C(sp3)-H bond arylations catalyzed by well-defined [Ru(O 2CMes)2(p-cymene)]

Article abstract of DOI:10.1021/jo400658d

The well-characterized ruthenium(II) biscarboxylate complex [Ru(O ₂CMes)₂(p-cymene)] enabled versatile direct (hetero)arylations of C(sp³)-H bonds with low (co)catalyst loading and ample substrate scope. Detailed mechanistic studies provided strong support for a facile and reversible C(sp³)-H bond metalation.

Full text of DOI:10.1021/jo400658d

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Article
C(sp3)–H Bond Arylations Catalyzed by
Well-Defined [Ru(O2CMes)2(p-cymene)]
N. Y. Phani Kumar, Rajkumar Jeyachandran, and Lutz Ackermann
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400658d • Publication Date (Web): 02 Apr 2013
Downloaded from http://pubs.acs.org on April 5, 2013
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The Journal of Organic Chemistry
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C(sp3)–H Bond Arylations Catalyzed by Well-
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Defined [Ru(O2CMes)2(p-cymene)]
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N. Y. Phani Kumar, Rajkumar Jeyachandran, and Lutz Ackermann*
Institut für Organische und Biomolekulare Chemie, GeorgꢀAugustꢀUniversität, Tammannstrasse 2,
37077 Göttingen, Germany
Lutz.Ackermann@chemie.uniꢀgoettingen.de
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RECEIVED DATE
Title running head: C(sp3)–H Bond Arylations Catalyzed by [Ru(O2CMes)2(p-cymene)]
Me
i-Pr
Ru
R1
R1
O
MesCO2
Br
Mes
O
(2.5-5.0 mol %)
N
NH
N
NH
+
H
o-xylene, Na2CO3
R3
R2
R3
R2
140 °C, 24 h
Abstract: The wellꢀcharacterized ruthenium(II) biscarboxylate complex [Ru(O2CMes)2(pꢀcymene)]
enabled versatile direct (hetero)arylations of C(sp3)–H bonds with low (coꢀ)catalyst loading and ample
substrate scope. Detailed mechanistic studies provided strong support for a facile and reversible C(sp3)–
H bond metalation.
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Introduction
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Catalyzed C–H bond functionalizations1 are increasingly viable tools that avoid the use of
prefunctionalized substrates, and thereby enable a streamlining of organic synthesis. In recent years,
significant progress has particularly been made in stepꢀeconomical rutheniumꢀcatalyzed C(sp2)–H bond
functionalization.2 Mechanistic insight into the importance of carboxylate assistance proved, hence,
instrumental for the development of direct C(sp2)–H bond arylations and alkylations,3 as well as
oxidative transformations.4,5 On the contrary, ruthenium(II)ꢀcatalyzed functionalizations of C(sp3)–H
bonds6 with organic electrophiles7 have unfortunately thus far met with limited success. A notable very
recent advance was, however, accomplished through direct arylations of benzyl amines with a catalytic
system derived from the cocatalyst KOPiv, along with K2CO3 as the base.8 Since the high loading of the
additive KOPiv of 30 mol % represents a considerable practical limitation of this approach, and in order
to gain insight into the catalysts working mode, we became interested in exploring the first use of wellꢀ
defined ruthenium(II) biscarboxylate complexes, which were hitherto solely utilized for C(sp2)–H bond
functionalizations.9 As a result, we report herein on a versatile wellꢀdefined ruthenium(II) catalysts for
direct functionalizations of C(sp3)–H bonds, and present detailed mechanistic insight into its mode of
action.
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Results and Discussion
At the outset of our studies, we tested the piano stool compounds [Ru(OPiv)2(pꢀcymene)] (4)10 and
[Ru(O2CMes)2(pꢀcymene)] (5)9 in the challenging direct arylation of substrate 1a (Table 1). Notably, the
catalyst 5 derived from the arylꢀsubstituted carboxylate outperformed the pivalateꢀanalogue 4, which
thereby allowed for a considerable reduction of the cocatalyst (entries 1, and 2) and the catalyst loading
(entry 3). Among various solvents, the desired C–H bond functionalization occurred most efficiently in
apolar organic solvent orthoꢀxylene, while H2O11 was not a suitable reaction medium (entries 2–5). As
to the nature of the stoichiometric base, Na2CO3 proved to be superior as compared to the previously
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employed bases K2CO3,8 KOAc, or K3PO4 (entries 2, and 6–9). It is noteworthy that the C(sp3)–H bond
transformation did not occur in the absence of the ruthenium catalyst (entry 10).
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Table 1. Optimization of C(sp3)–H Bond Arylationa
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Me
NH
Me
NH
cat. [Ru]
N
N
PhBr
+
additive
o-xylene, base
140 °C, 24 h
Ph
1a
3aa
2a
entry
catalyst
solvent
base
yield (%)
51
1
2
[Ru(OPiv)2(pꢀcymene)] (4)
oꢀxylene
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOAc
KOAc
[Ru(O2CMes)2(pꢀcymene)] (5)
oꢀxylene
oꢀxylene
DMF
60
51b
ꢀꢀꢀ
ꢀꢀꢀ
13
17
46
69
ꢀꢀꢀ
3
5
5
4
5
H2O
5
6
oꢀxylene
oꢀxylene
oꢀxylene
o-xylene
oꢀxylene
5
7
5
8
K3PO4
Na2CO3
Na2CO3
5
9
5
10
ꢀꢀꢀ
a
Reaction conditions: 1a (0.50 mmol), 2a (0.75 mmol), [Ru] (5.0 mol %), base (1.50 mmol), solvent
(2.0 mL), 140 °C, 24 h; isolated yields. b 5 (2.5 mol %).
With optimized reaction conditions in hand, we next studied the effect exerted by the substitution
pattern of the pyridine moiety in substrates 1 on the catalytic performance (Scheme 1). Thus, the
pyridine 1b being devoid of an additional substituent led unfortunately to unsatisfactory results. Among
various 3ꢀsubstituted pyridines, the substrate 1a bearing a 3ꢀmethyl group was found to be optimal.
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Scheme 1. Variation of the Pyridine Substitution Pattern
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Me
MesCO2
i-Pr
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Ru
O
R
R
Mes
O
5
(5.0 mol %)
PhBr
N
NH
+
N
NH
o-xylene, Na2CO3
140 °C, 24 h
H
Ph
Ph
Ph
---
1
2a
R = H (3ba):
R = OMe (3ca): < 8%
3da
R = Ph ( ):
R = CF3 (3ea):
R = Me (3aa):
20%
48%
69%
Subsequently, we evaluated the versatility of the C(sp3)–H bond arylation, employing a set of
representative (hetero)aryl bromides 2b–2k as the electrophiles (Scheme 2). The wellꢀdefined
biscarboxylate catalyst 5 proved to be broadly applicable, and its remarkable functional group tolerance
allowed inter alia for the chemoselective conversion of substrates 2, bearing a synthetically useful
chloride for subsequent derivatization (2e) or a free (NH)ꢀindole (2k).
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Scheme 2. Scope of C(sp3)–H Bond Arylation with Bromides 2
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Me
i-Pr
9
Ru
O
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MesCO2
Me
NH
Me
NH
Mes
O
5 (5.0 mol %)
ArBr
+
N
N
o-xylene, Na2CO3
H
Ph
Ar
Ph
140 °C, 24 h
1a
2
3
Me
NH
Me
NH
N
N
R
Ph
Ph
R
3ab
): 62%
3af
3ag
R = Me (
3ac
R = OMe ( ): 69%
R = t-Bu (3ad): 65%
R = Cl (
R = Me (
R = OMe (
):
63%
): 58%
3ae
):
53% (150 °C)
Me
NH
Me
NH
N
N
Ph
Ph
R
H
N
3ak
: 65%
R = 3,5-Me2 (3ah):
3ai
63%
R = 3,4-(OMe)2 ( ): 55%
3aj
R = 3,4,5-(OMe)3 ( ): 54%
Likewise, a variety of benzyl amines 1f–1k featuring substituents in paraꢀ, metaꢀ or orthoꢀposition
proved to be viable substrates for the C(sp3)–H bond arylation protocol (Scheme 3).
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Scheme 3. C(sp3)–H Bond Arylation with Amines 1
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9
Me
MesCO2
i-Pr
Ru
O
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Mes
Me
NH
Me
NH
O
5
(5.0 mol %)
Ar2Br
N
+
N
o-xylene, Na2CO3
H
Ar1
Ar2
Ar1
140 °C, 24 h
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2
3
Me
NH
Me
Me
NH
N
N
NH
N
R
R
R
F
OMe
CF3
R = 4-OMe (3fc): 79% R = 4-t-Bu (3gd): 71% R = 4-OMe (3hc): 52%
R = 4-t-Bu (3fd): 80% R = 3-OMe (3gg): 69% R = 4-t-Bu (3hd): 51%
R = 3-OMe (3fg): 75%
R = 3-OMe (3hg): 67%
Me
NH
Me
N
NH
N
R1
R
R2
H
N
R1 = 4-t-Bu, R2 = F (3id):
R1 = 3-OMe, R2 = F (3ig): 67%
64%
R = 3-F (3fk):
72%
R = 3-OMe (3gk): 60%
R = 3-CF3 (
R = 2-F (
1
2
3hk
):
3kk
):
3jd 61%
):
R = 4-t-Bu, R = CF3 (
61%
51%
1
2
3jf
R = 3-Me, R = CF3 ( ): 59%
Mechanistic Studies. Given the remarkably high catalytic activity of complex 5, we became intrigued
by studying its mode of action. To this end, we performed intermolecular competition experiments with
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substrates 1a and 1e, which clearly highlighted the importance of the electronꢀdonating abilities of the
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Lewisꢀbasic directing group (Scheme 4).
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Scheme 4. Competition Experiment with Substituted Pyridines
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Me
NH
CF3
NH
2a
5
(5.0 mol %)
1a
+
1e
+
N
N
o-xylene, Na2CO3
Ph
Ph
Ph
3ea: ---
Ph
140 °C, 24 h
(1.5 equiv each) 3aa/3ea = 13/1 (GC)
3aa: 36%
Conversely, the electronic nature of the substituents on the aromatic moiety of the benzyl amines 1
was found to be of minor importance for the efficacy of the catalyzed C(sp3)–H bond functionalization
(Scheme 5).
Scheme 5. Intermolecular Competition Experiments between Substituted Amines 1
Me
NH
Me
NH
2a
5
(5.0 mol %)
1f
+
1g
+
N
N
o-xylene, Na2CO3
(1.5 equiv each)
Ph
Ph
140 °C, 24 h
F
OMe
3ga: 27%
3fa: 25%
Intermolecular competition experiments with differently substituted organic electrophiles 2 revealed
the more electronꢀdeficient12 aryl bromide 2k to react preferentially (Scheme 6).
