Cationic iridium-catalyzed enantioselective activation of secondary sp 3 C-H bond adjacent to nitrogen atom

Article abstract of DOI:10.1016/j.tet.2012.08.071

A cationic Ir(I)-tolBINAP complex catalyzed an enantioselective C-C bond formation, which was initiated by secondary sp³ C-H bond cleavage adjacent to nitrogen atom. A wide variety of 2-(alkylamino)pyridines and alkenes were selectively transformed into the corresponding chiral amines with moderate to almost perfect enantiomeric excesses. Alkynes were also investigated as coupling partners. The effect of alkyl structure in substrates and directing groups were studied. This transformation represents the first example of a highly enantioselective C-H bond activation of a methylene group, not at allylic or benzylic position.

Full text of DOI:10.1016/j.tet.2012.08.071

Tetrahedron 68 (2012) 9009e9015
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cationic iridium-catalyzed enantioselective activation of secondary sp3 CeH bond
adjacent to nitrogen atom
,
Shiguang Pan a, Yusuke Matsuo a, Kohei Endo b, Takanori Shibata a
*
a Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku, Tokyo 169-8555, Japan
b Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 August 2012
Received in revised form 22 August 2012
Accepted 23 August 2012
Available online 31 August 2012
A cationic Ir(I)etolBINAP complex catalyzed an enantioselective CeC bond formation, which was initi-
ated by secondary sp3 CeH bond cleavage adjacent to nitrogen atom. A wide variety of 2-(alkylamino)
pyridines and alkenes were selectively transformed into the corresponding chiral amines with moderate
to almost perfect enantiomeric excesses. Alkynes were also investigated as coupling partners. The effect
of alkyl structure in substrates and directing groups were studied. This transformation represents the
first example of a highly enantioselective CeH bond activation of a methylene group, not at allylic or
benzylic position.
Keywords:
CeH activation
Enantioselective
Iridium
Ó 2012 Elsevier Ltd. All rights reserved.
Heterocycle
1. Introduction
sp3 CeH bond activation of 2-(ethylamino)pyridine with styrene
derivatives in good yields with high enantiomeric excesses.10 In
The efficient functionalization of CeH bonds has attracted much
attention from both academia and industry, especially with regard
to CeC bond formation based on transition-metal catalysis.1 In last
decade, various methods have been reported for the initiation of
CeH bond cleavage, and many synthetically useful transformations
have been disclosed.2 Among the CeH bond functionalizations,
activation of the sp2 CeH bond, such as aromatic and vinylic CeH
bonds, has been widely investigated. However, the examples of sp3
CeH bond activation are relatively few.3-5 In particular, those of
secondary sp3 CeH bond activation are scarce and limited to ben-
zylic and allylic positions.6 For example, Jun reported pioneering
work of a Ru-catalyzed reaction of 2-(benzylamino)pyridine with
alkenes, which was initiated by secondary sp3 CeH bond cleavage
at the benzylic position.6b Murai also reported a Ru-catalyzed re-
action of 2-(N-pyrrolidinyl)pyridine with alkenes.6c In contrast to
these achievements of secondary sp3 CeH bond activation, enan-
tioselective secondary sp3 CeH bond activation still remains highly
challenging.7,8 Against these backgrounds, we realized an enan-
tioselective cleavage of secondary sp3 CeH bond adjacent to ni-
trogen of 2-(alkylamino)pyridine at relatively lower temperature
by using a chiral Ir catalyst.9
this manuscript, we scrutinized the effect of alkyl group on the
nitrogen atom of amino group and directing group other than
pyridine. In the case of a longer alkyl group, higher reaction tem-
perature was required, but the successful transformation was
achieved. In contrast, the reaction of 2-(alkylamino)pyridine pos-
sessing a bulky alkyl group did not proceed. We screened various
nitrogen-containing heterocycles as directing groups and found
that pyridine and quinoline were the best directing groups. Then
we further examined the scope of alkenes: the reaction with ethyl
acrylate provided the corresponding amine with perfect enantio-
meric excess. Vinylsilanes and allylsilanes also gave the desired
products with moderate to good ee. Finally, alkynes were also
used as coupling partners to 2-(alkylamino)pyridines in this
transformation.
2. Results and discussion
2.1. Optimization of the reaction conditions
In previous report, we found that (S)-tolBINAP was the best
chiral ligand for enantioselective secondary sp3 CeH bond acti-
vation.10 We further examined the counteranion of iridium
complex, solvent and reaction temperature in this trans-
formation (Table 1). As for counteranion, the results of PF6, OTf,
or BARF did not exceed those of BF4 (entries 1e4).11 We next
examined various solvents other than chlorobenzene. Toluene
In the precedent communication, we reported that a cationic
Ir(I)etolBINAP complex catalyzed an enantioselective secondary
* Corresponding author. E-mail address: tshibata@waseda.jp (T. Shibata).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.071

9010
S. Pan et al. / Tetrahedron 68 (2012) 9009e9015
Table 2
and 1,2-dichloroethane (DCE) were tested, but the results were
not better than those of chlorobenzene (entries 5 and 6). In
contrast, the best yield of 95% was achieved by using dioxane,
yet along with significant decrease of ee (entry 7). At lower
temperature, the reaction sluggishly proceeded, but the ee was
significantly improved (entries 8 and 9). The mixed solvent of
dioxane and chlorobenzene gave the desired product 3aa, but
the ee was less than 80% (entries 10e12). When 1,2-
dimethoxylethane (DME) was used as a solvent, the reaction
proceeded efficiently even at 75 ꢀC and the enantioselectivity
reached ca. 90% (entry 15). Three equivalent amounts of styrene
were sufficient to achieve good yield and high ee at slightly
higher reaction temperature (entry 16). We decided to use the
reaction conditions of entry 15 for further investigation.
Effect of alkyl substituents on the nitrogen atom
Ph
R2
[Ir(cod)2]BF4
+ (S)-tolBINAP (10 mol%)
N
Ph
N
+
N
R2
N
DME
R1
R1
1a-1f
2a
3aa-3fa
Entrya
R1
R2
Cond.b
Yield (%)
Ee (%)
1
2
3
H
H
H
H
H
CH3
(1a)
(1b)
(1c)
(1d)
(1e)
(1f)
75/2
85/4
85/7
95/4
135/3
135/2
76 (3aa)
69 (3ba)
58 (3ca)
60 (3da)
d (3ea)
88
83
86
73
d
d
CH2CH3
(CH2)2CH3
(CH2)4CH3
CH(CH3)2
4
5c
6c
e(CH2)3e
Trace (3fa)
a
Condition: 1 (0.1 mmol), 2a (0.8 mmol), DME (0.2 mL), unless otherwise noted.
Cond.: bath temperature/time¼ꢀC/day.
Table 1
b
c
Investigation of the best reaction conditions
Chlorobenzene (0.2 mL) was used as solvent.
