only trace amounts of the desired prod-
À
zene ring participated in the reaction to afford the ucts. A substrate bearing a C Cl bond (1o) also did
corresponding products 3ba–3da in moderate yields, not participate in the reaction for unknown reasons.
while a para-dimethylamino group made the reaction
Attempts to use aromatic substrates other than 2-
rather sluggish (see 3ea). Substituents on the 4-posi- arylpyridines have been unsuccessful. Thus, only
tion of the pyridine ring did not interfere with the re- a trace amount of the desired product was detected
action (see 3fa and 3ga). A meta-methyl group on the by GC-MS in the reaction of 1-phenylpyrazole (1q)
benzene ring directed the reaction to take place pref- with 2a, while 2-phenylpyrimidine (1p) and the aryl-
erentially at the less hindered position, affording the
ACHTUNGTRENiNGNU mine derived from acetophenone and p-anisidine (1r)
product 3ha and its regioisomer in a ratio of 4:1, did not afford any of such products.
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Cobalt-Catalyzed ortho-C H Alkylation of 2-Arylpyridines
Table 3. Reaction of 2-phenylpyridine 1a with various aziri-
dines.
Scheme 2. Competition experiments.
not been utilized as electrophiles for the cobalt-cata-
lyzed cross-coupling.[15] To gain insight into the aziri-
dine ring-opening step, competition experiments were
performed (Scheme 2a, b). The reaction of 1a with an
equimolar mixture of aziridines 2b and 2e having 2-
(4-methoxyphenyl) and 2-(4-fluorophenyl) groups, re-
spectively, preferentially afforded the product of the
[a]
2 equiv. of t-BuCH2MgBr were used.
Next, the reaction of 2-phenylpyridine 1a and vari- former aziridine (i.e., 3ab; Scheme 2a). This observa-
ous aziridines was examined (Table 3). N-Phenylaziri- tion sounds reasonable if one invokes the develop-
dines bearing a series of 2-aryl groups participated in ment of a partial positive charge on the C-2 position
the reaction to afford the corresponding products during the ring-opening process. On the other hand,
3ab–3aj in moderate yields. An electron-donating or aziridines 2k and 2m bearing N-(4-methoxyphenyl)
neutral substituent (i.e., methoxy, tert-butyl, or and N-(4-fluorophenyl) groups, respectively, afforded
phenyl) on the 2-aryl group was beneficial for the re- the corresponding products 3ak and 3am in nearly
action (see 3ab–3ad). In contrast, electron-withdraw- equal yields in the same type of competition
ing fluoro and chloro substituents made the reaction (Scheme 2b). Note also that a competition of 2-aryl-
sluggish (see 3ae and 3af), and a trifluoromethyl pyridines bearing meta-methyl and meta-trifluoro-
group almost shut down the reaction (see 3ag). The methyl groups (1h and 1i) resulted in predominant
N-substituent of the aziridine could be changed to formation of the alkylation product of the latter (3ia),
other aryl groups such as 4-methoxyphenyl, 3-tolyl, indicating that the cobalt catalyst prefers to activate
À
and 4-fluorophenyl groups without significant de- the
more
acidic/electron-poor
C H
bond
crease in the reaction efficiency (see 3ak–3am), while (Scheme 2c).[13]
an N-methyl derivative did not give the desired prod-
uct. Note also that an N-sulfonylaziridine, which was ing alkylation reaction is shown in Scheme 3. A low-
used for the rhodium(III)-catalyzed reaction of 2-aryl- valent alkylcobalt species generated from the cobalt
pyridine,[6] did not participate in the present cobalt- salt, the NHC pre
ligand, and the Grignard reagent
catalyzed reaction. undergoes oxidative addition of the ortho-C H bond
A putative catalytic cycle of the present ring-open-
AHCTUNGTRENNUNG
A
A
À
À
Despite the significant development of C C bond of 2-phenylpyridine, which is followed by reductive
forming reactions with cobalt catalysts in the past de- elimination to afford a cyclometallated intermedi-
cades,[14] to the best of our knowledge, aziridines have ate.[16] This intermediate then undergoes nucleophilic
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Ke Gao et al.