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Scheme 6. Competition Experiment between Electrophiles 2c and 2l
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Me
Me
NH
1a
5
(5.0 mol %)
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2l
2c
+
+
N
N
NH
Ph
o-xylene, Na2CO3
Ph
(1.5 equiv each)
140 °C, 24 h
F3C
= 2.3/1.0 (GC)
MeO
3al 3ac
/
3al: 38%
3ac: ---
Finally, we performed studies in the presence of D2O, which unravelled a significant H/D exchange
(Scheme 7), thereby providing strong support for a reversible C(sp3)–H bond cleavage.
Scheme 7. H/D Exchange in the Presence of D2O
Me
i-Pr
Ru
O
MesCO2
Me
NH
Me
NH
Mes
O
5
(5.0 mol %)
N
N
o-xylene/D2O (1.8/0.2 mL)
D/H
Ph
Ph
D/H
Na2CO3, 140 °C, 24 h
65% D
[D]n-1a: 86%
1a
Conclusions
In summary, we have reported on the unprecedented use of wellꢀdefined ruthenium(II) biscarboxylate
complexes for C(sp3)–H bond functionalizations. Particularly, the highly chemoselective complex
[Ru(O2CMes)2(pꢀcymene)] (5) was found to be broadly applicable in direct arylations with aryl and even
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heteroaryl bromides, which also allowed for the use of low loadings of the carboxylate (co)catalyst.
Detailed mechanistic studies provided strong evidence for an initial, reversible (sp3)–H bond activation.
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Experimental Section
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General remarks. Catalytic reactions were carried out under an inert atmosphere of nitrogen using
predried glassware. Compounds 1a–1k8 were synthesized according to previously described methods.
All other chemicals were used as received without further purification unless otherwise specified. oꢀ
Xylene was dried over sodium. Yields refer to isolated compounds, estimated to be > 95% pure as
1
determined by HꢀNMR. NMR spectra were recorded in the solvent indicated; chemical shifts (δ) are
given in ppm. High resolution mass spectrometry (HRMS): FTICR.
Representative Procedure for Ruthenium–Catalyzed C(sp3)–H Bond Arylations: Synthesis of N-
Benzhydryl-3-methylpyridin-2-amine (3aa): NꢀBenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine (1a) (99 mg,
0.50 mmol, 1.0 equiv), bromobenzene (2a) (118 mg, 0.75 mmol, 1.5 equiv), [Ru(O2CMes)2(pꢀcymene)]
(5) (14 mg, 0.025 mmol, 5.0 mol %), Na2CO3 (159 mg, 1.50 mmol, 3.0 equiv) and oꢀxylene (2.0 mL)
were stirred under an atmosphere of nitrogen at 140 °C for 24 h. At ambient temperature, the suspension
was filtered through a short pad of Celite®, which was then washed with CH2Cl2 (50 mL). Evaporation
of the solvent in vacuo and purification by column chromatography on silica gel (nꢀhexane/EtOAc
1
99/1 → 98/2) yielded 3aa (95 mg, 69%) as a colorless solid (M.p. = 91–93 °C). HꢀNMR (300 MHz,
CDCl3):
δ = 7.98 (dd, J = 5.2, 1.7 Hz, 1H), 7.39–7.21 (m, 11H), 6.59–6.48 (m, 2H), 4.67 (d, J = 7.0 Hz,
1H), 2.15 (s, 3H). 13CꢀNMR (75 MHz, CDCl3):
δ
= 155.6 (Cq), 145.6 (CH), 143.5 (Cq), 136.9 (CH),
128.4 (CH), 127.5 (CH), 126.1 (CH), 116.3 (Cq), 113.1 (CH), 58.4 (CH), 17.0 (CH3). IR (neat): 3438,
1595, 1485, 1465, 1057, 695 cmꢀ1. MS (EI) m/z (relative intensity): 274 ([M+], 87), 182 (55), 167 (100),
+
165 (52), 98 (50), 43 (69). HRꢀMS (EI) m/z calcd for C19H18N2 274.1470, found 274.1462. The spectral
data were in accordance with those reported in the literature.7a
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N-Benzhydryl-3-phenylpyridin-2-amine (3da): The representative procedure was followed using Nꢀ
benzylꢀ3ꢀphenylpyridinꢀ2ꢀamine (1d) (130 mg, 0.50 mmol) and bromobenzene (2a) (118 mg,
0.75 mmol). Purification by column chromatography on silica gel (nꢀhexane/EtOAc 99/1 → 98/2)
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2
3
4
5
6
7
8
yielded 3da (34 mg, 20%) as a colorless solid. M.p. = 90–92 °C. 1HꢀNMR (300 MHz, CDCl3):
δ = 8.08
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(dd, J = 5.1, 1.8 Hz, 1H), 7.48–7.16 (m, 16H), 6.65 (dd, J = 7.3, 5.0 Hz, 1H), 6.52 (d, J = 7.5 Hz, 1H),
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5.20 (d, J = 7.5 Hz, 1H). CꢀNMR (125 MHz, CDCl3):
δ = 154.4 (Cq), 147.2 (CH), 143.3 (Cq), 137.9
(Cq), 137.1 (CH), 129.2 (CH), 128.8 (CH), 128.4 (CH), 127.8 (CH), 127.4 (CH), 126.9 (CH), 122.2
(Cq), 113.2 (CH), 58.5 (CH). IR (neat): 3447, 3023, 1596, 1463, 1280, 767, 696 cmꢀ1. MS (EI) m/z
(relative intensity): 336 ([M+], 100), 335 (20), 182 (45), 167 (87), 165 (45). HRꢀMS (EI) m/z calcd for
+
C24H20N2 336.1626, found 336.1629. The spectral data were in accordance with those reported in the
literature.7a
N-Benzhydryl-3-(trifluoromethyl)pyridin-2-amine (3ea): The representative procedure was followed
using Nꢀbenzylꢀ3ꢀ(trifluoromethyl)pyridinꢀ2ꢀamine (1e) (126 mg, 0.50 mmol) and bromobenzene (2a)
(118 mg, 0.75 mmol). Purification by column chromatography on silica gel (nꢀpentane/EtOAc
1
50/1 → 40/1 → 30/1) yielded 3ea (78 mg, 48%) as a yellow oil. HꢀNMR (300 MHz, CDCl3):
δ = 8.20
(ddd, J = 5.0, 1.9, 1.0 Hz, 1H), 7.67 (ddd, J = 7.6, 1.8, 0.8 Hz, 1H), 7.38–7.15 (m, 9H), 6.70–6.46 (m,
2H), 5.46 (d, J = 6.5 Hz, 1H). 13CꢀNMR (125 MHz, CDCl3):
δ
= 153.5 (Cq), 151.8 (CH), 142.6 (Cq),
134.9 (CH, J = 10.3 Hz), 128.6 (CH), 127.4 (CH), 127.2 (CH), 124.5 (Cq, J = 273.9 Hz), 111.9 (CH),
19
108.7 (Cq, J = 31.3 Hz), 58.4 (CH). FꢀNMR (282 MHz, CDCl3):
δ = –63.7 (s). IR (neat): 3476, 1602,
1582, 1493, 1465, 1301, 1102, 1024, 697 cmꢀ1. MS (EI) m/z (relative intensity): 328 ([M+], 90), 251
+
(25), 182 (45), 167 (100), 152 (35), 128 (30), 104 (20), 77 (15). HRꢀMS (EI) m/z calcd for C19H15F3N2
328.1187, found 328.1176. The spectral data were in accordance with those reported in the literature.7a
3-Methyl-N-[phenyl(p-tolyl)methyl]pyridin-2-amine (3ab): The representative procedure was
followed using Nꢀbenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine (1a) (99 mg, 0.50 mmol) and bromoꢀ4ꢀ
methylbenzene (2b) (128 mg, 0.75 mmol). Purification by column chromatography on silica gel (nꢀ
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hexane/EtOAc 99/1 → 98/2) yielded 3ab (90 mg, 62%) as a colorless solid. M.p. = 103–105 °C. Hꢀ
1
2
3
NMR (300 MHz, CDCl3): δ = 7.95 (dd, J = 5.1, 1.7 Hz, 1H), 7.36–7.09 (m, 10H), 6.55–6.46 (m, 2H),
4
5
6
13
4.63 (d, J = 7.0 Hz, 1H), 2.31 (s, 3H), 2.12 (s, 3H). CꢀNMR (75 MHz, CDCl3): δ = 155.7 (Cq), 145.6
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8
9
(CH), 143.6 (Cq), 140.5 (Cq), 136.9 (CH), 136.6 (Cq), 129.2 (CH), 128.4 (CH), 127.5 (CH), 127.4 (CH),
126.9 (CH), 116.3 (Cq), 112.9 (CH), 58.2 (CH), 21.0 (CH3), 17.1 (CH3). IR (neat): 3446, 3024, 1597,
1464, 771, 696 cmꢀ1. MS (EI) m/z (relative intensity): 288 ([M+], 75), 196 (33), 181 (100), 210 (35), 166
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+
(38), 165 (40). HRꢀMS (EI) m/z calcd for C20H20N2 288.1626, found 288.1637. The spectral data were
in accordance with those reported in the literature.7a
N-[(4-Methoxyphenyl)(phenyl)methyl]-3-methylpyridin-2-amine
(3ac):
The
representative
procedure was followed using Nꢀbenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine (1a) (99 mg, 0.50 mmol) and bromoꢀ
4ꢀmethoxybenzene (2c) (140 mg, 0.75 mmol). Purification by column chromatography on silica gel (nꢀ
hexane/EtOAc 99/1 → 98/2) yielded 3ac (105 mg, 69%) as a colorless solid. M.p. = 60–62 °C. 1HꢀNMR
(300 MHz, CDCl3): δ = 7.95 (dd, J = 5.1, 1.7 Hz, 1H), 7.34–7.16 (m, 8H), 6.83 (dt, J = 8.7, 3.0 Hz, 2H),
6.50 (dd, J = 7.2, 5.1 Hz, 1H), 6.40(d, J = 7.0 Hz, 1H), 4.60 (d, J = 7.0 Hz, 1H), 3.76 (s, 3H), 2.12 (s,
3H). 13CꢀNMR (75 MHz, CDCl3): δ = 158.6 (Cq), 155.7 (Cq), 145.6 (CH), 143.7 (Cq), 136.8 (CH), 135.7
(Cq), 128.7 (CH), 128.4 (CH), 127.4 (CH), 126.9 (CH), 116.2 (Cq), 113.8 (CH), 113.0 (CH), 57.8 (CH),
55.2 (CH3), 17.1 (CH3). IR (neat): 3026, 1596, 1508, 1482, 1243, 1172, 1029, 697 cmꢀ1. MS (EI) m/z
(relative intensity): 304 ([M+], 43), 198 (18), 197 (100), 153 (22). HRꢀMS (EI) m/z calcd C20H20N2O+
304.1576, found 304.1570. The spectral data were in accordance with those reported in the literature.7a
N-[{4-(tert-Butyl)phenyl}(phenyl)methyl]-3-methylpyridin-2-amine (3ad): The representative
procedure was followed using Nꢀbenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine (1a) (99 mg, 0.50 mmol) and bromoꢀ
4ꢀ(tertꢀbutyl)benzene (2d) (162 mg, 0.76 mmol). Purification by column chromatography on silica gel
(nꢀhexane/EtOAc 99/1 → 98/2) yielded 3ad (108 mg, 65%) as a colorless solid. M.p. = 121–123 °C. 1Hꢀ
NMR (300 MHz, CDCl3): δ = 7.96 (dd, J = 5.1, 1.7 Hz, 1H), 7.36–7.19 (m, 10H), 6.50 (dd, J = 7.1,
4.8 Hz, 2H), 4.67 (d, J = 7.1 Hz, 1H), 2.13 (s, 3H), 1.29 (s, 9H). 13CꢀNMR (75 MHz, CDCl3): δ = 155.7
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(Cq) , 149.8 (Cq), 145.6 (CH), 143.6 (Cq), 140.4 (Cq), 136.8 (CH), 128.4 (CH), 127.4 (CH), 127.3 (CH),
126.8 (CH), 125.4 (CH), 116.3 (Cq), 112.9 (CH), 58.0 (CH), 34.4 (Cq), 31.3 (CH3), 17.1 (CH3). IR
(neat): 3426, 2958, 1596, 1465, 785, 698 cmꢀ1. MS (EI) m/z (relative intensity): 330 ([M+], 100), 238
1
2
3
4
5
6
+
7
8
(32), 223 (93), 193 (20). HRꢀMS (EI) m/z calcd C23H26N2 330.2096, found 330. 2100. The spectral data
9
were in accordance with those reported in the literature.7a
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N-[(4-Chlorophenyl)(phenyl)methyl]-3-methylpyridin-2-amine (3ae): The representative procedure
was followed using Nꢀbenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine (1a) (99 mg, 0.50 mmol) and bromoꢀ4ꢀ
chlorobenzene (2e) (143 mg, 0.75 mmol) at 150 °C. Purification by column chromatography on silica
gel (nꢀhexane/EtOAc 99/1 → 98/2) yielded 3ae (82 mg, 53%) as a colorless solid. M.p. = 116–118 °C.