2.3. Scope of nitrogen-containing heterocycles
We next investigated the scope of nitrogen-containing hetero-
cycles bearing ethylamino substituent at 2-position (Table 3). Py-
rimidine and pyrazine could not operate as efficient directing group
in the secondary sp3 CeH bond activation (entries 1 and 2). How-
ever, when quinoline was used as a directing group in present re-
action, the desired product 3ia was obtained with good yield, and
its enantiomeric excess reached 98% (entry 3). Furthermore,
dependent on the position of methyl group on the pyridine ring, the
yield and ee were changed (entries 4e6): compared with pyridine
Entrya
X
Solvent
T (ꢀC)b
Yield (%)
Ee (%)
1
2
3
4
5
6
7
8
BF4
PF6
OTf
BARFc
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
PhCl
PhCl
PhCl
PhCl
PhCH3
DCE
Dioxane
Dioxane
Dioxane
Dioxane/PhCl (9:1)
Dioxane/PhCl (1:1)
Dioxane/PhCl (1:9)
DME
DME
DME
DME
135
135
135
135
135
135
135
95
62
24
48
9
80
74
81
40
68
76
63
80
77
52
79
79
82
87
88
86
66
43
95
49
21
95
72
47
62
40
76
75
9
75
Table 3
10
11
12
13
14
15d
16e
135
135
135
95
75
75
Scope of nitrogen-containing heterocycles
Ph
[Ir(cod)2]BF4
+ (S)-tolBINAP (10 mol%)
N
Ph
N
+
N
H
CH3
N
H
CH3
DME
85
a
1g-1m
2a
3ga-3ma
Ee (%)
Conditions: 1a (0.1 mmol), 2a (0.8 mmol), solvent (0.2 mL), unless otherwise
noted.
b
c
Entrya
Substrate
Cond.b
135/1
Yield (%)
Bath temperature.
BARF: tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
The reaction time was 48 h.
d
e
1c
d (3ga)
d
Styrene (0.3 mmol) was used, and the reaction time was 72 h.
2.2. Effect of alkyl substituents on the nitrogen atom
We achieved the good enantioselectivity in the reaction of 2-
(ethylamino)pyridine 1a with styrene 2a. The effect of alkyl
substituents on the nitrogen atom of 2-aminopyridine was next
investigated in the present reaction (Table 2). We first exam-
ined the effect of the length of alkyl chain. As a result, the
products 3ba and 3ca were obtained with moderate yields at
a slightly higher reaction temperature, and their enantiomeric
excesses were still high (entries 2 and 3). In the reaction of
aminopyridine 1d possessing six-carbon alkyl chain, further
high reaction temperature was required to give product 3da,
and the ee slightly decreased (entry 4). The steric effect of alkyl
chain plays an important role in this reaction: aminopyridine 1e
with more bulky alkyl group, such as isobutyl, was completely
unreactive at much higher reaction temperature (entry 5).
When 2-(N-pyrrolidinyl)pyridine (1f) was submitted to the re-
action, only a trace amount of the desired product was obtained
(entry 6). This result indicated that cyclic aminopyridine,
namely tertiary amine was an inappropriate substrate in the
present catalysis.12
2c
135/3
85/1
Trace (3ha)
72 (3ia)
d
3
98
4
85/3
47 (3ja)
55
5
R¼5-Me (1k)
R¼6-Me (1l)
R¼6-Cl (1m)
85/2
85/7
135/1
76 (3ka)
47 (3la)
d (3ma)
65
77
d
6
7c
a
Condition: 1 (0.1 mmol), 2a (0.8 mmol), DME (0.2 mL), unless otherwise noted.
Cond.: bath temperature/time¼ꢀC/day.
b
c
Chlorobenzene (0.2 mL) was used as a solvent.

S. Pan et al. / Tetrahedron 68 (2012) 9009e9015
9011
itself as directing group, the yields and enantiomeric excesses
generally decreased. The coordination of the nitrogen in the pyri-
dine ring to Ir would be crucial for the reaction efficiency and en-
antiomeric excess. Electronic effect on the backbone of pyridine
ring also plays an important role in this reaction: pyridine bearing
chloro group at 6-position rendered the reaction, and the desired
alkylated product 3ma could not be detected even at higher re-
action temperature (entry 7).
diastereomers. Therefore, the relative rates could be changed by
alkenes, which induces different selectivity to the formation of
(pro-S)-B and (pro-R)-B. Moreover, CeH bond cleavage and
hydroiridation are reversible steps.
2.4. Scope of alkenes
We further examined the scope of alkenes in the reaction with
2-(ethylamino)pyridine (Table 4). In previous report, we mainly
used styrene derivatives: in the reaction of p-methoxystyrene, the
absolute configuration of obtained pyridyl amine 3ab was de-
termined to be S by its derivation to a known chiral amine.10 We
next submitted a simple alkene to the reaction (entry 2). The re-
action of 1-nonene gave the corresponding product 3ac with low
yield, but the ee was high. In the reaction with allylbenzene, higher
reaction temperature was required, and the desired product 3ad
was obtained in moderate yield and ee (entry 3). 1,3-Diene was
a favourable substrate, and high ee was achieved at higher reaction
temperature (entry 4). The reaction with acrylate derivatives also
Scheme 1. Possible mechanism initiated by enantioselective cleavage of secondary sp3
CeH bond.
2.5. Reaction of 2-(alkylamino)pyridine with alkynes
proceeded to give g-amino acid derivatives 3af and 3ag (entries 5
and 6). In particular, ethyl acrylate was the best coupling partner,
and the enantiomeric excess reached 99%. Furthermore, vinylsilane
derivatives also reacted with 2-(ethylamino)pyridine (1a). Re-
gardless of the substituents on the silicon atom, the silylated
amines were obtained in the almost same yields and ee (entries
7e9). In the case of allylsilane, the choice of substituents on silicon
atom was important, and allyltriphenylsilane achieved high yield
and ee (entries 10 and 11).
Finally, the reaction of 2-alkylaminopyridines with alkynes was
examined (Table 5). The reaction of 2-(methylamino) pyridine (1n)
with diphenylacetylene (4a) proceeded efficiently to give alkeny-
lation product 5a in high yield by adding a catalytic amount of
trifluoromethanesulfonic acid (TfOH) (entry 1).14 The present re-
action proceeded without TfOH in moderate yield, but longer re-
action time was required (entry 2). Simple alkyne, 5-decyne (4b),
was also submitted to the reaction with 2-(methylamino)pyridine
(1n): it required a long reaction time, but the desired product 5b
was obtained in acceptable yield. We further examined the reaction
of 2-(ethylamino)pyridine (1a) with 5-decyne (4b): to our delight,
secondary sp3 CeH bond activation proceeded, and the alkenyla-
tion product 5c with a chiral centre was obtained, albeit in low
yield.15
Table 4
Scope of alkenes
3ab-3al
Ee (%)
1a
2b-21
Table 5
Reaction of 2-(alkylamino)pyridine with alkynes
Entrya
R
Alkene
Cond.b
Yield (%)
1
2
3
4
4-MeOC6H4
n-C7H15
CH2Ph
CH]CHPh
COOEt
COOt-Bu
SiMe3
SiEt3
2b
2c
2d
2e
2f
2g
2h
2i
75/2
85/5
95/2
95/2
85/3
85/3
85/3
85/3
85/3
85/3
85/1
76 (3ab)
27 (3ac)
57 (3ad)
84 (3ae)
75 (3af)
52 (3ag)
71 (3ah)
87 (3ai)
81 (3aj)
33 (3ak)
88 (3al)
87 (S)
78
61
87
99
89
76
69
72
5
6
7c
8
Entrya
R
R0
Time (h)
Yield (%), ee (%)
9
10
11
SiPh3
CH2SiMe3
CH2SiPh3
2j
2k
2l
1
H (1n)
H (1n)
H (1n)
Me (1a)
Ph (4a)
Ph (4a)
n-C4H9 (4b)
n-C4H9 (4b)
8
24
24
18.5
82 (5a)
59 (5a)
42 (5b)
32 (5c), 89%
2b
3
73
87
a
4b,c
Condition: 1a (0.1 mmol), 2 (0.8 mmol), DME (0.2 mL), unless otherwise noted.