cross-coupling of 2-halopyridines and aryl-Grignard re-
agents[18] or by copper-catalyzed condensation of oxime ace-
tates and a,b-unsaturated aldehydes.[19] 1,2-Diarylaziridines
were prepared by Corey–Chaykovsky reaction of dimethyl-
sulfonium methylide and the corresponding N-arylald-
AHCTUNGTRENNUNG
imines.[20] NMR spectra were recorded on Bruker AV-300
(300 MHz) and AV-400 (400 MHz) spectrometers, where tet-
ramethylsilane (1H) and CDCl3 (13C) were employed as in-
ternal standards. Gas chromatographic (GC) analysis was
performed on a Shimadzu GC-2010 system equipped with
an FID detector and a capillary column DB-5 (Agilent
J&W, 0.25 mm i.d.ꢁ30 m, 0.25 mm film thickness). High-res-
olution mass spectra (HR-MS) were recorded on a Waters
Q-Tof Premier LC HR mass spectrometer.
Representative Procedure for Cobalt-Catalyzed
Reaction of 2-Arylpyridine and 2-Arylaziridine
In an oven-dried Schlenk tube equipped with a magnetic stir
bar were placed cobalt(II) chloride (1.9 mg, 0.015 mmol),
1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (6.4 mg,
0.015 mmol), 2-phenylpyridine (1a, 43 mL, 0.30 mmol), 1,2-
diphenylaziridine (2a, 117.2 mg, 0.60 mmol), and THF
(0.68 mL). To the mixture was added a THF solution of neo-
pentylmagnesium bromide (1.67M, 0.32 mL, 0.54 mmol)
dropwise at 08C. The resulting mixture was stirred at room
temperature for 24 h, diluted with ether (1 mL), and then
quenched with a saturated aqueous solution of NH4Cl
(1 mL). The aqueous layer was extracted with ethyl acetate
(10 mLꢁ3). The combined organic layer was dried over
MgSO4 and concentrated under reduced pressure. The crude
Scheme 3. A possible catalytic cycle.
attack on 1,2-diarylaziridine, resulting in ring-opening
alkylation of the ortho-position. Possible pathways for
this step may involve SN2-type displacement, single-
electron transfer-radical coupling, and oxidative addi-
tion–reductive elimination. Further mechanistic ex-
periments, e.g., those using enantioenriched 1,2-
diaryl
possibilities. Transmetallation of the resulting cobalt
ACHTUNGTRENNUNG
aziridines,[17] are necessary to distinguish these
amide and the Grignard reagent affords the product product was purified by silica gel chromatography (eluent:
hexane/EtOAc=10/1 to 5/1) to afford N-{2-phenyl-2-[2-(pyr-
idin-2-yl)phenyl]ethyl}aniline (3aa) as a yellow oil; yield:
76.0 mg (72%).
bearing a magnesium amide moiety and regenerates
the alkylcobalt species.
In summary, we have demonstrated that a cobalt–
IPr catalyst, in combination with t-BuCH2MgBr, effi-
ciently promotes the ortho-alkylation of 2-arylpyri-
dines through regioselective ring-opening of N-aryl-
Acknowledgements
ACHTUNGTRENNUNGaziridines under mild conditions to afford 1,1-diaryl-
ethane derivatives in moderate to good yields. With
the present study and previous studies by us and
Ackermann et al.,[9–11,13] the combination of a cobalt
salt, an NHC ligand, and a Grignard reagent now ap-
This work was supported by Singapore National Research
Foundation (NRF-RF2009-05), Nanyang Technological Uni-
versity, and JST, CREST. We thank Dr. Laksmikanta Adak
for his early-stage experiments.
À
pears to offer versatile catalytic systems for ortho-C
H functionalization of arenes with electrophiles. Ef-
forts to further expand the scope of this chemistry are
currently ongoing.
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6 Cobalt-Catalyzed ortho-C H Alkylation of 2-Arylpyridines
via Ring-Opening of Aziridines
Adv. Synth. Catal. 2014, 356, 1 – 6
Ke Gao, Rupankar Paira, Naohiko Yoshikai*
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