1HꢀNMR (300 MHz, CDCl3): δ = 7.94 (dd, J = 5.2, 1.8 Hz, 1H), 7.36–7.21 (m, 10H), 6.53 (dd, J = 7.1,
5.0 Hz, 1H), 6.46 (d, J = 6.7 Hz, 1H), 4.58 (d, J = 6.7 Hz, 1H), 2.12 (s, 3H). 13CꢀNMR (75 MHz,
CDCl3): δ = 155.5 (Cq), 145.6 (CH), 143.0 (Cq), 141.1 (Cq), 136.1 (CH), 132.6 (Cq), 128.8 (CH), 128.7
(CH), 128.5 (CH), 127.6 (CH), 127.3 (CH), 116.4 (Cq), 113.4 (CH), 58.0 (CH), 17.0 (CH3). IR (neat):
3445, 2925, 1596, 1483, 1464, 1087, 755, 695 cmꢀ1. MS (EI) m/z (relative intensity): 308 ([M+], 100),
+
216 (40), 201 (65), 166 (43), 165 (77). HRꢀMS (EI) m/z calcd for C19H17ClN2 308.1080, found
308.1076. The spectral data were in accordance with those reported in the literature.7a
3-Methyl-N-[phenyl(3-tolyl)methyl]pyridin-2-amine (3af): The representative procedure was
followed using Nꢀbenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine (1a) (99 mg, 0.50 mmol) and bromoꢀ3ꢀ
methylbenzene (2f) (135 mg, 0.78 mmol). Purification by column chromatography on silica gel (nꢀ
1
hexane/EtOAc 99/1 → 98/2) yielded 3af (91 mg, 63%) as a colorless oil. HꢀNMR (300 MHz, CDCl3):
δ = 7.97 (dd, J = 5.2, 1.7 Hz, 1H), 7.39–7.02 (m, 10H), 6.56–6.48 (m, 2H), 4.65 (d, J = 7.0 Hz, 1H),
13
2.32 (s, 3H), 2.14 (s, 3H). CꢀNMR (75 MHz, CDCl3): δ = 155.7 (Cq), 145.6 (CH), 143.5 (Cq), 143.4
(Cq), 138.1 (Cq), 136.8 (CH), 128.4 (CH), 128.3 (CH), 127.8 (CH), 127.5 (CH), 127.5 (CH), 126.9
(CH), 124.5 (CH), 116.2 (Cq), 112.9 (CH), 58.4 (CH), 21.5 (CH3), 17.1 (CH3). IR (neat): 3025, 1596,
1482, 1463, 1406, 773, 696 cmꢀ1. MS (EI) m/z (relative intensity): 288 ([M+], 100), 287 (18), 196 (55),
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181 (100), 165 (58). HRꢀMS (EI) m/z calcd for C20H20N2 288.1626, found 288.1619. The spectral data
1
2
3
were in accordance with those reported in the literature.7a
4
5
6
7
N-[(3-Methoxyphenyl)(phenyl)methyl]-3-methylpyridin-2-amine
(3ag):
The
representative
8
9
procedure was followed using Nꢀbenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine (1a) (99 mg, 0.50 mmol) and bromoꢀ
3ꢀmethoxybenzene (2g) (143 mg, 0.76 mmol). Purification by column chromatography on silica gel (nꢀ
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1
hexane/EtOAc 99/1 → 98/2) yielded 3ag (88 mg, 58%) as a colorless oil. HꢀNMR (300 MHz, CDCl3):
δ = 7.96 (dd, J = 5.1, 1.9 Hz, 1H), 7.36–7.18 (m, 7H), 6.94–6.86 (m, 2H), 6.77 (ddd, J = 8.2, 2.5,
1.1 Hz, 1H), 6.60–6.45 (m, 2H), 4.64 (d, J = 6.9 Hz, 1H), 3.75 (s, 3H), 2.13 (s, 3H). 13CꢀNMR (75 MHz,
CDCl3): δ = 159.7 (Cq), 155.6 (Cq), 145.6 (CH), 145.1 (Cq), 143.3 (Cq), 136.9 (CH), 129.5 (CH), 128.5
(CH), 127.5 (CH), 127.0 (CH), 119.9 (CH), 116.3 (Cq), 113.5 (CH), 113.1 (CH), 112.0 (CH), 58.4 (CH),
55.1 (CH3), 17.0 (CH3). IR (neat): 2934, 1595, 1482, 1463, 1252, 1043, 773, 696 cmꢀ1. MS (EI) m/z
(relative intensity): 304 ([M+], 100), 303 (16), 212 (68), 197 (84). HRꢀMS (EI) m/z calcd for
C20H20N2O+ 304.1576, found 304.1588. The spectral data were in accordance with those reported in the
literature.7c
N-[(3,5-Dimethylphenyl)(phenyl)methyl]-3-methylpyridin-2-amine (3ah): The representative
procedure was followed using Nꢀbenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine (1a) (99 mg, 0.50 mmol) and bromoꢀ
3,5ꢀdimethylbenzene (2h) (142 mg, 0.76 mmol). Purification by column chromatography on silica gel
(nꢀhexane/EtOAc 99/1 → 98/2) yielded 3ah (96 mg, 63%) as a colorless solid. M.p. = 117–119 °C. 1Hꢀ
NMR (300 MHz, CDCl3): δ = 7.96 (dd, J = 5.1, 1.7 Hz, 1H), 7.34–7.18 (m, 6H), 6.92 (s, 2H), 6.87 (s,
1H), 6.50 (dd, J = 7.1, 5.1 Hz, 1H), 6.44 (d, J = 7.1, 1H), 4.63 (d, J = 7.1 Hz, 1H), 2.26 (s, 6H), 2.13 (s,
3H). 13CꢀNMR (75 MHz, CDCl3): δ = 155.7 (Cq), 145.7 (CH), 143.6 (Cq), 143.4 (Cq), 137.9 (Cq), 136.8
(CH), 128.8 (CH), 128.4 (CH), 127.4 (CH), 126.8 (CH), 125.4 (CH), 116.2 (Cq), 112.9 (CH), 108.7
(Cq), 58.4 (CH), 21.4 (CH3), 17.1 (CH3). IR (neat): 3446, 2918, 1596, 1465, 1404, 755, 698 cmꢀ1. MS
(EI) m/z (relative intensity): 302 ([M+] 100), 301 (14), 210 (35), 195 (75), 165 (35). HRꢀMS (EI) m/z
+
calcd for C21H22N2 302.1783, found 302. 1772.
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N-[(3,4-Dimethoxyphenyl)(phenyl)methyl]-3-methylpyridin-2-amine (3ai): The representative
procedure was followed using Nꢀbenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine (1a) (99 mg, 0.50 mmol) and 4ꢀ
bromoꢀ1,2ꢀdimethoxybenzene (2i) (173 mg, 0.79 mmol). Purification by column chromatography on
silica gel (nꢀhexane/EtOAc 99/1 → 98/2) yielded 3ai (91 mg, 55%) as a light brown solid. M.p.= 134–
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3
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5
6
7
8
9
1
136 °C. HꢀNMR (300 MHz, CDCl3): δ = 7.95 (dd, J = 5.2, 1.8 Hz, 1H), 7.37–7.15 (m, 6H), 6.87–6.74
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(m, 3H), 6.50 (dd, J = 7.0, 5.2 Hz, 1H), 6.44 (d, J = 7.0 Hz, 1H), 4.59 (d, J = 7.0 Hz, 1H), 3.82 (s, 3H),
3.78 (s, 3H), 2.11 (s, 3H). 13CꢀNMR (75 MHz, CDCl3): δ = 155.7 (Cq), 148.9 (Cq), 148.0 (Cq), 145.6
(CH), 143.5 (Cq), 136.9 (CH), 136.1 (Cq), 128.4 (CH), 127.4 (CH), 126.9 (CH), 119.5 (CH), 116.2 (Cq),
113.1 (CH), 111.2 (CH), 111.0 (CH), 58.1 (CH), 55.8 (CH3), 55.8 (CH3), 17.1 (CH3). IR (neat): 3398,
3005, 2934, 1595, 1512, 1269, 1137, 1021, 701 cmꢀ1. MS (EI) m/z (relative intensity): 334 ([M+], 52),
+
228(16), 227 (100). HRꢀMS (EI) m/z calcd for C21H22N2O2 334.1681, found 334.1673.