Cond.: bath temperature/time¼ꢀC/day.
b
c
a
Condition: 1 (0.1 mmol), 4 (0.2 mmol), TfOH (0.01 mmol), PhCl (0.2 mL), unless
Vinyltrimethylsilane (16 equiv) was used.
otherwise noted.
b
The reaction was examined without TfOH.
(S)-tolBINAP was used as a chiral ligand.
c
We showed a possible mechanism in Scheme 1. Enantioselective
cleavage of secondary sp3 CeH bond adjacent to a nitrogen atom is
an initiation step, and an asymmetric carbon atom is generated in
the intermediate A. Subsequent hydroiridation to alkene provides
intermediate B.13 Finally, reductive elimination gives a chiral amine
as an alkylated product. The enantioselectivities were significantly
changed from 61 to 99% by the alkenes (Table 4). These results
explained as follows: the chiral Ir catalyst affords (pro-S)-A or (pro-
R)-A by CeH bond cleavage. The subsequent hydroiridation rate of
(pro-S)-A and that of (pro-R)-A are not same because they are
3. Conclusions
In summary, we have developed the chiral Ir(I)-catalyzed
enantioselective CeC bond formation initiated by secondary sp3
CeH bond cleavage adjacent to nitrogen atom. Numerous 2-(alky-
lamino)pyridines and series of alkenes and alkynes were efficiently
transformed into alkylated and alkenylated pyridylamines with
moderate to almost perfect enantiomeric excesses. The structure of

9012
S. Pan et al. / Tetrahedron 68 (2012) 9009e9015
alkyl chain in 2-alkylaminopyridine and the directing group play
important roles in this transformation.
3H), 6.54e6.51 (m, 1H), 6.28 (d, J¼8.8 Hz,1H), 4.39 (d, J¼8.8 Hz, 1H),
3.66e3.59 (m, 1H), 2.77e2.63 (m, 2H), 1.95e1.86 (m, 1H), 1.80e1.71
(m, 1H), 1.70e1.61 (m, 1H), 1.58e1.48 (m, 1H), 0.94 (t, J¼7.6 Hz, 3H);
4. Experimental section
4.1. General
13C NMR
d 158.9, 148.3, 142.2, 137.5, 128.5, 128.4, 125.8, 112.4, 106.4,
52.1, 36.4, 32.2, 27.7, 9.9. IR (neat) 3255, 2962, 1601, 1485, 769 cmꢂ1
;
HRMS(ESI) calcd for C16H21N2 (MþþH): 241.1705; found: 241.1696.
31
[a
]
¼2.2 (c 0.81, CHCl3, 83% ee). Ee was determined by HPLC
D
All reactions were examined under an argon atmosphere in
oven-dried glassware with a magnetic stirring bar. The cationic
iridium complexes [Ir(cod)2]X (X¼BF4, PF6, OTf) were prepared
from [IrCl(cod)] and AgX according to the literature procedure.16
[Ir(cod)2]BARF was purchased from Umicore. 2-Alkylaminopyri
dines 1a and 1n are commercially available. 2-Alkylaminopyri
dines 1be1e and 1he1l were prepared from 2-aminopyridine
and the corresponding alkyl iodides (1b, 1e, and 1he1l) or bro-
mides (1c and 1d) using n-BuLi as a base according to the liter-
ature procedure.17 Aminopyridines 1f and 1m were prepared
from 2-bromopyridine and the corresponding amines using CuI
analysis using a chiral column (Daicel Chiralcel OD: 4.6ꢁ250 mm,
254 nm UV detector, rt, eluent: 1% isopropanol in hexane, flow rate:
1.0 mL/min, retention time: 20.2 min for major isomer and 22.3 min
for minor isomer).
4.2.3. N-(1-Phenylhexan-3-yl)pyridin-2-amine (3ca). Isolated by
thin-layer chromatography (hexane/AcOEt¼5/1, Rf¼0.5). The title
compound was obtained as colourless oil (58%). 1H NMR
d 8.05 (d,
J¼4.8, 1.6 Hz, 1H), 7.39e7.34 (m, 1H), 7.28e7.24 (m, 2H), 7.18e7.14
(m, 3H), 6.51 (dd, J¼6.4, 4.8 Hz, 1H), 6.26 (d, J¼8.4 Hz, 1H), 4.35 (d,
J¼8.8 Hz, 1H), 3.73e3.65 (m, 1H), 2.77e2.63 (m, 2H), 1.95e1.86 (m,
1H), 1.80e1.71 (m, 1H), 1.63e1.54 (m, 1H), 1.52e1.33 (m, 3H), 0.91 (t,
as
a
catalyst according to the literature procedure.18 2-
Ethylaminopyrimidine (1g) was prepared by the literature pro-
cedure.19 Dehydrated solvents were purchased from Kanto or
Wako, and dried over activated molecular sieves 3A or 4A. Flash
column chromatography was performed with silica gel (Kanto
J¼7.2 Hz, 3H); 13C NMR
d 158.8, 148.3, 142.1, 137.4, 128.4, 128.3,
125.8, 112.3, 106.3, 50.8, 37.6, 37.1, 32.2, 19.1, 14.1. IR (neat) 3255,
2931, 1601, 1496, 1452, 1333, 1288, 769 cmꢂ1; HRMS(ESI) calcd for
32
C
17H23N2 (MþþH): 255.1861; found: 255.1852. [
a]
¼3.1 (c 0.73,
D
Chemical Co., Inc. 60N 40e50
m
m). Preparative thin-layer chro-
CHCl3, 86% ee). Ee was determined by HPLC analysis using a chiral
column (Daicel Chiralpak IA: 4.6ꢁ250 mm, 254 nm UV detector, rt,
eluent: 1% isopropanol in hexane, flow rate: 1.0 mL/min, retention
time: 19.4 min for minor isomer and 21.0 min for major isomer).
matography (PTLC) was performed with silica gel-precoated glass
plates (Merck 60 GF254) prepared in our laboratory. IR spectra
were recorded with Horiba FT730 spectrophotometer. NMR
spectra were measured with JEOL AL-400 (400 MHz) using TMS
as an internal standard and CDCl3 was used as a solvent. High-
resolution mass spectra (HRMS) were measured on a JEOL JMS-
SX102A with FAB (Fast Atomic Bombardment) method or JMS-
T100CS with ESI (Electro Spray Ionization) method. Optical ro-
tations were measured with Jasco DIP-1000 polarimeter.
4.2.4. N-(1-Phenyloctan-3-yl)pyridin-2-amine (3da). Isolated by
thin-layer chromatography (hexane/AcOEt¼5/1, Rf¼0.6). The title
compound was obtained as pale yellow oil (60%). 1H NMR
d 8.06
(d, J¼5.2 Hz, 1H), 7.39e7.34 (m, 1H), 7.28e7.24 (m, 2H), 7.19e7.14
(m, 3H), 6.52 (t, J¼6.0 Hz, 1H), 6.26 (d, J¼8.4 Hz, 1H), 4.38 (d,
J¼9.6 Hz, 1H), 3.70e3.66 (m, 1H), 2.74e2.64 (m, 2H), 1.93e1.73 (m,
2H), 1.62e1.45 (m, 2H), 1.41e1.26 (m, 6H), 0.86 (t, J¼6.0 Hz, 3H);
4.2. Typical experimental procedure for 3
13C NMR
d 157.4, 146.9, 140.8, 136.1, 127.1, 127.0, 124.4, 111.0, 104.9,
[Ir(cod)2]BF4 (0.01 mmol) and (S)-tolBINAP (0.01 mmol) were
placed in a Schlenk tube, which was then evacuated and backfilled
argon (ꢁ3). To the reaction vessel were added 2-(alkylamino)pyr-
49.7, 35.7, 33.9, 30.9, 30.6, 24.1, 21.2, 12.7. IR (neat) 3255, 2929,
1604, 1496, 1454, 1333, 1153, 769, 700 cmꢂ1; HRMS(ESI) calcd for
33
C
19H27N2 (MþþH): 283.2174; found: 283.2166. [
a
]
¼ꢂ2.6 (c
435
idine
1
(0.10 mmol), alkene
2
(0.80 mmol), and 1,2-
0.58, CHCl3, 73% ee). Ee was determined by HPLC analysis using
a chiral column (Daicel Chiralcel OD: 4.6ꢁ250 mm, 254 nm
UV detector, rt, eluent: 5% isopropanol in hexane, flow rate:
0.5 mL/min, retention time: 14.6 min for minor isomer and
16.0 min for major isomer).
dimethoxylethane (0.2 mL), unless otherwise noted. The sealed
reaction vessel was immersed in a pre-heated oil bath. After the
reaction was complete, the mixture of the reaction was cooled to
room temperature and the solvent was removed under reduced
pressure, and the crude products were purified by thin-layer
chromatography to give desired product 3.
4.2.5. N-(4-Phenylbutan-2-yl)quinolin-2-amine (3ia). Isolated by
thin-layer chromatography (hexane/AcOEt/Et3N¼6/1/1, Rf¼0.6).
The title compound was obtained as yellow oil (72%). 1H NMR
4.2.1. N-(4-Phenylbutan-2-yl)pyridin-2-amine (3aa). Isolated by
thin-layer chromatography (hexane/AcOEt¼1/1, Rf¼0.6). The title
d
7.79 (d, J¼8.8 Hz, 1H), 7.65 (J¼8.0 Hz, 1H), 7.56 (d, J¼8.0 Hz, 1H),
compound was obtained as colourless oil (76%). 1H NMR
d
8.07 (dd,
7.53e7.49 (m, 1H), 7.29e7.24 (m, 2H), 7.21e7.18 (m, 4H), 6.54 (d,
J¼8.8 Hz, 1H), 4.60 (d, J¼8.0 Hz, 1H), 4,17e4.11 (m, 1H), 2.75 (t,
J¼8.0 Hz, 2H), 1.97e1.82 (m, 2H), 1.29 (dd, J¼6.4, 1.2 Hz, 3H); 13C
J¼5.0, 0.8 Hz, 1H), 7.41e7.36 (m, 1H), 7.29e7.26 (m, 2H), 7.20e7.14
(m, 3H), 6.54 (dd, J¼6.8, 5.0 Hz, 1H), 6.28 (d, J¼8.4 Hz, 1H), 4.35 (d,
J¼8.4 Hz, 1H), 3.84e3.70 (m, 1H), 2.79e2.65 (m, 2H), 1.92e1.79 (m,
NMR
d 156.5, 148.2, 142.0, 137.3, 129.5, 128.4, 128.4, 127.4, 126.1,
2H), 1.24 (d, J¼6.4 Hz, 3H); 13C NMR
d
158.4, 148.4, 142.0, 137.5,
125.8, 123.3, 121.9, 111.0, 46.5, 39.0, 32.5, 21.2. IR (neat) 3410,
128.4, 128.3, 125.9, 112.6, 106.6, 46.7, 38.9, 32.4, 20.9. IR (neat) 3261,
2924, 1618, 1522, 1400, 1248, 1144, 818, 754, 700 cmꢂ1; HRMS(ESI)
2925, 1601, 1495, 1446, 769 cmꢂ1; HRMS(ESI) calcd for C15H19N2
calcd for C19H21N2 (MþþH): 277.1705; found: 277.1713. [
a
]
¼34.4
30
D
26
(MþþH): 227.1548; found: 227.1558. [
a
]
¼ꢂ17.3 (c 0.61, CHCl3, 88%
(c 0.60, CHCl3, 98% ee). Ee was determined by HPLC analysis
using a chiral column (Daicel Chiralcel OD: 4.6ꢁ250 mm, 254 nm
UV detector, rt, eluent: 10% isopropanol in hexane, flow rate:
0.5 mL/min, retention time: 20.2 min for major isomer and
24.0 min for minor isomer).
D
ee). Ee was determined by HPLC analysis using a chiral column
(Daicel Chiralpak AD: 4.6ꢁ250 mm, 254 nm UV detector, rt, eluent:
2% isopropanol in hexane, flow rate: 1.0 mL/min, retention time:
17.1 min for minor isomer and 18.7 min for major isomer).
4.2.2. N-(1-Phenylpentan-3-yl)pyridin-2-amine (3ba). Isolated by
thin-layer chromatography (hexane/AcOEt¼3/1, Rf¼0.6). The title
4.2.6. 3-Methyl-N-(4-phenylbutan-2-yl)pyridin-2-amine (3ja). Iso-
lated by thin-layer chromatography (hexane/AcOEt¼3/1, Rf¼0.6).
The title compound was obtained as colourless oil (47%). 1H NMR
compound was obtained as colourless oil (69%). 1H NMR
d 8.06 (d,
J¼4.8 Hz, 1H), 7.40e7.35 (m, 1H), 7.28e7.25 (m, 2H), 7.19e7.15 (m,
d
8.01 (dd, J¼4.8, 0.8 Hz, 1H), 7.28e7.24 (m, 2H), 7.19e7.15 (m, 4H),

S. Pan et al. / Tetrahedron 68 (2012) 9009e9015
9013
30
6.48 (dd, J¼7.2, 5.2 Hz, 1H), 4.37e4.28 (m, 1H), 3.87 (d, J¼8.0 Hz,
found: 249.2322. [
a
]
D
¼ꢂ8.3 (c 0.26, CHCl3, 78% ee). Ee was de-
1H), 2.73 (dt, J¼7.6, 2.0 Hz, 2H), 2.00 (s, 3H), 1.93e1.86 (m, 2H), 1.28
termined by HPLC analysis using a chiral column (Daicel Chiralcel
OD: 4.6ꢁ250 mm, 254 nm UV detector, rt, eluent: 5% isopropanol in
hexane, flow rate: 0.5 mL/min, retention time: 11.4 min for major
isomer and 18.1 min for minor isomer).
(d, J¼6.4 Hz, 3H); 13C NMR
d 156.4, 145.5, 142.4, 136.7, 128.3, 128.2,
125.7, 116.2, 112.1, 64.2, 39.1, 32.6, 21.4, 17.0. IR (neat) 3414, 2964,
2927, 1601, 1497, 1452, 1145, 773, 700 cmꢂ1; HRMS(ESI) calcd for
34
C
16H21N2 (MþþH): 241.1705; found: 241.1716. [
a
]
¼11.6 (c 0.54,
D
CHCl3, 55% ee). Ee was determined by HPLC analysis using a chiral
column (Daicel Chiralcel OD: 4.6ꢁ250 mm, 254 nm UV detector, rt,
eluent: 5% isopropanol in hexane, flow rate: 1.0 mL/min, retention
time: 6.7 min for major isomer and 7.5 min for minor isomer).