3-Methyl-N-[(3,4,5-trimethoxyphenyl)(phenyl)methyl]pyridin-2-amine (3aj): The representative
procedure was followed using Nꢀbenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine (1a) (99 mg, 0.50 mmol) and 5ꢀ
bromoꢀ1,2,3ꢀtrimethoxybenzene (2j) (185 mg, 0.75 mmol). Purification by column chromatography on
silica gel (nꢀhexane/EtOAc 99/1 → 95/5 → 90/10) yielded 3aj (97 mg, 54%) as a violet solid.
M.p. = 174–176 °C. 1HꢀNMR (300 MHz, CDCl3): δ = 7.96 (dd, J = 5.1, 1.7 Hz, 1H), 7.34–7.19 (m, 6H),
6.55–6.49 (m, 3H), 6.44 (d, J = 6.9 Hz, 1H), 4.60 (d, J = 6.9 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 6H), 2.13 (s,
3H). 13CꢀNMR (125 MHz, CDCl3): δ = 155.6 (Cq), 153.1 (Cq), 145.5 (CH), 143.2 (Cq), 139.0 (Cq),
136.9 (CH), 136.8 (Cq), 128.4 (CH), 127.3 (CH), 126.9 (CH), 116.2 (Cq), 113.1 (CH), 104.7 (CH), 60.7
(CH3), 58.5 (CH), 55.9 (CH3), 16.9 (CH3). IR (neat): 3399, 2970, 1589, 1487, 1460, 1157, 1008 cmꢀ1.
MS (EI) m/z (relative intensity): 364 ([M+], 58), 349 (15), 258 (15), 257 (100). HRꢀMS (EI) m/z calcd
+
for C22H24N2O3 364.1787, found 364.1783.
N-[(1H-Indol-5-yl)(phenyl)methyl]-3-methylpyridin-2-amine (3ak): The representative procedure
was followed using Nꢀbenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine (1a) (99 mg, 0.50 mmol) and 5ꢀbromoꢀ1Hꢀ
indole (2k) (147 mg, 0.75 mmol). Purification by column chromatography on silica gel (nꢀ
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pentane/EtOAc 5/1 → 2/1) yielded 3ak (102 mg, 65%) as a colorless solid. M. p. = 148–149 °C. Hꢀ
1
2
3
4
NMR (300 MHz, CDCl3): = 8.57 (sbr, 1H), 7.98 (dd, J = 5.1, 1.7 Hz, 1H), 7.60–7.54 (m, 1H), 7.42–
δ
5
6
7
8
7.35 (m, 2H), 7.32–7.20 (m, 5H), 7.16–7.04 (m, 2H), 6.63 (d, J = 6.7 Hz, 1H), 6.52 (dd, J = 7.1, 5.1 Hz,
1H), 6.56–6.45 (m, 1H), 4.78 (d, J = 6.7 Hz, 1H), 2.15 (s, 3H). 13CꢀNMR (125 MHz, CDCl3):
δ
= 155.8
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(Cq), 145.5 (CH), 144.0 (Cq), 136.8 (CH), 135.0 (Cq), 134.9 (Cq), 128.2 (CH), 127.8 (Cq), 127.4 (CH),
126.6 (CH), 124.8 (CH), 122.1 (CH), 119.4 (CH), 116.3 (Cq), 112.8 (CH), 111.3 (CH), 102.4 (CH), 58.9
(CH), 17.1 (CH3). IR (neat): 3641, 3024, 1599, 1467, 1427, 1277, 1107, 896, 799, 772, 723, 696 cmꢀ1.
MS (EI) m/z (relative intensity): 313 ([M+], 85), 221 (45), 207 (45), 206 (100), 204 (55), 179 (40), 178
+
(30), 92 (25), 65 (10). HRꢀMS (EI) m/z calcd for C21H19N3 313.1579, found 313.1574.
N-[(3-Fluorophenyl)(4-methoxyphenyl)methyl]-3-methylpyridin-2-amine (3fc): The representative
procedure was followed using Nꢀ(3ꢀfluorobenzyl)ꢀ3ꢀmethylpyridinꢀ2ꢀamine (108 mg, 0.50 mmol) (1f)
and 4ꢀbromoanisole (2c) (140 mg, 0.75 mmol). Purification by column chromatography on silica gel (nꢀ
1
pentane/EtOAc 10/1) yielded 3fc (127 mg, 79%) as a colorless oil. HꢀNMR (300 MHz, CDCl3):
δ
= 7.94 (dd, J = 5.1, 1.7 Hz, 1H), 7.25–7.17 (m, 4H), 7.08 (dd, J = 7.7, 1.7 Hz, 1H), 7.01 (dt, J = 10.2,
2.1 Hz, 1H), 6.93–6.81 (m, 3H), 6.52 (dd, J = 7.1, 5.1 Hz, 1H), 6.42 (d, J = 6.7 Hz, 1H), 4.54 (d,
13
J = 6.7 Hz, 1H), 3.77 (s, 3H), 2.12 (s, 3H). CꢀNMR (125 MHz, CDCl3):
δ = 163.0 (Cq, J = 245.5 Hz),
158.8 (Cq), 155.5 (Cq), 146.4 (Cq, J = 6.4 Hz), 145.6 (CH), 137.0 (CH), 135.2 (Cq), 129.8 (CH,
J = 8.2 Hz), 128.8 (CH), 123.0 (CH, J = 2.8 Hz), 116.4 (Cq), 114.2 (CH, J = 22.0 Hz), 114.0 (CH),
113.6 (CH, J = 21.3 Hz), 113.3 (CH), 57.6 (CH), 55.3 (CH3), 17.0 (CH3). 19FꢀNMR (282 MHz, CDCl3):
δ
= –113.3 (ddd, J = 10.1, 8.7, 5.9 Hz). IR (neat): 3450, 2932, 1597, 1509, 1482, 1463, 1245, 1175,
1031, 775 cmꢀ1. MS (EI) m/z (relative intensity): 322 ([M+], 65), 230 (25), 215 (100), 183 (20), 171 (25),
92 (20), 65 (12). HRꢀMS (EI) m/z calcd for C20H19FN2O+ 322.1481, found 322.1471.
N-[(4-(tert-Butyl)phenyl)(3-fluorophenyl)methyl]-3-methylpyridin-2-amine
(3fd):
The
representative procedure was followed using Nꢀ(3ꢀfluorobenzyl)ꢀ3ꢀmethylpyridinꢀ2ꢀamine (108 mg,
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0.50 mmol) (1f) and bromoꢀ4ꢀ(tertꢀbutyl)benzene (2d) (160 mg, 0.75 mmol). Purification by column
1
2
3
chromatography on silica gel (nꢀpentane/EtOAc 30/1 → 20/1) yielded 3fd (140 mg, 80%) as a yellow
4
5
6
1
oil. HꢀNMR (300 MHz, CDCl3):
δ = 7.93 (dd, J = 5.1, 1.7 Hz, 1H), 7.35–7.28 (m, 2H), 7.25–7.15 (m,
7
8
4H), 7.10 (dd, J = 7.6, 1.7 Hz, 1H), 7.06–6.98 (m, 1H), 6.93–6.80 (dt, J = 8.5, 2.6 Hz, 1H), 6.50 (dd,
9
13
J = 7.1, 5.1 Hz, 1H), 6.44 (d, J = 6.7 Hz, 1H), 4.60 (d, J = 6.7 Hz, 1H), 2.11 (s, 3H), 1.28 (s, 9H). Cꢀ
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NMR (125 MHz, CDCl3):
δ = 163.0 (Cq, J = 245.5 Hz), 155.5 (Cq), 150.2 (Cq), 146.4 (Cq, J = 6.6 Hz),
145.6 (CH), 139.9 (Cq), 136.9 (CH), 129.7 (CH, J = 8.2 Hz), 127.4 (CH), 125.6 (CH), 123.0 (CH,
J = 2.7 Hz), 116.3 (Cq), 114.2 (CH, J = 21.9 Hz), 113.6 (CH, J = 21.3 Hz), 113.3 (CH), 57.8 (CH,
J = 1.6 Hz), 34.5 (Cq), 31.3 (CH3), 17.1 (CH3). 19FꢀNMR (282 MHz, CDCl3):
δ = –113.3 (ddd, J = 10.2,
8.7, 5.9 Hz). IR (neat): 2962, 1596, 1481, 1463, 1242, 776 cmꢀ1. MS (EI) m/z (relative intensity): 348
([M+], 100), 256 (50), 241 (95), 226 (28), 211 (25), 183 (18), 92 (20). HRꢀMS (EI) m/z calcd for
+
C23H25FN2 348.2002, found 348.1999.
N-[(3-Fluorophenyl)(3-methoxyphenyl)methyl]-3-methylpyridin-2-amine (3fg): The representative
procedure was followed using Nꢀ(3ꢀfluorobenzyl)ꢀ3ꢀmethylpyridinꢀ2ꢀamine (108 mg, 0.50 mmol) (1f)
and 3ꢀbromoanisole (2g) (140 mg, 0.75 mmol). Purification by column chromatography on silica gel (nꢀ
1
pentane/EtOAc 30/1 → 20/1) yielded 3fg (121 mg, 75%) as a yellow oil. HꢀNMR (300 MHz, CDCl3):
δ
= 7.94 (dd, J = 5.0, 1.6 Hz, 1H), 7.29–7.19 (m, 3H), 7.09 (ddt, J = 7.7, 1.8, 0.8 Hz, 1H), 7.05–6.98 (m,
1H), 6.91–6.84 (m, 3H), 6.79 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 6.52 (dd, J = 7.1, 5.0 Hz, 1H), 6.44 (d,
J = 6.8 Hz, 1H), 4.59 (d, J = 6.8 Hz, 1H), 3.75 (s, 3H), 2.13 (s, 3H). 13CꢀNMR (125 MHz, CDCl3):
δ
= 163.0 (Cq, J = 245.7 Hz), 159.8 (Cq), 155.4 (Cq), 146.1 (Cq, J = 6.6 Hz), 145.6 (CH), 144.6 (Cq),
137.0 (CH), 129.9 (CH, J = 8.2 Hz), 129.7 (CH), 123.1 (CH, J = 2.8 Hz), 120.0 (CH), 116.4 (Cq), 114.3
(CH, J = 22.0 Hz), 113.8 (CH, J = 21.3 Hz), 113.7 (CH), 113.4 (CH), 112.4 (CH), 58.1 (CH,
J = 1.9 Hz), 55.2 (CH3), 17.0 (CH3). 19FꢀNMR (282 MHz, CDCl3):
δ = –113.2 (ddd, J = 10.3, 8.8,
5.9 Hz). IR (neat): 3450, 2937, 1595, 1481, 1463, 1244, 1043, 776 cmꢀ1. MS (EI) m/z (relative intensity):
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322 ([M+], 100), 230 (70), 215 (58), 183 (27), 171 (17), 107 (18), 92 (20). HRꢀMS (EI) m/z calcd for
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C20H19FN2O+ 322.1481, found 322.1482.