4.2.11. N-(5-Phenylpentan-2-yl)pyridin-2-amine (3ad). Isolated by
thin-layer chromatography (hexane/AcOEt¼1/1, Rf¼0.6). The title
compound was obtained as colourless oil (57%). 1H NMR
d 8.06 (d,
J¼4.8 Hz, 1H), 7.40e7.36 (m, 1H), 7.29e7.26 (m, 2H), 7.19e7.16 (m,
3H), 6.52 (t, J¼6.0 Hz, 1H), 6.31 (d, J¼8.2 Hz, 1H), 4.28 (d, J¼8.2 Hz,
1H), 3.81e3.75 (m, 1H), 2.63 (t, J¼7.6 Hz, 2H), 1.77e1.66 (m, 2H),
4.2.7. 5-Methyl-N-(4-phenylbutan-2-yl)pyridin-2-amine (3ka). Iso-
lated by thin-layer chromatography (hexane/AcOEt¼4/1, Rf¼0.5).
The title compound was obtained as (pale) yellow oil (76%). 1H NMR
1.65e1.48 (m, 2H), 1.19 (d, J¼6.4 Hz, 3H); 13C NMR
d 158.4, 148.4,
142.3, 137.4, 128.4, 128.3, 125.8, 112.4, 106.7, 46.9, 36.7, 35.8, 27.8,
20.9. IR (neat) 3268, 2963, 1603, 1496, 1447, 1330, 1285, 1152, 770,
d
7.89 (s, 1H), 7.28e7.16 (m, 6H), 6.22 (d, J¼8.0 Hz, 1H), 4.22 (d,
J¼8.4 Hz, 1H), 3.76e3.69 (m, 1H), 2.74e2.69 (m, 2H), 2.16 (s, 3H),
699 cmꢂ1; HRMS(ESI) calcd for C16H21N2 (MþþH): 241.1705; found:
1.88e1.77 (m, 2H), 1.22 (d, J¼6.4 Hz, 3H); 13C NMR
d
156.6, 147.8,
241.1706. [
a
]
¼ꢂ9.5 (c 0.35, CHCl3, 61% ee). Ee was determined by
30
D
142.0, 138.4, 128.4, 128.3, 125.8, 121.2, 106.3, 46.9, 39.0, 32.4, 21.0,
17.3. IR (neat) 3408, 2920, 1614, 1500, 1394, 1155, 814, 746,
HPLC analysis using a chiral column (Daicel Chiralcel OD:
4.6ꢁ250 mm, 254 nm UV detector, rt, eluent: 2% isopropanol in
hexane, flow rate: 1.0 mL/min, retention time: 17.2 min for major
isomer and 18.6 min for minor isomer).
698 cmꢂ1; HRMS(ESI) calcd for C16H21N2 (MþþH): 241.1705; found:
31
241.1708. [
a
]
¼ꢂ9.6 (c 0.82, CHCl3, 65% ee). Ee was determined by
D
HPLC analysis using
a chiral column (Daicel Chiralpak AD:
4.6ꢁ250 mm, 254 nm UV detector, rt, eluent: 5% isopropanol in
hexane, flow rate: 0.5 mL/min, retention time: 21.4 min for minor
isomer and 24.8 min for major isomer).
4.2.12. N-(6-Phenylhex-5-en-2-yl)pyridin-2-amine (3ae). Isolated
by thin-layer chromatography (hexane/AcOEt¼1/1, Rf¼0.6). The
title compound was obtained as colourless oil (84%, E/Z>20:1). 1H
NMR
d
8.07 (d, J¼4.8 Hz, 1H), 7.41e7.37 (m, 1H), 7.33e7.25 (m, 4H),
4.2.8. 6-Methyl-N-(4-phenylbutan-2-yl)pyridin-2-amine (3la). Iso-
lated by thin-layer chromatography (hexane/AcOEt¼3/1, Rf¼0.6).
The title compound was obtained as colourless oil (47%). 1H NMR
7.21e7.17 (m, 1H), 6.55e6.52 (m, 1H), 6.40e6.33 (m, 2H), 6.25e6.18
(m, 1H), 4.35 (d, J¼8.8 Hz, 1H), 3.88e3.78 (m, 1H), 2.35e2.29 (m,
2H), 1.77e1.63 (m, 2H), 1.24 (d, J¼6.4 Hz, 3H); 13C NMR
d 158.4,
d
7.33e7.26 (m, 3H), 7.20e7.16 (m, 3H), 6.42 (d, J¼6.8 Hz, 1H), 6.09
148.4, 137.7, 137.4, 130.3, 130.1, 128.5, 126.9, 126.0, 112.5, 106.7, 46.6,
36.7, 29.5, 20.9. IR (neat) 3257, 2964, 1601, 1572, 1495, 1446,
(d, J¼8.8 Hz, 1H), 4.42 (d, J¼8.4 Hz, 1H), 3.69e3.59 (m, 1H), 2.73 (dt,
J¼8.0, 2.4 Hz, 2H), 2.36 (s, 3H), 1.91e1.79 (m, 2H), 1.23 (d, J¼6.4 Hz,
769 cmꢂ1; HRMS(ESI) calcd for C17H21N2 (MþþH): 253.1705; found:
25
3H); 13C NMR
d
157.9, 157.1, 141.9, 137.9, 128.4, 128.3, 125.8, 111.9,
253.1694. [
a
]
¼ꢂ28.1 (c 1.08, CHCl3, 87% ee). Ee was determined
D
102.5, 46.8, 38.9, 32.4, 24.3, 20.9. IR (neat) 3404, 3280, 2924, 1597,
by HPLC analysis using a chiral column (Daicel Chiralcel OD:
4.6ꢁ250 mm, 254 nm UV detector, rt, eluent: 5% isopropanol in
hexane, flow rate: 0.5 mL/min, retention time: 31.1 min for major
isomer and 37.8 min for minor isomer).
1496,1415,1331,1155, 777, 700 cmꢂ1; HRMS(ESI) calcd for C16H21N2
33
(MþþH): 241.1705; found: 241.1716. [
a
]
¼ꢂ33.6 (c 0.33, CHCl3, 77%
D
ee). Ee was determined by HPLC analysis using a chiral column
(Daicel Chiralcel OD: 4.6ꢁ250 mm, 254 nm UV detector, rt, eluent:
5% isopropanol in hexane, flow rate: 1.0 mL/min, retention time:
6.4 min for major isomer and 7.2 min for minor isomer.