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N-[{4-(tert-Butyl)phenyl}(3-methoxyphenyl)methyl]-3-methylpyridin-2-amine
(3gd):
The
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representative procedure was followed using Nꢀ(3ꢀmethoxybenzyl)ꢀ3ꢀmethylpyridinꢀ2ꢀamine (1g)
(114 mg, 0.50 mmol) and bromoꢀ4ꢀ(tertꢀbutyl)benzene (2d) (160 mg, 0.75 mmol). Purification by
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column chromatography on silica gel (nꢀpentane/EtOAc 20/1 → 10/1) yielded 3gd (128 mg, 71%) as a
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yellow oil. HꢀNMR (300 MHz, CDCl3):
δ = 7.97 (dd, J = 5.1, 1.7 Hz, 1H), 7.32 (dt, J = 8.6, 2.1 Hz,
2H), 7.25–7.20 (m, 4H), 6.95–6.89 (m, 2H), 6.77 (ddd, J = 8.1, 2.5, 1.0 Hz, 1H), 6.53–6.45 (m, 2H),
4.66 (d, J = 7.2 Hz, 1H), 3.75 (s, 3H), 2.12 (s, 3H), 1.30 (s, 9H). 13CꢀNMR (125 MHz, CDCl3):
δ
= 159.6 (Cq), 155.7 (Cq), 149.8 (Cq), 145.6 (CH), 145.3 (Cq), 140.3 (Cq), 136.8 (CH), 129.3 (CH),
127.2 (CH), 125.4 (CH), 119.8 (CH), 116.2 (Cq), 113.5 (CH), 113.0 (CH), 111.8 (CH), 58.0 (CH), 55.1
(CH3), 34.4 (Cq), 31.3 (CH3), 17.1 (CH3). IR (neat): 3448, 2960, 1596, 1482, 1463, 1523, 1045, 775,
730 cmꢀ1. MS (EI) m/z (relative intensity): 360 ([M+], 93), 268 (60), 253 (100), 238 (25), 223 (25), 197
(20), 165 (17), 92 (20). HRꢀMS (EI) m/z calcd for C24H28N2O+ 360.2202, found 360.2193.
N-[Bis(3-methoxyphenyl)methyl]-3-methylpyridin-2-amine (3gg): The representative procedure was
followed using Nꢀ(3ꢀmethoxybenzyl)ꢀ3ꢀmethylpyridinꢀ2ꢀamine (1g) (114 mg, 0.50 mmol) and 3ꢀ
bromoanisole (2g) (140 mg, 0.75 mmol). Purification by column chromatography on silica gel (nꢀ
1
pentane/EtOAc 20/1 → 10/1 → 5/1) yielded 3gg (115 mg, 69%) as a yellow oil. HꢀNMR (300 MHz,
CDCl3):
δ = 7.97 (dd, J = 5.0, 1.6 Hz, 1H), 7.27–7.19 (m, 3H), 6.94–6.90 (m, 4H), 6.77 (ddd, J = 8.2,
2.5, 1.0 Hz, 2H), 6.51 (dd, J = 7.2, 5.1 Hz, 1H), 6.46 (d, J = 7.0 Hz, 1H), 4.64 (d, J = 7.0 Hz, 1H), 3.75
13
(s, 6H), 2.13 (s, 3H). CꢀNMR (75 MHz, CDCl3):
δ = 159.6 (Cq), 155.6 (Cq), 145.6 (CH), 145.0 (Cq),
136.9 (CH), 129.4 (CH), 119.8 (CH), 116.3 (Cq), 113.5 (CH), 113.1 (CH), 112.0 (CH), 58.3 (CH), 55.1
(CH3), 17.0 (CH3). IR (neat): 3411, 2998, 1593, 1463, 1431, 1248, 1162, 1033, 777, 694 cmꢀ1. MS (EI)
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m/z (relative intensity): 334 ([M+], 100), 242 (70), 227 (80), 212 (25), 196 (25), 92 (20). HRꢀMS (EI)
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+
m/z calcd for C21H22N2O2 334.1681, found 334.1685.
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N-[(4-Methoxyphenyl){3-(trifluoromethyl)phenyl}methyl]-3-methylpyridin-2-amine (3hc): The
representative procedure was followed using 3ꢀmethylꢀNꢀ[3ꢀ(trifluoromethyl)benzyl]pyridinꢀ2ꢀamine
(133 mg, 0.50 mmol) (1h) and 4ꢀbromoanisole (2c) (140 mg, 0.75 mmol). Purification by column
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chromatography on silica gel (nꢀpentane/EtOAc 10/1 → 5/1) yielded 3hc (97 mg, 52%) as a colorless
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oil. HꢀNMR (300 MHz, CDCl3):
δ = 7.96 (dd, J = 5.2, 1.5 Hz, 1H), 7.62 (s, 1H), 7.56–7.36 (m, 3H),
7.28–7.18 (m, 3H), 6.91–6.84 (m, 2H), 6.55 (dd, J = 7.2, 5.2 Hz, 1H), 6.51 (d, J = 6.5 Hz, 1H), 4.60 (d,
J = 6.5 Hz, 1H), 3.78 (s, 3H), 2.14 (s, 3H). 13CꢀNMR (125 MHz, CDCl3):
δ
= 158.9 (Cq), 155.4 (Cq),
145.5 (CH), 144.7 (Cq), 137.0 (CH), 135.0 (Cq), 130.7 (CH), 130.5 (Cq, J = 31.1 Hz), 128.9 (CH), 128.7
(CH), 124.2 (Cq, J = 273.9 Hz), 124.0 (CH, J = 3.8 Hz), 123.6 (CH, J = 3.8 Hz), 116.4 (Cq), 114.1 (CH),
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113.4 (CH), 57.8 (CH), 55.2 (CH3), 17.0 (CH3). FꢀNMR (282 MHz, CDCl3):
δ = –62.4 (s). IR (neat):
3449, 2935, 1597, 1464, 1325, 1247, 1117, 1070, 701 cmꢀ1. MS (EI) m/z (relative intensity): 372 ([M+],
67), 266 (35), 265 (100), 153 (15), 92 (25). HRꢀMS (EI) m/z calcd for C21H19F3N2O+ 372.1449, found
372.1447.
N-[{4-(tert-Butyl)phenyl}{3-(trifluoromethyl)phenyl}methyl]-3-methylpyridin-2-amine (3hd): The
representative procedure was followed using 3ꢀmethylꢀNꢀ[3ꢀ(trifluoromethyl)benzyl]pyridinꢀ2ꢀamine
(1h) (133 mg, 0.50 mmol) and bromoꢀ4ꢀ(tertꢀbutyl)benzene (2d) (160 mg, 0.75 mmol). Purification by
column chromatography on silica gel (nꢀpentane/EtOAc 20/1 → 10/1) yielded 3hd (102 mg, 51%) as a
yellow oil. 1HꢀNMR (300 MHz, CDCl3):
δ = 7.94 (dd, J = 5.2, 1.6 Hz, 1H), 7.64 (s, 1H), 7.54–7.45 (m,
2H), 7.41 (d, J = 7.6 Hz, 1H), 7.37–7.31 (m, 2H), 7.26–7.16 (m, 3H), 6.53 (dd, J = 7.2, 5.1 Hz, 1H),
6.51 (d, J = 6.6 Hz, 1H), 4.63 (d, J = 6.6 Hz, 1H), 2.14 (s, 3H), 1.30 (s, 9H). 13CꢀNMR (125 MHz,
CDCl3):
δ = 155.5 (Cq), 150.4 (Cq), 145.6 (CH), 144.6 (Cq), 139.7 (Cq), 137.0 (CH), 130.7 (CH), 130.6
(Cq, J = 29.7 Hz), 128.7 (CH), 127.4 (CH), 125.7 (CH), 124.2 (Cq, J = 272.3 Hz), 124.0 (CH,
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J = 3.9 Hz), 123.6 (CH, J = 3.8 Hz), 116.4 (Cq), 113.4 (CH), 58.0 (CH), 34.5 (Cq), 31.3 (CH3), 17.0
(CH3). 19FꢀNMR (282 MHz, CDCl3):
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δ
= –62.4 (s). IR (neat): 3452, 2963, 1597, 1464, 1326, 1160,
1119, 989, 704 cmꢀ1. MS (EI) m/z (relative intensity): 398 ([M+], 100), 306 (50), 291 (90), 276 (25), 261
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+
(20), 107 (20), 92 (20). HRꢀMS (EI) m/z calcd for C24H25F3N2 398.1970, found 398.1975.
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N-[(3-Methoxyphenyl){3-(trifluoromethyl)phenyl}methyl]-3-methylpyridin-2-amine (3hg): The
representative procedure was followed using 3ꢀmethylꢀNꢀ[3ꢀ(trifluoromethyl)benzyl]pyridinꢀ2ꢀamine
(1h) (133 mg, 0.50 mmol) and 3ꢀbromoanisole (2g) (140 mg, 0.75 mmol). Purification by column
chromatography on silica gel (nꢀpentane/EtOAc 30/1 → 20/1 → 10/1) yielded 3hg (125 mg, 67%) as a
1
yellow oil. HꢀNMR (300 MHz, CDCl3):
δ = 7.94 (dd, J = 5.0, 1.6 Hz, 1H), 7.60 (s, 1H), 7.49 (t,
J = 7.4 Hz, 2H), 7.43–7.36 (m, 1H), 7.28–7.20 (m, 2H), 6.89–6.78 (m, 3H), 6.54 (dd, J = 7.2, 5.0 Hz,
1H), 6.51 (d, J = 6.6 Hz, 1H), 4.61 (d, J = 6.6 Hz, 1H), 3.76 (s, 3H), 2.14 (s, 3H). 13CꢀNMR (125 MHz,
CDCl3):
δ = 159.9 (Cq), 155.4 (Cq), 145.6 (CH), 144.3 (Cq), 137.1 (CH), 131.1 (Cq, J = 33.1 Hz), 130.8
(Cq), 130.7 (CH, J = 1.1 Hz), 129.8 (CH), 128.8 (CH), 124.2 (Cq, J = 273.2 Hz), 124.1 (CH, J = 3.8 Hz),
123.8 (CH, J = 3.8 Hz), 120.0 (CH), 116.5 (Cq), 113.8 (CH), 113.5 (CH), 112.5 (CH), 58.3 (CH), 55.2
(CH3), 17.0 (CH3). 19FꢀNMR (282 MHz, CDCl3):
δ = –62.4 (s). IR (neat): 3450, 2938, 1596, 1464,
1326, 1160, 1117, 1072, 699 cmꢀ1. MS (EI) m/z (relative intensity): 372 ([M+], 100), 280 (80), 265 (55),
152 (15), 107 (35), 92 (30). HRꢀMS (EI) m/z calcd for C21H19F3N2O+ 372.1449, found 372.1447.
N-[{4-(tert-Butyl)phenyl}(4-fluorophenyl)methyl]-3-methylpyridin-2-amine
(3id):
The
representative procedure was followed using Nꢀ(4ꢀfluorobenzyl)ꢀ3ꢀmethylpyridinꢀ2ꢀamine (1i) (108 mg,
0.5 mmol) and 1ꢀbromoꢀ4ꢀ(tertꢀbutyl)benzene (2d) (160 mg, 0.75 mmol). Purification by column
chromatography on silica gel (nꢀpentane/EtOAc 10/1) yielded 3id (112 mg, 64%) as a colorless solid.
1
M. p. = 66–67 °C. HꢀNMR (300 MHz, CDCl3):
δ = 7.98 (dd, J = 5.1, 1.6 Hz, 1H), 7.38–7.27 (m, 4H),
7.26–7.20 (m, 3H), 7.04–6.94 (m, 2H), 6.53 (dd, J = 7.2, 5.1 Hz, 1H), 6.49 (d, J = 6.8 Hz, 1H), 4.64 (d,
13
J = 6.8 Hz, 1H), 2.14 (s, 3H), 1.32 (s, 9H). CꢀNMR (75 MHz, CDCl3):
δ = 161.7 (Cq, J = 244.3 Hz),
155.6 (Cq), 150.0 (Cq), 145.6 (CH), 140.3 (Cq), 139.3 (Cq, J = 2.9 Hz), 136.9 (CH), 128.9 (CH,
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J = 8.1 Hz), 127.3 (CH), 125.5 (CH), 116.3 (Cq), 115.1 (CH, J = 21.2 Hz), 113.1 (CH), 57.5 (CH), 34.4
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3
4
19
(Cq), 31.3 (CH3), 17.0 (CH3). FꢀNMR (282 MHz, CDCl3):
δ = –116.3 (tt, J = 8.5, 5.2 Hz). IR (neat):
3429, 2962, 1597, 1488, 1467, 1224, 838, 785 cmꢀ1. MS (EI) m/z (relative intensity): 348 ([M+], 75),
256 (25), 241 (100), 226 (20), 211 (20), 92 (10). HRꢀMS (ESI) m/z calcd for [C23H25FN2+H]+ 349.2075,
found 349.2071.
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N-[(4-Fluorophenyl)(3-methoxyphenyl)methyl]-3-methylpyridin-2-amine (3ig): The representative
procedure was followed using Nꢀ(4ꢀfluorobenzyl)ꢀ3ꢀmethylpyridinꢀ2ꢀamine (1i) (108 mg, 0.5 mmol) and
3ꢀbromoanisole (2g) (140 mg, 0.75 mmol). Purification by column chromatography on silica gel (nꢀ
1
pentane/EtOAc 10/1) yielded 3ig (108 mg, 67%) as a colorless solid. M. p. = 96–97 °C. HꢀNMR
(300 MHz, CDCl3): δ = 7.95 (dd, J = 5.0, 1.7 Hz, 1H), 7.35–7.17 (m, 4H), 7.02–6.92 (m, 2H), 6.92–6.84
(m, 2H) 6.79 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 6.52 (dd, J = 7.1, 5.1 Hz, 1H), 6.45 (d, J = 6.9 Hz, 1H),
4.59 (d, J = 6.9 Hz, 1H), 3.75 (s, 3H), 2.13 (s, 3H). 13CꢀNMR (125 MHz, CDCl3):
δ
= 161.8 (Cq,
J = 245.0 Hz), 159.8 (Cq), 155.5 (Cq), 145.6 (CH), 145.0 (Cq), 139.1 (Cq, J = 3.1 Hz), 137.0 (CH), 129.6
(CH), 129.0 (CH, J = 8.0 Hz), 119.9 (CH), 116.3 (Cq), 115.2 (CH, J = 21.3 Hz), 113.6 (CH), 113.3
(CH), 112.2 (CH), 57.8 (CH), 55.1 (CH3), 17.0 (CH3). 19FꢀNMR (282 MHz, CDCl3):
δ
= –(115.9–116.1) (m). IR (neat): 3443, 1598, 1479, 1464, 1279, 1213, 1046, 780 cmꢀ1. MS (EI) m/z
(relative intensity): 322 ([M+], 95), 230 (55), 215 (100), 183 (30), 171 (20), 92 (20), 43 (45). HRꢀMS
(EI) m/z calcd for C20H19FN2O+ 322.1481, found 322.1477.
N-[{4-(tert-Butyl)phenyl}{4-(trifluoromethyl)phenyl}methyl]-3-methylpyridin-2-amine (3jd): The
representative procedure was followed using 3ꢀmethylꢀNꢀ[4ꢀ(trifluoromethyl)benzyl]pyridinꢀ2ꢀamine
(1j) (133 mg, 0.5 mmol) and bromoꢀ4ꢀ(tertꢀbutyl)benzene (2d) (160 mg, 0.75 mmol). Purification by
column chromatography on silica gel (nꢀpentane/EtOAc 20/1 → 10/1) yielded 3jd (122 mg, 61%) as a
1
colorless oil. HꢀNMR (300 MHz, CDCl3):
δ = 7.94 (dd, J = 5.2, 1.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H),
7.46 (d, J = 8.0, 2H), 7.35 (dd, J = 8.4, 2.0 Hz, 2H), 7.23–7.17 (m, 3H), 6.54 (dd, J = 7.2, 5.1 Hz, 1H),
6.49 (d, J = 6.4 Hz, 1H), 4.64 (d, J = 6.4 Hz, 1H), 2.14 (s, 3H), 1.30 (s, 9H). 13CꢀNMR (125 MHz,
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CDCl3):
δ
= 155.5 (Cq), 150.5 (Cq), 147.7 (Cq), 145.6 (CH), 139.7 (Cq), 137.0 (CH), 128.9 (Cq,
1
2
3
J = 32.2 Hz), 127.5 (CH), 127.5 (CH), 125.7 (CH), 125.3 (CH, J = 3.7 Hz), 124.3 (Cq, J = 278.2 Hz),
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6
19
116.4 (Cq), 113.4 (CH), 58.1 (CH), 34.5 (Cq), 31.3 (CH3), 17.0 (CH3). FꢀNMR (282 MHz, CDCl3):
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δ
= –62.3 (s). IR (neat): 2923, 1596, 1464, 1406, 1321, 1159, 1106, 1064, 1016 cmꢀ1. MS (EI) m/z
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(relative intensity): 398 ([M+], 100), 306 (60), 291 (85), 276 (40), 261 (35), 107 (30), 92 (30), 57 (20).
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+
HRꢀMS (EI) m/z calcd for C24H25F3N2 398.1970, found 398.1978.
3-Methyl-N-[3-tolyl{4-(trifluoromethyl)phenyl}methyl]pyridin-2-amine (3jf): The representative
procedure was followed using 3ꢀmethylꢀNꢀ[4ꢀ(trifluoromethyl)benzyl]pyridinꢀ2ꢀamine (1j) (133 mg,
0.5 mmol) and 3ꢀbromotoluene (2f) (128 mg, 0.75 mmol). Purification by column chromatography on
1
silica gel (nꢀpentane/EtOAc 20/1 → 10/1) yielded 3jf (106 mg, 59%) as a colorless oil. HꢀNMR
(300 MHz, CDCl3): δ = 7.95 (dd, J = 5.2, 1.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H),
7.31–7.18 (m, 2H), 7.14–7.05 (m, 3H), 6.55 (dd, J = 7.1, 5.2 Hz, 1H), 6.49 (d, J = 6.6 Hz, 1H), 4.62 (d,
J = 6.6 Hz, 1H), 2.33 (s, 3H), 2.15 (s, 3H). 13CꢀNMR (125 MHz, CDCl3):
δ
= 155.4 (Cq), 147.6 (Cq),
145.6 (CH), 142.7 (Cq), 135.5 (Cq), 137.0 (CH), 128.9 (Cq, J = 32.5 Hz), 128.7 (CH), 128.5 (CH), 128.3
(CH), 127.6 (CH), 125.3 (CH, J = 3.7 Hz), 124.8 (CH), 124.3 (Cq, J = 278.3 Hz), 116.4 (Cq), 113.5
19
(CH), 58.5 (CH), 21.5 (CH3), 17.0 (CH3). FꢀNMR (282 MHz, CDCl3):
δ = –62.3 (s). IR (neat): 3025,
1597, 1405, 1321, 1101, 1016, 777, 702 cmꢀ1. MS (EI) m/z (relative intensity): 356 ([M+], 100), 264
+
(75), 249 (60), 165 (30), 107 (25), 92 (20), 65 (15). HRꢀMS (EI) m/z calcd for C21H19F3N2 356.1500,
found 356.1498.
N-[(3-Fluorophenyl)(1H-indol-5-yl)methyl]-3-methylpyridin-2-amine (3fk): The representative
procedure was followed using Nꢀ(3ꢀfluorobenzyl)ꢀ3ꢀmethylpyridinꢀ2ꢀamine (108 mg, 0.50 mmol) (1f)
and 5ꢀbromoꢀ1Hꢀindole (2k) (147 mg, 0.75 mmol). Purification by column chromatography on silica gel
1
(nꢀpentane/EtOAc 10/1 → 5/1) yielded 3fk (119 mg, 72%) as a colorless solid. M. p. = 69–70 °C. Hꢀ
NMR (300 MHz, CDCl3): δ = 8.39 (s, 1H), 7.96 (dd, J = 5.1, 1.7 Hz, 1H), 7.56–7.48 (m, 1H), 7.32–7.18
(m, 3H), 7.17–7.04 (m, 4H), 6.88 (dt, J = 8.3, 2.6 Hz, 1H), 6.60–6.44 (m, 3H), 4.69 (d, J = 6.4 Hz, 1H),
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2.13 (s, 3H). 13CꢀNMR (125 MHz, CDCl3):
δ = 163.0 (Cq, J = 245.0 Hz), 155.6 (Cq), 147.0 (Cq,
1
2
3
4
5
6
7
8
J = 6.4 Hz), 145.6 (CH), 136.9 (CH), 135.1 (Cq), 134.6 (Cq), 129.6 (CH, J = 8.1 Hz), 127.9 (Cq), 124.9
(CH), 123.0 (CH, J = 2.7 Hz), 122.2 (CH), 119.8 (CH), 116.4 (Cq), 114.1 (CH, J = 21.9 Hz), 113.4 (CH,
J = 21.2 Hz), 113.1 (CH), 111.4 (CH), 102.7 (CH), 58.7 (CH, J = 1.5 Hz), 17.1 (CH3). 19FꢀNMR
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(282 MHz, CDCl3):
δ = –113.6 (ddd, J = 10.1, 8.6, 5.7 Hz). IR (neat): 3413, 1598, 1466, 1339, 1241,
1135, 749 cmꢀ1. MS (EI) m/z (relative intensity): 331 ([M+], 55), 239 (25), 224 (100), 222 (25), 197 (10),
+
92 (10), 43 (15). HRꢀMS (EI) m/z calcd for C21H18FN3 331.1485, found 331.1479.