4.2.13. Ethyl 4-(pyridin-2-ylamino)pentanoate (3af). Isolated by
thin-layer chromatography (hexane/AcOEt¼1.5/1, Rf¼0.6). The title
compound was obtained as pale yellow oil (75%). 1H NMR
d 8.05 (d,
4.2.9. N-(4-(4-Methoxyphenyl)butan-2-yl)pyridin-2-amine
(3ab). Isolated by thin-layer chromatography (hexane/AcOEt¼1/1,
Rf¼0.5). The title compound was obtained as white solid (76%). Mp:
J¼5.0 Hz, 1H), 7.40e7.36 (m, 1H), 6.53 (dd, J¼5.0, 6.4 Hz, 1H), 6.36
(d, J¼8.8 Hz, 1H), 4.31 (d, J¼8.0 Hz, 1H), 4.11 (q, J¼7.2 Hz, 2H),
3.99e3.84 (m, 1H), 2.41 (t, J¼7.2 Hz, 2H), 1.89e1.84 (m, 2H), 1.22 (t,
135 ꢀC. 1H NMR
d
8.07 (dd, J¼5.0, 1.2 Hz,1H), 7.44e7.32 (m, 1H), 7.08
J¼7.2 Hz, 3H), 1.22 (d, J¼7.2 Hz, 3H); 13C NMR
d 173.7, 158.2, 148.2,
(d, J¼8.6 Hz, 2H), 6.82 (d, J¼8.6 Hz, 2H), 6.53 (dd, J¼6.8, 5.0 Hz, 1H),
6.28 (d, J¼8.4 Hz, 1H), 4.37 (d, J¼8.4 Hz, 1H), 3.85e3.68 (m, 4H),
2.73e2.59 (m, 2H), 1.88e1.72 (m, 2H), 1.23 (d, J¼6.4 Hz, 3H); 13C
137.3, 112.6, 107.0, 60.4, 46.6, 32.0, 31.1, 21.0, 14.2. IR (neat) 3388,
2976,1731,1602, 1485, 1448,1228, 1180, 771 cmꢂ1; HRMS(ESI) calcd
27
for C12H19N2O2 (MþþH): 223.1447; found: 223.1461. [
a]
¼ꢂ11.3 (c
D
NMR
d
158.4, 157.8, 148.4, 137.4, 134.0, 129.3, 113.8, 112.5, 106.6,
0.22, CHCl3, 99% ee). Ee was determined by HPLC analysis using
a chiral column (Daicel Chiralcel OD: 4.6ꢁ250 mm, 254 nm UV
detector, rt, eluent: 10% isopropanol in hexane, flow rate: 0.5 mL/
min, retention time: 13.3 min for major isomer and 15.0 min for
minor isomer).
55.2, 46.6, 39.1, 31.4, 20.9. IR (CH2Cl2) 3418, 2965, 1601, 1512, 1270,
1036, 756, 698 cmꢂ1; HRMS(ESI) calcd for C16H21N2O (MþþH):
27
257.1654; found: 257.1641. [
a
]
¼ꢂ20.4 (c 0.83, CHCl3, 87% ee). Ee
D
was determined by HPLC analysis using a chiral column (Daicel
Chiralcel OD: 4.6ꢁ250 mm, 254 nm UV detector, rt, eluent: 2%
isopropanol in hexane, flow rate: 1.0 mL/min, retention time:
22.1 min for major isomer and 25.0 min for minor isomer).
4.2.14. tert-Butyl 4-(pyridin-2-ylamino)pentanoate (3ag). Isolated
by thin-layer chromatography (hexane/AcOEt¼2/1, Rf¼0.6). The
title compound was obtained as pale yellow oil (52%). 1H NMR
4.2.10. N-(Undecan-2-yl)pyridin-2-amine (3ac). Isolated by thin-
layer chromatography (hexane/AcOEt¼5/1, Rf¼0.4). The title com-
d 8.06e8.05 (m, 1H), 7.40e7.36 (m, 1H), 6.53e6.51 (m, 1H), 6.35 (d,
J¼8.4 Hz, 1H), 4.33 (d, J¼8.4 Hz, 1H), 3.88e3.81 (m, 1H), 2.33 (t,
pound was obtained as pale yellow oil (27%). 1H NMR
d 8.06e8.05
J¼7.2 Hz, 2H), 1.81 (d, J¼7.2 Hz, 2H), 1.43 (s, 9H), 1.21 (d, J¼6.8 Hz,
(m, 1H), 7.41e7.37 (m, 1H), 6.52 (dd, J¼6.4, 5.2 Hz, 1H), 6.34 (d,
3H); 13C NMR
d 173.1, 158.3, 148.2, 137.3, 112.5, 106.9, 80.3, 46.7,
J¼8.8 Hz, 1H), 4.32 (d, J¼7.6 Hz, 1H), 3.75e3.68 (m, 1H), 1.57e1.25
32.3, 32.0, 28.1, 21.1. IR (neat) 3392, 2976, 1726, 1601, 1485, 1448,
(m,16H),1.19 (d, J¼6.8 Hz, 3H), 0.88 (J¼7.0 Hz, 3H); 13C NMR
d
158.4,
1255, 1153, 847, 771 cmꢂ1; HRMS(ESI) calcd for C14H23N2O2
28
148.3, 137.3, 112.3, 106.5, 47.2, 37.2, 31.9, 29.6, 29.6, 29.5, 29.3, 26.0,
22.7, 20.9, 14.1. IR (neat) 3263, 2925, 1603, 1485, 1446, 1331, 1151,
769 cmꢂ1; HRMS(ESI) calcd for C16H29N2 (MþþH): 249.2331;
(MþþH): 251.1760; found: 251.1763. [
a]
¼ꢂ12.6 (c 0.13, CHCl3, 89%
D
ee). Ee was determined by HPLC analysis using a chiral column
(Daicel Chiralcel OD: 4.6ꢁ250 mm, 254 nm UV detector, rt, eluent:

9014
S. Pan et al. / Tetrahedron 68 (2012) 9009e9015
5% isopropanol in hexane, flow rate: 1.0 mL/min, retention time:
The title compound was obtained as colourless oil (88%). 1H NMR
7.0 min for major isomer and 9.8 min for minor isomer).
d
8.05 (d, J¼5.2, 1H), 7.50e7.48 (m, 6H), 7.40e7.23 (m, 10H),
6.52e6.49 (m, 1H), 6.28 (d, J¼7.6 Hz, 1H), 4.22 (d, J¼7.2 Hz, 1H),
3.81e3.75 (m, 1H), 1.63e1.52 (m, 4H), 1.43e1.33 (m, 2H), 1.12 (dd,
4.2.15. N-(4-(Trimethylsilyl)butan-2-yl)pyridin-2-amine (3ah). Iso-
lated by thin-layer chromatography (hexane/AcOEt¼7/1, Rf¼0.4).
The title compound was obtained as yellow oil (71%). 1H NMR
J¼6.4, 1.2 Hz, 3H); 13C NMR
d 158.3, 148.2, 137.2, 135.6, 135.0, 129.3,
127.8, 112.3, 106.7, 46.3, 41.1, 20.9, 20.5, 13.0. IR (neat) 3269, 3068,
d
8.08e8.06 (m, 1H), 7.44e7.38 (m, 1H), 6.56e6.52 (m, 1H), 6.36 (d,
2927, 1601, 1502, 1485, 1427, 1288, 1111, 771, 702, 515 cmꢂ1
;
J¼8.4 Hz, 1H), 4.38 (d, J¼8.0 Hz, 1H), 3.71e3.61 (m, 1H), 1.59e1.44
HRMS(ESI) calcd for
423.2263. [
HPLC analysis using a chiral column (Daicel Chiralcel OD:
4.6ꢁ250 mm, 254 nm UV detector, rt, eluent: 5% isopropanol in
hexane, flow rate: 0.5 mL/min, retention time: 32.3 min for minor
isomer and 38.0 min for major isomer).