N-[(1H-Indol-5-yl)(3-methoxyphenyl)methyl]-3-methylpyridin-2-amine (3gk): The representative
procedure was followed using Nꢀ(3ꢀmethoxybenzyl)ꢀ3ꢀmethylpyridinꢀ2ꢀamine (1g) (114 mg,
0.50 mmol) and 5ꢀbromoꢀ1Hꢀindole (2k) (147 mg, 0.75 mmol). Purification by column chromatography
on silica gel (nꢀpentane/EtOAc 5/1 → 2/1) yielded 3gk (103 mg, 60%) as a colorless solid. M. p. = 70–
1
71 °C. HꢀNMR (300 MHz, CDCl3):
δ = 8.49 (sbr, 1H), 7.96 (dd, J = 5.1, 1.7 Hz, 1H), 7.55 (s, 1H),
7.27–7.19 (m, 3H), 7.14–7.08 (m, 2H), 6.99–6.92 (m, 2H), 6.75 (ddd, J = 8.2, 2.6, 1.0 Hz, 1H), 6.57 (d,
J = 6.7 Hz, 1H), 6.54–6.43 (m, 2H), 4.73 (d, J = 6.7 Hz, 1H), 3.71 (s, 3H), 2.13 (s, 3H). 13CꢀNMR
(125 MHz, CDCl3):
δ = 159.5 (Cq), 155.8 (Cq), 145.8 (Cq), 145.5 (CH), 136.8 (CH), 135.1 (Cq), 134.7
(Cq), 129.2 (CH), 127.8 (Cq), 124.7 (CH), 122.1 (CH), 119.8 (CH), 119.5 (CH), 116.3 (Cq), 113.3 (CH),
112.8 (CH), 111.8 (CH), 111.3 (CH), 102.5 (CH), 58.9 (CH), 55.1 (CH3), 17.1 (CH3). IR (neat): 3411,
1596, 1464, 1249, 1038, 747 cmꢀ1. MS (EI) m/z (relative intensity): 343 ([M+], 65), 251 (25), 236 (100),
220 (15), 204 (15), 92 (15). HRꢀMS (EI) m/z calcd for C22H21N3O+ 343.1685, found 343.1690.
N-[(1H-Indol-5-yl){3-(trifluoromethyl)phenyl}methyl]-3-methylpyridin-2-amine
(3hk):
The
representative procedure was followed using 3ꢀmethylꢀNꢀ[3ꢀ(trifluoromethyl)benzyl]pyridinꢀ2ꢀamine
(1h) (133 mg, 0.50 mmol) and 5ꢀbromoꢀ1Hꢀindole (2k) (147 mg, 0.75 mmol). Purification by column
chromatography on silica gel (nꢀpentane/EtOAc 5/1 → 2/1) yielded 3hk (116 mg, 61%) as a colorless
1
solid. M. p. = 148–149 °C. HꢀNMR (300 MHz, CDCl3):
δ = 8.37 (sbr, 1H), 7.95 (dd, J = 5.0, 1.8 Hz,
1H), 7.64 (s, 1H), 7.58–7.42 (m, 3H), 7.40–7.22 (m, 3H), 7.16 (t, J = 2.8 Hz, 1H), 7.10 (dd, J = 8.4,
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1.7 Hz, 1H), 6.59 (d, J = 6.3 Hz, 1H), 6.53 (dd, J = 7.2, 5.0 Hz, 1H), 6.51–6.48 (m, 1H), 4.69 (d,
J = 6.3 Hz, 1H), 2.13 (s, 3H). 13CꢀNMR (125 MHz, CDCl3):
1
2
3
4
δ
= 155.6 (Cq), 145.5 (CH), 145.2 (Cq),
5
6
7
8
137.0 (CH), 135.2 (Cq), 134.5 (Cq), 130.7 (CH), 130.4 (Cq, J = 29.6 Hz), 128.6 (CH), 128.0 (Cq), 124.9
(CH), 124.3 (Cq, J = 275.5 Hz), 124.0 (CH, J = 3.8 Hz), 123.5 (CH, J = 3.9 Hz), 122.2 (CH), 119.9
9
19
(CH), 116.5 (Cq), 113.3 (CH), 111.5 (CH), 102.7 (CH), 58.9 (CH), 17.1 (CH3). FꢀNMR (282 MHz,
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CDCl3):
δ
= –62.3 (s). IR (neat): 3416, 1598, 1466, 1326, 1160, 1116, 1070, 951 cmꢀ1. MS (EI) m/z
(relative intensity): 381 ([M+], 55), 274 (100), 204 (25), 92 (10). HRꢀMS (EI) m/z calcd for C22H18F3N3
+
381.1453, found 381.1464.
N-[(2-Fluorophenyl)(1H-indol-5-yl)methyl]-3-methylpyridin-2-amine (3kk): The representative
procedure was followed using Nꢀ(2ꢀfluorobenzyl)ꢀ3ꢀmethylpyridinꢀ2ꢀamine (1k) (108 mg, 0.50 mmol)
and 5ꢀbromoꢀ1Hꢀindole (2k) (147 mg, 0.75 mmol). Purification by column chromatography on silica gel
1
(nꢀpentane/EtOAc 5/1 → 2/1) yielded 3kk (85 mg, 51%) as a yellow solid. M. p. = 176–177 °C. Hꢀ
NMR (300 MHz, DMSOꢀd6):
δ = 11.0 (sbr, 1H), 7.86 (d, J = 4.7 Hz, 1H), 7.65 (t, J = 6.8 Hz, 1H), 7.49–
7.05 (m, 8H), 6.88 (d, J = 7.9 Hz, 1H), 6.52 (dd, J = 7.1, 4.8 Hz, 1H), 6.40 (s, 1H), 6.09 (d, J = 8.1 Hz,
1H), 2.22 (s, 3H). 13CꢀNMR (125 MHz, DMSOꢀd6):
δ
= 160.9 (Cq, J = 244.2 Hz), 156.5 (Cq), 145.6
(CH), 137.6 (CH), 135.9 (Cq), 133.7 (Cq), 132.5 (Cq, J = 14.2 Hz), 129.5 (CH, J = 4.2 Hz), 129.1 (CH,
J = 8.0 Hz), 128.3 (Cq), 126.5 (CH), 125.0 (CH, J = 3.3 Hz), 122.1 (CH), 119.5 (CH), 117.8 (Cq), 115.8
19
(CH, J = 21.7 Hz), 113.3 (CH), 112.1 (CH), 101.9 (CH), 52.7 (CH, J = 3.3 Hz), 17.8 (CH3). FꢀNMR
(282 MHz, DMSOꢀd6):
δ = –(101.2–127.2) (m). IR (neat): 3461, 3195, 1602, 1498, 1473, 1403, 1222,
1184, 757 cmꢀ1. MS (EI) m/z (relative intensity): 331 ([M+], 50), 239 (15), 224 (100), 222 (20), 92 (10).
+
HRꢀMS (EI) m/z calcd for C21H18FN3 331.1485, found 331.1482.
Intermolecular Competition Experiment between Substituted Pyridines 1a and 1e (Scheme 4).
According to the representative procedure, Nꢀbenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine (1a) (149 mg,
0.75 mmol), Nꢀbenzylꢀ3ꢀ(trifluoromethyl)pyridinꢀ2ꢀamine (1e) (189 mg, 0.75 mmol), bromobenzene
(2a) (79 mg, 0.50 mmol), [Ru(O2CMes)2(pꢀcymene)] (5) (14 mg, 0.025 mmol, 5.0 mol %) and Na2CO3
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(159 mg, 1.50 mmol) were reacted in oꢀxylene (2.0 mL) at 140 °C for 24 h. Purification by column
chromatography on silica gel (nꢀpentane/EtOAc 20/1 → 10/1) yielded 3aa (50 mg, 36%). The ratio
between 3aa and 3ea was found to be 13:1 as determined by GCꢀanalysis.
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Intermolecular Competition Experiment between Substituted Arenes 1f and 1g (Scheme 5).
According to the representative procedure, Nꢀ(3ꢀfluorobenzyl)ꢀ3ꢀmethylpyridinꢀ2ꢀamine (1f) (162 mg,
0.75 mmol), Nꢀ(3ꢀmethoxybenzyl)ꢀ3ꢀmethylpyridinꢀ2ꢀamine (1g) (171 mg, 0.75 mmol), bromobenzene
(2a) (79 mg, 0.50 mmol), [Ru(O2CMes)2(pꢀcymene)] (5) (14 mg, 0.025 mmol, 5.0 mol %) and Na2CO3
(159 mg, 1.50 mmol) were reacted in oꢀxylene (2.0 mL) at 140 °C for 24 h. Purification by column
chromatography on silica gel (nꢀpentane/EtOAc 30/1 → 20/1 → 10/1 → 5/1) yielded 3fa (36 mg, 25%)
and 3ga (41 mg, 27%).
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Intermolecular Competition Experiment between Electrophiles 2l and 2c (Scheme 6). According to
the representative procedure, Nꢀbenzylꢀ3ꢀmethylpyridinꢀ2ꢀamine (1a) (99 mg, 0.50 mmol), bromoꢀ4ꢀ
(trifluoromethyl)benzene (2l) (169 mg, 0.75 mmol), 4ꢀbromoanisole (2c) (140 mg, 0.75 mmol),
[Ru(O2CMes)2(pꢀcymene)] (5) (14 mg, 0.025 mmol, 5.0 mol %) and Na2CO3 (159 mg, 1.50 mmol) were
reacted in oꢀxylene (2.0 mL) at 140 °C for 24 h. Purification by column chromatography on silica gel (nꢀ
pentane/EtOAc 20/1 → 10/1) yielded 3al (65 mg, 38%) as a yellow oil. The ratio between 3al and 3ac
1
was found to be 2.3:1.0 as determined by GCꢀanalysis. 3al: HꢀNMR (300 MHz, CDCl3):
δ = 7.96 (dd,
J = 5.2, 1.6 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.44–7.25 (m, 6H), 6.70–6.49
(m, 2H), 4.64 (d, J = 6.5 Hz, 1H), 2.16 (s, 3H). 13CꢀNMR (125 MHz, CDCl3):
δ
= 155.4 (Cq), 145.7 (Cq,
J = 1.6 Hz), 145.5 (CH), 142.7 (Cq), 137.1 (CH), 129.1 (Cq, J = 32.2 Hz), 128.8 (CH), 127.7 (CH),
127.6 (CH), 127.5 (CH), 125.3 (CH, J = 3.7 Hz), 124.2 (Cq, J = 273.7 Hz), 116.4 (Cq), 113.5 (CH), 58.4
(CH), 17.0 (CH3). 19FꢀNMR (282 MHz, CDCl3):
δ = –62.3 (s). IR (neat): 3451, 1597, 1465, 1321, 1161,
1106, 1065, 1016, 699 cmꢀ1. MS (EI) m/z (relative intensity): 342 ([M+], 100), 250 (90), 235 (75), 215
+
(25), 165 (75), 107 (20), 92 (15). HRꢀMS (EI) m/z calcd for C20H17F3N2 342.1344, found 342.1341.
The spectral data were in accordance with those reported in the literature.7a
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H/D Exchange in Substrate 1a in the Presence of D2O (Scheme 7). NꢀBenzylꢀ3ꢀmethylpyridinꢀ2ꢀ
amine (1a) (99 mg, 0.50 mmol, 1.0 equiv), [Ru(O2CMes)2(pꢀcymene)] (5) (14 mg, 0.025 mmol,
5.0 mol %) and Na2CO3 (159 mg, 1.50 mmol, 3.0 equiv) were placed in a 25 mL sealed tube with a
septum screw cap under an atmosphere of nitrogen. After adding oꢀxylene (1.8 mL) and D2O (0.2 mL),
the septum screw cap was removed and a teflon lined cap was fixed. The reaction mixture was stirred at
140 °C for 24 h. At ambient temperature, the suspension was filtered through a short pad of Celite®,
which was then washed with CH2Cl2 (50 mL). Evaporation of the solvents in vacuo and purification by
column chromatography on silica gel (nꢀhexane/EtOAc 99/1 → 98/2) yielded [Dn]ꢀ1a as a colorless oil
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1
1
(85 mg, 86%, 65%ꢀD), as determined by HꢀNMR. HꢀNMR (300 MHz, CDCl3):
δ = 8.04 (dd, J = 5.1,
1.7 Hz, 1H), 7.43–7.19 (m, 6H), 6.55 (dd, J = 7.1, 5.1 Hz, 1H), 4.68 (d, J = 5.4 Hz, 2H), 4.35 (sbr, 1H),
13
2.07 (s, 3H). CꢀNMR (125 MHz, CDCl3):
δ = 156.6 (Cq), 145.4 (CH), 140.0 (Cq), 136.8 (CH), 128.5
(CH), 127.8 (CH), 127.1 (CH), 116.4 (Cq), 112.9 (CH), 45.8 (CH2), 45.5 (CHD, J = 21.0 Hz), 17.0
(CH3). IR (neat): 3447, 3027, 1597, 1490, 1466, 1381, 696 cmꢀ1. MS (EI) m/z (relative intensity): 200
(23), 199 (77), 198 (100), 197 (33), 108 (27), 107 (80), 106 (77), 93 (47), 92 (65), 91 (38), 65 (38). HRꢀ
MS (ESI) m/z calcd for [C13H12D2N2+H]+ 201.1355, found 201.1355, m/z calcd for [C13H13DN2+H]+
200.1293, found 200.1292, m/z calcd for [C13H14N2+H]+ 199.1230, found 199.1230.
Acknowledgement. Support by the CaSuS PhD program, the DAAD (fellowship to NYPK), and the
European Research Council under the European Community’s Seventh Framework Program (FP7 2007–
2013)/ERC Grant agreement no. 307535 is gratefully acknowledged.
Associated Content
1
Supporting Information Available: Copies of H and 13C NMR spectra for all products. This
material is available free of charge via the Internet at http://pubs.acs.org.
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References
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(1) Illustrative recent reviews: (a) Kozhushkov, S. I.; Potukuchi, H. K.; Ackermann, L. Catal. Sci.
Technol. 2013, 3, 562ꢀ571. (b) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936ꢀ946. (c)
Engle, K. M.; Mei, T.ꢀS.; Wasa, M.; Yu, J.ꢀQ. Acc. Chem. Res. 2012, 45, 788ꢀ802. (d) WencelꢀDelord,
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Thansandote, P.; Lautens, M. Chem. Eur. J. 2009, 15, 5874ꢀ5883 and references cited therein.
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5918. (b) Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292, 211ꢀ229.
(3) Examples of carboxylateꢀassisted rutheniumꢀcatalyzed C(sp2)–H bond arylations, alkynylations
and alkylations: (a) Diers, E.; Kumar, N. Y. P.; Mejuch, T.; Marek, I.; Ackermann, L. Tetrahedron
2013, DOI:10.1016/j.tet.2013.01.006. (b) Ano, Y.; Tobisu, M.; Chatani, N. Synlett 2012, 2763ꢀ2767. (c)
Li, B.; Devaraj, K.; Darcel, C.; Dixneuf, P. H. Tetrahedron 2012, 68, 5179ꢀ5184. (d) Stefane, B.; Fabris,
J.; Pozgan F. Eur. J. Org. Chem. 2011, 3474ꢀ3481. (e) Ackermann, L.; Lygin, A. Org. Lett. 2011, 13,
3332ꢀ3335. (f) Ouellet, S. G.; Roy, A.; Molinaro, C.; Angelaud, R.; Marcoux, J.ꢀF.; O'Shea, P. D.;
Davies, I. W. J. Org. Chem. 2011, 76, 1436ꢀ1439. (g) Ackermann, L.; Hofmann, N.; Vicente, R. Org.
Lett. 2011, 13, 1875ꢀ1877. (h) Pozgan, F.; Dixneuf, P. H. Adv. Synth. Catal. 2009, 351, 1737ꢀ1743. (i)
Arockiam, P.; Poirier, V.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Green Chem. 2009, 11, 1871ꢀ
1875. (j) Ackermann, L.; Vicente, R. Org. Lett. 2009, 11, 4922ꢀ4925 and references cited therein.
(4) Ackermann, L. Chem. Rev. 2011, 111, 1315ꢀ1345.
(5) Selected recent examples of carboxylate assistance in oxidative rutheniumꢀcatalyzed C–H bond
functionalizations: (a) Wang, L.; Ackermann, L. Org. Lett. 2013, 15, 176ꢀ179. (b) Singh, K. S.; Dixneuf,
P. H. Organometallics 2012, 31, 7320ꢀ7323. (c) Zhao, P.; Wang, F.; Han, K.; Li, X. Org. Lett. 2012, 14,
5506ꢀ5509. (d) Parthasarathy, K.; Senthilkumar, N.; Jayakumar, J.; Cheng, C.ꢀH. Org. Lett. 2012, 14,
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3478ꢀ3481. (e) Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011,
13, 706ꢀ708. (f) Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem. Int. Ed. 2011, 50, 6379ꢀ
6382. Recent reviews: (g) Kozhushkov, S. I.; Ackermann, L. Chem. Sci. 2013, 4, 886ꢀ896. (h)
Ackermann, L. Acc. Chem. Res. 2013, 46, DOI:10.1021/ar3002798.
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(6) For reviews on challenging C(sp3)–H bond transformations, see: (a) Li, H; Li, B.ꢀJ.; Shi, Z.ꢀJ.
Catal. Sci. Technol. 2011, 1, 191ꢀ206. (b) Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902ꢀ4911. (c) Wasa,
M.; Engle, K. M.; Yu, J.ꢀQ. Isr. J. Chem. 2010, 50, 605ꢀ616. (d) Jazzar, R.; Hitce, J.; Renaudat, A.;
SofackꢀKreutzer, J.; Baudoin, O. Chem. Eur. J. 2010, 16, 2654ꢀ2672.
(7) For notable progress in ruthenium(0)ꢀcatalyzed transformations with aryl boronates as the arylating
reagents, see: (a) Dastbaravardeh, N.; Kirchner, K.; Schnürch, M.; Mihovilovic, M. D. J. Org. Chem
2013, 78, 658ꢀ672. (b) Bergman, S. D.; Storr, T. E.; Prokopcova, H.; Aelvoet, K.; Diels, G.; Meerpoel,
L.; Maes, B. U. W. Chem. Eur. J. 2012, 18, 10393ꢀ10398. (c) Dastbaravardeh, N.; Schnürch, M.;
Mihovilovic, M. D. Org. Lett. 2012, 14, 3792ꢀ3795. (d) Prokopcova, H.; Bergman, S. D.; Aelvoet, K.;
Smout, V.; Herrebout, W.; Van der Veken, B.; Meerpoel, L.; Maes, B. U. W. Chem. Eur. J. 2010, 16,
13063ꢀ13067. (e) Pastine, S. J.; Gribkov, D. V.; Sames, D. J. Am. Chem. Soc. 2006, 128, 14220–14221.
See also: (f) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N. J. Am. Chem. Soc. 2005, 127, 5936ꢀ5945.
(g) Jun, C.ꢀH.; Hwang, D.ꢀC.; Na, S.ꢀJ. Chem. Commun. 1998, 1405ꢀ1406.
(8) Dastbaravardeh, N.; Schnürch, M.; Mihovilovic, M. D. Org. Lett. 2012, 14, 3792ꢀ3795.
(9) For the use of [Ru(O2CMes)2(pꢀcymene)] (5) in the catalyzed functionalization of C(sp2)–H bonds,
see: Ackermann, L.; Pospech, J.; Potukuchi, H. K. Org. Lett. 2012, 14, 2146ꢀ2149 and references cited
therein.
(10) Flegeau, E. F.; Bruneau, C.; Dixneuf, P. H.; Jutand, A. J. Am. Chem. Soc. 2011, 133, 10161ꢀ
10170.
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(11) Selected examples of rutheniumꢀcatalyzed C(sp2)–H bond functionalizations with water as the
reaction medium: (a) Arockiam, P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Angew. Chem. Int.
Ed. 2010, 49, 6629ꢀ6632. (b) Ackermann, L. Org. Lett. 2005, 7, 3123ꢀ3125. (c) A recent review: Li, B.;
Dixneuf, P. H. Chem. Soc. Rev. 2013, DOI: 10.1039/C3CS60020C.
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(12) For examples of competition experiments between aryl halides in ruthenium(II)ꢀcatalyzed C(sp2)–
H bond arylations, see: (a) Aihara, Y.; Chatani, N. Chem. Sci. 2013, 4, 664ꢀ670 (b) Ackermann, L.;
Vicente, R.; Potukuchi, H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032ꢀ5035.
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