C
28H31N2Si (MþþH): 423.2257; found:
30
(m, 2H), 1.21 (d, J¼6.4 Hz, 3H), 0.65e0.49 (m, 2H), 0.00 (s, 9H); 13
C
a
]
¼ꢂ9.9 (c 1.69, CHCl3, 87% ee). Ee was determined by
D
NMR
d
158.4, 148.3, 137.4, 112.3, 106.4, 49.6, 31.1, 20.3, 12.5, -1.8. IR
(neat) 3265, 2954, 1603, 1485, 1331, 1248, 1186, 862, 769 cmꢂ1
;
HRMS(ESI) calcd for
223.1623. [
HPLC analysis using
C
12H23N2Si (MþþH): 223.1631; found:
29
a
]
¼4.2 (c 0.45, CHCl3, 76% ee). Ee was determined by
D
a
chiral column (Daicel Chiralcel OD:
4.6ꢁ250 mm, 254 nm UV detector, rt, eluent: 1% isopropanol in
hexane, flow rate: 3.0 mL/min, retention time: 31.5 min for minor
isomer and 34.9 min for major isomer).
4.3. Typical experimental procedure for 5
[Ir(cod)2]BF4 (0.01 mmol) and rac-BINAP (0.01 mmol) were
placed in a Schlenk tube, which was then evacuated and back-
filled argon (ꢁ3). To the reaction vessel were added 2-
alkylaminopyridine 1 (0.10 mmol), alkyne 4 (0.20 mmol), TfOH
(0.01 mmol) and PhCl (0.2 mL), unless otherwise noted. The
sealed reaction vessel was immersed in a pre-heated oil bath.
After the reaction was complete, the mixture of the reaction was
cooled to room temperature and NEt3 (0.1 mmol) were added,
then the solvent was removed under reduced pressure, and the
crude products were purified by thin-layer chromatography to
give desired product 5.
4.2.16. N-(4-(Triethylsilyl)butan-2-yl)pyridin-2-amine (3ai). Isolated
by thin-layer chromatography (hexane/AcOEt¼5/1, Rf¼0.6). The title
compound was obtained as pale yellow oil (87%). 1H NMR
d
8.06e8.05 (m, 1H), 7.41e7.37 (m, 1H), 6.53e6.50 (m,1H), 6.34 (d,
J¼8.4 Hz, 1H), 4.36 (d, J¼7.0 Hz, 1H), 3.67e3.60 (m, 1H), 1.56e1.44
(m, 2H), 1.19 (d, J¼5.9 Hz, 3H), 0.911 (t, J¼8.0 Hz, 9H), 0.53e0.47 (m,
8H); 13C NMR
d 158.1, 148.3, 137.3, 112.3, 106.5, 49.8, 30.9, 25.3, 7.4,
7.0, 3.1. IR (neat) 3259, 2952, 1601, 1485, 1448, 1238, 1186, 1014,
733 cmꢂ1; HRMS(ESI) calcd for C15H29N2Si (MþþH): 265.2100;
27
found: 265.2088. [
a
]
¼3.1 (c 0.83, CHCl3, 69% ee). Ee was de-
D
termined by HPLC analysis using a chiral column (Daicel Chiralcel
OD: 4.6ꢁ250 mm, 254 nm UV detector, rt, eluent: 5% isopropanol in
hexane, flow rate: 1.0 mL/min, retention time: 4.3 min for minor
isomer and 5.2 min for major isomer).
4.3.1. (E)-N-(2,3-Diphenylprop-2-enyl)pyridin-2-amine
(5a).
Isolated by thin-layer chromatography (hexane/AcOEt¼4/1,
Rf¼0.4). The title compound was obtained as pale yellow solid
(82%). Mp: 118e120 ꢀC; 1H NMR
d
8.10 (dd, J¼5.2, 1.2 Hz, 1H),
7.45e7.40 (m, 1H), 7.34e7.28 (m, 3H), 7.23e7.21 (m, 2H), 7.10e7.07
(m, 3H), 6.96e6.94 (m, 2H), 6.66 (s,1H), 6.59 (ddd, J¼7.2, 4.8, 0.8 Hz,
1H), 6.43 (d, J¼8.4 Hz, 1H), 4.85 (dd, J¼6.0, 5.6 Hz, 1H), 4.27 (dd,
4.2.17. N-(4-(Triphenylsilyl)butan-2-yl)pyridin-2-amine (3aj). Iso-
lated by thin-layer chromatography (hexane/AcOEt¼5/1, Rf¼0.4).
The title compound was obtained as pale yellow oil (81%). 1H
J¼6.0, 1.2 Hz, 2H); 13C NMR
d 158.5, 148.1, 139.2, 138.9, 137.6, 136.5,
NMR
d
8.05e8.03 (m, 1H), 7.50e7.48 (m, 6H), 7.41e7.32 (m, 10H),
129.2, 128.8, 128.6, 127.9, 127.5, 127.0, 126.7, 113.2, 106.6, 50.2. IR
(CH2Cl2) 3423, 3255, 3022, 1601, 1493, 1323, 1290, 1153, 771,
698 cmꢂ1; HRMS(ESI) calcd for C20H19N2 (MþþH): 287.1548; found:
287.1541.
6.53e6.50 (m, 1H), 6.26 (d, J¼8.5 Hz, 1H), 4.32 (d, J¼8.5 Hz, 1H),
3.76e3.69 (m, 1H), 1.73e1.66 (m, 2H), 1.52e1.36 (m, 2H), 1.18 (d,
J¼6.3 Hz, 3H); 13C NMR
d 158.3, 148.3, 137.3, 135.6, 134.8, 129.4,
127.9, 112.4, 106.7, 49.5, 30.7, 20.3, 9.0. IR (neat) 3338, 2968, 1603,
1485, 1429, 1290, 1111, 953, 702, 513 cmꢂ1; HRMS(ESI) calcd for
4.3.2. (E)-N-(2-Butylhept-2-enyl)pyridin-2-amine (5b). Isolated by
thin-layer chromatography (hexane/AcOEt¼6/1, Rf¼0.6). The title
28
C
27H29N2Si (MþþH): 409.2100; found: 409.2106. [
a]
¼9.0 (c 1.01,
D
CHCl3, 72% ee). Ee was determined by HPLC analysis using a chiral
column (Daicel Chiralcel OD: 4.6ꢁ250 mm, 254 nm UV detector,
rt, eluent: 10% isopropanol in hexane, flow rate: 1.0 mL/min, re-
tention time: 5.7 min for minor isomer and 7.1 min for major
isomer).
compound was obtained as brown oil (42%). 1H NMR
d 8.06 (dd,
J¼4.8, 0.8 Hz, 1H), 7.43e7.39 (m, 1H), 6.55 (ddd, J¼7.2, 5.2, 0.8 Hz,
1H), 6.36 (d, J¼8.4 Hz, 1H), 5.39 (t, J¼7.2 Hz, 1H), 4.70 (s, 1H), 3.79
(d, J¼5.2 Hz, 2H), 2.09e2.01 (m, 4H), 1.42e1.25 (m, 8H),
0.93e0.88 (m, 6H); 13C NMR
d 159.0, 147.9, 137.5, 136.0, 127.0,
112.7, 106.4, 48.0, 32.0, 30.8, 28.6, 27.3, 22.8, 22.4, 14.0, 12.2. IR
(neat) 3257, 2956, 2858, 1603, 1512, 1458, 1325, 1290, 769,
733 cmꢂ1; HRMS(ESI) calcd for C16H27N2 (MþþH): 247.2174;
found: 247.2185.
4.2.18. N-(5-(Trimethylsilyl)pentan-2-yl)pyridin-2-amine
(3ak).
Isolated by thin-layer chromatography (hexane/AcOEt¼5/1,
Rf¼0.5). The title compound was obtained as pale yellow oil (33%).
1H NMR
d 8.10e8.09 (m, 1H), 7.45e7.41, (m, 1H), 6.57e6.54 (m, 1H),
6.38 (d, J¼8.0 Hz, 1H), 4.36 (d, J¼7.6 Hz, 1H), 3.78e3.75 (m, 1H),
4.3.3. (E)-N-(3-Butyloct-3-en-2-yl)pyridin-2-amine (5c). Isolated
by thin-layer chromatography (hexane/AcOEt¼7/1, Rf¼0.4). The
title compound was obtained as brown oil (32%). 1H NMR
1.62e1.40 (m, 4H), 1.22 (d, J¼6.4 Hz, 3H), 0.54 (t, J¼8.4 Hz, 2H), 0.00
(s, 9H); 13C NMR
d 158.4, 148.3, 137.3, 112.3, 106.5, 46.9, 41.2, 20.8,
20.5, 16.6, ꢂ1.7. IR (neat) 3267, 2954, 1603, 1485, 1248, 837,
d
8.05e8.04 (m, 1H), 7.41e7.36 (m, 1H), 6.53 (dd, J¼7.2, 5.2 Hz, 1H),
769 cmꢂ1; HRMS(ESI) calcd for C13H25N2Si (MþþH): 237.1787;
6.30 (d, J¼8.8 Hz, 1H), 5.39 (dd, J¼7.2, 6.8 Hz, 1H), 4.63 (d, J¼7.2 Hz,
1H), 4.05e3.98 (m, 1H), 2.05e1.99 (m, 4H), 1.38e1.25 (m, 11H),
28
found: 237.1781. [
a]
¼ꢂ27.1 (c 0.23, CHCl3, 73% ee). Ee was de-
D
termined by HPLC analysis using a chiral column (Daicel Chiralcel
OD: 4.6ꢁ250 mm, 254 nm UV detector, rt, eluent: 5% isopropanol in
hexane, flow rate: 0.5 mL/min, retention time: 10.1 min for major
isomer and 11.5 min for minor isomer).
0.91e0.86 (m, 6H); 13C NMR
d 158.4, 148.1, 140.5, 137.3, 125.6, 112.5,
106.4, 53.0, 32.0, 31.7, 28.1, 27.3, 23.2, 22.3, 21.4, 14.0, 13.9. IR (neat)
3257, 2956, 2858, 1601, 1506, 1444, 1153, 769 cmꢂ1; HRMS(ESI)
32
calcd for C17H29N2 (MþþH): 261.2331; found: 261.2334. [
a]
¼18.8
D
(c 0.22, CHCl3, 89% ee). Ee was determined by HPLC analysis using
a chiral column (Daicel Chiralcel OD: 4.6ꢁ250 mm, 254 nm UV
detector, rt, eluent: 10% isopropanol in hexane, flow rate: 1.0 mL/
4.2.19. N-(5-(Triphenylsilyl)pentan-2-yl)pyridin-2-amine (3al). Iso-
lated by thin-layer chromatography (hexane/AcOEt¼4/1, Rf¼0.3).

S. Pan et al. / Tetrahedron 68 (2012) 9009e9015
9015
6. Examples of secondary sp3 CeH bond activation, see: (a) Ishii, Y.; Chatani,
N.; Kakiuchi, F.; Murai, S. Organometallics 1997, 16, 3615; (b) Jun, C.-H.;
Hwang, D.-C.; Na, S.-J. Chem. Commun. 1998, 1405; (c) Chatani, N.; Asaumi,
T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001, 123,
10935; (d) DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126,
6556; (e) Pastine, S.; Gribkov, D. V.; Sames, D. J. Am. Chem. Soc. 2006, 128,
min, retention time: 3.4 min for major isomer and 4.1 min for minor
isomer).
Acknowledgements
ꢀ
14220; (f) Prokopcova, H.; Bergman, S. D.; Aelvoet, K.; Smout, V.; Herrebout,
This work was supported by Grant-in-Aid for Scientific Research
on Innovative Areas, ‘Molecular Activation Directed towards
Straightforward Synthesis,’ MEXT, Japan, and Global COE program
‘Practical Chemical Wisdom’, Waseda University, Japan. We also
thank Takasago International Corp. for the gift of several chiral
diphosphine ligands.
W.; Veken, B. V.; Meerpoel, L.; Maes, B. U. W. Chem.dEur. J. 2010, 16, 13063;
(g) Shibata, T.; Hirashima, H.; Kasagawa, M.; Tsuchikama, K.; Endo, K. Synlett
2011, 2171; (h) Dastbaravardeh, N.; Schnurch, M.; Mihovilovic, M. D. Org.
Lett. 2012, 14, 3792; (i) Liskey, C. W.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134,
12422.
7. For enantioselective sp3 CeH oxidation/CeC bond formation: (a) Li, Z.; Li, C.-J.
Org. Lett. 2004, 6, 4997; (b) Li, Z.; MacLeod, P. D.; Li, C.-J. Tetrahedron: Asymmetry
2006, 17, 590; (c) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2008, 47, 4882; (d) Benfatti, F.; Capdevila, M. G.; Zoli, L.; Benedetto, E.; Cozzi,
P. G. Chem. Commun. 2009, 5919; (e) Guo, C.; Song, J.; Luo, S.-W.; Gong, L.-Z.
Angew. Chem., Int. Ed. 2010, 49, 5558; (f) Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo,
E. J.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19598.
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Deb, I.; Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2009, 131, 13226; (b) Kang, Y. K.;
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Angew. Chem., Int. Ed. 2011, 50, 2144.
9. From an organometallic aspect, CeH bond cleavage of 2-(dimethylamino)- and
2-(diethylamino)pyridine by using Ir(III)edihydride complex was reported,
where Irecarbene complexes were obtained: (a) Lee, D.-H.; Chen, J.; Faller, J.
W.; Crabtree, R. H. Chem. Commun. 2001, 213; (b) Clot, E.; Chen, J.; Lee, D.-H.;
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11. When [Rh(cod)2]BF4 was used in place of [Ir(cod)2]BF4, no desired product was
detected.
3. For selected examples, see: (a) Tokunaga, Y.; Sakakura, T.; Tanaka, M. J. Mol.
Catal. 1989, 56, 305; (b) Sakaguchi, S.; Kubo, T.; Ishii, Y. Angew. Chem., Int. Ed.
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K.; Takagi, J.; Miyaura, N. Chem. Lett. 2001, 30, 1082; (b) Shimada, S.; Batsanov,
A. S.; Howard, J. A. K.; Marder, T. B. Angew. Chem., Int. Ed. 2001, 40, 2168; (c)
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12. When [Ir(cod)2]BARF was used in place of [Ir(cod)2]BF4, the reaction of 2-(N-
pyrrolidinyl)pyridine (1f) with styrene gave the mono- and dialkylated prod-
ucts in 17% and 21% yield, respectively.
13. Hydroiridation is more probable than carboiridation based upon the organo-
metallic study (Ref. 9), but the carboiridation pathway cannot be completely
excluded.
14. The role of TfOH is yet uncertain, but it probably activates the alkyne moiety,
because no effect on the reaction of styrene with 2-(methylamino)pyridine (1n)
was observed by the addition of TfOH (10 mol%).
15. In the reaction of 2-(ethylamino)pyridine (1a) with alkynes, yields and enan-
tiomeric excesses were not improved by the addition of TfOH (10 mol%).
16. Schenck, T. G.; Downes, J. M.; Milne, C. R. C.; Mackenzie, P. B.; Boucher, T. G.;
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directing group: (a) Dong, C.-G.; Hu, Q.-S. Angew. Chem., Int. Ed. 2006, 45, 2289;
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